Connecting science with society

ISSN 2517-7028
ISSUE 107

FEATURING RESEARCH FROM:

University of Catania and National Institute for Nuclear Physics; Japan Aerospace Exploration Agency; University of Cambridge;
University of Illinois; University of Edinburgh; National Institute of Advanced Industrial Science and Technology; Stony Brook
University; Spelman College; Kaetsu University; Kyoto University of Advanced Science; Frankfurt University of Applied Sciences;
INSEAD and Collegio Carlo Alberto; Kyoto University; Harvard Medical School; Purdue University; University of Freiburg;
Savannah River National Laboratory, Clemson University, the University of South Carolina, and Savannah River Consulting;
Universidad Católica del Norte of Chile; University of Guelph; USDA Forest Service; Invicro; University of Pennsylvania; University
of Lynchburg and University of Georgia Costa Rica; University of New Mexico; Baylor College of Medicine; The Quaich Inc.;
Erasmus Medical Centre; National Prostate Cancer Register; Moffitt Cancer Center, Polish Academy of Sciences and the
Research Features 3
Helmholtz Centre for Infection Research; The Ministry of Health of Russia and IlmixGroup; Avera Cancer Institute; Seoul National
University Bundang Hospital; Institute of Biomedical Sciences, Academia Sinica.
500 Women Scientists
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 RESEARCH OUTREACH ISSUE 107
WELCOME
Connecting science with society
ISSN 2517-701X
ISSUE 107

TO ISSUE 107
Research Outreach continues to showcase research from FEATURING RESEARCH FROM:
University of Catania and National Institute for Nuclear Physics; Japan Aerospace Exploration Agency; University of Cambridge;
University of Illinois; University of Edinburgh; National Institute of Advanced Industrial Science and Technology; Stony Brook
University; Spelman College; Kaetsu University; Kyoto University of Advanced Science; Frankfurt University of Applied Sciences;
INSEAD and Collegio Carlo Alberto; Kyoto University; Harvard Medical School; Purdue University; University of Freiburg;

a broad range of institutions around the globe. In this issue,

Savannah River National Laboratory, Clemson University, the University of South Carolina, and Savannah River Consulting;
Universidad Católica del Norte of Chile; University of Guelph; USDA Forest Service; Invicro; University of Pennsylvania; University

ISSN 2517-701X
of Lynchburg and University of Georgia Costa Rica; University of New Mexico; Baylor College of Medicine; The Quaich Inc.;
Erasmus Medical Centre; National Prostate Cancer Register; Moffitt Cancer Center, Polish Academy of Sciences and the
Research Features 3
Helmholtz Centre for Infection Research; Ministry of Health of Russia and IlmixGroup; Avera Cancer Institute; Seoul National
University Bundang Hospital; Institute of Biomedical Sciences, Academia Sinica.

we are excited to celebrate some of the pioneers driving

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www.researchoutreach.org 3
CONTENTS 30 THE MATERIALS
MAKING POTASSIUM-ION
58 INSTITUTIONAL INVESTORS
AND INFORMATION
BATTERIES POSSIBLE ACQUISITION: IMPLICATIONS
Dr Titus Masese FOR ASSET PRICES AND
Exploring high performance INFORMATIONAL EFFICIENCY
6 NUMEN PROJECT: next-generation rechargeable Adrian Buss
EXPLORING KEY ASPECTS battery systems. Investigating the impact of
OF NEUTRINOLESS DOUBLE financial frictions and institutional
BETA DECAY BY NUCLEAR 34 SUSTAINABLE WATER investors on asset prices
REACTIONS PURIFICATION USING and financial-market efficiency.
Professor Francesco BIOMASS
Cappuzzello and Dr Benjamin S. Hsiao 62 HONEYCOMB WINGS
Dr Clementina Agodi Using nanocellulose enabling CREATED BY NATURE’S
Using cutting edge technology membranes and adsorbents MECHANICS
to enhance our understanding for water purification. Dr Kaoru Sugimura
of fundamental physics. Exploring the physical
38 INQUIRY LEARNING: principles behind the regulation
10 AKATSUKI: PIONEERING THE EMPOWERING AFRICAN of cell mechanics.
PLANETARY METEOROLOGY AMERICAN WOMEN IN STEM
OF VENUS Dr Leyte Winfield 66 DROSOPHILA FEZF FOUND
Professor Takehiko Satoh Teaching chemistry through TO BE ESSENTIAL IN NEURAL
Understanding the cause authentic, culturally relevant CIRCUIT FORMATION
and maintenance mechanism learning experiences. Dr Matt Pecot
of the Venus environment. Understanding how the
42 MEASURE WHAT nervous system is assembled
14 RECONSTRUCTING YOU TREASURE during development.
ASTRONOMICAL IMAGES Global Footprint Network
WITH MACHINE LEARNING Education initiatives to 70 PREDICTING PROTEIN
Edward Higson reduce our ecological deficit. FUNCTION AND
Bayesian inference and machine ANNOTATING COMPLEX
learning methods applied to 46 INTEGER-DIMENSIONAL PATHWAYS WITH
astrophysics and cosmology. FRACTALS OF NONLINEAR MACHINE LEARNING
DYNAMICS Dr Daisuke Kihara
18 REFINING THE SEARCH Dr Zonglu He Developing new techniques
FOR THE LARGEST Exploring the control for computational protein
GRAVITATIONAL WAVES mechanisms of function prediction.
A. Miguel Holgado nonlinear dynamics.
Exploring gravitational wave 74 MACHINE METAPHORS:
signatures of black holes, 50 MEASURING SHARED ETHICAL AND
neutron stars and white dwarfs. KNOWLEDGE WITH GROUP PHILOSOPHICAL
FALSE MEMORY CHALLENGES IN
22 THE MATHEMATICS OF Dr Yoshiko Arima SYNTHETIC BIOLOGY
LIFE: METABOLIC CONTROL Estimating the complexities Dr Joachim Boldt
IN LIVING CELLS of our collective Using machine metaphors
Dr Diego A. Oyarzún intelligence through shared to describe biological systems,
Using mathematics knowledge structure. and how language affects
to understand the function our approach towards synthetic
of natural networks. 54 THE ROLE OF SOCIAL biology research.
CAPITAL IN THE HEALTH
26 WILL AN OLD PROBLEM DEVELOPMENT OF CHILDREN 78 IN-SITU MONITORING
YIELD A NEW INSIGHT? Andreas Klocke OF MICROBIAL CIRCUITRY
Jim Tilley and Sven Stadtmüller Dr Charles Turick
Finding alternative solutions Is there a causal effect of social Electrochemical techniques
to one of the most famous capital on the health of children? to monitor microbial
mathematical conundrums, metabolic activity.
the 4-colour problem.

Our goal is to engage people by helping

them fall in love with the most significant
and intriguing challenges we are facing
– how to thrive within the means
of our planet.
MATHIS WACKERNAGEL, CO-FOUNDER OF

43 Nikifor Todorov/Shutterstock.com
THE GLOBAL FOOTPRINT NETWORK
Page 43

4 www.researchoutreach.org
 35
82 THE ACIDIC BRINE LAKES
OF CHILE: A SURPRISING
MICROBIAL COMMUNITY
Drs Cecilia Demergasso
and Guillermo Chong
Characterising the microbiota
of an acidic brine lake in Chile.
86 SECRETS OF THE STALK:
REGULATING PLANT
TEMPERATURE FROM
THE INSIDE OUT
Dr Peter Kevan
How do plant stems help
to regulate temperature?
90 ARE WILDFIRES FOLLOWING
BARK BEETLES MORE SEVERE?
Carolyn Sieg, Rod Linn, Chad
Hoffman, Joel McMillin, L. Scott
Baggett, Judy Winterkemp,
Francois Pimont
Computer-based models to better
understand the complex interplay
of factors behind forest fires.
94 ADVANCES IN CNS DRUG
DEVELOPMENT
Dr Eugenii (Ilan) Rabiner
Molecular and functional
imaging to understand brain
pathophysiology and facilitate
drug development.
98 FRUIT FLIES HELP SHED LIGHT
ON DRUG DISCOVERY FOR ALS
Drs Nancy Bonini
and Leeanne McGurk
Promising new molecules could
help lead to new treatments
for amyotrophic lateral sclerosis
(ALS).
102 GOING WITH THE FLOW:
WATER QUALITY AND
COMMUNITY HEALTH
IN COSTA RICA
Dr Thomas Shahady
Understanding the relationship
between water quality,
community health and water
use in Costa Rica.
Physical Informatics &
Sciences Technology
83
106 DRILLING FOR KNOWLEDGE:
A COLLABORATIVE
APPROACH TO OCEAN
DRILLING IN THE ARCTIC
Dr Lindsay Worthington
Subsurface imaging of the
Earth’s crust to understand
geologic processes.
110 EUROSCIENCE: SUPPORTING
SCIENTISTS ACROSS
EUROPE TO WORK
TOGETHER FOR A BRIGHTER
EUROPEAN FUTURE
EuroScience
Enhancing the contribution
of science, technology
and innovation.
114 HOMELESSNESS IN WESTERN
SOCIETY: THE DARK SIDE
OF THE MOON
Dr Fabrizia Faustinella
Exploring the root causes
of homelessness and the
challenges of street life.
118 A FRAMEWORK FOR GLOBAL
HEALTH PROMOTION:
THE CIRCLE OF HEALTH
Patsy Beattie-Huggan,
Professor Dr. med. Kirsten
Steinhausen & Stefanie Harsch
Supporting knowledge
translation and innovation
in applications of the Circle
of Health© (COH).
122 USING EHEALTH TO
MONITOR IDIOPATHIC
PULMONARY FIBROSIS
Dr Marlies Wijsenbeek
and Dr Karen Moor
Evaluating a new home
monitoring programme for
idiopathic pulmonary fibrosis.
126 NPCR: NEXT GENERATION
CANCER REGISTER
The National Prostate
Cancer Register
A tool for quality assurance and
Arts & Behavioural Health &
Humanities Sciences Medicine
106
ggw/Shutterstock.com
quality improvement of health
care for all men with prostate
cancer in all ages in Sweden.
130 TOWARDS A QUANTITATIVE
PERSONALISED ONCOLOGY
Dr Heiko Enderling
Integrating mathematical,
biological and clinical sciences
to model, simulate and
predict treatment response
for individual patients.
134 EXCITING ADVANCEMENTS
IN OVARIAN CANCER
TREATMENT
Lev Ashraphyan, Vsevolod
Kiselev, Ekaterina Muyzhnek,
Gennady Sukhikh
Fresh insights into the
biology and progression
of ovarian cancer may lead
to new therapies.
138 FLUORESCENT IMAGING
SHEDS NEW LIGHT
ON APOPTOSIS
Dr Nandini Dey
Novel tools to explore the
physical and biochemical
processes behind apoptosis.
142 RNA SEQUENCING REVEALS
SECRETS OF SKIN AGING
Dr Jeong-Sun Seo
Signs of skin aging are directly
linked to over-exposure
of UV light.
146 ADHD AND ITS
COMORBIDITIES:
IMPLICATIONS FOR
MANAGEMENT
Dr Wen-Harn Pan
Investigating risks for
attention deficit hyperactivity
disorder and implications
for its management.
150 APOLLO: FIFTY YEARS ON
Biology Earth &
Environment
www.researchoutreach.org 5
 Physical Sciences ︱ Professor Francesco Cappuzzello and Dr Clementina Agodi
NUMEN Project:
Exploring key aspects of neutrinoless double beta decay
by nuclear reactions
The Standard Model of particle
physics may represent our
most advanced understanding
yet of the universe’s
fundamental building blocks,
but many physicists believe it
is incomplete. One of the most
enticing prospects for updating
the model lies with ‘neutrino-less
double beta decay’ – a process
which has been theorised for
many decades, but has yet
to be observed. Professor
Francesco Cappuzzello at
University of Catania and Dr
Clementina Agodi at National
Institute for Nuclear Physics
(Laboratori Nazionali del Sud)
are the lead researchers of the
NUMEN Project. Representing
the efforts of a global team of
physicists, they ultimately aim
to unveil the key nuclear aspects
of neutrino-less double beta
decay for the first time.
Vire Animations/Shutterstock.com
6 www.researchoutreach.org
B
eta decay is one of the most well-
understood processes in subatomic
physics. It occurs when an atomic
nucleus is composed of particular
arrangements of protons and neutrons
which make it unstable, causing it to
either release a beta particle (an electron)
from one of its neutrons, turning it into a
proton, or an anti-beta particle (a positron)
from one of its protons, transforming
it into a neutron. In some very rare cases,
double beta decay can occur, where two
neutrons will simultaneously transform
into protons, or vice versa, releasing either
two positrons or two electrons.
In our current understanding of particle
physics, defined by a set of rules called
the Standard Model, there are several
fundamental values which need to
be conserved in every process, one
of which is the ‘lepton number’. Leptons
are a family of fundamental particles
which include positrons and electrons,
along with chargeless and extremely
light particles, named neutrinos. Since
electrons are ‘matter’ and positrons,
‘antimatter’, the Standard Model dictates
that during beta decay, they must be
released alongside either an anti-neutrino
or a neutrino, respectively.
However, another type of beta decay
has been predicted theoretically where
this is not necessarily the case. In
‘neutrino-less double beta’ (0νββ) decay,
two beta particles are emitted, but no
neutrinos. On the surface, this process
would appear to violate lepton number
conservation, but for several decades,
physicists have had reason to believe it
may still be possible. Therefore, observing
the process experimentally would have
profound consequences for our current
understanding of fundamental physics.
BREAKING THE STANDARD MODEL
In 1937, Italian physicist Ettore Majorana
made an intriguing proposal: that it
could be possible for some particles to
be their own antiparticles. We know for
a fact that this can’t be the case for a
majority of fundamental particles, since
one particle cannot have both positive
and negative charges, for example.
However, based on our currently-
The MAGNEX spectrometer at INFN-LNS
limited understanding of neutrinos, the
possibility remains that they could be
so-called ‘Majorana particles’.
Since 0νββ-decay emits no neutrinos,
its observation would confirm for the first
time that elementary Majorana particles
can exist. “0νββ-decay is potentially the
best resource to probe if neutrinos are
their own antiparticles, as predicted by
Majorana, and to extract their effective
masses,” explains Professor Cappuzzello.
“Moreover, if observed, 0νββ-decay will
signal that the exact balance between
matter and antimatter can be violated
in nature.”
This disparity in the enormous amount
of matter compared with antimatter
in the universe is currently one of the
biggest problems faced by physicists.
The direct confirmation that 0νββ-decay
can occur would, therefore, be a big
deal for particle physics, nuclear physics
and cosmology; potentially giving
researchers the tools they need to re-draw
If observed, 0νββ-decay will signal that
the exact balance between matter and
antimatter can be violated in nature.
the Standard Model to more accurately
describe the fundamental constants
of the universe.
“Presently, this physics case is among
the most important research into ‘beyond
the Standard Model of Particle Physics’,”
Professor Cappuzzello continues. “It
might guide the way toward a Grand
Unified Theory of fundamental forces
(electromagnetic, weak and strong
interactions) and unveil the source
of matter-antimatter asymmetry observed
in the Universe.”
THE RACE FOR 0νββ DETECTION
Shaking up our understanding of the
most fundamental building blocks of
the universe is, understandably, an
enticing prospect for physicists. As Dr
Agodi describes, this has meant that the
hunt for 0νββ-decay has ramped up in
recent years. “Despite the fact that the
process has never been observed, there
is a kind of worldwide race, involving large
scientific collaborations and international
laboratories in the fields of neutrinos,
nuclear and particle physics, in order
to detect it,” she says.
Theoretical physicists have proposed
a variety of methods to infer the extremely
long decay time for 0νββ process (more
than 1016 times longer than the life
of universe), stemming from the rules
which must be obeyed by atomic nuclei
in all double-beta decay (ββ) processes.
“Since the ββ-decay process involves
transitions in atomic nuclei, nuclear
structure issues must be also accounted
for, in order to describe it,” Professor
Cappuzzello continues. “In particular,
the key quantities are the so-called
Nuclear Matrix Element (NME), which
Detail of the Superconducting Cyclotron
accelerator at INFN-LNS
express the probability that the parent
nucleus can spontaneously convert into
a daughter nucleus, as result of ββ-decay.”
Based on state-of-the-art theoretical
calculations, physicists in worldwide
studies are now aiming to evaluate
the NMEs which control the 0νββ-decay
time specifically. However, since it
would be incredibly difficult to detect
the process occurring directly, these
calculations are faced with significant
challenges in providing the meticulous
levels of precision which physicists require
in their experiments.
“Despite the tremendous efforts
and improvements achieved by nuclear
structure studies, the ambiguities
in the present models are still too large
to provide NMEs with the necessary
accuracy,” says Dr Agodi. In their
research, Professor Cappuzzello, Dr Agodi
and their colleagues are aiming to realise
this level of accuracy for the first time, with
the help of cutting-edge facilities based
at the INFN Laboratori Nazionali del Sud
in Catania.
www.researchoutreach.org 7
OBSERVING A CLOSE ANALOGY
ββ-decays are not the only processes in
physics where two charges are exchanged
simultaneously. As Professor Cappuzzello
explains, other ‘Double Charge Exchange’
(DCE) processes would be far easier to
observe directly than 0νββ-decay. “In this
scenario, the experimental study of DCE
reactions, which are processes promoting
analogous nuclear transitions as ββ-decay,
could provide important information,”
he says. “The advantage is that DCEs
can be studied under controlled
laboratory conditions.”
Professor Cappuzzello and Dr Agodi’s
team take advantage of the fact that
the processes underlying 0νββ-decay are
comparable with those governing easier-
to-observe DCE reactions. Therefore, the
physicists suggest that 0νββ-decay NMEs
could be inferred by observing DCEs
occurring in one particular controllable
environment: collisions between heavy,
fast-moving ions.
The team have attempted to do just
this in previous studies. So far, however,
their efforts have been hindered by the
tiny probabilities by which the products
of their heavy ion collisions were
scattered – a value named the collision
‘cross-section’. With such imperceptible
cross-sections, it has been incredibly hard
for the physicists to know where to look
for the collision products, where DCEs are
occurring. But since these setbacks, new
upgrades have been made to the INFN-
LNS facility of Catania, owned by Italy’s
National Institute for Nuclear Physics,
which could make their task far easier.
With the new equipment, Professor
Cappuzzello and Dr Agodi’s team
now hope to make cross-section
measurements of heavy ion collisions
far more easily. “Recently, we
established an innovative experimental
approach at the INFN-LNS laboratory
in Catania, which allows us to
largely overcome such experimental
challenges, and consequently, to
extract quantitative information on
NMEs from DCE reactions,” recounts
Professor Cappuzzello.
INTRODUCING:
THE NUMEN PROJECT
In 2014, Professor Cappuzzello, Dr Agodi
8 www.researchoutreach.org
The INFN-LNS laboratory in Catania
and their colleagues unveiled their
plans for the ‘NUclear Matrix Elements
for Neutrino-less double beta decay’
(NUMEN) Project. “The aim of NUMEN
is to investigate the nuclear response
to DCE reactions for all the isotopes
explored by present and future studies
of 0νββ-decay,” says Dr Agodi. “Several
aspects of the project require the
development of innovative techniques, for
both experiment set-up and theoretical
interpretation of the collected data.”
At the heart of the new capabilities of the
NUMEN Project are two, state-of-the-art
installations at the INFN LNS laboratory
NUMEN is a challenging project at the
intersection of nuclear and neutrino physics,
driven by an important physics case.
Catania. The first piece of equipment
is named the K800 Superconducting
Cyclotron – a particle accelerator capable
of accelerating heavy ions to high speeds,
while ensuring precise, head-on collisions
between ions. Secondly, the MAGNEX
spectrometer will analyse the products of
these collisions to incredibly high degrees
of precision. “While K800 accelerates
the heavy-ion beams with the required
high resolution and low emittance,
MAGNEX detects the reaction products
with large acceptance and high resolution
in mass, energy and angle,” Professor
Cappuzzello explains.
With the help of these facilities, along with
new cutting-edge theoretical calculations
which have been developed in view of
the NUMEN results, the researchers soon
hope to embark on the most extensive
search for 0νββ NMEs ever undertaken.
“The INFN-LNS facility is today unique
for this research in worldwide context, and
will likely be in view of a major upgrade
of the whole research infrastructure, which
is going to start in the coming months,”
says Professor Cappuzzello.
A PROMISING FUTURE
The NUMEN Project represents the
coming together of minds encompassing
a diverse range of fields in physics. As
Professor Cappuzzello and Dr Agodi
conclude, the researchers at NUMEN
believe this is exactly what is needed to
make a major new discovery. “NUMEN
is a challenging project at the intersection
of nuclear and neutrino physics, driven
by an important physics case and opening
interesting scientific scenarios and
potential technological fallout,” they say.
In the coming years, the researchers
involved with the project look set to be
at the forefront of the global race to unveil
0νββ-decay experimentally, and provide
the first clear evidence for the existence
of Majorana particles. If they are successful,
a long-awaited shakeup to the Standard
Model could finally be realised, allowing
for an unprecedented opportunity
to explore the most fundamental building
blocks of the universe.
 Behind the Research
Professor Francesco Cappuzzello
E: cappuzzello@lns.infn.it
T: +39 095542384 (Office) +39 3281646400 (Mobile)
W: www.dfa.unict.it/docenti/francesco.cappuzzello
W: https://www.lns.infn.it/
W: https://web.infn.it/NUMEN/index.php/en/
Dr Clementina Agodi
E: agodi@lns.infn.it
T: +39 095542642 (Office) +39 3283780365 (Mobile)
W: www.researchgate.net/profile/Clementina_Agodi
W: https://www.lns.infn.it/
W: https://web.infn.it/NUMEN/index.php/en/

Research Objectives
The NUclear Matrix Elements for Neutrino-less ‘double beta decay’ (NUMEN) Project is an innovative project based at the
INFN-Laboratori Nazionali del Sud. Using cutting edge technology, it aims to enhance our knowledge and understanding
of fundamental physics.

Detail
Professor Francesco Cappuzzello
and Dr Clementina Agodi
Via S.Sofia n. 62 95123
Catania, Italy
Bio
Clementina Agodi is an experimental
nuclear physicist working in the field of
reactions and structure of atomic nuclei.
She holds a degree in Physics from
Catania University and is currently senior
researcher at INFN Laboratori Nazionali
del Sud. In 2007–2015 she was member
of Nuclear Physics board of INFN.
Dr Agodi is Spokesperson of NUMEN
Project.
Francesco Cappuzzello is Associate
Professor of Experimental Nuclear
Physics of the Catania University
and Associate Researcher of the Istituto
Nazionale di Fisica Nucleare. He was
awarded his doctorate from the Catania
University in 1999, discussing a thesis
about the MAGNEX spectrometer
project. He is Spokesperson
of the NUMEN project.
Funding
Istituto Nazionale di Fisica Nucleare
(INFN), Università di Catania
Collaborators
• Dr Manuela Cavallaro INFN – LNS
• Dr Diana Carbone INFN – LNS
• The NUMEN Collaboration

References Personal Response

Cappuzzello, F. Agodi, C. Cavallaro, M. Carbone, D. Tudisco,
S. Presti, D.L. Oliveira, J.R.B. Finocchiaro, P. Colonna, M.
Rifuggiato, D. Calabretta, L. et al. (2018). The NUMEN project:
NUclear Matrix Elements for Neutrinoless double beta decay.
The European Physical Journal A, 54(5), 72.
Cappuzzello, F. Agodi, C. Carbone, D. Cavallaro, M. (2016).
The MAGNEX spectrometer: Results and perspectives.
The European Physical Journal A, 52(6), 67.
Vergados, J.D. Ejiri, H. Šimkovic, F. (2012). Theory
of neutrinoless double-beta decay. Reports on Progress
in Physics, 75(10), 106301.
Dell’Oro, S. Marcocci, S. Viel, M. Vissani, F. (2016).
Neutrinoless double beta decay: 2015 review. Advances
in High Energy Physics, (10):1-37.
The NUMEN Project is a truly global collaboration.
Can you give us a bit of the history behind how this
collaboration was formed?
We proposed NUMEN in 2014 within the initiative,
“WHAT NEXT?”, in which INFN questioned itself on
possible future avenues in the physics of fundamental
interactions.
The project was based on a pioneering experiment, DoCET,
proposed by our group (spokespersons: M.Cavallaro and
F.Cappuzzello). NUMEN was considered worthy of the INFN
challenge and was reviewed by a prestigious international
evaluation committee, that strongly supported it. Initially,
we were only few researchers of Catania, but before long
NUMEN attracted several colleagues, allowing us to cover
all the aspects of the challenge. Today, we are about 100
researchers from 35 Institutions in 15 countries.

www.researchoutreach.org 9
 Physical Sciences ︱ Professor Takehiko Satoh
Akatsuki:
Pioneering the planetary meteorology of Venus
Venus may be the closest
known planet to Earth in both
size and distance from the
Sun, but the atmosphere of
our nearest neighbour is so
thick that much of its dynamics
remain shrouded in mystery.
Professor Takehiko Satoh at the
Japan Aerospace Exploration
Agency (JAXA) is exploring
the Venusian atmosphere. His
research utilises the orbiting
probe, Akatsuki. Named after
the Japanese for ‘dawn’,
Akatsuki has transformed our
understanding of the diverse,
often violent dynamics which
play out in our neighbour’s
atmosphere, and is also helping
us to understand more about
our own weather.
Image of Venus © ISAS/JAXA; image of Akatsuki probe by
Akihiro Ikeshita, courtesy of NASA, public domain.
Tha Akatsuki probe has been
orbiting Venus since 2015.
10 www.researchoutreach.org
W
ith a radius just 5% smaller
than our Earth’s, and an orbital
path 28 percent closer to
the sun than Earth’s, astronomers often
refer to Venus as Earth’s ‘twin sister’.
However, within the dense clouds of
our twin, the environment could hardly
be more different.
“The planet is completely shrouded by
thick cloud layer composed of sulfuric
acid, its dense atmosphere is mostly CO2,
the surface pressure is 90 times stronger
than Earth’s, and the temperature is
around 460°C due to the extremely strong
greenhouse effect,” explains Professor
Takehiko Satoh, a researcher at JAXA’s
Institute of Space and Astronautical
Science. With a climate vastly more
hostile than any to be found on Earth,
it isn’t surprising that the weather patterns
astronomers have observed on Venus
so far are entirely unlike our own.
But the local weather patterns aren’t
the only mystery our twin holds; there
is also a significant, large-scale disparity
between the incredibly slow “retrograde”
rotation of the planet itself and the
far more rapid rotation of its upper
atmosphere. “The atmospheric dynamics
of Venus are represented by its ‘super-
rotation’,” Professor Satoh continues.
“While the solid body completes one
rotation every 243 earth days, the
atmosphere encircles the planet in only 4
earth days at the cloud-top level, 60 times
faster than the more massive body.”
AKATSUKI ENTERS ORBIT
In 2001, Professor Satoh and a group
of his colleagues at several institutes
in Japan began work on designing
the first spacecraft ever to orbit Venus
in its equatorial plane, aiming to discover
the causes of a wide variety of properties
observed in the planet’s atmosphere.
After almost a decade of careful planning,
Akatsuki was launched from JAXA’s
Tanegashima Space Centre in May 2010.
A mishap in manoeuvring (December
2010) meant that Akatsuki orbited
the Sun for five years with only a little data
acquisition, but thanks to expert recovery
efforts from the Akatsuki team, the
spacecraft finally began its orbit of Venus
in December 2015. “Akatsuki has now
been in Venus orbit for more than three
earth years and has transmitted valuable
data about the atmospheric dynamics of
Venus back to Earth,” Professor Satoh says.
Akatsuki collects this data using five
onboard cameras, each of which observes
Venus using different wavelengths, ranging
from ultraviolet to infrared. Since these
wavelengths can penetrate to different
depths, each infrared or ultraviolet image
of Venus which Akatsuki sends back
to Earth can tell us something different
about the dynamics of Venus’ atmosphere.
 The launch of the Akatsuki
probe. in May 2010.

The team at JAXA after the successful orbit

insertion on 7 Dec 2015.

In addition, Akatsuki is carrying out a ‘radio

occultation’ experiment, in which it fires
a radio beam straight through Venus’
atmosphere, back to an antenna station
on Earth. By measuring changes in these
radio waves, astronomers can explore
the Venusian atmosphere right down to its
thick lower depth. So far, a comprehensive
analysis of these images has yielded
three major discoveries about Venus’
unique atmosphere.

STUBBORN GRAVITY WAVES

Photo Credit: Narita Masahiro CC BY-SA 3.0
Just three hours after its arrival at Venus,

For more than three Earth years,

Akatsuki made its first major discovery.
The orbiter’s mid-infrared and ultraviolet
imagers revealed a vast, stationary
bow-shaped wave in Venus’ sulfuric acid
cloud tops, 65 kilometres above its solid
surface. At 10,000 kilometres across, the
feature appeared to be in a fixed position,
despite its surrounding, smaller-scale
features moving at speeds of super-
rotating atmosphere around 100 metres
per second.
The Akatsuki team believe that this
stubborn feature is a ‘gravity wave’.
Not to be confused with gravitational
waves, these features are created when
two different fluids, each with a different
density, meet at an interface. Waves can  the atmosphere are coupled, and how this
subsequently form at this interface as the
force of gravity acts to restore equilibrium
in the overall system. The phenomenon
is common on Earth, particularly at the
interface between the air and the ocean.
However, gravity waves can never be
found on this scale on our home planet.
In this case, the astronomers propose
that the vast gravity wave observed by
Akatsuki was caused by mountain ranges
on Venus’ surface pushing its dense lower
(Akatsuki) has transmitted valuable data
about the atmospheric dynamics of Venus
back to Earth.
atmosphere to higher altitudes, where
gases are far less dense. “This is a striking
discovery, since we have seen features
extending horizontally for thousands
of kilometres that are not super-rotating
but are stationary, or fixed to the highlands
of the slowly-rotating solid planet,”
comments Professor Satoh. “This would
hint at how strongly the solid body and
works to the production and maintenance
of super-rotation.”
Mysteries still remain over how such
a gravity wave could have formed,
given our current knowledge of the
conditions of Venus’ atmosphere just
above its surface. If Professor Satoh and
his colleagues are correct about the cause
of the feature, these surface conditions
could be far more dynamic than
astronomers currently realise.
VENUS’ EQUATORIAL JET
Akatsuki’s next discovery was the evidence
of a fast-moving jet encircling Venus’
equator in its mid-to-low atmosphere (50
to 60 km altitudes). The Akatsuki team
made the discovery after analysing the
planet’s ‘atmospheric window’ – a band
of relatively weak CO2 absorption in
the near-infrared region, through which
radiation from deeper levels can escape
to space. The astronomers calculated wind
speeds at different altitudes by tracking
the silhouettes of clouds in Venus’ mid-
to-low atmosphere, against the backdrop
of the atmospheric window.
The astronomers found that at these
altitudes, cloud speeds increased
the closer they were to Venus’ equator,
suggesting the presence of an equatorial
jet encircling the planet. Their finding
was particularly unusual, as atmospheric

www.researchoutreach.org 11
physics predicts that wind speeds will The team conduct the final check before
the probe is loaded onto the launch vehicle.
be lower close to the equator – a rule that
is obeyed by Venus’ super-rotating upper
atmosphere. “It is not easy to accelerate
the atmosphere in the equator,” explains
Professor Satoh. “If conservation of
angular momentum is considered,
acceleration at mid- or high-latitudes
could naturally be produced, but this
generally cannot happen at the equator.”

The astronomers hope to uncover the

mechanisms causing this jet through
further research. Professor Satoh
believes that these studies could further
unravel the mystery of why Venus’
upper atmosphere is rotating so much
faster than the planet itself. “Solving
this problem would also be a key to
understand the mechanism to accelerate
the entire atmosphere to the super-
rotation,” he says.

WAVES, JETS, AND THERMAL TIDES
Akatsuki’s observations of Venus’
night-time atmospheric window also
indicated unusual patterns of streaky
clouds extending some thousands of
kilometres across the planet. To explain
their formation, the Akatsuki team
proposed that Venus’ atmosphere
was flowing strongly downwards in
localised regions; an idea they tested
using computer simulations. “The
numerical simulation group successfully
reproduced the large streaky features
seen in Venus’ atmosphere,” Professor
Satoh says. “Surprising enough, these
large-scale streaks seem to be produced
by interaction of atmospheric waves and
mid-latitude jets that are commonly seen
in our Earth’s atmosphere as well.” The
success of reproducing such phenomena
may imply that the numerical simulation
of Venusian atmospheric dynamics
enters a new stage, not only to simulate
observed phenomena but to reveal the
mechanism underlying what we see.
The Akatsuki team also found increased
wind speeds in the early half of the night
near the equatorial region, indicative
of the aftermath of solar heating in the
cloud layer. “This may tell us how solar
heating at the upper cloud layer drives
the dynamics and effects to lower levels,”
says Professor Satoh. These heating
dynamics are known as ‘thermal tides’;
caused by the periodic localised heating
of the upper atmosphere by the Sun,
strongest at the sub-solar point, the
effect which can be seen on Earth to
an extent. Instabilities in lower layers of
the atmosphere subsequently cause this
heat to move around vertically, to lower
altitudes. The astronomers believe that
thermal tides could at least partially be a
cause of Venus’ mysterious super-rotation.
By enhancing our understanding
of meteorology in our sister planet,
[the Akatsuki mission] ultimately benefits
our lives on the earth.
As Professor Satoh explains, this would
be the case if thermal tides were acting
to slow Venus down in its direction
of rotation, while boosting the speed of its
upper atmosphere. “One hypothesis for
super-rotation is the heating of clouds
and the generation of thermal tides,” he
says. “This ultimately transfers ‘eastward’
momentum to the solid planet, leaving
‘westward’ momentum in the atmosphere,
which accumulates to the super rotation.”
GROWING OUR
KNOWLEDGE OF VENUS
From the insights provided by these
three discoveries, Professor Satoh
and his colleagues are now working
on improving their computer simulations
to more accurately reproduce Akatsuki’s
observations. These simulations are
an important supplement to the limited
amount of data Akatsuki is able to
provide. “For the earth, we have many
meteorological satellites and a huge
number of ground stations to monitor
the weather,” Professor Satoh explains.
“For Venus, in contrast, we have only
one satellite, Akatsuki. Therefore,
numerical simulation of the observed
data is quite important. Data assimilation,
a modern and powerful technique in
Earth’s meteorology, will help us better
understand the dynamical phenomena
observed by Akatsuki.”
The work of the Akatsuki team
has already greatly enhanced our
understanding of Venus’ unique
atmosphere, and the fascinating
mechanisms which drive its dynamics.
Professor Satoh believes that by
learning more about how Venus’
atmosphere differs from the Earth’s,
we can understand more about our own
weather. As he concludes, “the Akatsuki
mission is unveiling Venus’ meteorology,
and by enhancing our understanding
of meteorology in our sister planet,
ultimately benefits our lives on the Earth.”

12 www.researchoutreach.org
 Behind the Research
Professor Takehiko Satoh
E: satoh@stp.isas.jaxa.jp T: +81 50 3362 3838 W: www.isas.jaxa.jp/about/researchers/takehiko_
sato.html W: www.isas.jaxa.jp/en/missions/spacecraft/current/akatsuki.html

Research Objectives
Professor Satoh’s research links with previous and on-going Venus missions, with a specific focus on understanding the cause
and maintenance mechanism of the Venus environment.

Detail
Professor Takehiko Satoh
Department of Solar System Sciences,
Institute of Space and Astronautical
Science,
Japan Aerospace Exploration Agency
3-1-1 Yoshinodai, Chuo-ku, Sagamihara
Kanagawa 252-5210, Japan.
Bio
Takehiko Satoh is Professor at
Department of Solar System Sciences,
Institute of Space and Astronautical
Science, Japan Aerospace Exploration
Agency (ISAS/JAXA). He has been with
Japan’s Venus orbiter mission, Akatsuki,
since 2001, serving as PI of the IR2 near-
infrared camera and Project Scientist
of the mission.
Collaborators
All Akatsuki team members (science,
engineering, modelling, and secretaries),
and people in industry.

References Personal Response

Fukuhara, T. Futaguchi, M. Hashimoto, G.L. Horinouchi, T.
Imamura, T. Iwagaimi, N. Kouyama T. Murakami, S.Y. Nakamura,
M. Ogohara, K. Sato, M. (2017). Large stationary gravity wave
in the atmosphere of Venus. Nature Geoscience, 10(2), 85.
Horinouchi, T. Murakami, S.Y. Satoh, T. Peralta, J. Ogohara,
K. Kouyama, T. Imamura, T. Kashimura, H. Limaye, S.S.
McGouldrick, K. Nakamura, M. (2017). Equatorial jet in the lower
to middle cloud layer of Venus revealed by Akatsuki. Nature
Geoscience, 10(9), 646.
Your research has significantly enhanced our
understanding of the unique atmosphere of Venus.
What’s next for your work?
Too many things remain “invisible” to us (what we have
revealed are mere speculations). I love “Seeing is believing”
and would love to visualise all we want to know. How the
solid body pushes the atmosphere, how momentum is
transferred, how waves/eddies decay to release the energy
that they carry, where the source of molecules for enormous

Photo Credit: CC BY-SA 4.0

Peralta, J. Muto, K. Hueso, R. Horinouchi, T. Sánchez-Lavega, clouds in Venus is, etc. Even for our Earth, many of these
A. Murakami, S.Y. Machado, P. Young, E.F. Lee, Y.J. Kouyama, are not yet visualised. But we need to know and understand
T. Sagawa, H. (2018). Nightside Winds at the Lower Clouds of through that which we see. Explorations of planets
Venus with Akatsuki/IR2: Longitudinal, Local Time, and Decadal are to realise such dreams.
Variations from Comparison with Previous Measurements. The
Astrophysical Journal Supplement Series, 239(2), 29.
Kashimura, H. Sugimoto, N. Takagi, M. Matsuda, Y. Ohfuchi, W.
Enomoto, T. Nakajima, K. Ishiwatari, M. Sato, T.M. Hashimoto,
G.L. Satoh, T. (2019). Planetary-scale streak structure reproduced
in high-resolution simulations of the Venus atmosphere with
a low-stability layer. Nature communications, 10(1), 23.
Sugimoto, N. Yamazaki, A. Kouyama, T. Kashimura, H.
Enomoto, T. Takagi, M. (2017). Development of an ensemble
Kalman filter data assimilation system for the Venusian
atmosphere. Scientific Reports, 7, article
number: 9321. DOI:10.1038/s41598-017-
09461-1
Physical Sciences ︱ Edward Higson
Reconstructing
astronomical images
with machine learning
Much of what we know about
how our universe works has
been learnt by analysing the
astronomical signals captured
from the sky. However, these
signals will inevitably have some
noise associated with them –
so how can astronomers be
sure that their observations of
strange, unexpected signals
reflect reality? Edward Higson
at the University of Cambridge
and his colleagues have made
progress in dealing with this
issue, by constructing machine
learning algorithms which can
process noisy astronomical
images to reconstruct clear
ones. Using Bayesian statistics,
their software provides
astronomers with useful tools for
processing their observations.
Nerthuz/Shutterstock.com
14 www.researchoutreach.org
T
o gain knowledge about the
universe, astronomers use a wide
variety of telescopes to gather
electromagnetic radiation from across
the sky. As telescopes improve, and
researchers observe the sky in ever-
increasing detail, intriguing observations
which have yet to be explained by
theoretical physicists continue to roll in.
However, obstacles ranging from dust
clouds to imperfections in telescopes
mean that no observation can be perfect;
inevitably astronomical signals will have
some degree of noise associated with
them. Because of the complex nature
of these signals, astronomers struggle
to work out what their more unexpected
signals should look like without any
noise. In their research, Dr Higson and his
colleagues have devised a cutting-edge
solution to the issue involving image
processing based on machine learning.
A LITTLE HELP FROM BAYES
When researchers need to make
predictions about the likelihood
of certain events occurring, they have
a wide variety of statistical techniques
to choose from. Many popular methods
use Bayesian Statistics – an approach
named after the English statistician
Thomas Bayes in the 18th
century, who considered
how our confidence
that a proposition is true
changes as more information
is gathered about it through
experiments. Bayes modelled
this statistical behaviour with an
equation now known as ‘Bayes’
theorem’. Centuries later, Dr Higson
and his colleagues are using his
mathematics as a basis for neural
networks which can successfully
reconstruct noisy astronomical images.
“My research is focused on methods
for using data to make inferences about
the universe, including in cases where
we do not have a good theoretical
model for the signal we are observing,”
Dr Higson explains. “I use Bayesian
statistics, which defines probability as a
‘degree of belief’ in a proposition and can
analyse non-repeatable events where our
uncertainty is due to limited information.”
Using these methods to analyse inputs
as complex as mysterious astronomical
images is, understandably, a tall order.
However, statistical techniques have
advanced significantly since Bayes’ time,
and are now allowing Dr Higson’s team
to reliably reconstruct these images,
based on the computing technique
of ‘nested sampling’.
APPLYING NESTED SAMPLING
Nested sampling is an increasingly
popular computational technique
for performing Bayesian statistics
calculations. The approach was
invented by Cambridge astrophysicist
John Skilling in 2004 and is capable of
handling challenging data sets and high-
dimensional probability distributions.
Dr Higson is particularly interested
in using nested sampling to reconstruct
noisy astronomical images. The
nested sampling software his team has
developed can be used to analyse these
images using Bayes’ mathematics. This
allows a neural network to predict what
a clear image should look like by trying
to find a simple (‘sparse’) mathematical
description of the image.
“We implement ‘Bayesian Sparse
Reconstruction’ using nested sampling
- a popular method for Bayesian
 8 E. Higson et al.
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www.researchoutreach.org 15
 signal noisy data fit Bayesian sparse
posteriorreconstruction
distribution of N 13
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“We demonstrate
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In each row, the left image shows galaxies photographed by the Hubble Space Telescope. Given 0.5
the number of basis functions N
very noisy versions of these images (middle of each row), Bayesian spares reconstruction produces 0.4
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a fit of the noisy data
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Reproduced from Edward Higson et al. Bayesian sparse reconstruction: a brute-force approach to astronomical it allows us to work
numberout the
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Figure 13. As for Figure 11 but fitting 32 × 32 images from the Hubble Space Telescope
imaging and machine learning. MNRAS (2019) 483 (4): 4828-4846. Reproduced with permission by Oxford 0.0
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for fitting the
(Illingworth et al. 2013
University Press onxbehalf of the Royal Astronomical
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containing several
y Creative Commons license data
galaxies. set.” Unlike
1 previous
2 algorithms,
3 4 5
of this publication. For permissions, please contact journals.permissions@oup.com. Dr Higson’s software
number allows
of the
basis models
functions N
Figure 13. As for Figure N = 1 11 but fitting 32 N×=322 images from theNHubble =3 Space Telescope = eXtreme
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complexity of the data.
continues. “The
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and diagnostics, are implemented In the 2019 study, Dr Higson’s team A NEW TOOLKIT
each pixel has added normally distributed y-errors with σy = 0.2. 1.0
0.6
in the ‘nestcheck’ software package.” first developed methods to reconstruct FOR ASTRONOMERS
x2

0.8
N =1 N =signals
2 by building upNmodels
= 3 of them Thanks
N = 4 to the work of Dr Higson
N =5 0.4
By integrating nestcheck into their through machine learning which seek and his colleagues, astronomers 1.0
0.6
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dynamic nested sampling algorithms, to express the signal as simply as possible. have access to a principled approach
0.8
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and accuracy of their software. In their of mathematical functions which can software can help to reconstruct clear
Figure 14.research,
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colleagues have used their advanced properties of astronomical signals. and unexpected of observations, for 0.2
software to demonstrate their Bayesian As Dr Higson explains, “we presented which theoretical physicists have yet
Figure 14. Fits of the data in Figure 13c conditioned on different numbers of basis functions N ; these plots use results from0.0 the vanill
Sparse Reconstructionx1 techniques. x1 a principled Bayesian framework
x1 to offer
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method.
that the reconstruction of increasingly
strange and diverse astronomical
popular method for Bayesian computation. observations can be truly reliable.
MNRAS in press, 1–20 (2015)

MNRAS in press, 1–20 (2015)

16 www.researchoutreach.org

MNRAS in press, 1–20 (2015)

 Behind the Research
Edward Higson
E: e.higson@mrao.cam.ac.uk
W: https://github.com/ejhigson/dyPolyChord W: https://github.com/ejhigson/nestcheck

Research Objectives References

Edward Higson’s research applies Bayesian inference and Higson, E., Handley, W., Hobson, M. and Lasenby, A. (2019).
machine learning methods to astrophysics and cosmology. Bayesian sparse reconstruction: a brute-force approach to
astronomical imaging and machine learning. Monthly Notices
of the Royal Astronomical Society, 483(4), 4828–4846.

Detail Higson, E., Handley, W., Hobson, M. and Lasenby, A. (2018).

Bio Sampling errors in nested sampling parameter estimation.
Edward Higson studied physics at Oxford University before Bayesian Analysis, 13(3), 873–896.
obtaining a PhD in physics at Cambridge University. Since
submitting his PhD thesis he has been working at Goldman Higson, E., Handley, W., Hobson, M. and Lasenby, A. (2019).
Sachs. nestcheck: diagnostic tests for nested sampling calculations.
Monthly Notices of the Royal Astronomical Society, 483(2),
Collaborators
• Dr Will Handley 2044–2056.
• Professor Mike Hobson
• Professor Anthony Lasenby Higson, E. (2018). nestcheck: error analysis, diagnostic tests
and plots for nested sampling calculations. Journal of Open
Source Software, 3(29), 916.

Higson, E., Handley, W., Hobson, M. and Lasenby, A. (2019).

Dynamic nested sampling: an improved algorithm for
parameter estimation and evidence calculation. Statistics and
Computing, 1-23.

Higson, E. (2018). dyPolyChord: dynamic nested sampling

with PolyChord. Journal of Open Source Software, 3(29), 965

Personal Response
What particular images do you think will yield
particularly interesting results after Bayesian sparse
reconstruction?
The technique is particularly useful when noise and
multiple overlapping sources make it difficult to determine
how many astronomical objects are present in the image
and what each looks like. A really exciting application is
to the most distant photographs ever taken by the Hubble
Space Telescope, which show a jumble of galaxies near
the edge of the observable universe. Bayesian sparse
reconstruction can be used to work out how many
separate overlapping galaxies are present in such
images, and what shape the individual galaxies are.

Marina Sun/Shutterstock.com

www.researchoutreach.org 17
Physical Sciences ︱ A. Miguel Holgado
Refining the search
for the largest
gravitational waves
I
Ask many astronomers, and they
will tell you that gravitational
waves are the greatest scientific
discovery of the 21st century
so far. In his research, Miguel
Holgado at the University
of Illinois studies the clever
astronomical techniques which
can be used to observe the very
largest of these elusive ripples,
originating from supermassive
black holes as they orbit around
each other. His results suggest
that these binaries are likely
far rarer than astronomers
originally thought, but could
also help them to refine their
observation techniques.
An artist’s depiction of a blazar, which is thought
18 www.researchoutreach.org
n September 2015, the world of
astronomy was changed forever, as
ripples in spacetime, first theorised
by Einstein over a century ago, were
directly observed for the first time.
The gravitational wave, discovered
by a global team of researchers at the
LIGO-Virgo collaboration, was created
as two black holes spiralled into each
other and merged, releasing colossal
amounts of energy.
Using kilometre-scale interferometers,
accurate to within the widths of single
atoms, physicists picked up the wave
as it passed through Earth, minutely
stretching and squeezing the fabric of
spacetime as it went. Nearly a dozen
more gravitational wave observations
have been made since then, and again
this year, astronomers are turning their
attention to detecting mergers of black
holes, neutron stars, and more.
to be an active supermassive black hole with a
relativistic jet pointed along our line of sight.
LIMITATIONS IN
LIGO’S DETECTIONS
So far, every gravitational wave LIGO has
detected has originated from mergers of
black holes and neutron stars with similar
masses to our sun. However, astronomers
predict that far larger waves could
originate from ‘supermassive’ black holes
– objects many millions of times heavier
than the Sun, which are thought to occupy
the centres of many galaxies.
As Holgado explains, these waves can
form when two galaxies merge together,
causing each of their supermassive black
holes to orbit each other. ‘Some of the
loudest gravitational waves are expected
from the orbital motion of supermassive
black hole binaries that may form within
the centres of merged galaxies,’ he says.
Yet despite their enormous size, these
waves are notoriously difficult to detect.
Where the ripple observed by LIGO-
Virgo in 2015 dramatically completed
a cycle in fractions of a millisecond,
those waves from supermassive black
hole binaries with periods of years
to decades can endure for thousands
to millions of years.
‘LIGO cannot detect gravitational-
waves from these sources because
the frequencies from in-spiralling
supermassive black hole binaries are
expected to be of order nanohertz,’
Holgado continues. ‘LIGO is only sensitive
to gravitational wave frequencies of order
tens to thousands of hertz, which mostly
correspond to the mergers of stellar-
mass black hole binaries and neutron-
star binaries.’ Astronomers have thus
The Fermi Gamma-Ray Space Telescope’s view of the gamma-ray sky. The disk of gamma-ray emission is from our own Milky Way Galaxy. A significant fraction
of the point-like gamma-ray sources above and below the Milky Way are gamma-ray emission from blazars.
been relying on a different technique to
detect nanohertz gravitational waves by
exploiting the most reliable timekeepers
known to astronomy.
RELIABLE ASTRONOMICAL
TIMEKEEPERS
Astronomers were baffled when
they first discovered a number of
mysterious objects which appeared
to emit relentlessly regular flashes
of high-energy radiation. The pulses
kept time so accurately that some
researchers were even drawn to extra-
terrestrial explanations of their origin
at first. However, as Jocelyn Bell and
Antony Hewish famously discovered
in 1967, these signals have a perfectly
natural explanation.
The duo revealed that the pulses are
actually beams of radiation, which are
continually emitted from the poles of
rapidly-rotating neutron stars – small,
dense objects which were once the cores
of massive stars. Once every rotation,
one of these beams would point straight
towards the Earth, resulting in a regular
sequence of flashes from our perspective.
The pulses are emitted with unwavering
uniformity like a highly precise
metronome, but as Holgado explains,
this could appear to change from our
perspective if a pulsar signal with was
affected by a gravitational wave. ‘If
gravitational waves pass through a pulsar
If gravitational waves pass through a
pulsar and the Earth, the arrival times
of the pulses are shifted due to the
stretching and squeezing of spacetime.
and the Earth, the observed pulse times-
of-arrival are shifted due to the stretching
and squeezing of spacetime,’ he says.
Astronomers are now using these
theorised shifts to monitor changes in
groups, or arrays, of these distorted pulsar
signals, over periods of several years. ‘In
order to detect gravitational waves, we
can time an array of pulsars and correlate
the observed shifts of the pulse arrival
times for each pulsar,’ Holgado continues.
‘A pulsar timing array (PTA) is a particular
type of gravitational wave detector that is
sensitive to nanohertz gravitational waves
from supermassive black hole binaries.’
A GROWING LIST
OF BINARY CANDIDATES
This technique is vital for detecting low-
frequency gravitational waves that LIGO
is not sensitive to. However, observations
of PTA signal shifts have yet to yield
concrete evidence of the low-frequency
ripples. All the same, researchers have
now begun the search in earnest; paying
particular attention to the dense, bright
clusters of gas which collect at the centres
of some galaxies.
‘Even though PTAs have yet to detect
nanohertz gravitational waves, their upper
limits are of astrophysical relevance and
importance,’ Holgado says. ‘A number
of telescopes have been finding and
observing active galactic nuclei (AGN),
which are the centres of galaxies that are
observed to be very bright compared to
normal galaxies due to a supermassive
black hole feeding on hot gas.’
In several of these bright galactic centres,
astronomers have found that the light
they emit dips and rises at regular
intervals. As Holgado explains, ‘some
AGN have light curves that show some
periodic behaviour, which is sometimes
thought to come from the orbital motion
of a supermassive black hole binary.’
If the orbit of the black hole binary is
inclined relative to our perspective, then
each black hole would routinely move
towards and away us as they orbit each
other. This motion relative to our line of
sight would cause the bright material
surrounding the black holes to become
even brighter when the motion is
towards us and to become dimmer when
www.researchoutreach.org 19
the motion is away from us. Another
possibility is that if the orbit is completely
face-on, i.e., no motion towards nor
away from us, then the gaseous material
can still fall into the black holes in a
manner driven by the orbital motion of
the binary. The rate at which the material
falls into the black holes can increase
and decrease on orbital timescales, and
as this accretion rate changes, so does
the luminosity of the gas that is falling
in. Astronomers can, therefore, refine
their search for nanohertz-frequency
gravitational waves by pointing their
telescopes at those periodic AGN
positioned behind PTAs.

LACK OF GRAVITATIONAL WAVES

If astronomers were right about
supermassive black hole binaries being
the main cause of periodic AGN, we
might expect to have a rapidly-growing
database of nanohertz gravitational wave
observations by now. Unfortunately,
however, this is not the case. ‘The growing
number of candidates that the telescopes
are finding imply a population of binaries
that may be emitting gravitational waves,
which pulsar timing arrays are sensitive
to,’ Holgado continues. ‘However, pulsar
timing arrays have not yet detected
gravitational waves. This must mean
that some fraction of the candidate
supermassive black hole binaries in AGN
may be false detections.’
If astronomers are wrong about
supermassive black hole binaries
being the sole cause of periodic AGN,
determining the proportion which are
responsible for them could be vital
for gravitational wave observations in
the future. In his research, Holgado is
working to determine just how many
time-variable AGN can be explained
by black hole binaries.
DETECTIONS IN BLAZARS
When AGN are particularly bright, they
will release vast amounts of energy
through colossal jets, which point
perpendicular to the galaxy’s disc.
AGN which display these jets are called
‘quasars’, and in special cases, they point
straight towards Earth, making them ideal
for our observation. The data gathered
in observations of these special quasars,
called ‘blazars’ is of particular interest to
Holgado. ‘Blazars are a particular type
of AGN whose jets are pointed directly
An artist’s depiction of a pulsar timing array, where a set of pulsars are observed for evidence of
gravitational waves from the cosmic population of supermassive black hole binaries with year-like
orbital periods.
Using PTA upper limits, we have shown
that only a small fraction of blazars may
be binaries.
towards us, making them particularly
bright among AGN,’ he explains. ‘NASA’s
Fermi Gamma-Ray Space Telescope has
obtained the most complete census of
blazars out to distances farther than what
pulsar timing arrays can observe.’
Many blazars exhibit the light variations
which caused astronomers to theorise
supermassive black hole binaries in the
first place, giving Holgado a highly-
developed database of observations
to work with. ‘Blazars are notorious for
showing quasi-periodic behaviour in their
light curves at a variety of wavelengths,
which is also sometimes thought to be
due to the presence of a binary,’ he
continues. With this information, Holgado
can use PTA upper limits on nanohertz
gravitational waves to directly quantify the
proportion of periodic blazars which may
host binaries.
LIMITED EVIDENCE FOR
SUPERMASSIVE BINARIES
So far, Holgado’s results have revealed
that only a small fraction of blazars can
host gravitational wave emitting binaries
that would be consistent with PTA upper
limits. This suggests that supermassive
black hole binaries are responsible for a
far smaller proportion of periodic AGN
than astronomers originally thought.
Instead, Holgado theorises that a
majority of periodic AGN must consist
of uneven distributions of light-emitting
gas orbiting individual supermassive
black holes.
‘Using PTA upper limits, we have shown
that only a small fraction of blazars,
around 0.01 to 0.1%, may be binaries,
which means that the quasi-periodicity
often seen in blazars is likely to be due
to periodic motions of the hot gas
surrounding the supermassive black hole,’
he explains.
Such a low fraction may be somewhat
disappointing to some astronomers,
but the result could prove vital in
ensuring potential future observations
of gravitational waves originating from
supermassive black hole binaries are
genuine. The constraints on the binary
fraction also provide some insights into
how efficiently supermassive black hole
binaries from in the centers of galaxies.
In the future, Holgado’s work could play
an important role in our understanding
of the dynamic ripples in spacetime which
we now know to permeate our universe.

20 www.researchoutreach.org
 Behind the Research
A. Miguel Holgado
E: holgado2@illinois.edu W: https://amholgado.gitlab.io/

Research Objectives References

A. Miguel Holgado’s research focuses on the gravitational
wave signatures of compact objects such as black holes,
neutron stars, and white dwarfs.
Holgado, A.M., Sesana, A., Sandrinelli, A., Covino, S., Treves,
A., Liu, X. and Ricker, P. (2018). Pulsar timing constraints on the
Fermi massive black hole binary blazar population. Monthly
Notices of the Royal Astronomical Society: Letters, 481(1),

Detail L74-L78.

Miguel Holgado Sesana, A., Haiman, Z., Kocsis, B., and Kelley, L. (2018).
1002 W. Green St., Testing the Binary Hypothesis: Pulsar Timing Constraints
Urbana IL, 61801 on Supermassive Black Hole Binary Candidates. The
Astrophysical Journal, Volune 856, Number 1.
Bio
A. Miguel Holgado completed his undergraduate studies
at Texas A&M University. He is now a PhD Candidate at
the University of Illinois at Urbana-Champaign researching
gravitational-wave astrophysics. Miguel will be attending
Personal Response
the 69th Lindau Nobel Laureate Meeting, which will focus
on Physics. There is increased effort towards finding potential
supermassive black hole binaries. With pulsar timing
arrays improving their upper limits, you must be excited
Funding about the future in this field.
NANOGrav Physics Frontier Center, NSF PIRE,
DOE Krell Institute Very much so! Even without a direct detection of
nanohertz gravitational waves, we can still do multi-
messenger astrophysics, where electromagnetic
Collaborators observations from telescopes tell us about the possible
• Alberto Sesana presence of binaries from periodic AGN and gravitational-
• Angela Sandrinelli wave upper limits tell us what fraction of these binary
• Stefano Covino candidates may be real. Once pulsar timing arrays finally
• Aldo Treves detect nanohertz gravitational waves, we hope to gain a
• Xin Liu clearer picture of how supermassive black hole binaries
• Paul Ricker form and how this is tied to the evolution of galaxies over
cosmic time.
DnG Photography/Shutterstock.com

www.researchoutreach.org 21
Physical Sciences ︱ Dr Diego A. Oyarzún
The mathematics of life:
Metabolic control in living cells
Cellular metabolism is a
complex network of chemical
processes that convert nutrients
into energy and molecules
for survival. Advances in
experimental and mathematical
techniques are paving the way
for quantitative descriptions of
how metabolism regulates itself
and of how it can be artificially
controlled for biotechnology.
Dr Diego A. Oyarzún
(University of Edinburgh)
uses computational models
to understand metabolism,
and to exploit it in cutting-edge
synthetic biology and healthcare
technologies.
Rost9/Shutterstock.com
22 www.researchoutreach.org
A
t its most fundamental level, life
is chemistry. Billions of chemical
reactions occur simultaneously
in living cells every second, which can
involve complicated macromolecules
like proteins and DNA, as well as smaller
and more mobile molecules that are
free to roam within the cell and even cell
membranes. These chemical reactions
do not happen in isolation: in order for
a cell to survive, thrive and reproduce, a
high degree of control of how and when
individual reactions take place is essential.
Cellular metabolism is an extremely
complex and robust network, in which
individual subunits (proteins and
metabolites) interact to keep the whole
network working and to guarantee
survival in unfavourable environmental
conditions. Understanding the details of
this enormously complicated machinery
appears to be well beyond the grasp of
traditional analytical approaches, but this
is set to change.
A HOLISTIC VIEW OF LIFE
Systems biology is a multidisciplinary field
of research that applies mathematical
and computational approaches to model
complex biological systems. It has gained
substantial importance in the last two
decades as a powerful set of methods
to study the interactions between the
components of a biological system (like,
for instance, proteins and metabolites
in cells) and to define how these
interactions determine the function of
the system, its behaviour and its response
to external perturbations. At its core,
systems biology attempts to describe
an emergent property of a biological
system by integrating information
about the interactions among its
constituents. At variance with traditional
reductionist approaches, which focus on
defining and identifying the elementary
constituents of large interacting systems,
systems biology aims to provide a
rigorous framework for the interpretation
of a system’s function and behaviour from
the quantitative observation of multiple
components simultaneously and from
the integration of these data with
mathematical models.
QUANTITATIVE MODELS
OF CELLULAR METABOLISM
For decades, cellular metabolism
has been largely seen as a process
isolated from the rest of the cellular
machinery. This traditional view has
been challenged in recent years, in light
of a number of studies that highlight
the interplay between metabolism and
other cellular functions. For example,
it is now established that metabolic
regulation plays an important role in
disease. Conditions such as cardiovascular
diseases and cancer have for instance
been linked to metabolic misregulation,
and pathogens can exploit their own
metabolic regulation systems to evade
drug treatments.
Dr Oyarzún has been pioneering
the application of systems biology to
metabolic regulation in living cells. His
work aims to understand the interplay
between metabolism and gene regulation
in natural systems. This is a cellular control
strategy that is widely conserved across
species and enables robust homeostatic
adaptations to fluctuating environments.
Various metabolic control systems
can be addressed, in order to elucidate
the role of the regulatory architecture
on metabolic phenotypes, including
pathways relevant for next-generation
antibiotics and synthetic biology.
The long term ambition of this work
is to develop a predictive theory of how
complex regulatory networks shape
the metabolic response of cells to the
environment. Such a theory is the key
to understand how cells self-regulate
in response to external perturbations,

including for instance the effects of
pathogens or antibiotic treatments.
ENGINEERING AND
SYNTHETIC BIOLOGY
Dr Oyarzún’s research applies
computational modelling to unravel the
complexity of the metabolic machinery
in cells and to understand the principles
of how its function can adapt to changing
environments. His approach is based
on the integration of mathematics,
engineering and biology and aims to
provide a quantitative description of
how life, as an emergent property of a
complex biological network, sustains itself
in diverse situations and under a variety
of external stimuli. This knowledge can
be exploited to make predictions on how
genetic modifications influence the cell
response, which can then in turn be used
to control the cell behaviour and adapt
it to serve human purposes, for instance
to produce new therapeutic drugs.
One of Dr Oyarzún’s interests concerns
the mechanisms of metabolic regulation
in bacteria. Bacteria use their metabolism
to consume nutrients from their
environment, which provides energy
and raw materials for synthesis of new
Carlos E. Santa Maria/Shutterstock.com
Dr Oyarzún’s research uses ideas from control
engineering and automation to study living systems.
Metabolism is an incredibly complex
network of chemical reactions essential
for the survival of cells.
molecules required for their survival
and reproduction. Depending on the
conditions of their environment, in
particular on the availability of nutrients,
bacteria need to adjust their metabolism.
This is accomplished through a complex
web of feedback mechanisms that
detect changes in nutrients and modify
metabolism accordingly. In order to shed
light onto this intriguing feedback effect
and to understand how bacteria self-adapt
to changing environments, Dr Oyarzún
has been pioneering the use of control
theory, a discipline borrowed from the
engineering world, whose objective is to
develop algorithms to robustly control
dynamical processes found in virtually
every technology, from manufacturing
to aircraft control and communication
systems. He applies this approach to
Computational models allow a detailed
Gorodenkoff/Shutterstock.com
understanding of metabolic networks in cells,
which can be exploited for cutting-edge
synthetic biology and healthcare technologies.
Vit Kovalcik/Shutterstock.com
Interactions between theory and experiments can
reveal the fundamental rules of biological processes.
understand how different regulatory
architectures found in nature enable
microbes to survive environmental shocks.
The novelty of Dr Oyarzún’s approach to
the problem is in the use of mathematics
to achieve what is virtually impossible
to obtain from purely experimental
approaches: a separation between the
intertwined roles of regulatory architecture
and regulatory parameters that control
metabolism. The goal of this effort is
to develop an understanding of how
microbes self-adapt their metabolism
to ensure their survival.
BIOTECHNOLOGY
Modelling cellular metabolism and
its regulation is an ambitious and far
reaching programme from a basic
science perspective, but it can also
www.researchoutreach.org 23
have important implications in rapidly
developing fields like biotechnology.
One of the current crucial challenges
in biotechnology is how to achieve
robust, predictable and economically
sustainable processes for a variety of
targets, like the synthesis of therapeutic
drugs, the development of new
materials and the production of food.
The quantitative biology approaches
developed by Dr Oyarzún and his

NicoElNino/Shutterstock.com
collaborators are providing a key
contribution towards achieving this goal.
In particular, the availability of robust and
quantitative models of cell metabolism
can pave the way for the design of
artificial biological systems, in which
cell metabolism is reprogrammed to
deliver custom functionalities. Promising
applications of this technique are in
Microbial metabolism can be controlled
microbial cell factories, which exploit through genetic engineering to produce
therapeutic drugs.
microorganisms to produce therapeutic
drugs and a variety of other chemicals.

MATHS AND MEDICINE:
PRECISION HEALTHCARE
The mathematical approaches
developed by Dr Oyarzún can have
far reaching impact even outside basic
science and biotechnology. Precision
medicine, whose holy grail is to deliver
the right medicine, to the right patient
and at the right time, is one field
that is likely to benefit greatly from
approaches based on the integration
of system biology, mathematics and
engineering. Progresses in screening
technologies (like DNA sequencing)
and image analysis algorithms now
offer physicians the ability to distinguish
between healthy and diseased
individuals and to identify stages in
disease progression. In this context,
Dr Oyarzún has been exploring the
application of tools from network
theory to analyse cancer omics datasets
and identify biomarkers and new drug
targets. This is part of the multiple
efforts devoted to developing the new
mathematical tools for data integration
and analysis that may transform
precision medicine into a mainstream
tool for wide segments of the
world’s populations.

Computational models reveal how

the growth of bacterial cells is governed
by the way they allocate their limited
resources to different cellular processes.
paulista/Shutterstock.com

24 www.researchoutreach.org
 Behind the Research
Dr Diego A. Oyarzún
E: d.oyarzun@ed.ac.uk T: +44 0131 651 1211
W: www.ed.ac.uk/profile/diego-oyarzun/ @doyarzunrod

Research Objectives
Dr Oyarzún’s group develops computational methods to analyse biological networks in living cells. His team uses mathematics
to understand the function of natural networks, as well as to design novel biomolecular systems for Biotechnology and Healthcare.

Detail
Dr Diego Oyarzún,
Lecturer in Computational Biology, School
of Informatics & School of Biological
Sciences, Informatics Forum,
10 Crichton St., EH8 9AB, UK.
Funders
• Human Frontier Science Program
• EPSRC Centre for Mathematics
of Precision Healthcare
• Cancer Research UK
• Wellcome Trust
Bio
Dr Oyarzún leads the Biomolecular
Control Group at the University of
Edinburgh, with a joint appointment at
the School of Informatics and School of
Biological Sciences. Previously he was
a Research Fellow in Biomathematics at
Imperial College London and a Marie
Curie Fellow at INRIA Sophia Antipolis.
He obtained his PhD in 2010 from the
Hamilton Institute, Maynooth University,
Ireland. In 2016, Dr Oyarzún was
appointed Global Future Council Fellow
by the World Economic Forum and in 2017
he was selected as one of the 100 Young
Global Changers by the Think 20 Summit,
mandated by the G20 presidency.

References Personal Response

Oyarzún, DA (2019). Diego Oyarzún, University of Edinburgh.
[online] Personal website. Available at: https://www.ed.ac.uk/
profile/diego-oyarzun/ [Accessed 17 March 2019].
Liu, D., Mannan, A. A., Han, Y., Oyarzún, D. A. & Zhang,
F. (2018). Dynamic metabolic control: towards precision
engineering of metabolism. Journal of Industrial Microbiology
and Biotechnology 45, 535–543.
Tonn, M. K., Thomas, P., Barahona, M. & Oyarzún, D. A.
(2019). Stochastic modelling reveals mechanisms of metabolic
heterogeneity. Communications Biology 1–9.
Chaves, M. & Oyarzún, D. A. (2019). Dynamics of complex
feedback architectures in metabolic pathways. Automatica 99,
323–332.
Beguerisse-Díaz, M., Bosque, G., Oyarzún, D., Picó, J. &
Barahona, M. (2018). Flux-dependent graphs for metabolic
networks. npj Systems Biology and Applications 4;32.
Oyarzún, DA; Lugagne, J-B; Stan, G-BV. (2015). Noise
propagation in synthetic gene circuits for metabolic control.
ACS Synthetic Biology, 4 (2), 116-125.
The ability to develop quantitative and predictive
models of cell metabolism, especially in bacteria,
is an extremely ambitious and sought after goal.
What do you think are the fields that will benefit
most from your work in the short term and what
are the major remaining challenges for the application
of the approaches you are developing to the field
of biotechnology?
The most direct benefits are in synthetic biology and
metabolic engineering. Our work is paving the way for
computer-aided design of cell factories, much like the
way things are done in other engineering disciplines. A
major challenge is the lack of methods to integrate various
layers of data, such as metabolomics, proteomic and
transcriptomic, into tractable models.
With the current big data revolution in biology, there
is huge potential for machine learning and artificial
intelligence to bridge this gap, so that we can harness
the full potential of such molecular data. Another big
challenge is the role of heterogeneity . Even genetically
identical cells display different metabolic phenotypes,
which not only negatively affects performance of
engineered cell factories, but is also thought to play key
roles in bacterial responses to antibiotics, one of the most
pressing challenges in global health.

Weisse, A. Y., Oyarzún, D. A., Danos, V. & Swain, P. S. (2015).

Mechanistic links between cellular trade-offs, gene expression,
and growth. Proceedings of the National Academy of Sciences
112, E1038–E1047.

www.researchoutreach.org 25
Physical Sciences ︱ Jim Tilley
Will an old problem
yield a new insight?
Perhaps an elegant proof of the 4-colour theorem?
The 4-colour problem is one of
the most famous mathematical
problems. It resisted proof for
more than a hundred years
before finally succumbing; in the
end, there was a valid proof, but
one that relied on more than
a thousand hours of computer
time. Jim Tilley’s research
suggests that a dramatic
simplification might ultimately
be possible. He has discovered
a property, Kempe-locking, that
a minimum counterexample
to the 4-colour theorem must
exhibit and has formulated a
conjecture, based on extensive
investigations, that the Birkhoff
diamond is the sole fundamental
Kempe-locking configuration.
Figure 1. A proper colouring of the
planar triangulation on 12 vertices
that represents the icosahedron.
The single red-blue Kempe chain
is shown highlighted.
26 www.researchoutreach.org
G
raph colouring involves assigning
labels, or colours, to the vertices
of a mathematical object known
as a graph. The 4-colour problem
provided one of the original motivations
for the development of algebraic graph
theory. Graph colouring is used in many
real-world problems, such as minimising
conflicts when scheduling sports events,
planning examination timetables and
organising seating plans, even for CCTV
camera placement in a building with
many corners in order to minimise camera
overlap. It also provides the foundation
for Sudoku puzzles.
THE 4-COLOUR PROBLEM
Francis Guthrie, a student of the famous
British mathematician and logician
Augustus De Morgan, posed the 4-colour
problem in 1852. He formulated the
problem with respect to maps that satisfy
certain conditions, such as not containing
any holes and having every region (e.g.
country or state) connected so that
no region exists in two or more non-
contiguous parts. Guthrie claimed that
for such maps it would never take more
than four colours to colour the map such
that no two neighbouring regions were
the same colour.
Nowadays, the 4-colour problem is
expressed in terms of graphs, and instead
of colouring regions in maps, one
colours vertices in graphs.
All existing proofs of the 4-colour
theorem demonstrate that a
minimum counterexample
cannot exist. (A minimum
counterexample is the
smallest planar graph
that requires more
than four colours
for a proper
colouring of its vertices.) Only planar
graphs that are triangulations need
to be considered, as any graph that is
not a triangulation can be turned into
one by inserting edges. If the resulting
triangulation is 4-colourable, then the
original graph is also 4-colourable. It is
highly useful to be able to restrict one’s
scrutiny to triangulations.
AN EARLY ATTEMPT AT PROOF
Of those who offered a proof, Alfred
Bray Kempe, an English barrister and
amateur mathematician, was the person
whose reputation was most tainted by his
failed effort. He announced his success
in 1879 and his ‘proof’ was published in
the American Journal of Mathematics.
Eleven years later, however, another
English mathematician, Percy Heawood,
created a map that he 4-colored up
to the final region in such a way that
Kempe’s method failed for that final
region. Despite his failure, Kempe
left a useful tool – a Kempe chain. It
is a maximal, connected (every vertex
reachable from any other by a path along
edges) subgraph in which all vertices use
exactly two colours. Kempe chains have
proven instrumental in colouring and re-
colouring graphs. See Figure 1.
PROOF AT LAST
The first valid proof was announced in
1976 by Kenneth Appel and Wolfgang
Haken. It required over a thousand hours
of computer time to verify particular
aspects of their argument. This notion
of relying on computer code, potentially
containing human-induced errors (and
their code did!), rather than a ‘human’
proof, has not satisfied a great part of
the mathematical community. Appel and
Haken’s proof was elegant in its overall
structure, but the details were ugly.
Converting a map into a graph; regions become vertices.

The proof was refined in 1996 by a team
of four mathematicians: Robertson,
Sanders, Seymour, and Thomas, but they
still relied on computer code to complete
their proof. In 2010, Steinberger offered
another variation. However, there is still
no completely satisfying answer as to
why the 4-colour theorem is true. (Once
the conjecture was proved, it gained
the status of a ‘theorem.’)
THE SEARCH FOR AN
ALTERNATIVE PROOF
The 4-colour problem is so easy to
articulate and comprehend that it has
attracted the interest of many thousands
of amateur mathematicians, all believing
they can find a simple classical proof and
associated with an edge in a
triangulation. The notion starts with
deleting an edge xy between adjacent
vertices x and y. If for every 4-colouring
of the resulting graph in which the
colours of x and y are the same, there
is no sequence of colour-interchanges
on Kempe chains that causes the colour
of x to differ from the colour of y, then
the original triangulation is said to be
Kempe-locked with respect to the
edge xy. Tilley proved that a minimum
counterexample to the 4-colour theorem
has to be Kempe-locked with respect to
every one of its edges; every edge in a
minimum counterexample must have this
colouring property.
entire map will be 4-colourable. Thus, a
minimum counterexample cannot contain
that particular configuration. It has come
to be known as the Birkhoff diamond.
Tilley found that a Kempe-locked edge
xy seems to arise only when x and y are
also the endpoints of the graph version
of a Birkhoff diamond. See Figure 2.
Not having encountered any Kempe-
locking configuration without a Birkhoff
diamond, he conjectured that the Birkhoff
diamond is the only ‘fundamental’
Kempe-locking configuration, one that
doesn’t contain a smaller Kempe-locking
configuration as a subgraph. However,
Tilley found that he could not prove

It would be an astounding simplification

thus become famous. Jim Tilley’s father,
a physicist and principal of Canada’s
Royal Military College from 1978-1984,
was one such dreamer. Whenever he felt
that he had made a breakthrough, he
would ask his son, Jim, to check his work.
Jim always found a flaw. Yet, despite his
initial scepticism that his father’s efforts
would ever bear fruit, he became infected
with an enthusiasm for the 4-colour
problem and began to study it intensely.
KEMPE-LOCKING
Jim Tilley’s research led to his discovering
a new property that a minimum
counterexample to the 4-colour theorem
must exhibit. He named it ‘Kempe-
locking.’ He realised that it was likely to
be incompatible with another property
that a minimum counterexample must
exhibit – viz., how connected a graph is
(how many vertices must be removed
from a graph before it falls apart).
Tilley’s Kempe-locking is a property
if the Birkhoff diamond alone is the key
to 4-colourability.
Kempe-locking is a particularly restrictive
condition that becomes more difficult to
satisfy as a triangulation gets larger. Tilley
set out to discover if there is anything
common to triangulations that have
Kempe-locked edges. His earliest search
for Kempe-locking led him to the Birkhoff
diamond.
THE BIRKHOFF DIAMOND
In 1913, G. D. Birkhoff discovered that
a certain configuration of ten countries
in a map (a boundary ring of six countries
that encloses a set of four countries)
has an important property. If that
configuration is present in a map and
Alfred Bray Kempe, an English barrister
if the submap with that configuration and amateur mathematician.
removed is 4-colourable, then the

www.researchoutreach.org 27
his critical conjecture. It was frustrating
because, if true, the conjecture would
directly prove the 4-colour theorem. x y
(To be a minimum counterexample, a
triangulation would have to contain a
Figure 2
Birkhoff diamond subgraph, but if it did, it
couldn’t be a minimum counterexample.)

AN OVERWHELMING
SUPPORTING CASE
Instead of proving his conjecture, Tilley
did the next best thing. He decided to
play the role of an experimentalist and
build an overwhelming case to support
his conjecture. He divided all relevant
planar triangulations into two classes:
those in which at least four vertices
have to be removed before the graphs
fall apart (4-connected) and those in
Figure 3
which at least five vertices have to be
removed before the graphs fall apart
(5-connected). See Figure 3. Helpful
in Tilley’s extensive search was that Figure 2. The Birkhoff diamond configuration with endpoint vertices x and y.
he had to examine only one member Figure 3. Two planar graphs, one a 4-connected triangulation on 6 vertices and one a 5-connected
of each isomorphism class (graphs triangulation on 17 vertices.

The conjecture is easily stated, understandable, and intriguing,

and offers a compelling explanation for why all planar graphs
are 4-colourable.
that are structurally identical). Tilley
examined all 8,044 isomorphism classes
of 4-connected planar triangulations
on up to 15 vertices and all 9,733
isomorphism classes of 5-connected
planar triangulations on up to 24 vertices.
He found only three Kempe-locked
Kenneth Appel and Wolfgang Haken.
triangulations. Each discovered Kempe-
locked edge featured a Birkhoff diamond
and each occurred in a 4-connected
triangulation. There were none at all
among 5-connected triangulations.
Tilley expanded his search among
4-connected triangulations by examining
all 30,926 isomorphism classes on 16
vertices and all 158,428 isomorphism
classes on 17 vertices. Computation-time
limitations meant restricting his search to
samples of 100,000 randomly generated
non-isomorphic triangulations each for
classes on 18,19, and 20 vertices. The
expanded search turned up 45 additional
Kempe-locked triangulations, but
exactly the same results as the original
search: each Kempe-locked edge in
a triangulation featured an associated
Birkhoff diamond.
WHERE FROM HERE?
Tilley’s extensive searches easily
confirmed that the Birkhoff diamond
is a fundamental Kempe-locking
configuration. He has thoroughly tested
his conjecture, but it remains unproven.
If (or when) Tilley’s conjecture is proved
true, i.e., that the Birkhoff diamond alone
is the key to 4-colourability, it would
be an astounding simplification of the
problem: a single configuration that
explains it all – mathematical elegance.
Proving the 4-colour conjecture
required the efforts of many prominent
mathematicians. Tilley’s conjecture
that the Birkhoff diamond is the
sole fundamental Kempe-locking
configuration may be even more difficult
to prove. However, the experimental
evidence is strong. Theorists might
say ‘why bother?’ Tilley’s answer is that
insatiable curiosity will win out: “After
all, the conjecture is easily stated,
understandable, and intriguing, and
offers a compelling explanation for why
all planar graphs are 4-colourable.”

28 www.researchoutreach.org
 Behind the Research
Jim Tilley
E: jimtilley@optonline.net T: +1 914 242 9081 W: https://en.wikipedia.org/wiki/Jim_Tilley
W: https://www.researchgate.net/scientific-contributions/2085779401_James_A_Tilley W: www.jimtilley.net/

References Research Objectives

Tilley, J. (2018). ‘Using Kempe exchanges to disentangle
Kempe chains.’ The Mathematical Intelligencer, 40, 50–54.
Tilley, J. (2018). ‘Kempe-locking configurations.’
Mathematics, 6(12), 309.
Jim Tilley’s primary mathematical research interest is graph
colouring and, in particular, finding an alternative solution to
the 4-colour problem that offers a compelling reason why the
4-colour theorem must be true.

Tilley, J. (2017). ‘The a-graph coloring problem.’ Discrete Detail

Applied Mathematics, 217, 304–317.
61 Meeting House Road
Tilley, J. (2017). ‘D-resolvability of vertices in planar graphs.’ Bedford Corners, New York 10549-4238
Journal of Graph Algorithms and Applications, 21(4), 649- USA
661.
Bio
Tilley, J. (2018). ‘The Birkhoff Diamond as Double Agent.’ Jim Tilley earned a doctorate in Physics from Harvard University.
Working paper at arXiv. Since retiring in 2001 as Morgan Stanley’s Chief Information
Officer, he has published original research on graph colouring.
He has also published three books of poetry. His debut novel,
Against the Wind, will be released in September 2019.
Personal Response
What initially prompted your enthusiasm for
the 4-colour problem and led you to study it so
intensely?
It was my father’s obsession with the problem
in his retirement and his desire to use me as the
sounding board for his ideas.

What are your plans for future research in this area?

I have recently reviewed a complicated paper
involving a wholly different approach to the 4-colour
problem. As the paper stands, I believe it has flaws.
Yet, it has promise. I might be tempted to explore
a collaboration.

Julia Sudnitskaya/Shutterstock.com

www.researchoutreach.org 29
Engineering and Technology ︱ Dr Titus Masese
The materials
making potassium-ion
batteries possible
You are probably familiar with
lithium-ion batteries that can
be found everywhere from
inside our mobile phones to
electric cars. However, lithium’s
larger brother potassium
may soon find its way into
the batteries that power our
everyday lives. Dr Titus Masese
at the National Institute of
Advanced Industrial Science
and Technology in Osaka,
Japan, has been developing
new materials for electrodes
to help overcome some of the
current limitations of potassium-
ion battery technologies to
allow them to reach their
potential as a promising low-cost
rechargeable battery material
for energy storage.
There are multiple possible applications for potassium ion batteries.
These range from industry, renewable energy, domestic uses, electric
vehicles and mobile phones.
30 www.researchoutreach.org
A
n electrical battery is any device
that stores energy that can be
converted to electrical energy.
A basic battery provides electricity, or
a flow of electrons, by having a positively
charged cathode and negatively charged
anode at each end, with an electrolyte,
a conductive solution, in between.
When a battery is connected to an
electrical circuit, chemical reactions
within the battery cause electrons to start
building up at the anode. Eventually, this
pile-up of electrons becomes unstable
and will move through the electrolyte
separating the anode and cathode,
and flow around the circuit, providing
the necessary electrical power.
However, each of these chemical
reactions depletes the stored potential
energy in the battery. Rechargeable
batteries try to overcome this by
reversing the oxidation and reduction
reactions, the chemical reactions that
occur at the cathode and anode and,
this time, convert electrical energy
to chemical energy.
One of the most famous types of
rechargeable batteries is the lithium-ion
battery, where its high-power density
makes it ideal for portable, energy-
hungry devices like smartphones.
However, lithium-ion batteries are
not the only option for rechargeable
battery technologies.
Dr Titus Masese at the National Institute
of Advanced Industrial Science and
Technology in Osaka, Japan has been
working on new, potassium-based
materials for developing potassium-
ion based rechargeable batteries.
There are good motivations for doing
this. Developments in higher-energy,
longer-lifetime and lower-cost battery
technologies are a key part of the
necessary energy storage strategy
required for a more sustainable future,
and potassium-ion batteries may
offer a lower-cost alternative, partly as
potassium is over eight hundred times
more abundant on Earth than lithium.
A MATERIALS CHALLENGE
Part of the reason that phones today
don’t come with potassium-ion batteries
is some of the technical challenges
with their development that people
like Dr Masese and his colleagues are
working to overcome. The name of
lithium or potassium-ion batteries comes
from the type of chemical element
 Schematic illustration of the operating
mechanism of potassium-ion batteries.
Akin to lithium ion batteries, potassium-
ions shuttle back and forth through the
electrolytes to the electrodes. A layered
cathode and graphite as anode is shown
for brevity. The cathode (highlighted
in red) principally restricts the energy
density of potassium-ion batteries and
was the central focus of this study.

that is embedded in the electrodes.

This ion, which is oppositely charged
to the electrons produced in the battery,
is released from the electrodes and moves
in the opposite direction to the electron.
The movement of the ions is as crucial
for the battery performance as the
The honeycomb structures that Dr Masese
movement of the electrons: if the ion fails has pioneered currently show the largest
to move, the battery can discharge and
fail to provide energy. voltage for any layered cathode material.
What Dr Masese and his colleagues have due to the large size of the potassium potential lifetimes of potassium-ion
been successfully able to do is create ions. Many electrode materials are made batteries based on these cathodes.
honeycomb layered cathode frameworks from highly organised, regular crystalline It is not just the cathode though that
that incorporate potassium ions and are structures, so any gaps left by a departing is important for battery stability and
capable of sustaining very high voltages. ion will remain in the same place. durability. As the electrolyte can also play
One of the challenges for using potassium However, recombination processes and a role in detrimental chemical reactions,
ions in rechargeable batteries is that unwanted chemical reactions between this too must be as benign as possible.
their large sizes can make it difficult to the electrolyte and electrode can lead to
incorporate them in the tight-packed damaging and aging of the battery. This FUTURE OF ELECTROLYTES
lattice frameworks that make up the type is why many phones undergo significant Dr Masese and his colleagues have been
of electrons used in lithium-ion batteries. deterioration of battery performance even using ionic liquids as the electrolyte
In an ideal battery, the ions would be fast within a few years of manufacture. materials in the development of
to release from the framework, move potassium-ion cells, or tellurate-based
through the electrolyte and then be These honeycomb materials have shown materials where a solid electrolyte is
reincorporated back into the frameworks to be thermally stable and maintain desirable. Ionic liquids are unusual
as required. the high voltages they are capable of in their behaviour as they are liquids
producing, which bodes well for the that contain dissolved salts that
The honeycomb structures that Dr Masese
and his colleagues have pioneered
currently show the largest voltage for
any layered cathode material, meaning
it could potentially show the highest
energy delivery as part of a battery. He
has also been working to incorporate
these into rechargeable potassium-ion
batteries as a step towards more practical
potassium-ion battery technologies.

DURABLE ELECTRODES
The secret of the success of Dr Masese’s
honeycomb structures lies in their
ability to facilitate reliable potassium
ion recombination, a significant challenge
Schematic showing the protocols employed in screening potential cathode
materials for rechargeable potassium-ion batteries. Potassium-based compounds were
screened using reliable computational processes after which potential candidates were
selected. The selected material powders were assembled as electrode materials and their
performance evaluated in coin cells using standard electrochemical measurement procedures.

www.researchoutreach.org 31
Snapshot of the various novel potassium-based compounds (cathode candidates) synthesised over
the course of this study.
Dr Masese’s materials are helping to
herald in the post-lithium-ion battery age.
exist as charged ions. Conventional
electrolytes contain organic solvents,
rendering them flammable. They also
tend to decompose at high voltages
and temperatures. Ionic liquids do not
contain flammable organic solvents.
Therefore, they are safe and stable
at high voltages and high temperatures
which are beyond the capacity
of conventional electrolytes.
CRYSTAL STRUCTURE
P2-Type layered structure
SIDE VIEW
The figure on the left shows the layered crystal structure. On the right is the same structure viewed
from above.
32 www.researchoutreach.org
Solid electrolytes are also highly desirable
to combat some of the safety concerns
about rechargeable ion batteries. Liquid
electrolytes can leak if the battery is
damaged and are also highly flammable,
which is the origin of many of the high-
profile stories about mobile phone
battery fires. The problem with solid
electrolytes is that, although they are
better from a safety perspective, they
Honeycomb structure
TOP VIEW
Dr Masese at work in the lab.
do not show the same efficiency as their
liquid counterparts, but Dr Masese has
demonstrated that the tellurate-based
materials do show high conductivity
for the potassium ions and may well play
an important role in the development
of solid electrolytes for potassium-ion
batteries of the future.
LIGHTENING THE LOAD
One of the key advantages of the
potassium-ion batteries that Dr Masese
is helping to realise is their very high
voltage capabilities, that he has
demonstrated through the performance
of the electrode material. High-voltage
supplies reduce the need for so many
cells within a battery pack. This then
entails small volume, cost and weight
battery packs, something that is essential
for improving the performance of, for
instance, electric vehicles. The 85 kWh
battery pack in the Tesla Model S weighs
in excess of an enormous 500 kg and
accounts for nearly a quarter of the
total weight of the car. Although
40 litres of petrol weighs around
30 kg and there is the weight of
the fuel tank and fuelling system
to consider, finding a solution for
the heavy weight and bulky sizes of
electrical batteries would dramatically
increase the feasibility of electric vehicles
and significantly increase their efficiency.
Dr Masese’s materials are helping
to herald in the post-lithium-ion battery
age and demonstrate a significant
advance in the feasibility of potassium-ion
based technologies.
 Behind the Research
Dr Titus Masese
E: titus.masese@aist.go.jp T: +81-72-751-9224 W: www.aist.go.jp/index_en.html
W: https://unit.aist.go.jp/riecen/index_en.html W: https://www.youtube.com/watch?v=HQl8AJxCAlw

Research Objectives References

Working with the Advanced Battery Research Group
at AIST, Dr Masese’s research explores high performance
next-generation rechargeable battery systems.
Masese, T. et al., (2018), Rechargeable potassium-ion
batteries with honeycomb-layered tellurates as high
voltage cathodes and fast potassium-ion conductors,
Nature Communications, 9, 3823.

Detail Masese, T. et al., (2019). A high voltage honeycomb

layered cathode framework for rechargeable potassium-
Dr Titus Masese ion battery: P2-type K2/3Ni1/3Co1/3Te1/3O2, Chemical
National Institute of Advanced Industrial Science Communications, 55, 985.
and Technology (AIST)
1-8-31 Midorigaoka, Ikeda-shi, Osaka, Japan Kato, M. et al., (2019), Organic positive-electrode material
PO Box 563-8577 Kansai Center utilizing both an anion and cation: a benzoquinone-
tetrathiafulvalene triad molecule, Q-TTF-Q, for
Bio rechargeable Li, Na, and K batteries, New Journal of
Titus Masese hails from Kenya. He won a Japanese Chemistry, 43, 1626.
government scholarship after emerging amongst the top
students in KCSE 2002 national examinations. He obtained
his BEng, MSc and PhD degrees from Kyoto University
(BEng supervisor: Prof Haruyuki Inui; PhD supervisor: Prof
Yoshiharu Uchimoto). He is currently a researcher at AIST.
Personal Response
Funding What are the next steps in your work to turn
these honeycomb materials into a part of battery
• National Institute of Advanced Industrial Science
technologies?
and Technology (AIST)
• Japan Prize Foundation From a fundamental point of view, we have shown
that high voltages are attainable with the honeycomb-
layered tellurate materials. Although tellurium has
Collaborators
been studied intensively from both fundamental and
• Dr Kazuki Yoshii technological perspectives, its use may render these
• Dr Yoichi Yamaguchi honeycomb cathode materials unpractical. Part of our
• Dr Minami Kato ongoing work is the design of tellurium-free related
• Dr Satoshi Uchida materials also demonstrating high voltages. While
• Dr Toyoki Okumura we note that there are other challenges that should
• Dr Keigo Kubota ultimately be solved for the nascent potassium-ion
• Dr Hiroshi Senoh technology to reach the market, the insights garnered
in this study as well as other studies reported so far
• Prof Zhen-Dong Huang (Nanjing University)
have identified many exciting and promising routes
• Prof Yuki Orikasa (Ritsumeikan University) forward to designing a high-voltage battery prototype.
• Dr Hajime Matsumoto We believe that by reaching out to the wide-spanning
• Prof Martin Månsson (KTH Royal Institute of Technology) scientific community, we can bring the potassium-ion
• Many thanks to Ms Kumi Shiokawa for the relentless technology closer to reality.
technical assistance

www.researchoutreach.org 33
Physical Sciences ︱ Dr Benjamin S. Hsiao
Sustainable water
purification using biomass
Nanoscale cellulose materials
obtained from the chemical
treatment of biomass are
very effective agents for the
removal of toxic species from
water, including heavy metal
ions. Professor Benjamin S.
Hsiao and his collaborators
at Stony Brook University
have developed a simple,
inexpensive and environmentally
friendly approach to preparing
nanostructured cellulose for
water purification, based on a
nitro-oxidation reaction carried
out on biomasses of diverse
origins. In addition to providing
cellulose with a superior affinity
for dissolved toxic ions, this
process yields nitrogen-rich salts
as byproducts, which can be
recovered and used as fertilizers.
T
he ability to remove pollutants
quickly and efficiently at low cost
is a basic requisite for the human
utilisation of water in a large variety of
environments and situations. For instance,
in many developing countries, clean water
remains a rare and precious commodity,
since the available (and often very limited)
sources of water frequently contain
human pathogens of bacterial origin,
incompatible with human consumption.
In industrialised societies, metal pollutants
also pose a severe threat to health
and the environment.
Dr Hsiao’s team has been at the
forefront of research on the chemical
modification of nanostructured cellulose
(nanocellulose) for water purification,
and they have recently demonstrated a
simple, innovative, and environmentally
friendly approach to exploit nanocellulose
from virtually ubiquitous and low-cost
natural resources for water purification.
HEAVY METAL
CONTAMINANTS IN WATER
Heavy metal ions are among the most
common pollutants of drinking water
in modern societies. For instance, lead
ions are powerful neurotoxins and they
constitute the most prevalent form of
heavy metal water pollution on a global
scale. Over a hundred thousand deaths
attributed to lead poisoning have been
reported in 2016. Lead poisoning has also
been linked to the appearance of defects
at birth and to cancer. Lead is commonly
used in the infrastructures for water
transportation and supply around the
world, and the amount of metal dissolved
in drinking water increases with time
due to the progressive corrosion of the
infrastructure. Furthermore, the recent
practice to add chloramine for disinfection
in water treatment facilities has led to
even higher concentrations of lead ions
in drinking water, because of the reaction
of chlorine with lead in domestic pipes,
which promotes the metal dissolution.
Another major pollutant is cadmium,
which is extensively used in electronic
circuits, batteries, solar cells, paints
and pigments, and can enter water
sources through industrial waste and
run-offs. Consumption of water or food
contaminated with cadmium can lead
to severe gastrointestinal irritation and,
potentially, to death. Increasing levels
of cadmium contamination have been
reported in recent studies in some
areas of Africa, Asia and South America,
although the problem is by no means
limited to these regions.
Uranium is also a common water
contaminant. High levels of uranium salts
are observed not only in nuclear waste
but also in water sources from regions
(including New Mexico, Australia, Austria,
Kazakhstan, Canada, India and the Czech
Republic) in which this element exists in
large concentrations in the bedrocks and
in groundwater. Upon ingestion, uranium
can rapidly enter the bloodstream
and bind to red cells, to form a uranyl-
albumin complex, which can accumulate
in the kidneys and in bones.
Removal of heavy metal ions, as from the
above examples, or bacterial pathogens
from drinking water can be accomplished
by exploiting the ability of materials
with suitable functionality (for example
activated charcoal or synthetic polymers)
to bind the pollutants, whilst remaining
insoluble in water. After binding, they
form secondary contaminants and need
to be removed. The floc formed from the
interaction of nanocellulose and heavy
metal ions (as well as bacterial pathogens)
can be easily removed by gravity-driven
filtration or decanting, thus avoiding the
addition of costly means. Nanocellulose
is one of the most promising classes
 The village outside Ileret in Marsabit County near Turkana
Lake, Kenya, one of the poorest regions on Earth.

of materials for water purification,
in view of its availability, abundance
and low environmental impact, as it
can be extracted from any biomass such
as trees, plants and weeds.
CARBOXYCELLULOSE:
A FUNCTIONAL MATERIAL
FOR WATER PURIFICATION
Cellulose is the most abundant organic
polymer on Earth, and it is a primary
component of the cell walls in plants.
It is composed of long chains of
D-glucose units, connected by bridging
oxygen atoms. It is abundant in natural
fibres (for instance, its content in cotton
is roughly 90%) and in wood (40-50%)
and it is the raw material for the large-
scale production of important materials,
including paper, cellophane and
rayon. Cellulose derivatives obtained
by chemical treatment of raw cellulose
can also bind efficiently with metal ions
in water.
The work of Dr Hsiao has focused
specifically on carboxycellulose, which is
composed of cellulose chains that have
been chemically modified to include
carboxylate groups
(--COO-) in their structure. Nanostrcutured
carboxycellulose has two key features,
which make it highly attractive as an
ion-binding material. First, its nanoscale
structure originates from the existence
of building blocks (cellulose microfibrils)
in the cell walls of raw biomass materials,
rather than from the recombination of
dissolved cellulose chains. The production
of nanostructured carboxycellulose,
therefore, does not necessarily require
energy-intensive processes. Second,
the chemical modification of the cellulose
matrix (through processes like oxidation,
carboxymethylation, phosphorylation,
Biomass is a vast source of nanoscale
cellulose, which can be chemically
modified to act as an effective water
purification material.
acetylation and silylation) introduces
negative charges in the cellulose structure,
which promote nanofiber dispersion in
water and provide functional molecular
sites for the adsorption of dissolved
species. For example, carboxycellulose
nanofibers offer very large surface areas
and chemically active functional groups,
which make them ideally suited for
filtration membranes and adsorption
media for water treatment.
Cellulose
Plant cell wall
A hierarchical structure of cellulose fibres with different diameters in a plant cell wall.
NANOSTRUCTURED
CARBOXYCELLULOSE
FROM BIOMASS
Carboxycellulose nanofibers can be
obtained through several approaches.
One of the most efficient approaches
is the TEMPO-mediated oxidation
reaction, which converts -OH
groups in the cellulose polymer into
carboxylate groups in mild conditions.
This promotes the fibrillation of large
cellulose aggregate into nanofibers
whilst maintaining long fibre length
(submicrons to microns). However, this
Cellulose Cellulose
Fibre Nanofibre Microfibre

www.researchoutreach.org 35
method is carried out as a sequence of
several steps, and it requires speciality
chemicals (e.g. sodium hypochlorite,
sodium bromide and TEMPO reagents)
that generate dangerous radical
species. Its sustainability as a large-scale
process to produce nanostructured
carboxycellulose remains, therefore,
limited. Alternative approaches
have also been proposed, based on
etherification, oxidation, esterification
and carboxymethylation of cellulose,
which are only effective for cellulose
samples with small concentrations of
lignin and hemicellulose and require a
preliminary treatment with chemicals like
alkali and bleaching agents, along with
mechanical treatment, to fully fibrillate
the cellulose matrix into nanofibers.

NITRO-OXIDATION:
A CLEAN ROUTE TO FUNCTIONAL
NANOCELLULOSE
Dr Hsiao and his co-workers have Varying underutilised biomasses that are good resources for the extraction of nanocellulose.

developed a simpler and far more

sustainable approach to the production
of carboxycellulose nanofibers from
untreated biomass, based on the
use of a mixture of nitric acid (HNO3)
and sodium nitrite (NaNO2) as the only
required chemicals. This process has
been shown to work very efficiently
for untreated (raw) biomasses of various
origins (such as jute, spinifex grass
and bamboo cellulose) and, crucially,
to be a strictly single-step treatment.
This considerably reduces the electrical
energy and the water consumption
needs compared to other methods. It
has been hypothesised that HNO3 in the
mixture initiates the fibrillation process
of the untreated biomass by removing
non-cellulosic components. The
reaction of HNO3 and NaNO2 generates
nitrosonium ions (NO+) in the presence
Carboxycellulose nanofibres obtained
using the nitro-oxidation method exhibit
very exceedingly high affinity for several
common water contaminants.
of excess acid, which can attack hydroxyl
groups in cellulose and produce
carboxylate groups. The resulting
carboxycellulose fibres exhibit relatively
low crystallinity and substantially
higher fibre length and aspect ratio
than those of cellulose nanocrystals.
Furthermore, the effluent obtained
as a by-product can be neutralised
efficiently using (inexpensive) sodium or
potassium hydroxide, to give nitrogen-
rich salts that can be used as fertilizers
in agriculture.
Cellulose nanofibers obtained by nitro-
oxidation provide excellent adsorbent
materials for the removal of heavy metal
ions, including lead, cadmium, mercury,
chromium, uranyl and arsenic as well
as bacteria from water. For heavy metal
ions, adsorption capacities several
times higher than those of the most
effective adsorbents in the literature have
been reported. The metal-adsorbed
nanocellulose flocs can easily be removed
using simple and inexpensive gravity
driven microfiltration or decanting.

IMPACT
Vast amounts of biomass sources,
including agriculture waste, weeds
and shrubs, are available at low or zero
cost, and all of them provide ideal raw
materials for the nitro-oxidation process.
The approach developed by Professor
Hsiao represents a tremendous step
forward toward the exploitation of
underused resources like biomass to
develop efficient processes for the
removal of waterborne pathogens from
Nanocellulose suspension as effective adsorbent/flocculent capable of removing heavy metal ions.
Their maximum removal capacity (indicated below the picture) is significantly higher than those reported drinking water, particularly in developing
in the literature. countries and off-the-grid communities.

36 www.researchoutreach.org
 Behind the Research
Dr Benjamin S. Hsiao
E: Benjamin.hsiao@stonybrook.edu T: +1 631 839 4402 W: www.hsiaoglobal.org

Research Objectives References

Dr Hsiao and his collaborators are focusing their research Hsiao, BS (2019). Benjamin S. Hsiao. [online]. Benjamin S.
on the use of nanocellulose enabling membranes and Hsiao Research Group. Available at https://www.hsiaoglobal.
adsorbents for water purification. org/ [Accessed 27 February 2019].
Sharma, PR; Chattopadhyay, A; Sharma, SK; Hsiao, BS.
(2017). ‘Efficient Removal of UO22+ from Water Using
Detail Carboxycellulose Nanofibers Prepared by the Nitro-Oxidation
Method’. Industrial & Engineering Chemistry Research, 56,
Chemistry Department 13885-13893.
Stony Brook University
Sharma, PR; Joshi, R; Sharma, SK; Hsiao, BS. (2017). ‘A Simple
Stony Brook, NY 11794, USA
Approach to Prepare Carboxycellulose Nanofibers from
Untreated Biomass’. Biomacromolecules, 18 (8), 2333-2341.
Bio
Dr Hsiao is a Distinguished Professor in Chemistry at Stony Sharma, PR; Chattopadhyay, A; Zhan, C; Sharma, SK;
Brook University. He is also the Founding Director of Center Geng, L; Hsiao, BS. (2018). ‘Lead removal from water using
carboxycellulose nanofibers prepared by nitro-oxidation
for Integrated Electric Energy Systems in Stony Brook
method’. Cellulose, 25, 1961-1973.
University, with the mission to enhance the development
of advanced technologies for the innovative nexus of food, Sharma, PR; Chattopadhyay, A; Sharma, SK; Amiralian, N;
energy and water systems. Martin, D; Hsiao, BS. (2018). ‘Nanocellulose from Spinifex as
an Effective Adsorbent to Remove Cadmium(II) from Water’.
ACS Sustainable Chemistry & Engineering, 6, 3279-3290.
Funding
• The National Science Foundation (Division of Materials
Research) Personal Response
• The Claire Friedlander Family Foundation
What are the key advantages of the nitro-oxidation
Collaborators method you have developed compared to existing
• Dr Priyanka R. Sharma approaches for the production of water purification
• Dr Sunil K. Sharma agents, and what do you think are the most promising
environments in which its application will have
the largest impact?
There are three key advantages of the nitro-oxidation
method. First, the method greatly reduces the consumption
of chemicals, energy and water. Second, the processing
effluent can be efficaciously neutralised to produce
plant fertilisers. Third, the method is effective to extract
nanostructured cellulose from underutilised raw biomass
such as agriculture waste. The resulting nanocellulose
is proven to be an efficient water purification material
(membrane or adsorbent) that can treat a wide range of
water pollution problems. The demonstrated technology
represents an innovative means to enhance the nexus
of food, energy, and water systems, and has many
far-reaching impacts to improve quality of life.

www.researchoutreach.org 37
Education and Training ︱ Dr Leyte Winfield
Inquiry learning:
Empowering African American women in STEM
By employing modern
theories of learning such
as metacognitive skillfulness,
agency, and inquiry-based
learning, Dr Leyte Winfield,
former Chair of the Department
of Chemistry & Biochemistry
and current Chair of the
Division of Natural Sciences
and Mathematics at Spelman
College in Atlanta, GA, is
creating an environment where
African American women can
gain critical thinking skills to
thrive in Science, Technology,
Engineering and Mathematics.
Students learning chemistry at
the college are being educated
through authentic, culturally-
relevant learning experiences.
38 www.researchoutreach.org
A
frican Americans make up
almost 15% of the United
States’ population. Despite this,
in 2013, around 5% of PhD recipients
in the US were African Americans,
and fewer than 1% of PhDs were awarded
to African American women. Whilst
African American women are well-
represented early on in higher education
in Science, Technology, Engineering
and Mathematics (STEM) subjects, the
proportion of this demographic drops
at each point along the ‘STEM pipeline’ –
the journey through STEM education into
the workforce. The under-representation
of black women in academia may not
come as a surprise, but these statistics
reveal a startling injustice: African
American women face significant barriers
to progressing in STEM careers.
Research often highlights this issue,
but there is little information on successful
measures for improving retention of
under-represented groups in academia
and into the labour force. Measures
for broadening participation of African
American women in STEM may be
found amongst the many Historically
Black Colleges and Universities (HBCUs)
across the United States. These are
institutions which were set up to provide
higher education to African American
people before the Civil Rights Act of
1964 prevented racial segregation, when
most higher education institutes either
prevented African Americans
from attending or enforced
quotas on enrolment.
HBCUs are well-
versed in providing an education for
African Americans and facilitating their
progression through academic science.
SPELMAN COLLEGE
One such institution is Spelman College
in Atlanta, Georgia. Spelman College
has been educating African American
(AA) women since 1881, the first
institution created for this purpose,
and is the top bachelor degree granting
institution of origin for AA females
who go on to earn STEM PhDs; the
second for AA individuals in general.
More than half of the faculty members
in Spelman’s STEM departments are
female, 64% of whom are African
American. One-third of those entering
Spelman’s degree courses major
in STEM subjects.
Dr Leyte Winfield is the current Chair
for the Division of Natural Science
and Mathematics at Spelman College.
In her previous position as Chair of the
Department of Chemistry & Biochemistry,
she was able to redesign the organic
chemistry curriculum in order to better
engage the female students in her
courses. More specifically, the measures
were designed to increase the number
of chemistry and biochemistry majors
who persist in this course of study, as
part of a broader goal of creating better
equity for African American women
in STEM higher education.
SELF-GUIDED LEARNING
Dr Winfield’s approach to curriculum
design runs counter to the ‘chalk and talk’
approach common in university settings.
She uses interactive engagement
teaching strategies, which she hopes
will benefit institutions with culturally
and ethnically diverse populations, as
well as contributing to the general trend
away from lecture-based content delivery
in higher education.
COMMUNITY OF INQUIRY
The type of self-regulated learning Dr
SED
CU
Winfield is employing in the department
is based on a framework for learning Student-

FO
Teacher

W
called Community of Inquiry (CoI). The CoI Interaction Problem-
based

EB
Y
framework identifies that social, cognitive

AC
and teaching factors are all important in

&
TEACHING PRESENCE

SET & SELF-EFFIC

shaping how people learn. Combining

TEC
these factors creates an environment Confusion Inquiry-
Resolution Face-2- based
where learning can occur through

HNOLOGY ENHA
Face

group work on problem-solving, with Setting

Creating Climate
an emphasis on questioning and critical Self- Content
paced
thinking. Dr Winfield’s research explores ACTIVE
Mastery- LEARNING Peer
what happens when the CoI framework is Inde- Interactions
Team-
based based
used with students who have been taught pendent

theories of metacognition and agency. COGNITIVE Facilitating SOCIAL

PRESENCE Discourse PRESENCE
D

METACOGNITION AND AGENCY

N
Role
playing
MI

Metacognition, or more specifically Content

N
focused Project-
Meta- based
metacognitive skillfulness, is an awareness

CE
Collab-
TH

cognitive
orative
of how learning occurs – or more simply,

D
W

‘thinking about thinking’. It can be used

to self-evaluate and influence learning.
Agency is a description of someone’s
ability to control their own actions.
Learners with a sense of agency are
more able to engage with and invest
in learning. In combination, metacognitive
skillfulness and agency allow learners
to self-regulate by setting goals,
employing effective learning techniques,
and examining the results of their efforts.
O
GR
The structure of the chemistry course at Spelman College is loosely based on the Community
of Inquiry (CoI) framework which connects elements of social presence, cognitive presence,
and teaching presence.
active learning: they contain modular ‘flipped learning’ – so-called because
workstations for group work, holding data the impetus to learn is ‘flipped’ onto the
projectors and computers. Now more student. The benefit? More classroom

IMPLEMENTING THE FRAMEWORK

Statistics reveal a startling injustice:
Dr Winfield began to implement the African American women face significant
CoI framework to find out if this learning
environment would improve students’ barriers to progressing in STEM careers.
ability to learn and utilise key ideas in
organic chemistry. Could a Community than half of the STEM faculty use digital time is now free for face-to-face skills
of Inquiry framework encourage students teaching methods which facilitate active development, guided by worksheets.
to engage actively with their own learning. Instead of using classroom time
learning? Could self-regulated learning for organic chemistry lectures, students Dr Winfield hoped that this combination
still ensure that students were able now watch narrated presentations on of flipped learning with classroom-
to learn the content? Organic chemistry a digital platform, followed by an online based inquiry and digital learning would
is essential for advancement into many quiz, utilising a technique known as have a positive impact on her students.
biological and health-related careers.
It is a popular course at Spelman College,
despite its difficulty. As a result, a high
number of students struggle with the
academic rigor. For Dr Winfield, this
makes chemistry an excellent focal point
for innovative teaching methods that
could improve diversity across STEM
subjects at higher levels.

This framework for teaching manifests

itself very clearly at Spelman College.
For a start, the classrooms in the Albro-
Falconer-Manley Science Center, where
chemistry and biochemistry courses are The Community of Inquiry framework applied at Spelman College improves students’ ability to learn.
taught, have been remodelled to facilitate

www.researchoutreach.org 39
 Organic chemistry lab courses at Spelman College place emphasis
on inquiry and discovery.
After measuring performance over two
consecutive year-groups, Dr Winfield
had an answer: not only was the academic
performance of the students comparable
to those taught using traditional methods,
but pre- and post-testing of students
also showed that students remained
motivated throughout the course, and
demonstrated more responsibility for
their own learning. What’s more, students
interacted more with their peers – a skill
that Dr Winfield thinks is an important
one for student self-belief.
IN THE CLASSROOM
One challenging aspect of the chemistry
curriculum is organic chemistry, which
deals with large, complex molecules. In
organic chemistry, high-level concepts
are made even
more difficult by the
need to visualise
Now more than half of the STEM faculty
chemical structures use digital teaching methods which
in three dimensions.
Traditional facilitate active learning.
pen-and-paper
representations limited to two dimensions
mean that many students struggle to
make links between representations of
molecules and the three-dimensional
molecular world.
Dr Winfield’s approach here is to turn
to digital tools for inquiry-based and peer-
led learning. In one organic chemistry
course, students are given instruction
on how to use the digital tools, and by
visualising chemical structures on iPads
40 www.researchoutreach.org
Peer-led learning is encouraged in the organic chemistry course
at Spelman College.
and physical models, students work
individually through a problem sheet. This
inquiry-based approach is followed by
small-group discussions where peer-led
learning can occur, and an instructor
is available to answer questions and
confirm answers. Across the four years this
method has been used and evaluated,
71% of students felt that using technology
was valuable or extremely valuable, and
79% thought that the iPad app should be
used in future teaching courses for the
same material. Inquiry plays an important
role in laboratory work too. Lab courses
are being moulded into experiences
which place an emphasis on inquiry
and discovery. Prescriptive instructions
are removed, and experimental outcomes
are left to the students to discover.
By closely mimicking research procedures,
students learn problem-solving skills
important for STEM careers.
EXPANSION
More recently, Dr Winfield has been
able to complete a five-year assessment
of the flipped learning format. This
evaluation indicates that students
perform better under the flipped
learning teaching style than students
did previously. As a result, Winfield has
expanded and honed the format for other
organic chemistry courses: the courses
are topped and tailed by assessments
to check student progress, and include
timed elements of individual work,
group work and solutions given by the
instructor. Evaluations of these workshops
once again showed positive outcomes:
students valued the workshops, reported
higher confidence on completion of the
worksheets, and demonstrated learning
through the pre- and post-tests.
IMPACT
A major motivating factor in Dr Winfield’s
curriculum design is the introduction
of ‘culturally-relevant teaching’ – the idea
that curricula should be designed with
a regard to the culture and language
of the students
undertaking the
course. By utilising
discovery learning
methods, Dr
Winfield has created
a curriculum where
students encounter rigorous and authentic
problem-solving tasks which have
culturally-relevant, real-word implications.
Dr Winfield feels that her work is not done
yet – she highlights in her research that
evaluation of the courses is ongoing. One
thing can be said: Winfield’s influence
is one which, by utilising contemporary
teaching approaches, is empowering
many African American women with
critical thinking skills for careers in science.
 Behind the Research
Dr Leyte Winfield
E: lwinfield@spelman.edu T: +1 404 270 5748
Research Objectives
Dr Winfield is dedicated to creating culturally responsive
initiatives and curricula that result in the productive
engagement of minorities and women in various academic
settings and in activities that promote gender equity
in science careers.
Detail
350 Spelman LN, SW
Box 231
Atlanta, GA 30314-4395
USA
Bio
Leyte Winfield is the Division Chair for Natural Sciences
and Mathematics at Spelman College. She directed
departmental efforts to establish new strategies
for structured curricular reform. In doing so, she led
the department’s efforts to broaden the curriculum
to reflect a liberal arts education while simultaneously
providing students with resources that promote
improved engagement and performance in chemistry
and biochemistry courses. She is dedicated to creating
culturally responsive initiatives and curricula that result
in the productive engagement of minorities and women
in various academic settings and in activities that promote
gender equity in science careers. Her work currently
focuses on characterising agency in interactive and peer
learning spaces.
Funding
Funded in part by the National Science Foundation
Historically Black Colleges and Universities Program (HBCU-
UP) Targeted Infusion Project Award No. HRD-1332575 and
the National Science Foundation Improving Undergraduate
STEM Education (IUSE) Award No. 1626002
Collaborators
• Lisa Hibbard
• Shannon Sung
• Suazette Mooring
• Shanina Sanders
References
Winfield, L.; Hibbard, L.; Jackson, K.; Johnson S.S. (2019)
Cultivating Agency through the Chemistry and Biochemistry
Curriculum at Spelman College. Broadening Participation in
STEM, 152-181.
Winfield, L.; Jackson, K. (2014) Realigning the Crooked
Room: Spelman Claims a Space for African American Women
in STEM. Peer Rev. 2014. 16(2), 9−12.
Hibbard, L.; Fullilove, F.; Winfield, L. (2016) Engineering
Course Success Through Interactive Engagement. Teaching a
New Generation of Students, A National Symposium [online]
Available at: https://facultyresourcenetwork.org/publications/
teaching-a-new-generation-of-students/felicia-fullilove-lisa-
hibbard-leyte-l-winfield-engineering-course-success-through-
interactive-engagement/.
Winfield, L.; McCormack, K.; Shaw, T. (2019) Using
iSpartan To Support a Student-Centered Activity on Alkane
Conformations. Journal of Chemical Education, 96(1), 89-92.
Winfield, L. (2015) Community-based Interactive Engagement
in an Organic Chemistry Course. Appears in: Proceedings
of the International Conference of Education, Research
and Innovation 2015 (IC-ERI2015) Conference, 16th-18th
November 2015, Seville, Spain. ISBN: 978-84-608-2657-6.
Personal Response
Benefitting African American women is clearly
a driving force in your research into inquiry learning.
Why do you think these teaching approaches
specifically benefit African American women in STEM
over other demographics?
I don’t believe these practices benefit African American
women more than other demographics. I do believe that
these teaching approaches benefit diverse populations
in general as they are flexible. They speak to individuals
with different learning styles and they place students
at the centre of the learning activities. Active learning
strategies inspire science identities by showing students
that you have confidence in their ability to learn at a higher
level, thinking critically and acting without prompting
but with thoughtful facilitation from the instructor.
www.researchoutreach.org 41
 Thought Leader

Measure what
DrimaFilm/Shutterstock.com

you treasure
How Global Footprint Network is using data
to show people how to protect our planet
There is only one Earth, but humans are consuming biological resources as if there were more Earths available. Last year,
Global Footprint Network marked ‘Earth Overshoot Day’ on 1st August; humanity had used our budget of resources
for the year five months early. For over a decade, Global Footprint Network has been striving to reduce this ecological
deficit through education initiatives on both an individual and national scale. The organisation is intent on helping forge
a successful pathway to ‘one-planet prosperity.’

I
n 2008, a journalist suggested that
you were now more likely to hear
the term ‘footprint’ in relation to one’s
impact on the planet than the mark one’s
foot makes in the sand (www.nytimes.
com/2008/02/17/magazine/17wwln-
safire-t.html). This shift in thinking has
been led and further developed by Mathis
Wackernagel, co-creator of the Ecological
Footprint concept and co-founder of
the Global Footprint Network. Global
Footprint Network looks to change the
way the world uses its natural renewable
resources by publishing simple, scalable
data for everybody. The Footprint
Calculator, which assesses the Ecological
Footprint for each individual based on
their consumption and tells them how
many planets we’d need if everybody
lived like them, is the perfect example
of such a tool.
Global Footprint Network’s President,
Mathis tells us more about his vision
for the future, and how new digital
resources, tools and data are helping
people understand the grave predicament
our one and only planet is in.
Hi Mathis! Can you tell us more
about Global Footprint Network
in terms of its mission, background
and core principles?
Our vision is a world where all can thrive
within the means of one planet. Humanity
is currently operating an ecological
Ponzi scheme, where we are vastly
overusing our planet, thereby putting at
risk human well-being. Global Footprint

42 www.researchoutreach.org
 huyangshu/Shutterstock.com

WHAT IS YOUR ECOLOGICAL FOOTPRINT?

TO SUPPORT
1.7
IT TAKES
HUMANITY’S
DEMAND ON
EARTH ’ S N AT URE
We use more ecological resources and services than nature can regenerate through overfishing,
over-harvesting forests, and emitting more carbon dioxide into the atmosphere than forests
can sequester.

HOW MUCH DOES FOOD CONTRIBUTE TO YOUR

ECOLOGICAL FOOTPRINT?

FOOD WORLD ECOLOGICAL

FOOTPRINT OF FOOD
MAKES UP AFRICA

26%
Network’s mission has always been to TOTAL ECOLOGICAL
help end ecological overshoot by making FOOTPRINT
ASIA
ecological limits central to decision-
making. Since 2003, we have pursued LATIN AMERICA & CARIBBEAN
OF HUMANITY’S
this mission by producing the National
ECOLOGICAL EUROPE
Footprint Accounts, communicating
FOOTPRINT
the science of sustainability through OCEANIA
the Footprint Calculator and, now for
over a decade, Earth Overshoot Day NORTH AMERICA
www.overshootday.org. 0 1 2 3 4 5 6 7
(GLOBAL HECTARES PER PERSON)
We reach far and wide by partnering with
countries, cities and organisations around As we work with people around the new strategies, engaging with potential
the world. We have strived, since our world, my day starts with early morning supporters, etc.
inception, to most effectively contribute phone calls and often ends with late
to making the human enterprise one- night calls. In between, I work with my I have fabulous colleagues at Global
planet compatible. colleagues to deliver on our mission. This Footprint Network which makes doing
means working on projects, designing the work extra rewarding and intriguing.
Why did you set up Global Footprint
Network and what you do on a
daily basis?
There was and still is no other metric
Our vision is a world where all can thrive
available that comprehensively compares
human demand with what Earth
within the means of one planet.
can regenerate.

www.researchoutreach.org 43
 WHAT CAN WE DO TO REDUCE OUR FOOD FOOTPRINT?
INCREASE THE PROPORTION
OF CEREALS, VEGETABLES AND FRUITS
HOW?
DECREASE FOOD WASTE
Rich Carey/Shutterstock.com
Last year, Global Footprint Network
published an article titled ‘Has
humanity’s Ecological Footprint
reached its peak?’ Do you think the tide
has turned in favour of the planet in
recent years?
I wish we could report this. Carbon
emissions are still going up, and even
more quickly than in previous years. There
is a lot of promising technology and many
intriguing projects underway, but they
are still not reaching the speed and scale
necessary to turn the trend, let alone
reducing the demand fast enough to
MOVE DOWN THE PYRAMIDS TO #MOVETHEDATE
The Barilla Center for Food and Nutrition double pyramid shows that foods recommended
by nutritionists are also better for the planet. Move down the food pyramid for a healthier diet
and a healthier planet.
44 www.researchoutreach.org
The way we eat is a
fundamental agent of change
towards SUSTAINABILITY
IF EVERYONE IN THE WORLD
• CONSUMED WORLD
AVERAGE CALORIES
• REDUCED THE FOOTPRINT
INTENSITY OF THEIR DIET
• CUT FOOD WASTE IN HALF
We would
#MoveTheDate
of Earth Overshoot Day
avoid the predictable ecological damage.
The technology is available, the financials
add up, but society is still not willing.
Looking forward, what issues are high
on Global Footprint Network’s priority
list to tackle in terms of reducing human
impact on the planet?
I spend a lot of time thinking about
and exploring what is holding us back
most significantly. My current hypothesis
is that society is committed to a false
narrative. If we believe that ‘not being
one-planet compatible is not a risk to
our own success’, it is unlikely we will
act commensurably. Although, much
evidence demonstrates that humanity’s
ecological overshoot, and each person’s
unpreparedness vis-à-vis those trends, are
a significant risk to their success. Hence,
my priority is to make this more obvious.
Global Footprint Network has won a lot
of global awards; what campaign/tool
are you most proud of?
The things I am most proud of were
put in place by others. For instance,
the concept of Earth Overshoot Day is to
explain overshoot in more understandable
terms. Now, we are generating three
billion media impressions per year,
on a shoe-string campaign.
The ability to explain, with Earth
Overshoot Day, the challenge of
sustainability, even in quantitative terms,
without using complicated concepts or
more than two syllable words is invaluable:
‘From January to August 1, people have
taken more from nature than Earth can
renew in the entire year’. All two syllable
words, except for January with three –
but hopefully everyone knows that one!
#MoveTheDate is a great campaign –
the idea that if we moved Earth Overshoot
Day into the future, by just five days
every year we would be back to one

Nikifor Todorov/Shutterstock.com
planet before 2050. We currently use
the biological resources of 1.7 Earths.
#MoveTheDate is positive – it shows we
need to succeed collectively (it is not just
about individual suffering), and it is about
expanding our resource security.
The National Footprint and Biocapacity
Accounts reveal interesting realities –
check data.footprintnetwork.org for
results. They use 15,000 data points per
country and year, based on super basic
and therefore robust science principles.
We call it sometimes, pun intended,
‘pedestrian science’. Of course, the devil
is in the detail with such large amounts
of data. But the principle is simple: we
add up all the human demands that
compete for biologically productive space.
Any high-school student could do this.
Global Footprint Network’s visual data
tools appear to be reaching people
globally; what do you think it is about
presenting the information in this way
We need to shift our narrative
and shed our misconceptions about
our dependence on nature.
that impacts people?
Information must be accurate, relevant
and empowering. These are the
principles to follow. People must believe
it is accurate – and to build trust the
information needs to be transparent,
and without apparent conflicts of interest.
That is why we are now building a whole
new initiative to make the National
Footprint and Biocapacity Accounts
an independent organisation. We still
need to reach far more people though.
What do you see as the biggest barriers
to reducing the human Ecological
Footprint today?
Modern society has a distorted belief
system. Society would be better off
with a fresh narrative and recognise
its dependence on nature. Urbanites
believe that nature is no longer important,
while we humans have actually become
increasingly dependent on material inputs.
Beyond individuals, has Global Footprint
Network had positive experiences with
organisations and governments who
have employed it? How important are
these collaborations to the Network?
We called ourselves Network because
we realised that as a small group of
people, we can only have an impact
in collaboration with others, including
businesses and national governments.
Obviously, the best would be if we could
convince all policy advisors that eroding
Thought Leader
their resource security is a fundamental
risk to their country’s or city’s long-
term success. There are some timid
recognitions, but we still need to scale
this way up. And when I say ‘we’, I mean
everybody, business schools (who often
still teach 20th century understanding
of economics), climate advocates, high
school teachers, etc. – everybody.
Earth Overshoot Day fell on 1st August
last year. What campaigns have you got
planned to raise awareness for 2019?
Our goal is to engage people by helping
them fall in love with the most significant
and intriguing challenges we are facing
– how to thrive within the means of
our planet. We want to partner with
as many people as possible to engage
in this journey.
If you would like to work out your own
Ecological Footprint or find out more
about Global Footprint Network and
its work, you can visit their website at:
www.footprintnetwork.org.
Global Footprint Network
Oakland Office:
426 17th Street, Suite 700
Oakland, CA 94612, USA
E: media@footprintnetwork.org
T: +1 510 839 8879
W: www.footprintnetwork.org
@EndOvershoot
@GlobalFootprintNetwork
www.researchoutreach.org 45
 Informatics and Technology ︱ Dr Zonglu He
Integer-dimensional fractals
of nonlinear dynamics
Fractal dimension was
developed as a quantitative
measure of complex, irregular
objects, essentially because it
had been accepted that fractals
could not be characterised by
integer dimensions. Dr Zonglu
He, a Professor of Economics at
Kaetsu University, is challenging
this basic concept with her novel
finding that fractals actually
can occur in integer dimensional
space-times. Her research
demonstrates the consistency
of both fractional and
topological dimensions.
Moreover, she discovers the
control mechanisms of fractal
behaviour and explores the
effects of nonlinear dynamics.
Mardoz/Shutterstock.com
46 www.researchoutreach.org
F
ractals are never ending patterns.
They can be curves or geometric
figures, but each part appears
to be the same as the whole pattern,
a property known as self-similarity. They
are created by the iterative repetition of
a process or function. Fractals are images
of dynamic systems driven by recursion –
the image of chaos. Fractal patterns can
be found throughout nature, for example
snowflakes, seashells, flowers, trees,
coastlines and galaxies. Abstract fractals
can be generated by computing an
equation over and over. Fractals can be
used to model structures where patterns
recur repeatedly at gradually smaller
scales. They can also be used to describe
random or chaotic phenomena such
as crystal growth and fluid turbulence.
Fractals also have applications in
economics, such as modelling market price
fluctuation or market risk.
FRACTAL DIMENSION
Geometric shapes have dimensions.
For example, a point has a dimension
of 0, a line has a dimension of
1, an area has a dimension
of 2, a volume has a
dimension of 3,
and from these
we can derive
shapes such
as cones and spheres. In the same way,
fractals also have dimensions. These
provide a measure of how complicated
the fractal is. The fractal index, however,
can have non-integer values e.g. a
curve with a fractal dimension of 1.1 will
perform like a one-dimensional line, while
a curve with a fractal dimension of 1.9
twists through space almost like a two-
dimensional surface.
Fractal dimension was developed as
a quantitative measure of complex,
irregular objects, essentially because
it was accepted that fractals could not
be characterised by integer dimensions.
Dr Zonglu He, a Professor of Economics
at Kaetsu University, is challenging this
basic concept with her novel finding
that fractals actually can occur in integer
dimensional space-times.
RESEARCH BACKGROUND
In the late 1990s, Professor He was
initially interested in statistics, particularly
stochastic (random) processes,
and time series analysis. At that time,
a major discovery was that economic
large variations could result from the
cumulative effects of noise (such as
money demand-supply shocks – sudden
temporary increases or decreases
in demand and supply) caused by the
so-called ‘unit root’ structure. (A unit
root is a randomly determined trend
in a time series; its occurrence shows
an unpredictable systematic pattern.)
This finding challenged traditional
thinking of stationary fluctuations
about a deterministic trend where
money demand-supply shocks were
assumed to have no long-term impact
on the economy. A structural break
(an unexpected change in the economy
prompted by a sudden event such as
a war or a change in government policy)
and long-range dependence (also known
as long memory, a feature of statistical
 Ruth Black/Shutterstock.com
rootstock/Shutterstock.com
Dinozzzave/Shutterstock.com
Serg64/Shutterstock.com

Contrary to the underpining concept of fractal

dimension, Professor He’s ground breaking
findings challenge traditional thinking.

time series involving persistently strong

autocorrelation between remote
Using the NLARI framework, Professor
observations) were also recognised He was able to explain the nature and
as displaying unit root behaviour. It was
difficult to say whether either one of these causes of unit roots and trend breaks.
data features actually results in economic
fluctuations. While a plethora of analytical dimensional space could exhibit fractal RESEARCH FINDINGS
literature exists regarding the testing of behaviour over time, particularly in Using the NLARI framework, Professor
the data features, little attention has been the parameter ranges of nonlinear He was able to explain the nature
paid to their causes. stochastic and deterministic dynamics”. and causes of unit roots and trend
She derived the NLARI model by breaks. Further advances in the model
THE NONLINEAR AUTOREGRESSIVE applying Newton’s second law (force = meant that Professor He could clarify
INTEGRATED (NLARI) MODEL mass x acceleration) to stochastic self- the NLARI nonlinear dynamics, by
Professor He pointed out that non- restoring systems in order to achieve obtaining the analytic solutions of
integer fractal dimensions do not a unified data-generating process its deterministic system, and develop
explain what creates fractal behaviour of economic variables. the statistical method for the NLARI
and controls fractal levels. She believed
that the solution to these issues would Fractal patterns can be found throughout nature,
be found in modelling the processes including galaxies.
involved in generating the data in
different situations based on physical
laws. If not, the model parameters
would not have explicitly physical
effects. She went on to highlight
that an interdisciplinary unified time
series model was required in order to
systematically understand the essential
mechanisms of time series processes
in the real world. This led to Professor He
M.Aurelius/Shutterstock.com

inventing the nonlinear autoregressive

integrated (NLARI) model.

Professor He explains that she created

the NLARI model to, “explore whether
the data generating process for integer

www.researchoutreach.org 47
 a d
d
d
parameter estimation and hypothesis
testing. Using these, she was able
to investigate integer-dimensional
400 800 400 800
fractal behaviours and their control d'
400
400
400
800
800
800
a' d'
d'
mechanisms as well as the relationships
between fractal and dynamic
behaviours, and the effects of stochastic
400 800 80
80 160
160
disturbances on fractals. b e
e
e
80
80 160
160

CONSISTENCY WITH
TOPOLOGICAL DIMENSION 100 200 300
120 240 100
100 200
200 300
300
100 200 300
This study reveals that it is possible b' e'
e'
e'
for fractal dimension to be consistent
with topological dimension. Professor
He found that the properties of typical 120 240
400
400
400
800
800
800
400 800
nonlinear dynamics, such as stable c fff

fixed point, periodic and aperiodic

oscillations, and chaos, and those
of typical fractal behaviours including 40 80 120
400
400
400
400
800
800
800
800
1200
1200
1200
1200
f'f'f'
long-range dependence, together with c'

self-similarity, and power law were the

same as the properties of the data-
generating process in integer dimensional 40 80 120 160
3000
3000
3000
3000
6000
6000
6000
6000
9000
9000
9000
9000

space-times. (A power law is a functional

relationship between two quantities,
where independent of the initial size
of the quantities, one quantity varies
as a power of another.)
Professor He discovered that long-
range dependence and self-similarity
with power law were determined by
the comparative strength of external
environmental and internal organisational
influences. If the observation scale is large
enough, or the frequency of data is low
enough, it is possible to observe typical
fractals. Further research with the NLARI
model revealed that a stochastic (random)
stable fixed point had both self-similarity
and long-term memory properties, while
a deterministic (non-random) stable fixed
a and a’ One for precipitation (Philadelphia in 1820-01 to 1903-04) and the other for heartbeats with
ventricular tachycardia (0209.vt1). b and b’ One for peak streamflow (Wolf River at New London, 1914-
01 to 1938-10) and the other for brainwaves in a brainstorm project. c and c’ One for exchange rate
(EXSZUS, 1971Q1-2010Q2) and the other for heartbeats with ST segment alterations (s20641). d and d’
One for Changjiang flows (Han Kou, 1965-01 to 1948-04) and the other for heartbeats with ventricular
fibrillation (0217.vf1). e and e’ One for ozone thickness (Switzerland, 1926-01 to 1952-12) and the other
for heartbeats from an older adult (f1o04). f and f’ One for Saugeen River flows (Port Elgin, 1988-01-01
to 1991-11-01) and the other for nerve impulses from a snail neuron.
EFFECTS OF cycles or chaos, however, the extrinsic
NONLINEAR DYNAMICS disturbances can be ignored.
Plotting the data generated by NLARI
revealed that the fractal level of a stable CONCLUSION
fixed point is controlled by the wave Contrary to the underpinning
indicators reflecting the relative concept of fractal dimension,
strength of external and internal forces: Professor He’s ground breaking findings
a larger gradient disclosed a higher challenge traditional thinking and
positive dependence i.e. long memory, suggest that fractals of self-regulating
whereas a smaller amplitude indicator systems can in fact be measured
disclosed a higher level of self-similarity. by integer dimensions.

Non-integer fractal dimensions do not Professor He also indicates that other

explain what creates fractal behaviour
and controls fractal levels.
point usually only showed self-similarity.
Both stochastic and deterministic period
cycles together with chaos only display
long-term memory. The length of the
restorative delays also had a significant
effect with self-similarity being observed
when the restorative delay was an even
number. Self-similarity didn’t occur when
the restorative delay was an odd number.
Additionally, a larger amplitude indicator
or an even restorative delay could make
the sample autocorrelation function
oscillate. Professor He observed that
the fractal levels of period cycles and
chaos relied on the intrinsic resistance,
restoration, and regulative delays. Once
the internal structure becomes so robust
that the system can generate periodic
similar fractals and dynamics occur
in different disciplines and that these
could also be characterised by the
NLARI process that she has uncovered
by applying Newton’s second law
to self-regulating systems. Professor
He’s research suggests that the
pervasiveness of similarity in dynamics,
or fractals, of nonlinear models in areas
such as modelling rainfall, river stream
flow, ozone thickness, brainwaves
and nerve impulses could indicate
that Newton’s second law underpins
the phenomena in the real world.

48 www.researchoutreach.org
 Behind the Research
Dr Zonglu He
E: zongluhe@kaetsu.ac.jp T: +81 42 446 3711 W: http://www.kaetsu.ac.jp/
W: https://www.researchgate.net/profile/Zonglu_He

Research Objectives References

Professor He’s research focuses on control mechanisms He, Z. L. (2007). A new class of nonlinear integrated models.
of nonlinear dynamics. Far East Journal of Theoretical Statistics, 23, 31–50.

He, Z. L. (2013). Dynamics and stability of a new class of

Detail nonlinear integrated models with resilience mechanisms.

Faculty of Management and Economics
Kaetsu University
2-8-4 Minami-cho, Hanakoganei, Kodaira-shi
Tokyo 187-8578
Japan
Bio
Dr Zonglu He is a professor of Economics at Kaetsu
University. She received her PhD from Hiroshima University.
Her current research interests focus on control mechanisms
of nonlinear dynamics and fractals by modelling the data
generating processes of different fields in integrating
information, data, perspectives, concepts, background
knowledge and theories.
Far East Journal of Dynamical Systems, 21, 1–32.
He, Z. L. (2014). Estimation and tests of nonlinear
autoregressive integrated models. Far East Journal of
Theoretical Statistics, 49, 129–164.
He, Z. L. (2018). Integer-dimensional fractals of nonlinear
dynamics, control mechanisms, and physical implications.
Scientific Reports, 8, 10.1038/s41598-018-28669-3. Available
at https://www.nature.com/articles/s41598-018-28669-3
[Accessed 7th March 2019]
Personal Response
What initially prompted your research into integer-
dimensional fractals of nonlinear dynamics?
Fractal dimension seems not to be a physical scale
of complexity because it does not satisfy the uniqueness
condition as a physical scale. If fractals model complex
physical processes and dynamical systems, the nonlinear
dynamics and the control physical laws for these fractal-
dimension physical processes should result from fractal-
dimension spacetimes. Alternatively, fractals may occur
in integer-dimension spacetimes.

What are your plans for future developments with

the NLARI model?
I will use the NLARI model to extract depth information
from temporal fluctuations, for example, detect heartbeat
Number1411/Shutterstock.com

parameter alterations from heartbeat series to assess

cardiac, metabolic, and autonomic nervous functions and
the risk for cardiovascular diseases; and explore information
transmission in cortical circuits.

www.researchoutreach.org 49
 Behavioural Sciences ︱ Dr Yoshiko Arima
Measuring shared
knowledge with group
false memory
Research has shown that when
we make decisions, we are
influenced by biases relating
to the way we structure
knowledge in our brains. If these
biases are shared by others, they
can be exaggerated. This often
results in false memories, which
is the recall or recognition of
phenomena that did not occur.
Yoshiko Arima and colleagues
at Kyoto University of Advanced
Science investigated the
conditions that could lead to
false memories within a group
process, and the relationship
between false memories and
shared knowledge structure.
Pressmaster/Shutterstock.com
50 www.researchoutreach.org
C
ollaborative groups are known
to create a higher level of memory
accuracy than individuals. This
is thought to be the result of a larger
information pool, the opportunity
to revise errors and efficient decision-
making. Despite their improved accuracy,
collaborative groups tend to make errors
in recall tasks. Several studies have found
that people are more confident about
the accuracy of memories recalled by a
group than those recalled by individuals,
even when these memories are false.
Taken together, this suggests that group
false memory occurs when all group
members fail to detect errors.
REACHING CONSENSUS
IN GROUP DECISIONS
There is wide variability in the time
taken to reach consensus when
making a decision through a group
process. The two main factors which
influence the likelihood of reaching
agreement are within-group discrepancy
(differences among group members)
and between-group discrepancy
(difference among groups). The former
has been considered the basis for
intragroup disagreements and the latter
for intergroup disagreements. However,
previous research has suggested
that these behaviours can influence
each other. Studies have found that
between-group discrepancies influence
not only intergroup processes but also
intragroup processes.
FACTORS INFLUENCING
GROUP CONSENSUS
Group polarization is the tendency
for a group to make decisions that
are more extreme than the initial
inclination of its members (known as
the mean tendency). Groups polarize
their attitude to the direction of mean
 15.00
Pre-group Variance
10.00
5.00
30.00 40.00 50.00
Pre-group Mean
Scatter plots of the pre-test and post-test means and variances for the consensus and disagreement groups. Results of discussion: Consensus ( );
Disagreement ( ). Source: Y. Arima, R. Yukihiro & Y. Hattori Scientific Reports 8, Article number: 10117 (2018) www.creativecommons.org/licenses/by/4.0/.
tendency of whole sample even though
they do not know which direction it was.
Using the group polarization paradigm,
research conducted by Dr Yoshiko Arima
based at Kyoto University of Advanced
Science, explored the conditions that
lead to intragroup disagreement and
attitude change following a disagreement
among 269 participants. Her results show
that the probability of consensus was low
when the group means differed from the
mean of the whole sample. When small
differences among group members were
found, depolarization (reverse direction
to the polarization) followed
disagreement. This suggests that the
groups which deviated most from the
population tendency were the most likely
to cause within-group disagreement,
while within-group differences
determined the direction of attitude
change following disagreement within
the group.
Groups seem to reach a consensus
or not randomly, however, they are
controlled by the variance of the whole
society. There is an ‘Invisible Hand’
who controls public opinion from one
pole to another. The basic assumption
of Dr Arima’s study is the invisible hand
of our shared knowledge structure
that needs identity and difference.
The problem was, how to measure it?
Dr Arima investigated the effect of
shared knowledge, manipulated using
15.00
Post-group Variance
10.00
5.00
60.00
associated or randomly ordered word
lists, on the association between group
remembering and group polarisation.
In one experiment, 159 university
students answered a questionnaire
about the common stereotype that
blood type determines personality.
Half were given lists of words that were
consistent with this idea and the other
half were provided with randomly
ordered word lists. After completing
the questionnaire, students were tested
on how many words they could recall
from the lists that had appeared in the
questionnaire. Tests were conducted
in either a group or an individual
setting. The results demonstrated that
stereotype-consistency of the word list
reduced the groups’ ability to detect
incorrect answers, compared with
the individual condition.
In another experiment, 131 high school
and university students were divided into
three groups: group members having
the same blood type (low-diversity),
members with two different blood types
(medium-diversity), and members with
three or more different blood types
(high-diversity). This condition induces
three levels of variety of memories
There is wide variability in the time taken
to reach consensus when making
a decision in a group context.
30.00 40.00 50.00 60.00
Post-group Mean
because of self-reference effect, which
is the finding that information relating
to oneself is easier to recall than
unrelated information. The difference
of belief in blood type stereotypes
before versus after the recall task is called
the shift score and represents the extent
of group polarisation. The results showed
an association between the shift score
and the total number of recalled words
including false memories when the word
list was consistent with the blood type
stereotype. This suggested that shared
knowledge influenced group polarisation.
FALSE MEMORY VS ERRORS
To measure shared knowledge structure,
Dr Arima and her colleagues investigated
whether group collaboration increases
false memories if a word list is arranged
in a way that is consistent with pre-stored
group knowledge. This was studied using
the Deese-Roediger-McDermott (DRM)
paradigm. This involves participants first
taking a free recall test after learning a
word list associated with a certain non-
presented word (known as the critical
word) which is not presented within
the list. After several of these recall
tests, participants take a recognition test
that includes the presented associative
www.researchoutreach.org 51

1.0
Read.2F
Novel.2 Fast.3
0.5 Memory.5
Fireplace.6
Spring.6
Amusing.4
Dimension 2
0.0
Happy.5F Play.5 Television.4F
Warm.6F
Sleep.1
-0.5
-1.0
Rest.1F
-1.5
-2 -1
words (known as targets), non-presented
associative words (critical words whereby
a response indicates a false memory),
and non-presented irrelevant words
(known as distractors whereby a response
indicates an error). Usually, the proportion
of false memory is much higher than that
of errors.
The activation-monitoring hypothesis
predicts that false memory occurs
when critical words continually become
activated, eventually producing a
memory. Evidence for this idea has
been obtained from studies showing
that false recognition increases, and
accurate recognition decrease with
the number of targets in a word list.
Based on the activation-monitoring
hypothesis, Dr Arima predicted that
false memory would be dependent on
the strength of the critical word as a
semantic cue at the moment of learning.
‘Knowledge structure’ represents the
associative-semantic network related
to specific cues. ‘Shared knowledge
structure’ is the intersection of group
members’ knowledge structures. Two
hypotheses were tested: firstly, that group
false memory would be larger for the
The activation-monitoring hypothesis
predicts that false memory will occur when
critical words become activated continually,
and eventually produce a memory.
52 www.researchoutreach.org
ALL data
Correct False
Library.2 Fat.3
News.2
Painful.5
Screen.4
Leg.3F Tired.1
Antenna.4
Shoes.3
Cool.6
Absent.1
0 1 2 3 4
Dimension 1
consistent word list condition than for
the randomised word list condition, and
secondly, that after collaboration, group
false memory would increase more than
errors and the difference between the
consistent and randomised word lists at
the pre-test stage would remain the same.
Using the DRM, they conducted the first
experiment in 121 university students.
Participants collaborated to select
keywords using between-subject condition
from a consistent or randomised word list.
Between-subjects means that groups are
compared with each other. The proportion
of false responses was larger than that
of error responses, particularly for the
consistent word list condition and group
collaboration increased false recognition
for both word lists, which was not caused
by social contagion.
A second study on 119 university students
used a within-subjects design, where
differences within a group are compared
and confirmed the findings of the first
experiment. False memories increased
after group collaboration regardless of the
meaning of the words, maintaining the
difference between the consistent and
ALSCAL results for all data (S-stress = 0.13,
squared correlation (RSQ) =0.94). The horizontal
dimension represents the pleasure or not-
pleasure scales. The vertical dimension seems
to discriminate between intellectual activities
or rest. Source: Arima, Y., Vol 110, Issue 2, 2012.
Copyright © [2018] DOI: [10.2466/01.11.17.21.
PR0.110.2.607-623].
randomised word lists. Dr Arima also
measured the response latency of each
character using in word lists. The results
demonstrated that there are relationships
between response latency and the score
of knowledge structure analysed by Multi-
Dimensional Scale.
CONCLUSIONS
Dr Arima’s findings demonstrate that
group false memory is shaped by a shared
knowledge structure, a process which
can have both positive and negative
consequences. With shared knowledge,
it is easy to exchange concepts, but
this may mean that increasing mistakes
resulting to group polarization. If a group
has diverse knowledge structures among
group members, the group will be able
to detect these mistakes. However, within
the group process, there will be difficulties
as a result of miscommunication. To
overcome this problem, it is necessary
to have a complex shared knowledge
structure. However, a compromise
may exist between shared knowledge
and the amount of shared memory.
The results of the current study show
that group false memory can be an
index for a pre-stored and a post-shared
knowledge structure. False memories
in consistent word lists can be used
as a measure to understand what
associations are shared in pre-stored
knowledge, and randomised word lists
can reveal associations with which a group
creates a post-shared knowledge.
 Behind the Research
Dr Yoshiko Arima
E: arima@arimalab.com T: +81-75-406-9230 W: https://www.linkedin.com/in/yoshikoarima/

Research Objectives References

Dr Arima’s research investigates shared knowledge Arima, Y. (2012). Effect of Group Means on the Probability
structure with the aim of estimating complexities of our of Consensus. Psychological Reports, 110(2), 607-623.
collective intelligence.
Arima, Y. (2013). Effect of word-list consistency on

Detail the correlation between group memory and group

polarization. Psychological reports, 112(2), 375-389.
Dr Yoshiko Arima
Department of Psychology Arima, Y., Yukihiro, R., & Hattori, Y. (2018). Measuring shared
Kyoto University of Advanced Science knowledge with group false memory. Scientific Reports, 8(1),
18 Yamanouchi Gotanda Cho 10117.
Ukyo-ku, Kyoto 615-8577, Japan

Bio
Dr Yoshiko Arima obtained her undergraduate degree
Personal Response
within the Faculty of Human Science, Osaka University in
What is the focus of your future research?
1980 before obtaining her PhD in Social Physiology. She
is currently Professor at the Department of Psychology, The focus of my future research is to integrate group
Faculty of Humanities, Kyoto University of Advanced process studies with collective intelligence studies. Even if
Science. crowd deviated from the truth, expert crowds, or machine
learning from expert’s data, will perform over the best
member because crowds can integrate more variables
Collaborators
than a person does. However, there is no guarantee that
• Roji Yukihiro we can understand the complexities in the answer of
• Yosuke Hattori collective intelligence. The common knowledge effect and
cyber cascade polarize crowds and machines may learn the
biases. The study on measuring shared knowledge structure
is an attempt to estimate complexities of our knowledge
to prevent polarization of our society.

amasterphotographer/Shutterstock.com

www.researchoutreach.org 53
Behavioural Sciences ︱ Andreas Klocke and Sven Stadtmüller
The role of social
capital in the health
development of children
H
Social capital refers to networks
and ties, which deliver support,
information and trust for the
members. Being part of such
a network is your social capital,
which in turn can improve
health and wellbeing. Andreas
Klocke and Sven Stadtmüller
from Frankfurt University of
Applied Sciences investigated
the impact of social capital
on the health of children
in their developmental
process. Researchers aimed
to determine whether there
was a causal effect of social
capital and whether this
was consistent across socio-
demographic groups.
54 www.researchoutreach.org
ealth status and behaviours are
strongly linked with both wellbeing
and quality of life, as documented
in worldwide population studies.
However, determining how to improve
health in individuals and societies is more
uncertain. It is questionable whether
health is determined solely by income or
wealth. Interestingly, research shows that
not all wealthy and advanced countries
rank at the top of the global league
table of happiness. The Scandinavian
countries tend to rank highly in this
respect. These countries are characterised
by a comparatively high level of wealth
but also a high level of life expectancy,
low levels of corruption and a sense
of belonging, which together facilitate
greater trust and solidarity. It is likely
that the degree of social capital also
contributes to this sense of cohesion
and connectedness, a concept which
has become increasingly studied within
the social sciences in recent years.
DEFINING SOCIAL CAPITAL
The concept of social capital became
prominent through the work of
Putnam and was initially applied
to political science pertaining to
shared values and local networks.
Later, Bourdieu’s work was
rediscovered, who addresses
social capital on the level
of individuals. Today, there
is a lack of consensus about
how social capital should
be defined.
Halpern proposed that
social capital exists at three
different levels: the micro
level (family), the meso
level (neighbourhood)
and the macro level (nation).
The key feature of social
capital is its focus on the relationships
among individuals. Unlike human capital
(which focuses on individual abilities)
and economic capital (which refers
to possession), social capital addresses
the networks and ties, in which individuals
are woven. Being a member of a network
gives the person an advantage, through
obtaining information, support, access
and trust. These, in turn, improve life
satisfaction and wellbeing.
Three forms of social capital have been
defined by Putnam: bonding, bridging
and linking. Bonding refers to strong
direct links between individuals in a similar
socio-demographic and socio-economic
or socio-cultural environment. Bridging
pertains to comparatively weak horizontal
connections between different groups,
which originate from a similar social class.
Linking refers to vertical links between
privileged and less privileged groups.
Although the concept of social capital
is widely used in social science research,
it has not frequently been used in
the study of children. Andreas Klocke
and Sven Stadtmüller addressed this
gap in the literature by exploring
whether an intrapersonal change in
social capital affects children’s health
status and behaviour over time. They
used longitudinal panel-data (long-term
data), rather than cross-sectional data,
which looks at data at one point in time,
so that they could determine if the effect
of social capital on health was causal.
Researchers also investigated whether
the results varied across different socio-
demographic groups.
APPLYING SOCIAL
CAPITAL TO CHILDREN
Despite not being commonly studied
in children, all three types of social
An index of social capital in young people

QUALITY OF QUALITY OF QUALITY OF

RELATIONSHIP SCHOOL CLIMATE NEIGHBOURHOOD
TO PARENTS

MOST STUDENTS THE OTHER PEOPLE GREET SMALLER

EASY TO EASY TO MOST STUDENTS
IN MY CLASS STUDENTS EACH OTHER AND CHILDREN CAN ONE CAN TRUST
TALK TO FATHER TALK TO MOTHER IN MY CLASS LIKE
ARE KIND AND ACCEPT ME AS SPEAK TO EACH PLAY OUTSIDE PEOPLE
(STEP FATHER) (STEP MOTHER) BEING TOGETHER
HELPFUL I AM OTHER DURING THE DAY

capital are applicable to this group, with regard to this relationship. The with trust in children. In childhood and
as long as adjustments are made first is that children with a high amount adolescence, individuals usually gain trust
for different ages. Family ties and of social capital show a better health and support from their parents and thus
friendships (bonding) amongst similar

It is questionable whether health is

socio-demographic groups are common
throughout childhood.

However, children also make connections determined solely by income or wealth.

with those from different backgrounds
when they join organisations and
associations, such as schools and sports
clubs, which is characteristic of bridging.
The linking form of social capital is more
challenging for children as these are
inherently hard to establish and might
even have a marginalising effect of those
from less privileged backgrounds because
children can often decipher different
social backgrounds.
When applying social capital in children,
it is most useful to consider the concept
on the individual level. This is because
the other levels are largely unrecognised
in this age group. The individualistic
approach can be conceptualised with
Bourdieu’s definition of social capital,
which states: ‘Social capital is the
aggregate of the actual or potential
resources which are linked to possession
of a durable network of more or less
institutionalized relationships of mutual
acquaintance and recognition.’ For
children particularly, the concept can
be viewed as a trust-based network, which
can be accessed when social support is
needed. Children cannot usually change
their personal circumstances so they must
turn to trusted others, particularly adults.
status and health behaviour. Secondly,
researchers hypothesised that children
who gain more social capital over
time should see significantly improved
health. The third prediction was that
social capital is a causal protective factor
in the health development of children,
which holds true across different socio-
demographic groups.
MEASURING SOCIAL
CAPITAL IN CHILDREN
Klocke and Stadtmüller used three
indicators to measure social capital
in children, which were the quality of
relationship to parents, quality of school
climate and quality of the neighbourhood.
These elements were selected because
they were felt to be most strongly linked
this relationship is of high importance.
School is also highly significant for
children because it is where they spend
most of their day and involves a high
amount of socialisation. The quality of
the school environment was measured
by relying on the perceived relationships
with other pupils (mutual trust). The third
element considered important was the
quality of the immediate neighbourhood
because it concerns security. Health
was determined by asking children to
rate their general health on a five-point
scale. They were also asked about
sleep, concentration levels, perceived
fitness and wellbeing, and consumption
of soft drinks and vegetables. Socio-
demographic status was assessed by
adopting the Family Affluence Scale,

Based on the established link between

social capital and health in adults, a
similar relationship might be expected
to exist in children. This was the focus
of the work of Andreas Klocke and Sven
Stadtmüller, who made three predictions

www.researchoutreach.org 55
EFFECTS OF SOCIAL CAPITAL AND FAS ON HEALTH
Fixed effects regression models

Social Capital Family Affluence Constant

b se p b se p b se
Sleep difficulties -.164 (.018) *** -.017 (.019) 2.94 (.202)

Could not concentrate well -.202 (.016) *** .013 (.016) 2.62 (.172)

Feeling fit and comfortable .355 (.018) *** .019 (.019) 1.94 (.196)

Consumption of Coke and lemonade -.091 (.015) *** -.005 (.016) 2.01 (.170)

Consumption of salads and vegetables .152 (.016) *** .107 (.017) 2.22 (.176)

• A
 n (within-children) increase in the volume of social capital reduces
(mental) health problems and improves health behaviour
• Changes in FAS hardly play any role

asking about family cars, holidays,
whether they had their own bedroom
and whether there were books at home.
SOCIAL CAPITAL IN
THE HEALTH OF CHILDREN
Researchers found that social capital
was associated with better health
status, as indicated by higher perceived
fitness and wellbeing levels and greater
consumption of vegetables. In addition,
higher social capital was linked with
less likelihood of sleep difficulties,
Children cannot usually change their
personal circumstances so they must turn
behaviour, with the greatest effect for
the different features of mental health
(sleep and concentration, perceived
fitness and wellbeing) and smallest for
physical health behaviour (drinking soft
drinks and eating vegetables).
The study also found that a change in
social capital was significantly associated
with the health and health behaviour
of a child. Greater social capital over
time was linked with increased perceived
fitness and wellbeing, fewer problems
this holds true over time. In addition,
all three components of social capital
(quality of relationship to parents,
quality of school climate and quality of
neighbourhood) were equally important
in predicting health in children.
THE FUTURE
Klocke and Stadtmüller have
demonstrated that social capital is a
powerful tool in the analysis of health
and health behaviour in childhood. This
is especially true as children are in the
process of growing up. The research
findings highlighted that an intrapersonal
change in social capital over time has a
significant effect on the health and health

to trusted others, particularly adults. behaviour of an individual. Social capital

fewer problems with concentration
and reduced consumption of soft
drinks. With the exception of soft drink
consumption, social capital was a
greater predictor than family affluence
on health. Overall, the amount of social
capital was highly associated with
health status, mental health and health
with concentration, a reduced likelihood
of sleep difficulties, higher vegetable
consumption and improved health
status. These results held true regardless
of family affluence or background,
demonstrating that social capital is
a much greater predictor of health
than socio-demographic status and
can thus be conceptualised as a causal
factor affecting health development
in children, which operates independently
of socio-demographic status. In order
to improve the health of children in
both the short and long term, it is thus
important to establish and maintain
social networks and resources (social
capital) rather than merely providing
financial assistance.

RESEARCH DESIGN

Data base is the panel study

“Health Behaviour and Injuries
during School Age”, which
started on an annual cycle in
the school year 2014/15 in
Germany (for details see:
www.fzdw.de/gus)
The study initially surveyed
students of the 5th grade
(10-12 year olds), comprising
10,621 pupil, which we survey
for six waves (years).
Class room sampling, 587
classes in 148 schools (wave
Self-administered computer
one). Stratified sample by
assisted (tablets) survey.
Federal State, Schools Size and
Urbanity.

56 www.researchoutreach.org
 Behind the Research
Andreas Sven
Klocke Stadtmüller
E: andreas.klocke@fzdw.de E: sven.stadtmueller@fzdw.de
T: +0049 69 15332188 W: fzdw.de T: +0049 69 15333187 W: fzdw.de

Research Objectives References

Andreas Klocke and Sven Stadtmüller aim to determine Klocke, A., & Stadtmüller, S. (2018). ‘Social capital in the health
whether there was a causal effect of social capital on the development of children’. Child Ind Res: pp 1–19. https://doi.
health of children and whether this was consistent across org/10.1007/s12187-018-9583-y.
socio-demographic groups.

Detail Personal Response

Frankfurt University of Applied Sciences, Nibelungenplatz 1,
60318 Frankfurt, Germany
Bio
Andreas Klocke is Professor in Sociology and head of
the Research Centre on Demographic Change at Frankfurt
University of Applied Sciences, Germany. His main
areas of research are social inequalities, youth, health
and demography.
Does the relationship between social capital in
children and health appear to be linear or is there a
cut-off point whereby health benefits are maximised?
No, there is no threshold which we have to overjump
before we see a positive effect of social capital on the
health development of children. All improvements
in social capital are powerful. Furthermore, all socio-
demographic groups are benefitting from a higher
volume of social capital, which makes it applicable
to general health-promoting programs.

Sven Stadtmüller is Senior Researcher at the Research

Centre on Demographic Change at Frankfurt University
of Applied Sciences and at GESIS – Leibniz-Institute for
the Social Sciences. His main areas of research are survey
methodology, demography, and political attitudes.

Funding
German Social Accident
Insurance (DGUV)

www.researchoutreach.org 57
 Arts & Humanities ︱ Adrian Buss
Institutional investors
and information
acquisition:
Implications for asset prices and informational efficiency
The research of Dr Adrian Buss
(INSEAD) and Matthijs Breugem
(Collegio Carlo Alberto)
explores how the growth of
assets under management
by institutional investors with
relative performance concerns
influences the efficiency of
financial markets, asset prices
and investors’ portfolio returns.
The team have developed a
theoretical framework which
illustrates, among others, that
‘benchmarking’ distorts the
informational efficiency of stock
prices. Their work has important
implications for the ability of
financial markets to incorporate
and provide information in
the presence of institutional
investors and passive
investment management.
Photorasee/Shutterstock.com
58 www.researchoutreach.org
T
oday, roughly two-thirds of
all U.S. stocks are held by
institutional investors, such as
banks, pension funds, mutual funds,
insurance companies and hedge funds.
Consequently, institutional investors
are major players in financial markets
and have a substantial impact on asset
prices and financial-market efficiency.
The performance of these institutional
investors is usually evaluated relative
to a benchmark (stock-market index)
– a practice that has the potential
to substantially alter the investment
strategies of fund managers and, in
turn, affect financial-market equilibrium.
Understanding such effects is the
objective of the work by Adrian
Buss, Assistant Professor of Finance
at INSEAD, and Matthijs Breugem,
Collegio Carlo Alberto.
In a study recently published in The
Review of Financial Studies, Breugem
& Buss (2019) have developed a
theoretical framework that seeks to
explain how the rise of benchmarked
institutional investors affects financial
markets. Their model extends previous
theories by explicitly accounting for both
information and portfolio choice in the
presence of institutional investors who
are concerned about their performance
relative to a benchmark. Notably, their
findings suggest that benchmarking can
cause considerable distortions in the
value of private information and, hence,
informational efficiency.
INSTITUTIONAL INVESTORS
Over the last decades, the importance of
institutional investors has grown steadily.
For example, the fraction of U.S. equity
owned by institutional investors has risen
from about 7% in 1950 to 67% in 2010
(Stambaugh, 2014). Similarly, institutional
investors nowadays account for a majority
of the transactions and trading volume
(Griffin, Harris & Topaloglu, 2003).
Like other investors, institutional investors
try to manage their funds in order to
maximise the absolute value of these
investments. However, their performance
relative to a benchmark (or, their peers)
is also of great importance. That is, there
exists considerable academic evidence
that funds that beat their benchmark
attract more new capital in the future.
Also, many institutional investors get
paid more by their clients when they
deliver a return that is higher than that
Wpadington/Shutterstock.com
of the benchmark. For example, recently,
Japan’s Government Pension Investment
Fund, the world’s largest retirement
fund, has introduced a system whereby
it pays all active managers a fee based
on their relative return. The idea of such
performance-fees is to align the incentives
of fund managers with those of their
investors. In particular, a fund manager
will only receive a high fee if his/her
investment return is higher than the one
investors could achieve by simply buying
the benchmark.
PRIVATE INFORMATION AND
INFORMATIONAL EFFICIENCY
Investors in financial markets consistently
try to uncover information that other
investors do not possess. For that
purpose, they study financial statements,
gather information about consumers’
taste, hire outside financial advisers,
or subscribe to proprietary databases.
Such private information is particularly
valuable because – if not available to
other investors – it allows an investor
to generate trading profits; by buying
stocks that he/she has positive
Research by Buss and Breugem
demonstrates how the growth of assets
under management by benchmarked
institutional investors affects
informational efficiency and asset prices.
information about and selling stocks with
negative information.
However, whenever investors trade
stocks based on private information, part
of this information will be incorporated
into the price. For example, if an investor
has access to information that indicates
a good performance of a firm in the
future, he/she would buy shares of the
respective firm to benefit from this
information. This, in turn, will lead to an
increase in the firm’s stock price which
would then, partially, reveal the investor’s
positive information to the other
investors. As a result, by studying stock-
price fluctuations in financial markets,
investors can learn about the private
information of other investors.
Overall, this process implies that stock
prices (imperfectly) reflect the information
that the various investors in financial
markets possess. The degree to which
financial markets incorporate and
reflect private information is denoted
informational efficiency (Fama, 1970) and
is of foremost importance for an economy
because it determines the efficient
allocation of capital.
RESEARCH OBJECTIVE
The main objective of the work by
Breugem & Buss is to understand how
the growth of assets under management
by institutional investors with relative
performance concerns influences the
efficiency of financial markets, asset prices
and investors’ portfolio returns.
RESEARCH DESIGN
The research team has developed a
theoretical framework to address these
research questions. The model differs
from previous studies on the effects
of institutional investors on financial
markets (Cuoco & Kaniel, 2011; Basak &
Pavlova, 2013; and Buffa, Vayanos and
Woolley, 2018) in that it allows institutional
investors who are concerned about
their relative performance not only to
choose their optimal portfolio but also
to determine how much time and capital
they want to invest into the acquisition of
private information. This novel modelling
framework enables unique conclusions
to be drawn regarding the impact of
benchmarking on informational efficiency
and asset prices.
In the model there exist two types of
investors. While one group of investors
is concerned about its performance
relative to the benchmark (“benchmarked
investors”), the other one is not. To
understand how the growth in assets
www.researchoutreach.org 59

under management of institutional
investors that took place in the past
years affects financial markets, the
authors analyse how financial-market
equilibrium changes as the proportion
of benchmarked investors in the
economy rises.
MAIN FINDINGS
The research team documents that
benchmarking has two distinct effects
on the efficiency of financial markets.
First, institutional investors with relative
performance concerns acquire less
private information. That is, to minimise
the risk of underperforming their
benchmark, benchmarked investors
overweight the stocks that are part of
the benchmark in their portfolio. In that
regard, they diverge from traditional
share picking methods that are used by
non-benchmarked funds. Intuitively, by
partially replicating the benchmark, their
performance becomes more similar to
the benchmark and, hence, the risk of
under-performance declines. However,
note that such “hedging trades” are not
based on information, as they simply
require the purchase of the stocks
in the benchmark. Hence, a part of
benchmarked investors’ portfolios will not
benefit from private information and, as
a result, these investors will reduce their
acquisition of private information. Second,
benchmarked funds are less aggressive
in using their private information.
For example, in the case of positive
information about a firm, a benchmarked
institutional investor will acquire less
shares of the respective firm than a
comparable investor without relative
performance concerns. Consequently,
the firm’s stock price reacts less and,
hence, less of the benchmarked investors’
information will be reflected in the price.
Both effects imply a reduction in the
informational efficiency of financial
markets. However, the underlying
economic mechanisms are quite distinct.
The first mechanism implies that there
is less private information available in
financial markets due to the decline in
the information-production activities of
benchmarked investors. Hence, prices
can only reflect this lower amount of
information. In contrast, the second
mechanism implies that less of the
available information is incorporated
into prices because benchmarked
60 www.researchoutreach.org
0.6
0.5
Explained variance (R2 )
0.4
0.3
0.2
0.1
0.0
0 0.25
Fraction of benchmarked investors (Γ)
Price Informativeness. The figure depicts stock-price informativeness, measured by the fraction of the
variance of the payoff that is explained by the stock price, as a function of the fraction of benchmarked
institutional investors. The graph is based on the framework described in Section 3.1 of Breugem &
Buss (2019).
[Their model] allows to draw unique
conclusions regarding the impact of
institutional investors on financial markets.
investors are less aggressive in their
trading. Ultimately, less information is
known about the stocks in the index.
This prediction is consistent with the
empirical evidence that an increase in
ETF ownership is associated with less-
informative security prices (Israeli, Lee and
Sridharan, 2017).
The reduction in the informational
efficiency of financial markets has
important implications for asset prices and
fund managers’ returns. For example, the
prices of stocks in the benchmark should
fluctuate more than those not part of
the benchmark. Intuitively, because less
information is reflected in their price, the
arrival of any piece of news leads to a
stronger reaction in the stock price and,
hence, more pronounced fluctuations.
Another important prediction of the
model is that investors which are not (or
less) concerned about their performance
relative to an index should outperform
(more) benchmarked investors. Intuitively,
less-benchmarked funds who gather more
total
0.5 0.75 1
private information are better placed to
make correct investment decisions, which
in turn means that they outperform their
benchmarked rivals.
SUMMARY
The research by Buss and Breugem
demonstrates that the growth of assets
under management by benchmarked
institutional funds can have a
substantial impact on financial markets.
Benchmarking reduces informational
efficiency because benchmarked
investors acquire less information and
trade less aggressively on their available
information. As a result, the returns of
stocks in the benchmark become more
volatile. Moreover, fund managers
whose performance is not tied to a
benchmark outperform benchmarked
investors; increasingly so as the fraction of
benchmarked investors in the economy
rises. These results are of significance
not only to investment professionals,
corporate decision makers and regulators
but also to retail investors.
 Behind the Research
Dr Adrian Buss
E: adrian.buss@insead.edu T: +33 1 60 72 44 84
W: www.insead.edu/faculty-research/faculty/adrian-buss

Research Objectives References

The research of Adrian Buss investigates the impact of Basak, S., and A. Pavlova (2013) “Asset Prices and Institutional
financial frictions and institutional investors on asset prices Investors”, American Economic Review, vol. 103, pp. 1728-
and financial-market efficiency. 1758.
Breugem, M and A. Buss (2019) “Institutional Investors and
Detail Information Acquisition: Implications for Asset Prices and
Informational Efficiency”, Review of Financial Studies, https://
Dr Adrian Buss doi.org/10.1093/rfs/hhy103
INSEAD, Boulevard de Constance
Buffa, A., D. Vayanos, and P. Woolley (2019), “Asset
77305 Fontainebleau
Management Contracts and Equilibrium Prices”, CEPR
France
Discussion Papers.

Bio Cuoco, D., and R. Kaniel (2011) “Equilibrium Prices in the

Adrian Buss is an Assistant Professor of Finance at INSEAD.
He holds a PhD in Finance from Goethe University Frankfurt
and Masters in Mathematics and Business Informatics
from the University of Mannheim. His research has been
published in leading academic journals (Journal of
Finance, Review of Financial Studies, Journal of Monetary
Economics).
Funding
This work has received financial support from the Europlace
Institute of Finance, the Labex Louis Bachelier and the ‘Asset
Management Academy – An initiative by Paris Dauphine
House of Finance, EIF and Lyxor International Asset
Management’.
Presence of Delegated Portfolio Management”, Journal of
Financial Economics, vol. 101, pp. 264-296.
Fama, E.F. (1970) “Efficient capital markets II”, Journal of
Finance, vol. 46, pp. 1575-1617.
Griffin, J. M., J. H. Harris, and S. Topaloglu (2003) “The
Dynamics of Institutional and Individual Trading”, Journal of
Finance, vol. 58, pp.2285-2320.
Israeli, D., C. M. Lee, and S. A. Sridharan (2017) “Is There a
Dark Side to Exchange Traded Funds (ETFs)? An Information
Perspective”, Review of Accounting Studies, vol. 22, pp. 1048-
1083.
Stambaugh, R.F. (2014) “Investment Noise and Trends”,
Journal of Finance, vol. 69, pp. 1415-1453.

Collaborators
• Matthijs Breugem from Collegio Carlo Alberto
Personal Response
Does your research suggest that benchmarking should
be regulated?
No. Benchmarking plays an essential role in financial
markets. It aligns the incentives of retail investors with
those of their fund managers. Hence, in general, it
should lead to better portfolio returns for retail investors.
However, our research highlights a novel tension between
benchmarking as a tool to align incentives and its adverse
effects on informational efficiency and benchmarked
investors’ portfolio returns. Also, our research suggests
that non-benchmarked fund managers outperform their
benchmarked peers, so that there might be a natural limit
to the size of benchmarked (passive) funds.

www.researchoutreach.org 61
 Biology ︱ Dr Kaoru Sugimura
Honeycomb wings
created by nature’s
mechanics
Forces shape the world we
live in, including the bodies we
grow in to. Tiny motors in our
cells push and pull to create
different shapes, surrounding
cells respond and react to
create diverse patterns of
tissue resulting in a world full
of unique plants and animals.
Drs Sugimura and Ikawa, from
Kyoto University, studied the
Drosophila fly wing to uncover
the components involved in
resisting and responding to
external force, resulting in a
beautiful cellular honeycomb
arrangement.
nechaevkon/Shutterstock.com
Female adult fruit fly, Drosophila melanogaster.
62 www.researchoutreach.org
Y
ou probably don’t think all that
much about forces. You probably
didn’t have to think about whether
the chair you are sitting in would support
you or whether the building you work in
would keep its shape. But a mechanic
or engineer has put a lot of thought into
designing these things. Each part has to
be carefully assembled out of the correct
material to ensure you don’t topple off
your chair or the building doesn’t cave in.
It’s easy to think about forces in something
you might build but what about the forces
inside your body?
You and I, and all the other living things
on the planet, are made up of cells.
When a human infant develops, forces
act between tens of trillion cells to shape
our bodies. If you think of an animal off
the top of your head, the likelihood is
that they are a very different shape and
size to you. We live in a world full of
diverse animals and plants; to understand
how these different forms arise we need
to understand the forces underlying
development. We need to look at the
mechanics of nature.
Imagine two judo players in a wrestling
match. They push and pull one another
and use force to try and win. They also
respond to each other – a pull from one
player may result in a push from the other.
Just like the judo players, cells push and
pull during development to create shapes
and patterns. Within the cell, proteins
are hard at work generating forces whilst
cells communicate to each other through
mechanical movements. Cells also sense
and respond to their environment just like
the judo players.
The understanding of force generation
within cells and tissues has evolved in
the last decade. However, much less
is known about how cells are able to
respond to forces during development.
This mysterious area of research has been
pursued by Dr Kaoru Sugimura and her
colleagues, Dr Keisuke Ikawa from Kyoto
University and Dr Shuji Ishihara from the
University of Tokyo, who have heroically
uncovered the developmental story
of wing cells in Drosophila flies.
HONEYCOMB WINGS
When Drosophila are in the pupal stage
of development, the larva is changing
(metamorphosing) into an adult fly. During
metamorphosis, the cells rearrange
their positions to create adult fly tissue.
Mechanical forces push and pull cells and
 A snapshot of the left wing of Drosophila pupa. Cells are labeled with GFP-tagged cell adhesion molecules, E-cadherin. The vertical and horizontal directions
are aligned with the anterior-posterior (AP) and proximal-distal (PD) axes, respectively.
chemical signals trigger cell movement
and changes in configuration. Cells
respond in many different ways to the
mechanical force, including elongation,
increasing elasticity and directional
cell rearrangement. This is where cells
rearrange by changing the contact
they have with the cells around them.
In the Drosophila wing, directional cell
rearrangement causes the cells in the
wing to align in hexagons, forming a
beautiful honeycomb structure.
As the Drosophila wings deform in
concert with the hinge (where the wing
connects to the body) the tension of the
tissue increases, causing the wing cells to
Pupa of Drosophila melanogaster.
Tomasz Klejdysz/Shutterstock.com
…these forces cause the cells in the wing
to align in hexagons, forming a beautiful
honeycomb structure…
elongate and stretch out horizontally. This
tissue tension pulls the cells into contact
with surrounding cells. The contact point
with these other cells is known as a cell
junction. At the cell junction forces act to
counterbalance the tension of the tissue. If
this tension is not resisted the cells would
be pulled apart. Stabilising the balance
of external tension and internal forces
allows the cells to comfortably rearrange
into a hexagonal shape. Sugimura and
her colleague, Ishihara, neatly unravelled
all these factors at play, but there is more
to be understood – what generates these
resisting forces in the cell? Sugimura dug
deep into the cell to find the individual
molecules within the cell that were
involved in this process.
ACTIN
Actin is a protein found in most cells
in the body. It’s important for muscle
contraction, for movement and division
of cells and giving cells their shape.
Actin senses and resists forces, and can
react and respond to the mechanical
environment by altering its elasticity or
changing its structure.
Actin exists in two forms – fibrous and
globular. The small globular actin proteins
come together to form a chain or fibre.
In its chain form it’s useful for all sorts of
things including shaping and moving
cells! Actin could also be involved in the
organisation of lots of cells within a tissue
because actin is connected up between
cells through special junctions called
adherens junctions.
Actin can only change its structure with
the help of other proteins called actin-
www.researchoutreach.org 63
 elongation
Tissue
Tissue tension
Cell rearrangement
Tissue tension
Top: Still images from time-lapse recording of the pupal wing development. Orange rectangles indicate the elongation and shrinkage of wing tissue along
the PD and AP axes, respectively. The forces generated in the proximal region of the body stretch the wing along the PD axis (blue two-way arrow).
Bottom: In response to tissue tension (blue arrows), cells change their relative positions along the PD axis by remodeling cell junctions (magenta lines).
binding proteins, like AIP1 and cofilin.
Because of actin’s ability to sense and
resist forces, Sugimura and Ikawa studied
whether these proteins could be involved
in cell rearrangement in the Drosophila
fly wing tissue. Other studies have shown
that AIP1 and cofilin are important for
causing changes in actins shape and
behaviour in vitro, so was a great place
to start exploring further.
ACTIN’S COLLEAGUES
Sugimura and Ikawa started by
identifying AIP1 in the wing cells using
a fluorescent protein tagged onto
AIP1 so they could see exactly where
it was in the cells. They found it was
mainly located at the vertical sides of
the elongated cells (picture a cell being
stretched, like a horizontal baguette,
and imagine the two short curved sides
or ends of the baguette, these are the
vertical sides; aka AP junctions). As the
wing cells are being stretched it seems
to make sense that forces to resist the
tension during cell rearrangement
would originate from the AP junctions.
However, Sugimura and Ikawa previously
found other forces at play at the
elongated horizontal sides resisting
the tension.
Further research into AIP1 revealed
it was only present when cell
rearrangement was taking place. These
all point to the importance of AIP1
in cell rearrangement but the gold
standard test is disrupting the gene’s
function and seeing what happens!
64 www.researchoutreach.org
Tissue tension
…AIP1 and cofilin are like peanut butter
and jelly – they work better together.
The researchers disrupted the AIP1
gene so it wasn’t functioning and they
found a disturbance in hexagonal cell
packing and a defect in directional
cell arrangement. All of these results
point to the importance of AIP1
in cell rearrangement.
AIP1 has a partner in crime – cofilin.
Without cofilin, AIP1 only weakly binds to
actin, having little effect on changing its
behaviour. Sugimura and Ikawa found that
when cofilin was disrupted, AIP1 was no
longer localised to the AP junctions and
when AIP1 was disrupted, cofilin changed
its localization. Seems like AIP1 and cofilin
are like peanut butter and jelly – they work
better together.
MYOSIN AND CANOE/AFADIN
It turns out that it’s not just AIP1 and
cofilin involved in resisting the tissue
tension, there are other proteins that are
vital to prevent the cells being ripped in
two. Sugimura and Ikawa investigated
myosin, a motor protein previously
shown to be involved in regulating cell
rearrangement. Actin and myosin often
work so closely together that even their
names have merged. Actomyosin is the
name given to networks of actin and
myosin that work together to facilitate,
amongst other things, cell movement and
stability. The researchers here identified
an important role for actomyosin in
cell rearrangement. They found that
actomyosin requires AIP1 to function
correctly. When AIP1 was disrupted
myosin fibres were disfigured into circles
but this didn’t occur when AIP1 was
present. The researchers also identified
Canoe/Afadin as an important protein for
connecting actomyosin to the adherens
junction so that when actomyosin moves
it pulls the cell membrane with it. Without
any one of these proteins the cells
don’t rearrange in the right way, leading
to mismatched shapes and irregular
hexagons in the wings.
BRINGING IT TOGETHER
Building on their findings, Sugimura
and Ikawa have put together a chain
of events suggesting how cells respond
to tissue tension resulting in cell
rearrangement. The tissue tension causes
actin to twist at the AP junctions, this
twisting allows cofilin to bind to actin.
Cofilin causes AIP1 to arrive at the AP
junctions, the combination of the AIP1
and cofilin (peanut butter and jelly)
results in actin turnover maintaining the
Canoe/Afadin link between actomyosin
at the adherens junction. This resists the
tissue tension that would otherwise break
the cells in two. Now these mechanisms
have been uncovered, Sugimura
and Ikawa are keen to conduct further
experiments to reveal their importance
in other developmental contexts.
 Behind the Research
Dr Kaoru Sugimura
E: ksugimura@icems.kyoto-u.ac.jp T: 81-(0)75-753-9866 W: www.koolau.info

Research Objectives References

Research in Dr Sugimura’s lab combines mechanical and
genetic perturbations with live imaging and Bayesian
force-inference to explore the physical principles underlying
regulation of epithelial morphogenesis.
Ikawa K., Sugimura K. (2018). AIP1 and cofilin ensure a
resistance to tissue tension and promote directional cell
rearrangement. Nature Communications 9, 3295
Sugimura K., Ishihara S. (2013). The mechanical anisotropy
in a tissue promotes ordering in hexagonal cell packing.

Detail Development 140, 4091-4101

Dr Kaoru Sugimura
iCeMS Research Building
Kyoto University
Yoshida Honmachi
Sakyo-ku
Kyoto 606-8501 Personal Response
Japan
Will understanding directional cell rearrangement be
Bio useful in understanding aetiology of diseases?
Kaoru Sugimura received her PhD from the Graduate I would say yes. Directional cell rearrangement is
School of Science, Kyoto University in 2006. She is a essential for various developmental processes such as
currently an associate professor at WPI-iCeMS, Kyoto neural tube closure and hearing tube formation (Nishimura
University. Sugimura uses a wide range of techniques, et al. Cell, 2012; Kidokoro et al. Development, 2018). Their
including live imaging, Bayesian statistics, and physical failure leads to serious birth defects in humans, including
modelling, to understand the mechanisms by which anencephaly. Some disease-related proteins also function
mechanical forces shape the body. in directional cell rearrangement. For instance, Pten,
a tumor suppressor, controls the elongation of newly
generated adherens junctions (Barder et al. Dev. Cell, 2013).
Funding Understanding directional cell rearrangement would help
JSPS KAKENHI Grants us understand how serious birth defects and fatal diseases
The JST PRESTO Program are caused.
The AMED PRIME Program

Collaborators
• Dr Keisuke Ikawa
Omelchenko/Shutterstock.com

www.researchoutreach.org 65
Health and Medicine ︱ Dr Matt Pecot
Drosophila Fezf found
to be essential in neural
circuit formation
Billions of neurons are wired
up to into highly organised
neural circuits in the brain.
The creation of these circuits
is a complex process and it is
essential that neurons find the
correct partners. Matt Pecot
and colleagues from Harvard
Medical School are interested
in understanding this neural
circuit formation. In their studies,
by using Drosophila, they have
identified the gene dFezf as an
important part of the puzzle.
66 www.researchoutreach.org
B
rains are grey, squishy and wrinkly,
they are not all that exciting to look
at. But if you use a microscope it
gets a whole lot more interesting, you
can see long, thin and wire-like neurons
that are important for pretty much
everything you do – thinking, planning,
feeling, seeing, typing, understanding,
reading this article, and the list goes on
and on.
Neurons connect like wires at points
called synapses to send signals and
messages across the brain. When you
are young your brain is making loads
of synapses because it is learning lots
of new things – it’s learning how to
understand what you see and hear, how
to remember a name, recognition of
family, how to speak, how to walk and so
on. So, it’s important that these neurons
connect correctly. But how do they do it?
There are so many neurons how do they
know which ones to partner up with?
Imagine I gave you a box
of wires and asked you to
connect them all up to make
a robot. This sounds tricky but
I wonder if there are some
instructions somewhere?
Instructions in living things
are found in genes in our
DNA. Matt Pecot and his
research group are interested
in finding the genes that
help neurons find the right
connections in the brain.
WHY THE FLY?
Do you fancy donating a
portion of your brain for
Anatomy of the Drosophila visual system (Adapted from Fischbach and Diettrich 1989).
This figure was previously published in Millard, S. S., & Pecot, M. Y. (2018). Strategies for
assembling columns and layers in the Drosophila visual system. Neural Development, 13(1).
doi:10.1186/s13064-018-0106-9 and is under the Creative Commons Licence CC BY 4.0.
research? Most likely not, this is why
researchers use models to help figure
out what is going on in humans, by
studying a model, researchers can gain
insights into the biology of humans.
Matt Pecot and his researchers use
the Drosophila melanogaster, the fruit
fly, to study how neurons connect to
one another. One of the main reasons
for using the fly is because of its
similarities with the human brain. Both
the Drosophila and the human brain
have complex layered circuits in the
optic lobe (the part of the brain that
interprets what you see). Examining
this area also allows researchers to see
and study individual neurons – another
great reason to use Drosophila! Matt’s
group is interested in how the layered
circuits are formed in Drosophila.
TRAFFIC INTO THE M3
Confusingly the optic lobe is divided
up into more small parts – we just
need to know about two of those, the
lamina and the medulla. Neurons from
the lamina, helpfully named lamina
neurons, synapse in the medulla. In an
adult Drosophila, the medulla is clearly
organised into distinct layers: M1 – M10
formed by the synapsing of laminar
neurons. But how are these layers
formed? It’s all down to Earmuff! Let me
explain further, L3 is a lamina neuron
that synapses in the medulla. In the adult
Drosophila, L3 neurons synapse in the
M3 layer. The research group previously
identified a gene called Drosophila
Fezf (dFezf for short, aka Earmuff) in
L3 neurons and were interested to see
if it had a role in targeting L3 to the
M3 layer.
Outer layers develop in a stepwise manner from broad domains. h APF = hours after puparium formation (a) A representation of the adult
morphologies of lamina neuron axons L1-L5. The arborizations of lamina neuron axons help define specific outer medulla layers. (b) A drawing of lamina
neuron growth cones L1-L5 in early pupal development. Prior to arborizing in discrete layers lamina growth cones terminate in distal or proximal domains
within the outer medulla. This figure was previously published in Millard, S. S., & Pecot, M. Y. (2018). Strategies for assembling columns and layers in the
Drosophila visual system. Neural Development, 13(1). doi:10.1186/s13064-018-0106-9 and is under the Creative Commons Licence CC BY 4.0.

BYE-BYE EARMUFF
One way that researchers try to
understand the importance of a gene
is to get rid of it! When the gene is gone
or knocked-down you can see what
effects this has on the neuron. In this case,
the scientists were interested in looking
at whether the L3 neurons synapsed
on M3 without dFezf. Matt’s group used
flies that were still developing neuronal
connections to see the importance
of dFezf. The chosen flies were in the
pupal stage of development, where the
larva is metamorphosing into an adult
fly. Here the researchers encountered
a problem, they found that the mature
M1-10 layers don’t exist in pupal flies!
Matt suggests this mechanism for
assembling circuits may have remained
unchanged throughout evolution so it will
be found in multiple species.
At this stage, the layers in the medulla
haven’t fully formed, but they observed
two broader regions– the distal and
proximal regions. The researchers
conducted the knockdown experiments
and saw in pupal flies without dFezf that
L3 neurons stopped growing in the distal
domains of the medulla. However, in the
control pupal flies with functioning dFezf,
the researchers found L3 synapsed in the
proximal domain. It seems that dFezf is
important in targeting L3 to the proximal
domain during development. The
researchers continued to study the flies
throughout development. They found
in flies without dFezf that the mature
layers, M1-10, weren’t distinguished
and the neurones displayed abnormal

DFezf coordinates the formation of laminar-specific connections.

(A) Early in medulla development, dFezf promotes the targeting of L3 growth cones to the proximal versus distal domain of the outer medulla. DFezf may
regulate this step by controlling a program of dpr gene expression. (B) L3 growth cones segregate into the developing M3 layer and secrete Netrin, which
regulates the attachment of R8 growth cones within the layer. DFezf also regulates this step by activating the expression of Netrin in L3 neurons. (C) Within the
M3 layer, L3 and R8 axons synapse onto Tm9 dendrites. When dFezf function is lost in L3 neurons, L3 and R8 axons innervate inappropriate layers while Tm9
dendrites innervate the M3 layer normally. As a result, connectivity with Tm9 neurons is disrupted. This figure was previously published in Pecot, M. Y. et al.
(2018). Drosophila Fezf coordinates laminar-specific connectivity through cell-intrinsic and cell-extrinsic mechanisms. eLIFE,7:e33962. https://doi.org/10.7554/
eLife.33962 and is under the Creative Commons Licence CC BY 4.0.

www.researchoutreach.org 67
 architecture. However, in the flies with
dFezf, they found L3 neurons had
integrated into the developing M3 layer.
By knocking down dFezf the researchers
were able to answer their question – dFezf
is important for targeting neurons to the
correct layer during development!
The team dug down even further to
figure out exactly what dFezf was doing
to ensure that L3 neurons
synapse in the M3. They dFezf has an important role in directing
wanted to see whether
dFezf had direct control the growth of neurons.
(instructional) over where
L3 synapsed or whether a third factor may
be involved. To do this they expressed
dFezf in two other lamina neurons that
also synapse in the medulla. L5 neurons
have been found to synapse in the
proximal domain so expressing dFezf
had no effect on the synapsing location,
it still synapsed in the proximal domain.
L2 neurons, however, usually synapses
the distal domain, so if dFezf is expressed
you would expect L2 to synapse in the
proximal domain if dFezf is instructional.
Matt and his group found exactly this! This
means that dFezf has an important role
in directing the growth of neurons!
WHAT’S GOING ON?
We know that dFezf is important in
targeting L3 neurons to M3. But what
kurt_G/Shutterstock.com
68 www.researchoutreach.org
does dFezf actually do? Does it yell
instructions like a pirate to the crew on a
ship? Probably not. In fact, Matt’s research
group have some compelling evidence
demonstrating that some other more
favourable mechanisms of communication
may be at play. They had a good look at
the levels of expression of the genes in
neurons where dFezf was removed and
where it was functioning correctly. They
found lots of genes were affected by the
lack of dFezf, including genes involved
in regulating the cell surface and release
of molecules. It’s possible that dFezf could
be a master regulator gene that initiates
layer formation through regulating the
expression of other genes. Faced with
altering levels of multiple genes, the
research group had to choose their
best candidate to study in more detail.
The lucky winner this time was Netrin.
NETRIN
Netrin or Net for short exists in two
forms – A and B. The researchers here
focused on NetB as there is more of it
in L3 neurons. They found that disrupting
expression of dFezf in L3 neurons caused
a reduction in NetB confirming their
initial thoughts that dFezf is required
for NetB expression. They also found
that NetB is important in supporting
other communications as well including
regulating the synapsing of another type
of neuron called R8 into the M3. It seems
that dFezf is quite busy, not only does
it regulate the expression of genes that
target L3 neurons to the M3 but it also
regulates NetB expression to recruit other
cells to the M3
layer! Remember
there are nine other
layers so it is likely
that similar genes
coordinate their assembly like dFezf
coordinates targeting of different cells to
the M3 layer.
Researchers from other groups have
also identified Fezf as being important
for assembling these layered circuits
in mammals (mice). Matt’s group propose
that this mechanism for assembling
circuits is evolutionary conserved – it
has remained unchanged throughout
evolution so it will be found in multiple
species. Before this can be said for sure,
more research is required. The group
would like to study the other genes that
dFezf regulates to pin down exactly
what dFezf does to assemble these
layered circuits.
 Behind the Research
Dr Matt Pecot
E: matthew_pecot@hms.harvard.edu T: +1 617 432 5157 W: http://www.Pecotlab.com

Research Objectives References

Matt’s laboratory at Harvard Medical School seeks to Millard S. & Pecot M. (2018). ‘Strategies for assembling
understand how the nervous system is assembled columns and layers in the Drosophila visual system’. Neural
during development. Development, 13:11.

Pecot M., Chen Y., Akin )., Chen Z., Tsui C., Zipursky L. (2014).
‘Sequential Axon-derived Signals Couple Target Survival and
Layer Specificity in the Drosophila Visual System’. Neuron:16;
Detail 82(2): 320–333.

Pecot M., Tadros W., Nern A., Bader M., Chen Y., Zipursky L.
Matt Pecot (2013). ‘Multiple Interactions Control Synaptic Layer Specificity
220 Longwood Ave, in the Drosophila Visual System’. Neuron, 23; 77(2): 299–310.
Armenise 203,
Boston, Peng J., Santiago I., Ahn C., Gur B., Tsui C., Su Z., Xu C.,
MA 02446 USA Karakhanyan A., Silies M., Pecot M. (2018). ‘Drosophila Fezf
coordinates laminar-specific connectivity through cell-intrinsic
and cell-extrinsic mechanisms’. eLife;7:e33962 Available at:
Bio
10.7554/eLife.33962.
For his PhD, Matt worked with Vivek Malhotra at UCSD
investigating the biogenesis of the Golgi apparatus, and
he performed post-doctoral studies with Larry Zipursky at
UCLA studying neural circuit formation. Matt’s laboratory
at Harvard Medical School seeks to understand how the
nervous system is assembled during development.
Personal Response
Funding Do you think studying neural circuit formation will
provide insights into aetiology or cures for diseases
• NIH K01NS094545
that affect the brain?
• NIH-NINDS R01 NS103905 01A
• NIH-NINDS R01 NS110713 01 Absolutely. It is becoming clear that developmental
defects in neural connectivity are causal to neurological
disorders. Thus it’s imperative to understand the
fundamental molecular principles underlying how neural
Collaborators connections are established during development.
Marion Silies
Johannes-Gutenberg-Universität Mainz Using these principles as a guide will allow us to develop
iDN: Institute for Development and Neurobiology therapeutic strategies to restore proper circuitry
Hanns-Dieter-Hüsch Weg 15 in diseased individuals.
55099 Mainz, Germany

www.researchoutreach.org 69
Biology ︱ Dr Daisuke Kihara
Predicting protein function and
annotating complex pathways
with machine learning
Dr Daisuke Kihara’s team at
Purdue University have created
novel computational approaches
for predicting protein functions.
Instead of following a one-
protein-one-function approach,
their algorithms can predict the
functional relationships of entire
groups of proteins related to a
specific biological process. The
team has also expanded into
mining oversighted or previously
unknown proteins that have
multiple, independent functions.
The team’s methods challenge
the logic behind conventional
protein function studies and
propose tools that may better
capture the complicated
nature of protein interactions
in biological processes.
KJ07/Shutterstock.com
70 www.researchoutreach.org
P
roteins are the main working
units of biology. Identifying
and understanding what proteins
do is crucial for biologists hoping to solve
the complex interactions and systems that
drive cellular processes. Although protein
function needs to be ultimately validated
by hand in the wet lab, researchers
first need a hypothesis in order to
design assays, which can then define
the probable function of a protein.
BIOINFORMATICS FOR
PREDICTING PROTEIN FUNCTION
Biologists can build such hypotheses
of gene function with computers.
As genome sequencing becomes
routine in experimental laboratories,
computational gene function prediction
has also become increasingly important.
Computational methods are very
suitable for function prediction because
function information of a gene can be
inferred from a database search that
identifies similarity between the gene and
known proteins or experimental data.
Sequence similarity tools like the Basic
Local Alignment Search Tool (BLAST) is
one such method that searches against
all previously recorded sequences
and suggests a scored list of possible
roles for it.
PROBLEMS WITH PREVIOUS
COMPUTATIONAL METHODS
However, existing bioinformatic tools can’t
always predict protein function accurately,
and often end up incorrectly annotating
proteins within a biological system.
Traditional protein function prediction
tools like BLAST are usually reliable when
a high sequence similarity is detected, but
their accuracy falls quickly for sequences
with lower similarities. For example,
enzyme functions differ immensely when
similarity scores fall below a certain level.
Moreover, in many cases traditional
methods do not annotate any function
if highly similar sequences are not found,
leaving many genes unannotated. In
addition, other metrics such as similarity
in three-dimensional structure, gene
expression, or interaction data could
be used. However, each of these metrics
are often missing for many proteins
under investigation, and so have limited
applicability in reliable research.
NEW TOOLS FOR
BETTER ACCURACY
Recently, several new protein annotation
methods have been developed to
improve overall prediction accuracy. One
such developer is Dr Daisuke Kihara from
Purdue University, who develops function
prediction methods with new logical
frameworks. In 2009, his team created
an automated predictive algorithm,
called the extended similarity group
(ESG) method, which runs a continual
comparing system, instead of a single
search. From each sequence found from
the first inquiry, the ESG algorithm runs a
second search through the database. By
combining results from this multi-levelled
tactic, the ESG method significantly
improves functional scoring for query
proteins and outperforms previous
function prediction algorithms.
 Gorodenkoff/Shutterstock.com
Yet the team did not stop here. In a 2019 logical framework at its core. The iGFP Moreover, the system automatically
paper, they combined phylogenetic algorithm considers a set of proteins as assumes that some proteins are unknown
tree construction tools with traditional input, and predicts the role of the function and uses a range of other comparative
sequence-based prediction, called the of the entire group, as well as its individual features to make an accurate prediction.
Phylo-PFP method. They first confirmed members. The iGFP algorithm blends During this scan, the algorithm considers
that close similarities of protein sequences sequence data from multiple sources protein-protein interactions, phylogenetic
did not align with the proteins’ distances and builds a complementary network. profile similarity, gene co-expression,
on a phylogenetic tree. By adding these The method then separates the proteins large-scale pathway similarity, and
distances into the sequence homology into clusters that have functional relevance gene ontology similarity. This type of
score, the protein query ranks became and compares them based on functional comprehensive group function prediction
more reliable, and they could be more and interaction relationships. could be an altogether improved
accurately linked to their gene source.
Unsurprisingly, the study established
Phylo-PFP significantly improved
Dr Daisuke Kihara from Purdue University
the function prediction accuracy over develops function prediction methods
existing methods.
with new logical frameworks.
PROTEIN GROUP
FUNCTION ANNOTATION
Protein function annotation is typically run
on a one-protein-one-function approach,
yet this mindset can grossly oversimplify
the protein function universe. In fact, most
experiments find dozens of interacting
proteins related to a single biological
event. To understand the role of an entire
protein set, their function should be
determined from the group as a whole,
even if the function of each individual
protein is unknown. This is no simple task.

Therefore, Dr Kihara’s team focused

on a new computational approach for
annotating the functions of protein
groups. In 2019, they proposed an
iterative Group Function Prediction (iGFP)
method, which holds a completely new The iGFP algorithm iteratively assigns functions to protein groups and to individual proteins in the groups.

www.researchoutreach.org 71

Aashish Jain and Dr Kihara discuss functions assigned to a metabolic pathway.
reflection of the real mechanisms at
work in, for example, developmental
or disease-causing pathways.
IDENTIFYING PROTEINS
WITH MULTIPLE FUNCTIONS
In addition to analysing protein groups,
the Kihara team has taken another
step away from the one-protein-one-
function scheme by studying multi-
functional proteins. Most bioinformatic
tools do not take into account that
proteins, enzymes in particular, can be
multi-functional. The Kihara lab has
thus aimed to predict whether a query
protein is a moonlighting protein – one
that has multiple autonomous and often
unrelated functions. These proteins are
difficult to annotate, since their functions
are not genome or protein family
specific, nor linked to other indicators,
such as a shared switching mechanism.
Yet these proteins play key roles in
The iGFP algorithm considers a set
of proteins as input and predicts the
function of the entire group, as well
as its individual proteins.
SmirkDingo/Shutterstock.com
72 www.researchoutreach.org
cellular disease states such as cancers,
and so identifying them is important.
To solve the problem, Dr Kihara’s
team has developed a new systematic
approach to study moonlighting
proteins. In 2016, the team proposed
an automated prediction framework
which uses several non-sequence-based
data to identify moonlighting proteins.
They used machine learning classifiers
to predict multi-functional proteins, after
which they cross validated the results
using existing databases. Dr Kihara’s
team could predict moonlighting
proteins that had previous gene
sequence data with 98% accuracy.
Even if no sequence data was available,
the system showed an impressive
75% accuracy.
Furthermore, in a 2018 paper the
team used deep learning to sniff
out moonlighting proteins from
previously published literature. Their
text mining tool DextMP could find
out whether a protein had multiple
functions or not based on information
from journal publications and functional
descriptions from protein databases.
Using systematic literature processing
tools, the researchers could significantly
reduce time to annotate moonlighting
proteins and move closer to clarifying
the complex interplay of proteins within
the cell.
IMPROVEMENTS AND
FUTURE PREDICTIONS
Computational biology desperately
needs new ways to accurately reflect
the true nature of biological processes.
Dr Kihara’s team has made innovative
strides to step away from a traditional
one-protein-one-function effort
and identified functions for entire
protein groups. Their algorithms
outperform previous sequence-based
methods by layering multiple protein
characteristics and taking into account
evolutionary relationships, which can
be better indicators of shared functions
than the simple amino acid backbone.
Further, the team’s machine learning
methods can predict whether a protein
serves a double role, and whether
such proteins have unknowingly been
described in previous literature.
Despite these promising developments,
bioinformatic prediction tools are
only as intelligent as their design, and
there is still a way to go towards fully
automated, AI-driven research in protein
function annotation. Overall, Dr Kihara’s
team suggests that combining previous
methods with emerging ones from omics
experiments and evolution distance
analysis will further solidify functional
prediction accuracies in the future.
 Behind the Research
Dr Daisuke Kihara
E: dkihara@purdue.edu T: +1 765 496 2284 W: http://kiharalab.org

Research Objectives References

Dr Kihara’s work focuses on developing new techniques Chitale, M., Hawkins, T., Park, C., & Kihara, D. (2009). ESG:
for computational protein function prediction. extended similarity group method for automated protein
function prediction. Bioinformatics, 25(14), 1739–1745.

Detail Jain, A., & Kihara, D. (2019). Phylo-PFP: improved automated

protein function prediction using phylogenetic distance
Department of Biological Sciences of distantly related sequences. Bioinformatics. 35(5):753-759.
Department of Computer Science
Purdue University Jain, A., Gali, H., & Kihara, D. (2018). Identification
249 S. Martin Jischke Dr of Moonlighting Proteins in Genomes Using Text Mining
West Lafayette, IN 47907, USA Techniques. Proteomics, 18(21–22), 1800083.

Bio Khan, I. K., & Kihara, D. (2016). Genome-scale prediction

Dr Kihara is a full professor in the Department of Biological of moonlighting proteins using diverse protein association
Sciences and the Department of Computer Science at information. Bioinformatics, 32(15), 2281–2288.
Purdue University, West Lafayette, Indiana. He received
a BS degree from the University of Tokyo, Japan in 1994, Khan, I. K., Jain, A., Rawi, R., Bensmail, H., & Kihara, D. (2019).
and a PhD degree from Kyoto University, Japan in 1999. Prediction of protein group function by iterative classification
After studying as a postdoctoral researcher with Prof on functional relevance network. Bioinformatics, 8, 1388-1394.
Jeffrey Skolnick he joined Purdue University in 2003. He
was promoted to full professor in 2014. Since 2018, he
has held an adjunct professor position at Department of
Pediatrics, University of Cincinnati. He has been working
Personal Response
in various topics in protein bioinformatics. His current
What kind of role will machine learning play
research projects include the developments of algorithms
in protein function prediction and understanding
for protein-protein docking, protein tertiary structure
biological processes?
prediction, structure modelling from low-resolution
image data, structure- and sequence-based protein Machine learning has already been playing a big
function prediction, and computational drug design. role in protein function prediction, and more widely,
in bioinformatics. It is particularly effective in identifying
He has published over 150 research papers and book
subtle signatures that are easily overlooked by humans
chapters. His research projects have been supported by in input data including protein sequences that are
funding from the National Institutes of Health, the National relevant to particular functions. It is also very suitable
Science Foundation, the Office of the Director of National for integrating many different types of data together
Intelligence, and industry. He has served on the program to make predictions.
committee of various bioinformatics conferences including
the Intelligent Systems for Molecular Biology (ISMB) where
he is a track chair in 2019. In 2013, he was named a University
Faculty Scholar by Purdue University.

Funding
• National Science Foundation (NSF)
• National Institutes of Health (NIH)

Collaborators
• Aashish Jain
• Ishita Khan

www.researchoutreach.org 73
Biology ︱ Dr Charles Turick
In-situ monitoring
of microbial circuitry
Microbial metabolisms are
valuable tools in industrial
biotechnology. The ability
to monitor and measure
the productivity of microbes
is essential, but many
standard techniques are
limited by issues of labour-
and time-intensity. With
funding from the Department
of Energy’s Bioenergy
Technologies Office, Office of
Science, and Environmental
Management Program as
well as the Department of
Defense’s Defense Threat
Reduction agency. Dr Charles
(Chuck) Turick at the Savannah
River National Laboratory and
collaborators from Clemson
University, the University of
South Carolina, and Savannah
River Consulting, have applied
electrochemical techniques
to enable in-situ monitoring
of microbial metabolic activity
uninhibited by the
limitations of standard
technologies.
74 www.researchoutreach.org
M
icroorganisms are incredibly
valuable tools in industrial
biotechnology. The plasticity
and repertoire of microbial metabolisms
are further increased through genetic
engineering, giving rise to a vast array
of potential uses for the microbes. They
can clean oil spills from oceans, yield
fuel from plants, as well as produce
pharmaceuticals such as penicillin. The
biotechnology industry, therefore, forms
a significant part of the economy (known
as the bioeconomy), with U.S. revenues
totalling $350 billion, or 2.5% of their
GDP, in 2012.
For quality control purposes and to
maximise process efficiency, the activity
of the microbes in the bioprocess must
be monitored. Slight changes in oxygen
concentration, pH, temperature, etc.
can have large impacts on the metabolic
activity of microorganisms
and therefore on
product yields. By
looking at changes
in cell numbers and
a range of metabolites
within a microbial culture, scientists
can gain insight into the metabolic status
of the bioprocess and how this can
be manipulated and optimised.
MEASURING MICROBES
However, many methods to sample
and analyse the conditions of microbial
cultures are time-consuming, labour-
intensive and costly. This is particularly
evident when microbes must be grown
in the absence of oxygen or at a harsh
pressure, making sampling a much more
complex procedure. The time and labour
taken when samples are manually
collected and analysed (termed offline
monitoring) limit the amount of data
that may be collected as well as the
opportunity to detect issues in the process
as they develop and, therefore, the
capacity to optimise the bioprocess. The
discontinuous nature of offline monitoring
also leaves gaps in data, which can lead
to misinterpretation. To avoid such issues,
automated sensors can be submerged
within a microbial culture to facilitate
continuous and real-time monitoring
of conditions (so-called online in-situ
monitoring). However, because the
sensor remains in-situ, microbes
can accumulate on the sensor
itself and reduce the accuracy
of its measurements (known
as biofouling). Costly and time-
consuming cleaning and maintenance
of the sensor is then required. The ideal
technology to monitor bioprocesses
should navigate around these limitations
 A typical microbial growth curve (green
circles) can be defined electrochemically
(below) and modelled mathematically
(black circles) using an equivalent circuit
(inset) to provide physiological data,
relative to abiotic controls (white circles).

whilst providing accurate and useful data.

Dr Chuck Turick at the Savannah River
National Research Laboratory with his
colleagues Ms Ariane L. Martin and Dr J.
Michael Henson at Clemson University, Dr
Sirivatch Shimpalee, Dr John Weidner, Mr
Pongsarun Satjaritanun, and Mr Blake A.
Devivo at the University of South Carolina,
and Dr Scott Greenway at Savannah River
Consulting have developed an automated,
non-invasive approach to monitor microbial
Dr Chuck Turick and his collaborators
activity with real-time data acquisition began to consider microbes as electric
to do just this. Part of this work has also
resulted in a patent for monitoring microbial circuits as well as chemical catalysts.
growth on surfaces (biofilms).
monitor microbial growth and metabolic switch between oxidised and reduced
Microorganisms are traditionally activity in-situ, offering an attractive forms through the loss or gain of one
considered as sources of biochemical alternative to standard analytical methods. or more electrons, respectively. As
catalysts (enzymes) and are typically increasing potentials are applied to an
analysed using chemical methods, such HOW DOES IT WORK? electrode submerged in a microbial
as chromatography and mass spectrometry. Cyclic voltammetry works by measuring culture, the current of this electrode
As in all chemical reactions, those occurring the current that is generated as a range increases over time as it gains more
within microbes are driven by the flow of potentials are applied to a redox electrons. The electrode then reaches
of electrons. For example, the microbial cell active system, such as a microbial the reduction potential of a metabolite
surface is negatively charged which attracts culture. A redox-active metabolite can of interest – meaning the potential at
positive ions, resulting in the formation
of a double layer on the cell membrane.
Dr Chuck Turick and his collaborators,
therefore, began to consider microbes as
electric circuits as well as chemical catalysts.
Any disturbances to the bioprocess may
be detected by looking at changes in both
electron flow and chemical composition.
The combination of these methods gives
rise to the growing fields of electrochemical
monitoring and electromicrobiology.

WHAT IS ELECTROMICROBIOLOGY?
Electromicrobiology uses electrochemical
techniques, such as cyclic voltammetry and
electrochemical impedance spectroscopy,
to study microbial activity. Dr Chuck Turick
has been using such technologies for
over a decade to study how microbes
can sequester uranium in contaminated
Electrochemical monitoring is being developed for use in bioreactors at various scales. Future applications
soils. More recently, Dr Chuck Turick has of this technology include monitoring biopharmaceutical processes in conjunction with studies in Dr Sarah
developed electrochemical techniques to Harcum’s Cell Culture and Fermentation Optimization Laboratory at Clemson University.-

www.researchoutreach.org 75
which the metabolite will switch between
reduced and oxidised forms, also known
as peak current or charge density – and
the electrons pass from the electrode to
the metabolite via extracellular electron
transfer. This reduces the metabolite
and oxidises the electrode, resulting in a
detectable drop in the electrode’s current.
The current is then reversed and the redox
reaction reverses, repeating in a cycle.
When microbial cultures are monitored in
this way, the charge density of reduction
Electrochemical techniques are used to
peaks is measured as an average across follow and define electron flow in microbes
the entire culture. Changes in the charge during growth. Studies incorporate
density of the peak can correspond to conventional microbial methods. This
approach provides abundant data related
changes in the ratio of living cells to dead to microbial activity.
cells within a culture, as well as changes
in the metabolic status of the cells.
Electrochemical techniques reduce
Electrochemical impedance spectroscopy
(EIS) is used to gain insight into the the labour and time-intensity of data
composition of cells within a culture.
In simple electrical circuits, resistance
collection [and] avoid the limitations
is a measure of the circuits ability to resist posed by biofouling.
the current flow. In complex circuits, such
as microbial cultures, resistance also In Dr Chuck Turick and his collaborators The key advantages of using
becomes a more complex parameter latest publication, cyclic voltammetry electrochemical techniques include
and is instead described by impedance. and EIS were demonstrated to accurately its capacity for real-time data acquisition
The impedance of a microbial culture is and effectively monitor microbial growth. and its ability to monitor in-situ, thereby
measured by applying potential to an in- The techniques show both impedance minimising disruption to the microbial
situ electrode and monitoring the change and charge density of reduction peaks culture and reducing the labour and time-
in current as it passes through the culture. correspond to the number of cells intensity of data collection. In addition,
By using a range of frequencies, the in a culture and their growth status. Now cyclic voltammetry was demonstrated
impedance values can be analysed to a patented technology, impedance to effectively prevent microbes from
understand how the composition of a was also shown to change as cellular accumulating on electrodes submerged
culture varies as cells grow and their growth slowed, indicating shifts in cultures. This suggests the technology
metabolisms change over time. in metabolic activity. can be used to clean electrodes without
removing them from the bioprocess,
avoiding the limitations posed
by biofouling.

The field of electromicrobiological

research has gained great interest in
the last decade since Dr Turick organised
the first international symposium on
the subject in 2008. Electrochemistry
is already a well-established technology
amongst physical scientists but was rarely
used beyond traditional electric circuits.
Its novel application in microbiology
has now inspired greater collaboration
between scientists and engineers from
different backgrounds to continue
developing and expanding the field
of electromicrobiology, changing how
microbial metabolisms are considered,
monitored, and even manipulated.

76 www.researchoutreach.org
 Behind the Research
Dr Charles (Chuck) Turick
E: Charles.Turick@srnl.doe.gov T: +1 803 507 2714 T: +1 803 819 8407 W: https://amb-express.springeropen.com/articles/10.1186/
s13568-018-0692-2 W: www.youtube.com/watch?v=7pjtjsj2Wu0&list=PLcR_7p639ABWvSLYpr6IXgxtjvkUDlQHu&index=12&t=199s
W: www.srs.gov/general/srnl/tech_transfer/tech_briefs/SRNL_TechBriefs_AutoElectrochemicalTechnique.pdf

Research Objectives References

Dr Turick studies electron transfer mechanisms in microbes Carlson, R. (2014) ‘The U.S. Bioeconomy in 2012’.
incorporating electrochemical techniques to define [online] Synthesis. Available at: http://www.synthesis.
microbes as tiny electrical circuits for applications cc/synthesis/2014/01/the_us_bioeconomy_
in_2012?rq=bioeconomy%20in%202012 [Accessed
in industrial biotechnology.
13/01/2019].
Martin, A. L., Satjaritanun, P., Shimpalee, S., Devivo, B. A.,
Weidner, J., Greenway, S., Henson, J. M., Turick, C. E. (2018).
Detail ‘In-situ electrochemical analysis of microbial activity’. AMB
Express, 8(162).
Environmental Science and Biotechnology
Savannah River National Laboratory Turick, C. E., Beliaev, A. S., Zakrajsek, B. A., Readon, C. L,
Lowy, D. A., Poppy, T. E., Maloney, A., Ekechukwu, A. A.
BLDG 999W
(2009). ‘The role of 4-hydroxyphenylpyruvate dioxygenase in
Aiken, SC 29808
enhancement of solid-phase electron transfer by Shewanella
USA oneidensis MR-1’. FEMS Microbiol Ecol, 68, 223-235.

Bio Turick, C. E., Ekechukwu, A. A., Milliken, C. E., Casadevall,

A., Dadachova, E. (2011). ‘Gamma radiation interacts with
Chuck Turick received his BS in biology from California
melanin to alter its oxidation-reduction potential and results in
University of Pennsylvania, MS and PhD in microbiology electric current production’. Bioelectrochemistry, 82, 69-73.
from West Virginia University and the University of New
Hampshire, respectively.

Funding
Personal Response
• Savannah River National Laboratory Directed Research
and Development Program Can electrochemical techniques replace standard
methods such as measuring optical density of microbial
• Department of Energy (DOE)/ Office of Energy Efficiency
cell cultures?
& Renewable Energy - Bioenergy Technologies Office
• DOE/Office of Science At this stage of the technology, we are interested
• DOE/Environmental Management Program in providing additional information to fill the gaps between
conventional analyses or to detect sudden unexpected
• DoD/Defense Threat Reduction Agency (DTRA)
changes between conventional sampling intervals.
As this technology matures, it may very well replace
Collaborators conventional techniques. 
• Ariane L. Martin, J. Michael Henson
Department of Biological Sciences, Life Sciences Facility,
Clemson University, Clemson, SC, USA.
• Sirivatch Shimpalee, John Weidner,
Pongsarun Satjaritanun, Blake A. Devivo
Department of Chemical Engineering and Computing,
University of South Carolina, 541 Main Street, Columbia,
SC, USA
• Scott Greenway
Savannah River Consulting, 301 Gateway Drive, Aiken, SC,
USA

www.researchoutreach.org 77
Biology ︱ Drs Cecilia Demergasso and Guillermo Chong
The acidic brine
lakes of Chile:
A surprising microbial community
The Andean salt flats of Chile are
well known for their vast natural
beauty. Interspersed within their
white salt-crusts, small lakes,
springs and creeks can be found
alongside the unique microbial
communities that inhabit them.
Drs Cecilia Demergasso and
Guillermo Chong along with a
multidisciplinary research team
from the Universidad Católica
del Norte of Chile, are currently
investigating the inhabitants
of the rare acidic brine lakes
found in Chile with the aim to
learn more about the extreme
microorganisms surviving in
these hostile environments
and how they contribute to
the complex local environment
through biogeochemical cycling.
T
he Andean salt flats are the
remnants of former saline lakes
of Neogene/Cuaternary age that
dried up along geological and recent
times. Originally and in different spans
of time, large bodies of water sat within
basins of the mountainous regions of the
Andes, before severe and cyclic climatic
changes gradually led to the evaporation
of water from these lakes exceeding the
rate of precipitation. Basins were originally
closed to store the lakes with no outlet to
drain and the evaporation caused them
to leave behind thick crusts of salt, and,
in several smaller cases, brine lakes mainly
fed by underground recharge from the
High Andes were also closed as the large
basins dried up.
WHY SO ACIDIC?
Typically, brines of salt lakes are neutral
or alkaline. However, in Chile, of the many
brines in salt lakes of the region, two
rarer acidic brine lake systems – Salares
Gorbea and Ignorado (Salar means salt
flat in Spanish) – have become the focus
of research for Demergasso and Chong’s
team. A large variety of hydrated minerals
found on Mars using spectrometry,
has been shown to potentially be
genetically linked to the volcanic activity
and the occurrence of acid sulphate
solutions like those observed in Gorbea.
The combination of both a highly saline
and acidic environment means that
only the toughest and most resilient
microorganisms can survive. The study
of the ability of the microorganisms that
inhabit and persist in this kind of saline
ecosystem has prompted researchers at
the terrain as a potential Mars analogue.
Demergasso and Chong’s research
hopes to shine a light on the diverse
microbial communities living within the
acidic brine lakes to further improve our
understanding of our planet’s unique
microbial diversity, which could have wide-
ranging implications on conservation and
potential applications in Biotechnology.
SALAR DE GORBEA
Acidic brine lakes have only been
studied outside of Chile in places like
Australia. Salar de Gorbea (the subject
of the Demergasso and Chong’s team
investigations) could provide a useful
site to compare differences in microbial
populations due to the contrasting
geological and environmental conditions.
The acidic brine lake is located in the
high Andes (4000m above sea level)
with a salinity of 28% – eight times
saltier than average sea water. Flanked
by the Cerro Bayo complex – a volcano
found on the Chile-Argentine border –
geochemical studies have suggested
that the local acidity of the lakes (pH
2 – 4) may have arisen due to several
reasons: the presence of volcanic native
sulphur; the oxidation of sulphur releasing
sulphuric acid, which seeped into the
lakes; and a change in the buffering
capacity of local rocks (the ability of
the rocks to help maintain and control
pH change in the system).

Demergasso and Chong were keen to

find out whether microorganisms (known
to play a relevant role in acid production
by using sulphur as their energy source),
such as the bacteria Acidithobacillus
thiooxidans, were contributing to the
acidity of the system as similar microbes
have been detected in other acidic
environments such as hot springs and
acid mine/rock drainage systems. To A THIOTROPHIC COMMUNITY salt to survive (halophilic) or can grow
do this, several sampling expeditions from Microorganisms are usually grouped under saline conditions (halotolerant)
five zones across the Salar de Gorbea together according to their metabolic predominate, but analysis of sediment
were carried out over a six-year period. activity which enables the basic and water samples were taken from
Sediments and brine samples collected

The combination of both a highly saline

in the 2009 and 2011 campaigns were
then selected for further analysis.

Microbiological analysis was firstly carried

out by extracting DNA from the brine
and sediments samples. Then the DNA
was subjected to Denaturing Gradient
Gel Electrophoresis (DGGE) – a technique
used in molecular microbial ecology
to separate out different fragments of
DNA – creating a fingerprint of a complex
microbial community living within the
samples. Recently, metagenomic analysis
have been performed and phylogenetic
analysis and bioinformatics tools were
then used to determine the species found
and characterize the functional content
of the genes discovered.
and acidic environment means that only
a specialized and resilient microbiota
can survive.
functions of life – growth, repair and
reproduction. Unlike us, who require
oxygen and energy from sugars to
survive, microorganisms can exploit a
range of other elements found in Nature
to sustain their activities, including
making their own energy sources from
inorganic compounds. Typically in
salty environments, such as salt lakes,
heterotrophic microbes that need
the Salar de Gorbea did not detect
any of these species, suggesting that
oligotrophy – organisms able to live in
an environment with very low nutrient
levels – is an important feature of
survival in such an extreme ecosystem.
Instead, Demergasso and Chong found
an unusual microbiota characterized
by living supported by the energy
of sulphur.

www.researchoutreach.org 79
A minor range of sulphur metabolising
bacteria was also detected from other
groups, including sequences related
to Alicyclobacillus, Sulfobacillus and
Leptospirillum – chemolithotrophic
microorganisms that produce energy
by oxidation of sulphur.
Based on the metagenome analysis
performed by Demergasso and Chong´s
team, many of the organisms described
were found to be potentially capable of
carbon fixation and sulphur oxidation.
Carbon fixation is a process whereby
inorganic carbon (such as carbon dioxide)
Above: Native sulphur at one of the active
solfataras in Lastarria Volcano.
80 www.researchoutreach.org
is converted to organic compounds,
perhaps the most well-known example
of organisms capable of carbon fixation
are plants, which convert CO2 into
sugars using photosynthesis exclusively
(autotrophs). Yet, in Demergasso and
Chong´s team studies, they found that
One of the most surprising findings was
the detection of an abundant Mycobacteria
population living in the acidic brine lakes.
carbon fixation capability appears to
be part of a mixotrophic model that
microbes in the acidic brine lakes exploit:
their primary production is through the
oxidation of reduced sulphur compounds,
which allows them to efficiently conserve
energy for fixing carbon if necessary.
Demergasso and Chong have discovered
a specialized microbiota supported by
volcanic sulphur in a salty environment
with low iron and organic matter content:
a thiotrophic community.
NON-TUBERCULOUS
MYCOBACTERIA
One of the most surprising findings
from the analysis was the detection of
Mycobacteria living in the acidic brine
lakes. The most well-known species
Mycobacterium tuberculosis and
Mycobacterium leprae have been well
studied due to the pathogenic role they
play in causing the diseases tuberculosis
and leprosy. Yet, there are many other
less well-known species that belong to
the genus, these are known as non-
tuberculous forms and are found in an
array of different ecosystems, including
engineered and natural water systems,
soils and even swamps. This is the first
time that Mycobacterium has been
found living in an acidic brine system
and given that they are representatives
of the discovered specialized microbiota,
Demergasso and Chong´s team hope to
analyze the genomes of the Mycobacteria
isolated from Salar de Gorbea to better
understand the reason of their abundance
in this system.
A MICROBIAL PLANET
Microorganisms inhabited the earth
long before animals and as such, their
ability to adapt and survive in a range of
different habitats has led to them being
the most abundant organisms on the
planet. Microorganisms involvement in
biogeochemical cycling makes them
important research subjects to help us
understand how ecosystems respond
to environmental change. By learning
more about the microbiota that can
survive in these extreme environments,
Demergasso and Chong´s team hope
that their data can be used to inform
conservation which respects and protects
our microbial planet.
 Behind the Research
Cecilia Susana Guillermo
Demergasso Chong Diaz
E: cdemerga@ucn.cl T: +56 553 55622 E: gchong@ucn.cl T: +56 55 2355745
W: www.ucn.cl W: www.cbar.cl W: www.ucn.cl W: www.cbar.cl

Research Objectives
Drs Cecilia Demergasso and Guillermo Chong Díaz research aims to characterise the microbiota of an acidic brine lake in Chile
to improve understanding of these complex environments.

Detail
Biotechnology Center, Universidad Católica del Norte
Avda Angamos 0610, 1240000 Antofagasta, Chile
Bio
Cecilia Susana Demergasso is the Director of the Center
of Biotechnology, Universidad Católica del Norte as well
as associate researcher in the Centro de Investigación
Científica y Tecnológica para la Minería. Cecilia conducts
research in i) Microbiology and their current project is
‘Microbial diversity in the saline domain in Northern Chile’
and in ii) Biotechnology, mainly in the biomining subject.
Guillermo Chong Diaz is a Chilean geologist and Professor
at the Universidad Católica del Norte at Antofagasta,
Northern Chile. The mineral chongite is named after
him. Guillermo’s main research interest is the “Saline
Domain” of Northern Chile including items like Climatic/
paleoclimatic evolution in Cenozoic times; salt flats and
its geomicrobiological environments; salt flats economic
settings including lithium/potash deposits and the unique
world around nitrate/iodine deposits.
Funding
• BHP Minerals Americas Project 32002137
• Fondecyt Project 1100795
Collaborators
• Lorena Escudero González
• Cinthya Tebes-Cayo
• Juan José Pueyo Mur
• Karen Gallardo
• Nia Oetiker
• Juan José Pueyo Mur
• Karen Gallardo
• Nia Oetiker
• Paulina Cortéz-Rivera
• Mayra Cortés Cabrera
• Alex Echeverría-Vega
• Roberto Véliz Cruz
References
L. Escudero, Noetiker, K Gallarado, et al. (2018). ‘A thiotrophic
microbial community in an acidic brine lake in Northern Chile’.
Antonie Van Leeuwenhoek; 111:1967.
Personal Response
How can an understanding of acidic brine lakes inform
conservation in the region?
Salars and saline lakes are extremely fragile
environments in the Andes framework. Over the last 20-30
years, they have been systematically exploded for their
industrial minerals (B, Li, K), but mostly for water extraction.
This situation, in some cases, compromises its conservation
and its flora, fauna and microbiota. However, there are
some existing evaporitic deposits that are practically intact,
like Salars with acid brines.
By using publications, describing Salars in terms of geology,
microbiota and other characteristics, directly emphasise
its importance as a landscape, its unique content in
microorganisms, and its biochemical potential as well
as its unique habitat worldwide. 
What effects do you think a changing climate
may have on the unique lake systems?
Salars and saline lakes ages are not measured in
historical time but in geological time. These deposits
have already suffered climate changes that can be
observed in the size diminution of the original saline
basin, paleocoasts, isolated terraces, and fossils of
organic structures (stromatolites), indicating a previous
development during a more humid climate. 

www.researchoutreach.org 81
 Biology ︱ Dr Peter Kevan
Secrets of the stalk:
Regulating plant temperature from the inside out
Have you ever questioned
the reasoning behind hollow
stems in some plants? When
we think about it there are
a surprising number of plants
with this feature. A common
misconception would be to
believe it is solely for nutrient
or water transport. In fact,
the reality has much more
to do with temperature
regulation. Dr Peter Kevan
from the University of Guelph
is one of the first in the field
to pursue an understanding
of this mechanism, in the hope
that it will provide economic,
environmental, and horticultural
benefits to both nature
and society.
maoyunping/Shutterstock.com
82 www.researchoutreach.org
T
he plant stem is a complex
structure, providing a transport
system, mechanical support,
and also the freshly explored function
of thermal regulation. To this day, the
physiology of the inside of stems has
rarely been examined with respect to heat
transfer, a process normally associated
with the leaves and flowers. In order
to fill this research gap, Dr Peter Kevan
from the University of Guelph is studying
differences in plant stem type, and how
effectively they regulate temperature.
This rather intriguing study, also known
as micrometeorology, is literally as the
name describes – studying ‘weather’
on a miniature scale. Factors that normally
Over half of the plant species collected
had hollow stems.
contribute to air temperature on a large
scale are simply applied to the inside
of a hollow stem. There are numerous
factors that can affect this, both biotic
(with respect to the plant), and abiotic
(the external conditions). Dr Kevan wanted
to examine a variety of different plant
species with different hollow stem traits
to understand the relationship between
climate and plant stem physiology.
LUMEN MICROMETEOROLOGY
The temperature inside the lumen
(hollow centre) of a stem is dependent
on the amount of solar radiation (energy
from the sun). When this hits the stem
wall, some is reflected, some absorbed
into the stem tissue itself, and some
transmitted through the stem wall into
the lumen. This is what maintains the
temperature of hollow stems through
energy absorption into the ambient gases
in the lumen – these circulate through
convection, conduction, and re-radiation.
This entire process has been referred
to as the ‘microgreenhouse effect’
as it is an exact replica of this on a tiny
scale inside the plant stem. Previously
this has been studied with reference
to flowers – an increase in temperature
encourages growth of the sexual organs,
which in turn helps the flower develop
quickly, and have a more prominent
presentation for enhanced attraction
of pollinators. This, however, is one of
the first times it has been considered with
respect to the stem and stem growth.
The lumen also loses energy through
emissivity to the outside air. Some energy
also becomes absorbed into the liquid
transport system, and is used up during
photosynthesis and plant metabolism
(growth). It’s clear that by understanding
these physical properties, Dr Kevan will
be able to decipher why particular traits
of a plant stem have evolved for certain
climactic conditions. For example, a
translucent stem may allow more energy
through; however, it may also mean much
is lost – a weak stem tends to droop,
so a compromise is required.
 Quality Stock Arts/Shutterstock.com
A PRELIMINARY STUDY
To start answering these
questions, Dr Kevan and his team
began collecting and examining
plants from across temperate
regions including Canada and
the UK. Primarily, over half of the plant
species collected had hollow stems,
even discounting those with a pith-filled
lumen. Of these, there was a large variety
in lumen diameter, stem wall width,
and stem wall texture.

Temperature probes were inserted into

the lumen and results compared with
the ambient air and presence of light.
Generally, in the presence of sunlight, the Slicing plant stems open reveals the hollow lumen inside. This lumen allows the plant to maintain
a distinct internal microclimate.
temperature in the lumen was above that
of the ambient air. In particular, the hollow
stem of a dandelion was up to 8°C higher temperature aids the success of a plant. organs) and increases the plant’s chance
than the ambient air in sunlight. However, Enzyme activity in the cells increases with of reproduction. Similarly, the stem
lumen temperature normally dropped temperature until a certain denaturation contains much of the fluid transport,
slightly below ambient when shaded. This threshold. Maintaining this increased including xylem and phloem tissues
certainly reinforces the theory that there activity is important for optimum growth, which move nutrients and water around
is a distinct microclimate within the stem with the hollow stem acting as a form the plant. A higher energy in this area
which changes dependent on abiotic of ‘thermos flask’ for the air inside. further improves these natural physical
and biotic conditions. and chemical processes.
Although not the primary point of
In Magadan, far northeastern Russia, photosynthesis, the stem is the primary It is also possible that having the
studies on oat, dandelion, thistle and growth point of the plant with respect previously mentioned ‘microgreenhouse’
sneezewort plants displayed the same to height, so ensuring a high metabolic effect, can protect the plants from
trend of hot stems, from 1˚C to 7˚C, rate here encourages improved temperature shock, or changes in
depending on species, location, weather presentation of sporophylls (sexual temperature over time. Dr Kevan’s study
and other factors. This large temperature
difference could go some way to suggest
a high metabolic rate, high growth
and also high tolerance – often seen in
weed species. Pubescent (hairy) stems,
were also recorded as having a higher
temperature. Hairs on the stem trap
a layer of air acting as insulation. But why
is it important to maintain an increased
stem microclimate?

BENEFITS OF STAYING WARM

Many plants in temperate climates, including the
There have certainly been many studies daffodil, have hollow lumens.
to show that keeping a high enough

www.researchoutreach.org 83
Kasabutskaya Nataliya/Shutterstock.com
Milk thistle grows in Europe and Southern Russia.
Tatyana Mi/Shutterstock.com
Flowers of the sneezewort,
one of the plants collected by Dr Kevan.
sites ranged across Canada and the
northern UK, two geographic regions
prone to seasonal weather changes.
This research reinforces the theory that
there is a distinct microclimate within
the stem which changes dependent
on abiotic and biotic conditions.
The high number of hollow stems found
in these plants may reflect an adaptation
geared towards surviving in these
conditions.
PLANTING THE SEED
It is surprising that something seemingly
so important has been academically
neglected until now when one begins
to think of the economic and agricultural
benefits of this research. As soon as
we understand the physical properties
for improved plant fitness, we can
begin to genetically examine these
traits. With this knowledge, we can
use basic gene-editing techniques to
greatly improve plant strength, yield,
and resilience. Could the creation of a
‘microgreenhouse’ inside every plant
put an end to actual greenhouses (which
require far more resources and produce
84 www.researchoutreach.org
Quality Stock Arts/Shutterstock.com
When sunlight hits leaves, it is used for photosynthesis. However, the warmth from
sunlight also contributes to the microclimate within the stem.
waste)? Perhaps we could double the
yield of certain crops, or grow plants
where previously the land was deemed
unsuitable. Ornamental flower growers
and horticulturalists benefit from
increased knowledge about regulating
plant growth, as flowering, seed setting,
floral and seed presentation all require
growth and development of plants that is
stimulated by heat. Thus, understanding
the micrometeorology within plant stems
and other plant organs is an area of
study that will greatly contribute to the
viability and marketability of ornamental
and crop plants.
Dr Kevan’s research plants the seed
for a whole new avenue of research,
stemming from thermodynamics, all
the way through to genetic engineering
and agriculture. These traits could
also be harnessed by horticultural
specialists to grow more resilient plants
for recreational/ornamental use.
THE NEXT STUDY
In order to further this work and
present these ideas to the next
generation of researchers, Dr Kevan
is about to embark on a new multi-
year study looking into hollow stem
physiology in much more detail.
This study will include a detailed
database of horticulturally important
plants, recording their anatomical
and microscopic morphologies. The
microscopic focus will hopefully shed
light on some of the important cellular
and physical structures which dictate
the heat transfer properties of the
plant stem.
The investigation will examine the
microclimate inside the stems of these
plants, and how that relates to their
particular morphologies. The outcomes
of these observations will then be used
to create, and systematically refine,
biophysical mathematical models. These
will be able to simulate how various stem
types manage heat transfer, allowing
scientists to project the morphologies
of ‘optimum plants’ for a specific
geography, climate, and purpose. This
knowledge will go a long way to help
improve commercial and recreational/
ornamental plant production worldwide.
 Behind the Research
Dr Peter Kevan
E: pkevan@uoguelph.ca T: +1 519 824 4120 Ext: 52479 W: www.uoguelph.ca/~cabrnet/Peter%20
G%20Kevan.html W: https://www.uoguelph.ca/ses/people/peter-kevan

Research Objectives References

Kevan, P.G., Nunes-Silva, P. & Sudarsan, R. Int J Biometeorol
Dr Peter Kevan’s research examines how plant stems help
regulate temperature. (2018) 62: 2057. https://doi.org/10.1007/s00484-018-1602-7

Kevan, P. G., E. A. Tikhmenev and P. Nunes-Silva 2019

Detail Temperatures within flowers and stems: Possible roles in plant

reproduction in the north. Vestnik of the Far-Eastern Science
(Prof) Peter G Kevan, PhD Centre DVO RAN No. 1;  pp 38 - 47.
University of Guelph
50 Stone Road East
Guelph, Ontario, N1G 2W1
Canada

Bio
Peter G. Kevan was Scientific Director at the Canadian
Personal Response
Pollination Initiative Strategic Network and is University
Professor Emeritus at the School of Environmental Sciences, In your opinion, what is the most exciting aspect
of this research?
University of Guelph. He has published over 200 peer-
reviewed papers, book chapters, encyclopaedia entries The most exciting aspect of this research is the
and many popular articles. He is a Fellow of the Royal Society novelty of the phenomenon, the fact that no one seems
of Canada. to have investigated it before, and its likely importance
in understanding the rapidity of plant growth to both
basic and applied plant science.
Funding
COHA, NSERC, Russian Academy of Sciences

Collaborators
• Dr Patrícia Nunes-Silva
• Research associate: Charlotte Coates
• Dr Rangarajan Sudarsan
• E. A. Tikhmenev

rvika/Shutterstock.com

www.researchoutreach.org 85
Biology ︱ Carolyn Sieg
Are wildfires
following bark
beetles more severe?
Bark beetles are responsible for
large numbers of dead trees in
ponderosa pine forests in the
United States. The relationship
between tree mortality caused
by bark beetles and increasingly
severe wildfires has been
analysed by Carolyn Sieg and
colleagues using a detailed
physics-based fire behaviour
model. The team seeks to
understand if fires that follow
beetles are more severe, that is
if they leave less green foliage,
or if the tiny beetles could have
more complex interactions
with subsequent wildfires than
previously understood.
Bark beetles (Ips species).
86 www.researchoutreach.org
T
hroughout western North America,
native bark beetles (Dendroctonus,
Ips spp.) are thriving. Unfortunately,
their success contributes to widespread
tree mortality. The impact of tree
mortality caused by bark beetles is one
of the many factors which are studied to
better understand the causes of severe
wildfire in ponderosa pine forests in the
USA. Whether extensive tree mortality
caused by bark beetles causes more
severe fires to occur has been debated
among scientists and conflicting results
have led to lots of confusion in the press.
Research by Carolyn Sieg, of the USDA
Forest Service, and her team presents a
new method of analysing the complex
interplay of factors involved in forest
fires. The team uses a physics-based
fire model developed by Rod
Linn of the Los Alamos National
Laboratory in collaboration with
the Rocky Mountain Research
Station, to explore how fires burn
in bark beetle-impacted forests.
Their work contributes towards
scientific understanding of the
relationship between tree
mortality caused by the tiny
bark beetles and the severity
of subsequent wildfires.
Forest wildfires can kill large swaths of
trees and are notoriously difficult to
predict, control and prevent. There are
many factors which affect fire severity of
fires burning through trees killed by bark
beetles. These factors include forest type,
amount and stage of tree mortality, and
weather conditions. Due to the complexity
of the interplay of so many factors, it
would be virtually impossible to replicate
the conditions for forest fires in order to
analyse a single variable in an experimental
scenario. Consequently, computer based
simulations can be a useful tool for
researchers to study forest fires.
COMPUTER MODELS PREDICTING
FOREST FIRE BEHAVIOUR
Carolyn Sieg currently works as a research
ecologist with the USDA Forest Service
Rocky Mountain Research Station and has
studied the effects of wildfires for many
years. To conduct her latest research,
Sieg managed a team of people with
diverse research backgrounds to maximise
the benefit of shared knowledge and
experience. The combination of skills has
allowed for the application of a physics-
based model to predict fire behaviour.
The multidisciplinary team of
 FIRE BEHAVIOUR SIMULATIONS
researchers was led by Sieg to explore the
relationship between forest fires and bark No mortality 20% mortality
beetles. The team included researchers
from national laboratories in the U.S. (Rod
Linn of Los Alamos National Laboratory)
and France (Francois Pimont of Ecologie
des Forêts Méditerranéennes), universities
(Chad Hoffman of Colorado State
University), plus other Forest Service
staff (Joel McMillin of Idaho and L. Scott
58% mortality 100% mortality
Baggett of Colorado).

Research for the project was conducted

in the USA where forest fires occur
frequently, and their severity in some
forest types continues to grow. As it would
be unrealistic to the complexity of the Fire behaviour simulations: field data was used to create analogous forest. 4 levels of fire mortality
issue to eliminate too many factors, the were simulated.
research team was keen to use computer
modelling software to analyse and predict Research by Carolyn Sieg, of the USDA
Forest Service, and her team, presents
patterns in data, thus allowing them
to acknowledge the numerous factors
at play. Though studying the factors
a new method of analysing the complex
interplay of factors involved in forest fires.
independently is important, the physics-
based model used by the team allowed
for even more of the complex relationships
between factors to be considered. contribute to amplification or dampening beetles had caused moderate levels of
of forest fire severity. Other simulations tree death resulting in large quantities
RUNNING THE SIMULATIONS showed the presence of bark beetles of needles that had already fallen to the
The team used three-dimensional had no significant effect. ground, then any subsequent fire was less
physics-based modelling software to severe under these same wind conditions.
build large virtual forests based on actual One of the factors which played an
field data. The team gathered extensive important role in the analysis of the model IMPROVING FIRE MANAGEMENT
field data about forest characteristics data was wind speed. At low or medium AND PUBLIC UNDERSTANDING
in a ponderosa pine forest with varying wind speeds the fire severity was greater OF BARK BEETLES
levels of tree mortality caused by bark if bark beetles had already caused some There are wide ranging consequences
beetles. They then used the data to create level of tree death, but the pine needles of this research. Broadly, any action which
a virtual forest where they could explore remained on the trees. In contrast, if bark can be taken to better understand forest
fire behaviour and severity at different
stages of mortality, with different levels
of mortality, and under different wind Ponderosa pine forest, post-fire.
levels. When bark beetles attack a tree Linda Wadleigh (left) and Mary Lata (right), from
the USFS, carrying out post-fire measurements.
it causes the needles to change in colour
from green to red due to the loss in fuel
moisture. In the next stage, the needles
fall to the ground, which decreases
the amount of fuel in the tree canopies
and increases the amount of fuel on the
ground. The wind speed effects the ability
of a fire to bridge gaps in the tree canopy.
The influence of all these changes in fuel
moistures, fuel loadings, and wind speed
on how fires burn can be captured in their
physics-based model.

The model simulations showed a range

of results. Some simulations showed
that the presence of bark beetles can

www.researchoutreach.org 87
 Ponderosa pine trees, with many dying due
to bark beetle kill. But does this set forests
up for more risk from fire?
rk beetle activity on >1.2 million
trees in Arizona during 2002
Bark Beetle Activity in
Ponderosa Pine and Pinyon Pine
(2003 Aerial Detection Survey)
National Forest Boundary
Reservation Boundary
Pinyon Pine Bark Beetle Activity
Ponderosa Pine Bark Beetle Activity
Pinyon Pine Range
Ponderosa Pine Range
Area affected by bark beetle activity in
ponderosa and pinyon pine trees in Arizona.
Courtesy of USFS.
fires is important progress and will
benefit land managers. Forest fires in
pine forests are particularly difficult
to predict due to the many factors
which can affect their spread and their
severity. The activity of the bark beetle
is just one of the exacerbating factors
which may lead to the effects of the fire
being intensified.
More specifically, the research by
Sieg and her team is important to
the scientific community as it helps
to clarify some of the confusion
88 www.researchoutreach.org
This research emphasises the complexity
of forest fire analysis and highlights
the reality that one factor should
not be attributed undue weight.
3
concerning the role of the bark beetle
on fire behaviour. Not only did the
study reveal that the influence of bark
beetle-induced mortality depended on
the stage and amount of tree mortality,
but it revealed that unexpected high
fire severity can occur at low wind
speeds and in forests with only a small
amount of mortality. Also of interest to
land managers, the simulations suggest
that bark beetle-induced tree mortality
may actually decrease fire severity of
remaining trees when the dead needles
have fallen to the ground.
Ultimately, the team has developed
model simulations which highlight
the complex interactions between
the influence of tree mortality caused
by bark beetles and any subsequent
fires. With the help of their research
it becomes clear why current reporting,
and research, can often appear
confused or conflicting. The impact
of tree mortality induced by bark
beetles does not appear to be a simple
calculation and the models developed
by this team of researchers will continue
to be used to provide novel insights
into the behaviour of wildfires.
Most importantly, this research
emphasises the complexity of forest
fire analysis and highlights the
reality that one factor should not
be attributed undue weight. The
complex interplay of factors which
produce forest fires will continue to
be studied for many years to come,
with the tools for analysis provided
by Sieg and her team a useful addition
to the resources available.
 Behind the Research
Carolyn Sieg
E: csieg@fs.fed.us T: +1 928-380-5422
Joel McMillin L. Scott Baggett
Research Objectives
Carolyn Sieg’s research aims to understand how to
better manage forests impacted by severe wildfires,
whether beetle-infested areas present serious fire
threats, and strategies for lessening the impact of exotic
invasive species.
Detail
USDA Forest Service
Rocky Mountain Research Station
2500 S. Pine Knoll Dr.
Flagstaff, AZ 86001 USA
Bio
Carolyn Sieg is a research ecologist with the USDA Forest
Service Rocky Mountain Research Station, where she studies
the role of changing disturbance regimes in forests and
woodlands in the Intermountain West, USA. Her research
aims to quantify the effects of wildfires and their interaction
with other disturbances such as bark beetles.
Funding
USDA Forest Service (FS) Research Rocky Mountain
Research Station and Washington Office National Fire
Plan, USDA FS Forest Health Monitoring, and Los Alamos
National Laboratory’s Institutional Computing Program
provided computational resources.
Collaborators
• Rod Linn
• Chad Hoffman
• Francois Pimont
• Joel McMillin, and L. Scott Baggett
Rod Linn Chad Hoffman
Judy Winterkemp Francois Pimont
References
Sieg, C.H., Linn, R.R., Pimont, F., Hoffman, C.M., McMillin,
J.D., Winterkamp, J. and Baggett, L.S., (2017). Fires
following bark beetles: Factors controlling severity and
disturbance interactions in ponderosa pine. Fire Ecology,
13(3), pp.1-23.
Hoffman, C.M., Linn, R., Parsons, R., Sieg, C. and
Winterkamp, J., (2015). Modeling spatial and temporal
dynamics of wind flow and potential fire behavior following
a mountain pine beetle outbreak in a lodgepole pine
forest. Agricultural and Forest Meteorology, 204, pp.79-93.
Hoffman, C.M., Sieg, C.H., Morgan, P., Mell, W.R., Linn, R.,
Stevens-Rumann, C., McMillin, J., Parsons, R. and Maffei,
H., (2013). Progress in understanding bark beetle effects on
fire behavior using physics-based models. Technical Brief
CFRI-TB-1301. Fort Collins, CO: Colorado State University,
Colorado Forest Restoration Institute. pp.10.
Linn, R.R., Sieg, C.H., Hoffman, C.M., Winterkamp, J.L.
and McMillin, J.D., (2013). Modeling wind fields and fire
propagation following bark beetle outbreaks in spatially-
heterogeneous pinyon-juniper woodland fuel complexes.
Agricultural and Forest Meteorology, 173, pp.139-153.
Personal Response
Which of the potential benefits of your research has
been the biggest source of motivation throughout
this project?
Using the physics-based model has allowed us to
understand how spatial variations in forest fuels interact
with the fire and wind flow. We gained insights that
could not be captured in simpler models that cannot
account for how changes in fuel moisture, amounts, and
arrangements influence fire-wind interactions following
bark beetle-induced tree mortality.
www.researchoutreach.org 89
 Biology ︱ Dr Eugenii (Ilan) Rabiner

Advances in CNS
drug development
The global prevalence of
diseases affecting the central
nervous system (CNS) demands
the development of efficacious
therapies for these unmet needs.
However, drug development
for CNS diseases is complicated
by a limited ability to measure
whether a drug candidate
is accessing and affecting the
human brain, particularly in early-
stage human trials. Research
by Dr Eugenii (Ilan) Rabiner
and his colleagues: Dr Roger
Gunn and Dr Jan Passchier
at Invicro, highlights the unique
capacity for translational
imaging technologies, such
as PET and MRI scanning,
to provide this information.
These advances in early-stage
drug development have
the potential to dramatically
reduce the costs of developing
a drug and help deliver effective
new medications.
Andrii Vodolazhskyi/Shutterstock.com
O
ver one billion people suffer
from diseases of the central
nervous system (CNS) globally.
Whilst pharmaceutical treatments for
many diseases have made huge strides
in the past decades, the development
of pharmaceuticals for diseases of the
CNS has been relatively stunted. This is,
in part, because of our limited ability to
determine how effective pharmaceutical
compounds are in the early stages
of drug development. Instead, millions
of dollars are spent researching and
testing compounds that are found to be
ineffective during late-stage where large-
scale human trials are long and expensive.
Translational imaging methods such as
Positron Emission Tomography (PET)
and Magnetic Resonance Imaging (MRI)
are non-invasive technologies capable
of providing direct and quantitative data
on drug distribution, drug interaction
with its intended target and the resulting
drug efficacy in the human body. Such
information can be used to stop the
development of compounds that
will not be successful and define the
dose range for testing of promising
compounds in later phase clinical trials.
This allows resources to be concentrated
on developing only the most promising
pharmaceutical compounds, thereby
reducing the size and cost of later phase
drug development. Dr Eugenii Rabiner
at Invicro, London with Dr Roger Gunn
and Dr Jan Passchier have focused
their research on such translational
imaging technologies to advance drug
development for CNS disorders.

90 www.researchoutreach.org
DRUG DEVELOPMENT PROCESS
The development of pharmaceutical
drugs is a long and costly process,
spanning nearly a decade and costing
over $2 billion for each new drug
brought to market. Numerous stages
of testing must be performed before
it may be deemed safe and effective
for use in patients.

Firstly, a specific molecular target

within the body is identified and many
compounds are screened for appropriate
properties to allow interaction with this
target. If this yields a promising lead
compound, a library of analogues is
created and screened to determine
the most effective. The identified
candidate compounds initially undergo
in vitro and in vivo preclinical testing
Study volunteer undergoing
to understand if they might be effective a brain PET scan.
and whether any toxicity issues manifest
themselves. In vitro testing will typically
make use of isolated cells and tissues, that can be obtained in early phase Substitution of a carbon or a fluorine
while in vivo testing will be performed development to significantly enhance atom in a candidate compound with
in animal models. Whilst the use of the probability of drug candidate success. a positron emitting isotope ( 11C or 18F)
animals in drug testing is controversial, The Three Pillars are (1) evidence of tissue does not change its pharmacological
it remains a necessary step in the process exposure (the extent to which the drug or physicochemical properties and allows
of drug development. Efforts to reduce penetrates the target tissue of interest), (2) the visualisation of the compound’s
animal testing (the so-called 3Rs – evidence of molecular target engagement distribution in the body. The absolute
Replace, Reduce, Refine) benefit from (the extent to which the drug interacts concentration of the drug in body tissues,
access to non-invasive imaging methods, with the biological target) and (3) such as the brain, can be quantified
as they allow repeated testing in a smaller
number of subjects, and provide more The richness of information from
occupancy studies also allows estimates
physiologically relevant data.

If the candidate compound is found

to be effective and no unacceptable
safety signals are seen, it may then
be trialled in humans. Human trials have
4 phases designed to demonstrate
the safety and efficacy of new
medications, with each phase growing
in size, resource intensity, and cost.
Phase III studies can cost hundreds
of millions of dollars and all too often
provide the stage for candidate failure.
There is, therefore, a desperate need
to improve the characterisation of drug
candidates in early Phase I and II clinical
trials to increase the probability of
success when progressing them to long
and expensive Phase III studies.
THE THREE PILLARS
OF DRUG DEVELOPMENT
The Three Pillars approach has been
formulated to define the information
to be made [that are] typically not
possible until later phase human trials.
evidence of pharmacological activity
(the ability of the drug to modulate
its molecular target and subsequent
pathways).
Whilst many drug effects can
be monitored by measuring drug
concentration in blood, monitoring
the effects of CNS drugs is more difficult
due to the presence of the blood-brain
barrier that prevents many drugs from
entering the brain. PET imaging is
uniquely placed to be able to monitor
drug tissue distribution and target
engagement, and can provide useful
information on drug pharmacological
activity in combination with a variety
of MRI techniques.
accurately and compared to that
measured in plasma to understand
its tissue distribution.
A radio-labelled tool compound,
or radio-ligand, that is specific for a
molecular target, allows quantification
of the density of that molecular target.
Comparing the density of the available
target (such as a particular receptor or
an enzyme) in the brain at baseline with
that following the administration of a dose
of the candidate drug allows calculation
of the proportion of the total target that is
occupied by a particular dose of the drug.
This information enables confirmation of
drug-target engagement. This approach
often termed an “occupancy study”,

www.researchoutreach.org 91
is preferred to the drug distribution
study described above, as it allows
the quantitative evaluation of drug target
engagement in addition to brain entry.
The rich information obtainable from
such a study enables the prediction
of the levels of target engagement
produced by repeat dose studies in
patients in later phases of development.
The use of appropriate experimental
design and analysis methods mean
that such information can be available
following a first in human, single
ascending dose study in Phase I.

The performance of an “occupancy Examples of PET occupancy data demonstrating target engagement by CNS active compounds.
study” requires the availability of
a specific radio-ligand for the particular
molecular target. Unless already
available (true for around 40 CNS
targets), a new radio-ligand has to be
developed, a complex process that
requires 12 months or longer, and
one that should be planned early in
the course of a drug development
programme. The introduction of in silico
biomathematical modelling in recent
years has accelerated the process of
biomarker development by optimising
the choice of candidate molecules
from a starting series to develop
the novel radio-ligand.

Techniques such as blood oxygen level

dependent (BOLD) and arterial spin
labelling (ASL) functional Magnetic
Resonance Imaging (fMRI) can provide
non-invasive information on the
changes in brain activity following drug
administration. fMRI can be combined
fruitfully with PET to provide information
on both target engagement and resulting
pharmacological modulation by the drug
in the same study.
Alternative imaging avenues to evaluate
target modulation or downstream
effects include measuring the change
in the density of a protein involved
with disease progression (such as
the misfolded proteins β-amyloid
or τ-protein characteristically found
aggregated in the brain of Alzheimer’s
patients). Other approaches include the
Imaging modalities and applications across the drug development pipeline.
Applications of PET and MRI technologies in drug development
measurement of the direct or indirect the determination of the relationship
(downstream) effect of drug candidates between the dose administered and
on the proliferation of brain immune cells, the resulting pharmacological effects.
microglia, as a sign of brain inflammation,
or on changes in the release of Dr Eugenii Rabiner and Dr Roger
neurotransmitter molecules such as Gunn’s 2017 paper describes the
dopamine and serotonin across synapses current state of the art in the application
(the gaps between brain cells) to indicate of translational imaging in support
changes in brain function. Detection of CNS drug development. With a
of target modulation or downstream growing number of biomarkers being
effects provides confidence that the developed, the amount of information
novel compound is pharmacologically that occupancy studies and PET imaging
active – and in combination with data can provide will rapidly expand. This
acquired in an occupancy study can allow has a huge significance in accelerating
the field of CNS drug development,

PET imaging is uniquely capable reducing the money and resources spent

researching ineffective pharmaceutical
of quantifying each of the three pillars compounds, and concentrating
efforts to develop effective treatments
of CNS drug development. for CNS diseases.

92 www.researchoutreach.org
 Behind the Research
Dr Eugenii (Ilan) Rabiner
E: ilan.rabiner@invicro.co.uk T: +44 7717801552 W: www.invicro.com/
www.linkedin.com/in/eugenii-a-ilan-rabiner-a953866/

Research Objectives References

Dr Rabiner’s research focuses on molecular and functional Ereshefsky, L., Evans, R., Sood, R., Williamson, D., English, B.
imaging to understand brain pathophysiology and facilitate A. (2015). Venturing into a new era of CNS drug development
drug development. to improve success. Available at: https://www.parexel.com/
files/4314/4113/4032/Venturing_Into_a_New_Era_of_CNS_
Drug_Development_to_Improve_Success.pdf [Accessed
Detail 07/02/2019].
Gunn, R.N. and Rabiner, E.A., (2017). Imaging in central
Invicro, Burlington Danes Building, nervous system drug discovery. Seminars in nuclear
Hammersmith Hospital, Du Cane Road, medicine. 47(1), 89-98.
London,
W12 0NN
UK
Personal Response
Bio
Dr Rabiner trained at the University of the Witwatersrand, With such advances, how much of a reduction
the University of Cape Town and the MRC Cyclotron in the time and money spent developing drugs
for CNS diseases can be expected?
Unit, Hammersmith Hospital, London. From 2001-2011,
he was the Head of Clinical Imaging Applications at The intelligent use of translational biomarkers will
GlaxoSmithKline Clinical Imaging Centre, London. He is accelerate the process of drug development by allowing
now the Executive VP and Global Head of Translational a better choice of doses to be tested in clinical trials. That
may lead to a saving of one to two years in the life of a drug.
Applications at Invicro.
However, the main benefit of these technologies is not
in accelerating the development of individual compounds,
Collaborators but by allowing us to discard unsuccessful compounds
• Roger N Gunn, Invicro very early in the development process and reallocate
• Jan Passchier, Invicro the resources to more promising candidates – thus
increasing the total number of drugs being developed.

Andrii Vodolazhskyi/Shutterstock.com

www.researchoutreach.org 93
 Biology ︱ Drs Nancy Bonini and Leeanne McGurk
Fruit flies help shed light
on drug discovery for ALS
Amyotrophic lateral sclerosis
(ALS) is a devastating and
incurable neurodegenerative
disease that affects people in
adulthood. It leads to the death
of neurons involved in muscle
control, eventually affecting
almost all facets of the body,
including walking, swallowing
and breathing. Drs Nancy Bonini
and Leeanne McGurk at the
University of Pennsylvania are
using fruit flies, mammalian
cellular systems like neurons,
and in vitro protein preparations
to investigate promising new
molecules that could open
avenues to new treatments
for this devastating condition.
nechaevkon/Shutterstock.com
94 www.researchoutreach.org
A
myotrophic lateral sclerosis (ALS)
– also known as motor neuron(e)
disease – is a severe and incurable
disease that has a devastating effect on
the quality of life of people living with
the condition as well as their carers and
families. ALS most resonates with the
general public in relation to high-profile
personalities who have experienced the
condition, including American baseball
player Lou Gehrig – hence, the disorder
is sometimes referred to as Lou Gehrig’s
disease – and world-renowned British
physicist, Stephen Hawking.
The first signs and symptoms of ALS
might include tripping, leg weakness and
difficulty controlling hand movements, or,
what people might first dismiss as simple
clumsiness. Diagnosis is usually aided by
imaging and scanning techniques that can
rule out other causes of nerve damage
and lack of motor control, including brain
tumours and neuropathy. Over time,
symptoms of ALS gradually become
worse and affect almost all areas of the
body causing muscle weakness, stiffness
and paralysis. As the disease advances,
people living with ALS find their breathing
becomes more difficult and eating
becomes impossible as muscles associated
with swallowing are affected. Almost
all people with ALS will eventually find
their ability to speak frustratingly difficult,
leading some to rely on technology to
communicate – with early versions
of this technology perhaps best
represented by Stephen Hawking’s
infamous computerised voice.
The most common cause of
death for people with ALS is
respiratory failure as the disease
interferes with patients’ ability to
breathe or cough. Many people
with ALS die within two to five years
of their diagnosis with many still
in middle age.
Risk factors are not well understood but
include older age, with most people
diagnosed in middle to older adulthood.
A small proportion of cases are inherited
and run in families, whilst most cases are
apparently sporadic in nature. Although
several genes have been linked to ALS,
no one gene that has been discovered
can account fully for the disease.
The urgent need for more research into
ALS has gained awareness after high-
profile campaigning by advocacy and
patient groups. A very successful ‘Ice
Bucket Challenge’ online campaign
firmly cemented ALS in the public
conscientiousness in the past years and
raised over $100 million to support vital
research and services for the people living
with the disease.
Despite increased awareness and funding
for the condition, there is a paucity of
effective treatments available for people
living with the condition. After decades of
research, there are currently no cures for
people living with ALS. Existing treatments
are limited and can help patients manage
some symptoms of the condition but only
extend life by up to three months. Clinical
trials for desperately-needed treatments
are few and far between and relatively little
is known about the molecular processes
that are responsible for its widespread
effects on the central nervous system.
PROMISING NEW HORIZONS
Dr Leeanne McGurk, a postdoctoral
researcher is based in Dr Nancy Bonini’s
laboratory at the Department of Biology
at the University of Pennsylvania, has
committed her working life thus far to
understanding more about the molecular
mechanisms underlying ALS in the hope
of uncovering new avenues in the quest
for successful drug treatments. Together,
McGurk and Bonini have made important
strides to pinpoint molecules that could
 In healthy individuals, TDP-43 is in the
nucleus, in ALS and related disorders,
TDP-43 leaves the nucleus and
accumulates in the cytoplasm.
help tackle some of the processes
that go awry in the condition. As part
of their research tool kit, Drs McGurk
and Bonini have made some of their most
fundamental discoveries using a small
but powerful model of neurodegenerative
disease – common fruit flies. They extend
their findings from the tiny fly to other
systems and approaches in studies with
their team of collaborators.
FRUIT FLIES TO MODEL ALS
Drosophila melanogaster – more
commonly known as fruit flies – are
surprisingly more similar to humans than
they may first appear and have been
used in scientific studies of disease for
over 100 years. Fruit flies share
many of the genes that are seen
in humans and display more
complex behaviours than may
be expected, from movement to
social interactions. The fact that
fruit flies have a smaller genome
than other laboratory animals, such as
mice, means that their DNA can be studied
more easily than mammals. Their shorter
life spans that can be measured in days
rather than months make it easier, quicker
and less expensive for researchers to track
disease-related changes that occur over a
Healthy
Healthy rodent nerve cells can be grown in a dish (left panel). Nerve cells, infected with a virus engineered to make TDP-43 protein, mimic disease by showing
neural loss (middle panel). McGurk and Bonini found that treating the nerve cells with an inhibitor to PARP-1/2 reduces the nerve cell loss caused by expression
of TDP-43. This figure was previously published in L. McGurk, et al. “Nuclear Poly(ADP-Ribose) Activity Is a Therapeutic Target in Amyotrophic Lateral
Sclerosis.” (2018). Acta Neuropathologica Communications, BioMed Central, 6:84, and is under the Creative Commons Licence CC BY 4.0.
lifetime. A number of molecules have been
tested in these tiny creatures, some have
even ended up in clinical trials for a range
of diseases.
TDP-43 – A VITAL INSIGHT INTO ALS
Many patients with ALS show cells that
have a build-up of a protein known as
TDP-43. In healthy human cells, this
protein is contained in the heart of the
cell, known as the nucleus. However, in
ALS, TDP-43 seeps out of this cell core
and accumulates in clumps elsewhere in
the cell. Protein clumping is seen in other
neurodegenerative diseases, including
Alzheimer’s disease, characterised by
clumping of proteins known as amyloid
After decades of research,
there are currently no cures
for people living with ALS.
and tau, and frontotemporal degeneration,
which also involves the TDP-43 protein
in approximately half of all cases.
As an early postdoctoral researcher, Dr
McGurk, as well as other members of the
Bonini lab, modelled ALS in fruit flies by
TDP-43
Rat spinal cord cultures
In cells undergoing a stress response,
TDP-43 accumulates in the cytoplasm.
McGurk and Bonini found that under stress,
disease-like TDP-43 accumulations form
near structures called stress granules.
Photo credit: Dr Leeanne McGurk.
manipulating cells in the nervous system to
express human TDP-43. Flies expressing
this human protein showed both
neurodegeneration and a shortened life
span, similar to features reflective of ALS.
This advance was a vital milestone
as it offered the team a model for
efficiently studying ALS on the
molecular level. Further studies
with fruit flies shed light on the
behaviour of TDP-43, focusing
on protein clumping, TDP-43
transportation throughout the cell and the
response of the protein in conditions of
stress, such as that seen in the disease.
TDP-43 TARGETED THERAPIES
In exciting follow-up experiments, Bonini
and McGurk’s team found that the damage
TDP-43 + PARP inhibitor
= nucleus = nerve cells
www.researchoutreach.org 95
Several well-known individuals have lived with
and died of ALS, including the baseball player
Lou Gehrig and the physicist Stephen Hawking.
caused by expressing TDP-43 in the fly can
be rescued. They discovered that reducing
levels of an enzyme known as PARP-5
meant that the flies expressing TDP-43
stopped the early death. The researchers
believe that PARP enzymes could be key to
understanding why proteins accumulate in
the cell cytoplasm outside of the nucleus
and further, could shed light on ways to
reduce the build-up of TDP-43 in this part
of the cell.
When McGurk and Bonini investigated this
with their collaborators in human spinal
cord cells, they found that PAR – a chain of
molecules tagged on to target proteins by
PARP and controls the toxicity of TDP-43
– were found in high levels in the nucleus
of motor nerve cells. This suggested that
levels of PARP activity in the human spinal
cord were elevated in the presence of ALS.
Together, McGurk and Bonini have made
important strides to pinpoint molecules
that could help tackle some of the
processes that go awry in the condition.
In ALS patients, McGurk Healthy
and Bonini saw high levels
of PAR in the nucleus (arrow)
of the nerve cells that
degenerate in ALS. This
suggests that the enzymes
that make PAR are active
in these cells in disease.
This figure was previously
published in L. McGurk, et al.
“Nuclear Poly(ADP-Ribose)
Activity Is a Therapeutic
Target in Amyotrophic
Lateral Sclerosis.” (2018)
and is under the Creative
Commons Licence CC BY 4.0.
Patient motor neurons
96 www.researchoutreach.org
The ALS ice bucket challenge
was an internet phenomenon,
raising over 100 million US
dollars for resources and
research into ALS.
To test this theory further, the researchers
tested a drug to reduce activity of
PARP-1/2 in a rat nerve cell model of ALS
expressing human TDP-43. Promisingly,
the drug – originally developed as a cancer
treatment – was shown to reduce neural
death caused by TDP-43. The findings
ALS
Marcos Mesa Sam Wordley/Shutterstock.com
suggest that PARP enzymes could be
a vital target for investigating new drug
treatments in diseases linked to
TDP-43 clumping.
FUTURE STEPS
There is still much to learn about PARP
enzymes before they could be used to
treat ALS patients, including how the
subtypes of PARP enzymes work together
and how they affect the transport of
TDP-43 throughout the cell. However,
these findings shed light on the molecular
mechanisms underlying the disease and
are a beacon of hope in a drug discovery
landscape blighted by a drought of
advances in recent years. The findings
could also shed light on treatments for
disorders that share some of the same
molecular characteristics, including
frontotemporal degeneration. Whilst
there is some way to go before it can
be determined whether PARP-based
therapies could work for ALS, scientists
such as Drs McGurk and Bonini continue
to strive towards understanding ALS at
the molecular level, offering hope to those
living with this devastating condition.
 Behind the Research
Dr Nancy Bonini
E: nbonini@sas.upenn.edu T: +1 215 573 9267
W: www.bio.upenn.edu/people/nancy-bonini
W: http://web.sas.upenn.edu/bonini-lab/
Research Objectives
Drs Nancy Bonini and Leeanne McGurk are using fruit flies, mammalian systems and in vitro protein preparations to investigate
promising new molecules that could help lead to new treatments for amyotrophic lateral sclerosis (ALS).
Detail
204G Lynch Laboratory, Department of Biology, University
of Pennsylvania, Philadelphia, PA. 19104, USA
Bio
Bonini received her PhD from the University of Wisconsin-
Madison, then performed postdoctoral research at
Caltech. She then launched her laboratory at Penn,
where she developed Drosophila as a model for human
neurodegenerative disease. She is an elected member
of the National Academy of Sciences, National Academy
of Medicine and American Academy of Arts and Sciences.
McGurk received her PhD from the University of Edinburgh
and joined Bonini at Penn as a National Ataxia Foundation
Investigator. As a post-doctoral researcher, she uncovered
that the post-translational modification poly(ADP-
ribosylation) may play a role in mediating amyotrophic
lateral sclerosis. This coming Fall, she will join the Division of
Cell & Developmental Biology in the School of Life Sciences
at the University of Dundee, as an independent investigator.
Funding
NIH/NINDS
Collaborators
Investigators at Penn:
• Dr Vivianna Van Deerlin
• Dr Edward B Lee
• Dr Virginia M-Y Lee
• Dr John Q. Trojanowski
• Dr James Shorter
An investigator at Northwestern:
• Dr Robert G. Kalb
Dr Leeanne McGurk
E: lmcgurk@sas.upenn.edu
W: https://leeannemcgurk.wordpress.com/
@LeeanneMcgurk
References
McGurk, L. et al (2015). ‘Drosophila as an In Vivo Model for Human
Neurodegenerative Disease’. Genetics, 201(2): 377-402.
McGurk, L. et al (2018). ‘Poly(ADP-Ribose) Prevents Pathological
Phase Separation of TDP-43 by Promoting Liquid Demixing and
Stress Granule Localization’. Molecular Cell, 71(5):703-717.
McGurk, L. et al. (2018). ‘Nuclear poly(ADP-ribose) activity
is a therapeutic target in amyotrophic lateral sclerosis’. Acta
Neuropathol Commun, 6(1):84.
McGurk, L. et al (2018). ‘Poly(ADP-ribose) engages the TDP-43
nuclear-localization sequence to regulate granulo-filamentous
aggregation’. Biochemistry, 57 (51), 6923-6926.
Personal Response
What steps would have to be taken before PARP
enzyme-based therapies could be tested in a clinical
trial?
ALS is a heterogeneous disease, meaning that there
are many different genes that when mutated give rise
to the disease. We need to understand if PARP inhibitors
are beneficial to all, or only some of these disease gene
situations using our model systems of cells and animals.
These types of studies will inform if certain patients may
be better suited to these compounds, should they prove
promising. Many of the developed PARP inhibitors have
very specific modes of action and some are better at
crossing the blood-brain-barrier than others. We need
to first understand if there are differences in these PARP
inhibitors in treating ALS-associated toxicity in cells and
in neurons so that we can select the best compound or
compounds for further testing. Traditionally, drugs are tested
in rodent models of disease before they can move forward
into a clinical setting. The field has made much progress
in rodent models that recapitulate aspects of the disease
process. Once we know which inhibitors are most promising
in our settings, the next step will be to advance and test
in a rodent system.
www.researchoutreach.org 97
Earth and Environment ︱ Dr Thomas Shahady
Going with the flow:
Water quality and community health in Costa Rica
Water quality is one of the most
pressing issues facing the world,
with solutions to combat poor
water quality remaining elusive.
This is what makes the work of Dr
Shahady and fellow researchers
at the University of Lynchburg
and the University of Georgia
Costa Rica so important. Their
pioneering work in promoting
community engagement with
a macroinvertebrate index to
ensure effective water resource
management has the potential
to drive governmental agencies
to react to water pollution.
This work in Costa Rica has the
potential to ensure both river and
community health in the future.
Researcher José Montero discusses water quality
observations with Dr Shahady.
98 www.researchoutreach.org
W
ater quality is one of the
most important issues facing
Latin America today. In
Costa Rica, issues such as agricultural
development, pollutant runoff,
inadequate sanitation and legislation
all contribute to water pollution.
These problems are compounded
by seasonable patterns in rainfall,
challenging terrain, a lack of effective
water quality monitoring and ineffective
water resource management. Solutions
to these problems remain elusive due
to centralised governmental control
of decision making. Often information
about local water bodies is scarce, the
needed environmental testing complex,
changes across landscapes rapid and
local control minimal. However, the need
to find solutions to poor water quality is
paramount. Climate change is estimated
to significantly alter water quantity
and quality in the future as a result of
its effect on environmental services,
agricultural activities and biodiversity.
Dr Shahady of the University of Lynchburg
and fellow researchers at the University
of Georgia are at the forefront of
researching solutions to these problems.
With a background in understanding
the relationship between water quality,
community health and water use and
funded by the University of Georgia
Costa Rica, the University of Lynchburg
and Bosqueterno S.A, Dr Shahady is well
placed to conduct this research.
A BACKGROUND TO WATER
QUALITY ISSUES IN COSTA RICA
While the availability of potable water
in Costa Rica is good, serving over
99% of the population, wastewater
treatment is highly lacking. Mounting
concern with septic tanks and agricultural
waste contributing significantly to water
pollution in the country is increasing.
Although on paper water quality is
managed by the central government
in San Jose and through a variety
of five government agencies, due
to disparities in clear regulatory authority
and unclear governmental responsibility,
wastewater and greywater generally
remain unregulated.
To make matters worse, the physical
terrain of Costa Rica and seasonal
rains also significantly contributes to
the ineffective management of water
quality. Steep and rugged slopes
often limit accessibility for stream
monitoring, Heavy seasonal rains
wash away existing roads and prevent
access to waterways unless individuals
have experienced knowledge of local
infrastructure. Wet and dry seasons
limit consistent application of water
quality indices. Without effective water
monitoring, water quality problems
cannot be pinpointed. To further
compound the issue, equipment,
adequate laboratory space and
analytical knowledge are also limited.
As a result, local communities often
use anecdotal assumptions regarding
their local water quality, which leads to
poor decision making concerning local
sources of water.
 Measuring discharge and
water depth in a stream.

Dr Shahady and his research team suggest

that their trialled macroinvertebrate index
is a vehicle to this awareness and change.
USING INSECTS TO sites traversed different elevations, and community volunteers can provide water
MEASURE WATER QUALITY different land-use types. At each site, quality index calculations similar to more
To solve this problem, a clear, usable, water quality was measured in three ways: sophisticated scientific studies.
affordable and easily measurable using a water quality metre for chemical
methodology is needed for water quality analysis, and collecting insects for the CONTAMINATED WATER AND THE
prediction that takes into consideration BMWP-CR index and simpler PMA index FUTURE OF COMMUNITY HEALTH
the concerns and abilities of local simultaneously. This simpler PMA index During their study, Dr Shahady’s team
communities. One possible solution is the was used by volunteers from local areas found that several of the sites they tested
use of a macroinvertebrate index. This is who used a worksheet which explained were contaminated with bacteria such as
a methodology whereby the ecological insect identification based on descriptions E. coli, especially during the wet season,
condition of water bodies is inferred and drawings. likely as a result of pollution from the
using information about what insects live inadequate collection and treatment
there. This is already a well-established The simpler PMA index was found to be of wastewater. Inadequate sanitation
technique for assessing the quality of better at predicting water contamination burdens health care systems, but solutions
natural water bodies. The government of than the more complex BMWP-CR index, to this problem remain elusive.
Costa Rica implemented such an index suggesting that the simpler index, which
in 2007. Known as the BMWP-CR Index, locals can use, is practical as a predictor Unfortunately, building and maintaining
this methodology standardises the use of of water quality. This further suggests that wastewater treatment plants is not
aquatic insects for water quality detection.
However, there are issues associated with
using this index. Its use requires certain
ways of collecting insects and demands
expertise in insect identification skills.
Dr Shahady and his team therefore set
about testing whether an alternative and
more appropriate macroinvertebrate
index (known as the PMA Index) could be
used by communities that required less
expertise and knowledge.

Dr Shahady and fellow researchers set

out to compare these two indices, by
conducting research as part of a larger
water quality monitoring project in the
Bellbird Biological Corridor in Costa
Water Quality Laboratory on
Rica. They tested 16 sampling sites Campus of UGA – Costa Rica.
between 2015 and 2016. The sampling

www.researchoutreach.org 99
 Using nets to collect aquatic
macroinvertebrates for the index.
a solution. Current ones already in place
in Costa Rica are currently not well
maintained and future construction is very
expensive. They often have unrepairable
structural damage and are blocked by
build-ups of sewage sludge. To make
matters worse, there is not one specific
government agency, programme or law
directly assigned to protect rivers from
inadequate sanitation, despite strong
evidence suggesting that improved
water quality leads to reductions
in disease occurrences.
Compounding the issue, climate change
is expected to have a significant impact
on water quality and river health in Costa
Rica in the future. Models suggest that
predicted increases and variability in
precipitation will alter the ways that rivers
flow, which means that water bodies that
are currently considered to be healthy
may become contaminated in the future.
Contaminated surface water exchange
with groundwater is unknown. There
is a real possibility that drinking water
contamination may occur in Costa Rica
in the next few decades.
The bottom line is that communities need
engagement with water issues to drive
local and collective governments to react
in order to aid public health. Dr Shahady
and his research team think that community
science and their simplified index used for
water quality monitoring will do just that.
Community volunteers are capable
of providing water quality index
calculations similar to more sophisticated
scientific studies.
100 www.researchoutreach.org
Using the metre to measure
water chemistry in the streams.
CITIZEN SCIENCE TO ENSURE
COMMUNITY HEALTH
In Costa Rica, one method in place
to protect water quality are payments
for environmental services (PSA). These
are incentives offered to landowners
in exchange for managing their land
to provide some sort of environmental
service. PSA programmes focus on
maintaining adequate supplies of water
for purposes valued by the community
such as hydroelectric power. Decisions
to create PSA programmes are locally
made and driven by economic factors
that make sense to local land-owners.
But indirectly, these programmes provide
improved water quality management
for entire communities.
People that live in areas with PSA
programmes are more likely to think
positively about the environment, and
therefore expect better water quality.
However, outside of PSA areas, locals have
very different ideas about water quality.
While they have may have concerns,
they perceive government programmes
as being responsible for water quality
maintenance. With this perception,
sources of water pollution are generally
ignored, and disease risk significantly
increased. However, if these pollutants
were to be monitored, water quality
concerns could be heightened, and
residents would become more concerned
about the water they are actually drinking.
If locals are aware of the benefits to
be gained from maintaining good water
quality, it is likely that they would make
decisions to benefit themselves, just
as with areas with PSA programmes.
Dr Shahady and his research
team suggest that their trialled
macroinvertebrate index is a vehicle
to this awareness and change. Using their
tested simplified index, a community
group would be able to provide
information otherwise unavailable to
residents that may make them care more
about their water quality and make local
decisions about how to deal with water
pollution. Areas of contamination could
be identified, and this information could
be used to begin an improved legal
framework for river protection. Locals
involved could begin to establish long-
term monitoring stations and organise
efforts to improve water quality.
THE FUTURE
Although drinking water in Costa
Rica is in adequate supply, sanitation
management, particularly in rural areas,
is highly lacking. Rivers carry high levels
of pollutants and could be a significant
source of disease. A simple index to
measure water quality, as trialled by Dr
Shahady and his team’s work, may be
the catalyst to change this. By monitoring
their own water, Dr Shahady and his
team hope that communities will work
together to install management practices
for agricultural and sanitary wastewater,
in order so that water quality can be
improved. They believe that engagement
and support for water monitoring practices
is the only way forward in ensuring
the future of water health in Costa Rica.
 Behind the Research
Dr Thomas Shahady
E: shahady@lynchburg.edu T: +1 434 944 5684 T: +1 434 544 8545 W: https://www.lynchburg.edu/academics/academic-
community-centers/center-for-water-quality/stream-ecology-management/costa-rica/ W: https://costarica.uga.edu/
W: https://ugacostaricablog.com/2016/10/14/research-spotlight-video-water-quality-with-darixa-hernandez/
www.facebook.com/ugacostarica/
Research Objectives
Dr Shahady’s research focus centres on understanding the
relationship between water quality, community health and
water use in Costa Rica.
Detail
1501 Lakeside Drive
Lynchburg VA 24501, USA
Bio
Dr Shahady is an Environmental Scientist and Researcher.
He earned his PhD from North Carolina State University
in Zoology and his master’s of science in public health
and engineering from UNC – Chapel Hill.
Funding
• University of Georgia Costa Rica for Logistical and
Matching Support
• University of Lynchburg for Direct Funding of Research
• Two BESA (Bosqueterno S.A.) grants for direct financial
support
Collaborators
• Jose’ Montero – Researcher UGA-CR
• Martha Garro – Researcher UGA-CR
• Fabricio Camacho – Director UGA-CR
• Scott Connelly – Professor UGA
• Veronica Sheehan – Sustainability Center
References
Arias, A. (2010). ‘Situación de Potabilización y Saneamiento en
Costa Rica’. En: Decimosexto In- forme Estado de la Nación
en Desarrollo Humano Sostenible, pp. 36.
Bower, K. (2014) ‘Water supply and sanitation of Costa Rica’.
Environmental Earth Sciences, Vol. 71, pp. 107-123.
Cairns, J. & Pratt, J. (1993). ‘A history of biological monitoring
using benthic macroinvertebrates’, in Rosenburg, D. &
Resh, V. (eds.) Freshwater biomonitoring and benthic
macroinvertebrates. New York: Chapman and Hall.
Karmalkar, A., Bradley, R & Diaz, H. (2011). ‘Climate change
in Central America and Mexico: regional climate model
validation and climate change projections’. Climate Dynamics,
Vol. 37, pp. 605-629.
Kuzdak, C. & Wiek, A. (2014). ‘Governance scenarios for
addressing water conflicts and climate change impacts’.
Environmental Science and Pollution Research, Vol. 42, pp.
181-196.
Schwarzenbach, R., Egli, T., Hofstetter, T., von Gunten, U. &
Wehrli, B. (2010). ‘Global water pollution and human health’.
Annual Review of Environment and Resources, Vol. 35, pp.
109-136.
Wood, M., Sheridan, R., Feagin, R., Castro, J. & Lacher, T.
(2017). ‘Comparison of land use change in payments for
environmental services and National Biological Corridor
programs’. Land Use Policy, Vol. 63, pp. 440-449.
Personal Response
What made you so interested in researching and
analysing water quality in Costa Rica in particular?
Teaching students of all ages and the discovery of
needs in local communities. The people of Costa Rica are
wonderful and have helped me teach, learn and enjoy
everything about Costa Rica. I wanted to give something
back and use my expertise to help them solve problems.
The streams also piqued my interest in tropical stream
ecology and patterns of insect worldwide distribution.
Discoveries in nature, ecological response to both natural
and human disturbance, and teaching about living
sustainably with these amazing natural resources are some
of my greatest interests. 
www.researchoutreach.org 101
 Earth and Environment ︱ Dr Lindsay Worthington
Drilling for knowledge:
A collaborative approach to ocean drilling in the Arctic
The Arctic contains important
records of tectonic and
geological oceanic history, yet
is a vastly under-sampled area.
However, a better knowledge
of the past climate and tectonic
history of this region is crucial
to understanding contemporary
climate change and modern
geological hazards. This is
what makes the research of
Dr Lindsay Worthington at the
University of New Mexico and
fellow researchers so important.
Their collaborative work to
develop new proposals and
reinvigorate existing proposals
for scientific ocean drilling in the
region will combat the issue of
under-sampling in the Arctic.
sirtravelalot/Shutterstock.com
102 www.researchoutreach.org
T
he Northern Pacific, Bering Sea
and Western Arctic regions
contain important tectonic data,
paleoclimatic records (data concerning
the earth’s past climatic changes) and
paleoceanographic records (data
concerning the history of the oceans
in the geologic past with regard to
circulation, chemistry, biology, geology
and patterns of sedimentation and
biological productivity). These records can
be used to obtain a better understanding
of modern day climate change as well as
geologic hazards in the area, including
volcanism and tsunamis, as well as the
Alaska-Aleutian margin. This is a boundary
between two tectonic plates in the region
that has been associated with several
large magnitude earthquakes in the last
decade alone.
These regions remain seriously under-
sampled by scientific ocean drilling
however, and is necessary for obtaining
these tectonic, paleoclimatic and
paleoceanographic records. Only one
International Ocean Discovery Program
(IODP) drilling expedition has been north
of the Aleutian Islands (a volcanic island
chain belonging to both Russia and the
USA in the North Pacific) since 1971, and
only one expedition has recovered cores
from the Arctic Ocean. The entire eastern
Gulf of Alaska has never been drilled.
Both tectonic, paleoclimatic and
paleoceanographic records can be
collected via the coring and drilling
of sea floor sediments and sea ice via
the US National Science Foundation’s
(NSF) funded drill ship, the R/V JOIDES
Resolution which serves the NSF
International Ocean Discovery Program
(IODP). This ship is scheduled to operate
in the North Pacific in 2023. This presents
a tremendous opportunity for planning
and achieving high-priority science
objectives in this region. In order to ensure
that this ship is used to its best advantage,
it is necessary that drilling expeditions are
proposed prior to this time.
Well-conceived and coordinated drilling
expeditions are needed, both to expand
scientific understanding and to make
effective use of the NSF’s funded drill
ship. This is why in September of 2018,
76 scientists from nine different countries
participated in the workshop ‘Scientific
Exploration of the Arctic and North
Pacific: Community-driven Priorities for
Ocean Drilling’. Convened by Dr Lindsay
 EQRoy/Shutterstock.com
The Bering Strait on the western edge of Alaska.
ggw/Shutterstock.com
Worthington from the University of New
Mexico, as well as Dr Kristen St. John from
James Madison University, Dr Bernard
Coakley from University of Alaska, Dr
Juliane Mueller from the Alfred Wegenger
Institute and Dr Matthias Forwick from
the University of Tromso, the workshop
aimed to develop new proposals and
reinvigorate existing proposals for
scientific ocean drilling in the area.
Funded by the International Ocean
Discovery Program, the US National
Science Foundation, the US Bureau of
Ocean and Energy Management and the
Norwegian Petroleum Directorate, this
project and associated workshop focused
on regional coordination, therefore
encouraging the development of new
coordinated drilling strategies. Successful
drilling proposals usually take four years
from initial submission. Therefore, the
rationale for the workshop was to form
proponent groups to submit proposals for
scientific drilling to IODP, in order to take
full advantage of the planned availability
of the JOIDES Resolution.
WHAT WILL OCEAN
DRILLING ACHIEVE?
Ocean drilling is necessary in order
to explore and study the composition
and structure of the Earth’s oceanic
basins. Ocean drilling can enable access
to marine sediments, which contain
important archives for better constraining
past climate and tectonic history. This
information is critical to understanding
modern climatic changes as well
as geologic hazards.
In the North Pacific, the Bering Sea and
This is just one such proposal that has
the potential to extraordinarily advance
knowledge on modern climate change
and geologic hazards.
the Arctic Ocean region, previously limited
drilling is currently hampering scientific
understanding of fundamental Earth
processes such as the impacts of oceanic
exchange between the Arctic and North
Pacific Oceans on long-term climate
evolution. Variations in climate change
can be seen in marine sediment cores
that enable reconstructions of changes
in sea level, ocean salinity, temperature,
sea-ice extent, and the response of marine
ecosystems. This paleoclimatic data
can be used to inform understanding
of contemporary climate change. It is
therefore pertinent that these historical
records are accessed via ocean drilling.
This is just one example of how ocean
drilling can help to inform researchers
on contemporary climate change. Sea
ice records accessed via ocean drilling
can also shed light on how ice and sea
levels respond to warming and cooling.
Information such as this is also important
in expanding knowledge of climate
change today.
Not only can ocean drilling inform current
knowledge of contemporary climate
change, it can also expand knowledge of
Alaskan earthquakes, and other tectonic
activity in the area. By finding out more
about past tectonic activity in the area
through obtaining data on the evolution
of the mantle magmatic source in the
www.researchoutreach.org 103
Everett Historical/Shutterstock.com
Paleoceanographic data concerning patterns of subduction zone
earthquakes and tsunamis can be accessed through ocean drilling.
region, understanding of subduction
and tectonics in the North Pacific can
be increased. Further paleoceanographic
data concerning patterns of subduction
zone earthquakes, submarine landslides
and tsunamis can also be accessed
through ocean drilling. Increasing
knowledge on these fundamental issues
has great potential to help modern
understanding of tectonic activity
and climate change through the use
of paleoceanographic reconstructions.
WORKSHOP SUMMARY AND
THE FUTURE OF OCEAN DRILLING
FOR RESEARCH IN THE ARCTIC
A particular focus of the Scientific
Exploration of the Arctic and North Pacific
workshop was to get early-career scientists
involved with the drilling program, in
order to ensure longevity of research. To
support this goal, a pre-workshop session
discussed the process of preparing,
submitting, and revising drilling proposals,
as well as what happens after a proposal
is selected for scheduling. Notably, the
workshop was successful in engaging
early-career scientists, but was also crucial
in developing new collaborations, as well
as strengthening existing partnerships in
order to create proposals that have the
potential to advance scientific knowledge
in the region.
During the workshop, a total of 15
proposal ideas were recognised as
priorities, and science and data leads
were identified. These proposals spanned
the geographic region of interest,
and included three for the Bering Sea,
four for the Arctic and eight for the
North Pacific. These proposals were
written by proponents at the meeting
as well as by other researchers in the
broader community.
104 www.researchoutreach.org
It is safe to say that the Scientific
Exploration of the Arctic and North
Pacific project has made a significant
contribution to future knowledge.
UNDERSTANDING MEGA-THRUST
EARTHQUAKES
One such proposal addressed the lack of
knowledge that surrounds understanding
the variability of mega-thrust
earthquakes. Mega-thrust earthquakes
occur when one tectonic plate is pushed
under another. These earthquakes are
the planet’s most powerful, and can cause
intense damage. Currently, the variability
of these mega-thrust earthquakes are
thought to be caused by a number of
factors such as the location of splay faults,
smaller fault lines that branch off from
the main tectonic fault.
Through the study of higher resolution
paleoseismic records (records of past
tectonic and seismic activity), it is likely
that more can be learned about the
factors that contribute to the intensity
of mega-thrust earthquakes. Southern
Alaska presents a great opportunity
to investigate these factors, due to the
excellent conditions thought to have
preserved high resolution data. It is
thought that through ocean drilling, more
Vladimir Endovitskiy/Shutterstock.com
could be learnt about how mega-thrust
earthquakes progress.
This is just one such proposal that has
the potential to extraordinarily advance
knowledge on modern climate change
and geologic hazards through ocean
drilling in the North Pacific, the Bering
Sea and Arctic Ocean region.
The Scientific Exploration of the Arctic
and North Pacific project has made
substantial progress in bringing together
interested parties, significantly pushing
forward the potential for ocean drilling
research in the Arctic region. With 2023
oncoming, the JOIDES Resolution’s arrival
in the Pacific is highly anticipated; the
potential for using this ship to uncover
paleoclimatic and paleoceanographic data
in the area is huge. With this data comes
knowledge, of both geologic hazards
and contemporary climate change. It
is safe to say that the Scientific Exploration
of the Arctic and North Pacific project
has made a significant contribution
to future knowledge on pressing issues.
 Behind the Research
Dr Lindsay Worthington
E: lworthington@unm.edu T: +1 505-277-3821

Research Objectives References

Dr Lindsay Worthington’s research focuses on subsurface
imaging of the Earth’s crust to understand geologic
processes such as mountain-building and feedback
between surface processes and tectonics.
Detail
University of New Mexico
Dept of Earth and Planetary Sciences
1 University Place – MSC0203
Albuquerque, NM 87131
Bio
Dr Worthington is an assistant professor at the University
of New Mexico. She uses seismology and geophysics to
study Earth structure, mountain-building, glacial dynamics
and plate boundary fault processes.
Funding
International Ocean Discovery Program, US National
Science Foundation, US Bureau of Ocean and Energy
Management, Norwegian Petroleum Directorate
Collaborators
• Kristen St. John
• Bernard Coakley
• Juliane Mueller
• Matthias Forwick
Oleksandr Umanskyi/Shutterstock.com
Bufe, C., Nishenko, S., and Varnes, D. (1994) Seismicity trends
and potential for large earthquakes in the Alaska-Aleutian
region. Pure and Applied Geophysics. Volume 142, pp. 83-99.
Coakley, B., & Stein, R. (2010) Arctic Ocean Scientific Drilling:
The Next Frontier. Scientific Drilling. Volume 9, pp. 45-49.
Finn, S., Liberty, L., Haeussler, P., & Pratt, T. (2015) Landslides
and megathrust splay faults captured by the late holocene
sediment record of eastern Prince William Sound, Alaska.
Bulletin of the Seismological Society of America, Volume
105(5), pp. 2343–2353.
Liberty, L., Finn, S. Haeussler, P. Pratt, T. & Peterson, A. (2013)
Megathrust splay faults at the focus of the Prince William
Sound asperity, Alaska. Journal of Geophysical Research: Solid
Earth, Volume 118.
Worthington, L., St. John, K. and Coakley, B. (2019) The
future of scientific drilling in the North Pacific and Arctic, Eos,
Volume 100. 
Personal Response
Other than the NSF’s funded drill ship, what made you
and your collaborators realise the need for a workshop
to address a lack of ocean drilling in the North Pacific,
the Bering Sea and the Arctic Ocean region?
The Arctic region is one of the last frontiers in
oceanography and tectonics and has essentially operated
as a ‘black box’ for many questions addressing global
and hemisphere-wide processes. Further, climate change
at these high latitudes presents a scientific challenge with
far reaching societal implications. Accessing archives of past
climate can help us understand what to expect as the Arctic
warms in the future. In Alaska, multiple large scientific
initiatives in recent years have contributed significant
insight into Earth structure. Ocean drilling is the next step
in ground-truthing observations.

www.researchoutreach.org 105
Thought Leader

EuroScience:
Reception offered by EU Commissioner
Carlos Moedas at ESOF2018.

Supporting scientists across Europe to work together

for a brighter European future
EuroScience is a non-profit grassroots organisation that believes that science is an essential part of Europe’s cultural
heritage and that it forms the basis for the continued health and prosperity of the continent and its citizens. By supporting
European scientists at all levels of their career and promoting research and development, since 1997, the organisation
has been enhancing the contribution of science, technology and innovation to people’s wellbeing and culture.

W
hether they are into physical
or biological sciences, social
sciences or humanities,
work for a public sector institution,
university, research institute or the
business sector, are early career or
top of their field, EuroScience aims
to support, encourage and represent
all European scientists.
In an interview with EuroScience’s
President, Michael Matlosz, we found
out how the organisation has become
ESOF2018 sculpture.
an anchor point for anyone who wants
to interact with the European science
community, a platform that policy-makers
can approach for advice and expertise,
and an open space for discussion, debate
and creativity for thousands of members
in nearly 80 countries.
Hi Michael! Can you tell us more
about your role and responsibilities
as the President of EuroScience?
My role as President is to provide
direction and leadership for the
development of the action and visibility
of EuroScience. EuroScience is a unique
pan-European organisation representing
the voice of individual researchers and
science professionals in both the public
and private sectors, regardless of their
institutional affiliation and across all
geographic and disciplinary boundaries.
The role of the President of EuroScience
is particularly rewarding for me as a
university researcher and educator, having
spent the majority of my scientific career
in Europe and with strong involvement
in collaborative action on a pan-European
level. Providing a voice for researchers
and science professionals as individuals,
is the unique role of EuroScience as
a contributor to the creation of a dynamic
European Research Area.

Can you tell us more about EuroScience’s

history, mission and core principles?
EuroScience was founded in 1997 at

106 www.researchoutreach.org
Plenary session ESOF2018, Toulouse, France.

Past and present EuroScience Presidents (from

left) Jean-Patrick Connerade, Enric Banda,
Michael Matlosz, and Lauritz Holm-Nielsen.

a public meeting open to scientists from

all of Europe. The basic idea was to
create a platform for individual European
scientists to meet, exchange views, have
their voices heard in European policy
discussions, work on proposals to enhance
their careers, discuss how science impacts

EuroScience is a unique pan-European

society and in general advance science
to the benefit of Europe. The mission

of EuroScience is to contribute to an
integrated European continent of science
and to the development of prosperity
and mutual understanding among all
Europeans through the advancement
of scientific research.
Are there any specific scientific fields
you would personally like to see moved
forward and be invested within Europe
in the next few years?
The future of European science does
not depend on any specific field, but
rather on our collective ability to attract
the best and the brightest scientific
talents in all fields to Europe. The priority
for Europe, not only on the supra-
national level of the European Union,
but also on the level of all European
member states and associated states,
should be the promotion of attractive
scientific careers for those bright talents
who wish to remain in Europe or to come
organisation representing
the voice of individual researchers
and science professionals.
to Europe to live and work. EuroScience
promotes geographic and professional
mobility and equal opportunity for
women and men, regardless of their
national origins.
What do you feel are the most troubling
political blocks facing European
scientists today? How is EuroScience
trying to help overcome these?
Among the issues of preoccupation that
European scientists face today, I would
cite: continued weakening of public trust
in scientific expertise; increasing disregard
for academic freedom; unnecessary
opposition between short-term innovation
and long-term research in public science
policy; inequalities and insufficient
investment and capacity building in
research and innovation across Europe;
and rapidly changing career opportunities
and working conditions.
EuroScience is working actively to
address these and other major issues.
In particular, we are collaborating with
several organisations representing early-
career researchers, such as the Marie
Curie Alumni Association and EuroDoc,
and we have also developed contacts

www.researchoutreach.org 107
 ESOF Party at Cité de l’Espace, Toulouse:
Ariane 5 rocket.
with informal movements such as those
created in Southern European countries
in the wake of the austerity policies
implemented after the financial crisis.
The EuroScience Open Forum (ESOF)
is a major platform for debate and
discussion on joint action. ESOF’s career
programme is an important opportunity
and the EuroScience magazine
EuroScientist provides a powerful vector
for expression. EuroScience also issues
joint policy papers and statements
regularly with sister organisations
throughout the world. One such statement
ESOF2016 Manchester, UK.
108 www.researchoutreach.org
Plenary session discussion ESOF2018.
was a joint declaration on the importance
of public sector support for long-term
research. The declaration was presented
jointly to European Commissioner
Carlos Moedas at the ESOF conference
in Manchester in 2016.
What do you feel are the biggest
challenges facing European
scientists today?
There are many challenges facing
European scientists, among which I
would like to mention the challenges
to: contribute to the solutions required
to face global societal concerns, but
without sacrificing the quality of highly
original scientific research; maintain focus
on true frontier research and disruptive
innovation, despite cumbersome
organizational structures; engage much
more strongly with the public at large; and
interact with policymakers to ensure that
scientific evidence is taken into account.
EuroScience aims to influence scientific
policy change in Europe – are there
any policies in particular that the
organisation has contributed to in the
last few years that you are particularly
proud of?
EuroScience contributed significantly to
the development of the European Charter
for Researchers and the Code of Conduct
for the Recruitment of Researchers,
and as a founder and contributor to the
Initiative for Science in Europe, we were
also a major factor in the effort to mobilise
the European scientific community to
promote the creation of the European
Research Council.
In 2017, EuroScience and the Royal
Institution organised a high-profile
debate on the impact of Brexit on science
in the United Kingdom and the EU-27.
The debate contributed to a much better
understanding of what is at stake and what
options are available for moving forward.
EuroScience is also strongly involved in the
Open Science agenda, including support
for initiatives in Open Access, Open
Data and Citizen Science. The increasing
importance of digital technologies
on scientific practice and scientific
communication is changing in many
significant and profound ways the exercise
of the scientific profession, and it is
important that the voice of active scientists
in this context be heard, independently
of their institutional affiliation.
How does EuroScience raise awareness
of scientific research in society in general?
Our most successful visible action is ESOF
and associated actions such as the
Science in the City events. The European
Cities of Science title is a very visible
celebration of science and its relation
to society.
An ESOF event is organised once
every two years in a major European
city and the event has been constantly
growing in participation and visibility
since its first edition (Stockholm 2004).
The most recent edition (Toulouse 2018),
was a major success with over 4000
registered participants. The 400-500
media representatives present spread
the message, and the Science in the City

Opening Ceremony ESOF2018.
component of ESOF goes well beyond
the conference itself to bring science
to the public and promote engagement.
EuroScience has also granted in recent
years several European Science Writers
Awards at the conference, underlining
how important science journalists
are in connecting science to society.
EuroScience gives out awards each
year (Rammal Award, European Young
Researchers Award, European Science
Writers Award) – why do you feel it
is important to recognise researchers
in this way?
For researchers themselves, awards
are important for their careers. They
encourage them to persevere on their
path to break new ground. Awards also
make visible to society as a whole that
science is a vital pillar for progress, and
that individual creativity is crucial for
success. The Rammal Award recognises
not just scientific achievements but also
contributions to building bridges between
societies in the wide Mediterranean area
torn apart by history, politics and religion.
Are there any movements within the
organisation to connect with scientists/
institutions outside of Europe?
Since 2012, several global general science
organisations have established a Liaison
Group. They share common interests in
scientific endeavour and in advancing
science to the benefit of mankind. In
some cases, we have common sessions at
conferences, and sometimes – such as the
example of the Manchester declaration –
we publish joint statements. The current
EuroScience promotes geographic
and professional mobility and equal
opportunity for women and men,
regardless of their national origins.
member organisations of the International
Liaison Group are the American
Association for the Advancement
of Science; the Brazilian Society for
the Advancement of Science; the Chinese
Association for Science and Technology;
the Korean Society for the Promotion
of Creativity and Science; and the
Japanese Agency for Science and
Technology. Organisations from India and
Australia have participated in meetings
of the Liaison Group as well. We are also
working closely with the Department
of Science and Technology in South
Africa, and the Programme Committee of
the Next Einstein Forum (NEF) in Africa.
There appears to be a clear focus
on young and new researchers within
EuroScience programmes – why
are your researchers so important
to the organisation?
As in all professional sectors,
organisations involved in research and
innovation, whether they be universities,
public research institutes or commercial
enterprises, need to create the best
conditions for renewal of their talents
and to prepare the path for the
Thought Leader
generations to come. To do so, requires
not only high-quality education, but
also working conditions that allow future
researchers and science professionals to
be successful in their careers and combine
that professional success with a positive
and rewarding personal and family life.
If you would like to find out more,
please visit their website at https://www.
EuroScience.org/.
EuroScience
1, Quai Lezay-Marnesia
67000 Strasbourg
France
E: office@euroscience.org
T: +33 (0) 3 88 24 11 50
W: www.euroscience.org
@EuroScience
www.facebook.com/
euroscience.association
www.researchoutreach.org 109
 Behavioural Sciences ︱ Dr Fabrizia Faustinella
Homelessness in
Western Society:
The Dark Side of The Moon
Homelessness is becoming a
relevant phenomenon in western
nations despite improvements
across economic and healthcare
indices over the last decades. Dr
Fabrizia Faustinella, Associate
Professor of Medicine at Baylor
College of Medicine, Houston,
Texas, has crafted a compelling
documentary on homelessness
exploring both its causes and
consequences and giving a voice
to those living on the streets.
The documentary, entitled The
Dark Side of The Moon, sheds
light on this often unspoken and
much-maligned aspect of society
and those facing its challenges
on a daily basis.
Followtheflow/Shutterstock.com
110 www.researchoutreach.org
A
lmost all of us living in the urban
west encounter homelessness
on a nearly daily basis. The sight
of people living on the streets is very
frequent and yet we barely acknowledge
this problem or give it a second thought.
The fact that there is no internationally
agreed definition for homelessness makes
it difficult to compare homelessness
rates across nations. The term ‘literally
homeless’ refers to those staying in
shelters, abandoned buildings or living
on the streets. This group is further
characterized as ‘sheltered homeless’
or ‘unsheltered homeless,’ depending
on whether they are using some form
of accommodation or not. Furthermore,
those who stay with family or friends as
a result of having no alternative lodging
arrangements are termed ‘precariously
housed.’ Despite the complexity of
measuring homelessness, however,
available data paint a striking picture of
its prevalence. A 2007 study, for example,
shows that 1 in 13 people in the UK have
been homeless at one point in their lives
and the number is now increasing.
According to official UK Government
statistics that do not even include people
sleeping in a shelter or in an overnight
hostel, the number of homeless in
England has doubled over the period
2012-2018. Some figures suggest that
rates in the United States are decreasing,
with 100,000 fewer people sleeping
in shelters and on the streets over the
past nine years. Other figures, however,
suggest that homelessness, in fact, has
been steadily increasing since the 1970s
in smaller, rural townships as well as
in America’s biggest cities. More than
550,000 people, including about 36,000
unaccompanied youth under the age of
25, are homeless in the US on any given
night, according to data from 2018, and
homelessness remains a widespread
phenomenon. According to The National
Center on Family Homelessness, a
staggering 2.5 million children are now
homeless in the US. Why, despite the
obvious wealth of developed western
nations, the prevalence of homelessness
is so high?
THE DARK SIDE OF THE MOON
Dr Fabrizia Faustinella, Associate
Professor in the Department of Family
and Community Medicine, Baylor College
of Medicine, Houston, Texas, takes a
holistic view of homelessness. Trained as
a physician and with a PhD in genetics,
Dr Faustinella has created a documentary
to shine a light on homelessness, its root
causes, its effects, and ultimately, possible
solutions. What makes people vulnerable
to homelessness? What are the links
between drug use, mental illness, crime
and homelessness? These are some of
the questions that she addresses in her
film, evocatively named The Dark Side
of The Moon.

WHY PEOPLE BECOME HOMELESS?

THE HARDSHIP OF STREET LIFE
There are many reasons why people
become homeless: loss of income or
insufficient income, lack of affordable
housing, poverty, marriage breakdown,
domestic violence, mental and physical
illness are, among others, common
causes. Many people talk of a spiral
sparked by one event, for example,
the loss of a job, resulting in financial
instability and eviction, which, combined
with family breakdown, lack of support
and lack of needed services, eventually
leads to homelessness.

In the United States, racial and ethnic

minorities are disproportionately affected
by this problem. When compared to the
total population, those who are homeless
are more likely to be adult, male, African
American, unaccompanied/alone, and
disabled. More than 10% of adults living
on the streets in the US are veterans.
Many people experiencing homelessness
often have serious mental illness and
issues with drug and alcohol abuse, likely
to be both the cause and consequence of
their condition. While approximately up to
6% of Americans are affected by a mental
health condition that can severely impact
behaviour and quality of life – more than
20% of homeless people fall under this
category. Furthermore, about 45% of
the homeless population in the US has a
history of mental health diagnoses. This
number does not consider those living
with mental health problems that have disorders, schizophrenia and psychosis, processes. All these factors do increase
not been diagnosed or addressed by often lead to chaotic living and strained the likelihood that a person may end up
healthcare professionals. relationships, in addition to impacting living on the streets.
a person’s ability to work and provide
It is easy to see why mental illness could for themselves financially. Mental illness As explained in The Dark Side of The
make someone vulnerable to becoming can also impact an individual’s ability Moon, many of those living on the
homeless. Severe mental health issues, to care for their own health, leaving streets come from abusive families and
such as major depression, bipolar them more susceptible to other disease have suffered neglectful, traumatizing
experiences as a child. This can have

Dr Faustinella has created a documentary

long-lasting, negative effects on their
neuro-biological development, leaving

film to shine a light on homelessness, its them at increased risk of behavioural

problems and mental illness. Sadly, these
root causes, its effects, and ultimately, fractured family dynamics also mean
that these individuals are less likely to
possible solutions. have family support when they fall on

www.researchoutreach.org 111
hard times, again compounding their risk
of homelessness.
While there have been great strides in
trying to improve understanding and
treatment of mental illness in recent years,
most wealthy nations’ healthcare systems
still do not provide adequate resources
and funding for much needed mental
health services. As a result, mental health
issues are not properly addressed and
once people are living on the streets, the
chances of being treated appropriately
are even lower or non-existent. Early
intervention is key to supporting those
at highest risk and yet many services are
insufficient and woefully underfunded.
A powerful aspect of The Dark Side of
the Moon is the amount of on-screen
time dedicated to giving the homeless
their own voice, allowing them to explain
their own situation and talk about their
own personal experiences. Many speak
of living in a vicious cycle of struggling
to get formal identification documents,
therefore being denied access to support
services, which creates insurmountable
obstacles when trying to come out of
homelessness. Their accounts tell a tale
of life on the streets being a demeaning,
humiliating and, at times, dehumanising
experience. Clearly, living without
material comforts is only one part of their
plight. The mental struggle caused by
isolation and abuse is often an even more
difficult burden to bear.
During the film, Alexis, a young homeless
woman, speaks of her experiences
of being ignored and the issue of
homelessness being unseen, likening
it to the ‘dark side of the moon’. This
metaphor is woven throughout the
film – as well as being its title – as those
living on the streets talk about their daily
experiences of being overlooked, or even
feared, by their fellow citizens. Studies
show, however, that people who are
homeless are more likely to be victims of
crime than perpetrators. Sleeping on the
street with all their worldly possessions
makes them extremely vulnerable to
attacks. Rates of rape in homeless women
stand at approximately 30%. Those with
serious mental health conditions are even
more likely to suffer abuse. Unfortunately,
particularly in the US, these individuals
are also at higher risk of incarceration.
In fact, across the United States, people
112 www.researchoutreach.org
Many people experiencing homelessness
are affected by serious mental illness,
likely to be both cause and consequence
of this tragic human condition.
with serious mental health issues are more
likely to be jailed than to be hospitalized.
It has been found that 17.3% of prison
inmates with severe mental illness were
homeless prior to being arrested and 40%
were homeless at one point in their lives,
compared to 6% of undiagnosed inmates.
To complicate matters, homeless people
are often targeted by a number of city
ordinances which prohibit particular
behaviours such as obstructing
sidewalks, loitering, pan-handling,
trespassing, camping, being in particular
places after hours, sitting or lying in
particular areas, wearing blankets,
sleeping in public, storing belongings in
public places, and so forth. Under these
laws, homeless people are regularly
cycled through prisons and jails, which
perpetuate abuse and discrimination.
Homelessness and incarceration increase
the risk of each other causing a cycle of
hardship and uncertainty.
WHERE TO GO FROM HERE?
As emphasized in the documentary,
there is no easy, clear-cut solution for
how to deal with homelessness. It’s
apparent that a viable approach from
policy-makers needs to address multiple
issues at the same time: early housing,
affordable housing, job training, access
Tero Vesalainen/Shutterstock.com
to healthcare and rehabilitation services,
access to social services, in addition
to engaging the wider community. As
homeless people don’t vote and many
of us remain oblivious to their struggles,
the onus for politicians to tackle the
issue is reduced. What is obvious from
available data is that doing nothing to
alleviate the problem is costlier than
intervening. The chronically homeless
population uses expensive public services
at very high rates. As cities deal with
increasing emergency department visits
and hospitalisations, shelters, mental
health services, incarceration, court time
and so forth, the cost of preventing
homelessness and helping people
coming out of it pales in comparison.
In the film, a social worker credits the
‘grace of God’ as the sole reason for
being homed and living a comfortable
life while others are on the streets.
His narrative, as long as many other
testimonials, conveys how quickly any
one of us could become homeless due
to a dramatic life change, compelling
the viewers to re-evaluate their own
personal attitudes and prejudices towards
homeless people, to understand the
complexity of the human condition
and find within themselves elements
of shared humanity.
 Behind the Research
Dr Fabrizia Faustinella
E: fab7faust@gmail.com E: Fabrizia.Faustinella@bcm.edu T: +1 281 450 2449
W: www.bcm.edu/people/view/fabrizia-faustinella-m-d-ph-d-facp/5cc974e8-abd6-11e4-8d53-
005056b104be
Research Objectives
Dr Fabrizia Faustinella’s documentary, The Dark Side of
the Moon, explores the root causes of homelessness and
the challenges of street life, as long as societal biases and
prejudices towards homeless people. It also focuses on
how a difficult upbringing, amidst abuse and neglect, can
have a devastating impact on the cognitive and physical
development of a child.
The documentary discusses possible solutions to the
widespread and devastating problem of homelessness.
Detail
Dr Fabrizia Faustinella
3718 South MacGregor Way
Houston, TX 77021, USA
Bio
Dr Faustinella is currently associate professor of medicine
at Baylor College of Medicine, Houston, TX. She’s also a
filmmaker and has recently written, directed and produced
a documentary on homelessness entitled The Dark Side
of the Moon which will compel the viewers to re-evaluate
their own personal attitudes and prejudices towards
homeless people, to understand the complexity of the
human condition and find within themselves elements
of shared humanity.
References
Toro, P. A. et al. (2007). ‘Homelessness in Europe and the
United States: A comparison of prevalence and public
opinion’. Journal of Social Issues, 63(3), 505-524.
Criminalizing Homelessness Violates Basic Human Rights:
https://www.hrw.org/news/2018/07/05/criminalizing-
homelessness-violates-basic-human-rights.
Homelessness. Available at: https://ourworldindata.org/
homelessness.
Mental Illness and Homelessness: Facts and Figures: http://
www.hcs.harvard.edu/~hcht/blog/homelessness-and-mental-
health-facts.
The National Law Center on Homelessness and Poverty
(2015). Homelessness in America: Overview of Data and
Causes: https://www.nlchp.org/documents/Homeless_Stats_
Fact_Sheet.
Personal Response
What else do you think needs to be done to raise
awareness and tackle the issue of homelessness?
Sooner rather than later, political leaders will have to
recognize that it’s far less expensive to prevent homelessness
and help people coming out of homelessness than
to maintain the status quo. In fact, there will never be
shortage of homeless people, if the conditions leading to
homelessness won’t be addressed and solved. Homelessness
is only the tip of the iceberg and is the end result of
many social ills including poverty, unaffordable housing,
unemployment, untreated mental illness, lack of social safety
nets, incarceration and family disintegration, among others.
It is therefore of paramount importance to educate the public
and spread awareness of this problem, its causes and its
solutions. The documentary also reminds us that this is an
issue our society cannot afford to ignore if anything for no
other reason at all but doing what’s humane.
Many of us choose to look away and ignore the homeless
because it’s easier to do that than accepting a painful reality
that doesn’t align with our own, or because we harbour
prejudices against them and don’t see them as worthwhile
human beings. Understanding the complexity of the problem
will lead to a positive shift in attitudes and intentions toward
homelessness, eventually resulting in increased support for
changes in social, political and economic policies.
Srdjan Randjelovic/Shutterstock.com
www.researchoutreach.org 113
Health and Patsy Beattie-Huggan BN, MScN, Professor Dr. med. Kirsten
Medicine Steinhausen & Stefanie Harsch, MA Health Education
A framework
for global health
promotion:
The Circle of Health
The Circle of Health (COH) is
an interactive and exemplary
framework that bridges gaps
in health promotion and draws
together both the external
and internal factors that drive
our health. Spearheaded by
Patsy Beattie-Huggan, BN,
MScN, founder and president
of The Quaich Inc., this novel
tool was developed, refined
and evaluated through broad
consultation in PEI, Canada.
With collaborators Kirsten
Steinhausen and Stephanie
Harsch, the team is now focusing
on how it can be used to identify
translational gaps in WHO
declarations, and disseminated
more broadly.
Elnur/Shutterstock.com
114 www.researchoutreach.org
A
n individual’s health is a
combination of many driving
internal and external factors. To
protect and to promote health, various
interventions have been developed but
often many factors are overlooked, and
these therefore lack sustainability. The
Circle of Health (COH) is a translational
tool and value-based framework that
effectively links together all these health
factors to provide effective education,
planning, collaboration and evaluation
in health promotion. By simplifying the
complexity of health into a usable tool,
it plays an important role in helping to
bridge gaps in health promotion and
disease prevention versus lifestyle and
social factors. The COH integrates the
concepts required to plan for health at an
individual, family, community, system and
societal level. The COH can also be used
“The Quaich” is a
Scots rendering of the
Gaelic word meaning
“cup”. They date back
centuries, and are a
symbol of friendship
and community.
to re-analyse findings and provide the
whole picture for the dynamics of health.
Its particular strength compared to other
models is its relevance. Taking a holistic
approach, the framework incorporates a
complete understanding of health, health
promotion strategies, determinants of
health and six key values such as caring
and justice.
It is written in plain language text and
arranged as a multi-coloured tool with
moveable rings which reminds one of a
compass. Visual and kinetic learners find
it easy to use. The COH is designed to
overcome barriers of low literacy, and is
structured to provide a holistic, ‘health in
all settings’ approach. Today, the COH is
used worldwide and has been validated
and internationally evaluated. The COH
is also delivered in a workshop format,
and is available in six different languages
and is transferable to diverse settings
in 20 countries.
The COH was developed in 1996
during health reforms in Prince Edward
Island, Canada. Originally created
to generate a shared understanding
of health promotion amongst many
sectors, COH was developed from
a consultative community-based,
community development process: a
collaboration involving individuals from
government and marginalised sectors.
Funding came via a partnership including
the Prince Edward Island (PEI) Health and
Community Services, Canadian Public
Health Association, Health Promotion
Network Atlantic and the PEI Women’s
Network. Patsy Beattie-Huggan, founder
and President of The Quaich Inc. has
been at the forefront of the development,
use and education of the COH since
the outset. Together with collaborators
Kirsten Steinhausen and Stefanie Harsch,
with the support of Luis Saboga-Nunes,
the team is now focused on using the
COH in different environments and for
diverse target groups to bridge the gap in
the release of World Health Organization
(WHO) declarations where translational
strategies are missing.

UPTAKE AND EVALUATION

Soon after the launch of the COH, it
was observed that there had been
a spontaneous uptake of the COH
in Canada and other countries. This
prompted an evaluation in 1997, which
reported that users in multiple settings
including education, research, and
planning rated both the concept and
design highly at 91%. Patsy Beattie-
Huggan explains: “The unanticipated
uptake of the COH internationally speaks
to a need for tools that focus on holistic
health and empower stakeholders in
multiple sectors to work together.” In
2004, international reviewers from the
UK, USA, Australia and Canada provided
positive feedback on the relevancy of
the COH. With further work, a website,
online workshops, facilitator manual and
supplemental knowledge translation tools
were developed.
The Quaich started delivering online
workshops in 2008. In 2014, the
evaluation of the online workshops
As a shared framework in addressing
complex organisational and global issues
[the COH] could fill the gap.
showed that 100% learned from the
online workshops; 91% regard the COH
as useful to engage others; and 83%
found it beneficial to address social
justice and health equity. In 2018 the
online workshops were adapted and
delivered as credit courses for students at
Furtwangen University, Germany. Positive
evaluations were received from students
and it was concluded that implementing
online training is an ideal method to train
facilitators in different places.
As of 2018, over 10,000 English and
700 copies in other languages of the
COH have been distributed. Workshops
have also been held internationally and
many facilitators trained. Researchers,
practitioners, and academics have found
it to be clear, easy to use and all inclusive.
Some are introducing it to students and
encouraging them to use it as a planning
and assessment tool.
The tool has been utilized in contexts
where students’ first language is not
English. A 2018 study conducted by
researchers in Freiburg, Germany
analysed existing health interventions for
refugees in Germany and assessed the
Rawpixel.com/Shutterstock.com

www.researchoutreach.org 115
 Circle of Health Workshop - EUPHA Conference
2018, Ljubljana, Slovenia.
feasibility of the COH as an analysing
tool. Over 150 interventions were
identified and analysed. Notably,
the COH helped to identify and
systematically organise the broad field
of interventions, analyse the approaches
in general, explore gaps, raise
awareness of unaddressed areas (e.g.
critical health literacy) and of underlying
principles and inspire the development
of new interventions.
BRIDGING THE GAPS:
WHO DECLARATIONS
It is vital to analyse the health
promotion approaches in a country
comprehensively, considering its most
relevant factors and how they link
together. The COH is therefore ideally
placed to bridge the theory to practice
gap in health promotion because it is
holistic. Importantly, the COH can also
assist policy makers and community
leaders undertake steps to promote
health at a system-level.
A gap in the release of the WHO
declarations (Ottawa Charter-Shanghai
Declaration) highlights that translational
strategies have been missing. There
are a number of reasons why the COH
can plug these gaps. It is already used
worldwide and is a translational tool for
116 www.researchoutreach.org
The continued relevance of the COH
demonstrates that tools based on values,
validated with multiple stakeholders,
with a holistic approach resonate with a
wide range of users and can be applied
across different languages and cultures.
health promotion. The COH promotes
the inclusion of values, the Ottawa
Charter, determinants of health and
the aboriginal medicine wheel. It has
been validated by multiple stakeholders
and demonstrates a holistic approach
to areas such as culture and literacy.
As a shared framework in addressing
complex organisational and global
issues it could fill the gap.
VALIDATION AND REDESIGN
Multiple stakeholders have validated
the COH concept. These include
Aboriginal elders, self-help groups and
people with intellectual disabilities. They
recommended adding the Aboriginal
Medicine Wheel, determinants of
gender and culture and plain language
materials to the original prototype
design. As a model of best practice,
the COH has a global potential to be
the ‘people’s framework’. It appeals
to a range of different learning styles
and level of education, and has the
ability to inspire new approaches
to health promotion.
CONCLUSION AND
LESSONS LEARNED
The continued relevance of the COH
demonstrates that tools that employ
a holistic approach and are based on
values resonate with a wide range of
users. The COH has been successfully
applied across different languages and
cultures. It is relevant to practitioners,
educators, researchers, policy makers,
and the general public. Patsy Beattie-
Huggan explains: “This speaks to its
global potential as a useful framework
and tool for collaboration to address
complex issues.” Because of these
qualities, COH is well-placed to meet
the demand for translational tools
to implement WHO declarations.
 Behind the Research
Patsy
Beattie-Huggan
BN, MScN
E: patsy@thequaich.pe.ca T: +1 902-894-3399 W: www.thequaich.pe.ca
E: stefanie.harsch@ph-freiburg.de E: kirsten.steinhausen@hs-furtwangen.de
Research Objectives
To support knowledge translation and innovation in
applications of the Circle of Health© (COH). One of the
leading consulting tools in health promotion, the COH aims
to analyse, plan and implement programs and identify gaps.
Detail
The Quaich Inc., Charlottetown, PEI, Canada
www.thequaich.pe.ca
www.circleofhealth.net
Bio
Patsy Beattie-Huggan BN, MScN, founder and President
of The Quaich Inc. has provided leadership in nursing
education, health system redesign, health promotion
and development of the Circle of Health©, holding a
Bachelor of Nursing from the University of New Brunswick
and MSc in Nursing and Health Studies from the University
of Edinburgh.
Professor Dr. med. Kirsten Steinhausen holds the position of
Professor for Health Sciences and Vice Dean at The Faculty
of Health, Safety and Security, Furtwangen University.
She has experience of hospital project management where
she has implemented evidence-based guidelines. Her
research interests include public health, health policy, health
economics, evidence based practise and health promotion
in the workplace.
Stefanie Harsch, MA, Ph.D. student, works as a research
associate at the University of Education Freiburg, Germany
in a research project supported by the German Federal
Ministry of Education and Research focussing on promoting
health literacy of people with migration and refugee history
in German as a second language course.
Funding
Funding for the development of the Circle of Health
came via a partnership including the PEI Government,
Canadian Public Health Association, PEI Women’s Network,
and Health Promotion Network Atlantic.
Collaborators
Gratitude is expressed to the many people who
contributed to the development, evaluation and
dissemination of the Circle of Health, with special thanks to
Luis Saboga-Nunes, President, EUPHA Health Promotion
Section for more recently encouraging its application in
the European context.
Professor
Dr. med. Kirsten Stefanie Harsch, MA
Steinhausen
References
Beattie-Huggan, P. (2016). Circle of Health - A holistic and
systematic approach to health promotion research, education
and practice. SpiritualitéSanté, Vol. 9, No. 1 (Published in
French; available in English in (Health Promotion Preliminary
Research Report: Looking Back ... Moving Forward, p. 33-38,
Alliance for Health Promotion, Versoix, Switzerland (2016).
Beattie-Huggan, P. (2018). Circle of Health – a unique
knowledge transitional tool with global potential. European
Journal of Public Health, Volume 28, Issue suppl_4, November
2018, cky214.185, https://doi.org/10.1093/eurpub/
cky214.185.
Harsch, S., Beattie-Huggan, P., Steinhausen, K., Saboga-
Nunes, L., & Bittlingmayer, U. H. (2018). Applying the circle of
health to analyse health interventions for people with refugee
experiences in Germany. European Journal of Public Health,
28(suppl_4), cky213-823.
Mitchell, T., Beattie-Huggan, P. (2006). Bridging the distance
between lifestyle and determinants of health approaches:
The Circle of Health as a synthesis tool. International Journal
of Health Promotion & Education, Volume 44 (2): 78 – 82.
PEI Health and Community Services Agency. (1996). Circle
of Health©, Charlottetown (PE, Canada).
Rocha, D., Beattie-Huggan, P., (2016). Potential of distance
learning using a shared framework amongst a community
of dispersed learners across large geographic areas for
implementing a local, national, regional, and global strategy
Presented at 22nd IUHPE Conference, 2016, Curitaba, Brazil.
Personal Response
The Circle of Health has gone from strength to strength.
What is next for the tool?
The potential for the Circle of Health to be used in
additional settings such as those working with children,
refugees and vulnerable populations is endless. The hope
is to expand its use internationally - and share stories
of its use to facilitate a shift to a more holistic approach
to promoting global health. 
www.researchoutreach.org 117
 Health & Medicine ︱ Dr Marlies Wijsenbeek and Dr Karen Moor
Using eHealth to
monitor idiopathic
pulmonary fibrosis
Dr Marlies Wijsenbeek and
Dr Karen Moor from the
Erasmus Medical Centre are
developing novel eHealth tools,
in collaboration with patients,
to enable home monitoring
of patients with idiopathic
pulmonary fibrosis (IPF). Patients
are able to use the eHealth
tool to find information about
IPF, record their symptoms and
conduct consultations via video
or email. Furthermore, the
patient can take regular real-time
spirometry measurements which
can be immediately assessed
by healthcare providers. This
alerts the patient and healthcare
provider to changes in a patient’s
condition leading to potential
treatment adjustments.
michaeljung/Shutterstock.com
118 www.researchoutreach.org
I
diopathic pulmonary fibrosis (IPF) is
a devastating progressive lung disease
with a median survival of only three to
five years. IPF typically occurs more often
in men than women and generally affects
elderly patients, aged 50 years and
above. IPF has a highly variable disease
course. Some patients experience slow
disease progression, whereas others
suffer from a rapid decline in lung
function. The incidence of IPF is steadily
increasing and according to the British
Lung Foundation, over 6,000 people are
diagnosed with IPF every year in the UK.
IPF is characterised by an accumulation
of scar tissue (fibrosis), reducing lung
elasticity which impacts oxygen uptake.
The term ‘idiopathic’ means that the
cause of fibrosis is unknown. However, it
is thought that scar tissue accumulates
due to lung damage from either acid
reflux, viruses, or environmental factors
such as breathing in certain kinds of
dangerous dust. Furthermore, some
patients may be more genetically prone
The uptake of oxygen via the lungs is key for good health. The scarring in IPF
reduces the lung’s elasticity and makes this process less effective.
to developing IPF when their lung
is damaged.
Patients experience symptoms such
as breathlessness, coughing and fatigue.
These symptoms greatly lower the
patient’s quality of life, affecting even
simple tasks such as going to the shops.
Patients lose their independence and
often have to rely on friends and family
for support. Currently, there is no cure
for IPF. In very rare cases, patients may
be given a lung transplant. In general,
patients are given medication and may
also attend therapy to deal with their
symptoms. For example, pulmonary
rehabilitation consists of a specific
exercise programme which helps the
patient cope with feeling short of breath.
There are two anti-fibrotic drugs which
are specifically used to slow down lung
scarring – pirfenidone and nintedanib.
However, these drugs could have
bothersome side-effects such as nausea,
fatigue and diarrhoea. Sebastian Kaulitzki/Shutterstock.com
 REASSESSMENT DURING DISEASE COURSE

Genome

BIOLOGY
Biomarkers

Microbiome MONITORING ON
INTERVENTION
Environmental factors • Patient-reported
outcomes
ENVIRONMENT PERSONALISED
Lifestyle TREATMENT • Patient-collected
outcomes
Comorbidities • Physiological
parameters
Co-medication • Imaging
• Biology (ie. biomarkers,
Patient needs comorbidities)
PATIENT PERSPECTIVE

and perspective

Patient experiences

Home monitoring
INDIVIDUAL PATIENT
Patient-reported PROFILE
outcomes

TREATMENT ADJUSTED
This diagram illustrates the numerous elements involved in personalised treatment,
as well as the reassessments and adjustments needed.

A personalised approach to IPF requires However, Dr Wijsenbeek and Dr Moor allowing for frequent home monitoring,
frequent monitoring due to the highly believe that patient factors, such as evaluation of treatment response and
variable nature of IPF and the variation lifestyle, comorbidities, preferences potential treatment adjustments. In fact,
in response to therapy by different and experiences should also play a a previous study in IPF showed that
patients. Dr Wijsenbeek and Dr Moor role in personalised medicine. Patient home-based measurements predicted
from the Erasmus Medical Centre were engagement is also an important aspect. disease decline better than less frequent
inspired by the possibility of using eHealth For example, it is vital to assess the hospital-based measurements of lung
tools to monitor function. Moreover,
the patient more home monitoring
frequently at home eHealth involves the use of information could be invaluable
with a low burden
for the patients. and communication technologies to for IPF patients as
they often struggle
They aimed to exchange health-related data between to attend frequent

the patient and healthcare provider.

investigate whether
this could improve
patient quality
of life.
PERSONALISED MEDICINE
Lately, there has been increasing interest
in the use of personalised medicine to
treat and monitor disease in IPF. Until
now, personalised medicine has mainly
focused on understanding the molecular
mechanisms underpinning IPF. Little
is understood about the influence of
interactions between environmental,
molecular and genetic mechanisms
and how biological factors affect
disease progression and influence the
effectiveness of different treatment
options. Improving our knowledge
of these mechanisms could lead to the
identification of specific biomarkers
which could be used to develop
targeted therapy.
perspectives of patients before treatment.
In randomised controlled trials, medication
may show beneficial results at a group
level. However, for some individuals,
certain drugs may prove ineffective or
the side effects may outweigh the benefits
of treatment. Currently, over-use and
under-use of medication is fairly common
in IPF. However, this may not be the case
if the patient’s preferences are considered.
These preferences may alter as the disease
progresses, so personalised treatment
plans must be regularly evaluated.
Dr Wijsenbeek and Dr Moor recognise
the importance of personalising treatment
for IPF, taking into consideration the
patient’s perspective, physiology and
lifestyle. They believe that eHealth could
contribute to personalised medicine by
hospital visits due
to reduced motility
and breathlessness.
As a result, the team developed an
award-winning eHealth tool for patients
to improve their understanding of their
health and become actively involved in
managing their disease.
eHEALTH AND HOME MONITORING
eHealth involves the use of information
and communication technologies to
exchange health-related data between
the patient and healthcare provider.
Dr Wijsenbeek and Dr Moor developed
a novel eHealth tool, IPF Online,
in collaboration with patients. This
innovative eHealth tool won two Dutch
prizes - the Patient Participation Prize
in 2018 and the Lung Foundation public
prize in 2016. IPF Online has many
features for patients to utilise including:
an information library, the possibility for

www.researchoutreach.org 119
 econsultations and video consultations,
information about medication and
possible side-effects, an area for patients
to fill in their symptoms and possible side-
effects they may be experiencing and
other patient-reported outcomes, such
as quality-of-life questionnaires. Patient-
reported outcomes are reports of the
patient’s quality of life, health or functional
status that come directly from the patient,
without, for example, interpretation
by clinicians.
IPF Online is integrated with real-time
wireless spirometry. This is a simple test
used to monitor lung conditions using
a spirometer to measure how much air is
breathed out in one forced breath (forced
vital capacity or FVC). Interestingly, the
team believed that a major challenge
would be patient engagement as
many elderly people could possibly be
hesitant using online tools. However,
the majority of IPF patients who were
asked to participate wanted to use
IPF Online. By using IPF Online, the
patient can gain insight into their own
health condition and become involved
in the management of their disease.
The team performed multiple studies
to determine the feasibility of the home
monitoring programme/eHealth tool and
patient satisfaction.
PILOT STUDY
Ten IPF patients from the Erasmus
Medical Centre were involved in the pilot
Mr Aesthetics/Shutterstock.com
Patients can see a daily overview of their lung function results (FVC) in IPF
Online. Healthcare providers can also see these results and receive an alert
if FVC declines >10% for three consecutive days.
120 www.researchoutreach.org
study with home spirometry. Patients
were asked to test IPF online for one
month using a tablet. During this time
patients performed daily home spirometry
and online patient-reported outcomes
at baseline and after four weeks. The
spirometry data is transmitted real-time
and is directly available for analysis
IPF patients found real-time spirometry
very useful and would recommend
it to others.
by both patients and healthcare providers.
Additionally, automated email alerts are
sent if the patient reports troublesome
side-effects or if the FVC declines by
>10% for three consecutive days.
Overall, the results revealed that home
spirometry highly correlated with hospital
spirometry, showing that home spirometry
is a reliable test. Furthermore, 80% of
patients considered daily spirometry easy
and 90% thought that the process was not
burdensome at all. All patients found real-
time spirometry very useful and would
recommend it to other IPF sufferers.
Patients and hospital staff in the study
group did identify several potential issues
with home monitoring and spirometry
and recommendations were made. For
example, a handheld spirometer may be
difficult for patients to use. Therefore,
the team suggested that patients should
be provided with clear training before
they start the programme. Furthermore,
some patients had no internet access. To
tackle this issue, these patients could be
supplied with a 4G SIM card to guarantee
internet access. Patients who had never
used the internet before were able to
use the tablet with ease and perform
spirometry due to the simple design.
Additionally, some patients may not
comply with taking measurements daily.
In these situations, patients could be sent
email reminders.
A limitation of the pilot study is that it
was performed at a single centre with a
relatively small sample size. Although this
was effective at highlighting reliability,
patient satisfaction and identifying
potential barriers, a larger scale, multi-
centre study is needed to see whether
it improves patients’ quality of life in
the long term. The study team is currently
addressing this by performing a multi-
centre randomised clinical trial with three
other centres in the Netherlands. The
team is following patients for six months to
investigate whether the home monitoring
programme/eHealth tool improves quality
of life compared to standard care.
FUTURE PERSPECTIVES
Dr Wijsenbeek and Dr Moor, in
collaboration with patients and healthcare
staff, have designed a novel eHealth tool
that enables personalised, individually-
tailored therapy. Patients can understand
their own condition and have
a say in managing their
own disease. Furthermore,
by performing real-time
spirometry measurements,
which are immediately
available to health care
providers, changes in condition are quickly
identified and the right treatment can
be given. eHealth tools could revolutionise
how we treat chronic, long-term
conditions. In the future, eHealth tools
could be integrated in clinical practice
to truly embrace personalised medicine.
 Behind the Research
Dr Marlies
Wijsenbeek Dr Karen Moor
E: m.wijsenbeek-lourens@erasmusmc.nl E: c.moor@erasmusmc.nl T: +31650031750 W: www.ipfonline.nl

Research Objectives
Drs Wijsenbeek and Moor evaluated a new home monitoring programme with real-time wireless home spirometry in idiopathic
pulmonary fibrosis.

Detail
Erasmus Medical Center Rotterdam
Department of Respiratory diseases
Dr. Molewaterplein 40
3015 GD
Rotterdam
Bio
Marlies Wijsenbeek is a pulmonary
physician and associate professor at the
Erasmus MC in Rotterdam. She is chair
of the Erasmus MC multidisciplinary
interstitial lung disease center (ILD) centre,
secretary of the Idiopathic Pulmonary
Pneumonia Group of the European
Respiratory Society and the Dutch
National ILD section, and board member
of the Netherlands Respiratory Society.
Her research interests include eHealth
and other patient-centred outcome
measures in interstitial lung diseases, and
new therapies in IPF and sarcoidosis.
Karen Moor is a PhD candidate at the
Respiratory Department of the Erasmus
MC in Rotterdam. The aim of her research
is to improve clinical outcome measures
and quality of life for patients with IPF,
with a special focus on the development
and use of eHealth tools.
Funding
ZonMw, Roche, Boehringer Ingelheim,
Erasmus MC Thorax Foundation
Collaborators
Currently a randomised controlled trial
is being carried out together with the
hospitals Zuyderland MC, St. Antonius
hospital and OLVG in the Netherlands.

References Personal Response

Moor, C.C., Heukels, P., Kool, M. and Wijsenbeek, M.S., 2017.
Integrating patient perspectives into personalized medicine in
idiopathic pulmonary fibrosis. Frontiers in medicine,4, p.226.
Moor, C.C., van Manen, M.J., Tak, N.C., van Noort, E.
and Wijsenbeek, M.S., 2018. Development and feasibility
of an eHealth tool for idiopathic pulmonary fibrosis. European
Respiratory Journal,51(3), p.1702508.
Moor, C.C., Wapenaar, M., Miedema, J.R., Geelhoed, J.J.M.,
Chandoesing, P.P. and Wijsenbeek, M.S., 2018. A home
monitoring program including real-time wireless home
spirometry in idiopathic pulmonary fibrosis: a pilot study on
experiences and barriers. Respiratory research,19(1), p.105.
How could eHealth tools, such as IPF Online,
improve patients’ quality of life in the long term?
eHealth tools enable frequent monitoring at home
at a low burden for patients. This is especially important
in a chronic progressive disease such as IPF, which has a
huge impact on patient quality of life and a high symptom
burden. Our home monitoring programme IPF Online
has the potential to improve quality of life through patient
engagement, better medication use, low-threshold
communication, stimulation of self-management
and earlier detection of disease deterioration. 

Idiopathic Pulmonary Fibrosis. British Lung Foundation.

Available at: https://www.blf.org.uk/support-for-you/
idiopathic-pulmonary-fibrosis-ipf [Accessed 12/02/2019]

www.researchoutreach.org 121
Health and Medicine ︱ The National Prostate Cancer Register
NPCR: Next generation
cancer register
Knowledge is power and in
this modern age, data is often
our most valuable commodity.
Nowhere is this truer than in
healthcare, where patient data
is revolutionizing the way we
treat diseases such as cancer.
To that end, the National
Prostate Cancer Register
(NPCR) is providing a valuable
resource for physicians, patients,
and researchers. And it has
already contributed to several
improvements to prostate
cancer care in Sweden.
Figure 1. Linkages and number of cross-linked
men in the Prostate Cancer
data Base Sweden (PCBaSe) 4.0.
The Prostate Cancer data Base Sweden (PCBaSe) 4.0
Swedish cancer
register
39,039 cases
The
multi-generation
register
61,719 men with
brothers;
97,170 men with
fathers
122 www.researchoutreach.org
T
he National Prostate Cancer
Register (NPCR) of Sweden is
a clinical cancer register, which
serves as a tool for quality assurance and
research. The ultimate goal of the NPCR
is to ensure that every man diagnosed
with prostate cancer receives optimal
treatment. The NPCR enables this by
collecting information on men diagnosed
with prostate cancer, their treatments
and the outcome of treatments.
Information in NPCR is used in a number
of ways by patients, physicians and
researchers to improve patient outcomes.
The forerunner to the NPCR was the
Southeast Regional Prostate Cancer
Registry, set up in 1987. Other healthcare
regions joined and by 1998 all six of
Sweden’s healthcare regions were
part of NPCR. Since 1998, NPCR has
captured information from 98% of all
newly diagnosed cases of prostate cancer
as compared to the National Cancer
Registry to which reporting is mandated
by law. As of March 2018, a total of
181,660 cases of prostate cancer had
been registered.
Management and operation of the
register is overseen by its steering
committee, consisting of one urologist
The cause of The prescribed
death register drug register
80,381 cases 160,121 cases
NPCR
185,729 cases
x 5 controls
The LISA The national
database patient register
185,714 cases 184,416 cases
and one oncologist from each of the
six healthcare regions in Sweden, as
well as two patient representatives.
The Swedish Association of Local
Authorities and Regions is a major
funding body of NPCR.
Using the unique Swedish person
identity number, the NPCR has been
linked with a number of other registries
such as The National Patient Registry,
the Cause of Death Registry and
the Prescribed Drug Registry in the
Prostate Cancer data Base Sweden (Fig
1). This means that researchers now
have access to a database of close to
200,000 prostate cancer cases and one
million prostate cancer-free men to
use as controls, creating an invaluable
resource for research. The usefulness
of PCBaSe as a tool for researchers
is evident from the fact that it has
formed the basis of more than 130
peer-reviewed research articles since
its inception in 2010.
RAISING STANDARDS OF CARE
The reports generated from data
in NPCR allow both patients and
physicians to access information on
quality of care in all departments in
Sweden and their adherence to the
national treatment guidelines.
The first of these reports, termed
“What’s going on” is a dashboard
panel that enables healthcare
professionals to access data on patient
treatment in real-time on a secured
server (Fig 2). Data is collected,
collated, and reported promptly,
and the system is designed to
provide information in a user-friendly
format that enables efficient quality
control of patient care. The service
allows physicians to select specific
groups of patients and compare the
care provided by their department
with national standards and other
departments in Sweden. The dashboard
 INDICATORS PATIENTS My clinic PERFORMANCE Legend to indicators
Sweden overall 2010-2013 1. Proportion of men who were reported to NPCR within 30 days of their
cancer diagnosis.
1 1. Reported to NPCR 45/99 45%
10% 2. Proportion of men who have named navigator nurse.
30 60 % 10 22 31 40 % 3. Proportion of men who had a first outpatient visit due to suspicion or
1 2. Navigator nurse 70/87 80% prostrate cancer within 50 days of referral.
50% 4. Proportion of men who were informed of their cancer diagnosis within 18
45 90 % - - - - % days after prostate biopsy.
0 3. Waiting time to first 50/86 58% 5. Proportion of men up to 80 years of age with high risk cancer who ere
visit 40% investigated for bone metastases. High Risk Cancer: T1,2 and Gleason
70 95 % 62 59 72 71 % 8-10 or PSA 20-50 ng/ml or T3 and PSA<50ng/ml.
0 4. Waiting time to cancer 5/99 5% 6. Proportion of men with very low risk cancer who were who were started
diagnosis 10% on active surveillance. Cancer with very low risk. T1c, Gleason 6 or lower,
30 60 % 1 1 2 4 % PSA below 10ng/ml, PSA density below 0.15ng/ml, no more than four
1 5. Bone Imaging, high 20/25 80% cores with cancer, no more than 8mm of cancer in total at biopsy.
risk cancer 82% 7. Proportion of men with high risk cancer for whom curative Tχ can be
70 95 % 50 64 81 75 % considered who were discussed at a multidisciplinary team meeting.
2 6. Active surveillance, 21/22 95% 8. Proportion of men not older than 75 years with localized high risk cancer
very low risk cancer 75% who received curative treatment. Localized high risk cancer: T1, 2 and
70 95 % 50 64 68 81 % Gleason 8-10 and/or PSA 20-50 ng/ml and no metastases.

1 7. Multidisciplinary team 15/30 50% 9. Proportion of men for whom nerve sparing intention at radical
meeting, high risk cancer 45% prostatectomy was documented preoperatively.
30 70 % 15 25 39 49 % 10. Proportion of men diagnosed with pT2 cancer at prostatectomy who
1 8. Curative treatment, 75/87 86% had negative margins, ie. radically removed tumour.
localized high risk cancer 71% Patients
70 95% 61 74 84 85 % Number of patients for whom high quality level was reached out of all
2 9. Nerve sparing intention 33/24 138% reported patients.
45% My clinic/Sweden overall
70 95 % 45 46 59 61 % Number of patients for whom inidcator level was reached. Vertical lines
1 10. Negative margins 36/48 75% indicate upper and lower level cut-offs. Mean value for the whole country
64% Patients
70 95 % 75 77 69 80 % Performance in the last four years.

Figure 2. ‘What’s Going On’ online report on the performance on 10 quality indicators at each urological department based on data reported to the National
Prostate Cancer Register (NPCR) of Sweden. The definition of each indicator is seen to the left of the page. In the far left column, a colour-coded indicator
demonstrates the performance level achieved by the clinic. Red = 0 points, lowest category of performance; yellow = 1 point, intermediate level; and green
= 2 points, highest level. The number of cases for whom the goal was reached, i.e. the numerator, and all patients eligible for the specific indicator, i.e.
the denominator, is displayed in the third column. The horizontal bars in this diagram show the proportion of men for whom the goal was reached, for the
reporting clinic in blue and the national mean in grey. The vertical bars are the cut-offs for the three target levels. The next column with vertical bars shows
the performance for the clinic during the preceding 4 years.

report presents results for ten indicators
of the quality of care taken from Swedish
National Prostate Cancer Guidelines.
Another public reporting system has
recently been set up. RATTEN (www.
npcr.se/RATTEN) is an online portal where
patients and other stakeholders can
access a database and create reports
according to their own requirements (Fig
3). At the RATTEN home page, the viewer
is presented with a short report and
some key data, they can then select the
healthcare region, year of diagnosis, age
and cancer risk category they desire in
order to create a report for their
desired population. The data can then
be presented as a table, figure, or
heatmap, and users can export the results
as a spreadsheet.
The steering committee of the NPCR
strongly promotes the use of the What’s
going on and RATTEN reporting systems,
as they firmly believe that use of these
systems by healthcare professionals
and patients will improve standards of
care in the treatment of prostate cancer.
Indeed, improvements have already been
seen as a result of the work of NPCR.
For example, the NPCR has repeatedly
drawn attention to the number of men
with low-risk prostate cancer who
received bone scans at each department
in its annual report. In 2008 and 2009,
the number of patients receiving these
unnecessary investigations was as low
as 3%, down from 45% in 1998. The use
of active surveillance, the recommended
treatment strategy for low-risk cancer,
increased from 40% to 74% between
2009 and 2014. Although this is also the
recommended treatment in many other
countries, no other register has reported
such high use of active surveillance.
A randomized clinical trial showed the
superiority of radiotherapy and androgen

Figure 3a. Median waiting times (days) from Figure 3b. Diagnostic median waiting time (days) Figure 3c. Radiotherapy treatment in men aged
referral to first visit for 2018 diagnoses. per region for 2018 diagnoses. 70-80 years with high risk prostate cancer.
Data source: www.npcr.se/RATTEN. Data source: www.npcr.se/RATTEN. Data source: www.npcr.se/RATTEN.

www.researchoutreach.org 123
deprivation therapy (ADT) as compared
to ADT alone in decreasing mortality.
Accordingly, in men aged 70–80 with high
risk, non-metastatic prostate cancer, use
of radiotherapy plus ADT has increased
from 10% in 2001 to almost 50% in 2012
(https://statistik.incanet.se/npcr/; Fig 3c).
The steering committee believes the
NPCR shares the credit for bringing about
these positive changes.
Erectile Dysfunction
1) No ED (IIEF-5 score 22-25)
2) Mild ED (IIEF-5 score 17-21)
3) Mild to moderate ED (IIEF-5 score 12-16)
4) Moderate ED (IIEF-5 score 8-11)
5) Severe ED (IIEF-5 score 5-7)
Baseline 26
RP: Surgeon #1
Figure 4. NPCR’s electronic Patient Reported Outcome
Questionnaire (PROM) allows quality control of results
from treatments that carry a risk of erectile dysfunction.
This data is fictive.
No. cases
3 months 24
1 year 26

NPCR AS A RESEARCH TOOL Baseline 45

Post-authorisation safety studies (PASS) RP: Surgeon #2 3 months 42
are investigations of rare adverse events 1 year 37
from drugs that are in common use.
To perform such studies, data on drug Baseline 102
use and outcome from very large RP: Surgeon #3
3 months 99
populations are required. PCBaSe is 1 year 92
the perfect basis for PASS. In a paper
published in JAMA in 2015, Loeb and Baseline 75
colleagues used information from the RP: Surgeon #4 3 months 72
PCBaSe to investigate a purported link
1 year 69
between one of the drugs most commonly
used to treat erectile disfunction (Viagra, Baseline 50
a phosphodiesterase Type 5 Inhibitor RP: Surgeon #5 3 months 46
PDEi) and an increased risk of malignant
1 year 46
melanoma. They found no clinically
meaningful increase in risk. Baseline 298

RP: Hospital 3 months 283

The comprehensive data in PCBaSe 1 year 270
combined with data from the Melanoma
Register demonstrated that men taking Baseline 2536
Viagra had higher risk of malignant RP: Sweden 3 months 2409
melanoma than expected. For example,
1 year 2282
men taking Viagra had a higher level
of education and income, which 0 20 40 60 80 100
are associated with more sun exposure
Very low risk Localised high risk
RISK GROUP

and higher risk of melanoma. Low risk (other) Locally advanced

In a more recent study, Robinson et al
found little support for an association
between the use of GnRH agonists, a
drug used by men with advanced prostate
cancer and Alzheimer’s dementia, which
had been reported in some previous
publications. These studies show the
value of a comprehensive and readily
accessible clinical database with
complete data on drug exposure, cancer
outcome and other relevant factors such
as socioeconomic status.
FUTURE OUTLOOK
The NPCR and PCBaSe continue
to be improved. For example, NPCR
now implements electronic patient
reported outcome (PROM) questionnaires
distributed before radical radiotherapy
and prostatectomy, and after 3 months,
1, 3 and 5 years after treatment. This
Low risk (type missing) Regionally metastatic Percent
Intermediate risk Distant metastases 1) 2) 3) 4) 5)
NPCR, a clinical cancer register is
used in a number of ways by patients,
physicians and researchers to improve
cancer care and patient outcomes.
enables the quality control of the results of of prostate cancer has drastically changed
radical treatments that carry an important with the advent of improved magnetic
risk of erectile dysfunction and urinary resonance imaging. The effect of this
incontinence (Fig 4). NPCR has also new diagnostic must be documented
initiated Patient-overview Prostate Cancer and assessed and here also NPCR has
(PPC) that longitudinally records data an important role to play. NPCR continues
on men with metastatic prostate cancer. to strive to reach the goal that every man
This is an invaluable resource since there diagnosed with prostate cancer receives
are now several drugs that can increase optimal treatment, maximal cancer
survival and quality of life in men with treatment with minimal side-effects.
metastatic prostate cancer. At the other For more information about NPCR visit
end of the disease spectrum, diagnosis http://npcr.se/

124 www.researchoutreach.org
 Behind the Research
The National Prostate Cancer Register
E: npcr@npcr.se T: +46 18 611 46 61 W: www.npcr.se

Research Objectives References

The National Prostate Cancer Register (NPCR) is a tool for Loeb S, Folkvaljon Y, Lambe M, Robinson D, Garmo H,
quality assurance and quality improvement of health care Ingvar C, Stattin P. (2015). Use of Phosphodiesterase Type
for all men with prostate cancer in all ages in Sweden. 5 Inhibitors for Erectile Dysfunction and Risk of Malignant
Melanoma. AMA. 313(24):2449-55.

Stattin P, Sandin F, Sandbäck T, Damber JE, Franck Lissbrant

Detail I, Robinson D, Bratt O, Lambe M. (2016). Dashboard report
on performance on select quality indicators to cancer care
Pär Stattin, register holder, professor and consultant in
providers. Scand J Urol. 50(1):21-8.
Urology, Department of Surgical Sciences,
Uppsala University Hospital, Sweden, entrance 70 Stattin, P., Sandin, F., Hellström, K, Ingela R, Lissbrant F.
751 85 Uppsala, Sweden. (2017). The National Prostate Cancer Register of Sweden,
basis for quality assessment, quality improvement, and
Bio research. Tijdschr Urol; 7:50.
NPCR is a nationwide, population-based clinical register
that captures 98% of all newly diagnosed prostate cancer Stattin P, Sandin F, Loeb S, Robinson D, Lissbrant IF, Lambe
M. (2018). Public online reporting from a nationwide
cases in Sweden since 1998. Through the use of the unique
population-based clinical prostate cancer register. BJU Int.
Swedish person identity number, NPCR has been linked 122(1):8-10. doi: 10.1111/bju.14213. Epub 2018 Apr 17.
to other health care registers and demographic databases
in prostate Cancer data Base Sweden (PCBaSe). Van Hemelrijck M, Garmo H, Wigertz A, Nilsson P, Stattin
P. (2016). Cohort Profile Update: The National Prostate
Funding Cancer Register of Sweden and Prostate Cancer data
Swedish Association of Local Authorities and Regions, Base--a refined prostate cancer trajectory. Int J Epidemiol.
45(1):73-82.
Prostate Cancer Patient Association, Swedish Cancer
Society, Swedish Research Council, Uppsala University
Robinson D, Garmo H, Van Hemelrijck M, Damber JE,
Bratt O, Holmberg L, Wahlund LO, Stattin P, Adolfsson J.
Collaborators Androgen deprivation therapy for prostate cancer and risk
The National Prostate Cancer Register of Sweden (NPCR) of dementia. BJU Int. ePUB 2019 Jan 13.
steering group:
• Pär Stattin (register holder) • Ingela Franck Lissbran
• Anders Widmark • Maria Nyberg
• Camilla Thellenberg • Ola Bratt
Karlsson • Olof Ståhl
• Ove Andrén • Olof Akre Personal Response
• Lennart Åström • Per Fransson
• Magnus Törnblom • Eva Johansson What does the NPCR steering committee see as the
• Stefan Carlsson • Mats Lambe important trends in the future of prostate cancer
• Marie Hjälm-Eriksson • Fredrik Sandin treatment, and how will the NPCR and PCBaSe evolve
• David Robinson • Karin Hellström to meet those needs?
• Mats Andén • Calle Waller The NPCR steering committee are focusing
• Jonas Hugosson • Gert Malmberg. on reporting of patient reported outcome (PROM)
questionnaires as it is a crucial part of the evaluation of the
quality of care. PROM is collected both in conjunction with
radical therapy and longitudinally in men with advanced
prostate cancer.

www.researchoutreach.org 125
Health and Medicine ︱ Dr Heiko Enderling
Towards a quantitative
personalised oncology
Dr Heiko Enderling from Moffitt
Cancer Center, together with
researchers from the Polish
Academy of Sciences and the
Helmholtz Centre for Infection
Research, focus on Mathematical
Oncology, and radiotherapy
in particular, highlighted
by the interconnectivity of
metastatic disease through a
patient’s immune system. Studies
show that different radiation
doses induce anti-tumour
immunity at different strengths.
This prompted the research
team to develop a variety of
mathematical models to calculate
the best radiation protocols
and optimum timing of treatment
in their quest to maximally
synergise radiation-induced cell
death and the subsequent waves
of immune responses.
Dr Enderling and a colleague
examine the results from their work.
126 www.researchoutreach.org
M
ore than half of cancer patients
receive radiation treatment at
some point during their care.
Radiation therapy is prescribed more
often than any other oncology treatment.
CURRENT RADIATION PROTOCOLS
Currently, radiation treatment involves
delivering the maximum tolerable
doses to patients. This protocol was
established after many dose escalation
trials in order to increase average survival
rates. Unfortunately, patients’ side effects
can include severe radiation toxicities.
Radiation, however, is also thought to
boost the immune system to help fight
cancer. Research suggests that the
success of radiotherapy treatment could
well be a combination of killing tumour
cells by direct cytotoxicity, and maybe
even more importantly, its anti-tumour
immunity effect. Current radiation
protocols do not focus on enhancing
these immune responses. Research
studies have shown that various radiation
doses stimulate anti-tumour immunity
at different rates. This has led researchers
to search for the best possible radiation
dose and dose fractionation to optimise
the amalgamation of cell death by direct
radiation cytotoxicity and the ensuing
anti-tumour immune responses.
Dr Heiko Enderling and Dr Rachel Howard
from the Department of Integrated
Mathematical Oncology at H. Lee Moffitt
Cancer Center & Research Institute,
Florida, together with Dr Jan Poleszczuk
from the Polish Academy of Sciences,
Poland and Dr Juan Carlos Lopez Alfonso
from the Helmholtz Centre for Infection
Research, Germany, are integrating
mathematical, biological, and clinical
sciences to model, simulate, and predict
treatment response for individual patients.
They have developed a variety of
mathematical models to calculate the best
radiation protocols and optimum timing
of treatment. Their work is at the forefront
of ‘virtual trials’ to personalise cancer
treatment in order to provide optimal
adaptive cancer therapy for each patient.
METASTATIC CANCER
The researchers have observed patients
with metastatic cancer. This is where the
cancer cells have spread from the place
where they first formed to another part
of the body. The cancer cells break away
from the initial tumour and travel through
the blood or lymph system, forming
a new tumour in another location. This
new, metastatic tumour is the same
type of cancer as the original tumour
although it is located in a different place.
Dr Enderling and his team have studied
the response of tumours outside of the
radiation field, known as the Abscopal
Effect. In patients with metastatic disease,
the irradiation of a single tumour site
causes regression of tumours elsewhere
in the patient body as well. As Dr
Enderling explains: “This highlights the
interconnectivity of metastatic disease
 Dr Enderling engages in teaching
as well as research activities.

through the patient’s immune system,

and local therapy such as radiotherapy,
or even surgery, changes the number of
immune cells within the treatment field.
Some of the immune cells are killed while
others are stimulated. These changes
will manifest systemically as the immune
system is body-wide.” These exciting
observations have prompted the research
team to depart from the concept of
‘local therapy’ in order to develop their
understanding of radiation as a biological
agent that acts on the entire body.

The researchers’ work shows that in

metastatic disease, tumours in different
parts of the body participate differently
in immune surveillance. Most intriguingly,
the interdependence of different cancers
in a patient’s body through the immune
system is challenging our current
understanding of cancer metastases.
The traditional belief that tumours
metastasise when they are big may
not always be accurate. Rather, some
tumours may be big because they have
metastasised. If tumours with a strong
immune response shed metastases
throughout the body, some cells of
the immune system will be re-routed
to the distant metastases. This divide-
and-conquer strategy will allow for escape
from immune-mediated tumour control.
Dr Enderling and his team therefore need
to identify the best radiation treatment
target so as to induce systemic responses
and kill the tumours that were not directly
targeted by radiation.
More than half of cancer patients receive
radiation treatment at some point during
their care.
theory concepts to help identify those
treatment approaches with the highest
likelihood of success. These treatments
can then be put forward for subsequent
experimental and clinical validation.
The research team have developed
a mathematical model that simulates
radiation response, radiation-induced
immune activation, immune checkpoint
blockade therapy and inter-exchange of
activated T cells (a type of white blood
cell that kills cancer cells) between
tumour sites. This model differs from
the theoretical constructs of predator-prey
systems that have gone before.
The new model is first compared
to experimental data. Based on the
experimental setting, tumour sites are
modelled at different spatially-separated
locations and each one is characterised
by a time-dependent volume. At each
site, the researchers add data of four
co-existing and interacting populations:
(1) viable cancer cells, (2) cancer cells

MATHEMATICAL
MODELLING APPROACH
Radiation is often prescribed with
Tumour 1 Tumour 2
other therapies such as surgery,
chemotherapy, targeted agents and Tumour 1 Tumour 2
antigen presenting cells antigen presenting cells
immunotherapy. The vast number of
possible radiation doses together with
GI tract
the different combinations of various and
lymph spleen lymph
therapies, in various orders, at various node node
lungs liver
times for patients with metastatic
diseases render it impossible to other
organs
experimentally and clinically test all the
possible permutations. The researchers’
mathematical modelling approaches effector T cells
Activated against Tumour 2
use the available preclinical data and
effector T cells
outcomes from clinical studies to simulate activated against Tumour 1
all possible permutations of treatment
protocols. Dr Enderling and his team are
using machine learning and optimisation Schematic illustrating how tumours are connected through the patient’s blood system.

www.researchoutreach.org 127
dying in a non-immunogenic manner, (3)
cancer cells dying in an immunogenic
manner and (4) activated tumour-specific
cytotoxic T cells (effector cells). This data-
fitting procedure allows the researchers
to estimate the model parameters. These
are then used to predict responses to
those dosages that have not already been
considered in the experimental setting.
Complex interactions occur between
tumours and the patient’s immune
system, the outcomes of which can range
from tumour eradication to tumour-
immune co-existence (or dormancy)
and rapid outgrowth of the cancer cell
population. This issue becomes more
Their work is at the forefront of ‘virtual
trials’ to personalise cancer treatment
in order to provide optimal adaptive
cancer therapy for each patient.
complex when we learn that cytotoxic
T cells can move through the patient’s
circulatory system. Dr Enderling and
his team have coupled mathematical
models of local tumour-immune dynamics
and systemic T cell trafficking in order
to simulate the evolution of tumour
and immune cell populations following
local radiation and model the immune
interconnectivity. Their results suggest
that the presence of a second tumour
may either inhibit or promote the growth
of the original tumour, depending on
their capacity for immune recruitment and
the resulting systemic redistribution of
The team takes a collaborative approach to their work.
128 www.researchoutreach.org
T cells. The researchers are able to model
the effects of treatment such as surgical
resection and radiotherapy to estimate
both the decrease in the original tumour
volume and the change in the overall
tumour burden. The model provided
qualitatively similar responses to those
reported in the clinical setting. It would
also suggest that if metastatic sites are
interconnected through the patient’s
immune system, truly local therapy does
not exist.
MATHEMATICAL ONCOLOGY
The numerous clinically feasible radiation
doses and dose fractionations render
an exhaustive pre-clinical evaluation
impossible. Progress in integrated
mathematical oncology, however,
may make such analyses possible. Dr
Enderling and his research team are
introducing novel mathematical models
which are calibrated with experimental
data in order to make inroads into
deciphering the complexity of radiation
and immune system synergy. The model
estimates the optimal number of radiation
fractions and radiation dose per fraction
to obtain the most beneficial systemic
immune-mediated tumour responses for
clinically relevant total and biologically
effective radiation doses. This will enable
a departure from the current protocol
of giving patients the maximum tolerable
doses, a one-size-fits-all approach, and
instead provide patient-specific precision
radiation therapy and move towards
personalised medicine.
DISCUSSION
The ground-breaking model simulations
are trained on specific experimental
datasets in order to highlight the
treatment that will have the highest
likelihood of success. Importantly, this
may contribute to the eradication of the
tumour targeted by the radiation, as well
as those tumours and individual cancer
cells outside the radiation field through
activation of systemic immunity.
Dr Enderling’s team have found their
model simulations making predictions
suggesting that conventional radiation
schemas may not be able to obtain strong
immune-mediated tumour responses. It
is plausible that systemic responses would
be especially important for metastatic
patients with lymph node involvement,
circulating tumour cells or subclinical or
undiagnosed metastatic deposits. This will
add a further layer of complexity to the
modelling so the researchers can balance
the different biological consequences
of radiation therapy in order to induce
maximum cell killing, while sparing
immune cells and maximising subsequent
radiation-induced immunity.
The researchers are aware that their
results to date may be biased by the
experimental data that they have used
for model calibration. To further develop
the model, they will be examining more
complex metastatic disease distributions,
comprising combinations of tumours
in different organs, using the proposed
framework. Nevertheless, their work so
far provides the quantitative foundations
to evaluate radiation fractionation
protocols in order to induce immune-
mediated systemic anti-tumour responses.
With the continuously increasing number
of clinical trials combining radiation
and various forms of immunotherapy,
this model could become an invaluable
tool for evaluating clinical responses.
Excitingly, it could also be employed to
help design subsequent clinical protocols
and, eventually, support individual patient
treatment planning, providing quantitative
personalised oncology.
 Behind the Research
Dr Heiko Enderling
T: +1.813.745.3562 W: http://labpages2.moffitt.org/enderling/

Research Objectives
Positioned at the forefront of ‘virtual’ trials to personalise cancer treatment, the Quantitative Personalised Oncology Lab, housed
within Moffitt Cancer Center, integrates mathematical, biological and clinical sciences to model, simulate and predict treatment
response for individual patients.

Detail
H. Lee Moffitt Cancer Center & Research
Institute,
19202 USF Magnolia Dr., Tampa, FL,
33612, USA
Bio
Dr Enderling received his PhD in
Mathematical Biology from the University
of Dundee before taking up position
of Postdoctoral Researcher at Dundee
and then Postdoctoral Fellow at Tufts
University School of Medicine. He is
currently an Associate Member of the
Integrated Mathematical Oncology
Department at Moffitt Cancer Center,
where his research interests lie in
developing patient-specific optimal
cancer treatments.
Collaborators
• Dr Jan Poleszczuk (Polish Academy
of Sciences, Poland)
• Dr Rachel Howard (Moffitt
Cancer Center)
• Dr Juan Carlos Lopez Alfonso
(Helmholtz Centre for Infection
Research, Germany)

References Personal Response

JC Lopez Alfonso, J.C., Poleszczuk, J., Walker, R., Kim,
S., Pilon-Thomas, S., Conejo-Garcia, J.J., Soliman, H.,
Czerniecki, B., Harrison, L.B., Enderling, H. (2019). On
the immunological consequences of sequencing cancer
radiotherapy and surgery. JCO Clin. Cancer Inform. 3:1-16.
Poleszczuk J., Enderling H. (2018). The Optimal Radiation
Dose to Induce Robust Systemic Anti-Tumor Immunity. Int
J Mol Sci. 19(11).
Walker, R., Poleszczuk, J., Pilon-Thomas, S., Anderson, A.,
Czerniecki, B., Harrison, L., Moros, E., Enderling, H. (2018).
Immune interconnectivity of anatomically distant tumors
as a potential mediator of systemic responses to local
therapy. Sci. Rep. 8(1), 9474.
Poleszczuk, J., Luddy, K., Chen, L., Lee, J.K., Harrison,
L.B., Czerniecki, B.J., Soliman, H., Enderling, H. (2017).
Neoadjuvant radiotherapy of early-stage breast cancer and
long-term disease-free survival. Breast Cancer Res. 19, 75.
Poleszczuk, J., Luddy, K.A., Prokopiou, S., Robertson-Tessi,
M., Moros, E.G., Fishman, M., Djeu, J.Y., Finkelstein, S.E.,
Enderling, H. Abscopal benefits of localized radiotherapy
depend on activated T cell trafficking and distribution
between metastatic lesions. Cancer Res. 2016, 76,
1009–1018.
What is your next move towards providing optimal
adaptive cancer therapy for individual patients?
Our mathematical models generate a number of
very exciting hypotheses. The next step is to validate
mathematical predictions experimentally and ultimately
clinically. We have designed intriguing experiments
together with our colleagues in cell biology, cancer
immunology, radiation biology, and radiation oncology
to fully decipher the complex, adaptive dynamics of cancers
when confronted with an immune response before, during
and after radiation therapy. We have begun to amend
ongoing clinical trials to specifically collect biological
specimens from biopsies, surgery and blood draws during
the long treatment course. These samples will be analysed
for the role of all participating players in the tumour-immune
ecosystem, and how such roles and interactions might
change over time. Then, we might be able to prescribe
radiation not only to kill as many cancer cells as possible,
but also with the intent to activate robust immune
responses to help fight the tumour.

www.researchoutreach.org 129
 Health and Medicine ︱ Ekaterina Muyzhnek
Exciting advancements in
ovarian cancer treatment
O
Ovarian cancer is treacherous
and challenging to treat. With
standard treatment unchanged
since the 1990s and newer costly
treatments failing to restrain
the tumour’s growth over long
periods of time, an overhaul in
anti-cancer treatment is urgently
needed. With fresh insights into
the biology and progression of
ovarian cancer, Lev Ashraphyan,
Vsevolod Kiselev from Institute
of Gynecologic Oncology
and Mammology of Acad.
V.I.Kulakov National Medical
Research Centre of Obstetrics,
Gynecology and Perinatology,
the Ministry of Health of Russia,
and Ekaterina Muyzhnek
from the pharmaceutical
company, IlmixGroup, and
Gennady Sukhikh from Acad.
V.I.Kulakov National Medical
Research Centre of Obstetrics,
Gynecology and Perinatology,
the Ministry of Health of Russia
have uncovered a promising
new treatment.
CI Photos/Shutterstock.com
130 www.researchoutreach.org
varian cancer is treacherous
and crafty. Laying low and
silently spreading, the tumour
thrives undetected. When it’s finally
identified the tumour is often advanced
and is a formidable challenge to treat.
Its aggressiveness leaves women with
a five year survival rate of anywhere
between 12-42%, taking 150,000
lives annually worldwide. For this, it is
known as the ‘Silent Killer’. A promising
new therapy for this cruel cancer has
been developed by clinicians and
scientists including Academician of
the Russian Academy of Sciences,
Prof Lev Ashraphyan and Associate
academician of the Russian Academy
of Sciences, Prof Vsevolod Kiselev from
Institute of Gynecologic Oncology and
Mammology of Acad. V.I.Kulakov National
Medical Research Centre of Obstetrics,
Gynecology and Perinatology, the
Ministry of Health of Russia; Dr Ekaterina
Muyzhnek from the pharmaceutical
company, IlmixGroup, and Academician
of the Russian Academy of Sciences, Prof
Gennady Sukhikh from Acad. V.I.Kulakov
National Medical Research Centre of
Obstetrics, Gynecology and Perinatology,
the Ministry of Health of Russia.
TENACIOUS TUMOURS
Treatment for ovarian cancer has
changed little since the late 1990s.
The standard treatment involves surgery
to remove as much of the tumour as
possible (maximal cytoreductive surgery)
followed by a cocktail of platinum-based
drugs and taxanes (chemotherapy),
aimed at killing cancer cells. One
would think that attacking the tumour
from all angles would wipe it out for
good, yet this is not the case. Within
6 – 24 months after the treatment,
60-80% of patients relapse and further
cycles of chemotherapy are required.
Unfortunately, chemotherapy doesn’t kill
all the cancer cells, some are resistant to
the drugs. When a drug attempts to kill
a cancer cell, it has no effect on resistant
cancer cells and they stay alive. Once
the resistant cells start multiplying they
form chemoresistant tumours, whichs
can’t be destroyed, leading to medical
complications and early deaths.
The need for more effective treatments
has never been more urgent.
In recent years, targeted anti-tumour
drugs known as ‘Breakthrough
Therapies’ have been made widely
available. With a catch phrase like that
we should all be jumping for joy. For
some, targeted therapy has helped
extend patient’s lives for months, this
is viewed as a success, as success is
often measured in days. This truly
sounds like a breakthrough so why
is there a growing scepticism about
targeted therapies amongst researchers
and clinicians?
Imagine this, you have a rubbish bin
in your house but you don’t understand
rubbish collection days so you keep
filling it with rubbish. As the pile gets
bigger you squash it down and pack
it in, trying to contain it, but one day
you know that if you don’t figure out
the collection day the rubbish will
take over your house. Now, imagine
the rubbish bin is a tumour and the
human trying to control the waste is
the targeted therapy. According to
the original vision, targeted therapies
aimed to decrease tumour size and,
eventually, eliminate the tumour.
Actually, it turns out that targeted
therapies are unable to get rid of
the tumour. The main positive effect
of targeted drugs is usually less about
decreasing tumour size than achieving
prolonged stabilisation of tumour
management process. Like the human
not understanding collection days,
if scientists don’t figure out how to
get rid of the tumour, or rather to
remove tumour’s source (its root system)
instead of reducing its size, the patient
could relapse. Another drawback is that
over time, tumours develop resistance
to the monotargeted drugs, just like
their predecessors, so the positive
effects don’t last long. Targeted
therapies cannot be used alone or
even in combination with conventional
chemotherapy to effectively fight
ovarian cancer. For the next generation
of cancer therapies, a better
understanding of chemoresistant and
recurrent ovarian tumours is needed
to help promote patients’ survival.
Indole-3-carbinol
3,3’-Diindolylmenthane
Figure 1: Indole-3-carbinol, 3,3’-diindolylmethane, and epigallocatechin-3-gallate: chemical structure
THE NEXT CHAPTER
It’s not all doom and gloom. In recent
years there has been a huge effort
to understand tumour recurrence
and resistance. A recent scientific
breakthrough in cancer research involves
the discovery of a population of hardy
cancer cells, known as cancer stem
cells, or CSCs. Research into this rare
population of immortal cells suggests
they are responsible for chemoresistance
and recurrent tumours in many different
cancers, including ovarian cancer. This
Its aggressiveness leaves women with
a five year survival rate of anywhere
between 12-42%, taking 150,000 lives
annually worldwide.
discovery has opened up a whole new
opportunity for cancer research scientists,
who over the last decade, have been
searching and developing new drugs
to destroy CSCs.
Astonishing findings reveal that
combining conventional chemotherapy
with ovarian CSCs inhibitors is essential
for tackling the tumour. In the first
round of chemotherapy the bulk of
ovarian tumour cells are eliminated
but hardy, chemoresistant CSCs survive
the treatment. While the symptoms for
the patient disappear, CSCs silently grow
into tumours. At recurrence the patients
have large tumours full of CSCs that
cannot be destroyed with chemotherapy.
Epigallocatechin-3-gallate
There are also lots of CSCs in ascites
(the abnormal buildup of fluid in the
abdomen) which commonly occurs in
advanced ovarian cancer and its relapse.
However, if the patients are treated with
CSCs inhibitors during the chemotherapy
this may reduce or prevent recurrence
and even promote patient survival.
It’s about time anti-cancer therapy started
a new chapter. Equipped with a greater
understanding of tumour chemoresistance
and recurrence, scientists and clinicians
can begin to uncover more effective anti-
cancer treatments.
BACK TO NATURE
Today, natural agents play a dominant
role in the discovery of leads for the
development of drugs against many
human diseases, especially cancer.
Currently, over 60% of anti-cancer drugs
are derived in one way or another from
natural sources, with the rest being
artificially synthetised.
In the recent study led by Academicians
Lev Ashraphyan and Vsevolod Kiselev
and their colleagues, compounds of
natural origin were used in a clinical trial
to identify their effectiveness in treating
www.researchoutreach.org 131
advanced ovarian cancer. Indoles - indole-
3-carbinol (I3C), 3,3'-diindolylmethane
(DIM) and flavonoid epigallocatechin-
3-gallate (EGCG) are the rock stars of
anti-cancer treatment and widely called
“a therapeutic marvel”. Their humble
origins in cruciferous vegetables,
including sprouts, and green tea has not
set them back. These natural substances
have been comprehensively studied in
various cancers, including ovarian cancer,
and have unique anti-cancer properties.

In contrast to monotargeted drugs

that hit only one molecular target
of the tumour for some time, these
compounds possess multiple anti-
tumour activity and attack cancers
simultaneously from multiple angles.
They stop tumour cells from growing
and dividing and can even instruct
cells to die. They fight off molecules
important for fuelling cancer cell growth
and spread including aggressive
estrogens, inflammatory molecules,
oxidants, growth factors. Incredibly,
they are also capable of inhibiting CSCs
by inducing their death and blocking
key pathways responsible for their
aggressiveness and chemoresistance.
All these activities, including development
of chemoresistance, are being
implemented by reversible epigenetic
mechanisms changing gene expression.
All three above natural substances
have demostrated epigenetic anti-
tumour activity.
In the study, these substances were used
Figure 2: Multiple anti-cancer activity of indole-3-carbinol (I3C), 3,3’-diindolylmethane (DIM),
and epigallocatechin-3-gallate (EGCG)
to remove the tumour). The results were
shocking. Maintenance therapy with I3C
and EGCG in advanced ovarian cancer
dramatically increased median overall
survival by almost one and a half times
over five years and 5-year overall survival
increased from 37% to 67%.
What’s more, researchers found
patients were living longer without the
tumour getting worse and there was
a dramatic reduction in relapses with
ascites. A huge benefit was identified
from taking agents based on I3C and
EGCG along with chemotherapy prior
to surgery; in these patients, surgeons
were able to completely remove all
daily activities. In addition, these drugs
do not demonstrate any significant
toxicity to patients, they are safe and
have no additional side effects. This
safe approach to treating ovarian cancer
is also inexpensive and affordable.
Current anti-cancer therapies can cost
anywhere from $10,000 - $30,000 per
month, a huge problem for patients.
Oncologists worry about the rising costs
of cancer treatment, in the USA there
has been a 100-fold increase in cost
per patient over the last 50 years.
The recent clinical trial with agents based
on I3C and EGCG shows huge promise
in tackling this problem allowing people

…therapy with I3C and EGCG in

in the form of the medical drug Indinol®
Forto and dietary supplement Promisan®
(both MiraxBioPharma, Joint-Stock
Company, Russia) manufactured under
a special technology according to current
GMP standards. Unique properties like
this make these agents an excellent
contender for the next generation of anti-
cancer treatments.
LIGHT IN THE DARK
In a first of its kind clinical trial conducted
by the research team, 284 women with
untreated advanced ovarian cancer were
assigned maintenance therapy with orally
administered I3C as well as I3C with
EGCG as Indinol® Forto and Promisan®
pharmaceutical agents. Maintenance
therapy was administered before,
during, and for five years after combined
treatment (chemotherapy and surgery
advanced ovarian cancer dramatically
increased median overall survival by
one and a half times and 5-year overall
survival increased from 37% to 67%.
visible tumours. This was not the case in
the control patients who hadn’t received
the maintenance treatment. The scientists
believe that this radical tumour removal
important for improvement of treatment
outcomes is due to the anti-tumour
effects of I3C and EGCG, including their
ability to kill CSCs.
Prolonged treatment with I3C and EGCG
showed a measurable improvement
in the patient’s quality of life and their
to afford effective anti-cancer treatments.
A fresh understanding of the biology
of ovarian tumours has allowed
Academicians Lev Ashraphyan and
Vsevolod Kiselev and their colleagues
to develop a promising, effective, safe
and affordable treatment to tackle the
formidable ovarian cancer. In the future
it’s possible these results may be used
to develop more effective and safer
treatment approaches for other difficult
to treat cancers.

132 www.researchoutreach.org
 Behind the Research

Lev Ashraphyan Vsevolod Kiselev Ekaterina Muyzhnek Gennady Sukhikh

E: vkis10@mail.ru E: MuyzhnekEL@ilmixgroup.ru
T: +7 495 765-87-87 (19-74) W: http://ncagp.ru/ W: http://ncagp.ru/index.php?_t8=537 W: www.ilmixgroup.ru

Detail Research Objectives

Bio
Lev Ashraphyan:
A highly regarded gynaecologic oncologist and a surgeon
in gynaecologic cancers, Honoured Doctor of the Russian
Federation. Director, Institute of Gynecologic Oncology and
Mammology of Acad. V.I.Kulakov National Medical Research
Centre of Obstetrics, Gynecology and Perinatology, the
Ministry of Health of Russia (Moscow). Academician of the
Russian Academy of Sciences, Professor, MD. A member
of Russian and foreign Associations of gynecologists and
gynecologic oncologists, President of Russian Association
of specialists in the treatment of female reproductive
system tumours.
The research is focused on an effective and safe approach
of maintenance therapy for advanced ovarian cancer that
is both inexpensive and affordable.
References
Kiselev V., Ashrafyan L., Muyzhnek E., Gerfanova E., Antonova
I., Aleshikova O. & Sarkar F. (2018). A new promising way
of maintenance therapy in advanced ovarian cancer:
a comparative clinical study. BMC Cancer 18:904.

Vsevolod Kiselev: Personal Response

A highly regarded clinician-scientist, specialist in molecular
biology, molecular medicine and biotechnology. Deputy
Director, Institute of Gynaecologic Oncology and
Mammology of Acad. V.I.Kulakov National Medical Research
Centre of Obstetrics, Gynaecology and Perinatology,
the Ministry of Health of Russia (Moscow). Associate
academician of the Russian Academy of Sciences, Professor,
D. Biol. Sci. Twice winner of Russian Government Award
in Science and Engineering, a laureate of the International
Prize Galen (Prix Galien Russia), a winner of the National
Prize to the best doctors of Russia “Vocation”.
Ekaterina Muyzhnek:
Chief Scientific Officer, Joint-Stock Company “IlmixGroup”,
Moscow, Russia. PhD (Biochemistry, Biol. Faculty,
M.V.Lomonosov Moscow State University). A winner
of the Russian Academy of Medical Sciences Prize.
How long will it take for this treatment to be available
to all people with ovarian cancer?
We believe it depends on two points: the speed at
which available information on this new treatment approach
would be distributed in public space and on the ability
of oncologists (who are known as the most conservative
clinicians) to accept current ideas and knowledge
and their desire to apply them in clinical practice. But
importantly, safety, affordability, simple peroral usage,
and clinically proven efficacy of the preparations used
in the trial could give a hope for a long happy life to large
number of oncological patients and their relatives with
no participation of physicians if they aren’t ready yet.

Gennady Sukhikh:
Honoured Scientist of the Russian Federation, Director,
Acad. V.I.Kulakov National Medical Research Centre of
Obstetrics, Gynaecology and Perinatology, the Ministry
of Health of Russia (Moscow). Academician of the Russian
Academy of Sciences, Professor, MD.

Collaborators
• Evgeniya Gerfanova
• Irina Antonova
• Olga Aleshikova (doctors who participated in this study)

www.researchoutreach.org 133
Health and Medicine ︱ Dr Nandini Dey
Fluorescent imaging sheds
new light on apoptosis
Researchers at the Avera Cancer
Institute are using state-of-
the-art fluorescent imaging to
shed new light on the physical
and biochemical processes
behind apoptosis - also known
as ‘programmed cell death’.
The novel, cost-effective and
user-friendly method uses three
fluorescent stains, enabling the
real-time, structure-function
based identification of apoptosis
in live, apoptotic tumour
cells. This unique protocol
developed by Dr Nandini Dey,
in collaboration with Dr Pradip
De, and with the help of Mrs
Jennifer Carlson Aske is enabling
the translational oncology
research team to explore the
efficacy of anti-cancer drugs
in tumour models.
Jezper/Shutterstock.com
E
very second, approximately
one million cells in our body
are destroyed by apoptosis and
replaced with new ones. This process of
‘cellular suicide’ is critical for maintaining
our cellular homeostasis and bodily
health, and plays an important role
in embryological, physiological and
pathological conditions. In pathological
conditions, cells bypass apoptosis,
essentially living past their ‘use-by
date’ and can become tumourigenic
or cancerous by virtue of oncogenic
alterations. In these cases, chemotherapies
and anti-cancer drugs are used to induce
apoptosis, preventing further tumour
proliferation, with the aim of curing
patients. Apoptosis is a therapeutic goal
following the treatment of anti-cancer
drugs. To ensure these drugs are working
properly, it’s vital that researchers and
health practitioners can accurately identify
and quantify apoptotic cells. While several
methods currently exist, most require
This tool allows the efficacy of anti-cancer
drugs to be determined, and has the
potential to identify new drug targets.
expensive and sophisticated equipment
and procedures such as cryo-microscopy,
incredibly high resolution microscopy
or specialised confocal microscopy. In
addition, these methods use processed
cell samples, rather than live cultures and
cannot show the drugs’ mechanisms of
action in the process of inducing apoptosis
event-by event in a real-time manner
in a standard laboratory set-up.
Changing this are Dr Nandini Dey,
Dr Pradip De and Ms Jennifer Carlson
Aske, based at the Avera Cancer
Institute, South Dakota. The research
group have spent many years
studying anti-cancer drugs and
their mode of action. In particular,
their interest lies in the behaviour
of tumour cells in response to treatment,
and apoptosis is one of the main areas
of focus in their laboratory. The method
established by the group presents
an event-based identification of the
phenomenon of apoptosis in live cells
which is enabling them to monitor the
apoptotic cells following the anti-cancer
drug treatment including conventional
chemotherapy drugs, targeted therapy
drugs and immune-therapy drugs in cells.
Setting out to improve the identification
of apoptosis in live cells, the Avera Cancer
Institute team have developed a cost-
effective and user-friendly method to
visualise the physical and biochemical
processes behind apoptosis in live cells in
real time. Recently published in Scientific
Reports, the team show that this unique
tool allows the efficacy of anti-cancer
drugs to be determined, and has the
potential to identify new drug targets. The
novelty of this approach is that it identifies
three sequential cardinal biochemical,
enzymatic, and morphological events
of apoptosis in a laboratory-friendly way.
WHAT IS APOPTOSIS?
In a time of crisis, would you sacrifice
one to save many? This is what our cells
do: they are genetically programmed
to ‘self-destruct’ if they suffer irreparable
DNA damage, protecting the body from
further harm. This ’programmed cell
death’ is called apoptosis. Apoptosis
is the hallmark of cancers. It involves
certain morphological, biochemical,
and physiological sequential steps
controlled by a dying cell. Apoptosis
is characterised by physical signs
of cell shrinkage, rounding, nuclear
shrinkage and loss of nuclear membrane
Live triple-fluorescence in OVK18 cells treated with paclitaxel plus BKM120.
Live OVK18 cells were stained with MitoView Blue + NucView488 Casp3
substrate +CF 594 Annexin V (A–D). Insets represent non-apoptotic and
apoptotic cells with various combination of staining as mentioned within
each inset (a-d for non-treated cells and e-h for treated cells). In separate
experiments, the validation of the effect of paclitaxel (2.5 nM) plus BKM120
(1 μM) was tested by the changes in real-time proliferation (E), mitochondrial
potential (F), expression of apoptotic markers by Western blot (G) and
apoptosis by flow cytometry (H).

integrity, plasma membrane blebbing, To induce

nuclear fragmentation and finally,
cell fragmentation.
Apoptotic cells also undergo a series
of biochemical changes including
executioner caspase activation,
mitochondrial membrane alterations
and release of a protein called cytochrome
C, externalisation of phosphatidylserine
– an ‘eat me’ signal for scavenging
macrophages – to the cell surface, poly
(ADP-ribose) polymerase (PARP) cleavage
and nuclear DNA fragmentation.
By tracking these well-regulated and
sequential processes, researchers can
observe the apoptotic effects of anti-
cancer drug treatments on tumour cells
and potentially identify new drug targets.
This is where the research of Dr Dey
and her group comes in.
apoptosis,
the team treated
two ovarian cancer
cell lines – OVK18
and A2780 –
with anti-cancer
drugs called paclitaxel (conventional cells fluoresced bright blue, since their
chemotherapy drug) and BMK120 mitochondria were still intact. In contrast,
(targeted pan PI3K inhibitor), either alone treated cells fluoresced green and/or red.
or in combination. The cells’ fluorescent This was expected given that caspase
patterns were then compared with those 3 initiation and phosphatidylserine
of untreated cells. presentation only occur during apoptosis.
Upon examination under the microscope, VALIDATING THE CONCEPT
the researchers found that most untreated To ensure that the anti-cancer drugs were

APOPTOSIS IN A NEW LIGHT

Using a fluorescence microscope and
three fluorescent dyes (fluorophores),
the Avera Cancer Institute team have
coupled these three sequentially occurring
rate-limiting features of apoptosis in
live cells. In their ‘triple-fluorescence Figure: Ki67
staining’, they can observe the enzymatic
activity of executioner caspase 3 (green Ki67 and cleaved Caspase3 double staining of fixed MDA-MB468 cells, control and treated (ABT888+
fluorophore), external presentation of Carboplatin+GDC0980) for 72 hrs: Treated and control cells cell fixed and double stained with Ki67
phosphatidylserine (red fluorophore) (Ki67 Alexa Fluor 647) and cleaved Caspase3 (Cleaved Caspase-3 Alexa Fluor 488). Confocal pictures
were captured from 3-dimensional (XYZ coordinates were included in the picture) Z-sections. Projected
and altered mitochondrial functions (blue images were reconstituted for a 3D-movie. Actin (Alexa Fluor® 555 Phalloidin) was used as a counter
fluorophore) in live ovarian cancer cells. stain in the immunofluorescence images.

www.researchoutreach.org 135
responsible for these apoptotic effects,
the researchers treated the ovarian
cancer cells with different doses of
paclitaxel or paclitaxel and BMK120 and
imaged them at different magnifications
and at different time points.
Unsurprisingly, proliferation of paclitaxel-
treated OVK18 cells decreased or
stopped, depending on the dose given,
with apoptosis setting in after 48 hours
and the simultaneous expression of
apoptotic markers. Furthermore, these
samples had a larger number of dead
cells overall, compared to the untreated
samples. Similar results were seen in
paclitaxel and BMK120-treated OVK18
cells, with apoptosis setting in at 48
hours, however, this time, changes in
mitochondrial activities first appeared
at 24 hours.
Paclitaxel-treated A2780 cells took the
longest to reach an apoptotic state, with
the process occurring 48 and 72 hours
after treatment. However, changes in
mitochondrial activity occurred 24 and
48 hours post-treatment. This sample
also had a larger number of dead cells
than the untreated samples, proving
that the paclitaxel causes cell death,
therefore verifying the microscopy
results. Thus using this protocol the
group successfully identified the
temporal and eventual pattern of drug-
action in inducing apoptosis.
IDENTIFYING LIVE
AND DEAD CELLS
In order to identify living and dead cells,
Dr Dey and her group treated their
samples with a new set of fluorophores.
Dead cells fluoresced red while live cells
were green. The mitochondrial potential
was measured by flow cytometer
while live-dead cells were read under
fluorescent microscope. Fluorescent
136 www.researchoutreach.org
xecutioner
fE
Ca
tivation
spases
Ac
Activated Caspase
Membrane
Asymmetry
Due to Flipped
Phosphatidyl-Serine
Loss of
Mitochondrial
Potential
Schematic showing salient features of apoptosis used in triple-fluorescence staining of live cells.
Every second, approx one million cells
in our body are destroyed by apoptosis
and replaced with new ones.
imaging comparisons using the ‘live and
dead cell assay’ showed no overlapping
of red (dead) cells and green (live) cells
in treated and untreated samples.
In contrast, fluorescent imaging
comparisons using their ‘triple-
fluorescence staining assay’ showed
overlapping of red (Annexin V positive
apoptotic cells) and green (active
caspase3 positive apoptotic cells)
in treated and untreated samples; this
is because green cells and red cells
were at different stages of apoptosis.
No overlap was observed between
blue and red and/or green cells, and
is to be expected since blue cells with
active mitochondria were less likely
to exhibit apoptosis, while red and/
or green or both red and green cells
were less likely to exhibit functional
blue mitochondria. Interestingly,
however, a few drug treated cells
From left to right: Dr Pradip De,
Dr Nandini Dey, Mrs Jennifer Carlson Aske
Activation of
Initiator Caspases
Apoptotic
Stoptotic
& its Products
Damaged Membranes
& EthD-1 Binds to
Buclecic Acids
Loss of Cellular
Esterase Activity
still displayed mitochondrial activity
(blue fluorescence).
WHY IS THIS IMPORTANT?
While not all of these biochemical
processes are specific to apoptosis
and apoptotic events are stage-, time-
and stimuli-dependent, the strength
of the triple-fluorescence staining
method lies in its ease of use and its
ability to simultaneously stain three
critical morphological and biochemical
apoptotic steps – making it much easier
to accurately identify apoptotic versus
non-apoptotic cells. In comparison,
most existing techniques rely on one
apoptotic (but not necessarily apoptosis-
specific) characteristic to identify
and quantify these cells. Furthermore,
triple-fluorescence staining can show
apoptotic processes in live cells in real
time – allowing researchers to see anti-
cancer drugs’ mechanisms of action,
and their efficacy.
This laboratory friendly method can be
standardized with minimalistic laboratory
equipment and resources, making it a
relatively cheap and accessible method
that can be applied to any relevant drug
treatment. Notably, it has already been
used to observe the effects of different
drug combinations on other tumour
cell lines. The strength of this assay lies
in its ability to identify modes of action
of pro-apoptotic drugs in an event-
based manner.
 Behind the Research
Dr Nandini Dey
E: Nandini.Dey@avera.org
T: USA-605-322-3298
Research Objectives
The Avera Cancer Institute team study anti-cancer drugs and
their mode of action, in the context of tumour cell behaviour,
including cell death by apoptosis.
Detail
Dr Nandini Dey
Translational Oncology Laboratory, Avera Cancer Institute,
1000 E 23rd Street, Sioux Falls, SD, 57105, USA
3rd Floor of Prairie Center, Suite # 3611; Room # 3610
&
Departmental of Internal Medicine, SSOM, University of South
Dakota, Sioux Falls, SD 57105, USA
Dr Pradip De
Translational Oncology Laboratory, Avera Cancer Institute,
1000 E 23rd Street, Sioux Falls, SD, 57105, USA
3rd Floor of Prairie Center, Suite # 3611; Room # 3609
& live cells as green and dead cells as red. There is no blue
Departmental of Internal Medicine, SSOM, University of South
Dakota, Sioux Falls, SD 57105, USA
& under treatment conditions because, during the initial stage
Consultant, Viviphi, Greenwood Village, CO 80112, USA
Jennifer Carlson Aske
Translational Oncology Laboratory, Genomic Oncology
Institute, Plaza 2, 1301 South Cliff Avenue, Plaza 2, Suite 703,
Sioux Falls, SD, 57105
Bio
Dr Nandini Dey, M.S., PhD is a Senior Scientist, & Director of
Translational Oncology Laboratory, Avera Cancer Institute,
USA. She studies the biology of tumour cells in solid tumours
with a special interest in cell phenotypes. Dr Dey is a member
of the Royal Society of Medicine.
Dr Pradip De, M.S., PhD is a Senior Scientist of the laboratory
with 25 years’ experience in signal transduction biology.
Together, Dey & De have over 50 years’ experience in
translational research and have authored or co-authored over
100 publications.
Mrs Jennifer Carlson Aske, M.S. is the Research Laboratory
Supervisor with 10 years of research experience.
Funding
Avera Cancer Institute, Sioux Falls, SD, USA
Dr Pradip De Jennifer
E: Pradip.De@avera.org Carlson Aske
T: USA-605-322-3297 E: Jennifer.Aske@avera.org
T: USA-605-322-3289
References
De, P., Carlson, J., Leyland-Jones, B., Williams, C. and Dey, N.
(2018). Triple fluorescence staining to evaluate mechanism-based
apoptosis following chemotherapeutic and targeted anti-cancer
drugs in live tumour cells. Sci Rep, 8, 13192-13202. Available
at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123436/
[Accessed 18.03.2019]
Ulukaya, E., Acilan, C. and Yilmaz, Y. (2011). Apoptosis: why and
how does it occur in biology? Cell Biochem and Function, 29
(6), 468-480. Available at: https://onlinelibrary.wiley.com/doi/
abs/10.1002/cbf.1774 [Accessed 18.03.2019]
Personal Response
Why would some cells show red and blue staining
in the ‘live and dead cell assay’?
The ‘live and dead cell assay’ was carried out to show
colour in the assay. During the ‘triple fluorescence staining’
however, a few cells rarely showed red and blue staining
of apoptosis, mitochondria are still functional (blue) while
their cell membranes have just started to show apoptotic
features (red). These are really rare events and dependent
on the drug used to induce apoptosis. In culture conditions,
all cells are not in the same stage of apoptosis, and all cells
were not synchronized for their stages of cell cycle.
What do you see for the future of this research?
Considering the laboratory friendly nature of the
‘triple-fluorescence staining’ in live cells, we expect that
this method will become a commonly used laboratory tool
to study drug effects in cancer research.
Although currently the protocol is validated and used in
translational oncology, we think that this procedure will be
meaningfully adapted in studies of apoptosis in other fields.
For example, the phenomenon of apoptosis is a critical
event in the field of developmental biology, regenerative
medicine, and stem cells research. We envision that studies
in the field of Parkinson’s disease, Alzheimer’s disease,
myocardial ischaemia, myocardial infarction, and trauma-
induced apoptosis will have the opportunity to use this
protocol effectively. 
www.researchoutreach.org 137
 Health and Medicine | Dr Jeong-Sun Seo

RNA sequencing
reveals secrets
of skin aging
O
As we age, so does our skin. One of the factors that affects how ur skin has to tolerate a great
quickly skin appears to age is exposure to UV light. Dr Jeong-Sun Seo deal. Exposure to sun, wind
of Seoul National University Bundang Hospital, Republic of Korea, is and rain, harsh soaps, pore-
investigating how UV light affects skin aging at the genetic level. Using clogging cosmetics, a poor diet; these are
RNA sequencing data, Dr Seo and his team demonstrate that some signs just a few of the challenges our skin might
of skin aging, such as the development of wrinkles, are directly linked endure throughout a lifetime. Our skin
to over-exposure to UV light. also accounts for a large part of our
appearance and is, for many people,
where the most obvious signs of aging
can be seen. Our skin condition reflects
our apparent age; no wonder, then, that
skin care is such a huge market.

Many factors are known to affect the

way that skin ages. Some of these factors,
such as genetic qualities, are intrinsic
to the body while others are extrinsic.
Of all the extrinsic factors, perhaps the
one that has received the most publicity
is excessive exposure to sunlight. The
harmful part of sunlight is ultraviolet (UV)
light, which is also the type of light used

Skin offers a
unique opportunity
to investigate the
effects of UV light
on aging.
in tanning beds and lamps. Exposure to
UV light is not only an important factor
iconogenic/Shutterstock.com

in skin aging: excessive exposure to UV

also increases the risk of skin cancer. The
dangers of sunburn and the importance
of sunscreen are well-known, but the
exact ways in which UV damages skin
are still under investigation.

138 www.researchoutreach.org
Thomas Andreas/Shutterstock.com

UV AND SKIN AGING the transcriptome therefore allows ANGIOGENESIS AND

Previous research has shown that UV
light affects the aging process of skin
by causing changes in gene expression
(when and how a gene produces a
protein). Exactly how this happens,
however, is not well understood. Using
state-of-the-art technology, Dr Seo and
his team can explore genetic information
to investigate how skin ages, with the aim
of reaching a better understanding of this
process. In particular, the team looked at
the various effects of UV light on skin,
a process known as photo-aging.
ANALYSING THE TRANSCRIPTOME
Although there has been some previous
research on the effect of UV light on skin
researchers to characterise the genetic
activity of a tissue, such as skin,
as a whole; it shows which genes
are active (and how active they are)
and which are not.
SKIN CHANGES AND UV EXPOSURE
Skin offers a unique opportunity to
investigate the effects of UV light
on aging. Some parts of our skin are
frequently exposed to sunlight, while
other parts are usually kept covered.
In his study, Dr Seo and his colleagues
compared UV-exposed skin from the
lower leg with UV-protected skin from
the suprapubic region (the area between
the navel and the pubic bone).
WRINKLE FORMATION
Wrinkles are probably the most obvious
sign of aging in skin. Angiogenesis – the
formation of new blood vessels – is
known to play a significant role in the
development of wrinkles. In this study,
the researchers found that certain
genes involved in angiogenesis were
up-regulated (became more active) in
photo-damaged skin. In fact, there was
Tefi/Shutterstock.com

aging, it has focussed on the behaviour

of just a few genes. While this is useful,
genes are known to interact with one
another in myriad ways. Focusing on
a few individual genes therefore risks
missing important genetic pathways that
could influence the aging process.
To avoid this problem, Dr Seo utilised
a much broader type of genetic
information to investigate gene
expression changes in skin. Ribonucleic
acid (RNA) is produced from DNA
during the process of protein synthesis.
The complete set of RNA transcripts
produced by the genome of a particular
species – in this case, humans – is
known as the transcriptome. Analysing
Dr Seo’s team used transcriptomic
RNA sequencing data to examine the
behaviour of a very large number of
different genes at the same time. In total,
the researchers assessed genetic data
from almost 600 samples of skin. This
in-depth investigation allowed the team
to pin-point the actual biological changes
caused by exposure of skin to UV light.
Their results showed a clear difference
between the transcriptomes of the
lower leg and suprapubic skin samples,
suggesting that gene activity is notably
different in these two areas of skin. This
difference could be due to variation
in exposure to UV light.

www.researchoutreach.org 139
 a significant difference in the activity of
these genes in the skin from the lower
leg, when compared with skin from the
suprapubic region. Greater angiogenesis
means a higher rate of development
of new blood vessels, so this result
suggests that exposure to UV light directly
influences wrinkle formation.
UV LEAVES SKIN VULNERABLE
Lipid metabolism, the process by which
fats are either made or broken down
in cells, is one of the factors vital to
maintaining the function of the skin as a
protective barrier. When lipid metabolism
is impaired, the barrier function becomes
less effective, leaving the skin more
vulnerable to damage. Dr Seo found
that lipid metabolism is dramatically
reduced by photo-aging, suggesting
that over-exposure to UV light can leave
skin lacking protection. Three lipid
metabolism-related genes in particular
(known as LIPN, LIPK, and SMPD3) were
found to be important in this process.
Similarly, water loss regulation in skin was
found to decrease with age. This could
adversely affect both the condition and
the appearance of the skin.
As skin ages, it tends to lose elasticity,
which can contribute to development
of wrinkles. This is partly due to a falling
amount of collagen, an important
connective protein, in the skin. Dr Seo
and his colleagues were able to show that
a certain class of genes, known as MMP
genes, are up-regulated in skin damaged
BLACKDAY/Shutterstock.com
140 www.researchoutreach.org
Aged skin loses elasticity compared to younger skin due to broken elastic fibre and decreased
collagen and hyaluronic acid.
Dr Seo’s team used transcriptomic
RNA-sequencing data to investigate
the genetic pathways of aging.
by exposure to UV light. In normal cells,
MMP genes are known to play a role in
breaking down collagen. When MMP
genes become more active, collagen is
broken down faster, leading to reduced
elasticity in the skin.
AGE-RELATED SKIN CHANGES
Some skin changes occur with aging
whether or not the skin has been
exposed to excessive sunlight. Previous
work has shown that wound healing can
be between 20% and 60% slower in
Designua/Shutterstock.com
older skin. Dr Seo found that the rate of
wound healing decreased with aging in
both types of skin. A set of genes known
to be involved in wound healing were
down-regulated (became less active) in
both UV-exposed and UV-protected skin.
This result suggests that slower healing
is an inevitable consequence of aging,
whether skin has been exposed to a lot
of sunlight, or not.
THE FUTURE
In many parts of the world, life
expectancies have been steadily
increasing. This has triggered increased
research interest in the various aspects
of aging. In the field of skin aging
research, Dr Seo’s team is the first to use
transcriptomic RNA-sequencing data
to investigate the genetic pathways of
aging. Photo-aging due to excessive
exposure to sunlight can only be studied
in the skin; it is therefore crucial that the
consequences of photo-damaged skin
are properly understood. This work is an
important step in that direction.
In future, the knowledge gained from
Dr Seo’s work could be used to develop
innovative treatments for skin aging,
increasing health and well-being in old
age. In the meantime, his work confirms
a vital message, one that is well-known
but bears repeating: wear sunscreen.
 Behind the Research
Dr Jeong-Sun Seo
E: jeongsunseo@gmail.com T: +82 31 600 3011

Research Objectives References

Cho, B, Yoo, S & Seo, J. (2018). Signatures of photo-aging and
A leading scientist in the field of genomics, Dr Jeong-Sun
intrinsic aging in skin were revealed by transcriptome network
Seo has broadened our understanding of human variations
analysis. Aging, 10, 1-14.
in cancer and rare diseases.

Detail Personal Response

Precision Medicine Center
How can transcriptomic RNA sequencing be used
Seoul National University Bundang Hospital
in other areas of aging research?
Dolma-ro 172, Seongnam
Bundang-gu, Gyeonggi-do 13605 With advanced medical care and technology,
Republic of Korea the elderly population has greatly increased compared
to several decades ago. Although aging is not a
pathological process, it still influences some diseases. If the
Bio
transcriptome of each organ is fully analysed, we may able
Dr Jeong-Sun Seo is a Distinguished Professor at Seoul to predict the occurrence of diseases through assessing
National University Bundang Hospital, where he is also the levels of gene expression or use it as a tool to find
Director of Precision Medicine Center. He established a therapeutic target for each disease.
Macrogen Inc. 22 years ago, one of the first biotechnology
companies in Korea. Recently, his team built the most
contiguous reference genome, AK1, using de novo
assembly and phasing, taking another step forward
for precision medicine in Northeast Asia.
watchara/Shutterstock.com

www.researchoutreach.org 141
Health & Medicine ︱ Dr Wen-Harn Pan
ADHD and its
comorbidities:
Implications for management
Dr Wen-Harn Pan, Institute of
Biomedical Sciences, Academia
Sinica, is interested in the
relationship between nutrition
and health. One of her most
recent projects, published
last year, investigated the
link between attention deficit
hyperactivity disorder and
whether risk factors such as
allergy and anaemia could
be modified to improve the
ways in which attention deficit
hyperactivity is both identified
and treated.
142 www.researchoutreach.org
A
ttention deficit hyperactivity
disorder (ADHD) appears to be
becoming more prevalent in
children. Although not clear whether this
is due to an increase in the incidence of
the disorder, or whether better diagnostic
tools simply detect more cases, ADHD
can have substantial impacts on children
and their families. The work of Dr Wen-
Harn Pan at the Institute of Biomedical
Sciences, Academia Sinica, explores
some of the risk factors associated with
the disorder, with the ultimate aim to
improve its diagnosis, prevention and
management.
ADHD is one of the most commonly
diagnosed neuropsychiatric disorders
in children and is characterised by a
lack of impulse control, inattention
and hyperactivity. ADHD can have
The presence of four biochemical factors
was associated with a 6-7-fold increase
in the risk of having ADHD.
significant impact on a child’s
performance at school, family
relationships and social
interactions between the child
and their friends and family.
Interestingly, ADHD
is associated with
several comorbidities,
defined as additional
conditions occurring
alongside the main
disorder, including
allergic disease,
anaemia
(low levels
of haemoglobin,
the red pigment
in red blood cells that carries oxygen), and
low levels of serotonin (a neurotransmitter,
sometimes called the happy chemical).
If this association can be better
understood, then there may be potential
to modify some of these risk factors,
and in turn to improve quality of life
for children diagnosed with ADHD.
UNDERSTANDING ADHD FURTHER
Dr Pan and her colleagues recruited
216 children diagnosed with ADHD,
and 216 children without ADHD but
who were similar in terms of age, sex,
height and weight from 31 schools in
Taiwan. The students were aged between
8-10 years old, and a diagnosis of ADHD
was confirmed by a child psychologist.
The International Study of Asthma
and Allergies in Childhood (ISAAC)
questionnaire to measure signs of allergy
and blood samples were analysed
to link to the number of white blood
cells, immunoglobulin E levels (IgE)
and serotonin levels. The researchers
measured IgE because it is an antibody
which is often elevated in allergic
diseases. In addition to IgE, a type of
white blood cell, eosinophils, are often
found in allergic diseases as they respond
to tissue damage and inflammation.
The most common cause of anaemia,
defined as a reduction in haemoglobin
concentration, is a lack of iron. Indeed,
low levels of iron have previously been
associated with behavioural problems
in children. Understanding the role
of anaemia in ADHD is also important
Allergies and asthma may be associated with ADHD as
the immune responses resulting from allergic diseases
may affect the central nervous system.

Dr Pan’s study showed that children with signs of

allergy were two times as likely to have ADHD.

in treating ADHD, as previous studies
have shown that iron deficiency may also
reduce the effectiveness of drugs used
to treat the condition.
Serotonin was included in Dr Pan’s study
as mutations in the serotonin gene have
been shown to influence impulsivity
in humans and there is a link between
serotonin levels and immune responses,
potentially showing a link between
serotonin, allergy and ADHD. However,
previous studies have not been able to
show an association between ADHD
and serotonin levels. This study with
larger sample size therefore provides
valuable evidence for confirming this
relationship. Other neurotransmitters,
RISK RATIO OF ADHD
levels, family income, lifestyle and disease
history of students and their parents that
was collected using a questionnaire.
Four indicators were found following
statistical analysis of the results and Dr Pan
and her team identified haemoglobin,
eosinophil, IgE and serotonin as being
associated with ADHD. The researchers
found that children with signs of allergy
were two times as likely to have ADHD
and those with ADHD often had low levels
7
6
of haemoglobin, a marker of anaemia,
as well as lower level of serotonin but
high IgE and eosinophil levels. One of
the reasons that allergies, such as allergic
rhinitis (hay fever-like symptoms), atopic
dermatitis (eczema) and asthma may be
associated with ADHD is that the immune
responses resulting from allergic diseases
may affect the central nervous system.
Due to this, children may be more likely
to develop or aggravate neurological
disorders. In addition, treatment of
6.53***

5
such as dopamine or norepinephrine, 4.47***
may also be involved in ADHD but were 4
not measured in this study.
2.90*
3
The research team wanted to investigate
whether common comorbidities or 2
1.87
biochemical factors are singly or
additively associated with an increased 1
1
risk of ADHD as there may be a
cumulative effect of risk factors.
0
Allergic disease Anaemia Low-serotonin High IgE High eiosinophil
FINDINGS FROM THE STUDY
Blood samples from the students were PRESENTING RISK FACTORS
analysed and interpreted in combination Effects of the number of biochemical risk factors on ADHD. (Numbers denoted above the bar
with information on family education are the exact risk ratios of corresponding groups; *p < 0.05, **p < 0.01, ***p < 0.001).

www.researchoutreach.org 143

allergies has also been associated with
an improvement in ADHD symptoms.
Overall, the greater the number of
comorbidities the child had, the greater the
chance that they would be diagnosed with
ADHD. The presence of four biochemical
factors was associated with a 6-7-fold
increase in the risk of having ADHD.
The statistical analysis also considered
social factors and the study revealed
that the children with ADHD were
more likely to have parents with lower
education levels,
unstable incomes, This study is one of the first to examine
the relationship between ADHD and
from manual jobs,
potentially leading to
high levels of stress,
siblings with ADHD
allergies, in combination with indicators
and previous health of inflammation and immune responses.
problems during or
after birth. In addition, children with ADHD
tended to have mothers who were current
smokers, smoked during pregnancy and
had experienced miscarriage symptoms
in their first trimester of pregnancy. This
is interesting as these results suggest
there may be sociological influences
on the occurrence of ADHD, as well
as biological influences.
Whilst it is important to remember that
these relationships may not be causal,
e.g. allergy does not cause ADHD or vice
versa, the findings of Dr Pan’s research
144 www.researchoutreach.org
increase understanding of underlying
mechanisms of ADHD and offer potential
novel therapeutic and treatment options.
WHAT DO THESE FINDINGS MEAN?
This study is one of the first to examine
the relationship between ADHD and
allergies, in combination with indicators
of inflammation and immune responses.
The findings of Dr Pan and her team
suggest that the causes of ADHD are
multidimensional and other conditions,
such as allergy, anaemia, inflammation
and low levels of serotonin may have
similar underlying causes to ADHD.
Children with ADHD had more allergic
conditions than children without, although
the causal relationship between the two
is not currently clear. Dr Pan proposes that
allergic reactions result in inflammation
and the immune reactions may stimulate a
neuroimmune mechanism in the brain and
affect emotional and behavioural control.
Iron is also involved in neurotransmitter
production, so iron deficiency could
be the link between anaemia and
ADHD. Whilst the blood samples from
Dr Pan’s research increases understanding of
underlying mechanisms of ADHD and will offer
novel therapies and treatment options.
children with ADHD did not reach the
threshold criteria for anaemia, a trend
towards lower levels of haemoglobin
was observed.
Although this study was much larger than
previous studies, the finding that lower
levels of serotonin was associated with
ADHD is controversial, suggesting that
further work still needs to be done in this
area in order to confirm this relationship.
In particular, more longitudinal studies
observing subjects repeatedly over a
longer time period and intervention
studies are needed
to determine
whether ADHD risk
could be modified
by managing
allergic symptoms,
haemoglobin levels
and serotonin levels.
Limitations of the study include the
lack of causal relationships and the
oversimplification of ADHD and allergy
diagnosis, however the findings are
another piece in the puzzle of ADHD
causal pies.
Routine screening for these risk factors
is straightforward and can be easily
performed, therefore the findings of
Dr Pan’s study play an important role
in devising comprehensive diagnostic
and treatment strategies for ADHD
in the future.
 Behind the Research
Dr Wen-Harn Pan
E: pan@ibms.sinica.edu.tw T: +886 922423324

Research Objectives References

Dr Pan’s research is focused on nutritional epidemiology,
food-disease omics, dietary therapy for geriatric diseases,
and worksite health promotion programs.
Detail
N141, Institute of Biomedical Sciences
Academia Sinica
No.128, Sec. 2, Academia Rd.
Taipei, Taiwan 11529
Bio
Dr Wen-Harn Pan is currently a Distinguished Research
Professor in the Institute of Biomedical Sciences, Academia
Sinica, Taiwan. She is a nutrition epidemiologist and has
led the Nutrition and Health Survey in Taiwan since 1992.
Dr Pan won the Life Time Achievement Award from Asia
Pacific Society of Clinical Nutrition. Dr Pan is a Fellow
of the American Heart Association (FAHA).
Wang, LJ, Yu, YH, Fu, ML, Yeh, WT, Hsu, JL, Yang, YH,
Chen, WJ, Chiang, BL & Pan, WH. (2018). Attention deficit-
hyperactivity disorder is associated with allergic symptoms
and low levels of hemoglobin and serotonin. Scientific
Reports. 8:10229, DOI:10.1038/s41598-018-28702-5.
Personal Response
How will you take the findings of this study forward
and do you have other studies planned to further
investigate the association between ADHD and other
clinical indicators?
My colleagues and I are undertaking a prospective
study to investigate whether children with allergic diseases
will develop ADHD. Furthermore, since poor quality of
diet has been linked to allergic disease and poor-school
performance, I am investigating the association between
ADHD and dietary and nutritional factors. 

Funding
Academia Sinica, Taiwan
National Science Council, Taiwan

Collaborators
• Liang-Jen Wang, MD
• Min-Lin Fu, PhD

www.researchoutreach.org 145
COMMUNICATION
Apollo: Fifty years on
This year marks the 50th anniversary since the first historic Moon landings. Not only did the groundbreaking innovations
that made Apollo 11 such a success leave a legacy of beneficial spin-off technologies that are used in our daily lives,
the iconic mission also reshaped how we see the Earth.

J
uly 20, 1969 saw NASA’s famous
achievement, the moment that Neil
Armstrong and Edwin ‘Buzz’ Aldrin
first set foot on our very own Moon. Five
decades after Neil Armstrong took his
giant leap for mankind, people are still in
orbit. Launched in 1998, the International
Space Station is still going strong. And
excitingly, we’re seeing a new era of
growth in the commercial space sector,
pushing technological advances ever
more rapidly to enable more people
to get to space.
LUNAR EXPLORATION
Cosmonaut Yuri Gagarin became the
first man in space in April 1961, closely
followed four months later by fellow
Russian Gherman Titov. The 20th century
‘space race’ saw the USA’s Apollo 8
astronauts orbit the Moon in ’68 before
the iconic Apollo 11 mission. Apollo
17’s Harrison Schmitt was the last man
on the Moon, 47 years ago. Over
time, space endeavours became less
competitive. The first joint US-Soviet
spaceflight, ‘Apollo-Soyuz’ in 1975 paved
the way for the International Space
Station programme.
ONE GIANT LEAP
We’re all familiar with Neil Armstrong’s
‘One Small Step’ speech. But not so
many are aware of the unpractised
first words of the second man on the
Moon. As Buzz Aldrin stepped off the
lunar lander, he radioed back to mission
control: ‘Beautiful, beautiful. Magnificent
desolation.’ One commentator at the
time concluded that, “on the way to
the Moon we’d discovered the Earth.”
BLUE MARBLE
Space travel has changed the way we
think about the planet we call home. The
famous image of Earth taken in 1972 by
Apollo 17’s crew in the last manned lunar
mission is one of the most reproduced
images in history. Dubbed the ‘Blue
Marble,’ it captures how fragile, precious
Space travel has changed the way we
think about the planet we call home.
The iconic Apollo 11 mission reshaped
how we see the Earth.
and beautiful our world is. A reminder that
actually, in such a harsh and punishing
cosmos, we ain’t got it bad.
Summing it up nicely is Michael Collins,
Apollo 11’s third astronaut who stayed
in orbit while Armstrong and Aldrin
explored the lunar surface: “There seems
to be two Moons now, the one I see in
my backyard and the one I remember
from up close. Intellectually, I know they
are one and the same, but emotionally
they are separate entities. The small
Moon, the one I have known all my life,
remains unchanged, except that I now
know it is three days away. The new one,
the big one, I remember primarily for its
vivid contrast with the Earth. I really didn’t
appreciate the first planet until I saw
the second one.”

MOONSTRUCK
Around 240,000 miles away from Earth,
our very own satellite is all too familiar
a presence. We take it for granted. But
life would be quite different without it.
Here on Earth we’re closely attuned to
the Moon’s phases: our calendar months
are roughly the same length of time as
it takes to go from one full moon to the
next (the time it takes for the Moon to
orbit Earth – 29.5 days). Our planet is
subject to the pull from Moon’s gravity,
causing tides – the predictable rises
and falls in sea levels. Many argue that life
on Earth would never have come about
if it weren’t for the Moon.

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