11 Scientific American - 11 2019

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SOCIAL MEDIA SCARE PHAGE FIGHTERS SONGBIRD GENETICS

Fears about kids and tech Fresh hope for Solving the mystery of their
are wildly overblown PAGE 44 drug-resistant infections PAGE 50 immense diversity PAGE 58
TIME
CRYSTALS
Exotic new states of matter contain
patterns that repeat like clockwork
S
PLU
GRAVITATIONAL WAVES
Inside the world’s first
underground detector PAGE 62
IS INEQUALITY
INEVITABLE?
An intriguing NOVEMBER 2019
mathematical model PAGE 70 © 2019 Scientific American ScientificAmerican.com
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N ov e m b e r 2 0 1 9
VO LU M E 3 2 1 , N U M B E R 5
PHYSIC S 20th century is showing promise

62
28 Crystals in Time in the struggle against deadly
Surprising new states of matter multidrug-resistant infections.
called time crystals show the same By Charles Schmidt
symmetry properties in time that
E VO L U T I O N
ordinary crystals do in space.
By Frank Wilczek 58 Winged Victory
The discovery of a strange chromo-
S U S TA I N A B I L I T Y
some in songbirds might explain
36 Conservation after Conflict their astonishing diversity.
After 50 years of war, Colombia By Kate Wong
wants to create an economy based
on the country’s astonishing A STROPHYSIC S
biodiversity. By Rachel Nuwer 62 Center of Gravity
T E C H N O LO G Y The first major gravitational-wave
44 The Kids Are All Right observatory to be built under
New findings suggest that the angst Earth’s surface—KAGRA in Japan—
over social media is misplaced is set to start operations.
and that more nuance is required By Lee Billings
to understand the technology’s ECONOMIC S ON THE C OVER
effect on the well-being of users. Physicists recently discovered the first
70 The Inescapable Casino real-world time crystals, states of matter in
By Lydia Denworth A novel mathematical approach which patterns repeat over time. Materials of
MEDICINE to inequality describes the this kind could be used in new, ultra-accurate
ENRICO SACCHETTI
clocks, and the study of time crystals in

50 Is Phage Therapy distribution of wealth in modern
general could lead to insights in fundamental
Here to Stay? economies with unprecedented physics and cosmology.
A treatment first used in the early accuracy. By Bruce M. Boghosian Illustration by Mark Ross Studio.
November 2019, ScientificAmerican.com 1
© 2019 Scientific American

4 From the Editor

6 Letters
10 Science Agenda
Vaccination exemptions are a public health risk.
By the Editors
12 Forum
A psychologist general could provide greater oversight
of the nation’s mental health. By Kirk J. Schneider
14 Advances
A startling new measurement of the Mekong Delta’s
elevation. AI assistance for procrastination. The powerful
10
eyes of baby jumping spiders. A firmer age for the Sahara.
24 The Science of Health

Are new drugs better than the old ones? B
y Claudia Wallis
26 Ventures
Has texting supplanted our ability to reach out and
talk to someone? By Wade Roush
79 Recommended
Ecosystem of a crime scene. Our AI future. Undercover
patients changed psychiatric care. B
y Andrea Gawrylewski
82 The Intersection
Don’t glorify mass shooters in the media. By Zeynep Tufekci
14 83 Anti Gravity
A tale of type A personality and upholstery. B
y Steve Mirsky
84 50, 100 & 150 Years Ago

86 Graphic Science
Proven: today’s climate isn’t natural. By Mark Fischetti
and Pitch Interactive
SPECIAL REPORT
S1 Nature Outlook: Influenza

The “flu” is annoying to many and lethal to some. This report,
from N
ature,looks at our latest defenses: better vaccines and
treatments, speedier diagnosis of the sick, and closer moni-
toring of the natural reservoir of the virus.
82
Scientific American (ISSN 0036-8733), Volume 321, Number 5, November 2019, published monthly by Scientific American, a division of Nature America, Inc., 1 New York Plaza, Suite 4600, New York, N.Y. 10004-1562. Periodicals
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2 Scientific American, November 2019

FROM
THE EDITOR Curtis Brainardis acting editor in chief of Scientific American.
Follow him on Twitter @cbrainard
Lucy in the Sky Models developed by physicists and mathematicians, which dis
play features of physical systems, reveal that in free-market
with Crystals
economies capital naturally trickles up from the poor to the rich,
leading to oligarchy. And these models match the extreme con
centration of wealth that we see in the world today.
Inequality is also at the heart of journalist Rachel Nuwer’s
When our creative director, Michael Mrak, sent around the il account of biodiversity research in postconflict Colombia (“Con
lustration for this month’s cover story—a conceptual rendering of servation after Conflict,” on page 36). The country, which emerged
so-called time crystals—our features editor, Seth Fletcher, re from decades of civil war in 2016, is home to nearly 63,000 known
sponded, “Cool. Very prog rock.” The artwork certainly seems species and likely many more. Ironically, the years of strife acted
ready-made for a Pink Floyd album (Roger Waters, if you’re read to protect this rich natural history, which is now coming under
ing this, the offer’s on the table) or at least one of those velvet threat as farmers, extractive industries and others move into once
blacklight posters. And time crystals are indeed pretty trippy stuff. dangerous areas. But biologists can now travel more freely as well,
Whereas conventional crystals are orderly states of matter and the race is on to tally Colombia’s abundant fauna. Yet docu
whose patterns repeat at regular intervals in space, these more mentation alone won’t save those species. Economic disparity led
exotic materials have patterns that repeat at regular intervals in to war in the first place, so putting biodiversity in service of bet
time. Theoretical physicist and Nobel laureate Frank Wilczek ter livelihoods for Colombians is a critical part of the equation.
and his wife, Betsy Devine, coined the term “time crystals” in Almost everywhere we look, science and society are inextrica
2012, and scientists created the first bona fide examples in the bly intertwined, which is why we must hold researchers to such
lab in 2017. Still a nascent field of research, it is one that could high standards. Take, for instance, contributing editor Lydia Den
lead to unprecedentedly precise measurements of time and dis worth’s description (page 44) of efforts to improve studies of
tance, with myriad applications. For more mind-bending details, social media’s impact on young people. Science will only ever sug
turn to Wilczek’s article, “Crystals in Time,” on page 28. gest how to resolve our problems, however—the rest is up to us.
Coincidentally, a few of the concepts that appear in Wilczek’s Fortunately, the next generation appears up to the challenge,
story—phase transitions, symmetry breaking and “exquisite” and we were proud to sponsor the Scientific American Innovator
accuracy—also come up, in a more disheartening context, in Award at the Google Science Fair, held in August. The 16-year-old
mathematician Bruce M. Boghosian’s piece about the origins of winner was Tuan Dolmen of Turkey, who found a way to harness
economic inequality, “The Inescapable Casino,” on page 70. It energy from tree vibrations to power digital applications in agri
turns out that they have been “hiding in plain sight,” he writes. culture. Explore Tuan’s project at www.googlesciencefair.com.
BOARD OF ADVISERS Drew Endy Alison Gopnik Satyajit Mayor Daniela Rus
Leslie C. Aiello Professor of Bioengineering, Professor of Psychology and Senior Professor, Andrew (1956) and Erna Viterbi Professor
President, Wenner-Gren Foundation Stanford University Affiliate Professor of Philosophy, National Center for Biological Sciences, of Electrical Engineering and Computer
for Anthropological Research Nita A. Farahany University of California, Berkeley Tata Institute of Fundamental Research Science and Director, CSAIL, M.I.T.
Robin E. Bell Professor of Law and Philosophy, Lene Vestergaard Hau John P. Moore Eugenie C. Scott
Research Professor, Lamont-Doherty Director, Duke Initiative for Mallinckrodt Professor of Physics and Professor of Microbiology and
Earth Observatory, Columbia University Chair, Advisory Council,
Science & Society, Duke University of Applied Physics, Harvard University Immunology, Weill Medical College
Emery N. Brown National Center for Science Education
Edward W. Felten Hopi E. Hoekstra of Cornell University
Edward Hood Taplin Professor Director, Center for Information Terry Sejnowski
of Medical Engineering and of
Alexander Agassiz Professor of Zoology, Priyamvada Natarajan
Technology Policy, Princeton University Professor and Laboratory Head of
Computational Neuroscience, M.I.T., Harvard University Professor of Astronomy and Physics,
Jonathan Foley Yale University Computational Neurobiology Laboratory,
and Warren M. Zapol Professor of Ayana Elizabeth Johnson
Executive Director and William R. and Salk Institute for Biological Studies
Anesthesia, Harvard Medical School Founder and CEO, Ocean Collectiv Donna J. Nelson
Gretchen B. Kimball Chair, California Meg Urry
Vinton G. Cerf Christof Koch Professor of Chemistry,
Chief Internet Evangelist, Google Academy of Sciences Israel Munson Professor of Physics
President and CSO, University of Oklahoma
Emmanuelle Charpentier Jennifer Francis and Astronomy, Yale University
Allen Institute for Brain Science Robert E. Palazzo
Scientific Director, Max Planck Institute Senior Scientist,
Morten L. Kringelbach Dean, University of Alabama at Michael E. Webber
for Infection Biology, and Founding Woods Hole Research Center
Associate Professor and Birmingham College of Arts and Sciences Co-director, Clean Energy Incubator,
and Acting Director, Max Planck Unit Kaigham J. Gabriel
for the Science of Pathogens Senior Research Fellow, The Queen’s Rosalind Picard and Associate Professor,
President and Chief Executive Officer,
George M. Church College, University of Oxford Professor and Director, Department of Mechanical Engineering,
Charles Stark Draper Laboratory
Director, Center for Computational Robert S. Langer Affective Computing, M.I.T. Media Lab University of Texas at Austin
Harold “Skip” Garner
Genetics, Harvard Medical School Executive Director and Professor, Primary David H. Koch Institute Professor, Carolyn Porco George M. Whitesides
Rita Colwell Care Research Network and Center for Department of Chemical Engineering, Leader, Cassini Imaging Science Team,
Professor of Chemistry and Chemical
Distinguished University Professor, Bioinformatics and Genetics, Edward Via M.I.T. and Director, CICLOPS, Space Science
Biology, Harvard University
University of Maryland College Park College of Osteopathic Medicine Meg Lowman Institute
and Johns Hopkins Bloomberg School Amie Wilkinson
Michael S. Gazzaniga Director and Founder, TREE Foundation, Lisa Randall
of Public Health Professor of Mathematics,
Director, Sage Center for the Study of Rachel Carson Fellow, Ludwig Maximilian Professor of Physics, Harvard University
Kate Crawford University Munich, and Research University of Chicago
Director of Research and Co-founder,
Mind, University of California, Martin Rees
Santa Barbara Professor, University of Science Malaysia Astronomer Royal and Professor Anton Zeilinger
AI Now Institute, and Distinguished
Research Professor, New York University, Carlos Gershenson John Maeda of Cosmology and Astrophysics, Professor of Quantum Optics, Quantum
and Principal Researcher, Research Professor, National Global Head, Computational Design + Institute of Astronomy, Nanophysics, Quantum Information,
Microsoft Research New York City Autonomous University of Mexico Inclusion, Automattic, Inc. University of Cambridge University of Vienna
4 Scientific American, November 2019 Illustration by Nick Higgins

LETTERS
editors@sciam.com
“It is no mystery Consider as well the costs of Chernobyl

and Fukushima.
why the nuclear It is no mystery why the nuclear power
power industry industry has been in decline: it is ulti-
mately dirty and inherently dangerous,
has been in decline: and it meets its exorbitant costs with a
it is ultimately blank check from taxpayers.
Gary D. LaverLos Osos, Calif.
dirty and inherently
dangerous.” Having had responsibility for the licens-
ing of several nuclear plants, I agree with
gary d. laver l os osos, calif.
Roush that we have far more to fear from
climate change than nuclear power. Its
continued use makes sense and should
Boeing had a woman writer who helped be part of the solution, so long as it pen-
its engineers with procedures. cils out.
But Roush is wrong that carbon tax is
NUCLEAR POWER DEBATE a “political nonstarter.” As of early Sep-
July 2019 For the second time in three months, Sci- tember, the Energy Innovation and Car-
entific Americanhas published an item bon Dividend Act (H.R. 763) pending in
promoting the promise of a revival in the U.S. House of Representatives already
WOMEN’S SPACE nuclear energy. In “Reactor Redo” [May had 62 House members signed on. It is a
“One Small Step Back in Time,” by Clara 2019], Rod McCullum describes current revenue-neutral, free-market approach
Moskowitz, includes a picture of the fir- research on “safer and more efficient” that would impose an effective accelerant
ing room for Apollo 11’s launch in 1969. reactor designs. In “I’ve Come Around on to the transition to clean energy.
I found, amid a sea of crew cuts, white Nuclear Power” [Ventures], Wade Roush Doug Nicholsvia e-mail
shirts and dark ties, nasa engineer JoAnn shares how his fear of global warming
Morgan seated at her console. Against converted him to support “the nuclear MOON EVOLUTION
the far wall, I could make out three other industry’s rebirth in the U.S.” Both ar- “Origin Story,” by Simon J. Lock and Sarah
women. I, and undoubtedly other readers, ticles ignore some long-term, practical T. Stewart, asserts that Earth’s moon was
would like to know more about the wom- shortcomings of nuclear power: First, the formed from a doughnut-shaped mass of
en in the control room that day—who failure to develop reliable technology and rock vapor—a synestia—after a collision
they were and why they were there. policy regarding spent nuclear fuel. And with a Mars-sized body.
Isaac Freund D epartment of Physics, second, the ongoing cost of nuclear plants The Fermi paradox asks why we
Bar-Ilan University, Israel once they stop generating electricity. haven’t detected technologically capa-
Nuclear plants may not generate car- ble extraterrestrials yet. There are many
MORGAN REPLIES: I cannot identify the bon dioxide, but they certainly produce suggested answers, but among the least
women against the wall. They came in radioactive waste. Regardless of how fuel far-fetched are “rare Earth” theories that
the back door to hear the VIP speeches, is initially processed or actually used posit aliens might not exist because the
which occurred 40 minutes or longer af- within a reactor, the radioactive proper- conditions that allowed humans the time
ter launch. I did not know them, and they ties of spent nuclear fuel remain funda- to evolve are very rare. One such possible
could have been clerical staff, procedure mentally hazardous. If we feel carbon di- condition is the existence of a moon that
or mail-delivery distribution employees, oxide is dangerous, let’s consider the con- can help stabilize a planet’s rotational
or any variety of administrative contrac- sequences of a growing worldwide cache axis because an unstable axis implies a
tors in the building. of spent uranium. wildly fluctuating climate.
There were very few nasa women at Roush claims that if the social cost of Lock and Stewart state that synestias
the facility. In tests, Judy Kersey, the first carbon were properly considered, nuclear might be the norm in new planetary sys-
female guidance systems engineer, would power would become more economical tems. If they are indeed common, does
come in to brief her division chief, who than fossil-fuel plants. Besides promoting this increase or decrease the probabil-
sat in my row. But I think she may have the false dichotomy of fossil fuels versus ity that extrasolar planets might have
been in the Central Instrumentation Fa- nuclear energy, he ignores the substantial a “dual planet” system (akin to our Earth
cility during the Apollo 11launch. Note cost of nuclear plants even after their util- and moon)?
that the firing room doors are unlocked ity has passed. Consider how the citizens John Takao Colliervia e-mail
within 30 minutes after launch and once of California will be charged billions of
the engine burns of the first and second dollars for decommissioning the San THE AUTHORS REPLY: A lthough synes-
stages are successful. I also remember Onofre and Diablo Canyon nuclear plants. tias are common, not all of them will

LETTERS
editors@sciam.com
ESTABLISHED 1845
ACTING EDITOR IN CHIEF

Curtis Brainard
form a large moon. They come in a wide COPY DIRECTOR Maria-Christina Keller CREATIVE DIRECTOR Michael Mrak
EDITORIAL
variety of shapes, sizes, and thermal and CHIEF FEATURES EDITOR Seth Fletcher CHIEF NEWS EDITOR Dean Visser CHIEF OPINION EDITOR Michael D. Lemonick
rotational states. Key to the size of the FEATURES
SENIOR EDITOR, SUSTAINABILITY Mark Fischetti SENIOR EDITOR, SCIENCE AND SOCIETY Madhusree Mukerjee
satellite that can be formed from a synes- SENIOR EDITOR, CHEMISTRY / POLICY / BIOLOGY Josh Fischman SENIOR EDITOR, TECHNOLOGY / MIND Jen Schwartz
tia is the amount of mass that is injected SENIOR EDITOR, SPACE / PHYSICS Clara Moskowitz SENIOR EDITOR, EVOLUTION / ECOLOGY Kate Wong
into orbit in the outer regions of the body. SENIOR EDITOR, MIND / BRAIN Gary Stix
NEWS
ASSOCIATE EDITOR, SUSTAINABILITY Andrea Thompson
Only a small fraction of impacts will in- SENIOR EDITOR, SPACE / PHYSICS Lee Billings ASSOCIATE EDITOR, HEALTH AND MEDICINE Tanya Lewis
ASSOCIATE EDITOR, TECHNOLOGY Sophie Bushwick ASSISTANT NEWS EDITOR Sarah Lewin Frasier
ject enough mass into orbit to form a MULTIMEDIA
SENIOR EDITOR, MULTIMEDIA Jeffery DelViscio SENIOR EDITOR, MULTIMEDIA Steve Mirsky
moon as large as ours, and we are still ENGAGEMENT EDITOR Sunya Bhutta SENIOR EDITOR, COLLECTIONS Andrea Gawrylewski
working out what range of conditions ART
could make it. ART DIRECTOR Jason Mischka SENIOR GRAPHICS EDITOR Jen Christiansen
PHOTOGRAPHY EDITOR Monica Bradley ART DIRECTOR, ONLINE Ryan Reid
Synestias are a new part of the grand ASSOCIATE GRAPHICS EDITOR Amanda Montañez ASSISTANT PHOTO EDITOR Liz Tormes
mystery of how rare life on Earth is. And COPY AND PRODUC TION
whether a “dual planet” system like our SENIOR COPY EDITOR Daniel C. Schlenoff SENIOR COPY EDITOR Aaron Shattuck SENIOR COPY EDITOR Angelique Rondeau
MANAGING PRODUCTION EDITOR Richard Hunt PREPRESS AND QUALITY MANAGER Silvia De Santis
own is common is still very much an D I G I TA L
open question. We will keep working to PRODUCT MANAGER Ian Kelly SENIOR WEB PRODUCER Jessica Ramirez
understand which of our planet’s special CONTRIBUTOR S
Mariette DiChristina, John Rennie
EDITORS EMERITI
characteristics were determined during EDITORIAL David Biello, Lydia Denworth, W. Wayt Gibbs,
its formation. Ferris Jabr, Anna Kuchment, Robin Lloyd, Melinda Wenner Moyer,
George Musser, Christie Nicholson, Ricki L. Rusting
ART Edward Bell, Zoë Christie, Lawrence R. Gendron, Nick Higgins, Katie Peek
LUNAR LITTER EDITORIAL ADMINISTRATOR Ericka Skirpan EXECUTIVE ASSISTANT SUPERVISOR Maya Harty
I read “Mapping the Mission,” Edward
SCIENTIFIC A MERIC AN CUS TOM MEDIA
Bell’s breakdown of A pollo 11’s landing, MANAGING EDITOR Cliff Ransom Wojtek Urbanek
CREATIVE DIRECTOR
with great interest. Could you clarify MULTIMEDIA EDITOR Kris Fatsy Ben Gershman
MULTIMEDIA EDITOR
ENGAGEMENT EDITOR Dharmesh Patel
what happened to the equipment and to
the Stars and Stripes banner that was left PRESIDENT
on the moon’s surface? Were they blown Dean Sanderson
away by the exhaust gases and hidden by EXECUTIVE VICE PRESIDENT Michael Florek
CLIENT MARKETING SOLUTIONS
dust when the explorers departed in the
VICE PRESIDENT, COMMERCIAL Andrew Douglas
lunar module? PUBLISHER AND VICE PRESIDENT Jeremy A. Abbate
MARKETING DIRECTOR, INSTITUTIONAL PARTNERSHIPS AND CUSTOMER DEVELOPMENT Jessica Cole
Jacques Van GeersdaeleBelgium PROGRAMMATIC PRODUCT MANAGER Zoya Lysak
DIRECTOR, INTEGRATED MEDIA Jay Berfas
DIRECTOR, INTEGRATED MEDIA Matt Bondlow
THE EDITORS REPLY: According to nasa, MANAGER, GLOBAL MEDIA ALLIANCES Brendan Grier
SENIOR ADMINISTRATOR, EXECUTIVE SERVICES May Jung
the American flag indeed was likely
CONSUMER MARKETING
knocked over by the rocket blast as the lu- HEAD, MARKETING AND PRODUCT MANAGEMENT Richard Zinken
MARKETING MANAGER Chris Monello
nar module lifted off from the moon. Ei- SENIOR COMMERCIAL OPERATIONS COORDINATOR Christine Kaelin
ther way, its stars and stripes are proba- ANCILL ARY PRODUC TS
bly long gone, faded by the intense ultra- ASSOCIATE VICE PRESIDENT, BUSINESS DEVELOPMENT Diane McGarvey
CUSTOM PUBLISHING EDITOR Lisa Pallatroni
violet radiation on our natural satellite. RIGHTS AND PERMISSIONS MANAGER Felicia Ruocco
The lunar module’s descent stage and sci- C O R P O R AT E

HEAD, COMMUNICATIONS, USA Rachel Scheer
entific instruments are thought to re-
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SCIENCE AGENDA
O PINI O N A N D A N A LYS I S FR OM
S C IENTIFIC A MERIC AN ’ S B OA R D O F E D ITO R S
End Vaccine
Exemptions
Religious and philosophical exceptions
are too dangerous to public health
By the Editors
As of late August,there had been more than 1,200 cases of

measles across 31 U.S. states this year. It’s a dispiriting come-
back for a disease that was declared eliminated in this country
in 2000. If the disease has not stopped spreading by the time
you read this, the U.S. will likely have lost this status. The ill-
ness has been cropping up mainly in pockets of unvaccinated
people. Those who choose not to immunize their families are
placing at risk not only themselves and their children but also
others who cannot be vaccinated because they are too young or Jewish communities in the neighborhood of Williamsburg in
have medical issues. Brooklyn and in Rockland County, New York. (It’s not just the
There isn’t an iota of doubt that vaccines are an overwhelm- Jewish community: the majority of New York City schools with
ingly safe and effective way to prevent measles and other diseas- relatively low rates of measles vaccination among students were
es, including mumps, rubella, poliomyelitis and pertussis. All Muslim or Christian academies or alternative-learning institu-
50 states mandate that children entering school get immunized tions.) The outbreak in New York City was declared over in Sep-
unless they have a medical exemption. Yet almost every state also tember, but cases have persisted in Rockland County.
offers religious exemptions, and more than a dozen offer person- Many people who choose not to vaccinate believe no govern-
al belief/philosophical ones as well. California, Mississippi, West ment should force them to put medicine into their bodies or
Virginia, Maine and, most recently, New York State have gotten their children’s. They frame the choice as a personal right, but
rid of all nonmedical waivers. The others must follow suit. It’s they are not taking into account the rights of others, including
imperative for protecting public health. their own children, to be free of disease. When it comes to bal-
It doesn’t take many unvaccinated people to cause an out- ancing the two, we need to consider the needs of the communi-
break. Measles was one of the first vaccine-preventable diseas- ty as well as those of the individual. The Supreme Court ruled in
es to reappear because it is so contagious; the threshold for Jacobson v. Massachusettsthat states have the authority to
resistance to a disease conferred by sufficient community-wide require vaccination against smallpox, and in P rince v. Massachu-
levels of immunity or vaccination—so-called herd immunity—is setts it reaffirmed that the right to religious liberty does not
93 to 95 percent. If vaccination levels fall below that threshold, include the right to expose a child or the community to disease.
an infected person can cause an outbreak. Some experts argue we should just make it more difficult to
Hesitancy about vaccines is nothing new. People have ques- obtain religious and philosophical exemptions. But unless the
tioned inoculations since Edward Jenner discovered the small- exemptions are removed completely, there will always be people
pox vaccine in 1796. Today vaccines are partly a victim of their who want to use them. Partial elimination, as the Washington
own resounding success. People rarely, if ever, see once common State Senate enacted in the case of philosophical exemptions for
diseases such as measles and polio, so they don’t understand the MMR (measles, mumps and rubella) vaccine alone, is also
their potential danger. On top of that, relentless misinformation shortsighted because it sends the message that some immuniza-
campaigns have touted such false claims as the idea that vac- tions are less important than others. The only surefire solution is
cines cause autism. Numerous studies have shown they do not. to eliminate nonmedical exemptions to recommended vaccines.
The discredited researcher Andrew Wakefield introduced this People who cannot be vaccinated for medical reasons—such as
idea in a now refuted study, and celebrities such as Jenny McCar- those with compromised immune systems—should of course
thy and Robert F. Kennedy, Jr., have given it credence. And social remain exempt. But there is no legitimate argument against vac-
media has made it easier than ever for vaccine deniers to find cination for the vast majority of healthy people, and there are
like-minded networks of people to confirm their false beliefs. many powerful arguments in favor of it. Refusing to vaccinate is
Despite the existence of religious exemptions to vaccines, not a matter of freedom. It’s a matter of public safety.
most major faith groups in the U.S. do not prohibit vaccination,
JOIN T HE CONVERSAT ION ONLINE
and many religious leaders encourage it. Nevertheless, a large Visit Scientific American on Facebook and Twitter
number of this year’s measles cases occurred in ultra-Orthodox or send a letter to the editor: editors@sciam.com
10 Scientific American, November 2019 Illustration by Rafa Alverez

FORUM
C OMM E N TA RY O N S C IE N C E IN
T H E N E W S FR OM T H E E X PE R T S Kirk J. Schneider is a psychologist and a current member
of the Council of the American Psychological Association.
and provides support to mental health services specifically, but it

tends to focus on addiction and shorter-term, behavioral modal-
ities. Moreover, it appears to be dominated by a medical orienta-
tion, which may not be adequate to address the intense psycho-
logical needs of many in the nation. And neither office appears to
have the staff, budget and expertise to tackle the diversity of prob-
lems in the mental health sector.
For that reason, Congress should create an office dedicated to
public mental health—the office of a “psychologist general.” He or
she would coordinate closely with the office of the surgeon gen-
eral, as well as related government agencies such as SAMHSA, to
oversee and advise the public regarding strictly psychological
(that is, nonmedical) approaches to public mental health care.
Such a position could be filled by a psychologist, a counselor, a
social worker, a researcher or a psychiatrist—but he or she must
have specific expertise in psychological a pproaches to public
mental health. In addition, the psychologist general should be a
distinguished professional who has a superlative knowledge of
evidence-based approaches to health care and who has a collab-
orative view of how psychology and medicine can work together
to optimize it.
Some of my colleagues have asked why we shouldn’t have a
psychiatrist general rather than a psychologist general as over-
seer of public mental health. My answer is that although these
The U.S. Needs specialists are integral to the health care system, the statistics
demonstrate that their contributions do not appear to be suffi-
a Mental
cient. Moreover, there are indications that many in our society
are overmedicated and that potent psychological methodologies
could give people the resources to function more sustainably on
Health Czar
their own or in conjunction with appropriate medical care.
A psychologist general at the forefront of mental health
research and delivery would send a strong message that psycho-
logical well-being is prized on a par with physical health—a mes-
The country is facing a psychological sage in keeping with the phrase “Life, Liberty and the pursuit of
crisis—and nobody is really in charge Happiness.” More important, it is a message that resonates with
contemporary needs. As a major review of the literature demon-
By Kirk J. Schneider strates, there is every indication that by addressing these needs
The U.S. is experiencing a mental health crisis. According to our nation will save on medical costs as well.
recent surveys, rates of depression, anxiety and opioid addic- Just as in the case of the surgeon general, the psychologist
tion, particularly among young people, are alarmingly high. Also general would be nominated by the president, with the advice
mounting are rates of suicide, hate crimes and rampage killings, and consent of Congress. Candidates might come from the U.S.
as is the demand for mental health services. A survey published Public Health Service—or it might make more sense for Con-
in January by the California Health Care Foundation and the gress to authorize selections outside of this corps because there
Kaiser Family Foundation found that more than half of those are many qualified psychologists, counselors, social workers,
surveyed thought their communities lacked adequate mental researchers and psychiatrists who may not officially be part of
health care providers and that most people with mental health the corps but who hold equivalent, and perhaps in some cases
conditions are unable to get needed services. superior, credentials in the promotion of psychological ap
These statistics indicate that there is a gap in state and feder- proaches to public mental health. In either case, the time is ripe
al oversight of public mental health. The federal office of the sur- for a psychologist general. It is both economically warranted
geon general oversees operations of the U.S. Public Health Ser- and morally imperative.
vice, which communicates health recommendations to the public,
but that is a huge portfolio that ranges from nutrition to vaccines
J O I N T H E C O N V E R S AT I O N O N L I N E
to environmental hazards to mental health. The Substance Abuse Visit Scientific American on Facebook and Twitter
and Mental Health Services Administration (SAMHSA) oversees or send a letter to the editor: editors@sciam.com
12 Scientific American, November 2019 Illustration by Matt Harrison Clough

ADVANCES
Boaters transport ice in

Vietnam’s Mekong Delta.

D I S PATC H E S FR OM T H E FR O N TIE R S O F S C IE N C E , T E C H N O LO GY A N D M E D I C IN E IN S ID E
• A projection of the economic price

all countries will pay for climate change
• Brazilian ants build a feathery trap
• Early warning for epileptic seizures
detected in the blood
• Space archaeology to preserve
humanity’s history
GEOGRAPHY
Delta Danger
Newly calculated elevation means
millions of residents may need
to leave Vietnam’s Mekong Delta
A stunning 12 million p eople could be
forced to retreat from rising seas in Viet-
nam’s Mekong Delta within half a century.
Geographer Philip Minderhoud and his
colleagues at Utrecht University in the
Netherlands arrived at this conclusion after
analyzing ground-based topography mea-
surements to which outside scientists’
access was limited for years. The new
analysis, published in August in N ature
Communications, shows that the Mekong’s
elevation above sea level averages just
0.8 meter—almost two meters lower than
commonly cited estimates.
The locally measured figures more than
double the number of Vietnamese people
living in low-lying areas that will be inun-
dated as the earth’s climate warms, with
some places likely to be underwater in only
a few decades.
For elevation readings in many develop-
ing countries, international researchers
rely on freely available global satellite data
because there are few on-the-ground
records—and because some governments
closely guard their own data. But satellite
elevation readings can be notoriously unre-
liable in low-lying areas. Torbjörn E. Törn-
qvist, a geologist at Tulane University, says
this is a concern not just for the Mekong but
also for other mega deltas inhabited by tens
BRUNO DE HOGUES G etty Images
of millions of people (such as the Ganges in

Bangladesh and India and the Irrawaddy in
Myanmar). “My hope is that these findings
will wake people up to the fact that we’re
dealing with terrible data sets that aren’t
J O I N T H E C O N V E R S AT I O N O N L I N E Visit Scientific American on Facebook and Twitter

ADVANCES Mek
ong Riv e r
CAMBODIA VIETNAM
appropriate for the problems these deltas meters or more. “Not so bad if you’re mod-
are facing,” he says. eling the Himalayas,” Törnqvist says. “But Ho Chi Minh City
Unlike rocky continental coasts, deltas for a low-lying delta, that’s a whole different
are made of soft river sediments that are story.” Organizations such as the World
Delta
deposited over thousands of years and can Bank rely on these assessments when mak-
i ver
easily compact and subside. Subsidence can ing policy decisions, including where to allo- Gulf of
gR
n
Thailand ko
grow worse when upstream dams block cate flood-preparedness resources. Me
the incoming flow of new sediments in riv- The gold-standard remote-sensing sys- South China Sea
ers or when groundwater or natural gas is tem used for measuring delta heights— 0 50
pumped up from below, removing underly- lidar, which is often mounted on aircraft—
Kilometers
ing support for the land. Urban infrastruc- is accurate to within a few centimeters. But
ture can also prevent water from seeping it is expensive and generally unavailable
into the earth and refilling aquifers. All these in developing countries. data can be used to support strategic mili-
forces are at play in the Mekong, which is Space shuttle data had put the Mekong’s tary operations, “they are not in the public
subsiding in some areas at rates approach- average elevation at 2.6 meters. But Min- domain,” Nicholls says. And governments
ing five centimeters a year—and the rate at derhoud, who was on-site with a Dutch may simply not want to stir drama among
which the entire delta is subsiding is among research team studying the delta, was local populations, Törnqvist notes.
the fastest in the world. According to Nguy- skeptical. He found that those measure- To gain access to the Vietnamese data,
en Hong Quan, a hydrogeologist at Viet- ments had strange elevation patterns that Minderhoud first had to build trust with
nam National University, flooding has were inconsistent with the local terrain. government institutions and identify oppor-
grown more common all across the delta. Minderhoud says his Vietnamese col- tunities for cooperation. “I tried to find out
Numerous international assessments leagues knew their government had been how my own research might contribute to
of deltas are based on topography informa- collecting ground-based survey data and their goals,” he says. “The key was to make
tion gathered in February 2000 by the even some lidar measurements. Vietnam- this a combined effort.” In time, he wound
space shuttle E ndeavour. K
nown as the Shut- ese academics, however, had not published up with almost 20,000 elevation points
tle Radar Topography Mission, this global the data in international journals, according measured throughout the delta.
survey was sponsored in part by the U.S. to Minderhoud. Minderhoud’s team also performed a
Department of Defense, and data from the Robert Nicholls, a coastal engineer at crucial step that is frequently neglected in
project are now publicly available. Elevation the University of Southampton in England, regional assessments: the researchers cali-
assessments use other space-based mea- says it is not unusual for governments to brated the data to a local benchmark for
surements as well, but in general they are withhold topography measurements for zero elevation at an island town called Hon
prone to vertical errors ranging up to 10 national security reasons. Because those Dau. This was necessary because ocean
Map by Mapping Specialists
H U M A N B E H AV I O R an individual’s subjective aversion to each
Procrastination and the amount of time available. The sys-

tem then assigns reward points to each
Tech Support
task in a way that is customized to encour-
age that person to complete them all.
“The idea was to turn the challenging
“Cognitive prosthesis” motivates projects that people pursue in the real
people to finish tasks world into a gamelike environment,” Lieder
says. “The point system [gives] people
Choosing betweeninstant gratification proximal, attainable goals that signal that
and future benefit can easily lead to short- they’re making progress.”
sighted decisions: streaming TV instead of The team tested the setup in a series
going to the gym, for example, or scrolling of experiments with human subjects.
through social media rather than working choices, Lieder and his colleagues de The results, published online in August in
on a challenging project. “Because of this signed a digital tool they call a “cognitive Nature Human Behaviour,revealed that the
misalignment between immediate reward prosthesis.” It helps to match a decision’s AI support system helped people make
and long-term value, people often struggle immediate reward with its long-term better, faster decisions and procrastinate
to do what’s best for them in the long run,” worth—using artificial intelligence to aug- less—and it made them more likely to
says Falk Lieder, a cognitive scientist at the ment human decision-making through a complete all the assigned tasks. In one
Max Planck Institute for Intelligent Sys- to-do list. The researchers developed a set experiment, in which the researchers pre-
tems in Tübingen, Germany. of models and algorithms that consider sented 120 participants with a list of sever-
To guide individuals toward optimal various elements such as a list of tasks, al writing assignments, they found that
16 Scientific American, November 2019 Illustration by Thomas Fuchs

currents and other forces can cause water to

“pile up” along certain local coastlines, making
sea surfaces higher in some areas. The more
typical approach is to use a global benchmark
for zero elevation, which may not reflect local
sea-surface height. By combining average rates
for sea-level rise and for subsidence, Minder-
houd estimates the water will effectively rise by
0.8 meter on average in 57 years.
A similar fate may await other major deltas.
Heri Andreas, a researcher at the Bandung
Institute of Technology in Indonesia, says Jakar-
ta—coastal home to 10 million people and one
of the fastest-sinking cities on earth—has been
modeled extensively with lidar. Scientists esti-
mate that almost all of the city’s northern dis-
trict could be submerged by 2050, and Presi-
dent Joko Widodo announced plans to build a
new capital on the island of Borneo. “But many
other cities in Indonesia are also experiencing
subsidence, and we don’t have accurate eleva-
tion models for most of them,” Andreas says.
Although the locally measured elevations
are disturbing to outside experts, Nguyen main-
tains that they were not a surprise to scientists
in Vietnam. He also says the Vietnamese gov-
ernment is developing what he claims is a new
and even more precise elevation map. As for
relocation, Nguyen says he is unaware of any
plans to that effect. “The challenge is to con-
vince people if the prediction is reliable enough
to take action,” he says. —Charles Schmidt
85 percent of individuals who used the

tool completed all their tasks; the rate was
only 56 percent for those not using it.
The difference in completion rates was
“quite impressive,” says Mike Oaksford,
a psychologist at Birkbeck, University of
London, who was not involved in the
study. “That seems to me to be a convinc- Over 50 New Features & Apps in this New Version!
ing demonstration that procrastination is
something that this strategy [can] help Over 500,000 registered users worldwide in:
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Lieder says one of the current tool’s ■ 6,000+ Companies including 20+ Fortune Global 500
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—Diana Kwon
www.originlab.com

For a 60-day FREE TRIAL, go to OriginLab.Com/demo and enter code: 9246
ADVANCES
C L I M AT E C H A N G E
financial suffering will be widespread. “It Limiting emissions in accordance with
The Price doesn’t matter what kind of country you

are, you are going to get hit by climate
the Paris climate agreement (which aims to
keep global temperature rise below two
of Warming change,” says study co-author Kamiar

Mohaddes of the University of Cambridge.
degrees Celsius by 2100) would substan-
tially stem the losses. Globally, the decline
Countries rich and poor In a preliminary report for NBER, in GDP would be a mere 1 percent; in the
Mohaddes and other economists compiled U.S. and Canada, it would about 2 percent.
will take a financial hit
per capita gross domestic product (GDP) Unlike earlier studies, this one looked
and temperature data for 174 countries not just at temperatures but at how they
When a majorheat wave engulfed west- going back to 1960 to capture how above- deviate from the normal conditions to
ern Europe in late July, Paris and other cities normal temperatures have impacted which societies have adapted. Although
recorded their highest temperatures ever. income levels historically. They then pro- rich countries such as the U.S. may have
The furnacelike weather did not just cause jected that relation into the future to see more resources to compensate for swings
sweaty brows—it also exacted a financial how further warming could affect GDP, away from those norms, the study results
toll in infrastructure damage, lost labor pro- a measure of all the goods and services make clear that adaptation alone will not
ductivity and potentially lower agricultural a country produces. prevent major losses, Mohaddes says. “All
yields. The situation illustrates how even If greenhouse gas emissions continued of the infrastructure and the technology
relatively wealthy countries can take an to grow along their current trajectory, that we have mitigates the cost but cannot
economic blow from climate change. about 7 percent of global GDP would be conceal it fully,” says World Bank econo-
That is a key message of a new study lost by 2100, the researchers found. Rich mist Stéphane Hallegatte, who was not
from the nonprofit National Bureau of Eco- and poor countries, as well as those with involved with the study.
nomic Research (NBER). Much earlier hot and cold climates, would all see GDP Both Mohaddes and Hallegatte say
research has suggested that climate-relat- losses (graphic). The U.S. would lose the projections most likely underestimate
ed losses would be higher for poorer, hot- 10.5 percent of its GDP, whereas Cana- GDP losses because the study does not
ter countries and that colder countries da—which some economists say could take into account the bigger variations in
could even see economic benefits from benefit from warming because of expand- climate extremes expected in the future.
warming. But the new analysis indicates ed agriculture—would lose 13 percent. —Andrea Thompson
The Costs of Climate Change in Lost GDP
Terms of Paris agreement Terms of Paris agreement

are met (green) are not met (red)
Solid line shows a scenario in which countries Dotted lines show scenarios in which countries
adapt to climate change at a moderate speed adapt to climate change very quickly (upper bound)
or very slowly (lower bound)
World Rich Countries Poor Countries Hot Countries Cold Countries

Percent Change in GDP
per Capita
SOURCE: “LONG-TERM MACROECONOMIC EFFECTS OF CLIMATE CHANGE: A CROSS-COUNTRY ANALYSIS,”

–5 2014
baseline
BY MATTHEW E. KAHN ET AL. NATIONAL BUREAU OF ECONOMIC RESEARCH, AUGUST 2019

–10
–15
2030 2050 2100
U.S. China European Union India Russia

Percent Change in GDP
per Capita
–5
–10
–15
2030 2050 2100
18 Scientific American, November 2019 Graphic by Amanda Montañez

CANADA GERMANY
IN THE NEWS In the famed Burgess Shale rock formation, A vengeful crowd attacked two intoxicated German
Quick paleontologists discovered hundreds of fossils

from a horseshoe crab–shaped, prehistoric
men who killed a western capercaillie they said
attacked them. The bird is endangered in Germany;
Hits predator that lived in the ocean 506 million years

ago. It measured up to a foot long.
species populations have shrunk because of habitat
loss and stress from increased human contact.
By Jennifer Leman
MEXICO CAMEROON AND

Researchers have rationed EQUATORIAL GUINEA
electricity and cut Scientists found that
temporary employees’ Goliath frogs, which are
jobs after Mexico’s Earth’s largest living frogs
president lowered funding and can be longer than a
for federal institutions, football, construct protect-
including those supported ed ponds for their young
by the National Council by pushing heavy rocks
of Science and Technology, across streams. They live
by 30 to 50 percent in only in this region.
certain budget items. COLOMBIA TANZANIA
Scientists confirmed a destructive fungus targeting Marine biologists discovered a colorful fish
banana plants has arrived in the country. No species, dubbed the vibranium fairy wrasse,
For more details, visit
www.ScientificAmerican.com/ treatment is available, so officials put potentially during a biodiversity assessment of largely
nov2019/advances infected crops under quarantine to stop its spread. unstudied deep reefs off Zanzibar’s coast.
A N I M A L B E H AV I O R
Feather Trap
Brazilian ants build an
unusual pitfall for bugs
Fallen feathers may appear innocuous, but
bugs in tropical Brazilian savannas should
think twice about approaching them. New
research suggests P heidole oxyops a nts
sometimes place feathers around their
underground nest’s single entrance as bait
for other creatures, which then tumble in. heidole oxyops nest entrance
P
This behavior is an unusual example of ants is surrounded by feathers.
using lures or traps rather than actively
hunting down their prey. feathers, suggesting they were not being certainly very few examples of ants acquir-
Inácio Gomes, an ecologist at the Fed- used for water. And the team found that ing food without leaving their nest.”
eral University of Viçosa in Brazil, had nev- artificial traps with feathers around them McCreery wonders why prey are attract-
er seen any description in scientific studies captured more wandering arthropods than ed to the feathers in the first place; Gomes
of ants building traps. He first noticed those without. suggests smell and shape are potential
feathers around ant nest entrances in city Gomes says that once prey such as draws. “In general, soil insects are very curi-
parks and on his college campus, and he mites, springtails or other species of ants ous—that’s why pitfall traps are so effective,”
found two hypotheses in scientific litera- fall in, the nest entrance’s soft walls make Gomes says. Scientists use similar traps to
ture: the feathers could collect morning it hard for them to climb out, and the capture wild specimens.
dew in dry areas, or they could act as lures. inhabitants quickly subdue them. P. oxyops f orage alone or in groups like
Gomes is lead author on an August Helen McCreery, a biologist at Harvard other ant species—Gomes once saw them
study in E cological Entomology that experi- University, who was not involved in Gomes’s take down a praying mantis—but he said
RICARDO SOLAR
mentally tested both ideas. The researchresearch, says the study is “really cool” and they most likely supplement hunting with the
ers provided a ready supply of wet cotton well done. “It’s a very charismatic, conspicu- feather traps to get through long dry seasons
balls but found the ants still collected ous behavior,” McCreery adds. “There are with scarcer prey. —Joshua Rapp Learn

ADVANCES
B I O LO G Y
cells per eye in early juvenile, late juvenile
Hatchlings and adult spiders. They also examined sev-

en of the spiders twice, four months apart,
with Vision and found that none of them produced

new photoreceptors.
Jumping spider babies are That measurement indicates the spi-
ders do not add receptors as they grow
the size of a grain of sand
but cram in all these cells by the time they
but see surprisingly well hatch—“Which is a crazy thing to do!”
Morehouse says. According to the team’s
Adult jumping spiders
spidersare littler than earlier genetic research, the tiny spiders
a fifingernail,
ngernail, but their vision is as clear most likely share an “ancient genetic tool
as a small dog’s. And the babies, with kit” with insects: their bodies fifirst
rst con-
heads a hundredth the size of their par- struct the photoreceptors, then top them
ents’, may see in almost as much clarity. off with lenses. That mechanism makes
off
Researchers have now discovered a sense for certain insects that add new pho-
mechanical secret behind this remarkable toreceptors, capped with separate lenses,
hatchling ability. to their eyes as they grow larger. But it is
“Even arachnophobic people find find these developmentally cumbersome for spiders,
little jumping spiders to be compelling— whose eyes each accommodate only one
they dance, they sing vibratory songs to lens and so need all their photoreceptors in
each other,” says Nathan Morehouse, a co- place early in life.
author of the study published in July in These results suggest spiderlings see as
Vision Research.
Vision Research.(Morehouse started the much detail as adults, with a comparable
research at the University of Pittsburgh fifield
eld of vision—although there are draw-
and fifinished
nished it at the University of Cincin- backs. For instance, baby spiders’ tiny pho-
nati.) And the spiders’ extraordinary visual toreceptors provide poor light sensitivity.
ability captivates many scientists. Morehouse has seen evidence of this him-
“Everyone I know who works on vision self: “They’re a little bit stumbly,” he says.
just loves jumping spiders,” says Jamie The eyes’ biological structure cannot
Theobald, who studies insect vision at tell scientists everything about how the
Florida International University and was spiders see. “They may be making trade-
not involved in the new study. “How they offss at the neural level,” Theobald says,
off
accommodate such amazing visual behav- such as restoring some sensitivity at the
iors is a pretty important question.” expense of spatial or temporal detail. For
Researchers have observed that young that reason, behavioral studies are neces-
jumping spiders can use complex visual sary to fully understand spiders’ vision. But
M orehouse Lab
cues while hunting. To fifindnd out how young- the biological results alone are surprising,
DANIEL ZUREK Morehouse

sters’ vision is so close to adults’, More- Theobald says: “To have to have all your
house and his colleagues peered into one of photoreceptors right from the beginning?
the spiders’ four sets of eyes (a forward-fac- It’s not the way I would build a spider.”
22 individuals
ing, motion-sensitive pair) in 22 individuals — Leila Sloman
—Leila
using a micro-ophthalmoscope, a miniature
version of an eye doctor’s tool.
The researchers counted
roughly 7,000 photoreceptor
Adult female
and spiderling
Phidippus
Phidippus audax
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mark of Apple Inc.
20 Scientific
20 Scientifi
oneThirdNonBleed.indd 17 c American, November 2019
9/17/19 3:31 PM

Brain scan shows activity

caused by epilepsy.
MEDICINE
Seizure
we see cycles running over seven, 28, 40
days,” Cook says. “These patterns control
Warnings
brain excitability, making you more or less li-
able to seizures.” The new findings
findings may thus
ultimately lead to a better understanding of
Molecules in the blood could alert the causes of epilepsy. “We haven’t known
those with epilepsy hours ahead what’s driving the cycles, but there may be
a clue here that there are genes driving the
More than 50 million p eople worldwide
people system, generating these fragments, which
have epilepsy, and one of its harshest as- allow prediction of seizures,” Cook says.
pects is its unpredictability. Sufferers
Sufferers rarely “That’s very exciting because it tells you
know when a seizure will occur. something not only about epilepsy but about
But molecular biologist Marion Hogg how the brain works.”
of FutureNeuro, a research institute hosted Cook’s group previously predicted sei-
at the Royal College of Surgeons in Ireland, zures by monitoring brain activity, but that
and her colleagues have found molecules required invasive surgery. FutureNeuro re-
whose levels in the bloodstream differdiffer be- searchers are working on a seizure-predic-
fore and after a seizure. This discovery tion device that uses pinprick blood tests
could lead to a blood test that gauges at home, similar to a glucose monitor. The
when seizures are likely to strike, enabling study’s analysis needed relatively large
patients to take fast-acting preventive amounts of plasma separated from blood—
drugs. The study, published in July in the so an immediate challenge is developing a
Journal of Clinical Investigation, may
Journal ay even
m device that works both with small samples
offer
off er clues about epilepsy’s causes. and with whole blood. “We anticipate such
The researchers analyzed plasma sam- a device may be available for patients to
ples from the blood of people with epilepsy use in the next five
five years,” Hogg says.
and found that certain fragments of trans- Advance warnings could make a major
fer RNA (tRNA)—a molecule involved in difference
diff erence in patients’ lives. “If you had an
translating RNA into proteins—appear to indication, perhaps you wouldn’t go into
spike hours before a seizure, then return to work, or drive, or go swimming,” Hogg
a normal level afterward. These fragments says. And although some epilepsy drugs
form when enzymes cut tRNAs in response are fast-acting, most are for long-term
to stress, possibly caused by increased management—but nearly a third of pa-
brain activity in the run-up to a seizure. tients do not respond to the latter. Cook
Neurologist Mark Cook of St. Vincent’s says that accurate seizure prediction
Hospital in Melbourne, Australia, who was would encourage drug development for
SCIENCE SOURCE
not involved in the work, says the tRNA fluc-

fluc- acute use, which could mean fewer side
reflect
tuations could refl ect the rhythms of biologi- effects
eff ects as compared with a daily regimen.
cal clocks. “In adults with chronic epilepsy, — —SSimon
imon Makin
Makin

ADVANCES
S PAC E A R C H A E O LO G Y
History
in Orbit
Space junk documents humanity’s
expansion into new frontiers
After two years on the moon, Surveyor 3
The word “archaeology”
“archaeology” typically brings
Apollo
has visitors from the A pollo 12 mission.
to mind crumbling ruins from ancient
civilizations—not gleaming rocket ships
or high-tech spacecraft. But more than exploration to learn about the human be-
60 years of space missions have scattered haviors behind them. So this covers infra-
countless artifacts throughout Earth orbit structure on Earth, objects in Earth orbit
and across the solar system, creating a his- and even sites on other worlds. The A Apollo
pollo
toric legacy of exploration for current and lunar landing areas are good examples—
future generations. Alice Gorman, a rere- to me, those are archaeological sites. And
searcher at Flinders University in Adelaide, that feeds into the related concept of
Australia, is one of a few pioneering “space “space heritage,” which assigns different
archaeologists” studying the Space Age. categories of significance—historical, aes-
She is also the author of a new book, thetic, social, spiritual and scientific—to
Dr Space Junk vs the Universe: Archaeology certain artifacts and sites for past, present
and the Future ((MIT
MIT Press, 2019). or future generations. Much of my work
Scientific AmericAn
merican spoke with Gorman involves gathering the information to help
about assessing the cultural significance of make those judgments.
orbital debris and how to preserve space
artifacts as a heritage for all humankind. You’re sometimes called Dr. Space
An edited excerpt follows. —Lee Billings Junk, but I get the sense you don’t
actually like the term.
What is “space archaeology?” That’s right. Even though I strongly identify
That’s
Space archaeology uses the physical mate-
Space with that persona, the term “space junk”
NASA
rial and the places associated with space is problematic. From an archaeological per-
G E O LO G Y these include studying desert dust found
Birth of in sediment under the Atlantic Ocean,

analyzing sandstone and modeling the
the Sahara
ancient climate. To help settle things,
geomorphologist Daniel Muhs of the U.S.
Geological Survey (lead author on the
Dust on nearby islands hides new research) and his colleagues looked
secrets of the desert’s origins at sediment on Spain’s Fuerteventura and
Gran Canaria islands, where they found
The Sahara
Sahara is the world’s largest and evidence of Saharan dust. The dust ap ap-
most legendary subtropical desert, but peared in ancient soil layers, whose age
knowledge about it is surprisingly limited. they assessed on the basis of fossils found
Even estimates of when it formed vary in the same layers—and that age agreed
widely, from more than five million years with earlier marine sediment studies.
ago to mere thousands. Now, however, The researchers reported their finding
geologists studying wind-carried Saharan Palaeogeography, Palaeo
in November in Palaeogeography,
Scientific American is a registered trademark
of Springer Nature America, Inc dust on the Canary Islands have come Palaeoecology.
climatology, Palaeoecology.
Scientific American is a registered trademark of
Springer Nature America, Inc.
closer to pinning this down: it is, they “The conclusion of the study is very
report, close to five million years old. good,” says Zhongshi Zhang, a climate
One reason for the uncertainty over modeler at the University of Bergen in
the Sahara’s age is that researchers use Norway, who was not involved in the
such different methods to estimate it; work. Because the dust found on the
22 Scientific
22
oneThirdNonBleed.indd 16 American, November 2019
9/17/19 3:22 PM

spective, junk can be very valuable. When else would gain that status. And, in terms
we call orbital debris “space junk,” we’re of scientific significance, the longer we
closing off the idea that it might have some leave it up there, the more precious it
positive qualities, now or in the future. becomes as a resource telling us the
Some space junk is still functional—satel- effects of long-term exposure to the space
lites that still have fuel and can still transmit. environment. We can and do study this
They’re only junk because no one is using remotely, measuring via reflectance how
them at this point in time. Not that these rough Vanguard 1’s once smooth surface is
things must be gathering and relaying data becoming over time. Also, if you put Van-
to be useful; space artifacts can have pri- guard 1 in a museum, most people will
marily social rather than scientific functions, never see it, only locals or tourists. But left
like Elon Musk’s now interplanetary red Tes- as is, anyone can go look for it in the sky.
la sports car, or Vanguard 1, the oldest satel-
lite [remaining] in space. Most of their value Are there any space artifacts or sites In
SCIENCE
comes from shaping people’s ideas of what that merit special protections?
space is and how they are connected to it. I’m very worried about lunar sites, particu-
I’m
larly those of the Apollo landings. Everyone
In your book, you argue that orbital
debris should be left in place when
seems to be talking about going to the
moon again, and people have talked about
We
there’s no risk of collision with opera-
tional satellites and spacecraft. But
visiting or approaching these places. If we
don’t make a solid case for their protec- Trust
why not bring something like Van- tion, then some cowboy might just send a
guard 1 down and put it in a museum? A
pollo 11’
rover right up to Apollo 11’s landing site and
I don’t think putting Vanguard 1 or other drive over Armstrong’s and Aldrin’s foot-
Join the nation’s
superlative artifacts in a museum is the prints. Even if they only get close enough largest association of
best strategy for preserving value. for a photo from a distance, that can still
An artifact’s setting can be an impor- stir up lots of lunar dust, which can be very
freethinkers, atheists
tant part of its significance. Some of Van- damaging for past exploration sites. On and agnostics working
Earth the archaeological principle is to not
guard 1’s significance depends on its being to keep religion
the oldest human-made object in orbit. unnecessarily destroy things and to always
Brought back to Earth, it can’t be the old- leave more for future researchers who may out of government.
est thing in orbit anymore—something use better, more advanced techniques.
For a free sample of
FFRF’s newspaper,
Freethought Today:
Call 1-800-335-4021
ffrf.us/reason
Caravan journeys across

Saharan dunes in Libya.
ffrf.org
islands is distinct from the marine record, Caribbean and the Amazon rain forest,
Zhang adds, it helps to build the case for Muhs notes. Amazon soils are poor in
a multimillion-year age. nutrients, and he says the new results help
Images
G etty Images
The Sahara is the biggest source of air- to show how nourishing dust from Africa
FFRF is a 501(c)(3) educational charity.
SERDYUK Getty
borne dust in the world—and that dust’s could have been supporting the South
journey does not end in the Canary Islands, American region’s incredible biodiversity
ANNA SERDYUK
Deductible for income tax purposes.

which lie just off the western coast of Afri- for millions of years—adding to the Ama-
ANNA
ca. It continues on to places such as the zon’s own origin story. —Lucas Joel
Untitled-113 1 11/09/2019 17:26

ScientificAmerican.com 23
THE SCIENCE Claudia Wallis is an award-winning science journalist whose

OF HEALTH work has appeared in the New York Times, Time, Fortune a nd the
New Republic. She was science editor at Time a nd managing editor
of Scientific American Mind.
author Beate Wieseler said in an interview. “It just means we have

no positive proof. Either we have no studies at all [comparing the
new medicine with the standard of care] or we have studies, but
they aren’t good enough.” The record was “particularly egregious,”
she and her colleagues wrote, for drugs that treat psychiatric and
neurological disorders and those for diabetes, with only 6 and
17 percent, respectively, offering a confirmed added benefit.
Wieseler and her co-authors work for Germany’s Institute for
Quality and Efficiency in Health Care, which evaluates new treat-
ments and advises on whether the country’s health care system
should pay a premium for them. Such organizations, known as
health technology assessment (HTA) agencies, have become
“enormously more powerful” in many countries’ efforts to manage
the spiraling cost of new drugs, says Sean Tunis of the not-for-
profit Center for Medical Technology Policy in Baltimore. HTA
works a little differently in the U.S., he explains: “If payers think a
new drug is not any better than a drug that we already have, they
will do things like requiring you try the cheaper drug first.” Insur-
ers and Medicaid will often insist on this kind of “step therapy.”
Germany’s HTA is probably the most persnickety about de-
manding head-to-head trials to prove that a new treatment beats
the existing standard. This is not always practical. For one thing,
such studies can be hugely expensive and time-consuming, with
A Dilemma no guarantee of success. “What the authors are focused on is get-

ting new, differentiated medicines at a low cost, and what they
with New Drugs

are missing is a sense of the complex economic underpinning of
developing new medicines,” says Ken Moch, president and CEO
of Cognition Therapeutics, a biotech firm in Pittsburgh. Requir-
ing trials that prove superiority, he says, can discourage compa-
Most of the time we don’t know nies from even attempting to develop new alternatives. This is al-
if they are better than the old ones ready happening. Drug developers are increasingly focused on
niches where there are no good treatments to compete with, such
By Claudia Wallis as rare diseases and advanced cancers. The sky’s the limit on pric-
es for these first-to-market drugs, which are often rushed through
“New and improved.” These words have been yoked together in fda approval with limited data on efficacy. Many new cancer
so many marketing campaigns that we tend to accept them as drugs are approved when it is shown they can shrink tumors by
inexorably linked. But when it comes to new medications, don’t 30 percent, even if there is no proof that they boost survival.
swallow them without a healthy dose of skepticism. Many or This lack of meaningful data to guide patients is a major point
most new drugs are not—or at least not provably—an improve- of Wieseler’s paper. Tunis shares her concern: with accelerated
ment over the best existing drug for a given condition, and the approval, “there are more products approved, with a greater
fast-track drug-approval processes that have prevailed in recent amount of uncertainty about risks and benefits.” But there are
years have added to the uncertainty about their advantages. other solutions besides head-to-head drug trials. One idea is for
A recent report in the British Medical Journal, e ntitled “New regulators and payers to require postmarket studies to track the
Drugs: Where Did We Go Wrong and What Can We Do Better?,” effectiveness of newly approved drugs—a step too often neglected.
offers an analysis of the issue. The authors looked at 216 drugs ap- Tunis’s center is taking another approach. Last year it helped to
proved by German regulators between 2011 and 2017; 152 were convene the makers of seven experimental gene therapies for he-
newly developed, and 64 were existing medications approved for mophilia with patient groups, regulators, HTA agencies and oth-
new uses. Only 25 percent of the medications were deemed as of- ers to agree on a set of meaningful end points for the companies’
fering a “considerable” or “major” advantage over the established final studies before they seek approval. Patients, for example,
treatment (termed the “standard of care”), and 16 percent had a asked that improvements in chronic pain and mental health be
minor or nonquantifiable advantage. Fully 58 percent had no prov- measured along with the frequency of bleeding episodes. The
en added benefit in terms of lowering mortality, reducing symp- center is now looking at sickle cell therapies. If developers all use
toms or side effects, or improving health-related quality of life. the same outcome metrics, it will be possible to compare the var-
“This doesn’t mean we are sure there’s no added benefit,” lead ious products. Patients and their doctors won’t be left in the dark.
24 Scientific American, November 2019 Illustration by Celia Krampien

VENTURES Wade Roush is the host and producer of Soonish, a podcast
T H E B U S IN E S S O F IN N OVATI O N about technology, culture, curiosity and the future. He
is a co-founder of the podcast collective Hub & Spoke and
a freelance reporter for print, online and radio outlets,
such as MIT Technology Review, Xconomy, WBUR and WHYY.
7,813 minutes per mobile line. By 2017 that had

dropped to just 5,539 minutes per line, or 6,686 min-
utes per U.S. resident.
That’s still 18 minutes per person per day, but it’s
a small slice of the five hours a day we spend doing
other things on our mobile devices: watching You-
Tube and TikTok, browsing Facebook and Twitter,
sending text messages, and all the rest. So at the in
quest over the falloff in voice communication, Exhib-
it A is digital data. We consumed 28.6 trillion mega
bytes of data on our phones in 2018, a dramatic
82 percent increase over 2017 levels, according to the
wireless industry group CTIA.
Exhibit B is robocalls. YouMail, which makes a
robocall-blocking app, says that 4.7 billion calls were
placed to U.S. phone numbers in July 2019 alone, an
average of 14 per person. My own phone log shows
that I got 36 spam calls that month—so many that
I’ve started ignoring all unscheduled or unidenti-
fied calls.
In July the U.S. House of Representatives voted
429–3 to approve a bill that would allow carriers to
block suspected robocallers and require them to
implement authentication technology to screen out
calls from spoofed numbers. The Senate had already
passed a similar bill, and the White House is expect-
ed to approve a joint version this fall. Representative
Requiem for the

Frank Pallone, Jr., of New Jersey, chair of the Energy
and Commerce Committee, predicted the measure will “restore
Americans’ confidence in the telephone system.”
Telephone Call
But the truth is, it’s too late for that. An entire generation of
Americans has grown up using phones as glorified pagers. Many
people in this group would rather not receive calls at all; speak-
ing on the phone “demands their full attention when they don’t
Can you really “reach out and touch want to give it,” as Sherry Turkle observed in Alone Together, h er
someone” via text? incisive 2011 book about the social price of the mobile revolution.
And to make a call is often seen as tantamount to aggres-
By Wade Roush sion—a point that’s satirized in a recent episode of Netflix’s
Tales of the City. Sixtysomething Brian is about to call a poten-
The world’s first t elephone call—“Mr. Watson, come here, I want tial blind date when his fortysomething neighbor Wren grabs
to see you”—was a request for a face-to-face meeting. his phone out of his hand. “What the hell are you doing?” she
I live in Boston, where Alexander Graham Bell made that his- exclaims. “I said reach out! That’s text! I mean, this is the 21st
toric call in 1876, and on a recent trip I passed through Brant- century. Who’s calling someone, you damn psychopath?”
ford, Ontario, where Bell first dreamed up his telephone in 1874. But what’s lost when texts and posts replace conversation is,
In Brantford, which bills itself as the “Telephone City,” there’s a briefly put, Joy and Sorrow: the emotional content conveyed by
giant memorial to Bell that includes a bronze casting with fig- the human voice. Stripped of this real-time engagement, we’re
ures meant to represent Knowledge, Joy and Sorrow—the vari- left only with Knowledge, which, as the past few years have
eties of information spread by the telephone. shown, is so easily warped and misrepresented. Our telephones
Today maybe we should reserve a bit of sorrow for the weak- may have evolved into machines for 24/7 tweeting and texting,
ening of the personal connections fostered by Bell’s miracu but we’re more alone than ever.
lous invention.
We own more “phones” than ever, but we don’t use them pri-
marily for voice calls. In 2010 Americans spent 2.24 trillion min- Visit Scientific American on Facebook and Twitter
utes talking on their mobile devices—which averages out to or send a letter to the editor: editors@sciam.com
26 Scientific American, November 2019 Illustration by Jay Bendt

PHYSIC S
CRYSTALS
IN
TIME Surprising new states of matter
called time crystals show the
same symmetry properties in time
that ordinary crystals do in space
By Frank Wilczek
Illustration by Mark Ross Studio


Frank Wilczek is a theoretical physicist at the Massachusetts

Institute of Technology. He won the 2004 Nobel Prize in
Physics for his work on the theory of the strong force, and
in 2012 he proposed the concept of time crystals.
CRYSTALS are nature’s most orderly substances. Inside them, atoms

and molecules are arranged in regular, repeating structures, giving rise to solids that are stable
and rigid—and often beautiful to behold.
People have found crystals fascinating and attractive since before the dawn of modern
science, often prizing them as jewels. In the 19th century scientists’ quest to classify forms
of crystals and understand their effect on light catalyzed important progress in mathematics
and physics. Then, in the 20th century, study of the fundamental quantum mechanics of elec-
trons in crystals led directly to modern semiconductor electronics and eventually to smart-
phones and the Internet.
The next step in our understanding of crystals is oc- These examples show that the mathematical concept
IN BRIEF curring now, thanks to a principle that arose from Al- of symmetry captures an essential aspect of its com-
bert Einstein’s relativity theory: space and time are in- mon meaning while adding the virtue of precision.
Crystals are orderly
states of matter in timately connected and ultimately on the same footing.
which the arrange- Thus, it is natural to wonder whether any objects dis- Rotational Symmetry
ments of atoms take play properties in time that are analogous to the prop-
on repeating pat- erties of ordinary crystals in space. In exploring that
terns. In the language question, we discovered “time crystals.” This new con-
of physics, they are cept, along with the growing class of novel materials
said to have “sponta- that fit within it, has led to exciting insights about
neously broken
physics, as well as the potential for novel applications,
spatial symmetry.”
Time crystals, a including clocks more accurate than any that exist now.
newer concept, Perfect symmetry Partial symmetry
are states of matter SYMMETRY
whose patterns Before I fully explain this new idea, I must clarify
repeat at set intervals what, exactly, a crystal is. The most fruitful answer for A second virtue of this concept of symmetry is that
of time rather than scientific purposes brings in two profound concepts: it can be generalized. We can adapt the idea so that it
space. They are sys- symmetry and spontaneous symmetry breaking. applies not just to shapes but more widely to physical
tems in which time
In common usage, “symmetry” very broadly indi- laws. We say a law has symmetry if we can change the
symmetry is sponta-
neously broken. cates balance, harmony or even justice. In physics and context in which the law is applied without changing
The notion of time mathematics, the meaning is more precise. We say the law itself. For example, the basic axiom of special
crystals was first pro- that an object is symmetric or has symmetry if there relativity is that the same physical laws apply when
posed in 2012, and are transformations that could change it but do not. we view the world from different platforms that move
in 2017 scientists dis- That definition might seem strange and abstract at at constant velocities relative to one another. Thus,
covered the first new first, so let us focus on a simple example: Consider a relativity demands that physical laws display a kind of
materials that fully fit circle. When we rotate a circle around its center, through symmetry—namely, symmetry under the platform-
this category. These
any angle, it remains visually the same, even though changing transformations that physicists call “boosts.”
and others that fol-
lowed offer promise every point on it may have moved—it has perfect rota- A different class of transformations is important
for the creation of tional symmetry. A square has some symmetry but less for crystals, including time crystals. They are the very
clocks more accurate than a circle because you must rotate a square through simple yet profoundly important transformations
than ever before. a full 90 degrees before it regains its initial appearance. known as “translations.” Whereas relativity says the
30 Scientific American, November 2019 Illustrations by Jen Christiansen

same laws apply for observers on moving platforms, Physicists say that in a crystal the translation sym-
spatial translation symmetry says the same laws apply metry of the fundamental laws is “broken,” leading to
for observers on platforms in different places. If you a lesser translation symmetry. That remaining sym-
move—or “translate”—your laboratory from one place metry conveys the essence of our crystal. Indeed, if we
to another, you will find that the same laws hold in the know that a crystal’s symmetry involves translations
new place. Spatial translation symmetry, in other through multiples of the distance d, then we know
words, asserts that the laws we discover anywhere a p- where to place its atoms relative to one another.
ply everywhere. Crystalline patterns in two and three dimensions
Time translation symmetry expresses a similar can be more complicated, and they come in many va-
idea but for time instead of space. It says the same rieties. They can display partial rotational and partial
laws we operate under now also apply for observers translational symmetry. The 14th-century artists who
in the past or in the future. In other words, the laws decorated the Alhambra palace in Granada, Spain,
we discover at any time apply at every time. In view of discovered many possible forms of two-dimensional
its basic importance, time translation symmetry de- crystals by intuition and experimentation, and mathe-
serves to have a less forbidding name, with fewer than maticians in the 19th century classified the possible
seven syllables. Here I will call it tau, denoted by the forms of three-dimensional crystals.
Greek symbol τ.
Without space and time translation symmetry, ex-
Complex Crystalline Pattern Examples
periments carried out in different places and at differ-
ent times would not be reproducible. In their everyday
work, scientists take those symmetries for granted. In-
deed, science as we know it would be impossible with-
out them. But it is important to emphasize that we can
test space and time translation symmetry empirically.
Specifically, we can observe behavior in distant astro-
nomical objects. Such objects are situated, obviously,
in different places, and thanks to the finite speed of
light we can observe in the present how they behaved
in the past. Astronomers have determined, in great
detail and with high accuracy, that the same laws do
in fact apply.
SYMMETRY BREAKING
For all their aesthetic symmetry, i t is actually the way Two dimensions (from the Alhambra palace) Three dimensions (diamond crystal structure)
crystals lack symmetry that is, for physicists, their de-
fining characteristic. In the summer of 2011 I was preparing to teach this
Consider a drastically idealized crystal. It will be elegant chapter of mathematics as part of a course on
one-dimensional, and its atomic nuclei will be located the uses of symmetry in physics. I always try to take a
at regular intervals along a line, separated by the dis- fresh look at material I will be teaching and, if possi-
tance d . (Their coordinates therefore will be n
d, w
here ble, add something new. It occurred to me then that
n i s a whole number.) If we translate this crystal to the one could extend the classification of possible crystal-
right by a tiny distance, it will not look like the same line patterns in three-dimensional space to crystalline
object. Only after we translate through the specific patterns in four-dimensional spacetime.
distance d ill we see the same crystal. Thus, our ide-
w When I mentioned this mathematical line of inves-
alized crystal has a reduced degree of spatial transla- tigation to Alfred Shapere, my former student turned
tion symmetry, similarly to how a square has a re- valued colleague, who is now at the University of Ken-
duced degree of rotation symmetry. tucky, he urged me to consider two very basic physical
questions. They launched me on a surprising scientif-
Translational Symmetry ic adventure:
What real-world systems could crystals in space-
time describe?
Atomic Might these patterns lead us to identify distinctive
nucleus states of matter?
d The answer to the first question is fairly straight-
forward. Whereas ordinary crystals are orderly ar-
rangements of objects in space, spacetime crystals are
orderly arrangements of events in spacetime.
As we did for ordinary crystals, we can get our
bearings by considering the one-dimensional case, in

which spacetime crystals simplify to purely time crys- breaks spatial translation symmetry “spontaneously.”
tals. We are looking, then, for systems whose overall An important feature of crystallization is a sharp
state repeats itself at regular intervals. Such systems change in the system’s behavior or, in technical lan-
are almost embarrassingly familiar. For example, guage, a sharp phase transition. Above a certain criti-
Earth repeats its orientation in space at daily inter- cal temperature (which depends on the system’s
vals, and the Earth-sun system repeats its configura- chemical composition and the ambient pressure), we
tion at yearly intervals.  Inventors and scientists have, have a liquid; below it we have a crystal—objects with
over many decades, developed systems that repeat quite different properties. The transition occurs
their arrangements at increasingly accurate intervals predictably and is accompanied by the emission of
for use as clocks. Pendulum and spring clocks were energy (in the form of heat). The fact that a small
superseded by clocks based on vibrating (traditional) change in ambient conditions causes a substance to
crystals, and those were eventually superseded by reorganize into a qualitatively distinct material is no
clocks based on vibrating atoms. Atomic clocks have less remarkable for being, in the case of water and ice,
achieved extraordinary accuracy, but there are impor- very familiar.
tant reasons to improve them further—and time crys- The rigidity of crystals is another emergent prop-
tals might help, as we will see later. erty that distinguishes them from liquids and gases.
Some familiar real-world systems also embody From a microscopic perspective, rigidity arises be-
higher-dimensional spacetime crystal patterns. For cause the organized pattern of atoms in a crystal per-
example, the pattern shown here can represent a pla- sists over long distances and the crystal resists at-
nar sound wave, where the height of the surface indi- tempts to disrupt that pattern.
cates compression as a function of position and time. The three features of crystallization that we have
More elaborate spacetime crystal patterns might be just discussed—reduced symmetry, sharp phase tran-
difficult to come by in nature, but they could be inter- sition and rigidity—are deeply related. The basic prin-
esting targets for artists and engineers—imagine a dy- ciple underlying all three is that atoms “want” to form
namic Alhambra on steroids. patterns with favorable energy. Different choices of
pattern—in the jargon, different phases—can win out
Planar Sound Wave under different conditions (for instance, various pres-
sures and temperatures). When conditions change,
we often see sharp phase transitions. And because
pattern formation requires collective action on the
Wave propagates over time ession xed tim
e
Co m p r tion, fi
part of the atoms, the winning choice will be enforced
X d ire c
over the entire material, which will snap back into its
Y dire previous state if the chosen pattern is disturbed.
ction Because spontaneous symmetry breaking unites
such a nice package of ideas and powerful implica-
tions, I felt it was important to explore the possibility
that τ can be broken spontaneously. As I was writing
up this idea, I explained it to my wife, Betsy Devine:
“It’s like a crystal but in time.” Drawn in by my excite-
ment, she was curious: “What are you calling it?”
“Spontaneous breaking of time translation symmetry,”
I said. “No way,” she countered. “Call it time crystals.”
Which, naturally, I did. In 2012 I published two papers,
one co-authored by Shapere, introducing the concept.
These types of spacetime crystals, though, simply A time crystal, then, is a system in which τ is sponta-
repackage known phenomena under a different label. neously broken.
We can move into genuinely new territory in physics One might wonder why it took so long for the con-
by considering Shapere’s second question. To do that, cepts of τ and spontaneous symmetry breaking to
we must now bring in the idea of s pontaneous symme- come together, given that separately they have been
try breaking. understood for many years. It is because τ differs from
other symmetries in a crucial way that makes the
SPONTANEOUS SYMMETRY BREAKING question of its possible spontaneous breaking much
When a liquid o r gas cools into a crystal, something subtler. The difference arises because of a profound
fundamentally remarkable occurs: the emergent solu- theorem proved by mathematician Emmy Noether in
tion of the laws of physics—the crystal—displays 1915. Noether’s theorem makes a connection between
less symmetry than the laws themselves. As this re- symmetry principles and conservation laws—it shows
duction of symmetry is brought on just by a decrease that for every form of symmetry, there is a correspond-
in temperature, without any special outside intervening quantity that is conserved. In the application rele-
tion, we can say that in forming a crystal the material vant here, Noether’s theorem states that τ is basically

equivalent to the conservation of energy. Conversely, and ℏ is the reduced Planck’s constant. Here, although
when a system breaks τ, energy is not conserved, and it the physical setup does not vary in time (in other
ceases to be a useful characteristic of that system. words, it respects τ), the resulting behavior does vary
(More precisely: without τ, you can no longer obtain an in time. Full time translation symmetry has been re-
energylike, time-independent quantity by summing up duced to symmetry under time translation by multi-
contributions from the system’s parts.) ples of the period ℏ /2eV. Thus, the AC Josephson effect
The usual explanation for why spontaneous sym- embodies the most basic concept of a time crystal. In
metry breaking occurs is that it can be favorable ener- some respects, however, it is not ideal. To maintain the
getically. If the lowest-energy state breaks spatial s ym- voltage, one must somehow close the circuit and sup-
metry and the energy of the system is conserved, then ply a battery. But AC circuits tend to dissipate heat, and
the broken symmetry state, once entered, will persist. batteries run down. Moreover, oscillating currents
That is how scientists account for ordinary crystalliza- tend to radiate electromagnetic waves. For all these
tion, for example. reasons, Josephson junctions are not ideally stable.
But that energy-based explanation will not work
for τ breaking, because τ breaking removes the appli-
AC Josephson Effect
cable measure of energy. This apparent difficulty put Constant
the possibility of spontaneous τ breaking, and the as- voltage in:
sociated concept of time crystals, beyond the concep-
tual horizon of most physicists.
There is, however, a more general road to spontane- Superconductor Insulator Superconductor
ous symmetry breaking, which also applies to τ break-
ing. Rather than spontaneously reorganizing to a low-
er-energy state, a material might reorganize to a state
that is more stable for other reasons. For instance, or-
dered patterns that extend over large stretches of space
or time and involve many particles are difficult to un-
ravel because most disrupting forces act on small, local
scales. Thus, a material might achieve greater stability
by taking on a new pattern that occurs over a larger
scale than in its previous state.
Ultimately, of course, no ordinary state of matter can Measured as alternating current across the junction
maintain itself against all disruptions. Consider, for ex-
ample, diamonds. A legendary ad campaign popularized
the slogan “a diamond is forever.” But in the right atmo- By using various refinements (such as fully super-
sphere, if the temperature is hot enough, a diamond will conducting circuits, excellent capacitors in place of
burn into inglorious ash. More basically, diamonds are ordinary batteries and enclosures to trap radiation),
not a stable state of carbon at ordinary temperatures it is possible to substantially reduce the levels of those
and atmospheric pressure. They are created at much effects. And other systems that involve superfluids or
higher pressures and, once formed, will survive for a magnets in place of superconductors exhibit analo-
very long time at ordinary pressures. But physicists cal- gous effects while minimizing those problems. In very
culate that if you wait long enough, your diamond will recent work, Nikolay Prokof 'ev and Boris Svistunov
turn into graphite. Even less likely, but still possible, a have proposed extremely clean examples involving
quantum fluctuation can turn your diamond into a tiny two interpenetrating superfluids.
black hole. It is also possible that the decay of a dia- Thinking explicitly about τ breaking has focused
mond’s protons will slowly erode it. In practice, what we attention on these issues and led to the discovery of
mean by a “state of matter” (such as diamond) is an or- new examples and fruitful experiments. Still, because
ganization of a substance that has a useful degree of sta- the central physical idea is already implicit in Joseph-
bility against a significant range of external changes. son’s work of 1962, it seems appropriate to refer to all
these as “old” time crystals.
OLD AND NEW TIME CRYSTALS “New” time crystals arrived with the March 9, 2017,
The AC Josephson effect is one of the gems of physics, issue of N ature, which featured gorgeous (metaphori-
and it supplies the prototype for one large family of cal) time crystals on the cover and announced “Time
time crystals. It occurs when we apply a constant volt- crystals: First observations of exotic new state of mat-
age V (a difference in potential energy) across an insu- ter.” Inside were two independent discovery papers.
lating junction separating two superconducting materi- In one experiment, a group led by Christopher Mon-
als (a so-called Josephson junction, named after physi- roe of the University of Maryland, College Park, creat-
cist Brian Josephson). In this situation, one observes ed a time crystal in an engineered system of a chain of
that an alternating current at frequency 2eV/ℏ flows ytterbium ions. In the other, Mikhail Lukin’s group at
across the junction, where e i s the charge of an electron Harvard University realized a time crystal in a system

pulse spacing. In all these experiments, the materials

received external stimulation—lasers or microwave
Making a Time Crystal pulses—but they displayed a different period than
that of their stimuli. In other words, they broke time
Just as the atoms in regular crystals repeat their arrangements over cer-
symmetry spontaneously.
tain distances, time crystals are states of matter that repeat over specific
These experiments inaugurated a direction in ma-
periods of time. The first new materials that fit into this category were
terials physics that has grown into a minor industry.
discovered in 2017 by two research teams, one led by Mikhail Lukin of
More materials utilizing the same general principles—
Harvard University and the other by Christopher Monroe of the Univer-
which have come to be called Floquet time crystals—
sity of Maryland, College Park.
have come on the scene since then, and many more are
Ordinary crystal: repetition of object position being investigated.
Floquet time crystals are distinct in important
ways from related phenomena discovered much earli-
Distance er. Notably, in 1831 Michael Faraday found that when
he shook a pool of mercury vertically with period T,
Time crystal: repetition of events the resulting flow often displayed period 2T. But the
symmetry breaking in Faraday’s system—and in many
other systems studied in the intervening years prior to
Time 2017—does not allow a clean separation between the
material and the drive (in this case, the act of shaking),
and it does not display the hallmarks of spontaneous
The Lukin Experiment symmetry breaking. The drive never ceases to pump
Lukin's group created a time crystal by manipulating the spins of atoms in energy (or, more accurately, entropy), which is radiat-
so-called nitrogen vacancy centers—impurities in a diamond lattice. The ed as heat, into the material.
researchers periodically exposed the diamond to laser pulses. Between pulses,
In effect, the entire system consisting of material
the spins continued to interact with one another. The entire system repeated
its overall configuration periodically—but not with the same period as the plus drive—whose behavior, as noted, cannot be clean-
microwave pulses. Rather the system took on its own timing period, cycling ly separated—simply has less symmetry than the drive
at a fraction of the frequency of the pulses. considered separately. In the 2017 systems, in contrast,
after a brief settling-down period, the material falls
Time into a steady state in which it no longer exchanges en-
ergy or entropy with the drive. The difference is subtle
Microwave Interactions Microwave but physically crucial. The new Floquet time crystals
pulse pulse represent distinct phases of matter, and they display
the hallmarks of spontaneous symmetry breaking,
whereas the earlier examples, though extremely inter-
esting in their own right, do not.
Likewise, Earth’s rotation and its revolution around
the sun are not time crystals in this sense. Their im-
pressive degree of stability is enforced by the approxi-
mate conservation of energy and angular momentum.
Spin pattern of Alternative They do not have the lowest possible values of those
nitrogen vacancy spin pattern
quantities, so the preceding energetic argument for
centers in diamonds
stability does not apply; they also do not involve long-
range patterns. But precisely because of the enormous
value of energy and angular momentum in these sys-
tems, it takes either a big disturbance or small distur-
of many thousands of defects, called nitrogen vacancy bances acting over a long time to significantly change
centers, in a diamond. them. Indeed, effects that include the tides, the gravita-
In both systems, the spin direction of the atoms (ei- tional influence of other planets and even the evolution
ther the ytterbium ions or the diamond defects) of the sun do slightly alter those astronomical systems.
changes with regularity, and the atoms periodically The associated measures of time such as “day” and
come back into their original configurations. In Mon- “year” are, notoriously, subject to occasional correction.
roe’s experiment, researchers used lasers to flip the In contrast, these new time crystals display strong
ions’ spins and to correlate the spins into connected, rigidity and stability in their patterns—a feature that of-
“entangled” states. As a result, though, the ions’ spins fers a way of dividing up time very accurately, which
began to oscillate at only half the rate of the laser could be the key to advanced clocks. Modern atomic
pulses. In Lukin’s project, the scientists used micro- clocks are marvels of accuracy, but they lack the guar-
wave pulses to flip the diamond defects’ spins. They anteed long-term stability of time crystals. More accu-
observed time crystals with twice and three times the rate, less cumbersome clocks based on these emerging

states of matter could empower exquisite measure- ly) broken by the universe as a whole. Some cosmolo-
ments of distances and times, with applications from gists have also suggested that ours is a cyclic universe
improved GPS to new ways of detecting underground or that the universe went through a phase of rapid
caves and mineral deposits through their influence on oscillation. These speculations—which, to date, remain
gravity or even gravitational waves. darpa—the Defense just that—bring us close to the circle of ideas around
Advanced Research Projects Agency—is funding re- time crystals.
search on time crystals with such possibilities in mind. Finally, the equations of general relativity, which
embody our best present understanding of spacetime
THE TAO OF τ structure, are based on the concept that we can speci-
The circle of ideas a nd experiments around time crys- fy a definite distance between any two nearby points.
tals and spontaneous τ breaking represents a subject This simple idea, though, is known to break down in
in its infancy. There are many open questions and at least two extreme conditions: when we extrapolate
fronts for growth. One ongoing task is to expand the big bang cosmology to its initial moments and in the
census of physical time crystals to include larger and central interior of black holes. Elsewhere in physics,
more convenient examples and to embody a wider va- breakdown of the equations that describe behavior in
riety of spacetime patterns, by both designing new a given state of matter is often a signal that the system
time crystal materials and discovering
them in nature. Physicists are also interest-
ed in studying and understanding the
phase transitions that bring matter into
It occurred to me that one could
and out of these states.
Another task is to examine in detail the
extend the classification of possible
physical properties of time crystals (and
spacetime crystals, in which space symme-
crystalline patterns in three-dimensional
try and τ are both spontaneously broken). space to crystalline patterns in
four-dimensional spacetime.
Here the example of semiconductor crys-
tals, mentioned earlier, is inspiring. What
discoveries will emerge as we study how
time crystals modify the behavior of elec-
trons and light moving within them? will undergo a phase transition. Could it be that space-
Having opened our minds to the possibility of states time itself, under extreme conditions of high pressure,
of matter that involve time, we can consider not only high temperature or rapid change, abandons τ?
time crystals but also time quasicrystals (materials Ultimately the concept of time crystals offers a
that are very ordered yet lack repeating patterns), chance for progress both theoretically—in terms of
time liquids (materials in which the density of events understanding cosmology and black holes from an-
in time is constant but the period is not) and time other perspective—and practically. The novel forms of
glasses (which have a pattern that looks perfectly rig- time crystals most likely to be revealed in the coming
id but actually shows small deviations). Researchers years should move us closer to more perfect clocks,
are actively exploring these and other possibilities. In- and they may turn out to have other useful properties.
deed, some forms of time quasicrystals and a kind of In any case, they are simply interesting, and offer us
time liquid have been identified already. opportunities to expand our ideas about how matter
So far we have considered phases of matter that can be organized.
put τ into play. Let me conclude with two brief com-
ments about τ in cosmology and in black holes.
The steady-state-universe model was a principled MORE TO EXPLORE
attempt to maintain τ in cosmology. In that model, Classical Time Crystals. A lfred Shapere and Frank Wilczek in Physical Review Letters, Vol. 109, No. 16,
popular in the mid-20th century, astronomers postu- Article No. 160402; October 2012.
Quantum Time Crystals. Frank Wilczek in P hysical Review Letters, Vol. 109, No. 16, Article No. 160401;
lated that the state, or appearance, of the universe on October 2012.
large scales is independent of time—in other words, it Observation of a Discrete Time Crystal. J iehang Zhang et al. in Nature, V ol. 543, pages 217–220;
upholds time symmetry. Although the universe is March 9, 2017.
always expanding, the steady-state model postulated Observation of Discrete Time-Crystalline Order in a Disordered Dipolar Many-Body System.
Soonwon Choi et al. in Nature, V ol. 543, pages 221–225; March 9, 2017.
that matter is continuously being created, allowing Time Crystals: A Review. Krzysztof Sacha and Jakub Zakrzewski in Reports on Progress in Physics,
the average density of the cosmos to stay constant. But Vol. 81, No. 1, Article No. 016401; January 2018.
the steady-state model did not survive the test of time. Time Crystals in Periodically Driven Systems. Norman Y. Yao and Chetan Nayak in Physics Today,
Instead astronomers have accumulated overwhelm- Vol. 71, No. 9, pages 40–47; September 2018.
ing evidence that the universe was a very different FROM OUR ARCHIVES
place 13.7 billion years ago, in the immediate after- Anyons. Frank Wilczek; May 1991.
math of the big bang, even though the same physical
s c i e n t if i c a m e r i c a n . c o m /m a g a zi n e /s a
laws applied. In that sense, τ is (perhaps spontaneous-

BIOLOGISTS ARE RACING t o record

new species at sites across Colombia.
They are using the data to recommend
economic policy that supports biodiversity
instead of destroying it.

Conservation
S U S TA I N A B I L I T Y
after Conflict
Now that 50 years of war are over, Colombia wants to
create an economy based on its biodiversity
By Rachel Nuwer

F
Rachel Nuweris a freelance journalist and author of Poached:

Inside the Dark World of Wildlife Trafficking ( Da Capo Press, 2018).
She lives in Brooklyn, N.Y.
at purple clouds had been gathering all day above Cubará,

kickingu p a dusty wind and cloaking the forested hills in shadow
and mist. When the rain finally came, it came as a torrent, ham-
mering metal roofs, overflowing ditches and transforming roads
into rivers. A team of biologists, freshly arrived from Bogotá,
could do little besides huddle on a porch in anticipation of their
mission: find and document as many bird species as possible.
Not since 1961 had such a survey been undertaken in this von Humboldt Biological Resources Research Institute, an inde-
remote northeastern Colombian town, primarily because until pendent nonprofit group that hopes to finally take stock of its na
a few years ago, it was simply too dangerous. tion’s formidable natural history. Sandwiched between two conti-
Cubará is in the center of an infamous no-go zone, an area nents and two oceans and crossed by both the equator and the
that was notorious for frequent clashes among guerrillas, para- Andes, Colombia contains 311 different ecological zones, from rain
military forces and the Colombian army. In 2016 the govern- forests and mountains to mangrove stands and coral reefs. Al
ment signed a cease-fire agreement with the Revolutionary ready researchers have documented nearly 63,000 species there—
Armed Forces of Colombia (FARC), the country’s largest rebel a whopping 10 percent of global biodiversity. Only Brazil has more
group, bringing an end to the longest-running conflict in the species than Colombia, and it is more than seven times larger.
Western Hemisphere. Although gunshots no longer ring out, This abundance was obvious even while the team took shel-
memories of the violence are still at the forefront of many peo- ter from the rain. Tropical kingbirds flitted around a streetlight,
ple’s minds. As Cubará’s vice mayor told me when we met, “Con- and invasive giant African snails inched along the porch. A bee-
gratulations for making it. Just a small number of people come tle as large as a human hand scuttled by, probably on the search
here because everyone is afraid of visiting.” for a mate, and a grapefruit-sized toad lapped up dinner from a
Now that a delicate peace has arrived, Cubará—and thousands cloud of termites. A strange wormlike creature that biologist
of other Colombian towns like it—is slowly coming back to life. Orlando Acevedo-Charry snatched from the flooded driveway
The fighting’s end marked a new beginning not only for commu- turned out to be not a snake or a caecilian, as he originally
nities eager to rebuild but also for the scientists at the Alexander hypothesized, but a marbled swamp eel.
PRECEDING PAGES: FELIPE VILLEGAS H umboldt Institute
IN BRIEF
Colombia has some of the highest biodiversity in Scientists from Colombia’s H umboldt Institute are Peacetime also u shered in rapid deforestation.
the world. But a half-century of conflict blocked in a unique position to show how preserving the So Humboldt scientists are urgently promoting an
field research, and science stagnated. A 2016 peace richness of biodiversity can be a core building block economy rooted in industries such as agroforestry
treaty opened up regions once inaccessible, and of a sustainable economy. They are making policy and ecotourism, which will help rural areas recover
biologists are racing to catalogue new species. recommendations to the government. and grow without destroying the environment.

1 2
SCIENTISTS ARE TEAMING UP with local experts such as Saul San

chez (1, 2) to survey bird diversity and develop ecotourism. Another
researcher picks up bird calls with a parabolic microphone (3).
It is likely that many more species still await discovery. In centerpiece of a society bolstered by sustainability, resilience
nine major expeditions conducted across the country since and green economics. “This is not the classical do-not-touch
2015, scientists have documented hundreds of plants, animals approach to biodiversity,” Didier says. “Instead we want to use
and fungi, dozens of which appear to be new to science—includ- biodiversity as an ingredient in the recipe for economic growth—
ing a freshwater ray with leopardlike polka dots, a peculiar without destroying it.” The ultimate goal, she says, is “to make
sponge that wraps itself around mangrove tree branches like an biodiversity a capital asset for development.”
insect nest, and a fish with no eyes. “Can you imagine it’s 2019 Since 2016 the institute’s 123 experts, along with other scien-
and we’re still discovering what we have?” remarks Gisele Didi- tists and nonprofit organizations from Colombia and beyond,
er Lopez, leader of the development unit at Humboldt. “It gives have frantically worked to draw up a vision of what a green
us goosebumps, like, ‘Oh, my God, this was there and we didn’t Colombia might look like—and to create a roadmap for getting
even know it!’” there. Didier and her colleagues may be in a unique position to
But as peacetime opens up places such as Cubará for explo- do so. By law, Humboldt—which receives half its funding from
ration, it simultaneously makes way for development. Roads the government and the other half from fundraising—is in
are being constructed, land is being cleared and forests are charge of studying and reporting on Colombia’s biodiversity. Its
disappearing. “The rate of landscape change is faster than mission goes beyond cataloguing: the staff also are responsible
our capacity to do research,” says Acevedo-Charry, who curates for pursuing applied science that informs policy-making deci-
the Collection of Environmental Sounds at Humboldt. “If sions and ultimately bridges the gap between society and gov-
we do not categorize biodiversity quickly and continuously ernment. Diego J. Lizcano, a biodiversity specialist at the
around Colombia, we will lose it before we even know what we Nature Conservancy, explained that because the institute is
need to protect.” directly connected to the government, officials take its findings
RACHEL NUWER
Acevedo-Charry, Didier and their colleagues at Humboldt more seriously than those of NGOs and university researchers.
are at the forefront of efforts not only to discover the breadth of But as Colombia races forward with postconflict develop-
Colombia’s biodiversity but also to find ways to turn it into the ment, the window is quickly closing on realizing a rosy future in

which biodiversity is both cherished and sustainably capital- least three quarters of the population. This point was largely
ized. Despite Humboldt’s relative influence, observers say that meant to address the rural discontent that ignited the conflict to
the environment remains low on the government’s priority list begin with, and it promises marginalized countryside residents—
and that deforestation continues to ravage much of the country. many of whom are members of Colombia’s 112 ethnic minority
Didier describes this trajectory as “putting in a bulldozer and groups—access to education and clean water, subsidies for devel-
chopping down everything in front of it. Everything is at stake.” opment programs in former rebel-held territories, and new roads
to connect their communities to the rest of the country. It also
WAR AND (GREEN) PEACE encourages illegal coca growers to switch to legal crops in ex
That so much wildlife a nd habitat remain in Colombia today is, change for cash payments and government assistance.
in part, a serendipitous side effect of conflict. Civil war officially “Because many of our problems come from lack of better
broke out in 1964, when members of the peasant class, a group livelihoods, education and health care in rural areas, that was
largely composed of small farmers, miners and land workers, the main part of the agreement for me,” says Julia Miranda Lon-
rose up to fight gross inequality and formed FARC. The half- doño, director general of the Colombian National Park System.
century of fighting froze not just ecological exploration but, in “If our development was more equitable, people would not need
some places, ecological destruction.
Millions of rural residents fled the
countryside to take refuge in cities,
giving nature time to reclaim their
properties. Rebels commanded those Colombia’s Hotspots
who stayed behind to keep out of cer- With 311 different ecological zones, Colombia is a bio
tain tracts of forest and forbade them COLOMBIA
diversity powerhouse: 10 percent of all species on Earth
from hunting and cutting down trees. are found here. After a half-century of civil war, scientists
What began as an ideological struggle are racing to document and preserve Colombia’s natural
for a Marxist-Leninist government heritage. But peacetime means deforestation has ramped
morphed into a conflict largely fueled up, as formerly rebel-occupied territories open up to mining,
by profit, especially from narcotics. logging and resettlement. Of the country’s nine hotspots for
Coca fields and cocaine labs sprang deforestation, five are located in the Amazon basin.
up alongside forest camps. “The guer-
rillas benefited from having forest
they could hide in, and other people
didn’t dare go there,” Didier says. “As a Caribbean Sea
result, biodiversity remained high in Barranquilla Maracaibo Caracas
hotspots for conflict.” Cartagena Maracay
As narcotics trafficking spread, vio- Colón
lence followed. Any scientist who dared Panama City
venture into rebel-controlled areas did PANAMA VENEZUELA
so at the risk of his or her life. Nearly
every field researcher in the country
Cubará
today seems to have a story of being
Medellín
kidnapped, interrogated at gunpoint or
S
otherwise scared away from study sites.

“Ten years ago the most dangerous
Pacific
E
Bogotá
thing you could come across in the field
was a person,” says Lizcano, who was
Ocean
D
Cali
held hostage for two days by rebels COLOMBIA
who kidnapped him while he was out
N
looking for tapirs. Lizcano continued

his work at a different location, but
A
Mitú
other studies were abandoned or never
attempted in the first place, and many
researchers chose to either leave Quito
Colombia or change careers. Ecological
knowledge stagnated. ECUADOR A M A Z O N
Hope for a reversal of this trend
came from one of the nearly 600 stipu-
Guayaquil BRAZIL
lations of the 2016 peace agreement: PERU
the country must develop sustainably
Iquitos
to improve the lives of all Colombians—
not just urbanites, who compose at
40 Scientific American, November 2019 Map by Mapping Specialists

1 4
2 UVALDINO VILLAMIZAR (1) grows cacao using agroforestry prac

tices. Such sustainable methods help to preserve Colombia’s bio
diversity, including species (2, 3, 4) discovered in the past few years.
3
REVEAL A NEW SPECIES OF GLASSFROG (ANURA: CENTROLENIDAE: IKAKOGI) FROM THE SIERRA NEVADA DE SANTA MARTA, COLOMBIA,” BY MARCO RADA ET AL.,
RACHEL NUWER (1 ); DIRK WEINMANN (2 ) ; FROM “THE POVERTY OF ADULT MORPHOLOGY: BIOACOUSTICS, GENETICS, AND INTERNAL TADPOLE MORPHOLOGY
to look for other ways of living like growing coca crops and Ministry of Finance is considering a bill that would expand
undertaking illegal mining.” Colombia’s carbon tax, which currently applies to six liquid fuels,
Although Humboldt scientists and other researchers believe to include coal and gas. The government also aims to establish its
that biodiversity can play a key role in this equitable development, first serious fleet of renewable energy sources through a special
the question is how to actually make that happen across an entire task force dedicated to energy transition.
nation. Colombians do not want their country to go the way of San The biggest focus is on reforming Colombian agriculture, a
Martín in Peru—a postconflict region that developed quickly yet sector set to grow by 2.5 percent annually and increase its land
now is completely deforested and suffers from frequent and use area by 44 percent over the next 15 years. “The way we use
IN P LOS ONE, VOL. 14, NO. 5, ARTICLE E0215349; MAY 8, 2019; (3 ) ; MARTA KOLANOWSKA (4 )
severe fires, landslides and flooding as a result. They also cannot land is very, very destructive,” says Brigitte Baptiste, who direct-
base their plans entirely on positive case studies of environmental ed Humboldt for 10 years before recently taking up a position
conservation in places such as Costa Rica and Rwanda, both of as head of EAN University in Bogotá. Ranchers clear-cut forests
which are much smaller and did not experience 50 years of war. to graze just a couple of cows per acre. Irrigation systems are
Nordic countries provide leading examples of sustainable energy woefully out of date and wasteful—something even the produc-
and natural resource use, but unlike Colombia, they benefit from ers acknowledge, Baptiste says. And pesticide use ranks among
having some of the strongest economies in the world. the highest worldwide, poisoning farmers and contaminating
So Colombia plans to forge its own path, led by the National the environment.
Planning Department and backed by the country’s scientists. In Agroforestry, which could be huge in Colombia, is one alter-
addition to growing a thriving ecotourism industry, ideas for this native, according to Baptiste and her colleagues. This agricul-
new bioeconomy range from helping indigenous and rural com- tural method incorporates livestock and crops into forests rath-
munities benefit from bioprospecting—the search for medicinal, er than cutting the trees down and in doing so brings benefits
edible and otherwise commercially useful plant and animal spe- such as water provision and mitigation of floods and droughts.
cies—to using technology to boost aquaculture production and Cattle account for about 70 percent of Colombia’s agricultural
increase recycling, which is nearly nonexistent in the region. The land use, but the country is also the third-largest coffee produc-

er, the fourth-largest oil palm producer and a major exporter of U NCERTAIN FORECAST
cacao, which is used to make chocolate. If agroforestry were For all of its promise,Colombia has “the same blocks or lack of
implemented across Colombia, the nation’s future forests would political will as any country trying to create a sustainable econ-
be not just islands of biodiversity dotting an otherwise human- omy,” says Andrés Gómez, a senior biodiversity researcher at
dominated landscape but an interconnected matrix of nature ICF International, a global consulting services company. And
supported by private landowners. then there are the issues specific to Colombia: narcotrafficking
In Cubará, much of the road into town is lined by barren continues to plague a number of regions; tensions remain high
fields sheared of trees, where cattle graze alongside the stumps. between many of Colombia’s 112 ethnic minorities and the gov-
As in many areas of rural Colombia, the shift to agroforestry is ernment; and Colombia is facing a migration crisis ignited by
happening slowly, although here it is driven mainly by grass- turmoil and economic collapse in neighboring Venezuela.
roots movements that are not waiting for the government to Meanwhile the National Liberation Army, another rebel group,
lead the charge. When organic farmers Monica and Uvaldino has yet to agree to a peace treaty.
Villamizar decided to branch out into commercial cacao farming Of all the threats to the country’s biodiversity, deforestation
in 2006, they designed their fields to accommodate around is the most dangerous. Nationwide it jumped 44 percent from
20 species of trees. Guided by information provided by the 2015 to 2016, and although Colombia has doubled the size of its
National Federation of Cacao Growers, they allowed their prop- protected areas over the past eight years, 84 percent of the
erty to remain dense with vegetation and the cacophony of bird- deforestation has taken place on these lands. According to
song. The diverse growing space has also brought comparatively Humboldt, more than 100,000 acres of national parks were cut
higher yields, they say, because the shade-to-sun ratio is better between 2013 and 2017.
for the plants. “We’re definitely happy with
this system; it’s why my family is eating and
my daughter is studying,” Uvaldino says.
“She wants to be a civil engineer.” If agroforestry is implemented
Globally, agroforestry and other “pay-
ment for ecosystem service” schemes are fre- across rural Colombia, it will
quently incentivized by tax breaks or direct
payment from governments or nonprofit
groups. For the past decade the Nature Con-
be not just islands of biodiversity
servancy, for example, with funding from the
World Bank and the U.K. government, has
but an interconnected
worked with more than 4,000 farmers to
convert 66,500 acres of high-biodiversity,
matrix of nature supported
low-income land across Colombia for agro-
forestry—specifically for sustainable cattle
by private landowners.
ranching. Under this system, farmers plant
trees from a list of more than 50 native spe-
cies, which provide shade and food for their cows. At the same The scientists did not analyze the drivers behind those losses,
time, the trees serve as habitats for other species and provide but they name a number of contributing forces. In some areas, it
carbon capture and storage services. is illegal gold mining or logging; in others, it is coca production.
Since the Nature Conservancy project began, participating Land grabs and subsequent sales are commonly used to launder
ranchers have reported an increase of up to 80 percent in milk and money from illegal activities, Baptiste says, and corruption greas-
meat production. Farmers’ profits have also gone up because sus- es the process. In addition, many of Colombia’s 6.9 million inter-
tainable products fetch higher prices in cities such as Bogotá, nally displaced persons have begun returning to their former
where an increasing number of people are willing to pay a premi- rural homelands, where they stake claims on land. Displaced per-
um for organic, responsibly produced meat, milk, chocolate, and sons undertaking deforestation “argue that they have suffered
more. Two Colombian meat and dairy companies are already pur- from the war,” Miranda Londoño says. “But there is no right to
chasing and advertising deforestation-free products, and a rising commit a crime to solve your needs.” Jaramillo suggests the need
number of restaurants—including a popular national chain called for “profound land reform,” which could give poor people access
Crepes & Waffles—are signing up as well, oftentimes as a direct to land that has already been deforested. But a project of this
result of pressure from clientele. “The market here is ready for scale is not currently being considered, she says.
milk, meat and crops free of deforestation,” Lizcano says. Trying to slow the forest losses, no matter the source, can be
Colombia’s Ministry of Agriculture is aiming to have a new deadly. More than 30 environmental defenders were murdered
sustainable cattle-ranching policy signed by the end of 2019—a in Colombia in 2017, and park rangers who interfere with land
move scientists and NGOs have been pushing for several years. grabs regularly receive death threats. Colombia’s laws are clear
Carolina Jaramillo, a representative of Colombia at the Global on the illegality of deforestation, and its courts are well equipped
Green Growth Institute, says implementing a policy that pro- to prosecute those who engage in it, Baptiste explains, but the
vides economic incentives and logistical guidance would repre- country still has little capacity for enforcement on the ground.
sent “a whole cultural, financial and technological transforma- Despite many arrests, there are few signs that deforestation is
tion across the country.” being curtailed. In a paper in preparation, Humboldt researchers

country, according to a 2017 paper in Tropi-

cal Conservation Science.(Peru, the authors
write, doubled its bird-watching tourism
from 2012 to 2013 and now enjoys $89 mil-
lion of annual revenue, much of which re
mains in local communities.) Despite this
wealth of bird life, it was not until 2015 that
Colombia participated in Cornell Universi-
ty’s Global Big Day, an annual event in which
birders around the world compete to see
which nation can log the most species in 24
hours. In 2017, after two years of “dysfunc-
tional participation,” as Acevedo-Charry puts
it, the country emerged victorious, with 1,486
species sighted. National pride soared.
Confident Colombia could hold on to the
title in 2018, national radio stations ran
commercials encouraging participation, and
television media and newspapers featured
stories about the event. The blitz worked:
Some 4,500 birders, including members of
the air force and police, turned out at 730
ECOLOGIST BRIGITTE BAPTISTE, who led the Humboldt Institute until September sites. In Cubará, Acevedo-Charry, Johana
2019, has become famous in Colombia for advocating for a green economy. Zuluaga-Bonilla, president of the Ornitholo-
gist Association of Boyacá-Ixobrychus, and
Saul Sanchez, a former hunter turned local
analyzed deforestation patterns from 2000 to 2015 to identify conservationist, recorded 111 species among the three of them,
contributing factors, including road expansion, coca plantation transforming the region from a question mark on the map to
presence, and conflict. They used those data to build a predictive one rich in verified biodiversity. Across the nation birders saw
model and found that if conditions do not change, Colombia will and heard 1,546 species—an “unfathomable” number for a sin-
lose an additional 18 million acres of forest—7 percent of the gle country in a single day, the competition organizers wrote. In
country’s total forest cover—by 2050. More than 50 percent of the 2019 Colombia took the gold yet again.
losses will occur in postconflict zones. This enthusiasm is translating into economically viable
Ultimately the fate of these forests and other natural re options for rural residents, where former hunters, monocrop
sources depends on whether Colombians embrace the environ- farmers and timber harvesters are turning to birding, ecotour-
ment as a pillar of the new green economy rather than seeing it ism and agroforestry. Less than a decade ago Colombians could
as an obstacle to improving their well-being. “Unless we create not conceive of coming together to celebrate their biodiversity
real opportunities for them based on value they can get out of through birding, let alone becoming a country powered by
biodiversity, conservation is not going to work,” says Jose Man- its natural heritage, Acevedo-Charry says. As more people
uel Ochoa Quintero, a program coordinator at Humboldt. gradually embrace this vision, there are signs it might be mak-
Baptiste has become something of a celebrity for taking on a ing a difference: Satellite imagery recently analyzed by re
leading role in pushing this agenda. She is famous in Colombia searchers at the University of Medellín indicates that defores-
for both her charismatic evangelizing about the environment tation rates, compared with the beginning of 2018, are going
and her status as a transgender woman in a conservative coun- down. “The biodiversity-based economy is injecting hope for
try. She regularly appears on television and is quoted in the those who need it most,” Acevedo-Charry says. “It is already
media—as are an increasing number of celebrities who have changing lives.”
aligned themselves with antideforestation initiatives.
The culture seems to be shifting. When Colombia’s new presi-
dent, Iván Duque Márquez, took office in August 2018, his M O R E T O E X P L O R E
administration’s plan to end deforestation entailed dousing coca Chocolate of Peace. D ocumentary directed by Gwen Burnyeat and Pablo Mejía Trujillo,
crops in herbicide and allowing that thousands of square miles of 2016. Available at https://vimeo.com/179038624
wild nature would still inevitably be lost. But the announcement Greening Peace in Colombia. Brigitte Baptiste et al. in N ature Ecology & Evolution, Vol. 1,
Article No. 0102; March 1, 2017.
received major condemnation from the public and the media,
Colombia: After the Violence. S ara Reardon in Nature,Vol. 557; May 2, 2018.
FELIPE VILLEGAS H umboldt Institute
and the Duque administration began preparing a new approach.

Deforestation is now considered a national security threat. FROM OUR ARCHIVES
Can Sustainable Management Save Tropical Forests? R ichard E. Rice et al.; April 1997.
If there is a cultural signal that national enthusiasm for bio- The Race to Save Colombia’s Uncontacted Tribes from Outsiders. A dam Piore;
diversity is on the rise, it might be associated with the fact that February 2019.
Colombia is home to 20 percent of the world’s recorded bird
species. Birding tourism holds “immense potential” for the


TECHNOLOGY
THE
KIDS
ARE
ALL
RIGHT
New findings suggest that the angst
over social media is misplaced and
that more nuance is required to
understand its effects on well-being
By Lydia Denworth
Illustrations by Mark Zingarelli

I
Lydia Denworth is a contributing editor for Scientific American
and is author of Friendship: The Evolution, Biology, and Extraordinary
Power of Life’s Fundamental Bond (W. W. Norton, in press).
t was the headlines that most upset Amy Orben. In 2017, when she was a graduate
student in experimental psychology at the University of Oxford researching how social
media influences communication, alarming articles began to appear. Giving a child
a smartphone was like giving a kid cocaine, claimed one. Smartphones might have
destroyed a generation, said another. Orben didn’t think such extreme statements were
warranted. At one point, she stayed up all night reanalyzing data from a paper linking
increases in depression and suicide to screen time. “I figured out that tweaks to the data
analysis caused major changes to the study results,” Orben says. “The effects were actually tiny.”
She published several blog posts, some with her Oxford colwell-being that come with very small but statistically significant
league Andrew K. Przybylski, saying so. “Great claims require costs.” The emphasis is on “small”—at least in terms of effect
great evidence,” she wrote in one. “Yet this kind of evidence size, which gauges the strength of the relation between two
does not exist.” Then Orben decided to make her point scientif- variables. Hancock’s meta-analysis revealed an overall effect
ically and changed the focus of her work. With Przybylski, she size of 0.01 on a scale in which 0.2 is small. Przybylski and
set out to rigorously analyze the large-scale data sets that are Orben measured the percent of variance in well-being that was
widely used in studies of social media. explained by social media use and found that technology was
The two researchers were not the only ones who were con- no more associated with decreased well-being for teenagers
cerned. A few years ago Jeff Hancock, a psychologist who runs than eating potatoes. Wearing glasses was worse. “The monster-
the Social Media Lab at Stanford University, set an alert to let of-the-week thing is dead in the water,” Przybylski says.
him know when his research was cited by other scientists in Furthermore, this new research reveals serious limitations
their papers. As the notifications piled up in his in-box, he was and shortcomings in the science of social media to date. Eighty
perplexed. A report on the ways that Facebook made people percent of studies have been cross-sectional (looking at individ-
more anxious would be followed by one about how social media uals at a given point in time) and correlational (linking two
enhances social capital. “What is going on with all these con- measures such as frequency of Facebook use and level of anxi-
flicting ideas?” Hancock wondered. How could they all be citing ety but not showing that one causes the other). Most have relied
his work? He decided to seek clarity and embarked on the larg- on self-reported use, a notoriously unreliable measure. Nearly
est meta-analysis to date of the effects of social media on psy- all assess only frequency and duration of use rather than con-
chological well-being. Ultimately he included 226 papers and tent or context. “We’re asking the wrong questions,” Hancock
data on more than 275,000 people. says. And results are regularly overstated—sometimes by the
The results of Orben’s, Przybylski’s and Hancock’s efforts are scientists, often by the media. “Social media research is the per-
now in. Studies from these researchers and others, published or fect storm showing us where all the problems are with our sci-
presented in 2019, have brought some context to the question of entific methodology,” Orben says. “This challenges us as scien-
what exactly digital technology is doing to our mental health. tists to think about how we measure things and what sort of
Their evidence makes several things clear. The results to date effect size we think is important.”
have been mixed because the effects measured are themselves To be clear, it is not that social media is never a problem.
mixed. “Using social media is essentially a trade-off,” Hancock Heavy use is associated with potentially harmful effects on well-
says. “You get very small but significant advantages for your being. But effects from social media appear to depend on the
IN BRIEF
Anxiety about t he effects of social media on young A close look at social media use shows that most Researchers are now examining these diverging
people has risen to such an extreme that giving young texters and Instagrammers are fine. Heavy viewpoints, looking for nuance and developing bet-
children smartphones is sometimes equated to use can lead to problems, but many early studies ter methods for measuring whether social media
handing them a gram of cocaine. The reality is and news headlines have overstated dangers and and related technologies have any meaningful
much less alarming. omitted context. impact on mental health.

user—age and mental health status are two important factors such as studies that looked only at overall social media use, as
that make a difference. Also, cause and effect appear to go in examples of what will not cut it anymore. “You might be spend-
both directions. “It’s a two-way street,” Hancock says. ing two hours a day clicking ‘like’ on pictures of cute puppies,
The hope is that the field will use these new findings to and I might be spending two hours a day having violent clashes
embark on a new science of social media that will set higher stan- about politics and religion and other hot-button issues. Studies
dards for statistical analysis, avoid preposterous claims, and like my early one would count [those activities] the same.”
include more experimental and longitudinal studies, which track Many people in the field have been particularly critical of
people at multiple time points. “We don’t want to be a field in work by psychologist Jean M. Twenge of San Diego State Univer-
which we say that potato eating has destroyed a generation,” says sity. In addition to her research papers, Twenge’s popular 2017
clinical neuropsychologist Tracy Dennis-Tiwary of Hunter Col- article in the A
tlantic, based on her book i Gen, was the one that
lege. “Despite our concerns, we need to pull ourselves together asked: “Has the Smartphone Destroyed a Generation?” Twenge
and act like scientists. We have to have adequate evidence.” is hardly the only researcher to publish negative findings about
social media use, but the publicity around her work has made
FEAR OF TECHNOLOGY her one of the most high profile. She points to a steep rise in
Anxiety and panic over the effects of new technology date back to mental health issues among the group born between 1995 and
Socrates, who bemoaned the then new tradition of writing things 2012 and writes that “much of this deterioration can be traced to
down for fear it would diminish the power of memory. Thomas their phones.” Her work compares rising rates of depression and
Hobbes and Thomas Jefferson both warned that communal rela- anxiety among young people to the proliferation of smartphones
tionships would suffer as industrial societies moved from rural to in the same time period. Twenge acknowledges that the link is
urban living. “Before we hated smartphones, we hated cities,” correlational but argues that her conclusions represent “a logi-
write sociologists Keith Hampton of Michigan State University cal sequence of events” based on the evidence—and care is war-
and Barry Wellman of the NetLab Network, based in Toronto, ranted: “When we’re talking about the health of children and
both of whom study the effects of technological innovation. teens, it seems to me we should err on the side of caution.”
Radio, video games and even comic books
have all caused consternation. Television
was going to bring about the dumbing
down of America. The science of social media
needs to set higher standards
Even so, the change that came about
from mobile phones, the Internet and
social networking sites feels seismic. Cell
phones were first widely adopted in the for statistical analysis, avoid
1990s. By 2018, 95 percent of American
adults were using them. Smartphones,
preposterous claims and study
which added instant access to the Inter-
net, entered the mainstream with the
people for a longer time.
introduction of the iPhone in 2007, and
now more than three quarters of U.S.
adults have them. Eighty-nine percent of those adults use the No one disagrees about the importance of young people’s
Internet. There is near saturation for all things digital among health, but they do think that Twenge has gotten ahead of the
adolescents and adults younger than 50 and among higher- science. “Why wait for causal evidence?” says Dennis-Tiwary.
income households. Nonusers tend to be older than 65, poor, or Because the story might not be so straightforward. She points
residents of rural areas or other places with limited service. to a longitudinal study done by researchers in Canada in re
Between 2005, when the Pew Research Center began tracking sponse to one of Twenge’s articles. They studied nearly 600 ado-
social media use, and 2019, the proportion of Americans using lescents and more than 1,000 young adults over two and six
social media to connect, keep up with the news, share informa- years, respectively, and found that social media use did not
tion and be entertained went from 5 to 72 percent—that means it predict depressive symptoms but that depressive symptoms
jumped from one in 20 adults to seven in 10. predicted more frequent social media use among adolescent
Because social media is so new, the science investigating its girls. “This is a much more nuanced story,” Dennis-Tiwary says.
effects is also new. The earliest study Hancock could find that “We know that problematic smartphone use may as likely be a
examined social media use and psychological well-being was result of mental health problems as a cause, and that calls for a
done in 2006. It came as no surprise that early approaches were different set of solutions.”
limited. Physician Brian Primack, who headed the Center for Correlational studies have their uses, just as epidemiological
Research on Media, Technology, and Health at the University of research can suggest a link between pollution and increased
Pittsburgh until moving to the University of Arkansas this year, cancer rates when a randomized clinical trial is not possible.
likens the field to initial research on nutrition: “It took a while to While he thinks it is important not to overstate findings, econo-
say, ‘Let’s split out fats and proteins and carbohydrates, and not mist Matthew Gentzkow of Stanford, who studies social media,
just that, but let’s split out trans-fats and polyunsaturated fats,’” says of Twenge’s work that “there are some pretty striking facts
he says. “It’s important for anyone who is doing good research to there. They don’t tell us whether smartphones are causing men-
adapt to what’s going on.” Primack points to his own early work, tal health problems, but they really shine some light on that

you have higher well-being, you use social

media less, which suggests that well-being is
driving [how much use is made of ] social
media to some degree,” Hancock says.
In a trilogy of papers about adolescent
technology use, Orben and Przybylski tack-
led three major pitfalls they had identified in
previous analyses of large-scale data sets.
The first paper, published in January in
Nature Human Behaviour, provided both
context and a method for improving trans-
parency. It included three data sets from the
U.S. and Europe made up of more than
350,000 adolescents. Such data sets are valu-
able but make it easy to turn up statistically
significant results that may not be of practi-
cal significance. Przybylski and Orben calcu-
lated that if they had followed standard sta-
tistical operating procedure, they could have
produced roughly 10,000 papers showing
negative screen effects, 5,000 indicating no
effect and another 4,000 demonstrating pos-
itive technology effects on young people—all
from the same data sets.
For their new analysis, they used a tech-
nique called specification curve analysis, a
tool that examines the full range of possible
correlations at once. It is the statistical
equivalent of seeing the forest for the trees.
Analyzed in this way, digital technology use
was associated with only 0.4 percent of the
possibility. What we need now is to dig in and try to do more variation in adolescent well-being. The wealth of information in
careful studies to isolate what’s really going on.” the data allowed for the telling comparisons with potatoes and
glasses. It also revealed that smoking marijuana and bullying
A TWO-WAY STREET? had much larger negative associations for well-being (at 2.7 and
That is what t he newest studies set out to do. Hancock’s meta- 4.3 times worse, respectively, than the average in one of the data
analysis highlighted the fact that many studies on social media sets), whereas positive behaviors such as getting enough sleep
and psychological well-being did not measure the same out- and regularly eating breakfast were much more strongly linked
comes. Effects generally fell into one of six categories. Three con- to well-being than technology use. “We’re trying to move from
cern positive indicators of well-being: eudaemonic happiness this mindset of cherry-picking one result to a more holistic pic-
(having a sense of meaning), hedonic happiness (joy in the mo ture,” Przybylski says. “A key part of that is being able to put
ment) and relationships. And three are negative: depression, these extremely minuscule effects of screens on young people in
anxiety and loneliness. Hancock and his team found that more a real-world context.” (Twenge and others question the useful-
social media use was associated slightly with higher depression ness of explaining percentages of variation and say it will always
and anxiety (though not loneliness) and more strongly associat- turn up small numbers that might mask practical effects.)
ed with relationship benefits (though not eudaemonic or hedon- Their second paper, published in April in P sychological Sci-
ic well-being). (The largest effect, at 0.20, was the benefit of ence, included stronger methods for measuring screen time.
stronger relationships.) He and his colleagues also found that They used three data sets from the U.S., the U.K. and Ireland that
active rather than passive use was positively associated with included time-use diaries in addition to self-reported media
well-being. (They found no effect for passive use, although oth- usage and measures of well-being. Over a period of five years the
ers have found it to be negative.) more than 17,000 teenagers in the studies were given a diary one
And how researchers asked questions mattered. Framing day each year. They filled in 10- to 15-minute windows all day
questions around “addiction” rather than more neutrally makes long about exactly what they were doing, including use of digital
a negative finding more likely. In all the literature, there were technologies. When Orben and Przybylski applied their statisti-
only 24 longitudinal studies, the “gold standard” that allows cal technique to the data, there was little evidence for substan-
researchers to compare the relation between well-being and tial negative associations between digital engagement and well-
social media use at two points in time and statistically assess being. The diaries also allowed them to look at w hen d
uring the
which variable is driving change in the other. In these, Han- day adolescents were using digital media, including before bed.
cock’s team found a further small but interesting result. “When Even that did not make a difference in well-being, although they

did not look at hours of sleep as an outcome, only more general Facebook accounts, which was verified electronically. He and his
psychological measures. colleagues were surprised that substitution of other digital tech-
And finally, in May, with psychologist Tobias Dienlin of the nologies went down, not up. “People perceive they’re spending
University of Hohenheim in Germany, Orben and Przybylski pub- less time on all these things,” Gentzkow says. The effect size was
lished a paper in the P roceedings of the National Academy of Sci- small, however, and masked a lot of individual variation. Some
ences USA, incorporating longitudinal data to analyze the effect people loved the break; others really missed their online social
of social media on adolescents’ life satisfaction over time. This world. “Facebook is delivering a lot of value to people, but never-
approach allowed them to ask whether adolescents who are on theless they may be using it more than is really optimal for them,”
social media more in a given year than average feel better or Gentzkow says. “There are many people for whom scaling back
worse at year’s end and whether feeling better or worse than nor- their usage a little could make them happier and better off.”
mal changes social media use in the coming year. Here, too, the Several researchers are trying to better measure screen time.
result was small and nuanced. “The change in social media use in Stanford communications researcher Byron Reeves and his col-
one year only predicts about 0.25 percent of the variance in the leagues have developed a technique called Screenomics, which
change in life satisfaction over one year,” Orben says. “We’re talk- takes a picture of people’s phones every five seconds (with per-
ing about fractions of 1 percent changes.” The researchers did, mission). Technology companies also have a role to play. Corpo-
however, see slightly stronger effects in girls than in boys, a find- rations are better able than scientists to count how much time
ing Orben intends to investigate further. The question of individ- individuals are spending on different activities, but they consid-
ual risk will also be important. “We really want to see if there are er that information proprietary, and there are privacy concerns
reproducible profiles of young people who are more or less vulner- for users to be addressed. Przybylski is pushing for that policy
able or resilient to different forms of technology,” Przybylski says. to change. “Companies shouldn’t get a free pass,” he says.
New research also seeks to do a better job of predicting indi-
WHAT ABOUT GENERATION Z? vidual variation. In Hancock’s lab, Stanford undergraduate
Teenage media u se has been a particular concern because of the Angela Lee developed a creative approach. She applied the idea
ubiquity of smartphones today and because adolescence is such of mindsets—that beliefs shape people’s realities—to social
a formative period of development. In choosing what to worry media. Through interviews, Lee found that views about social
about, parents have followed scientists’ lead, says psychologist media fell into two general buckets: whether someone thought
Candice Odgers of the University of California, Irvine. They wor- social media was good or bad for them (valence) and whether or
ry mainly about how much time their children spend online with- not they thought they were in control of it (agency). Over the
out giving equal attention to the critical question of what they are course of three studies, she and Hancock tested close to 700 peo-
doing there. Odgers’s own work suggests that amount of use is ple and found that social media mindsets predicted users’ well-
not the problem. In a study published online this summer in being. A sense of agency had the strongest effect. “The more you
Clinical Psychological Science, Odgers, Michaeline Jensen of the believe you are in control over your social media, the more social
University of North Carolina at Greensboro and their colleagues support you have, the less depression you report, the less stress,
followed nearly 400 adolescents for two weeks, sending ques- the less social anxiety, regardless of how much you’re actually
tions to the teenagers’ cell phones three times a day. The study saying you use social media,” says Lee, who is now a graduate
design allowed them to compare mental health symptoms and student in Hancock’s lab. She presented the work in May at the
technology immersion daily as well as over the weeks of the study. Association for Psychological Science meeting.
Was media use associated with individual adolescents’ well- The power of mindset serves as a reminder of the power of
being? The answer was not really. Routines in place at the start perspective. In the 1980s people were wringing their hands
did not predict later mental health symptoms, and mental about the time kids spent staring mindlessly at television
health was not worse on days teenagers reported spending more screens, says Gentzkow, who has studied that era. He imagines
or less time on technology. asking those worrywarts about new technologies that would
“It’s ironic that in the end the real danger is not smart- allow kids to instead interact with one another by sharing mes-
phones—it’s the level of misinformation that’s being directed at sages, photographs and videos. “Anybody then would have said,
the public and at parents,” Odgers says. “It’s consuming so ‘Wow, that would be amazing.’”
much of the airtime that it’s causing us to miss potentially some
of the real threats and problems around digital spaces.” For her
part, Odgers is far more worried about privacy and unequal MORE TO EXPLORE
access to technology for kids from families with lower socioeco- Has the Smartphone Destroyed a Generation? J ean M. Twenge in Atlantic,
nomic status. She also suspects that some adolescents find Vol. 320, pages 58–65; September 2017.
much needed social support online and that adults should pay The Association between Adolescent Well-Being and Digital Technology Use.
Amy Orben and Andrew K. Przybylski in N ature Human Behaviour, Vol. 3, No. 2,
closer attention to what works in that regard. pages 173–182; February 2019.
Screens, Teens, and Psychological Well-Being: Evidence from Three Time-Use-
SOCIAL MEDIA 2.0 Diary Studies. Amy Orben and Andrew K. Przybylski in P sychological Science, Vol. 30,
These studies are just the beginning. They have helped clarify the No. 5, pages 682–696; May 2019.
big picture on social media usage, but far more work is needed. FROM OUR ARCHIVES
Variety in the types of studies conducted will help tease out Your Brain in the Smartphone Age. Scientific American e Books; May 6, 2019.
nuance. In a recent experimental study, for instance, Stanford’s
Gentzkow asked more than 1,600 people to deactivate their

MEDICINE
Is
Phage
Therapy
Here to
Stay
A treatment from World War I
is making a comeback in
the struggle to beat deadly
multidrug-resistant infections
By Charles Schmidt
Illustration by Ashley Mackenzie


B
Charles Schmidtis a freelance journalist based in Portland, Me.,
covering health and the environment. He has written for us
about dangerous contaminants in drinking water and about
multigenerational effects from Agent Orange in Vietnam.
obby Burgholzer has cystic fibrosis, a genetic disease that

throughout his life has made him vulnerable to bacterial infec
tions in his lungs. Until a few years ago antibiotics held his symp
toms mostly at bay, but then the drugs stopped working as well,
leaving the 40-year-old medical device salesman easily winded
and discouraged. He had always tried to keep fit and played hock
ey, but he was finding it harder by the day to climb hills or stairs.
As his condition worsened, Burgholzer worried about having a disease with no cure. He had a
wife and young daughter he wanted to live for. So he started looking into alternative treatments,
and one captured his attention: a virus called a bacteriophage.
Phages, as they are known, are everywhere in Europe have generated some encouraging results—
nature. They replicate by invading bacteria and hijack particularly those from the Eliava Institute in Tbilisi,
ing their reproductive machinery. Once inside a Georgia, the field’s research epicenter—many Western
doomed cell, they multiply into the hundreds and then scholars say the work does not meet their rigorous
burst out, typically killing the cell in the process. Phag standards. Furthermore, a smattering of clinical trials
IN BRIEF es replicate only in bacteria. Microbiologists discov in Western Europe and the U.S. have produced some
ered phages in the 1910s, and physicians first used high-profile failures.
Harmful bacteria
them therapeutically after World War I to treat pa Yet despite the historical skepticism, phage therapy
are becoming ever
more resistant to tients with typhoid, dysentery, cholera and other bac is making a comeback. Attendance at scientific confer
antibiotics. Physi- terial illnesses. Later, during the 1939–1940 Winter ences on the treatment is skyrocketing. Regulators at
cians are turning to War between the Soviet Union and Finland, use of the the U.S. Food and Drug Administration and other
phages—viruses viruses reportedly reduced mortality from gangrene to health agencies are signaling renewed interest. More
that infect bacte- a third among injured soldiers. than a dozen Western companies are investing in the
ria—as a new line Treatments are still commercially available in for field. And a new wave of U.S. clinical trials launched
of attack. mer Eastern Bloc countries, but the approach fell out this year. Why the excitement? Phage treatments have
Doctors are testing
of favor in the West decades ago. In 1934 two Yale Uni been curing patients with multidrug-resistant (MDR)
several different
phage therapies in versity physicians—Monroe Eaton and Stanhope infections that no longer respond to antibiotics. The
clinical trials, which Bayne-Jones—published an influential and dismissive fda has allowed petitioning doctors to administer
kill bacteria in differ- review article claiming the clinical evidence that these experimental treatments on a “compassionate
ent ways. phages could cure bacterial infections was contradic use” basis when they could show that their patients
Researcherswill tory and inconclusive. They also accused companies had no other options—exactly what Burgholzer was
have to significantly that manufactured medicinal phages of deceiving the hoping to prove.
reduce the time public. But the real end of phage therapy came in the MDR infections are a rapidly growing public
and cost needed
1940s as doctors widely adopted antibiotics, which health nightmare. At least 700,000 people worldwide
to find the right
phage to defeat were highly effective and inexpensive. now die from these incurable maladies every year, and
a bacterium, if the Phage therapy is not approved for use in humans the United Nations predicts that number could rise to
therapies are to suc- in any Western market today. Research funding is 10 million by 2050. In the meantime, the drug indus
ceed commercially. meager. And although human studies in Eastern try’s antibiotic pipeline is running dry.

Like all viruses, phages are not really alive—they cannot phage killed them. The relatively few remaining P . aeruginosa
grow, move or make energy. Instead they drift along until by faced an evolutionary trade-off: their lack of efflux pumps
chance they stick to bacteria. Unlike antibiotics, which kill a meant they survived the virus attack, but it made them defense
range of helpful bacteria as they kill the strains making a per less against antibiotics. By taking the phages and antibiotics
son sick, a phage attacks a single bacterial species, and perhaps together, Khodadoust gradually recovered in just a few weeks.
a few of its closest relatives, and spares the rest of the microbi He died two years later, at age 82, from noninfectious illnesses.
ome. Most phages have an icosahedral head—like a die with After that first case, Chan supplied phages for nearly a dozen
20 triangular faces. It contains the phage’s genes and connects more experimental treatments at Yale, most involving cystic
to a long neck that ends in a tail of fibers, which bind to recep fibrosis patients with P. aeruginosalung infections. He asked
tors on a bacterium’s cell wall. The phage then plunges a kind of Burgholzer to send a sputum sample by overnight delivery so he
syringe through the wall and injects its own genetic material, could identify phages that might help.
which co-opts the bacterium into making more phage copies. I visited Chan at Yale last December, after the screening had
Other types of phages, not used medically, enter the same way begun. He was wearing a checkered oxford shirt, khakis and
but live dormantly, reproducing only when the cell divides. loafers, and before long he was calling me “dude,” his preferred
Phages have co-evolved with bacteria for billions of years moniker. After chatting briefly in his office, we headed for an
and are so widespread that they kill up to 40 percent of all the adjacent laboratory, where Chan showed me a petri dish. Burg
bacteria in the world’s oceans every day, influencing marine holzer’s bacteria had developed into a gray lawn spanning the
oxygen production and perhaps even Earth’s climate. The spot dish, but two thin, clear rows cut across it. The bacteria that
light on phages as medical tools is getting brighter as techno had been in those rows were all dead, Chan told me, killed by
logical advances make it possible to match the viruses to their drips of a phage solution Burgholzer would soon be treated
targets with better accuracy. The few facilities that are techni with. Burgholzer’s infection was caused by three species of the
cally able to provide phage therapy, under strict regulatory pro bacterial genus Achromobacter, and Chan planned to select
tocols, are being overwhelmed with requests. individual phages that could pick them off one by one—an
Clinical trials underway are beginning to generate the high- approach known as sequential monophage therapy. “We’re
quality data needed to convince regulators that phage therapy essentially playing chess in an antimicrobial war,” Chan said.
is viable, but considerable questions remain. The biggest is “We need to make calculated moves.”
whether phage therapy can tackle infections on a large scale. Chan hoped to induce an evolutionary trade-off similar to
Clinicians have to match phages to the specific pathogens in a the one he believes worked for Khodadoust. Unable to find a
patient’s body; it is not clear whether they can do that cost- phage that targets efflux pumps on A chromobacterbacteria, he
effectively and with the speed and efficiency needed to bring instead selected one that targets a large protein called lipopoly
phages into routine use. Also problematic is a shortage of regu saccharide (LPS) in the microbe’s cell wall. LPS has side chains
latory guidelines governing the production, testing and use of of molecules known as O antigens, which vary in length. The
phage therapy. “But if it has the potential to save lives, then we longer the chain, the better the bacteria’s ability to resist not
as a society need to know whether it will work and how best to only antibiotics but also the host’s immune system. Chan
implement it,” says Jeremy J. Barr, a microbiologist at Monash planned to kill the hardy long-chain strains with phages, leav
University in Melbourne, Australia. “The antibiotic-resistance ing the weaker short-chain pathogens behind. In the best sce
crisis is too dire to not embrace phage therapy now.” nario, he said, a succession of phages would shift the bacterial
population toward short-chain strains that might be more easi
TRADING VULNERABILITIES ly controlled by drugs and Burgholzer’s own immune defenses.
Burgholzer learnedabout phages by talking to other people “Bacteria compete for real estate in the body,” Chan said. “After
with cystic fibrosis around the country. While scouring the large numbers of one species are suddenly killed by phage, in
Internet for more information, he came on a YouTube video many cases, others move in.” He wanted the new occupants to
made by phage researchers at Yale University. Soon he was cor be less virulent than their predecessors.
responding with Benjamin Chan, a biologist in Yale’s depart Chan’s boss, Paul Turner, has devoted his career to studying
ment of ecology and evolutionary biology. Since arriving there evolutionary trade-offs in the microbial world. A professor in
in 2013, Chan has accumulated a “library” of phages, harvested Chan’s department, he explained later on the day of my visit
from sewage, soil and other natural sources, that he makes that phage treatments can work without completely ridding the
available to doctors at Yale New Haven Hospital and elsewhere. body of a disease-causing bacteria. Especially when treating
Chan’s first case, in 2016, was a resounding success. He iso chronic conditions, doctors can use phages to selectively shape
lated a phage from pond water, and doctors used it to cure Ali the population of the bad bacteria so it develops other vulnera
Khodadoust, a prominent eye surgeon. Khodadoust had been bilities. “Should those vulnerabilities be toward antibiotics,
suffering from a raging MDR infection in his chest, a complica then so much the better,” he told me. Combining antibiotics
tion from open-heart surgery four years earlier. He was taking with phages to achieve optimal effects for patients, he says,
massive daily doses of antibiotics to try to fight his invading “makes it easier to move forward with phage therapy quickly.”
pathogen, the tenacious bacterium P seudomonas aeruginosa. I drove with Chan to Yale New Haven Hospital to watch as
The virus Chan selected latches on to what is known as an efflux Burgholzer’s phage treatment got underway. We took an elevator
pump on the bacterial cell wall. The pumps expel antibiotics to the second floor, where we waited for Chan’s clinical collabora
and are frequently found in drug-resistant bacteria. Most of the tor, Jonathan Koff, to arrive. A pulmonologist and director of the
P. aeruginosain Khodadoust’s body had the pumps, and the Adult Cystic Fibrosis Program, Koff soon came bounding in, a

The Escalating Battle Harmful bacteria

(yellow)
to Beat Bacteria
Many infectious bacteria that in years past were killed by antibiotics have evolved defenses
that today thwart the drugs. Phages—viruses that infect bacteria—offer a different weapon. Resistant bacteria
(orange)
Physicians are experimenting with three approaches to phage therapy that might overcome
drug resistance in an ongoing contest of attacks and countermeasures, while trying to
determine whether bacteria might find ways to resist phages, too.
Helpful bacteria
(green)
1 A
NTIBIOTICS KILL BAD HAGES KILL BAD
2 P
AND GOOD BACTERIA BACTERIA ONLY
Antibiotics enter a variety of Phages can target a specific
bacteria and limit them in harmful bacterium, leaving
different ways—such as killing helpful ones untouched. But right
them by destroying their cell now it is difficult and costly to
walls or preventing them from find and characterize the right
reproducing. The drugs often phage in nature or to engineer
hurt helpful bacteria, too, but one that can effectively attack
they are inexpensive to make the particular bacterium causing
and easy to administer. a person’s illness.
A common way
a phage kills is by
attaching to a bacterium’s
exterior and injecting its own
genetic material through the
cell wall. This DNA hijacks the cell’s
reproductive machinery to make
many copies and assemble them
into new phages, which explode
out of the cell, killing it.
3 BUT BACTERIA CAN

DEVELOP RESISTANCE
Some harmful bacteria can mutate
to create novel cellular features
that resist the attacks. As these
resistant bacteria proliferate, they
can hurt an infected individual
without being neutralized by the
previous drugs or phages.
54 Scientific American, November 2019 Illustration by AXS Biomedical Animation Studio

4 D RUG-RESISTANT
BACTERIA FLOURISH
The newly evolved bacteria can hunker down in
the human body and become very difficult to
Bacteria eradicate. Physicians are trying different phage
(Achromobacter) therapies to counter the drug-resistant bacteria.
Bacteria
(A. baumannii)
Bacteria
(P. aeruginosa)
5 PHAGE THERAPIES WEAKEN RESISTANCE

Sequential monophage treatment Phage cocktails Phage plus antibiotics
Phage Efflux pump Antibiotic
LPS
Receptors
Phage 1 is given to a patient. It destroys Pseudomonas aeruginosahas efflux pumps
Achromobacter species 1, which has long that expel antibiotics that sneak inside it.
lipopolysaccharide (LPS) chains.
Phages
Phage 2 is then given to destroy Achromobacter Several different phages are given simulta Phages attach to the efflux pumps, shutting
species 2, which has moderately long LPS chains. neously to a patient. Each phage targets a them down.
different receptor on Acinetobacter baumannii.
Antibiotic
The immune system, which struggles against The A . baumanniicells cannot modify all types Antibiotics can now persist inside the
the longer-chain species, destroys the of receptors at once to resist the different P . aeruginosacells and kill them.
remaining short-chain Achromobacter species. phages and are killed.
6 B
ACTERIAL BALANCE
IS RESTORED
By killing only harmful bacteria,
phages allow helpful bacteria to
dominate a person’s microbiome—at
least until bad bacteria evolve again.

knapsack slung over his shoulder. Burgholzer met the three of us in three months. He still needed extensive rehabilitation, but he
in a treatment room and spoke with a rasp—the only outward sign remains healthy today.
of his disease. As Koff and Chan compared notes, he told me he The case drew worldwide media attention. The treating phy
wanted to stay healthy for his three-year-old daughter. When sicians were Robert Schooley, a friend of Patterson’s and chief of
treatment time arrived, he tossed his cell phone to his wife. “Here, infectious diseases at U.C. San Diego, and Patterson’s wife, Stef
take a photo for my mother,” he said with a grin. Then he raised a fanie Strathdee, then director of the university’s Global Health
nebulizer over his mouth and nose and began inhaling a vapor Institute. Two years later, with an initial investment of $1.2 mil
ized phage solution into his lungs. lion, Schooley and Strathdee launched the Center for Innova
tive Phage Applications and Therapeutics at U.C. San Diego to
PHAGE COCKTAILS fund clinical research and promote the field.
According to Koff, sequential monophage therapy makes sense Each phage Patterson was treated with was screened for its
for treating cystic fibrosis and certain other chronic diseases ability to kill A
. baumanniiin infectious samples obtained from
that sequester bad bacteria in the body. When there is no prov his body, using assays at the Naval Medical Research Center at
en way to eliminate the pathogens completely, he says, the tac Fort Detrick, Md., and at Texas A&M University. The assays can
tic is to chip away at the harmful strains. test hundreds of phages against bacterial pathogens simultane
Some clinicians are choosing a different approach: They give ously in just eight to 12 hours, according to Biswajit Biswas,
patients multiple phages in a therapeutic cocktail, trying to chief of the bacteriophage division at the center, which supplied
knock out an infection completely by targeting a variety of bac some of the phages used in Patterson’s treatment. Biswas, who
terial resistance mechanisms simultaneously. Ideally, each developed the assay and created the center’s phage bank, says
phage in a cocktail will glom on to a different receptor, so if bac the assay allows new viruses to be easily swapped in to counter
the onset of resistance. Patterson did develop
resistance to his first cocktail within two
Experts cannot say which of weeks, prompting the navy to prepare a sec
ond one with longer-lasting effects. A compa
the phage therapies may win out. ny called Adaptive Phage Therapeutics in
Gaithersburg, Md., has since licensed the
What is needed now are results navy’s assay and its phage bank and will soon
take them both into clinical trials in patients
from clinical trials that can help with urinary tract infections.
The navy assay checks only for bacterial
cell death; it does not reveal which receptors
overcome residual skepticism. are targeted. Whether cocktails should target
known receptors is in debate. Ry Young, a
phage geneticist at Texas A&M, who supplied
teria evolve resistance to one virus in the mixture, other viruses viruses for Patterson, argues they should. “We don’t even know
will keep up the attack. if phages were responsible for his successful outcome,” he says.
Chan and Koff argue that phage interactions with bacteria “Our best guess is that phage treatment lowered his infectious
are unpredictable and that when exposed to cocktails, patho load to a level where his immune system took over.” The better
gens might develop resistance to all the viruses in the mixture approach to cocktails, Young says, is to combine three or four
at once, which could limit future treatment options. “Splitting viruses targeting distinct receptors on the same bacterial strain.
the cocktail into sequential treatments allows you to treat The odds of a bacterium evolving resistance to a single phage
patients for longer durations,” Koff says. are about a million to one, he says, whereas the odds of it losing
Jessica Sacher, co-founder of the Phage Directory, an inde or developing mutant forms of receptors targeted by all the
pendent platform for improving access to phages and phage phages in a cocktail “are essentially zero.” Furthermore, the
expertise, says convincing arguments can be made for either identification of important receptors is critical if clinicians
method. “The science isn’t there yet to say one is necessarily hope to make bacteria sensitive to antibiotics again.
better than the other.” She notes that cocktails might be more Barr says scientists are working to identify the receptors tar
appropriate for acutely ill patients, who cannot always wait for geted by Patterson’s cocktails, but he disagrees on the need to
doctors to develop a sequential strategy. identify the receptors prior to use. “It’s an understandable view
Urgency was paramount in the now famous case of Tom Pat point and a hot topic in the field,” he says. “We know very little
terson, a professor at the University of California, San Diego, about these phages, and we need checks and balances before
who in 2016 was saved by phage cocktails after being stricken using them in therapy. Does that mean we need to identify host
by an MDR infection during a trip to Egypt. The invader was receptors? That is a huge amount of work currently, so I would
Acinetobacter baumannii,a notoriously drug-resistant microbe say it’s not required but definitely desirable.”
that is common in Asia and is spreading steadily toward the
West. Patterson was in multiorgan failure by the time doctors ENGINEERED PHAGES
delivered mixtures of four viruses through a catheter into his Given the vagary of cocktails,some researchers say phages
abdomen and a fifth intravenously. The physicians treated him should be genetically engineered to bind to specific receptors
twice a day for four weeks, and he was cleared of infection with and also to kill bacteria in novel ways. The vast majority of

phages used thus far have been natural, harvested from the ural phages targeted at S taphylococcus aureus bacteria, the
environment, but phage engineering is an emerging frontier cause of common staph infections often contracted at hospitals.
with a new success story under its belt. Isabelle Carnell, a Brit- It is in clinical trials in patients who have infected mechanical
ish teenager with cystic fibrosis, was suffering from life-threat- heart pumps. Armata’s plan is to monitor for treatment-resis-
ening infections in her liver, limbs and torso after undergoing tant staph in the general population, then introduce new cock-
a double lung transplant in 2017. Her bacterial nemesis—Myco- tails as needed, in much the same way that influenza vaccines
bacterium abscessus—was not responding to any antibiotics. are tuned every year to match the latest circulating strains.
Yet this year, in a first for the field, researchers from several Pharmaceutical executives said it was too soon to estimate what
institutions successfully treated the girl with an engineered the costs would be.
cocktail of three phages. One naturally rips apart M. abscessus Experts still cannot say which of the current strategies—
as it replicates. The other two also kill bacteria but not as com- sequential monotherapy, cocktails, engineered phages, and
pletely, leaving 10 to 20 percent surviving the process. So the general or personalized treatments—may ultimately win out,
team, led by Graham Hatfull, a professor of biological sciences assuming any do. An optimal approach “might not even exist,”
at the University of Pittsburgh, deleted a single gene from each says Barr, considering that “phage treatments in each case
of those two phages, turning them into engineered assassins. could depend on complicating issues, such as the target patho-
The cocktail of three phages cleared Carnell’s infection within gen, the disease and the patient’s medical history.”
six months. Phage therapy is still saddled by geopolitical biases, too, says
Researchers at Boston University first developed engineered Strathdee. What is really needed now, she says, are positive
phages in 2007. They coaxed one into producing an enzyme that results from well-controlled clinical trials that can help over-
more effectively degrades the sticky biofilms secreted by certain come residual skepticism. Alan Davidson, a biochemist at the
infectious bacteria for protection. Scientists have since modified University of Toronto, speculates that within a decade phage
phages to kill broader ranges of harmful bacteria or potentially therapy might be cheaper, easier and faster than it is today. He
to deliver drugs and vaccines to specific cells. These lab-designed leans toward the engineering approach, saying sequencing the
viruses are also more patentable than natural phages, which whole genome of a patient’s bacteria and then synthesizing a
makes them more desirable to drug companies. As if to under- phage to cure an infection could be quicker and less expensive
score that point, a division of the pharmaceutical giant Johnson “than screening the pathogens against a battery of viruses
& Johnson struck a deal in January with Locus Biosciences, drawn from nature.”
worth up to $818 million, to develop phages engineered with the Meanwhile Burgholzer, who was self-administering phage
gene-editing tool CRISPR. therapy with a nebulizer at home until March 2019, has not yet
Developing a phage therapy that is commercially viable will experienced the clinical improvements he was hoping for. In
not be easy. Barr and other scientists point out that it takes a March, Chan and Koff introduced a second phage targeted at
tremendous amount of time, money and effort to engineer a another Achromobacterstrain. By April the bacterial counts in
phage, and after all that the target bacteria might soon evolve Burgholzer’s lungs had fallen by more than two orders of mag-
resistance to it. Furthermore, regulatory approval for an engi- nitude since the initial treatment began. “So it does appear we
neered phage “could be a tough sell,” says Barr, echoing the view can pick off those strains successively,” Koff told me. Yet Koff
of several scientists interviewed for this story. But fda spokes- acknowledged that Burgholzer was not noticing a dramatic
person Megan McSeveney, in an e-mail, claimed the agency change in lung function. When I asked why, Koff responded,
does not distinguish between natural and engineered phages as “We know a lot more about the phage we use against P. aerugi-
long as therapeutic preparations are deemed safe. nosa than we do about phages targeting Achromobacter.” The
ability to manipulate the infection “is less informed.”
FUTURE PROSPECTS The next step, Koff says, will be to genetically sequence mucus
companies are now testing different ways to bring phages to samples from Burgholzer’s lungs. “We really need to understand
broader markets. Some companies want to supply patients with what’s happening with his bacteria so we can get to the high lev-
personalized therapies matched specifically to their infections. el of sophistication we have with P. aeruginosa.Bobby is letting
That is the strategy at Adaptive Phage Therapeutics. The com- us take a chance to see if, at a minimum, we can help.” Frustrated
pany’s chief executive officer, Greg Merril, says assays used to but still eager, Koff says, “Some patients respond better than oth-
screen the navy’s phages against infectious samples could be ers. We need to understand those dynamics.”
offered at diagnostic labs and major medical centers worldwide.
Phages effective against locally prevalent bacteria in each
region could be supplied in kiosks, bottled in fda-approved, M O R E T O E X P L O R E
ready-to-use vials. Merril says doctors could continually moni- Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery,
and Development of New Antibiotics. World Health Organization, 2017.
tor treated patients for resistance, swapping in new phages as Engineered Bacteriophages for Treatment of a Patient with a Disseminated Drug-
needed until the infections are under control. He estimates that Resistant Mycobacterium abscessus. Rebekah M. Dedrick et al. in Nature Medicine,
the per-patient cost under the current compassionate-use sys- Vol. 25, pages 730–733; May 2019.
tem is approximately $50,000, an expense that should fall with Phage Directory: https://phage.directory
economies of scale. FROM OUR ARCHIVES
Other companies reject this personalized strategy in favor of Infectious Drug Resistance. T sutomu Watanabe; December 1967.
fixed phage products more akin to commercial antibiotics.
Armata Pharmaceuticals’ lead product is a cocktail of three nat-

1 2
4 5

7 8
Winged
E VOLUTION
3
Victory
The discovery of a strange
chromosome in songbirds
might explain their
W
astonishing diversity
By Kate Wong
hen a 10-kilome-
ter-wide hunk
of burning space
rock slammed
into what is now
the Gulf of Mexico
66 million years
6 ago, it touched off widespread destruc-
tion, wiping out more than 75 percent of
life on Earth. The Chicxulub asteroid, as
it is called, is best known as the dinosaur
killer. But although it doomed Tyranno-
saurus rex and Triceratops, the sauro-
pods and the hadrosaurs, the asteroid
actually set one lineage of dinosaurs on
a path to glory: that of modern birds.
SONGBIRD SPECIES f ound to have the extra chromosome

include the Gouldian finch (1), Blyth’s reed warbler (2),
Eurasian skylark (3), Eurasian bullfinch (4), rook (5) ,
European siskin (6), common canary (7 ), pine bunting (8)
and barn swallow (9) .

9
Birds got their start more than 150 million years ago, evolving
from meat-eating dinosaurs called theropods, and they attained
an impressive degree of diversity in the first 85 million years or Kate Wong is a senior editor for evolution
so of their existence. But the ancestors of today’s birds—members and ecology at Scientific American.
of the neornithine lineage—were mere bit players compared with
archaic birds such as the enantiornithines, which ruled the roost.
When the asteroid struck, however, neornithine fortunes shifted.
The impact extinguished all of the nonbird dinosaurs and most
birds. Only the neornithines made it through that apocalyptic cells—eggs, sperm and their precursors—but not the rest of the
event. This clutch of survivors would give rise to one of the great- body’s cells, called somatic cells. Progenitors of both eggs and
est evolutionary radiations of all time. sperm contain GRC, but by the time a sperm cell has developed
Today there are more than 10,000 bird species, making them fully, the GRC has been eliminated from it. The chromosome is
the second most speciose class of vertebrate creatures alive, thus transmitted to offspring via the mother exclusively.
outnumbered only by the bony fish. They come in every shape Until recently the GRC was known only from two songbirds:
and size—the land-bound ostrich tips the scales at more than the zebra finch and its close relative the Bengalese finch. It
136 kilograms; the ever whirring bee hummingbird, less than seemed to be an oddity of these two species, nothing more. But
two grams. They have colonized virtually every major body of when researchers decided to look for it in other lineages of
land and water on the planet, from the sweltering tropics to the birds, a striking pattern emerged. In a paper published in the
frozen poles. And they have diversified to fill a vast array of June 11 Proceedings of the National Academy of Sciences USA,
dietary niches, evolving adaptations to eating everything from Anna Torgasheva and Pavel Borodin of the Russian Academy of
microscopic algae to large mammals. Sciences, Denis Larkin of the University of London and their
Incredibly, roughly half of these species are songbirds, which colleagues report that all 16 of the songbird species they exam-
are characterized by a special voice box. The group includes the ined—a sample that included representatives from across the
warblers, canaries, larks and other mellifluous singers but also family tree of songbirds—had the GRC; none of the eight spe-
the strident (to human ears, anyway) crows and their kin. To put cies representing other major bird groups did. What is more,
that number in perspective, there are approximately as many liv- the GRCs they found differed considerably from species to spe-
ing species of songbirds as there are of mammals. cies—even between closely related ones—suggesting that the
How did this particular group of birds come to be so extraor- chromosome has evolved quickly in these different songbird
dinarily diverse? Biologists have long sought to answer this ques- lineages since it first appeared in their common ancestor an
tion, scouring the fossil record and DNA sequences of modern estimated 35 million years ago.
CYRIL LAUBSCHER Getty Images (1); OLEG MINITSKIY Getty Images (2); LES STOCKER Getty Images (3); REINHARD HOLZL Getty Images (4); KIM TAYLOR Getty Images (5);
birds for clues. But apart from pinpointing where songbirds orig- Cells of other organisms have previously been found to carry
inated (Australia), many of these studies produced inconclusive extra chromosomes called B chromosomes. But their occur-
or conflicting results. A detailed picture of where and when the rence is erratic, varying between members of the same species
ALAMY (6); FERNANDO SANCHEZ DE CASTRO Getty Images (7); HANNE AND JENS ERIKSEN Nature Picture Library (8); DP WILDLIFE VERTEBRATES Alamy (9)
lineages leading to modern songbirds split off from one another— or even between different cells in the same individual. GRC, in
and thus the factors driving this radiation—remained elusive. contrast, is “an obligatory element in the germ line of song
In the absence of conclusive evidence to show how it all birds,” Larkin says. This ubiquity suggests that GRC is more
transpired, researchers have advanced a number of competing influential than B chromosomes.
theories for songbird diversification that center variously on cli- Exactly what GRC is influencing is largely a mystery, howev-
mate change, plate tectonics and sexual selection, in which er—researchers know very little about what its genes actually
mate preferences spur evolution. do. But some hints have come to light. In another recent GRC
Now a new finding has set the field atwitter. All songbirds, it study, which has been posted to the bioRxiv preprint server but
seems, have a weird extra chromosome that does not appear to not yet published in a peer-reviewed scientific journal, Cormac
exist in other birds. The discovery suggests a genetic mecha- M. Kinsella and Alexander Suh of Uppsala University in Sweden
nism for creating barriers to reproduction between populations and their colleagues found that the zebra finch GRC contains at
of a species, which promotes speciation. Much remains to be least 115 genes, including some that have been shown to make
learned about this auxiliary package of DNA, but already some proteins and RNA in the ovaries and testes of adult birds. This
researchers are wondering whether it just might be the secret of expression pattern hints that these genes may help guide the
the songbirds’ dazzling evolutionary success. development of sperm and eggs. Other genes on the zebra finch
GRC are comparable to genes that are known from mouse stud-
BACK POCKET GENES ies to be involved in early embryonic development.
The chromosomein question is called the germ-line-restricted To Borodin and Larkin, these findings suggest that the GRC
chromosome (GRC), so named for its presence in reproductive may have allowed songbirds to circumvent key constraints on
IN BRIEF
Songbirds are the most species-rich bird group, ac Biologists have long wondered how songbirds Recent studies show that songbirds have an extra
counting for roughly half of the more than 10,000 came to be so diverse. Traditional explanations chromosome not found in other birds, suggesting
bird species alive today. have focused on factors such as climate change. that it might have been the key to their diversification.

bird evolution. “The avian genome in general is very compact ros of Louisiana State University and his colleagues reported on
and conserved compared with, for example, the mammalian the results of their analysis of DNA from dozens of members of
genome,” Larkin explains. The genomes of today’s mammals the passerine order of birds, which comprises the songbirds and
range in size from less than two picograms to more than eight some other, far less speciose groups. Based on the DNA sequenc-
picograms and are packaged into anywhere from six chromo- es and a handful of fossils of known age, the team reconstructed
somes to 102. In the tens of millions of years over which they how the various passerine families were related and when they
have been evolving, their chromosomes have been sliced and branched off. It then compared this time line of diversification
diced and reshuffled and rejoined many times. These rear- against climate and geologic records to see if the passerine diver-
rangements have altered gene expression in ways that have pro- sification trends correlated with events in Earth history, as pre-
duced diverse traits. Birds, in contrast, have genomes ranging dicted by some hypotheses. On the whole, fluctuations in the
from just under one picogram to just over two. And they usual- diversification rates of these birds did not track changes in glob-
ly have right around 80 chromosomes, with comparatively little al temperature or dispersals of the birds into new continents.
of the “junk” DNA found in most mammals. The findings prompted the authors to suggest that more complex
The reason bird genomes are small and streamlined, some mechanisms than temperature or ecological opportunity were
experts surmise, has to do with flight. Flying is an energetically the main drivers of passerine speciation. “These conclusions are
expensive activity. Larger genomes require larger cells, and both very much in line with our hypothesis of GRC contribution to
are metabolically costlier than their smaller counterparts. The songbird diversification,” Larkin asserts.
Not everyone is ready to embrace the sug-
gestion that GRC drove songbird diversifica-
tion, however. “In general, it is hard to estab-
The GRC could have provided lish causation between any one given trait,
songbirds with a rare chunk like the presence of GRCs, and the evolution-
ary success of a particular group,” Oliveros
of extra DNA—fodder for the says. “The presence of the trait could by
evolution of new traits. chance have coincided with another trait—

nesting behavior, for example—that may
have played a larger role in a group’s evolu-
tionary success.”
intense metabolic demands of flying may have therefore limited But other researchers not involved in the new studies find the
bird genome size. Because the GRC occurs only in germ-line notion intriguing. “The fact that [GRCs] have been maintained
cells and not the far more numerous somatic cells, it could have over long evolutionary periods and also contain putatively func-
provided songbirds with a rare chunk of extra DNA—fodder for tional genes ... suggests that they could play a role in reproduc-
the evolution of new traits—without the metabolic costs associ- tive isolation in birds,” observes David Toews of Pennsylvania
ated with having a larger somatic genome. State University. If the sky-high diversification rate of songbirds
“Birds need additional copies of germ-cell-specific genes for a compared with that of other birds was promoted by a genomic
very short breeding period only to produce a lot of sperm and load mechanism such as GRCs, “it would definitely be exciting and
[egg cells] with large amounts of proteins. They have no reason to not something that I would have predicted,” Toews says. He cau-
carry these genes throughout the year and in [the rest of the tions, though, that “we need to know more about what they are
body’s] cells when and where they are of no use,” Borodin says. If actually doing to make that link with confidence.”
songbirds found a way to obtain additional genes on a temporary The work could have implications for understanding organ-
basis that could work during early stages of development while isms beyond birds. “We thought we knew a lot about how bird
keeping their basic genome intact, Larkin adds, such an arrange- genomes are organized,” Suh reflects, “but the GRC has been
ment would be tremendously advantageous and could lead to the right before our eyes yet has been overlooked.” Scientists have
huge variety seen in songbirds compared with other bird groups. found similar extra chromosomes in hagfishes and some insects.
In theory, the GRC could have created the reproductive iso- What if GRCs are more widespread in the tree of life, he won-
lation needed for new species to evolve by rendering those indi- ders: “The findings in songbirds open up a bunch of new direc-
viduals that carried the extra chromosome unable to interbreed tions for thinking about evolution and development.”
and produce fertile offspring with those that did not. Once the
GRC originated in the last common ancestor of songbirds,
MORE TO EXPLORE
members of that ancestral species that carried the GRC could
produce fertile offspring only with mates that also had the GRC. Programmed DNA Elimination of Germline Development Genes in Songbirds.
Cormac M. Kinsella et al. Posted to Biorxiv preprint server December 22, 2018.
As the GRC evolved, acquiring new genes, songbirds with a par- www.biorxiv.org/content/10.1101/444364v2
ticular variant of GRC could produce fertile offspring only with Germline-Restricted Chromosome Is Widespread among Songbirds.
mates that carried that same GRC variant. Anna Torgasheva et al. in Proceedings of the National Academy of Sciences USA,
Vol. 116, No. 24, pages 11,845–11,850; June 11, 2019.
ENGINE OF CHANGE? FROM OUR ARCHIVES
According to Borodin and Larkin, the discovery that GRC is Taking Wing. Stephen Brusatte; January 2017.
widespread among songbirds and absent in other birds dove-
tails with the results of another recent study. In April, Carl Olive-

IN THE PIPELINE
Cocooned in stainless steel and surrounded by water-
logged rock, one of two three-kilometer-long vacuum
chambers sprawls down a damp, dripping tunnel bored
underneath Mount Ikenoyama in Japan. An intricate
system of lasers and mirrors inside the chambers is
designed to tune in to gravitational waves moving
through our planet from across the cosmos.

CENTER
OF
GRAVITY
ASTROPHYSIC S
The first major gravitational-

wave observatory to be
built under Earth’s surface—
KAGRA in Japan—is set
to turn on
By Lee Billings
Gravitational waves—ripples in spacetime

produced by merging black holes, colliding neutron stars,
detonating supernovae and other cosmic cataclysms—
have sparked a revolution in astrophysics. First observed
in 2015, a century after Albert Einstein predicted their
existence, these elusive whispers in the fabric of reality
are already revealing otherwise hidden details of the exot-
ic objects that produce them. Studies of gravitational
waves have provided researchers with the first direct evi-
dence that black holes exist, produced new estimates of
the cosmic expansion rate, and shown that neutron stars
are the main sources of the universe’s supply of gold, plat-
ENRICO SACCHETTI
inum and other heavy elements. Eventually they could

allow researchers to glimpse the universe as it was in the
first fractions of a second after the big bang.

Lee Billings is a senior editor for space

and physics at Scientific American.
The forefront of this promising future can be found

in a subterranean complex of darkened tunnels. There
more than 200 meters below Mount Ikenoyama in the
Gifu prefecture of central Japan, an international team
of scientists, engineers and technicians is finishing
almost a decade of steady construction, readying the
Kamioka Gravitational-Wave Detector (KAGRA) to
begin operations by the end of this year. Soon KAGRA
will join the world’s three other active gravitational-
wave detectors—the twin stations of the U.S.-based
Advanced Laser Interferometer Gravitational-Wave
Observatory (LIGO) in Hanford, Wash., and in Living
ston, La., and the Advanced Virgo facility near Pisa,
Italy. KAGRA’s location in Japan and orientation with
respect to LIGO and Virgo will independently check
and enhance those detectors’ observations, allowing
researchers to better measure the orientations and
spins of merging black holes and neutron stars.
Collectively, this quartet of detectors will reach new
heights of sensitivity and precision, finding fainter grav-
itational-wave events than ever before and pinpointing
their celestial coordinates with unprecedented acuity for
follow-up with conventional telescopes. Here selected
photographs capture some of the final technical prepa-
rations before KAGRA is unleashed on the sky.
To find gravitational waves, KAGRA relies on the
same method used by LIGO and Virgo, a technique
called laser interferometry. In this approach, a laser
beam bounces between mirrors suspended at the ends
of two pipelike vacuum chambers. The chambers are
several kilometers long and oriented perpendicularly
to each other, forming what looks like a giant L. The
laser acts as a measuring stick, revealing when a pass-
ing gravitational wave briefly stretches and shrinks
spacetime, altering the chambers’ lengths (and thus
IN BRIEF
Studies of gravitational wavesusing three observatories are revolutionizing

our understanding of black holes, neutron stars and other astrophysical objects.
A fourth observatory,the Kamioka Gravitational-Wave Detector (KAGRA),
is set to begin operations by the end of 2019.
The first observatory of its kindto be built underground and kept at extreme-
ly low temperatures to increase sensitivity, KAGRA is demonstrating innova-
tions crucial for constructing a new generation of even more advanced gravi-
tational-wave detectors.

the total distance a beam of light travels). Such pertur-

bations are inconceivably tiny, far smaller than the
diameter of a single proton—meaning that each facility
must somehow account for or suppress an almost
countless assortment of contaminating noises, from
the enormous seismic motions of earthquakes and
tides to the softer vibrations caused by airplanes over-
head, passing cars, nearby wildlife or even a mirror’s
jiggling atoms. Distinguishing between legitimate
gravitational-wave signals and noise-induced “glitches”
is an almost overwhelming task—and one that has con-
tributed to numerous false alarms mixed in with the
dozens of authentic detections collaboratively
announced to date by LIGO and Virgo.
Buried deep below its mountain, KAGRA will be the
first major laser interferometer built and operated
entirely underground, far from the cacophony of back-
ground noise at the terrestrial surface. It is also the
first to use cryogenically cooled mirrors—each a pol-
ished 23-kilogram cylinder of sapphire crystal—which
can dramatically reduce thermal vibrations and deliver
corresponding boosts in sensitivity. LIGO’s and Virgo’s
mirrors are kept at room temperature; KAGRA’s will be
maintained at a frigid 20 degrees above absolute zero.
Although these two advances could in principle
allow KAGRA to find fainter sources of gravitational
waves than LIGO or Virgo, they are not without draw-
backs: Mechanical coolers keep the laser-bathed mir-
rors cold but also introduce their own vibrational noise
into measurements, and water from rain and melting
snow regularly infiltrates KAGRA’s tunnels, forcing
workers to install plastic sheets to protect delicate
equipment. Even with protection, the moisture may
halt operations during the wettest times of year.
If all goes according to plan, KAGRA will not only
help make additional major discoveries but also dem-
onstrate the new technologies likely to be used by the
next generation of more advanced gravitational-wave
observatories around the globe.
SHIELDING
VIBRATIONS
A technician squats beside the uppermost sec-
tion of a 14-meter-tall vibration isolation system
for one of KAGRA’s polished sapphire mirrors.
Such systems are necessary shields against
outside noises, allowing a passing gravitational
ENRICO SACCHETTI
wave’s minuscule signature—a mirror’s shift

by a fraction of a thousandth of the width of
a proton—to be detected.


TIGHT BEAM KEEPING COOL

To ensure that KAGRA’s lasers can accurately A technician checks a mirror’s suspension
register the almost imperceptible distortions system before its installation inside
of its mirrors caused by gravitational waves, KAGRA’s cryogenic containers. Once inside,
scientists must precisely control the location the mirror and its mounting are cooled to
and brightness of the laser beam. This almost absolute zero—all in an effort to
OPPOSITE PAGE: ENRICO SACCHETTI; THIS PAGE: ROHAN MEHRA
requires feeding the laser through what is minimize the thermal vibrations of their
effectively a telescope (shown here) mated to constituent atoms, allowing signatures of
another vibration isolation device and fainter gravitational waves to be seen.
housed inside a vacuum vessel.


MIRROR, MIRROR COMMAND CENTER

Another view of the delicate apparatus that All of KAGRA’s instruments are controlled
keeps a mirror in place, before installation in from this room at the surface, a 10-minute
KAGRA’s cryogenic system. The sapphire drive from the underground cavern’s
mirror is held in the cylindrical chamber in entrance. A wall-mounted bank of six large
the bottommost stage, suspended by four screens displays the temperature, humidity
thin sapphire fibers. The remaining three and operational conditions of the KAGRA
vertical stages contain components to iso- site, and smaller screens along the room’s
late the mirror assembly from seismic noise right wall show snapshots of laser light cas-
and are fabricated with a variety of materi- cading through the vacuum tunnels, as well
als that can withstand KAGRA’s extremely as information about seismic activity
cold operating conditions. throughout Japan.
OPPOSITE PAGE: INSTITUTE FOR COSMIC RAY RESEARCH,
UNIVERSITY OF TOKYO; THIS PAGE: ENRICO SACCHETTI
MORE TO EXPLORE
The Detection of Gravitational Waves with LIGO. Barry C. Barish. Paper presented at the American Physical Society Division of
Particles and Fields Conference, Los Angeles, Calif., January 5–9, 1999. Preprint available at https://arxiv.org/abs/gr-qc/9905026
Observation of Gravitational Waves from a Binary Black Hole Merger. T he LIGO Scientific Collaboration and the Virgo Collaboration
in Physical Review Letters,Vol. 116, No. 6, Article No. 061102; February 12, 2016.
KAGRA: 2.5 Generation Interferometric Gravitational Wave Detector. T he KAGRA Collaboration in Nature Astronomy, Vol. 3,
pages 35–40; January 2019.
FROM OUR ARCHIVES
The Future of Gravitational Wave Astronomy. Lee Billings; ScientificAmerican.com, February 12, 2016.


ECONOMIC S
TH
CASINO
INESC PABLE A novel
approach
developed by
physicists and
mathematicians
describes the
distribution
of wealth
in modern
economies with
unprecedented
accuracy
By Bruce M. Boghosian
Illustrations by Hanna Barczyk November 2019, ScientificAmerican.com 71

W ealth inequality is escalating at

an alarming rate not only within
the U.S. but also in countries as diverse
as Russia, India and Brazil. According
to investment bank Credit Suisse, the
fraction of global household wealth held
by the richest 1 percent of the world’s
population increased from 42.5 to 47.2 percent between the financial crisis of
2008 and 2018. To put it another way, as of 2010, 388 individuals possessed as
much household wealth as the lower half of the world’s population combined—
about 3.5 billion people; today Oxfam estimates that number as 26. Statistics
from almost all nations that measure wealth in their household surveys indicate
that it is becoming increasingly concentrated.
Although the origins of inequality are hotly debated, revealing a subtle asymmetry that tends to concen-
an approach developed by physicists and mathemati- trate wealth. We believe that this purely analytical
cians, including my group at Tufts University, suggests approach, which resembles an x-ray in that it is used
they have long been hiding in plain sight—in a well- not so much to represent the messiness of the real
known quirk of arithmetic. This method uses models of world as to strip it away and reveal the underlying
wealth distribution collectively known as agent-based, skeleton, provides deep insight into the forces acting
which begin with an individual transaction between to increase poverty and inequality today.
two “agents” or actors, each trying to optimize his or
her own financial outcome. In the modern world, noth- OLIGARCHY
ing could seem more fair or natural than two people In 1986 social scientist John Angle first described the
deciding to exchange goods, agreeing on a price and movement and distribution of wealth as arising from
shaking hands. Indeed, the seeming stability of an eco- pairwise transactions among a collection of “econom-
nomic system arising from this balance of supply and ic agents,” which could be individuals, households,
demand among individual actors is regarded as a pin- companies, funds or other entities. By the turn of
nacle of Enlightenment thinking—to the extent that the century physicists Slava Ispolatov, Pavel L. Krapiv-
many people have come to conflate the free market sky and Sidney Redner, then all working together at
with the notion of freedom itself. Our deceptively sim- Boston University, as well as Adrian Drăgulescu, now
Bruce M. Boghosian ple mathematical models, which are based on volun- at Constellation Energy Group, and Victor Yakovenko
is a professor of tary transactions, suggest, however, that it is time for of the University of Maryland, had demonstrated that
mathematics at a serious reexamination of this idea. these agent-based models could be analyzed with the
Tufts University, with
In particular, the affine wealth model (called thus tools of statistical physics, leading to rapid advances
research interests
in applied dynamical because of its mathematical properties) can describe in our understanding of their behavior. As it turns out,
systems and applied wealth distribution among households in diverse many such models find wealth moving inexorably
probability theory. developed countries with exquisite precision while from one agent to another—even if they are based on

fair exchanges between equal actors.

In 2002 Anirban Chakraborti, then at
the Saha Institute of Nuclear Physics Winners, Losers
in Kolkata, India, introduced what
The yard sale, a simple mathematical
came to be known as the yard sale
model developed by physicist Anirban
model, called thus because it has cer-
Chakraborti, assumes that wealth moves
tain features of real one-on-one eco-
from one person to another when the for
nomic transactions. He also used nu-
mer makes a “mistake” in an economic
merical simulations to demonstrate
exchange. If the amount paid for an object
that it inexorably concentrated wealth,
exactly equals what it is worth, no wealth
resulting in oligarchy.
changes hands. But if one person overpays
To understand how this happens,
or if the other accepts less than the item’s
suppose you are in a casino and are in-
worth, some wealth is transferred be
vited to play a game. You must place
tween them. Because no one wants to go
some ante—say, $100—on a table, and
broke, Chakraborti assumed that the
a fair coin will be flipped. If the coin
amount that can potentially be lost is some
comes up heads, the house will pay
fraction of the wealth of the poorer per
you 20 percent of what you have on
son. He found that even if the outcome of
the table, resulting in $120 on the ta-
every transaction is chosen by a fair coin
ble. If the coin comes up tails, the
flip, many such sales and purchases will
house will take 17 percent of what you
inevitably result in all the wealth falling
have on the table, resulting in $83 left
into the hands of a single person—leading
on the table. You can keep your money
to a situation of extreme inequality. —B.B.
on the table for as many flips of the
coin as you would like (without ever
adding to or subtracting from it). Each
time you play, you will win 20 percent
of what is on the table if the coin comes up heads, and sented here may seem surprising at first, but it is well
you will lose 17 percent of it if the coin comes up tails. known in probability and finance. Its connection with
Should you agree to play this game? wealth inequality is less familiar, however. To extend
You might construct two arguments, both rather per- the casino metaphor to the movement of wealth in an
suasive, to help you decide what to do. You may think, “I (exceedingly simplified) economy, let us imagine a IN BRIEF
have a probability of ½ of gaining $20 and a probability system of 1,000 individuals who engage in pairwise Wealth inequality
of ½ of losing $17. My expected gain is therefore: exchanges with one another. Let each begin with is escalating in many
some initial wealth, which could be exactly equal. countries at an
× (+$20) + ½ × (−$17) = $1.50
½ Choose two agents at random and have them transact, alarming rate, with
then do the same with another two, and so on. In oth- the U.S. arguably
which is positive. In other words, my odds of winning er words, this model assumes sequential transactions having the highest
inequality in the
and losing are even, but my gain if I win will be great- between randomly chosen pairs of agents. Our plan is
developed world.
er than my loss if I lose.” From this perspective it to conduct millions or billions of such transactions in A remarkably
seems advantageous to play this game. our population of 1,000 and see how the wealth ulti- simple model of
Or, like a chess player, you might think further: mately gets distributed. wealth distribution
“What if I stay for 10 flips of the coin? A likely outcome What should a single transaction between a pair of developed by physi-
is that five of them will come up heads and that the agents look like? People have a natural aversion to cists and mathema-
other five will come up tails. Each time heads comes going broke, so we assume that the amount at stake, ticians can repro-
up, my ante is multiplied by 1.2. Each time tails comes which we call ∆w (∆w is pronounced “delta w”), is a duce inequality in
a range of countries
up, my ante is multiplied by 0.83. After five wins and mere fraction of the wealth of the poorer person, Shau-
with unprecedented
five losses in any order, the amount of money remain- na. That way, even if Shauna loses in a transaction with accuracy.
ing on the table will be: Eric, the richer person, the amount she loses is always Surprisingly,
less than her own total wealth. This is not an unreason- several mathemati-
1.2 × 1.2 × 1.2 × 1.2 × 1.2 × 0.83 × 0.83 × 0.83 × able assumption and in fact captures a self-imposed cal models of free-
limitation that most people instinctively observe in market economies
0.83 × 0.83 × $100 = $98.02 display features
their economic life. To begin with—just because these
numbers are familiar to us—let us suppose ∆w is of complex macro
scopic physical sys-
so I will have lost about $2 of my original $100 ante.” 20 percent of Shauna’s wealth, w, if she wins and
tems such as ferro-
With a bit more work you can confirm that it would take –17 percent of w i f she loses. (Our actual model assumes magnets, including
about 93 wins to compensate for 91 losses. From this per- that the win and loss percentages are equal, but the phase transitions,
spective it seems disadvantageous to play this game. general outcome still holds. Moreover, increasing or symmetry breaking
The contradiction between the two arguments pre- decreasing ∆w will just extend the time scale so that and duality.
Illustration by Brown Bird Design November 2019, ScientificAmerican.com 73

more transactions will be required before we can see fers money from one agent to another, setting up an
the ultimate result, which will remain unaltered.) imbalance between the two. And once we have some
If our goal is to model a fair and stable market variance in wealth, however minute, succeeding trans-
economy, we ought to begin by assuming that nobody actions will systematically move a “trickle” of wealth
has an advantage of any kind, so let us decide the upward from poorer agents to richer ones, amplifying
direction in which ∆w is moved by the flip of a fair inequality until the system reaches a state of oligarchy.
coin. If the coin comes up heads, Shauna gets 20 per- If the economy is unequal to begin with, the poor-
cent of her wealth from Eric; if the coin comes up tails, est agent’s wealth will probably decrease the fastest.
she must give 17 percent of it to Eric. Now randomly Where does it go? It must go to wealthier agents
choose another pair of agents from the total of 1,000 because there are no poorer agents. Things are not
and do it again. In fact, go ahead and do this a million much better for the second-poorest agent. In the long
times or a billion times. What happens? run, all participants in this economy except for the
If you simulate this economy, a variant of the yard very richest one will see their wealth decay exponen-
sale model, you will get a remarkable result: after a tially. In separate papers in 2015 my colleagues and I
large number of transactions, one agent ends up as an at Tufts University and Christophe Chorro of Univer-
“oligarch” holding practically all the wealth of the econ- sité Panthéon-Sorbonne provided mathematical
omy, and the other 999 end up with virtually nothing. proofs of the outcome that Chakraborti’s simulations
It does not matter how much wealth people started had uncovered—that the yard sale model moves
with. It does not matter that all the coin flips were abso- wealth inexorably from one side to the other.
lutely fair. It does not matter that the poorer agent’s Does this mean that poorer agents never win or that
expected outcome was positive in each transaction, richer agents never lose? Certainly not. Once again, the
whereas that of the richer agent was negative. Any sin- setup resembles a casino—you win some and you lose
gle agent in this economy could have become the oli- some, but the longer you stay in the casino, the more
garch—in fact, all had equal odds if they began with likely you are to lose. The free market is essentially a
equal wealth. In that sense, there was equality of oppor- casino that you can never leave. When the trickle of
tunity. But only one of them did b ecome the oligarch, wealth described earlier, flowing from poor to rich in
and all the others saw their average wealth decrease each transaction, is multiplied by 7.7 billion people in
toward zero as they conducted more and more transac- the world conducting countless transactions every year,
tions. To add insult to injury, the lower someone’s the trickle becomes a torrent. Inequality inevitably
wealth ranking, the faster the decrease. grows more pronounced because of the collective
This outcome is especially surprising because it effects of enormous numbers of seemingly innocuous
holds even if all the agents started off with identical but subtly biased transactions.
wealth and were treated symmetrically. Physicists
describe phenomena of this kind as “symmetry break- THE CONDENSATION OF WEALTH
ing” [see box on page 76]. The very first coin flip trans- You might, of course, wonder how this model, even if
mathematically accurate, has any-
thing to do with reality. After all, it de
scribes an entirely unstable economy
that inevitably degenerates to com-
plete oligarchy, and there are no com-
plete oligarchies in the world. It is
true that, by itself, the yard sale model
is unable to explain empirical wealth
distributions. To address this defi-
ciency, my group has refined it in
three ways to make it more realistic.
In 2017 Adrian Devitt-Lee, Merek
Johnson, Jie Li, Jeremy Marcq, Hong-
yan Wang and I, all at Tufts, incorpo-
rated the redistribution of wealth. In
keeping with the simplicity desirable
in applied mathematics models, we
did this by having each agent take a
step toward the mean wealth in the
society after each transaction. The
size of the step was some fraction χ
(or “chi”) of his or her distance from
the mean. This is equivalent to a flat
wealth tax for the wealthy (with tax

Measuring Inequality A Lorenz Curves

In the early 20th centuryAmerican economist Max O. Lorenz 1.00
Cumulative Wealth (fraction of total)

designed a useful way to quantify wealth inequality. He Absolute equality
proposed plotting the fraction of wealth held by individuals (Gini coefficient = 0)
with wealth less than w against the fraction of individuals
0.75 U.S. (2016)
with wealth less than w. Because both quantities are fractions
ranging from zero to one, the plot fits neatly into the unit (Gini coefficient = 0.86)
square. Twice the area between Lorenz’s curve and the
diagonal is called the Gini coefficient, a commonly used mea 0.50
sure of inequality.
Let us first consider the egalitarian case. If every individual
has exactly the same wealth, any given fraction of the popu
0.25 Extreme inequality
lation has precisely that fraction of the total wealth. Hence,
(Gini coefficient = 1)
the Lorenz curve is the diagonal (green line in A ), and the
Gini coefficient is zero. In contrast, if one oligarch has all the
wealth and everybody else has nothing, the poorest fraction ƒ 0
of the population has no wealth at all for any value of ƒ that is 0 0.25 0.50 0.75 1.00
less than one, so the Lorenz curve is pegged to zero. But Cumulative Population (fraction of total)
when ƒ e quals one, the oligarch is included, and the curve
suddenly jumps up to one. The area between this Lorenz
B Empirical Data Compared to the Affine Wealth Model (AWM)
curve (orange line) and the diagonal is half the area of the
square, or ½, and hence the Gini coefficient is one. U.S. 1989 U.S. 2016
Gini coefficient = 0.79 Gini coefficient = 0.86
In sum, the Gini coefficient can vary from zero (absolute 1
Cumulative Wealth
equality) to one (oligarchy). Unsurprisingly, reality lies Empirical data

between these two extremes. The red line shows the actual AWM
Lorenz curve for U.S. wealth in 2016, based on data from the
Federal Reserve Bank’s Survey of Consumer Finances. Twice
the shaded area (yellow) between this curve and the diagonal
is approximately 0.86—among the highest Gini coefficients in 0
the developed world. Germany 2010 Greece 2010
The four small figures in B show the fit between the Gini coefficient = 0.76 Gini coefficient = 0.55
1
Cumulative Wealth
affine wealth model (AWM) and actual Lorenz curves for the
U.S. in 1989 and 2016 and for Germany and Greece in 2010.
The data are from the Federal Reserve Bank (U.S., as men
tioned above) and the European Central Bank (Germany and
Greece). The discrepancy between the AWM and Lorenz
curves is less than a fifth of a percent for the U.S. and less 0
than a third of a percent for the European countries. The Gini 0 1 0 1
coefficient for the U.S. (shown in plot) increased between 1989 Cumulative Population Cumulative Population
and 2016, indicating a rise in inequality. —B.B.
SOURCE: FEDERAL RESERVE BANK’S SURVEY OF CONSUMER FINANCES (U.S. empirical
rate χ per unit time) and a complementary subsidy for tages such as payday lenders and a lack of time to shop
the poor. In effect, it transfers wealth from those for the best prices. As James Baldwin once observed,
above the mean to those below it. We found that this “Anyone who has ever struggled with poverty knows
simple modification stabilized the wealth distribution how extremely expensive it is to be poor.” Accordingly,
data); EUROPEAN CENTRAL BANK (German and Greek empirical data)
so that oligarchy no longer resulted. And astonishing- in the same paper mentioned above, we factored in
ly, it enabled our model to match empirical data on what we call wealth-attained advantage. We biased the
U.S. and European wealth distribution between 1989 coin flip in favor of the wealthier individual by an
and 2016 to better than 2 percent. The single parame- amount proportional to a new parameter, ζ (or “zeta”),
ter χ seems to subsume a host of real-world taxes and times the wealth difference divided by the mean wealth.
subsidies that would be too messy to include separate- This rather simple refinement, which serves as a proxy
ly in a skeletal model such as this one. for a multitude of biases favoring the wealthy, improved
In addition, it is well documented that the wealthy agreement between the model and the upper tail of
enjoy systemic economic advantages such as lower actual wealth distributions.
interest rates on loans and better financial advice, The inclusion of wealth-related bias also yields—
whereas the poor suffer systemic economic disadvan- and gives a precise mathematical definition to—the
Graphics by Jen Christiansen November 2019, ScientificAmerican.com 75

phenomenon of partial oligarchy. Whenever the influ-

ence of wealth-attained advantage exceeds that of re-
distribution (more precisely, whenever ζ exceeds χ), a The Physics of Inequality
vanishingly small fraction of people will possess a fi-
When water boils at 100 degrees Celsiusand turns into water
nite fraction, 1 – χ/ζ, of societal wealth. The onset of
vapor, it undergoes a phase transition—a sudden and dramatic
partial oligarchy is in fact a phase transition for an-
change. For example, the volume it occupies (at a given pressure)
other model of economic transactions, as first de-
increases discontinuously with temperature. Similarly, the strength
scribed in 2000 by physicists Jean-Philippe Bouchaud,
of a ferromagnet falls to zero (orange line in A ) as its temperature
now at École Polytechnique, and Marc Mézard of the
increases to a point called the Curie temperature, Tc . At tempera
École Normale Supérieure. In our model, when ζ is
tures above Tc , the substance has no net magnetism. The fall to
less than χ, the system has only one stable state with
zero magnetism is continuous as the temperature approaches Tc
no oligarchy; when ζ exceeds χ, a new, oligarchical
from below, but the graph of magnetization versus temperature
state appears and becomes the stable state [see box on
has a sharp kink at Tc .
preceding page]. The two-parameter (χ and ζ) extend-
Conversely, when the temperature of a ferromagnet is reduced
ed yard sale model thus obtained can match empirical
from above to below Tc , magnetization spontaneously appears
data on U.S. and European wealth distribution be-
where there had been none. Magnetization has an inherent spatial
tween 1989 and 2016 to within 1 to 2 percent.
orientation—the direction from the south pole of the magnet to the
Such a phase transition may have played a crucial
north pole—and one might wonder in which direction it develops.
role in the condensation of wealth following the
In the absence of any external magnetic field that might indicate a
breakup of the Soviet Union in 1991. The imposition of
preferred direction, the breaking of the rotational symmetry is
what was called shock therapy economics on the for-
“spontaneous.” (Rotational symmetry is the property of being identi
mer states of the U.S.S.R. resulted in a dramatic de-
cal in every orientation, which the system has at temperatures
crease of wealth redistribution (that is, decreasing χ)
above T c .) That is, magnetization shows up suddenly, with the
by their governments and a concomitant jump in
direction of the magnetization being random (or, more precisely,
wealth-attained advantage (increasing ζ) from the
dependent on microscopic fluctuations beyond our idealization of
combined effects of sudden privatization and deregu-
the ferromagnet as a continuous macroscopic system).
lation. The resulting decrease of the “temperature” χ/ζ
Economic systems can also exhibit phase transitions. When the
threw the countries into a wealth-condensed state, so
wealth-bias parameter ζ of the affine wealth model is less than the
that formerly communist countries became partial
redistribution parameter χ, the wealth distribution is not even par
oligarchies almost overnight. To the present day at
tially oligarchical (blue area in B ). When ζ exceeds χ, however, a
least 10 of the 15 former Soviet republics can be accu-
finite fraction of the wealth of the entire population “condenses”
rately described as oligarchies.
into the hands of an infinitesimal fraction of the wealthiest agents.
As a third refinement, in 2019 we included nega-
The role of temperature is played by the ratio χ/ζ, and wealth con
tive wealth—one of the more disturbing aspects of
densation shows up when this quantity falls below one.
modern economies—in our model. In 2016, for exam-
Another subtle symmetry exhibited by complex macroscopic
ple, approximately 10.5 percent of the U.S. population
systems is “duality,” which describes a one-to-one correspondence
was in net debt because of mortgages, student loans
between states of a substance above and below the critical temper
and other factors. So we introduced a third parameter,
ature, at which the phase transition occurs. For ferromagnetism, it
κ (or “kappa”), which shifts the wealth distribution
relates an ordered, magnetized system at temperature T below T c
downward, thereby accounting for negative wealth.
to its “dual”—a disordered, unmagnetized system at the so-called
We supposed that the least wealth the poorest agent
inverse temperature, (Tc )2/T , which is above T c . The critical temper
could have at any time was –S, where S equals κ times
ature is where the system’s temperature and the inverse tempera
the mean wealth. Prior to each transaction, we loaned
ture cross (that is, T =(Tc )2/T ).Duality theory plays an increasingly
wealth S to both agents so that each had positive
wealth. They then transacted according to the extend-
ed yard sale model, described earlier, after which they
both repaid their debt of S.
The three-parameter (χ, ζ, κ) model thus obtained, better than a third to a half of a percent [see box above].
called the affine wealth model, can match empirical To obtain these comparisons with actual data, we
data on U.S. wealth distribution to less than a sixth had to solve the “inverse problem.” That is, given the
of a percent over a span of three decades. (In mathe- empirical wealth distribution, we had to find the val-
matics, the word “affine” describes something that ues of (χ, ζ, κ) at which the results of our model most
scales multiplicatively and translates additively. In closely matched it. As just one example, the 2016 U.S.
this case, some features of the model, such as the val- household wealth distribution is best described as
ue of ∆w, scale multiplicatively with the wealth of the having χ = 0.036, ζ = 0.050 and κ = 0.058. The affine
agent, whereas other features, such as the addition wealth model has been applied to empirical data from
or subtraction of S, are additive translations or dis- many countries and epochs. To the best of our knowl-
placements in “wealth space.”) Agreement with Euro- edge, it describes wealth-distribution data more accu-
pean wealth-distribution data for 2010 is typically rately than any other existing model.

enormous extent to which wealth distribution is

caused by symmetry breaking, chance and early ad
A Phase Change in a Ferromagnet vantage (from, for example, inheritance). And the
presence of symmetry breaking puts paid to argu-
Magnetization
Strong No net magnetism ments for the justness of wealth inequality that appeal
to “voluntariness”—the notion that individuals bear
all responsibility for their economic outcomes simply
Magnetized because they enter into transactions voluntarily—or
to the idea that wealth accumulation must be the
Weak Curie point result of cleverness and industriousness. It is true that
0 an individual’s location on the wealth spectrum corre-
lates to some extent with such attributes, but the over-
Low Curie temperature High
all shape of that spectrum can be explained to better
Temperature
than 0.33 percent by a statistical model that complete-
B Phase Transition in Economic Systems ly ignores them. Luck plays a much more important
role than it is usually accorded, so that the virtue com-
Wealth-Bias Parameter ζ
2.0 Greece
Spain Slovenia monly attributed to wealth in modern society—and,
Partial oligarchy Belgium
1.5 Malta Netherlands likewise, the stigma attributed to poverty—is com-
Italy pletely unjustified.
Lithuania
1.0 Finland Moreover, only a carefully designed mechanism for
Portugal redistribution can compensate for the natural tenden-
France
0.5 No oligarchy cy of wealth to flow from the poor to the rich in a mar-
Cyprus
0 Austria Germany ket economy. Redistribution is often confused with
taxes, but the two concepts ought to be kept quite sep-
0 0.5 1.0 1.5 2.0 arate. Taxes flow from people to their governments to
Wealth-Redistribution Parameter χ finance those governments’ activities. Redistribution,
in contrast, may be implemented by governments, but
it is best thought of as a flow of wealth from people to
people to compensate for the unfairness inherent in
important role in theoretical physics, including in quantum gravity.
market economics. In a flat redistribution scheme, all
Like ferromagnetism, the affine wealth model exhibits duality, as
those possessing wealth below the mean would re
proved by Jie Li and me in 2018. A state with ζ < χ is not a partial oli
ceive net funds, whereas those above the mean would
garchy, whereas a corresponding state with this relation reversed—
pay. And precisely because current levels of inequality
that is, with the “temperature” χ / ζ inverted to ζ /χ—is. Interestingly,
are so extreme, far more people would receive than
these two dual states have exactly the same wealth distribution if
would pay.
the oligarch is removed from the wealth-condensed economy (and
Given how complicated real economies are, we find it
the total wealth is recalculated to account for this loss).
gratifying that a simple analytical approach developed
Significantly, most countries are very close to criticality. A plot
by physicists and mathematicians describes the actual
of 14 of the countries served by the European Central Bank in the
wealth distributions of multiple nations with unprece-
χ-ζ plane in B shows that most lie near the diagonal. All except
dented precision and accuracy. Also rather curious is
one (the Netherlands) lie just above the diagonal, indicating that
that these distributions display subtle but key features of
they are just slightly oligarchical. It may be that inequality naturally
complex physical systems. Most important, however, the
increases until oligarchies begin to form, at which point political
fact that a sketch of the free market as simple and plau-
pressures set in, preventing further reduction of equality.—B.B.
sible as the affine wealth model gives rise to economies
that are anything but free and fair should be both a
cause for alarm and a call for action.
TRICKLE UP
We find it noteworthy t hat the best-fitting model for MORE TO EXPLORE
empirical wealth distribution discovered so far is one A Nonstandard Description of Wealth Concentration in Large-Scale
that would be completely unstable without redistribu- Economies. A drian Devitt-Lee et al. in S IAM Journal on Applied Mathematics,
Vol. 78, No. 2, pages 996–1008; March 2018.
tion rather than one based on a supposed equilibrium The Affine Wealth Model: An Agent-Based Model of Asset Exchange
EUROPEAN CENTRAL BANK (c ountry data)
of market forces. In fact, these mathematical models That Allows for Negative-Wealth Agents and Its Empirical Validation.
SOURCE: BRUCE M. BOGHOSIAN;
demonstrate that far from wealth trickling down to Jie Li et al. in P hysica A: Statistical Mechanics and Its Applications, V
ol. 516,
the poor, the natural inclination of wealth is to flow pages 423–442; February 2019.
upward, so that the “natural” wealth distribution in a FROM OUR ARCHIVES
free-market economy is one of complete oligarchy. It A Rigged Economy. Joseph E. Stiglitz; November 2018.
is only redistribution that sets limits on inequality.
The mathematical models also call attention to the

RECOMMENDED
By Andrea Gawrylewski
ONE OF DOZENS of decaying bodies studied at the Uni-

The Nature versity of Tennessee’s Anthropological Research Facility.
of Life
and Death:
Every Body
Leaves a Trace
by Patricia Wiltshire.
Putnam, 2019 ($27)
For many, pollen is a nuisance, r esponsible only for sniffles and sneezes. For forensic ecologist Wiltshire, pollen is a portal, transporting her to
the scene of a crime. Microscopic pollen particles that cling to a suspect’s jacket or a victim’s hair can reveal critical clues about a crime scene’s
ecosystem. Using this evidence, Wiltshire can often re-create, in brilliant detail, where a victim spent his or her final moments—often to the
surprise of the detectives working with her. Between gripping case studies, Wiltshire weaves in charming tales from her childhood in Wales and
hard-won lessons on navigating the male-dominated fields of science and law enforcement. —Jennifer Leman
You Look Like a Thing More Things in The Great Pretender:

and I Love You:How Artificial the Heavens: How Infrared The Undercover Mission That Changed
Intelligence Works and Why It’s Astronomy Is Expanding Our Understanding of Madness
Making the World a Weirder Place Our View of the Universe by Susannah Cahalan.
by Janelle Shane. Voracious Books/ by Michael Werner and Peter Eisenhardt. Grand Central Publishing, 2019 ($28)
Little, Brown, 2019 ($28) Princeton University Press, 2019 ($35)
In a famed e xperiment, psy-
Training anAI to write Infrared light f alls to the right chologist David Rosenhan and
pickup lines—the source of visible light on the electro- seven other “pseudopatients”
of this book’s title—might magnetic spectrum, with lon- faked their way into psychiatric
sound frivolous, but the ger wavelengths than what hospitals, claiming to hear
process can illuminate the the eye can see. And because voices. He subsequently published a 1973 paper in
often opaque inner workings of these computer the expansion of the universe stretches the wave- Science detailing how hospital staff pathologized
constructs. Shane is an optics researcher who length of light from distant objects, many of the normal behavior, mistreated patients and kept the
also explores the strange creations of AI systems farthest, oldest things in the cosmos are visible pseudopatients institutionalized for weeks. The
on her blog, and here she brings an analytical only in infrared. The best tool astronomers have paper caused an uproar and confirmed widespread
eye to explain how AIs operate, what problems for seeing the infrared universe is the Spitzer mistrust of the mental health system. Although
they can solve, and what will likely remain too Space Telescope. Launched in 2003, it has Rosenhan’s work influenced the future of psychiatric
hard, or too dangerous, for them to tackle. The glimpsed galaxies, planets, asteroids, and, espe- care in the U.S., his paper did not tell the whole sto-
DAVID HOWELLS Getty Images
programs tend to carry over and enhance bias cially, “the youngest, most distant galaxies yet ry. Writer Cahalan digs deeper—starting with the
from data they are given, for instance, and their discovered,” write Spitzer scientists Werner charismatic Rosenhan and his mysteriously unfin-
black box nature makes it difficult to catch errors and Eisenhardt. Now, before the telescope ished book about the experiment. In her quest to
and misinterpreted goals. Shane’s humorous but shuts down in January 2020, the authors recount track down the facts, Cahalan discovers that some
weighty discussion reveals the promise and peril the major sights that greeted Spitzer’s infrared of Rosenhan’s claims were, at best, overstated and
of an AI future. —Sarah Lewin Frasier eyes on the skies. —Clara Moskowitz may have been completely untrue. —Leila Sloman

THE INTERSECTION Zeynep Tufekci is an associate professor at the University

W H E R E S C IE N C E A N D S O C IE T Y M E E T of North Carolina School of Information and Library Science
and a regular contributor to the New York Times. Her book,
Twitter and Tear Gas: The Power and Fragility of Networked Protest,
was published by Yale University Press in 2017.
Shootings and Indeed, here I am, spreading it. In response to his terrible act,
Herostratus was given the damnatio memoriaetreatment:
Social Contagion
he was removed from all official historical records, and all pub-
lic mention of him was banned. The magnitude of his crime,
however, meant that he eventually found his way to some
It’s the one factor we keep overlooking accounts nonetheless.
Contrast d amnatio memoriaewith our own treatment of
By Zeynep Tufekci mass shooters. Most readers who were old enough when the
Columbine tragedy happened almost certainly know the names
Tragically, more than 20 percentof mass shootings, as tracked of the shooters. It is understandable because when confronted
by the National Institute of Justice for the past 50 years, have with the seemingly unimaginable, we want to understand, so we
occurred in the past five. The past three have been the deadliest. turn our attention to the individuals. Mass shooters’ names and
In the U.S., there is well-deserved attention on the availability of faces dominate the media, and if they leave manifestos, those
guns (because the deadliness of method and ease of access to spread virally as well. Even if they are being condemned, they
weapons matter greatly) and on whether we pay sufficient atten- are noted, remembered and immortalized.
tion to mental health support for troubled young men. Unfortunately, not everyone reacts in horror. The man who
But there is one more factor that is only recently getting some murdered 26 people at an elementary school in Newtown, Conn.,
of the scrutiny it deserves: the role that social contagion plays in an almost unfathomable crime, was obsessed with the fame and
inspiring those troubled individuals to choose this course. People attention the Columbine shooters received. He collected clippings
about their act and downloaded videos and other mate-
rial from other mass shootings, as well as gun suicides.
He then went on to commit his own horror.
This is not an isolated case. We have quantitative
evidence that reveals a spike in such shootings in the
period following extensive mass media coverage of
one, and reports and law-enforcement investigations
show that many shooters study previous shooters, col-
lect news stories about them and study their methods.
In a terrible twist, they even focus on the numbers of
their victims in an effort to up that count—realizing
that the higher the number, the more coverage and
attention they will receive in the “rankings,” so to
speak, as if it were a video-game scoreboard.
None of this is meant to make light of the other
factors—availability of guns or mental health sup-
port—and does not necessarily speak to all mass
shootings, some of which are more akin to terrorism.
It does, however, tell us something important about
ancient wisdom: d amnatio memoriaemay well be
the correct method, as hard as it may seem.
In the modern world, we cannot and should not
routinely underestimate how social humans are. We all have a censor media coverage of the event; however, we can definitely
viewpoint and an inner life, of course. But in the 20 years since change the way we report it and talk about it. Instead of profil-
Columbine and other mass shootings, we can say with increasing ing the murderers, we can focus on the victims; instead of pub-
confidence what is, in retrospect, almost blindingly obvious: the licizing their often incoherent ramblings, we can dismiss the
shooters are inspired by those who came before—and how we content as the pathetic words of murderers, and we can certain-
react to shootings is part of the unfortunate cycle feeding them. ly avoid plastering the faces and the names of the killers on
We can look all the way back to ancient Greece for the arche- media outlets and social media. That will not be a full solution,
type: Herostratus, the arsonist who burned down the second because the other factors need tackling as well, but it is one
Temple of Artemis in Ephesus to immortalize his name, albeit important step in denying these troubled men the one thing
in infamy. As Roman writer Valerius Maximus noted, “A man they seek above almost everything: posthumous infamy.
was found to plan the burning of the temple of Ephesian Diana
so that through the destruction of this most beautiful building Visit Scientific American on Facebook and Twitter
his name might be spread through the whole world.” or send a letter to the editor: editors@sciam.com
82 Scientific American, November 2019 Illustration by Thomas Fuchs

ANTI GRAVITY
Steve Mirsky h as been writing the Anti Gravity column since T H E O N G O IN G S E A R C H F O R
a typical tectonic plate was about 36 inches from its current location. FU N DA M E N TA L FA R C E S
He also hosts the S cientific American p odcast Science Talk.
Chair Man
Cardiovascular disease’s link
to stress sat in plain sight
By Steve Mirsky
Rarely does a speakerat a conference have to
abandon a talk because he’s seasick. But I saw it
happen in August on a S cientific American/Bright
Horizons cruise around the U. K. and Ireland, as
our ship hit rough seas. The nauseated narrator
finished his talk a few days later in calmer waters.
And for the porpoises of this ocean-going column,
all you need to know is that he was not Robert
Sapolsky. I mean purposes.
Sapolsky, a neurobiologist and primatologist
at Stanford University, got through his talks with
no lunch losses. One presentation dealt with the
health effects of chronic stress. “This link between
stress and cardiovascular disease is so solid,” he
said, “that it accounts for themost famous per-
sonality profile in all of medicine.” Type A person-
ality, that is. “And I would guess if you’re using a
cruise to sit and listen to S cientific Americanlec-
tures, this applies to like 80 percent of us in this room.” front two inches of the seat cushion and the arm rests are total-
Sapolsky continued, “Type A was first described by a pair of ly shredded. The rest of the seat is perfectly fine. It’s like every
cardiologists, [Meyer] Friedman and [Ray] Rosenman, in the night there’s dwarf beavers, and they’re clawing at the chairs.
1950s . . . time-pressured, hostile, poor self-esteem, joyless striv- What is this? This is what [a type A person] does when they’re
ing.” The docs announced that these traits actually raise your risk sitting in the waiting room of their cardiologist’s office waiting
of heart disease. to find out if there’s bad news. Not just figuratively but literally
“[Other] cardiologists hated these guys. You’re some 1950s sitting on the edge of their seat and clawing and squirming.
cardiologist, all you think about is Ozzie and Harriet and heart “So what’s supposed to happen at this point if things worked
valves ... and instead here’s these guys saying, ‘No, you need to right: Friedman grabs him and says, ‘Good God, man, what you’ve
sit down your patients and talk to them.’ Who wants to talk to discovered!’ [And there are] midnight conferences between uphol-
their patients?!” Indeed, the happiest doctors I have ever met sterers and cardiologists. And [there are] teams of idealistic young
are pathologists. upholsterers going across America and coming back with the news
“It wasn’t till the 1980s that there were enough data in for peo- that, no, you don’t find chairs like these in podiatrists’ offices.”
ple to say type A is for real,” Sapolsky said. “It is a bigger risk fac- What did the nonagenarian Friedman tell Sapolsky he actually
tor for cardiovascular disease than if you smoke, than if you are did back in the 1950s? “He said, ‘I told my nurse ... get this man out
overweight, than if you have elevated cholesterol levels.” of my face, he’s wasting time, give him his damn check.’ Hewas too
So how did Friedman and Rosenman identify this condition? type A to listen to the guy. And it wasn’t until five years later, they
“I actually got to hear this story from the horse’s mouth himself, were collaborating with psychologists, out popped the type A pro-
Meyer Friedman,” Sapolsky said. “He and his partner had this file, and they said, ‘Oh, my God, the upholsterer, he was right!’
cardiology practice in San Francisco—everything was going “To this date, they have no idea who that man was. Now I’m
great. They had this one problem, though. For some reason, they willing to bet ... go to some bar in the Mission District in San Fran-
were wearing out chairs in the waiting room at an incredibly cisco, and there’s gonna be this 110-year-old retired upholsterer.
high rate.... Every month this upholsterer comes in, fixes a chair And get him started, and he’s gonna go on and on about how he
or two. One month the upholsterer is on vacation. A replacement discovered type A personality.” And in so doing—you might want
upholsterer comes in, takes one look at the chairs and discovers to take a seat yourself for this—changed the fabric of medicine.
type A personality. He says, ‘What is wrong with your patients?
Nobody wears out chairs this way.’ ”
Sapolsky then showed a photograph of one of the chairs, Visit Scientific American on Facebook and Twitter
which you can see in his book Why Zebras Don’t Get Ulcers.“The or send a letter to the editor: editors@sciam.com
Illustration by Matt Collins November 2019, ScientificAmerican.com 83

50, 100 & 150 YEARS AGO S cienti f ic A m erican O N L I N E

FIND ORIGINAL ARTICLES AND IMAGES IN
IN N OVATI O N A N D D I S C OV E RY A S C H R O NI C L E D IN S c ientific A meric an THE Scientific American ARCHIVES AT
Compiled by Daniel C. Schlenoff scientificamerican.com/magazine/sa
NOVEMBE R
1969 Lung
Support
“Respiratory failure is now revers-
1919 Merry
Mountaineers
“France’s task of beating swords
propagated disease, while as a pre-
vention of mortality from small-
pox, it was utterly inefficient.
ible in a large percentage of cases if into ploughshares included the This article represented views
proper treatment is provided. Such conversion of tanks into some- now entertained by many upon
treatment is available in respirato- thing having peacetime value. this subject. The London L ancet
ry intensive-care units: properly Some have been employed for in an article in favor of vaccina-
equipped hospital facilities direct- 1969 towing canal barges; others have tion makes the following remarks:
ed by a new kind of medical spe- become agricultural tractors; oth- ‘The fact is, that the only people
cialist, the intensivist, and manned ers have made their way into the injured by the Compulsory Vacci-
by teams of trained physicians. The factory. But the most novel con- nation Act are medical men.
increasing capability of respiratory version is no doubt that of the There is no disease which pays
intensive care is the result of an in mountain-climbing tanks, now medical men better than small-
creasing discourse between respi- available to tourists of the French pox. A good attack of it makes
ratory physiologists and physicians Alps of Savoy. Shorn of its coat of man, or child, a patient for a
who treat patients. Data that have armor and its fighting equipment, solid month.’”
long been available are now being 1919 and provided with seats, it be
brought to bear through active comes an excellent passenger-car- “Cardiff Giant” Hoax
intervention to preserve the life of rying vehicle for traversing rough “Letter of John F. Boynton, Geolo-
critically ill patients. Treatment of terrain. Our illustration offers gist, to Prof. Henry Morton, of the
acute respiratory failure is proba- some idea of the thrills of a ride Pennsylvania University: ‘Dear Sir:
bly as close to being a quantitative in the mountain-climbing tank.” On Saturday last, some laborers
science as any field of clinical medi- engaged in digging a well on the
cine can be today. In this situation, The Unemployed Horse farm of W. C. Newell, near the vil-
precise measurement approaches “Professional horse-breeders still lage of Cardiff, about 13 miles
or exceeds in importance the ‘clini- 1869 boost for the business; but they are south of this city, discovered, lying
cal judgment’ that for so many merely whistling to keep up their about three feet below the surface
years has been the prime quality courage. The days of the horse as of the earth, what they supposed
of the good physician.” a beast of burden are numbered. to be the ‘petrified body’ of a
The automobile is taking the human being of colossal size. Its
place of the carriage horse; the length is ten feet and three inches,
truck is taking the place of the dray and the rest of the body is propor-
horse; and the farm tractor the tionately large. The excitement
place of the farm horse. Nor is in this locality over the discovery
there any cause to bemoan this is immense and unprecedented.
state of affairs. We all admit that Thousands have visited the locali-
the horse is one of the noblest of ty within the last three days.
animals; and that is a very good On a careful examination, I am
reason why we should rejoice at his convinced that it is not a fossil,
prospective emancipation from a but was cut from a piece of strati-
life of servitude and suffering. That, fied sulphate of lime. It was quar-
of course, is the humanitarian side ried, probably, somewhere in this
of it; the business side is more to county [Onondaga, N.Y.], from our
the point: the machine is going to Gypsum beds. My conclusion
do the hard work of the world regarding the object of the deposit
SCIENTIFIC AMERICAN, VOL. CXXI, NO. 21; NOVEMBER 22, 1919
much easier and much cheaper of the statue in this place is as fol-
than it ever has been done. At least lows: It was for the purpose of
50 percent of the horses will have hiding and protecting it from an
been laid off by January 1st, 1920.” enemy who would have destroyed
it, had it been discovered.’”
1869 Vaccination
“A long article
recently appeared in the N
The statue had actually been sculpted
the year before under the direction
ew York of one George Hull as either a joke
1919: A former military tank gets repurposed as Times, taking the strongest ground or a hoax and buried on the property
an all-terrain vehicle for the amusement of tourists. against vaccination, urging that it of his relative William C. Newell.

GRAPHIC SCIENCE
Text by Mark Fischetti | Graphic by Pitch Interactive
Climate Clincher
The argument that global warming is part of a natural cycle is dead
People who dismiss c limate change often lated regions at a given time—never the 1000s and in central South America
claim that the earth’s warm-up is simply across the entire globe simultaneously in the 1200s. But the current warm-up
part of “natural climate variability.” A pa B . For example, the so-called Little Ice has taken place across 98 percent of the
per published in July in N
atureputs that Age occurred in the 1400s across the cen- globe at the same time, from about 1900
argument to rest. The authors show that tral Pacific Ocean, in the 1600s across through today. “It’s completely different,”
warm and cold years were regularly in northwestern Europe and in the mid- states lead researcher Raphael Neukom
terspersed during the past 2,000 years 1800s in other places. The warm Medi- of the University of Bern in Switzerland.
A and that even the warmest and cold- eval Climate Anomaly occurred in the All regions have heated up relentlessly,
est periods were experienced only by iso- Pacific in the 900s, in North America in in unison.
A In almost every year from a.d. 0 to 1950, portions of the earth have been Temperature Anomaly (degrees C vs. average from year 0 to 2000)
warmer or cooler than average. But since 1950 or so, almost all years have been
overwhelmingly warmer, and the temperature rise (red) has been far greater. −1.2 −0.8 −0.4 0 0.4 0.8 1.2
100
Percent of Earth’s Surface (annual)
50
SOURCE: “NO EVIDENCE FOR GLOBALLY COHERENT WARM AND COLD PERIODS OVER THE PREINDUSTRIAL COMMON ERA,” BY RAPHAEL NEUKOM ET AL., IN NATURE, VOL. 571; JULY 25, 2019
0
50
100
Year: 0 200 400 600 800 1000 1200 1400 1600 1800 2000
B Six hundred analyses of 210 data sets from corals, glacier ice, lake sediments and other temperature markers worldwide are
shown by icons. Only some coalesce during any time period from a.d. 0 to 1950; at most, 70 percent of the earth warmed or cooled.
Since 1950, however, all 600 reconstructions have lined up; 98 percent of the planet has warmed at once—an unnatural variation.
Roman Warm Period Medieval Climate Anomaly Current Warm Period

North America, South Pacific Pacific North Central South
100 Europe Ocean Ocean America America 100
Percent of Earth’s Surface,
Averaged over 51 Years (color-filled curves)
Percent of Earth’s Surface Simultaneously

Experiencing the Warmest or Coldest 51-Year Span
(height of gray icons) within a Time Period
50 50
0 0
50 50
Australia, Southern Ocean North America, Atlantic Ocean Central Pacific Northwestern Asia,
Icon shapes represent six different analysis methods Ocean Europe Australia
100 100
Dark Ages Cold Period Little Ice Age
Year: 0 200 400 600 800 1000 1200 1400 1600 1800 2000

OUTLOOK
INFLUENZA
Produced with support from:

Science targets
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The week’s best science,

from the world’s leading science journal.
NATURE.COM/NATURE/PODCAST
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9/10/19 1:43
3:10PM
PM
OUTLOOK
INFLUENZA
F
or a disease that can resemble the common cold,
influenza packs a powerful — and sometimes lethal — CONTENTS
punch. As many as half-a-million people around the
world die annually from flu. The culprit is a virus that mutates
S4 PREVENTION
to evade our immune systems, leaving vaccines and therapies A shot for all seasons
scrambling to keep up. In some years, a mutation creates a The hunt for a universal flu vaccine
pathogen that is particularly nasty, resulting in pandemic S7 Q&A
flu. Last year marked 100 years since the 1918 ‘Spanish flu’ Resistance in the wild
Cover art: Antoine Doré pandemic, which killed at least 50 million people worldwide. Josef Järhult discusses how flu viruses
In 2009, another pandemic swept across the world at develop drug resistance in rivers
Editorial frightening speed, and in 2017–18 so-called seasonal flu (not S8 THERAPEUTICS
Herb Brody, Richard considered a pandemic) hit hard in the United States. A bigger arsenal
Hodson, Elizabeth More antiviral drugs are on the way
Batty, Nick Haines
Vaccines are the first line of defence against flu. Researchers
Art & Design
have made it a top priority to develop a vaccine that protects S10 DIAGNOSTICS
Mohamed Ashour, against as many strains of the virus as possible (see page S4). A sticking point for rapid flu tests?
Andrea Duffy, And because speed is of the essence in mounting a response Rapid molecular tests have slow uptake
Denis Mallet, S12 SURVEILLANCE
Wesley Fernandes
to flu, new methods are being pursued to speed up vaccine
production (S14). If prevention fails, there is only a limited The social forecast
Production Tackling flu requires accurate
Nick Bruni, Karl arsenal of antiviral drugs to treat flu, although researchers are predictions of its spread
Smart, Ian Pope, working to develop more (S8). But it is a never-ending battle,
Kay Lewis as the wily virus mutates its way to resistance (S7). S14 VACCINES
Sponsorship Breaking out of the egg
Marlene Stewart,
Treatment, of course, depends on diagnosis. For individual The race for faster vaccine production
Claudia Danci patients, molecular tests can now give conclusive results
S16 AGRICULTURE
Marketing more quickly than older methods, but adoption of the new Flu on the farm
Nicole Jackson tests has been slow, partly because of their high cost (S10). Farm animals are a major source of
Project Manager On a public-health level, it is important to know when and influenza pandemics
Rebecca Jones
where an outbreak is under way — a task made easier by
Creative Director
Wojtek Urbanek
information technology (S12). And because some of the most
Publisher
dangerous flu viruses make the leap from animals to humans,
Richard Hughes researchers are studying how to monitor the disease on farms
VP, Editorial and in wild bird populations (S16).
Stephen Pincock We are pleased to acknowledge the financial support of
Managing Editor Sanofi Pasteur in producing this Outlook. As always, Nature
David Payne
retains sole responsibility for all editorial content.
Magazine Editor
Helen Pearson
Editor-in-Chief Herb Brody
Magdalena Skipper Chief supplements editor
Nature Outlooks are sponsored supplements that aim to stimulate available for 6 months.
interest and debate around a subject of interest to the sponsor, SUBSCRIPTIONS AND CUSTOMER SERVICES
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This special report first appeared in Nature
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CITING THE OUTLOOK com. Personal subscriptions: UK/Europe/ROW, subscriptions@ [26 September 2019 | Vol. 573 | Issue No. 7775].
Cite as a supplement to Nature, for example, Nature Vol. XXX, nature.com; USA/Canada/Latin America, subscriptions@ Internal references may vary from
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OUTLOOK INFLUENZA
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so vaccinations
vaccinations are are impor-
impor- opmentof
opment oftechnologies
technologiesfor forinvestigating
investigatingthe the
Sometimesthese
Sometimes thesesubtypes
subtypesabruptly
abruptlyacquire
acquirethethe
tant.The
tant. Theproblem
problemisisthatthatflu
fluvaccines
vaccinesdeliver
deliver humanresponse
human responseto toinfluenza.
influenza.“Around
“Around2008 2008oror
abilityto
ability toinfect
infecthumans,
humans,leadingleadingto topandemics
pandemics
inconsistentperformance.
inconsistent performance.“In “Inaagood
goodseason,
season, 2009,people
2009, peoplestarted
startedfinding
findingaafew fewbroadly
broadlyneu-neu-
suchas
such asthe
theoneoneinin2009.
2009.EachEachyear
yearthetheseasonal
seasonal
GOPAL
we’reup
we’re uptoto60%
60%effectiveness,
effectiveness,but butin inbad,
bad,mis-
mis- tralizingantibodies
tralizing antibodiesagainst
againstthetheinfluenza
influenzavirus,
virus,””
fluvaccine
flu vaccineisisdesigned
designedto tocover
covertwo twostrains
strains
matchedyears
matched yearsititcan
canbebeasaslow
lowas as10%
10%or or20%,
20%,”” saysIan
says IanWilson,
Wilson,aastructural
structuralbiologist
biologistspecializ-
specializ-
eachof
each ofinfluenza
influenzaAAand andB, B,based
basedon onthethepublic-
public-
saysBarney
says BarneyGraham,
Graham,deputydeputydirector
directorof ofthe
the ingin
ing invaccine
vaccinedevelopment
developmentatatScripps
ScrippsResearch
Research
healthcommunity’s
health community’sbest bestinformed
informedguess guessabout
about
VaccineResearch
Vaccine ResearchCenter
Centerat atthe
theUS USNational
National Institutein
Institute inLaLaJolla,
Jolla,California.
California.“Once
“Oncepeople
people
whichstrains
which strainswill
willbebedominant
dominantthat thatyear.
year.
Instituteof
Institute ofAllergy
Allergyand andInfectious
InfectiousDiseases
Diseases startedlooking,
started looking,many
manymoremorewere
werediscovered.
discovered.””Every influenza
Every influenza virus virus isis studded
studded with with
(NIAID)in
(NIAID) inBethesda,
Bethesda,Maryland.
Maryland. Now,around
Now, around100 100years
yearsafter
afterthethe‘Spanish
‘Spanish
hundredsof
hundreds ofmolecular
molecularstructures
structuresformed
formedby byaa
Currentflu
Current fluvaccines
vaccinesprovide
provideprotection
protectiononly only flu’pandemic
flu’ pandemicof of1918
1918that
thatkilled
killedabout
about50 50mil-
mil-
multifunctional
multi functionalprotein
proteincalled
calledhaemagglutinin.
haemagglutinin.
againstthe
against thestrains
strainsthey
theyhave
havebeenbeenmatched
matched lionpeople,
lion people,multiple
multipleuniversal-vaccine
universal-vaccinepro- pro-
Haemagglutininhelps
Haemagglutinin helpsthe thevirus
virusto tobind
bindandand
to,so
to, soaa‘universal’
‘universal’flu fluvaccine
vaccinethat thatprovides
provides grammesare
grammes aredemonstrating
demonstratingpromise promisein inboth
both
penetratehost
penetrate hostcells.
cells.ItItcomprises
comprisesaabulky bulkyhead
head
broader protection
broader protection against
against most
most influenza
influenza preclinicaland
preclinical andclinical
clinicaltesting.
testing.ButButititremains
remains
attachedto
attached tothe
thevirus
virusby byaaslender
slenderstalk.
stalk.Most
Most
viruses has
viruses has been
been aa long-standing
long-standing dream. dream. tobe
to beseen
seenwhether
whetherany anywill
willultimately
ultimatelydeliver
deliver
ofthe
of theimmune
immuneresponse
responseisistargeted
targetedatatthethehead
head
The2009
The 2009swine-flu
swine-flupandemic,
pandemic,which whichcaught
caught thebroad
the broadprotection
protectionthat thatclinicians
cliniciansseek.
seek. becauseititisishighly
because highlyexposed,
exposed,but butthere
thereisisalso
also
thepublic-health
the public-healthcommunity
communityoff offguard
guardandand evidencethat
evidence thatthethehead
headcontains
containsfeatures
featuresthatthat
claimedthe
claimed thelives
livesofofas
asmany
manyas ashalf-a-million
half-a-million AAVARIABLE
VARIABLEVIRUS
VIRUS preferentiallyelicit
preferentially elicitaastrong
strongantibody
antibodyresponse.
response.
peopleworldwide,
people worldwide,gave gavethetheissue
issuenewnewurgency.
urgency. Peter Palese,
Peter Palese, aa microbiologist
microbiologist at
at the
the Icahn
Icahn “There
“Thereare arestructured
structuredloops,loops,and andantibodies
antibodies
“The2009
“The 2009pandemic
pandemicmade madeititobvious
obviousand and School of
School of Medicine
Medicine atat Mount
Mount Sinai
Sinai inin New
New easily
easilyrecognize
recognizeloops loopsthatthatstick
stickout
outlike
likethat,
that,””
clearthat
clear thatwewedidn’t
didn’thave
havegood
goodenough
enoughsolu- solu- YorkCity,
York City,believes
believesthat
thattoday’s
today’sflu
fluvaccines
vaccines explains
explainsJames
JamesCrowe,
Crowe,director
directorof ofthe
theVander-
Vander-
tionsfor
tions forinfluenza
influenzavaccines,”
vaccines,”says saysGraham.
Graham. come in
come in for
for too
too much
much criticism.
criticism. “They
“They areare bilt
biltVaccine
VaccineCenter
Centerin inNashville,
Nashville,Tennessee.
Tennessee.
“We knew
“We knew the the virus,
virus, but
but we we weren’t
weren’t able able fairlygood
fairly goodvaccines
vaccinesbut
butthey’re
they’renot
notperfect,
perfect,”” Unfortunately,
Unfortunately,these theseimmunodominant
immunodominantele- ele-
to make
to make enough
enough vaccine
vaccine quickly
quickly enough.”
enough.” hesays.
he says.The
Themain
mainproblem,
problem,he headds,
adds,isisthat
that ments
mentsarearealso
alsohighly
highlyvariable
variablebetween
betweenstrains.
strains.
SS44

INFLUENZA OUTLOOK
INFLUENZA OUTLOOK
InfluenzaAAviruses
Influenza virusesare areparticularly
particularlydiverse. diverse. generatednanoparticles
generated nanoparticlesdisplaying
displayingmultiple
multiple onhaemagglutinin
on haemagglutininthat thatcancanbe beexploited
exploitedto to
Theyare
They areclassified
classifiedby bynumbers
numbersbased basedon onthe
the copiesof
copies ofthese
theseengineered
engineeredstems stemsand showed11
andshowed achievefar-reaching
achieve far-reachingvirus virusneutralization
neutralizationfor for
subtypeof
subtype ofhaemagglutinin
haemagglutinin(H) (H)protein
proteinand and that these could generate strong
that these could generate strong protection protection bothprevention
both preventionand andtreatment.
treatment.
aasecond
secondviral viralprotein
proteinknown knownas asneuramini-
neuramini- againstentirely
against entirelydifferent
differentsubtypes
subtypesof ofinflu-
influ- Insome
In somecases casesthese
thesesearches
searcheshavehaverevealed
revealed
dase(N),
dase (N),with witheven evengreater
greaterstrain strainvariation
variation enzaA,
enza A,such
suchas asH5
H5— —at atleast
leastininanimal
animalmod- mod- unexpectedvulnerabilities
unexpected vulnerabilitiesin inthe
thevirus.
virus.Hae-
Hae-
observedamong
observed amongthose thosesubtypes.
subtypes.For Forexample,
example, els.This
els. Thisvaccine
vaccinedesign
designisisnow nowundergoing
undergoing magglutininnormally
magglutinin normallyassembles
assemblesinto intohighly
highly
the2009
the 2009pandemic
pandemicarose arosefromfromaanew newstrain
strainof of aaphase
phaseIIclinical
clinicaltrial
trialand
andcould
couldin inprinciple
principle stablecomplexes
stable complexesof ofthree
threeclosely
closelycoupled
coupledmol- mol-
theH1N1
the H1N1subtype.subtype.The Theextent
extentof ofhaemaggluti-
haemaggluti- conferprotection
confer protectionagainstagainstmanymanyof ofthe
themost
most ecules,but
ecules, butCrowe
Croweand andWilson discovered33this
Wilsondiscovered this
ninvariability
nin variabilitymeans meansthat thatpoor
poorstrainstrainselection
selection prominentpandemic
prominent pandemicvirus virussubtypes.
subtypes.AAnewernewer yearthat
year thatthese
thesetrimers
trimersoccasionally
occasionallyopen openup up
canleave
can leaverecipients
recipientslargely largelyunprotected
unprotected— —and
and haemagglutininstem
haemagglutinin stemconstruct
constructdeveloped
developedby by toexpose
to exposeaaweak weakpoint
pointto towhich
whichantibodies
antibodies
evenaagood
even goodvaccine
vaccineoffers offerslimited
limitedprotection
protection NIAIDcould
NIAID couldlead leadtotoeven
evenbroader
broaderprotection
protection canbind,
can bind,potentially
potentiallythwarting
thwartinginfection
infectionby byaa
againstfuture
against futurestrains.
strains.“In “Intwo
twoyears,
years,the thevirus
virus againstthe
against theremaining
remainingsubtypes.
subtypes. widerange
wide rangeof ofinfluenza
influenzaAAviruses.
viruses.“This
“Thistrimer
trimer
canchange
can changeagain againso sowe wecancangetgetre-infected
re-infectedand and Paleseand
Palese andFlorian
FlorianKrammer,
Krammer,aavirologist
virologist interfaceisisaawhole
interface wholenew newuniversal
universalflu fluepitope,
epitope,
getdisease,
get disease,””says saysPalese.
Palese. whoisisalso
who alsoat atMount
MountSinai,Sinai,have
havedeveloped
developed and everybody’s
and everybody’s going going crazy
crazy about
about it,”it,” says
says
Furthercomplicating
Further complicatingthe thequestquestfor foraauni-
uni- analternative
an alternativeapproach
approachto tostimulating
stimulatingstem- stem- Crowe.“It’s
Crowe. “It’snot
noteven
evenclear
clearhowhowititworks,
works,but butitit
versalflu
versal fluvaccine
vaccineisisthe thefact
factthatthatour ourimmune
immune specificimmunity.
specific immunity.They They clearlyworks
clearly worksin inanimals.
animals.””
systemisisstrongly
system stronglybiased biasedby byitsitsearliest
earliestencoun-
encoun- havegenerated
have multiple “This
generatedmultiple “Thistrimer
trimer Muchof
Much ofthe
thevariability
variabilitybetween
betweeninfluenza
influenza
terswith
ters withinfluenza
influenzathrough throughaaphenomenonphenomenon influenza viruses
influenza viruses with interfaceis
with interface is virusesisisonly
viruses onlyskin
skindeep.
deep.Probe
Probemore
moredeeplydeeply
calledimprinting
called imprinting— —or, or,asasitithas
hasbeenbeendubbed,
dubbed, haemagglu- aawhole
chimaerichaemagglu-
chimaeric wholenew new withinthe
within thevirus
virusparticle
particleand andyouyoufindfindgreater
greater
‘originalantigenic
‘original antigenicsin’ sin’..This
Thismeansmeansthat thatindi-
indi- tininproteins
tinin proteinsin inwhich universalflu
which universal flu similarityin
similarity inthe
theessential
essentialproteins.
proteins.TheseTheseare are
viduals have
viduals have aa strong
strong antibody
antibody response response to to thesame
the samestalk domain epitope,
stalkdomain epitope,and and beyondthe
beyond thereach
reachof ofantibodies
antibodiesbut buttheytheycan can
viruseswith
viruses withmolecular
molecularfeatures featuresshared sharedby bythe
the isis paired
paired withwith various everybody’s
various everybody’s berecognized
be recognizedby byTTcells
cells— —an anelement
elementof ofthethe
strainencountered
strain encounteredduring duringtheir theirfirstfirstexposure,
exposure, exotic head
exotic head domains
domains going goingcrazy crazy immunesystem
immune systemthat thatcancantarget
targetand
andeliminate
eliminate
butthey
but theyessentially
essentiallystart startfrom
fromscratchscratchwhen when from virus
from virus subtypes
subtypes about aboutit.” it.” influenza-infectedcells,
influenza-infected cells,which
whichpresent
presentpeptide
peptide
exposedto
exposed todistantly
distantlyrelatedrelatedstrains
strainsfor forthe
thefirst
first that primarily
that primarily infect infect signaturesof
signatures oftheir
theirviral
viralintruders.
intruders.
time.“It’s
time. “It’snot
notthat thatyouyoucannot
cannotsee seethethesecond
second birdsand
birds andare aretherefore
thereforeunlikely
unlikelyto totrigger
triggeran an Sofar,
So far,antibodies
antibodieshave havebeenbeenthe theprimary
primary
virus—
virus —it’sit’sjust
justlikelikeyou’re
you’reaababy babyand andyou’re
you’re imprinting-biased response
imprinting-biased response in in humans.
humans. “If “If focusof
focus ofthethevaccine
vaccinecommunity
communitybecause becausethey they
seeingititfor
seeing forthethefirst
firsttime,
time,””sayssaysCrowe.
Crowe. youthen
you thenrevaccinate
revaccinatewith withaavaccine
vaccinethat thathas
has representaacrucial
represent crucialfirst
firstline
lineofofdefence
defenceagainst
against
Imprintingisisaadouble-edged
Imprinting double-edgedsword swordbecause
because thesame
the samestalk
stalkbutbutaacompletely
completelydifferent
differenthead,
head, circulatingvirus
circulating virusparticles,
particles,but butTTcells
cellsprovide
provide
earlyexposure
early exposureto tothe
theright
rightstrain
straincouldcouldtheo-
theo- theimmune
the immunememory memoryagainstagainstthe thestalk
stalkcould
could critical protection
critical protection by by containing
containing infection
infection
reticallyproduce
retically producefar-reaching
far-reachingand andvigorous
vigorous beboosted,
be boosted,””explains
explainsKrammer.
Krammer. onceititisisunder
once underway.way.“People
“Peopleget getexposed
exposedand and
protectionin
protection inresponse
responseto tovaccination.
vaccination.But Butififaa Thisapproach
This approachuses usesthetheentire
entirevirus
virusparticle,
particle, infectedevery
infected everytwotwoor orthree
threeyears
yearson onaverage,
average,””
child’sfirst
child’s firstinfluenza
influenzaencounterencounterisiswith withaarela-
rela- creatingthe
creating thepotential
potentialto toelicit
elicitparallel
parallelimmune
immune saysSarah
says SarahGilbert,
Gilbert,whowhoheadsheadsvaccine
vaccinedevelop-
develop-
tivelyunusual
tively unusualor oratypical
atypicalstrain,
strain,vaccination
vaccination recognitionof
recognition ofother
otherinfluenza
influenzaantigens.
antigens.On On mentatatthe
ment theUniversity
Universityof ofOxford’s
Oxford’sJenner
JennerInsti-
Insti-
mightprove
might proveless lesseffective
effectivein interms
termsof ofrousing
rousing the basis
the basis of of promising
promising evidence
evidence of of cross-
cross- tute,UK.
tute, UK.“The“Thevastvastmajority
majorityof ofthese
theseinfections
infections
broadlyprotective
broadly protectiveimmunity.immunity. protectionagainst
protection againstdiverse
diverseinfluenza
influenzaAAsub- sub-
types in
types in animals,
animals, the the Mount
Mount SinaiSinai team
team isis
STALKINGSTABILITY
STALKING STABILITY nowconducting
now conductingphase phaseIItrials
trialstotoexplore
explorethe the
AAvaccine
vaccinethat
thatfocuses
focusesthe theimmune
immuneresponse
response vaccine’ssafety
vaccine’s safetyandandeffectiveness
effectivenessin inhumans.
humans.
GOPAL MURTI/SCIENCE PHOTO LIBRARY
UNIV.
VANDERBILT UNIV.
onaamore
on morestable
stabletarget
targeton onthe
thevirus
viruscould
couldover-
over-
RAYNER, VANDERBILT
comethe
come theproblem
problemof ofviral
viraldiversity.
diversity.Research-
Research- HIDDENWEAKNESSES
HIDDEN WEAKNESSES
ershave
ers haveknown
knownthat thatsuch
suchtargets
targetsexisted
existedforfor Inspiredby
Inspired bythe
thediscovery
discoveryof ofcross-protective
cross-protective
decades.In
decades. In1983,
1983,Palese
Paleseand andhishiscolleagues
colleagues stalkantibodies
stalk antibodiesin inthe
thewild,
wild,several
severalresearch
research
ANNE RAYNER,
determined that
determined that thethe haemagglutinin
haemagglutinin stalk stalk groupshave
groups havebeen
beencasting
castingthe thenet
netwider
widerto tofind
find
domainisisso
domain sosimilar
similarbetween
betweenstrains
strainsthat
thatanti-
anti- more such
more such molecules.
molecules. “We “We use use all
all kinds
kinds ofof
ANNE
bodiescan
bodies canrecognize
recognizespecific
specificphysical
physicalfeatures,
features, donors—
donors —people
peoplewhowhoare areactively
activelysick,
sick,people
people
knownas
known asepitopes,
epitopes,of ofhaemagglutinin
haemagglutininproteins
proteins whohave
who haverecovered
recoveredfrom fromavian
avianinfluenza,
influenza,or or
frommultiple
from multipleinfluenza
influenzasubtypes.
subtypes.Unfortu-
Unfortu- we’llgo
we’ll gototoother
othercountries
countriesto tofind
finddonors
donorswith with
nately,the
nately, thestalk
stalkisissomething
somethingof ofan
animmunolog-
immunolog- exposureto
exposure tounusual
unusualstrains,
strains,””says
saysCrowe.
Crowe.After After
icalwallflower,
ical wallflower,overshadowed
overshadowedby bythe
theinfluence
influence isolatingthe
isolating theantibody-producing
antibody-producingBBcells cellsfrom
from
ofthe
of thehead.
head.“We“Wehavehaveengineered
engineeredepitopes
epitopesinto
into theseindividuals,
these individuals,researchers
researcherscan cancomprehen-
comprehen-
thestalk
the stalkand
andthethesame
sameepitopes
epitopesintointothe
thehead,
head, sivelyprofile
sively profilethe
thespecific
specificinfluenza
influenzatargets
targetsthat
that
andwe
and weget
getaamuch
muchbetterbetterresponse
responseto toepitopes
epitopes elicitaanatural
elicit naturalimmune
immuneresponse
responseand andidentify
identify
inthe
in thehead,
head,””says
saysPalese.
Palese.ButButimmunity
immunitycan canstill
still antibodiesthat
antibodies thatmight
mighthave havebroad
broadinfection-
infection-
emergenaturally
emerge naturallyin insome
somecases,
cases,andandaaseries
series neutralizingcapabilities.
neutralizing capabilities.
ofstalk-specific
of stalk-specificantibodies
antibodieswere wereisolated
isolatedfrom
from Thesestudies
These studieshave
haverevealed
revealedthatthateven
evenin inthe
the
humandonors
human donorsin in2008
2008and and2009.
2009. variablehead
variable headdomain
domainof ofhaemagglutinin
haemagglutininthere there
Morerecently,
More recently,several
severalresearch
researchgroups
groupshave
have are structural
are structural elements
elements that that areare consistent
consistent
devisedmultiple
devised multiplevaccine
vaccinestrategies
strategiesforforselec-
selec- acrossinfluenza
across influenzasubtypes.
subtypes.In In2012,
2012,research-
research-
tivelyprovoking
tively provokingaastem-specific
stem-specificresponse.
response.Gra-Gra- ersat
ers atScripps
ScrippsandandJanssen’s
Janssen’sCrucell
CrucellVaccine
Vaccine
ham’steam
ham’s teamat atNIAID,
NIAID,for forexample,
example,undertook
undertook Institutein
Institute inLeiden,
Leiden,the theNetherlands,
Netherlands,identi- identi-
aapainstaking
painstakingprocess
processof ofprotein
proteinengineering
engineering fied22an
fied anantibody
antibodycalled
calledCR9114,
CR9114,which whichexhib-
exhib-
aastandalone
standaloneversion
versionof ofthe
thestem
stemfrom
fromananH1H1 itedunprecedented
ited unprecedentedbreadth breadthof ofrecognition.
recognition.
influenzavirus.
influenza virus.“It“Ittook
tookus usabout
aboutseven
sevenor oreight
eight “Thatcould
“That couldactually
actuallybind bindto toboth
bothinfluenza
influenza
yearsto
years toengineer
engineerititand andstabilize
stabilizeititenough
enoughto to AAand
andinfluenza
influenzaB, B,””says
saysWilson,
Wilson,who whohelped
helped
maintainthe
maintain theright
rightsurfaces
surfacesand andstructures,
structures,”” characterize the
characterize the antibody.
antibody. This This antibody
antibody isis Researchat
Research atthe
theVanderbilt
VanderbiltVaccine
VaccineCenter
Centerstudies
studies
saysGraham.
says Graham.The Theresearchers
researcherssubsequently
subsequently now being
now being used
used toto identify
identify target
target epitopes
epitopes theimmune
the immuneresponse
responseto
tothe
theinfluenza
influenzavirus.
virus.
SS55

OUTLOOK INFLUENZA
Woking, UK. This long-lived species could far from easy. Gilbert struggled for five years to
NIAID/NIH; VACCINE DESIGNED BY J. BOYINGTON & B. GRAHAM AT NIAID VACCINE RESEARCH CENTER;
STRUCTURE DERIVED BY A. HARRIS & J. GALLAGHER AT NIH LABORATORY OF INFECTIOUS DISEASES.
serve as both a useful test case and an obtain funding before launching her company,
important beneficiary for vaccines. which raised the capital needed to bring her
“The upper respiratory tract of the lab’s vaccine programme into phase II trials.
pig is very similar to the human More investment may be on the way. In the
and they tend to get infected with past few years, both NIAID and the US Bio-
the same viruses,” she says. “And medical Advanced Research and Development
there is a need for flu vaccines in Authority have prioritized the development
pigs — the 2009 H1N1 pan- of a universal vaccine, and the Bill & Melinda
demic virus is thought to Gates Foundation has joined forces with gov-
have come from pigs.” ernmental and non-governmental organiza-
Krammer has also tions to form the Global Funders Consortium
used pigs as a model for Universal Influenza Vaccine Development.
but says their large size
makes them difficult to RAISING THE BAR
use routinely in research. The vaccines now being developed promise
Moreover, he is hesitant much broader protection than current seasonal
about drawing too many conclusions shots but fall well short of being truly universal.
A nanoparticle vaccine from any animal model: “You can use them The World Health Organization (WHO) still
comprising a ferritin to down-select candidates and for safety, but sees considerable value in such vaccines, and
core (blue) with eight with universal influenza vaccines, the ultimate has called for a vaccine that prevents severe
haemagglutinin-stem animal model is Homo sapiens
sapiens.” disease from all forms of influenza A by 2027,
antigens (yellow). The ultimate proof for any flu vaccine is which would prevent pandemics. But Kram-
protection against disease in clinical trials. mer points out that seasonal influenza B infec-
are either asymptomatic or mild,” she says, But for a putative universal vaccine, such test- tions can also inflict a serious death toll, and
“and the reason is that people have a T-cell ing is more complicated. A growing number both he and Palese have focused their sites on
response that’s strong enough to protect them.” of groups are using ‘human challenge’ trials, true universality. “I think the WHO is making
In general, eliciting a truly protective T-cell in which healthy volunteers are deliberately the bar too low,” says Palese. “We really should
response entails reawakening memory T cells exposed to a particular influenza strain after be trying to aim high.”
that were formed in the aftermath of a previ- vaccination. This approach allows for faster Universal protection need not entail elimi-
ous exposure. Gilbert’s team uses a crippled trials with smaller cohorts and defined expo- nating all traces of influenza virus but simply
vaccinia virus that can infect human cells sure conditions — lowering the trial cost — providing sufficient immunity to minimize
and that synthesizes two different immunity- and it also allows researchers to hand-pick the the symptoms of infection. Even achieving
stimulating influenza proteins but is incapable viruses they wish to protect against. that more modest goal will probably require
of further replication. “With a single dose, we But challenge trials also have their critics. a multipronged attack. “Stem antibodies con-
saw a boost in pre-existing T-cell responses of “It’s not a natural infection. You have to inocu- tribute to protection but are probably not suf-
between eight- and tenfold in humans,” says late people with a million or even ten million ficient for very potent protection,” says Crowe.
Gilbert. She adds that the target proteins are virus particles,” says Krammer, “and it doesn’t “They would be just part of the scheme.”
90% identical across influenza A viruses, offer- seem to work like a Indeed, Gilbert is exploring the potential of
ing the potential for broad protection against “With natural infection.” These a broader immunological assault that melds
pandemic strains. universal trials also leave out very the Mount Sinai group’s chimaeric stem vac-
Gilbert’s vaccine is undergoing two phase influenza young and very old cine with her team’s vaccinia technique. “At
II trials under the guidance of Vaccitech, a vaccines, people, which are the least in mice,” she says, “combining these two
company she co-founded in Oxford. A potent the ultimate groups most vulnerable approaches was better than either alone.”
T-cell response also seems to contribute to the animal model to flu. A greater understanding of the human
apparent cross-protection offered by a replica- is Homo Another problem is immune system and its response to infection
tion-defective flu vaccine from FluGen, based sapiens.” that the US Food and could inform smarter vaccination strategies. In
in Madison, Wisconsin, which has reported Drug Administration May 2019, the US National Institutes of Health
success in a recent phase II clinical trial. still requires a real-world trial before giving awarded $35 million to an international team
approval, and these are difficult and costly. of researchers to profile the immunity of young
TRIALS AND TRIBULATIONS They require thousands of participants to children in the years after their initial exposure
Even with several promising series of human ensure that a sufficient number of people are to influenza, providing the deepest insights yet
trials under way, the road to the clinic remains exposed to flu, and they must span several sea- into the imprinting process.
fraught with difficulties. Mice are often used sons to demonstrate efficacy against multiple Their findings could help vaccine designers
for early studies of vaccine preclinical develop- virus strains or subtypes. figure out the best way to rewire the immune
ment but Palese points out that they are not a Many academic researchers say that even system while it remains malleable. And that,
natural reservoir for the influenza virus. Many embarking on a clinical trial can pose a nearly says Crowe, could be a game-changer. “You
researchers therefore quickly switch to using insurmountable challenge, because it requires could envision doing a universal vaccination
ferrets to test their vaccine candidates, because access to sophisticated production facilities as your first exposure, with beneficial imprint-
they are broadly susceptible to influenza and that meet the high bar of good manufacturing ing for the rest of your life,” he says. ■
are physiologically more like humans in that standards. “Even if it’s a simple construct, we’re
ferrets have a longer respiratory tract than talking about at least a year to make it and a cost Michael Eisenstein is a science writer in
mice. Both species are short-lived, however, of approximately US$1 million to $2 million,” Philadelphia.
making it difficult to study the effects of a vac- says Krammer. A few major companies such
1. Yassine, H. M. et al. Nature Med. 21, 1065–1070
cine over many rounds of influenza exposure. as GlaxoSmithKline and Janssen have made (2015).
Gilbert has started working on pigs in col- these investments, but obtaining that much 2. Dreyfus, C. et al. Science 337, 1343–1348 (2012).
laboration with the Pirbright Institute near funding from either public or private bodies is 3. Bangaru, S. et al. Cell 177, 1136–1152 (2019).
S6

INFLUENZA OUTLOOK
Q&A: Josef Järhult

STRUCTURE DERIVED BY A. HARRIS & J. GALLAGHER AT NIH LABORATORY OF INFECTIOUS DISEASES.
Resistance in the wild

Like all microorganisms, viruses can develop resistance to the drugs meant to treat them, and not
only in clinical situations. The rise of environmental resistance to antiviral drugs is a potential
disaster we can avert, argues Josef Järhult at Uppsala University in Sweden, especially when it
comes to influenza A, the virus that can lead to a human flu pandemic.
How could influenza A develop resistance to in their urine. Sewage treatment plants do not
MIKAEL WALLERSTEDT
antiviral medicines? have the technology to remove antivirals, or

The influenza A virus has high genetic pharmaceuticals in general, so these drugs end
variability and mutates rapidly. It needs only up in rivers and other natural waters.
one point mutation to develop resistance to
certain antiviral drugs, and such mutations Are antivirals reaching rivers in sufficient
happen all the time. quantities to bring about resistance?
For H1N1, the virus subtype that caused the The highest recorded levels of oseltamivir in
most recent influenza A pandemic in humans, river water, 865 ng l−1, were found in Japan dur-
the point mutation H274Y affected the shape of ing the 2004–05 influenza season (R. Takanami
the pocket where the antiviral drug oseltamivir et al. J. Water Environ. Technol. 8, 363–372;
(Tamiflu) binds to the protein neuraminidase. 2010). In our work with ducks, we found that
Neuraminidase inhibitors such as oseltamivir the lowest levels at which viruses developed
stop this protein cutting the virus loose from resistance was 950 ng l−1. That’s a little higher
a cell and so stop the virus spreading to other than the levels measured in the environment
cells. But the drug cannot do that if a mutation but it’s the same order of magnitude. opportunity to use them prudently or pro-
stops it binding. Such mutations rob us of a Japan is one of the top consumers of pose sewage treatment techniques to destroy
cornerstone of our defence against pandemics. oseltamivir, which is why it has such high levels the drugs before they get into the environment.
of the drug in its river water. But several other
Where in the environment is it most likely that countries, including the United States, have a What can we do to prevent antiviral resistance
influenza A will pick up resistance to antiviral liberal policy for oseltamivir. Environmental arising?
drugs? levels in those nations could be just as high, There is no simple solution. It’s good to keep
You have to consider where the virus is going but no one seems to be checking. a broad mindset and take a multidisciplinary
to meet the antiviral in the environment. One approach. The network One Health Sweden,
place that happens is in rivers. Mallard ducks Have viruses that are resistant to antiviral which I chair, brings together doctors, vet-
are natural reservoirs for influenza, and drug medicines been found in the wild? erinarians, epidemiologists, virologists and
residues can enter the rivers in which they live. There have been a few reports of viruses in wild others — everyone working on some aspect
We have seen in our experiments that low lev- birds that have an antiviral-resistance muta- of problems that include humans, animals and
els of the drug in water can lead to oseltamivir- tion. It’s uncommon but it’s there. Whether this the environment.
resistant influenza A viruses (J. D. Järhult et al. is due to drug pressure or just natural varia- In the same way we think about cutting
PLoS ONE 6, e24742; 2011), which can then tion, I can’t say. Examples from humans have antibiotics use to reduce antimicrobial resist-
be passed on through several generations of demonstrated that in some circumstances the ance, we also need to use antiviral drugs more
mallards, even if the drug is removed from the oseltamivir-resistant flu virus can outcom- prudently. For example, we should not use
water (A. Gillman et al. Appl. Environ. Micro- pete all other flu strains, even in the absence oseltamivir for uncomplicated seasonal influ-
biol. 81, 2378–2383; 2015). of drug pressure. It’s rare, but it happens. And enza in otherwise healthy people.
For some antivirals, rivers downstream of if a resistant virus is circulating in wild birds, We need effective treatment at sewage treat-
sewage treatment plants are likely breeding there is a risk that it will form the basis of a new ment plants to reduce the levels of antivirals
grounds of resistance. Humans pass the active pandemic or highly pathogenic flu. in rivers. Ozonation treatment works but is
ingredient of these drugs out of their bodies expensive and has practical problems. And we
Are some drugs more likely than others to give need drug manufacturers to not release anti-
rise to resistant viruses? virals and their precursors into natural waters.
Mallards act as reservoirs Our experiments have shown that zanamivir Researchers in Germany have found oseltami-
in which the influenza (Relenza) is less likely than oseltamivir to give vir’s parent compound in the Rhine, probably
virus can develop rise to genetic resistance in influenza A viruses from a pharmaceutical manufacturer (C. Prasse
drug resistance. in wild ducks. But it’s still possible. et al. Environ. Sci. Technol. 44, 1728–1735; 2010).
For any new class of drugs, such as the We also need more monitoring of both the
polymerase inhibitors recently approved in levels of drug residues in the environment and
the United States and Japan, we need to study the flu viruses themselves, particularly in wild
the mechanisms of environmental resistance as ducks. Our research shows that it is possible for
soon as possible, before they are used at high resistance to develop in the environment. Now
MAURIBO/GETTY
levels. If they are not chemically stable, or do it is time to go and find it in nature. ■
not pass through sewage treatment plants
intact, resistance may not be a problem. The INTERVIEW BY NAOMI LUBICK
sooner we know the better, so we have the This interview has been edited for length and clarity.
S7

OUTLOOK
OUTLOOK INFLUENZA
INFLUENZA
TH
THERA
ERAPEUTICS
PEUTICS
A bigger arsenal
Understanding
Understandinghow
howthe
theinfluenza
influenzavirus
virusreplicates
replicatesinside
insidethe
thebody
bodyis
ishelping
helpingresearchers
researchers
develop
developaawider
widerrange
rangeof
ofantiviral
antiviraldrugs.
drugs.
BBYY NNEEI ILL SSAVA

AVAGGEE Fortunately,
Fortunately, by by that
that time
time aa second
second class
but class
butantiviral
antiviraldrugsdrugssuch
suchas asbaloxavir
baloxavirhavehaveaa
ANTOINE DORÉ
DORÉ
of
of flu flu antivirals
antivirals hadhad been
been introduced
introduced that
crucial that
crucialrole
roleininreducing
reducingillness
illnessandanddeath
deathfrom
from
I
ANTOINE
nn2004,
2004,RickRickBright
Brightwaswaslooking
lookingfor foraanew
new attack
attack aa different
different mechanism
mechanism used used by
flu, by the
flu,says the
saysBright,
Bright,who
whonownowdirects
directsthetheBiomedi-
Biomedi-
project.
project.As Asan animmunologist
immunologistthen thenatatthetheUSUS virus
virusto toreproduce.
reproduce.These Thesedrugs
drugs— —oseltami-
oseltami-
cal
cal Advanced
Advanced Research
Research and and Development
Development
Centers
Centersfor forDisease
DiseaseControl
Controland andPreven-
Preven- vir,
vir,zanamivir
zanamivirand, and,more
morerecently,
recently,peramivir
peramivir
Authority
Authority(BARDA).
(BARDA).BARDA BARDAfunds fundsresearch
research
tion
tion(CDC)
(CDC)in inAtlanta,
Atlanta,Georgia,
Georgia,he hehadhadlearned
learned ——remained
remainedthe theonly
onlydrugs
drugsfor fortreating
treatingflu
into flu
intotreatments
treatmentsfor forvarious
variousdiseases
diseasesandandhealth
health
about
aboutaanew,new,faster
fastermethod
methodof ofsequencing
sequencingviral viral until
until2018 2018when
whenthe theUnited
UnitedStates
Statesand
andJapan
Japan
threats,
threats,including
includingflu.
flu.“Vaccines
“Vaccinesget getall
allthe
themar-
mar-
genomes.
genomes.He Hedecided
decidedto touse
useititto
totest
testwhether
whether approved
approvedbaloxavir,
baloxavir,which
whichtargets
targetsaathird
thirdpart
quee part
queelights,
lights,””Bright
Brightsays,
says,“but
“butwe wecan’t
can’tvaccinate
vaccinate
the
theinfluenza
influenzaAAvirus viruswaswasdeveloping
developingresist- resist- of
ofthe theviral
virallife
lifecycle.
cycle.But
Butthe
thearsenal
arsenalof ofdrugs
drugsto
everyone,
everyone,andtoandthethevaccines
vaccinesdon’tdon’toffer
offerfull
fullpro-
pro-
ance
anceto toadamantanes,
adamantanes,which whichatatthethetime
timewere
were combat
combatflu fluremains
remainslimited
limitedandandthere
therehas
hasbeen
tection been
tectionto toeveryone.
everyone.So Sothere’s
there’saalotlotof
ofroom
roomforfor
the
themain
mainantiviral
antiviraldrugsdrugsused
usedto totreat
treatflu.
flu. evidence
evidenceof ofresistance
resistanceto toall
allof
ofthem,
them,although
although
effective
effectivetherapeutics.
therapeutics.””
Bright
Brightcollected
collectedsamples
samplesof ofthe
theflufluvirus
virusandand ititisisnot
notyet
yetwidespread.
widespread.To Tobebeeffective,
effective,each
The each
Thefirst
firstantiviral
antiviraldrug,
drug,amantadine,
amantadine,was was
tested
testedthem
themforforananaltered
alteredamino-acid
amino-acidsequencesequence drug
drugmust mustbe begiven
givenwithin
withintwotwodays
daysof ofsymp-
symp-
approved
approvedby bythe
theUSUSFood
Foodand andDrug
DrugAdmin-
Admin-
known
knownto toconfer
conferresistance.
resistance.To Tohis hissurprise,
surprise, toms
tomsappearing.
appearing. istration
istration(FDA)
(FDA)back backin in1966.
1966.ItItworks
works— —oror
every
everyvirus
virusin inhishissample
samplehad hadthethemutation.
mutation. Researchers
Researchersaroundaroundthe theglobe
globeareareworking
working
rather,
rather,ititused
usedto tountil
untilviruses
virusesdeveloped
developedresist-
resist-
Bright
Brighttooktookhishisresults
resultstotothe
theCDC’s
CDC’sdirector,
director, to
todevelop
developfurther
furtherantiviral
antiviraltherapies
therapiesfor
ance forflu.
ance — flu.
— byby blocking
blocking the the virus’s
virus’s M2M2 proton
proton
Julie
JulieGerberding,
Gerberding,who whowas
wassure
surehe hemust
mustbe be They
Theyare aresearching
searchingfor fordrugs
drugsthat channels,
channels,which
thatattack
attackdiffer-
differ- whichthe thevirus
virususes usestotorelease
releaseitsits
mistaken
mistakenand andtold
toldhimhimtotorun
runthethetests
testsagain.
again. ent
entpartspartsofofthe
thevirus’s
virus’sreproductive
reproductivecycle,cycle,and
RNA
RNAfor and
forreplication
replicationby byaahost
hostcell.
cell.
Some
Some25,000
25,000samples
sampleslater,
later,Bright
Brightcame cameto toaa are
areexploring
exploringwhether
whetherthe thecombination
combinationof M2 oftwo
two
M2blockers
blockerswerewerethetheonly
onlywaywayto tointerfere
interfere
sobering
soberingconclusion.
conclusion.Nearly Nearlyallallthe
theviruses
virusesin in or
ormore moredrugs
drugsmight
mightleadleadto tofaster
fasterrecovery,
recovery,
with
withthetheflufluvirus
virusuntil
until1999,
1999,whenwhenthe theoral
oral
circulation
circulationaround
aroundthe theglobe
globehadhadaamutation
mutation reduce
reducethe thedevelopment
developmentof ofresistance,
resistance,or
drugorboth.
both.
drugoseltamivir
oseltamivirand andthetheinhaled
inhaleddrugdrugzana-
zana-
that
thatrendered
renderedamantadine
amantadineand andrimantadine
rimantadine— — They
Theyhope hopethat
thatby bythe
thetime
timethethenext
nextpandemic
pandemic
mivir
mivirwon wonFDAFDAapproval.
approval.TheseThesedrugs
drugsinhibit
inhibit
the
thetwo
twoadamantanes
adamantanesused usedto totreat
treatflu,flu,which
which comes
comesaround,around,they theywill
willhave
havebetter
betterweapons
weapons
neuraminidase,
neuraminidase,an anenzyme
enzymethat thatallows
allowsviruses
viruses
work
workby byblocking
blockingaaparticular
particularstep
stepin inviral
viralrep-
rep- to
tofight
fightthis
thisdeadly
deadlydisease.
disease. to
toescape
escapefrom fromoneonecell
cellandandspread
spreadto toothers.
others.
lication
lication— —completely
completelyuseless.
useless.In
InJanuary
January2006,
2006, Oseltamivir,
Oseltamivir,marketed
marketedas asTamiflu,
Tamiflu,has hasbecome
become
Bright
Brightand andGerberding
Gerberdingheld heldaapress
pressconference
conference VITAL
VITALANTIVIRALS
ANTIVIRALS the
thestandard
standardflu flutreatment
treatmentin inmost
mostcountries.
countries.
to
toissue
issuenewnewguidelines:
guidelines:do donotnotuseuseadaman-
adaman- Much
Muchofofthe
theattention
attentionpaid
paidto
tofighting
fightingflu
fluisis Another
Anotherneuraminidase
neuraminidaseinhibitor,
inhibitor,peramivir,
peramivir,
tanes
tanesto totreat
treatfluflubecause
becausethey
theywill
willnotnotwork.
work. aimed
aimedatatvaccination
vaccination(see
(seepages S4
S50and
pagesS50 andS14
and S60)
S60) which
whichisisadministered
administeredintravenously,
intravenously,has hasbeen
been
SS88

INFLUENZA
INFLUENZA OUTLOOK
OUTLOOK
approved
approvedfor foruse
useininthetheUnited
UnitedStates,
States,Japan
Japan ——ititdoes
doesnot
notchange
changemuch muchas asthe
thevirus
virusevolves.
evolves. ififapproved
approvedititwill
willexpand
expandthe
theclass
classof
ofdrugs
drugs
and
andSouth
SouthKorea.
Korea. Being
Beinghighly
highlyconserved
conservedisisusually usuallyaaclue
cluethat
that now
nowdominated
dominatedby bybaloxavir.
baloxavir.
The
Thelatest
latestaddition
additionto tothe
theantiviral
antiviralarsenal,
arsenal, something
somethingisisvitalvitalto tothe
thefunctioning
functioningof ofan
an
baloxavir,
baloxavir,targets
targetsaathird
thirdcomponent
componentof ofviral
viral organism,
organism, as as itit isis less
less likely
likely to
to successfully
successfully CHECKING
CHECKINGTHE
THEMEDICINE
MEDICINECABINET
CABINET
reproduction:
reproduction:the theenzyme
enzymepolymerase,
polymerase,whichwhich mutate.
mutate.In Inaddition,
addition,Wang’s Wang’scompounds
compoundsand and Instead
Insteadof ofdeveloping
developingnew newdrugsdrugsto totarget
targetflu, flu,
controls
controlsthe
thetranscription
transcriptionand andreplication
replicationof of baloxavir
baloxavirtarget
targetdifferent
differentparts partsof
ofthe
thepolymer-
polymer- researchers
researchersin inFrance
Franceare arescouring
scouringdatabasesdatabasesof of
viral
viralRNA.
RNA.Baloxavir
Baloxavirinhibits
inhibitstranscription
transcriptionby by ase
asecomplex,
complex,so sotogether
togetherthey theymight
mightbe beable
ableto
to known
knowncompoundscompoundsto toseeseewhether
whetherany anymight
might
preventing
preventingthe thevirus
virusfromfromcommandeering
commandeering cripple
cripplethe
thevirus
virusmore moreeffectively
effectivelythan
thaneither
either make
makeeffective
effectivetreatments.
treatments.“At “Atleast
leastin intheory
theory
the
thehost
hostcell’s
cell’smanufacturing
manufacturingfacilities.
facilities.Nor-
Nor- could
couldalone.
alone. it’s
it’saavery
veryinteresting
interestingand andvery veryquickquickstrategy
strategy
mally,
mally,in
inaaprocess
processknown
knownas ascap
capsnatching,
snatching, to
topropose
proposenew newdrugs,
drugs,””says saysOlivier
OlivierTerrier,
Terrier,aa
the
thevirus
virussteals
stealsaashort
shortstring
stringofofthe
thehost
hostcell’s
cell’s virologist
virologistatatthe theInternational
InternationalCentre Centrefor forInfec-
Infec-
CLAUDE BERNARD
BERNARD
RNA
RNAandandattaches
attachesititto toits
itsown
ownRNA,RNA,tricking
tricking tiology
tiologyResearch
Researchin inLyon.
Lyon.
the
thecell
cellinto
intoduplicating
duplicatingit. it.Baloxavir
Baloxavirblocks
blocks Terrier
Terrierand andhis hiscolleagues
colleaguesused usedaadatabasedatabase
UNIV. CLAUDE
the
thepart
partofofthe
thepolymerase
polymerasethat thatassists
assistsininthis
this known
known as as the
the Connectivity
Connectivity Map Map (CMap),
(CMap),
cap
capsnatching.
snatching. developed
developedby bythe theBroad
BroadInstitute
Instituteof ofMassa-
Massa-
VIRPATH, UNIV.
Although
Althoughbaloxavir
baloxavirisisavailable
availablein inJapan
Japanand
and chusetts
chusettsInstitute
Instituteof ofTechnology
Technologyand andHarvard
Harvard
the
theUnited
UnitedStates,
States,itithas
hasyet
yettotobe
beapproved
approvedby by University
Universityin inCambridge,
Cambridge,Massachusetts.
Massachusetts.The The
EQUIPE VIRPATH,
the
theEuropean
EuropeanMedicines
MedicinesAgency.
Agency.One Oneappeal-
appeal- CMap
CMapcontainscontainsgene-expression
gene-expressionprofiles profilesthat that
ing
ingaspect
aspectof ofbaloxavir
baloxavirisisthatthatititrequires
requiresjust
just are
areproduced
producedwhen whencells cellsareareexposed
exposedto tovarious
various
YVER, EQUIPE
one
oneoral
oraldose
dosecompared
comparedwith withten
tendoses
dosesover
overaa drugs.
drugs.First,First,the theLyon
Lyonteam teamdeveloped
developedaaprofile profile
MATTHIEU YVER,
five-day
five-dayperiod
periodfor foroseltamivir.
oseltamivir. of
ofhowhowaacell’scell’sgene
geneexpression
expressionisisaffected affectedby byaa
flu
fluvirus
virus— —“a “afingerprint
fingerprintof ofinfection”,
infection”,as asTer-
Ter-
MATTHIEU
FRESH
FRESHTARGETS
TARGETS rier
riercalls
callsit. it.Then
Thenthey theycombed
combedthrough throughCMap CMap
To
Toexpand
expandthe thetreatment
treatmentoptions,
options,researchers
researchers looking
lookingfor fordrugs
drugsthat thatproduce
produceaamirror mirrorimageimage
are
arebroadening
broadeningtheir theirsearch
searchto tofind
findaarangerangeof of of
ofthat
thatfingerprint.
fingerprint.If, If,for
forexample,
example,the thevirus
virus
different
differenttargets.
targets.Jun JunWang,
Wang,aapharmacologist
pharmacologist Plates
Platesof
ofcells
cellsinfected
infectedwith
withthe
theinfluenza
influenzavirus
virusare
are causes
causesaaparticular
particulargene geneto toexpress
expressless lessofofaacer-
cer-
atatthe
theUniversity
Universityof ofArizona
Arizonain inTucson,
Tucson,has hashis
his used
usedto
totest
testantiviral
antiviraldrugs.
drugs. tain
tainprotein,
protein,they theylooked
lookedfor foraadrug drugthat thatleads
leads
eyes
eyeson onseveral.
several.His Hismain
mainapproach
approachhas hasbeen
been ititto
toexpress
expressmore. more.They Theyhope hopethat thataadrug drugthat that
to
totarget
targetthe themutation
mutationin inthe
theM2 M2channel
channelthat that AAthird
thirdproject
projectin inWang’s
Wang’slab labthat
thatisisat atan
an
produces
producesan aneffect
effectopposite
oppositeto tothat
thatof ofthe
thevirus
virus
created
createdresistance
resistanceto toamantadine
amantadineand andrimanta-
rimanta- early
earlystage
stagefocuses
focuseson onhaemagglutinin,
haemagglutinin,aasur- sur-
could
couldpotentially
potentiallybe beused
usedto tocounteract
counteractthe theflu.
flu.
dine.
dine.One Oneparticular
particularmutation,
mutation,dubbeddubbedAM2- AM2- face
faceprotein
proteinthatthatallows
allowsthe thevirus
virusto tobind
bindto to The
Theteam teamscreened
screened1,309 1,309FDA-approved
FDA-approved
S31N,
S31N,confers
confersresistance
resistancein inmore
morethan than95% 95%of of aacell.
cell.“It’s
“It’san
aneasy
easytarget,
target,but butit’s
it’salso
alsoaareally
really
molecules
moleculesand andfoundfound35 35that
thatlooked
lookedpromis- promis-
influenza
influenzaAAviruses. viruses.Amantadine
Amantadineblocks blocksthe the difficult
difficultone,”
one,”Wang
Wangsays, says,because
becauseits itsmain
main
ing.
ing.Of Ofthese,
these,31 31showed
showedantiviralantiviralactivityactivityin in
process
processby bywhich
whichviral viralRNA
RNAisisreleased
releasedinto into part,
part,the
thehead,
head,mutates
mutatesreadily,
readily,letting
lettingititevade viruses
virusesswabbed
evade swabbedfrom fromthe thenasalnasalpassages
passagesof of
the
thehost
hostcell,
cell,and
andthe themutation
mutationprovides
providesaanew new attackers.
attackers.As Asaaresult,
result,drugs
drugstargeting
targetinghaemag-
haemag- people
people with with flu. flu. Studies
Studies in in mice
mice narrowed
narrowed
channel
channelthroughthroughwhich whichthe thevirus
viruscan canrelease
release glutinin
glutininmight
mightbe bemost
mosteffective
effectivewhen whenused usedin in
the
thesearch
searchto tojust
justone onecandidate,
candidate,the thecalcium-
calcium-
its
itsRNA.
RNA. combination
combinationwith withother
otherdrugs.
drugs. channel
channelblocker blockerdiltiazem,
diltiazem,which whichisisnormally
normally
“We
“Weknow knowthe themutation,
mutation,””Wang Wangsays. says.TheThe Different
Differentgroups
groupsof ofresearchers
researchershave havetriedtried
used
usedto totreat
treathypertension.
hypertension.The Theresearchers
researchers
question
questionnow nowisiswhether
whethernew newdrugs drugscan canbe be to
totarget
targetthethestem
stemof ofhaemagglutinin,
haemagglutinin,as asthis
this
founded
foundedaacompany companyin inLyon,
Lyon,Signia SigniaThera-Thera-
developed
developedto totarget
targetit. it.“If
“Ifwewecancando dothatthatthen
then isismore
moreconserved
conservedthan thanthe thehead.
head.Scientists peutics,
Scientistsatatpeutics,which whichisisrunning
runningaaphase phaseIIIIclinicalclinical
ANTOINE DORÉ
we
wecancantreat
treatcurrent
currentviralviralinfections,
infections,””he headds.
adds. Scripps
ScrippsResearch
ResearchInstitute
Institutein inLaLaJolla,
Jolla,Califor-
Califor-
trial
trialon onthe thedrug.
drug.The Thedrugsdrugsare arealready
alreadyFDA FDA
So
Sofar,
far,Wang
Wanghas hasfound
foundaamolecule
moleculethat thatblocks
blocks nia,
nia,and
andthe
thepharmaceutical
pharmaceuticalcompany companyJanssen Janssen
approved,
approved,Terrier Terriersays,says,which
whichcould couldshave shaveyearsyears
the
thenew newchannel
channelin incells
cellsininhis
hislaboratory.
laboratory.He He Research
Researchand andDevelopment,
Development,based basedin inRari-
Rari-
off
offthetheprocess
processfor forgetting
gettingthem themto toflu
flupatients.
patients.
now
nowaims aimsto tostudy
studyititin inmice.
mice. tan,
tan,NewNewJersey,
Jersey,foundfound Other
Otherresearchers
researchersare aretrying
tryingto touseuseantibodies
antibodies
Another
Anotherone oneof ofWang’s
Wang’sprojects,
projects,which whichisis “At
“Atleast
least aa small
small molecule
molecule that, that,
to
tofight
fightflu.flu.AAgroupgroupat atthe
theLiverpool
LiverpoolSchool School
still
stillatatan
anearly
earlystage,
stage,also
alsofocuses
focuseson onviral
viralpoly-
poly- in
intheory
theory like
likean anantibody,
antibody,could could
of
ofTropical
TropicalMedicine
Medicine(LSTM), (LSTM),UK, UK,and andImpe-
Impe-
merase
merasebut buthas hasaadifferent
differenttarget
targetto tobaloxavir.
baloxavir. it’s
it’saavery
very bind
bindto tothe
thestem
stemof ofhae-
hae-
rial
rialCollege
CollegeLondon Londonattached attachedextra extrasialicsialicacids
acids
Polymerase
Polymeraseconsists consistsof ofthree
threeparts
partsthat thatmust
must interesting
interesting magglutinin.
magglutinin.When Whenthey they
to
topart
partof ofananantibody.
antibody.The Theflu fluvirus
virusnormally
normally
work
worktogether.
together.Wang Wanghas hasfound
foundseveral
severalcom- com- and
andvery veryquick
quick gave gaveititto tomice
micethat thathad had
infects
infectscellscellsin inthe
thelungs
lungsby bybinding
bindingthrough throughits its
pounds
poundsthat thatseemseemto toblock
blockthe theassembly
assemblyof ofthe
the strategy
strategyto to been
been infected
infected with with 25 25
haemagglutinin
haemagglutininand andneuraminidase
neuraminidaseproteins proteins
enzyme,
enzyme,rendering
renderingitituselessuselessand andstopping
stoppingthe the propose
proposenew new times
timesthe thelethal
lethaldosedoseoftoof
tosialic
sialicacidacidon onthe thesurface
surfaceof oflung
lungcells.
cells.ButBut
virus
virusin inits
itstracks.
tracks.The Thebeauty
beautyof ofthis
thisapproach,
approach, drugs.”
drugs.” flu,
flu,all
allof
ofthem
themsurvived.
survived.when
whenthe thevirus
virusencounters
encountersantibodiesantibodiescovered covered
he
he says,
says, isis thatthat the
the virus
virus isis unlikely
unlikely to to get
get But
But Jason
Jason Chien,
Chien, who who
in
insialic
sialicacids,
acids,ititbinds
bindsto tothose
thoseinstead,
instead,stopping
stopping
around
aroundthe theblockage
blockagewith withaasingle
singlemutation.
mutation. leads
leadsJanssen’s
Janssen’sresearch
researchand anddevelopment
developmentteam team
ititattaching
attachingto tothe
thelunglungcells.
cells.Richard
RichardPleass, Pleass,aa
Wang’s
Wang’sdrug drugcandidates
candidatesbind bindto toone
onecom-com- for
forrespiratory
respiratoryinfections,
infections,says saysthat
thatalthough
although virologist
virologistatatLSTM, LSTM,says saysthat
thataatreatment
treatmentbased based
ponent
ponentof ofthethepolymerase,
polymerase,PA PACC,,and
andprevent
preventitit the
theproject
projectwas wasscientifically
scientificallyuseful,
useful,the themol-
mol-
on
onthese
theseantibodies
antibodiescould couldact actasasaaprophylactic
prophylactic
from
frombinding
bindingto toaasecond
secondcomponent,
component,PB1 PB1NN.. ecule
eculewas waseffective
effectiveonlyonlyagainst
againsttype typeAAinflu-influ-
for
forhospital
hospitalstaff, staff,slowing
slowingthe thespread
spreadof offlu.
flu.
AAsingle
singlemutation
mutationcould couldbe beenough
enoughto tostop
stop enza,
enza,not nottype
typeB, B,so
sothe
thecompany
companywill willnotnotbe be Despite
Despitethe thenumber
numberof ofapproaches
approachesto tonew
new
the
thedrug
drugbinding
bindingto tothe
thetarget,
target,WangWangexplains,
explains, pursuing
pursuingit. it. flu
flutreatments,
treatments,ititcan cantaketakeyearsyearsto totake
takeaadrugdrug
but
butthatthatmutation
mutationwould wouldprobably
probablymean meanthat that Chien
Chiensayssaysthat
thatteams
teamsatatJanssen
Janssenare arestudy-
study-
from
fromthe thelab labto tothe
theclinic.
clinic.But ButWang Wangisiscon- con-
the
theenzyme’s
enzyme’scomponents
componentswould wouldno nolonger
longerfit fit ing
ingother
otherpotential
potentialantivirals
antiviralsin inthe
thelablabbut fident
buthefidentthat
he thatan anexpanded
expandedarray arrayof ofantivirals
antiviralsisis
together.
together.“It “Itstill
stillwill
willnotnotbebeable
ableto toassemble,
assemble,”” declined
declinedto todisclose
disclosedetails.
details.The Thecompany
companyis, onis,
onthe thehorizon.
horizon.“We’re “We’regettinggettingthere,there,””he hesays.
says.
he
hesays,
says,because
becausethere therewould
wouldneed needto tobe beaasec-
sec- however,
however,conducting
conductingtwo twophase
phaseIII IIIclinical
clinical
“Within
“Withinthe thenextnextfew fewyearsyearswe wewill willdefinitely
definitely
ond
ondmutation
mutationto toallow
allowthethereshaped
reshapedpiece pieceof of trials
trialsononpimodivir
pimodivir— —one oneusing
usinghospitalized
hospitalized see
seeaafew fewother
othernew newflu fludrugs
drugson onthe themarket.
market.””■■
the
theenzyme
enzymeto tobind
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theother
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outpatientsatathigh high
The
Thepolymerase
polymerasecomplex complexisisan anattractive
attractivetar- tar- risk
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complications.Pimodivir
Pimodivirinhibitsinhibitsyet yet Neil Savageisisaascience
NeilSavage scienceand
andtechnology
technology
get
getforforantivirals
antiviralsbecause
becauseititisishighly
highlyconserved
conserved another
anotheraspect
aspectof ofthe
thepolymerase
polymerasecomplex, complex,and and journalist
journalistin
inLowell,
Lowell,Massachusetts.
Massachusetts.
SS99

OUTLOOK
OUTLOOK INFLUENZA
INFLUENZA
DIAGN
DIAGNOSTICS
OSTICS
A sticking point for rapid

flu tests?
Rapid
Rapidmolecular
moleculartests
testsfor
forinfluenza
influenzaare
areas
asquick
quickas
asolder
olderon-the-spot
on-the-spottests
testsand
andmuch
muchmore
more
accurate.
accurate.But
Butthat
thatmight
mightnot
notbe
beenough
enoughtotodrive
drivewidespread
widespreadadoption.
adoption.
BBYY EELLIIZZAABBEETTHH SSVVOOBBOODDAA virus

virus —— ifif any
any —— isis present
present in in the
the patient’s
patient’s hard
hardtotopredict
predictwhether
whetherthese
thesetests
testswill
willbecome
become
ANTOINE DORÉ
DORÉ
respiratory
respiratorytract.
tract. the
thestandard
standarddiagnostic
diagnostictool.
tool.
I
ANTOINE
ttbegins
beginslikelikemany
manyotherothertests
testsat
atthe
thedoctor’s
doctor’s The
Thedeveloper
developerof ofthe
theXpert
XpertXpress,
Xpress,Cepheid
Cepheid
surgery:
surgery:aaquick
quickswipe
swipeinside
insidethe
thenostrils
nostrils based
based in
in Sunnyvale,
Sunnyvale, California,
California, thinks
thinks that
that INCONSISTENT
INCONSISTENTRESULTS
RESULTS
with
with what
what looks
looks like
like aa giant
giant cotton
cotton bud,
bud, rapid
rapidmolecular
molecularteststestslike
likethis
thiswill
willtransform
transformflu flu Influenza
Influenzacutscutsaaseasonal
seasonalswath
swathof ofdestruction
destruction
which
whichisisthen
thenplunged
plungedinto intomedium
mediumdesigned
designed diagnosis.
diagnosis.AndAndother
otherpharmaceutical
pharmaceuticalcompa-compa- around
around the the world,
world, leading
leading to to more
more thanthan
to
tokeep
keepthethesample
samplefresh.
fresh. nies
niessuch
suchas asAbbott,
Abbott,based
basedin inChicago,
Chicago,Illinois,
Illinois, 200,000
200,000 hospitalizations
hospitalizations and and 30,000
30,000 deaths
deaths
But
Butititisiswhat
whathappens
happensnext nextthat
thatmakes
makesthe the and
andRoche
Rocheof ofBasel,
Basel,Switzerland,
Switzerland,have havecreated
created each
each year
year in
in the
the United
United States
States alone.
alone. The
The
Xpert
XpertXpress
Xpressmolecular
molecularinfluenza
influenzatest testdiffer-
differ- similar
similardiagnostic
diagnostictools.
tools.Since
Sincethese
thesetests
testswere
were virus
virusisishighly
highlycontagious
contagiousbut buttreatable,
treatable,so soitit
ent.
ent.AAtechnician
technicianplaces
placesthe thesample
sampleintointothe
the launched
launchedin inthetheUnited
UnitedStates
Statesseveral
severalyears
yearsago,
ago, isis important
important toto identify
identify itit as
as quickly
quickly andand as
as
machine,
machine, whichwhich then
then makes
makes copies
copies of of any
any medical
medicalproviders
providershave haveraved
ravedabout
abouttheir
theirspeed
speed accurately
accurately as as possible.
possible. Today,
Today, manymany people
people
genetic
geneticinformation
informationititcontains.
contains.Fluorescence
Fluorescence and
andaccuracy,
accuracy,whichwhichthey
theysaysaymakes
makestreatment
treatment who
whovisit
visitaaclinic
clinicwith
withflu
flusymptoms
symptomsreceive
receive
detectors
detectors scanscan for
for the
the presence
presence of of specific
specific decisions
decisionseasy
easyandandreduces
reducesthe theburden
burdenof ofdis-
dis- aa rapid
rapid influenza
influenza diagnostic
diagnostic test test (RIDT).
(RIDT).
genes.
genes. In
In less
less than
than half
half an
an hour,
hour, the
the doctor
doctor ease.
ease.But
Butaafewfewproblems,
problems,including
includinghighhighcosts
costs Unlike
Unlike molecular
molecular tests,
tests, such
such as as the
the Xpert
Xpert
knows
knows with
with near
near certainty
certainty which
which influenza
influenza and
andthe
therisk
riskof ofsample
samplecontamination,
contamination,make makeitit Xpress,
Xpress,RIDTs
RIDTscontain
containananantibody
antibodythatthatsticks
sticks
SS1100

INFLUENZA
INFLUENZA OUTLOOK
OUTLOOK
to
toananantigen
antigenprotein
proteinon onthetheflufluvirus,
virus,typically
typically AArapid,
rapid,accurate
accuratediagnosis
diagnosisallowsallowsdoctors
doctors
ABBOTT LABORATORIES
LABORATORIES
changing
changingcolour colourto toshow
showaapositive
positiveresult.
result. to
to prescribe
prescribe treatment
treatment faster,
faster, which
which brings
brings
The
Themainmainadvantage
advantageof ofRIDTs
RIDTsisistheirtheirspeed
speed noticeable
noticeablebenefits
benefitsto topatients.
patients.In study33of
Inaastudy of
——theytheyproduce
produceaaresult resultin inless
lessthan
than30 30min-
min- more
morethan than1,400
1,400peoplepeoplewith withflu,
flu,those
thosewho who
ABBOTT
utes.
utes.ButButtheytheysometimes
sometimesdeliverdeliverpoorpoorresults.
results. took
tookantiviral
antiviralmedication
medicationwithin within12 12hours
hoursof of
“You
“Youneed needaalot lotofofflu
fluto
tobebethere,
there,andandififthere’s
there’s the
the onset
onset of of fever
fever had had three
three fewer
fewer sick
sick days
days
not
notenough,
enough,you’ll you’llgetgetaanegative
negativeresult,
result,””says
says than
than those
those who who started
started medication
medication after after
Neil
NeilAnderson,
Anderson,who whostudies
studiesinfectious
infectiousdiseases
diseases 48 hours.
48 hours.“Getting
“Gettingtreatment
treatmentearlierearlierisisgoing
going
at
atthe
theWashington
WashingtonUniversity
UniversitySchoolSchoolof ofMedi-
Medi- to
tolessen
lessensymptoms,
symptoms,””AndersonAndersonsays. says.
cine
cinein inStStLouis,
Louis,Missouri.
Missouri.Children
Childrentend tendto to AA 2019 study44compared
2019 study comparedthe theoutcomes
outcomes of of
shed
shedaalot lotofofvirus
virusparticles,
particles,he headds,
adds,but butsome
some pregnant
pregnant women women with with flu-like
flu-like symptoms
symptoms
adults
adultsdo donot
notproduce
produceenough
enoughto togive
giveaapositive
positive at
at two
two time
time points:
points: before
before rapidrapid molecular
molecular
test
testresult
resultevenevenififthey
theyhave
havesevere
severesymptoms.
symptoms. flu
flutests
testswere
wereintroduced
introducedand andafterwards.
afterwards.In In
False-negative
False-negative results results areare therefore
therefore aa big big women
womenwith withflu,
flu,hospitalization
hospitalizationrates rateswere
were83%83%
problem.
problem.In Inone
oneclinical study11involving
clinicalstudy involving600 600 before
beforethe thetests
testswere
wereintroduced
introducedbut butonly
only38%38%
people,
people,77% 77%of ofthose
thosewith
withinfluenza
influenzainitially
initially in
inthose
thosegiven
giventhe therapid
rapidmolecular
moleculartests, tests,largely
largely Rapid
Rapidmolecular
moleculartests,
tests,such
suchas
asAbbott’s
Abbott’sIDIDNow,
Now,
received
receivedan anincorrect
incorrectnegative
negativeresultresultfrom fromaa because
becausethesethesewomen
womenwere weregiven
giveneffective
effectivetreat-
treat- quickly
quicklyand
andaccurately
accuratelyidentify
identifyviruses
virusesin
inaasample.
sample.
RIDT.
RIDT. Newer Newer RIDTs RIDTs have have beenbeen developed
developed ment
mentsooner.
sooner.Women Womengiven giventhe thenew
newtests
testsalso
also
to
to address
address such such accuracy
accuracy issues
issues but but several
several received
receivedfewerfewerthanthanhalfhalfasasmany
manyantibiotic
antibioticpre-pre- quickly
quickly and and correctly
correctly diagnosed
diagnosed consume consume
researchers
researcherssay saythat
thateven
eventhese
theseare arestill
stillnot
notsen-
sen- scriptions
scriptionsas asthose
thosewho whodid didnot,
not,because
becausetherethere fewer
fewer hospital
hospital resources.
resources. When When improvedimproved
sitive
sitiveenough
enoughto tobebereliable.
reliable.Another
Anothertype typeofof isisno
nobenefit
benefitin inprescribing
prescribingantibiotics
antibioticsfor forviral
viral patient
patientoutcomes
outcomesand andreduced
reducedresource
resourceuse useare
are
quick
quickinfluenza
influenzatest testknown
knownas asananimmunofluo-
immunofluo- diseases
diseasessuch suchas asflufluonce
oncetheytheyarearediagnosed.
diagnosed. considered,
considered,“the “thecost
costsavings
savingsalmost
almostcome cometo to
rescence
rescenceassay assayhas hassimilar
similarreliability
reliabilityproblems.
problems. As
As well
well asas streamlining
streamlining treatment,
treatment, rapidrapid the
thepoint
pointofofbalancing
balancingout”,out”,Anderson
Andersonsays, says,and
and
Rapid
Rapidmolecular
moleculartests, tests,however,
however,use useaadiffer-
differ- molecular
moleculartests testscould
couldalsoalsoreduce
reducethe therate
rateofof could
couldresult
resultin inaacost
costbenefit
benefitoverovertime.
time.
ent
entapproach.
approach.Rather Ratherthanthanrelying
relyingon onfinding
finding flu
flutransmission,
transmission,says saysRitu
RituBanerjee,
Banerjee,who whostud-
stud- Another
Anotherproblem
problemthat thathas
hasslowed
slowedthe theadop-
adop-
sufficient
sufficientquantities
quantitiesof ofantigen,
antigen,they theyinstead
instead ies
iesantimicrobial
antimicrobialdrugs drugsat atthe
theMayo
MayoClinic
Clinicin in tion
tion ofof rapid
rapid molecular
molecular testing
testing isis the the risk
risk of
of
copy
copylong longstretches
stretchesof ofviral
viralgenetic
geneticcode codecon-con- Rochester,
Rochester,Minnesota.
Minnesota.“If “Ifpatients
patientsare arediag-
diag- contamination.
contamination. Rapid Rapid molecular
molecular tests tests are
are
tained
tainedin inthe
thesample.
sample.Flu Fluviruses
viruseshave haveRNA RNAso so nosed
nosedwithwithinfluenza
influenzaquickly
quicklyusingusingan anaccurate
accurate designed
designed to to detect
detect and
and magnify
magnify snippetssnippets of of
the
thetests
testsfirst
firstimmerse
immersethe thesample
samplein inlab-made
lab-made test,
test,they
theywillwillspend
spendless lesstime
timein inhealth-care
health-care viral
viral RNA
RNA but but their
their high
high sensitivity
sensitivity means means
nucleotides,
nucleotides, creating creating aa matching
matching strand strand of of settings
settingswaiting
waitingfor fortest
testresults,
results,””Banerjee
Banerjeesays,says, they
theycancanpost
postan aninaccurate
inaccurateresult
resultififaalablabtech-
tech-
DNA.
DNA.Multiple
Multipleroundsroundsof ofheating
heatingand andcooling
cooling reducing
reducingthe theopportunity
opportunityfor forthe
thevirus
virustotospread
spread nician
nician hashas flu,
flu, for
for example,
example, or or ifif aa sample
sample isis
then
thencreate
createmanymanymore morestrands
strandsof ofDNA.
DNA.This This in
inbusy
busywaiting
waitingrooms.rooms.PeoplePeoplegivengivenaaquick,
quick, mishandled.
mishandled.“Monitoring
“Monitoringthat thatisissomething
somethingwe we
process,
process,calledcalledamplification,
amplification,makes makesititeasy easytoto definitive
definitivediagnosis
diagnosismight mightalso alsobe bemore
morelikely
likely do
doconsistently
consistentlyin inthe
theclinical
clinicallab,
lab,””Babady
Babadysays. says.
detect
detecteven evensmall
smallquantities
quantitiesof ofvirus.
virus.Abbott’s
Abbott’s to
to avoid
avoid going
going to to work
work or or school,
school, she she adds,
adds, “In
“Inaabusy
busyemergency
emergencyroom, room,ititbecomes
becomesmuch much
rapid
rapidmolecular
moleculartest, test,called
calledID IDNow,
Now,amplifies
amplifies lowering
loweringthe theodds
oddsof oftransmission
transmissioneven evenfurther.
further. more
morecomplicated.
complicated.””
the
theDNADNAat ataaconstant
constanttemperature.
temperature. Babady
Babadyisisnot notsure
surewhether
whetherrapid rapidmolecu-
molecu-
After
Afteramplification,
amplification,fluorescence
fluorescencedetectorsdetectors SLOW
SLOWUPTAKE
UPTAKE lar
lartests
testswill
willever
everbecome
becomecommonplace.
commonplace.But But
test
testwhether
whetherthe thegenetic
geneticsequences
sequencesmatch matchthosethose Despite
Despitethe thebenefits
benefitsof ofrapid
rapidmolecular
moleculartests,
tests, Anderson
Andersonthinksthinksthatthatearly
earlyinstitutional
institutionaladop- adop-
of
ofknown
knownflu fluviruses.
viruses.In InCepheid’s
Cepheid’stest, test,much
much hospitals
hospitalsandandhealth
healthsystems
systemshave havebeen
beenslow
slowtoto ters
ters— —such
suchas ashis
hisown
ownmedical
medicalcentrecentreat atWash-
Wash-
of
ofthis
thissample
sampleprocessing
processingtakes takesplace
placeinside
insideaa buy
buythem.
them.In In2016,
2016,the
theWorld
WorldHealth
HealthOrgani-
Organi- ington
ingtonUniversity
University— —could
couldencourage
encourageother other
maze
mazeof ofplastic
plasticchannels
channelsno nowider
widerthan thanaapokerpoker zation
zationfound
foundthat thatonly
only15%
15%of ofhospitals
hospitalswerewere health
healthproviders
providersto totry
trythe
thetests,
tests,asasthey
theypile
pileupup
chip.
chip. Within
Within 20–30 20–30 minutes,
minutes, the the machine
machine using
using rapid
rapid molecular
molecular tests
tests toto diagnose
diagnose flu.
flu. more
moreand andmore
moredata dataillustrating
illustratinghow howthe thetest
test
reveals
revealsnot notjust
justwhether
whetheraaperson personhas hasflu,
flu,but
but One
Oneof ofthe
thebiggest
biggestproblems
problemsisisthe thecost,
cost,Babady
Babady results
resultsaffect
affectpatient
patientoutcomes
outcomesand andhospitals’
hospitals’
which
whichstrainstrainandandsubtype
subtypeof ofthe
theinfluenza
influenzavirus virus says.
says. Whereas
Whereas RIDTs RIDTs cost
cost about
about US$15
US$15 perper bottom
bottomlines.
lines.
isiscausing
causingthe theillness.
illness. test,
test, rapid
rapid molecular
molecular And
Andconventional
conventionalhealthhealthsystems
systemsare arenot
notthe
the
“With
“Withthe the tests
testscan
cancostcostup
upto to$45
$45 only
onlypotential
potentialcustomers.
customers.As Asthethetests
testsbecome
become
AADEFINITIVE
DEFINITIVERESULT
RESULT molecular
molecular —— a
a financial
financial burden
burden more
morewidely
widelyaccepted,
accepted,Anderson
Andersonsays, says,“you’re
“you’re
There
There isis widespread
widespread consensus
consensus thatthat rapid
rapid tests
testsit’s done. that
it’sdone. that many
many health-care
health-care going
goingto tosee
seethem
themusedusedoutside
outsidehospital
hospitalset- set-
molecular
moleculartests
testsfor
forinfluenza
influenzaare aremuch
muchmore more It
Itdoesn’t
doesn’t providers,
providers, both
both pub-
pub- tings
tings— —at atpharmacies,
pharmacies,potentially
potentiallyeven evenat ataa
accurate
accuratethan
thanRIDTs.
RIDTs.A A2017 meta-analysis22
2017meta-analysis lic
lic and
and private,
private, would
would nurse’s
nurse’sroom
roomin inaahigh
highschool.
school.””
require
require
that
thatpitted
pittedRIDTs
RIDTsagainst
againstrapid
rapidmolecular
moleculartests
tests struggle
struggleto tobear.
bear.Rapid
Rapid The
Theunpredictability
unpredictabilityof ofthe
theinfluenza
influenzavirus’svirus’s
found
foundthat
thatboth
bothwere
weremore
morethan
than98%
98%accurate
accurate
additional
additional molecular
molecular testing
testing also
also evolution
evolution couldcould ultimately
ultimately be be what
what nudges
nudges
in
inidentifying
identifyingpeople
peoplewhowhodiddidnot
nothave
haveflu;
flu;the
the testing.”
testing.” requires
requires aa hefty
hefty initial
initial fine-tuned
fine-tunedrapidrapiddiagnostics
diagnosticsinto intoroutine
routineuse. use.
ANTOINE DORÉ
big
bigdifference
differencewas wasin inpeople
peoplewho whodid.
did.Using
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investmentin inaatesting
testing IfIfaavirulent
virulentfluflustrain
strainlays
layswaste
wasteto toschools
schoolsand and
RIDTs,
RIDTs, more
more than
than 45%
45% of of people
people with
with fluflu platform,
platform,such
suchas asCepheid’s
Cepheid’sGeneXpert
GeneXpertXpressXpress workplaces
workplacesin inaafew
fewyears,
years,aanearly
nearlyinstant
instanttest
test
received
receivedfalse
falsenegatives,
negatives,compared
comparedwith withjust
just or
or Abbott’s
Abbott’s ID ID Now.
Now. “Right
“Right now,now, everyone
everyone that
thatoffers
offersaccurate
accurateresults
resultsmight
mightjust justbebetoo
too
8%
8%using
usingrapid
rapidmolecular
moleculartests.
tests. has
hastotomake
makethe thecase
casetototheir
theirhospital
hospitalsystem
system compelling
compellingaaprospect
prospectto toignore.
ignore.■■
Greater
Greateraccuracy
accuracyalso alsoimproves
improvesthe thespeed
speed because
becauseof ofthe
theadded
addedcosts,
costs,””Anderson
Andersonsays. says.
of
ofdiagnosis
diagnosisbecause
becauseititeliminates
eliminatesthetheneed
needforfor Some
Someresearchers
researchersarguearguethat
thatthe
thecost
costof
ofrapid
rapid Elizabeth Svobodaisisaascience
ElizabethSvoboda sciencewriter
writerin
inSan
San
further
furtherlab
labtests,
tests,says
saysEsther
EstherBabady,
Babady,aamicro-
micro- molecular
moleculartesting
testingwould
wouldbe bepaid
paidfor
forby
byreduc-
reduc- Jose,
Jose,California.
California.
biologist
biologistat
atthe
theMemorial
MemorialSloanSloanKettering
KetteringCan-Can- tions
tions in
in flu
flu complications
complications and and the
the resulting
resulting
1.
1. Koul,
Koul,P.P.A.A.etetal.
al.Indian
IndianJ.J.Med. Microbiol.33
Med.Microbiol. 33(suppl.),
(suppl.),
cer
cerCenter
Centerin inNew
NewYork
YorkCity.
City.AAnegative
negativeresult
result unnecessary
unnecessarytreatments.
treatments.AAteam teamat atNewcastle
Newcastle 26–31
26–31(2016).
(2016).
from
fromananRIDT
RIDTisistreated
treatedasasmerely
merelyadvisory,
advisory,she she University,
University,UK, concluded55that
UK,concluded thatadopting
adoptingrapid
rapid 2.
2. Merckx,
Merckx,J.J.et etal.
al.Ann.
Ann.Intern. Med.167,
Intern.Med. 167,394–409
394–409
says:
says:“They
“Theywould
wouldstill
stillsend
sendthe
thesample
sampleto tothe
the molecular
moleculartests testswould
wouldsave
savethe theUKUKNational
National (2017).
(2017).
3.
3. Aoki,
Aoki,F.F.Y.Y.et
etal.
al.J.J.Antimicrob. Chemother.51,
Antimicrob.Chemother. 51,
clinical
clinicallab.
lab.””The
Themolecular
moleculartests
testschange
changethat that Health
Health Service
Service about
about £240,000
£240,000 ($295,000)
($295,000)
123–129
123–129(2003).(2003).
protocol.
protocol.“With
“Withthethemolecular
moleculartests
testsit’s
it’sdone,
done,”” each
eachyear
yearforforevery
every1,000
1,000people
peoplewith withflu-like
flu-like 4.
4. Anselem,
Anselem,O. O.etetal.
al.PLoS
PLoSONEONE14,
14,e0217651
e0217651(2019).
(2019).
she
shesays.
says.“It
“Itdoesn’t
doesn’trequire
requireadditional
additionaltesting.
testing.”” symptoms,
symptoms,largelylargelybecause
becausepatients
patientswhowhoareare 5.
5. Allen,
Allen,A.A.J.J.et
etal.
al.Diagnost.
Diagnost.Prognost. Res.2,
Prognost.Res. 2,15
15(2018).
(2018).
SS1111

OUTLOOK
OUTLOOK INFLUENZA
INFLUENZA
SSURVEILL
URVEILLAANNCE
CE
The social
forecast
Scientists
Scientistscan
cantrack
trackinfluenza
influenzain
inreal
real
time
timeby
bymonitoring
monitoringsocial
socialmedia,
media,
leading
leadingto
tomore
moreaccurate
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predictions.
BBYY CCHHAARRLLEESS SSCCHHMMI IDDTT
C
onventional
onventional influenza influenza surveillance
surveillance communication
communicationstrategies
strategiestotolimit
limitthe
theeffects
effectsofof computational
computationalscientist scientistatatHarvard
HarvardMedical
Medical
ANTOINE DORÉ
ANTOINE DORÉ
describes
describesoutbreaks
outbreaksof offlufluthat
thathave
have the
thevirus.
virus.Encouraged
Encouragedby byprogress
progressin inthe
thefield,
field, School
Schoolin inBoston,
Boston,Massachusetts,
Massachusetts,the thesystem
system
already
alreadyhappened.
happened.ItItisisbased basedon onreports
reports the
theCDC
CDCannounced
announcedin inJanuary
January2019 2019that
thatitit failed
failedbecause
becausemany manyof ofthetheselected
selectedsearchsearch
from
fromdoctors,
doctors,and andproduces
producesdata datathatthattake
take will
willspend
spendUS$17.5
US$17.5million
milliontotocreate
createaanetwork
network terms
termswere wereonly
onlyseasonal,
seasonal,with withlimited
limitedrel- rel-
weeks
weeksto toprocess
process— —often
oftenleaving
leavingthe thehealth
health of
ofinfluenza-forecasting
influenza-forecastingcentres
centresof ofexcellence,
excellence, evance
evanceto toflu
fluactivity,
activity,making
makingthe thepredictions
predictions
authorities
authoritiesto tochase
chasethe thevirus
virusaround,
around,ratherrather each
eachtasked
taskedwith
withimproving
improvingthe theaccuracy
accuracyand and noisy
noisyand andinaccurate.
inaccurate.AfterAfterthe theH1N1
H1N1debacle,
debacle,
than
thangetgetonontop
topof ofit.
it. communication
communicationof ofreal-time
real-timeforecasts.
forecasts. Google
Googlerevised
reviseditsitsflu-tracking
flu-trackingalgorithm.
algorithm.But But
But
Butevery
everyday,day,thousands
thousandsof ofunwell
unwellpeople
people The
TheCDC
CDCisisleading
leadingthetheway
wayon ondigital
digitalflu
flu the
thealgorithm
algorithmwas wasnot notroutinely
routinelyrecalibrated
recalibrated
pour
pourdetails
detailsof oftheir
theirsymptoms
symptomsand, and,perhaps
perhaps surveillance,
surveillance,but
buthealth
healthagencies
agencieselsewhere
elsewhereare are when
whenthe thecompany’s
company’ssearch-engine
search-enginesoftware software
unknowingly,
unknowingly,locations locationsinto intosearch
searchengines
engines following
followingsuit.
suit.“We’ve
“We’vebeen
beenworking
workingto todevelop
develop was
wasupgraded,
upgraded,and andthatthatcreated
createdadditional
additional
and
andsocial
socialmedia,
media,creating
creatingaatrove troveof ofreal-time
real-time and
andapply
applythese
thesemodels
modelswithwithcollaborators
collaborators problems.
problems.In In2015,
2015,Google
Googledropped
droppedthe theplat-
plat-
flu
fludata.
data.IfIfsuch
suchdata datacould
couldbe beused
usedto tomoni-
moni- using
usingaarange
rangeof ofdata
datasources,
sources,””sayssaysRichard
Richard form
formaltogether,
altogether,although
althoughititstillstillmakes
makessome some
tor
torflu
fluoutbreaks
outbreaksas asthey
theyhappen
happenand andto tomake
make Pebody,
Pebody,aaconsultant
consultantepidemiologist
epidemiologistatatPublicPublic ofofits
itsanonymized
anonymizeddata dataavailable
availableforforflu
flutracking
tracking
accurate
accuratepredictions
predictionsabout aboutits itsspread,
spread,that that Health
HealthEngland
Englandin inLondon.
London.The Thecapacity
capacityto to by
byresearchers.
researchers.
could
couldtransform
transformpublic-health
public-healthsurveillance.
surveillance. predict
predictflu
flutrajectories
trajectoriestwotwoto tothree
threeweeks
weeksin in The
Thedemise
demiseof ofGoogle
GoogleFlu FluTrends
Trendsraised raised
Powerful
Powerful computational
computational tools tools suchsuch as as advance,
advance,Pebody
Pebodysays,
says,“will
“willbebevery
veryvaluable
valuable concerns
concernsabout aboutthe therole
roleof ofbig
bigdata
datain intracking
tracking
machine
machinelearning
learningand andaagrowing
growingdiversity
diversityof of for
forhealth-service
health-serviceplanning.
planning.”” diseases.
diseases.But Butaccording
accordingto toVasileios
VasileiosLampos,
Lampos,
data
datastreams
streams— —not notjustjustsearch
searchqueries
queriesand and aacomputer
computerscientist
scientistatatUniversity
UniversityCollegeCollege
social
socialmedia,
media,but butalsoalsocloud-based
cloud-basedelectronic
electronic SPREAD
SPREADBETTING
BETTING London,
London,the theaccuracy
accuracyof offlu
fluforecasting
forecastingisis
health
healthrecords
recordsand andhumanhumanmobility
mobilitypatterns
patterns Digital
Digitalflu
flusurveillance
surveillancewas wastransformed
transformedwhen when improving.
improving.“We “Wehavehaveaalot lotmore
moredatadataand andthethe
inferred
inferredfromfromcensus
censusinformation
information— —are aremak-
mak- Google
Googleturned
turneditsitsattention
attentionto toflu
fluforecasting
forecasting computational
computationaltools toolshavehaveimproved,
improved,””he hesays.
says.
ing
ingititincreasingly
increasinglypossible possibleto tomonitor
monitorthe the in
in2008.
2008.The
Thecompany’s
company’ssurveillance
surveillanceplatform,
platform, “We’ve
“We’vehad hadaalotlotofoftime
timeto towork
workon onthem.
them.””
spread
spreadofofflufluthrough
throughthe thepopulation
populationby byfollow-
follow- called
calledGoogle
GoogleFluFluTrends,
Trends,used
usedmachine
machinelearn-
learn- Santillana
Santillanapoints
pointsout outthatthatmachine
machinelearn- learn-
ing
ingits
itsdigital
digitalsignal.
signal.Now,Now,models
modelsthat thattrack
trackfluflu ing
ingtotofit
fitflu-related
flu-relatedsearches
searchestogether
togetherwith with ing
inghashasmarkedly
markedlyimproved
improvedin inthe
theyears
yearssince
since
in
inreal
realtime
timeand andforecast
forecastflu flutrends
trendsare aremaking
making time-series
time-seriesdatadatagathered
gatheredby bythe
theCDC’s
CDC’sUS US Google
GoogleFlu FluTrends
Trendsfolded.
folded.“With
“Withmore
moresophis-
sophis-
inroads
inroadsintointopublic-health
public-healthpractice.practice. Outpatient
OutpatientInfluenza-like
Influenza-likeIllness
IllnessSurveillance
Surveillance ticated
ticatedapproaches,
approaches,it’s it’spossible
possibleto toautomati-
automati-
“We’re
“We’rebecoming
becomingmuch muchmore morecomfortable
comfortable Network
Network(ILINet).
(ILINet).With With3,500
3,500participating
participating cally
callyignore
ignorespuriously
spuriouslycorrelated
correlatedterms,
terms,so sothe
the
with
withhowhowthese
thesemodels
modelsperform,
perform,””says saysMatthew
Matthew clinics
clinics— —each
eachcounting
countinghow howmanymanypeople
people predictions
predictionsare aremore
morerobust,
robust,””he hesays.
says.
Biggerstaff,
Biggerstaff,an anepidemiologist
epidemiologistwho whoworks
workson on show
showup upwith
withsore
sorethroats,
throats,coughs
coughsand andfevers
fevers
flu
flupreparedness
preparednessatatthe theUSUSCenters
Disease higher
higherthan
than37.8
37.8°C °Cwith
withnonocause
causeother
otherthan
than COMPETITIVE
COMPETITIVEADVANTAGE
ADVANTAGE
Control
Controland andPrevention
Prevention(CDC) (CDC)in inAtlanta,
Atlanta, influenza
influenza— —ILINet
ILINetisisthethebenchmark
benchmarkfor forflu
flu The
Theproving
provingground
groundfor fornew
newapproaches
approachesto to
Georgia.
Georgia. monitoring
monitoringin inthe
theUnited
UnitedStates.
States.The
Theaimaimof of modelling
modellingisisananannual
annualforecasting
forecastingchallenge
challenge
In
In2013–14,
2013–14,the theCDCCDClaunched
launchedthe theFluSight
FluSight Google
GoogleFlu FluTrends
Trendswas wastotoestimate
estimateflu flupreva-
preva- hosted
hostedbybythe
theCDC.
CDC.About
About20 20teams
teamspartici-
partici-
Network,
Network,aawebsite
websiteinformed
informedby bydigital
digitalmod-
mod- lence
lencesooner
soonerthan
thanthetheILINet
ILINetdata
datacould.
could. pate
pateevery
everyyear,
year,and
andthe
thewinners
winnersare
arethose
thosethat
that
elling
elling that
that predicts
predicts the the timing,
timing, peak peak and and But
Buttwo
twohigh-profile
high-profilefailures
failuresbelied
beliedthethe perform
performbest
bestrelative
relativeto
tothe
theILINet
ILINetbenchmark.
benchmark.
short-term
short-termintensity
intensityof ofthe
theflufluseason
seasonin inten
ten media
mediafanfare
fanfareof ofits
itslaunch.
launch.First,
First,Google
GoogleFlu Flu In
Inthe
theabsence
absenceof ofthese
thesemodels,
models,thetheCDC’s
CDC’s
regions
regionsof ofthe
theUnited
UnitedStates Statesand andacross
acrossthe the Trends
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missedaaspring
springpandemic
pandemicof ofH1N1
H1N1flu flu approach
approachhas hasbeen
beentotoestimate
estimatefuture
futuretrends
trends
whole
wholecountry.
country.According
Accordingto toBiggerstaff,
Biggerstaff,flu flu in
in2009.
2009.Then
Thenititoverestimated
overestimatedthe themagnitude
magnitude based
basedononwhat
whatILINet
ILINetdata
datagathered
gatheredfrom
frompre-
pre-
forecasting
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respondersto toplan
planahead,
ahead, of
ofthe
the2012–13
2012–13flu fluseason
seasonbyby140%.
140%. vious
viousflu
fluseasons
seasonswould
wouldpredict
predictfor
foreach
eachregion
region
so
sothey
theycancanbe beready
readywith withvaccinations
vaccinationsand and According
According to to Mauricio
Mauricio Santillana,
Santillana, aa and
andfor
forthe
theUnited
UnitedStates
Statesasasaawhole.
whole.But
Butduring
during
SS1122

INFLUENZA
INFLUENZA OUTLOOK
OUTLOOK
the
the2017–18
2017–18flu fluseason,
season,most mostof ofthe
themodels
models
CARNEGIE MELLON UNIV.
CARNEGIE MELLON UNIV.
in
inthe
thechallenge
challengegenerated generatedpredictions
predictionsmore more
accurate
accuratethan thanthosethoseusingusingILINet’s
ILINet’shistorical
historical
baseline.
baseline.The TheCDC CDCnow nowincorporates
incorporatesseveral several
of
ofthe
thechallenge’s
challenge’stop-performing
top-performingmodels modelsinto into
its
itsFluSight
FluSightsystem.system.
For
Forthethepast pastfour fouryears,
years,the thewinner
winnerof ofthe
the
CDC’s
CDC’schallenge
challengehas hasbeen
beenaateam teamled ledbybycom-
com-
puter
puterscientist
scientistRoni RoniRosenfeld
Rosenfeldof ofCarnegie
Carnegie
Mellon
MellonUniversity
Universityin inPittsburgh,
Pittsburgh,Pennsylvania.
Pennsylvania.
Rosenfeld’s
Rosenfeld’steam, team,calledcalledthe theDelphi
DelphiResearch
Research
Group,
Group,bases basesits itspredictions
predictionson ontwotwocomple-
comple-
mentary
mentarysystems. systems.One Oneisisan anonline
onlinecrowd-crowd-
sourcing
sourcingwebsite websitecalled calledEpicast
Epicastthat thatallows
allows
people
peopleto toexpress
expresstheir theiropinions
opinionsabout abouthow how
the
thecurrent
currentflu fluseason
seasonmight mightplayplayout.out.“Epicast
“Epicast
exploits
exploitsthe thewisdom
wisdomof ofthe
thecrowds,
crowds,””Rosenfeld
Rosenfeld
says.
says.“The
“Theopinionopinionof ofanyanyoneoneperson
personwho who
responds
respondsisn’t isn’tas asaccurate
accurateas asthe
theaggregated
aggregated
opinions
opinionsof ofall
allthetheresponders
responderstogether.
together.””
The
Theteam’s
team’ssecondsecondsystemsystemrelies
relieson onmachine-
machine- The
TheDelphi
Delphiresearch
researchgroup
groupat
atCarnegie
CarnegieMellon
MellonUniversity
Universityforecasts
forecaststhe
thespread
spreadof
ofinfluenza.
influenza.
learning
learningalgorithms
algorithmsthat thatrepeatedly
repeatedlycomparecompare
trends
trendsobserved
observedduring duringthe thecurrent
currentflu fluseason
season high-performance
high-performancecomputing,
computing,Vespignani
Vespignani to
tousing
usingmodelled
modelledflu fluforecasts
forecastsin inreal-world
real-world
with
withthose
thoseseen seenin inprevious
previousdecades.
decades.The Thealgo-
algo- says,
says,“and
“andthey’re
they’realso
alsodata-hungry,
data-hungry,ininthat
thatthey
they settings.
settings.Many Manyof ofthese
theseindividuals
individualshave haveaa
rithm
rithmdraws
drawson onhistorical
historicalILINet
ILINetdata dataas aswell
wellasas require
requirevery
verydetailed
detailedsocietal
societaldescriptions.
descriptions.”” poor
poorunderstanding
understandingof ofhow
howthe thecomputational
computational
data
datafrom
fromsearchsearchenginesenginesand andsocial
socialmedia
mediato to Vespignani
VespignaniandandSantillana
Santillanaare
arenow
nowcollabo-
collabo- models
modelswork,work,he hesays,
says,and
andthethemodels
modelsare aremost
most
assemble
assembleaadistribution
distributionof ofall
allpossible
possibleseasonal
seasonal rating
ratingononways
waystotocombine
combinemachine
machinelearning
learning accurate
accurateatatforecasting
forecastingflu flutwo
twoto tofour
fourweeks
weeksin in
trajectories.
trajectories.ItItthen thenmodels
modelshow howthe thecurrent
current with
withthe
theagent-based
agent-basedapproach
approachto tocreate
createwhat
what advance,
advance,whichwhichdoes doesnotnotreally
reallyprovide
provideenough
enough
ANTOINE DORÉ
season
seasondiffers
differsatatthe themoment,
moment,and andhow howititisis they
theyclaim
claimwould
wouldbe bean
aneven
evenstronger
strongerflu-flu- time
timeto toallocate
allocateresources
resourceswherewherethey theyare aremost
most
likely
likelytotodiffer
differas asititcontinues.
continues. forecasting
forecastingmodel.
model. needed.
needed.Vespignani
Vespignanisays saysthat
thatmodels
modelsthat thatcould
could
As
Aswell
wellas asmachine
machinelearning,learning,researchers
researchers reliably
reliablypredict
predictthe thepeak
peakandandintensity
intensityofofthe theflu
flu
also
alsorely
relyon onmechanistic
mechanisticmodels modelsthat thatwork
workin inaa STRENGTH
STRENGTHININNUMBERS
NUMBERS season
seasonsix sixto toeight
eightweeks
weeksin inadvance
advancewould wouldbe be
fundamentally
fundamentallydifferent differentway. way.Machine
Machinelearn- learn- Researchers
Researchershave havestarted
startedto tocombine
combinemodels more
moreuseful.
models useful.
ing
ingmerely
merelylooks looksfor forpatterns
patternsin indata,
data,whereas
whereas into
into‘ensembles’
‘ensembles’that thathave
havemoremoreforecasting
forecasting
Santillana
Santillanasays saysthat
thatmore
moreresearch
researchisisneeded
needed
mechanistic
mechanisticapproaches approachesdepend dependon onspecific
specific power
powerthan thanthe theconstituent
constituentmodels modelsalone.alone.
into
intohowhowsocial
socialbehaviour,
behaviour,vaccination
vaccinationpro- pro-
assumptions
assumptionsabout abouthow howaaflu fluvirus
virusmoves moves “This
“Thisisissomething
somethingwe’ve we’velearned
learnedfrom fromthe the
grammes,
grammes,strain straincomposition,
composition,population population
through
throughthe thepopulation.
population. challenges,
challenges,””Biggerstaff
Biggerstaffsays. says.“Combinations
“Combinationsimmunity
immunityand andother
otherfactors
factorsaffect
affectthethemodels’
models’
“This
“Thisoften
oftenrequires
requiresbio- bio- work
workbetter.
better.””That
Thathas hascertainly
certainlybeenbeenthetheexpe-
expe-
accuracy.
accuracy.But Butresearchers
researchersalso alsoneed
needto tounder-
under-
“This
“Thisisis
logical
logicaland andsociological
sociological rience
rienceof ofthe
theFluSight
FluSightNetwork,
Network,which whichisisaacon-
con-
stand
standhowhowspatial
spatialscales
scalesfactor
factorintointoforecasting.
forecasting.
understanding
understanding about about
something
something sortium
sortiumof offour
fourindependent
independentresearch researchteamsteams
For
Forexample,
example,the theCDC’s
CDC’sforecasts
forecastsare arelimited
limited
the
the way
way disease
disease trans- trans- we’ve we’velearned learned that
thatcollaborate
collaborateon onaamultimodel
multimodelensemble.ensemble.
to
tonational
nationaland andregional
regionallevels
levelsbut butinvestiga-
investiga-
mission
mission really really works,”
works,” from
from the
the The
Theensemble
ensemblelinks links21 21models
models— —some
somethatthatuse
tors use
torshave
havebegun
begunto toconsider
considerthe theprospects
prospectsfor for
says
says Nicholas
Nicholas Reich, Reich, challenges.
challenges. machine
machinelearning
learningand andothers
othersthat
thatarearemechanis-
mechanis-
city-scale
city-scaleforecasts,
forecasts,as aswell
wellas asforecasting
forecastingacrossacross
aa biostatistician
biostatistician atat the the Combinations
Combinations tic
tic— —intointoaasingle
singlecomposite
compositemodel modelthatthattook
took
global
globalhemispheres.
hemispheres.
School
Schoolof ofPublic
PublicHealth Health workbetter.”
work better.” second
secondplace placein inthe
thelatest
latestCDC
CDCflu-forecasting
flu-forecasting
Meanwhile,
Meanwhile,work workisisunder
underway wayto toprovide
provide
and
andHealth
HealthSciences Sciencesatat challenge,
challenge,just justbehind
behindRosenfeld’s
Rosenfeld’steam. team. machine-learning-enabled
machine-learning-enabled forecasting forecasting in in
the
theUniversity
Universityof ofMassachusetts
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SS1133

OUTLOOK
OUTLOOK INFLUENZA
INFLUENZA
Moderna
ModernaTherapeutics
Therapeuticsproduces
producesmRNA
mRNAvaccines
vaccinesat
atits
itsfactory
factoryin
inNorwood,
Norwood,Massachusetts.
Massachusetts.
VACCIN
VACCINES
ES
Breaking out of the egg

Can
Canthe
thelatest
latesttechniques
techniquesspeed
speedup
upthe
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dangerouslyslow
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productionof
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BBYY EERRI ICC BBEENNDDEERR some

someseasons
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the2009 H1N1
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H1N1swine-flu pandemic,
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RickBright,
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directorof ofthe
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cal
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tracking about isis Whether
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coordi- around
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enza influenza
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its director,””says
says its
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Michael director,
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preparations, says
natorof
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DanielJernigan,
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SS6
11404 | N A T U R E | V O L 5 7 3 | 1 9 S E P T E M B E R 2 0 1 9
Outlook_FinalTemplate.indd
S60-S61 14 DM.indd 60
Outlook Influenza Bender 9/12/19
9/10/19 1:45
3:42 PM
INFLUENZA OUTLOOK
INFLUENZA
INFLUENZA OUTLOOK
OUTLOOK
months
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monthsin in which
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David Somevaccines
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uenza
uenza viruses (left) but are
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ernHemisphere,
ern Hemisphere,we wewould
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DanutaSkowronski,
Skowronski, HariHariPujar,
Hari Pujar,vice-president
Pujar, vice-presidentfor
vice-president fortechnical
for technicaldevel-
technical devel-
devel-
epidemiologylead
epidemiology leadfor
forinfluenza
influenzaand emerg-
andemerg-
emerg- opmentand
opment
opment andmanufacturing
and manufacturingat
manufacturing atatModerna
Moderna
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ingrespiratory
ing respiratorypathogens
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forDisease
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Europe the
the
theproduction
production
productiontime,
time,
time,Bright
Bright
Brightsays.
says.
says. normally
normally
normallyused used
usedto totoproduce
produce
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andother
other
other
and
andthetheUnited
UnitedStates.
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vaccinesmight might
mightbe be
be biological
biological
biologicaldrugs. drugs.
drugs.The The
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mRNAs
mRNAsare are
arethen
then
thenembed-
embed-
embed-
aacloser
closermatch
matchto tocirculating
circulatinghuman humanflu fluviruses
viruses
viruses PLANT
PLANT
PLANTPARENTHOOD
PARENTHOOD
PARENTHOOD ded
deddedin in
inlipid
lipid
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injection
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fluvaccines
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,the
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nanoparticles
nanoparticlesenter enter
entercellscells
cellsandandand
effective,
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Bright.This Thisisisbecause
becauseduring during
during particles
particles
particles(VLPs).
(VLPs).
(VLPs).Under Under
Underan an
anelectron
electron
electronmicro-micro-
deliver
deliver
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andtheythey
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proteins
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constitutethe the
thevaccine.
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passed
passedthrough
throughmany manygenerations,
generations,looking looking
looking trigger
trigger
triggersimilar
similar
similarimmuneimmune
immunereactions. reactions.
reactions.But But
Butthey
they
theyAs
As
Asreported
reported
reportedin ininMay
May
May2019, 2019,
2019,phase phase
phaseIIclinical
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for
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onethatthatgrows
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testedtwo twotwofirst-generation
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process,egg-based
egg-basedvaccines
vaccinesevolve evolve
evolve virus
virus
virusand
and
andposing
posing
posingno no
norisk
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ofinfection.
infection.
infection. mRNA
mRNA
mRNAvaccine vaccine
vaccinecandidates
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away
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strainstowards
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inyeast
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ous
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approved
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vaccines.The TheThe
work
workwellwellin inchickens,
chickens,something
somethingthat thatisisless less
less cells,
cells,
cells,but
but
butMedicago
Medicago
Medicagoin in
inQuebec
Quebec
QuebecCity, City,
City,Canada,
Canada,
studies
studies
Canada, studiesfound found
foundthat that
thatthe the
theModerna
Moderna
Modernavaccines vaccines
vaccineswere were
were
likely
likelytotohappen
happenin inmammalian
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takes
takesaaadistinctive
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distinctiveapproach approach
approach— ——growing
growing
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safe
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andoughtought
oughtto totobebebeeffective.
effective.
effective.ModernaModerna
Modernaisisistalk- talk-
talk-
Cell-based
Cell-based manufacturing
manufacturing might might have have
haveaaa vaccines
vaccines
vaccinesin in
intobacco
tobacco
tobaccoleaves. leaves.
leaves.“Plants
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“Plantsare are
arevery
very
ing
ingingto
very to
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potentialindustry industry
industryand and
andgovernment
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andare are
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ofmaking
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ners
ners
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commercial
commercialproduction. production.
production.
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notrelying
relyingon on900,000
900,000eggs eggscoming
comingin infrom
from
fromaaa very
very
verycomplex
complex
complexproteins,proteins,
proteins, ”””says
says
saysNathalie
Nathalie
NathalieLandry,
Landry,
Landry, Over
Over
Overat atatSanofi
Sanofi
SanofiPasteur,Pasteur,
Pasteur,Shiver Shiver
Shiversees sees
seesseveral
several
several
bunch
bunchof ofdifferent
differentfarms farmsand andwaiting
waiting11 11days
days
days the
the
thecompany’s
company’s
company’sexecutive executive
executivevice-president
vice-president
vice-presidentfor for
potential
potential
potentialadvantages
for advantages
advantagesof ofofmRNA
mRNA
mRNAvaccines,vaccines,
vaccines,which which
which
to
toinoculate
inoculatethose thoseeggs.eggs.””However,
However,even evenvac- vac-
vac- scientific
scientific
scientificand and
andmedical
medical
medicalaffairs.
affairs.
affairs. his
hishiscompany
company
companyisisisinvestigating
investigating
investigatingin inincollaboration
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cines
cinesproduced
producedin inmammalian
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based
based Medicago
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Medicagoproduces produces
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itsVLP
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with
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Bioof ofofLexington,
Lexington,
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on
oncandidates
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eggsbefore
beforethey they
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process
processknown known
knownas as
astransient
transient
transientexpression.
expression.
expression.Each Each
setts.
setts.
setts.He
Each HeHesayssays
saysthat
that
that“mRNA
“mRNA
“mRNAprobably probably
probablyhas has
hasaagood
agood
good
are
arerepeatedly
repeatedlygroomed groomedfor forgrowth.
growth. plant
plant
plantisisisdipped
dipped
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liquidthat that
thatcontains
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containsbac- bac-
potential
potential
potentialto
bac- to
toscale
scale
scaleup upupto totovery
very
verylarge
large
largescales,
scales,
scales,and andand
An
An alternative
An alternative method
alternative method
method of of
of production
production
production teria
teria
teriacarrying
carrying
carryingrecombi-
recombi-
frankly
frankly
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thesame
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samemanufacturing
manufacturing
manufacturingfacility facility
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away with
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eggsaltogether
altogether
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“We nant
nant
nantDNA DNA
DNAengineered
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engineeredto be
be to
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used
tousedfor for
formore
more
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thanone one
onetypetype
typeof ofofvaccine”.
vaccine”.
vaccine”.But But
But
involves
involvesrecombinant
recombinanttechnology.
technology. “Weare are
are
involves recombinant technology.The The
Thequadri-
quadri-
quadri- generating
generating encode
encode
encode the
the
the desired
desired
desired pro-
pro-
he
he heemphasizes
pro- emphasizes
emphasizesthat, that,
that,given
given
giventhe the
thehuge
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investment
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valent
valentFluBlok
FluBlokvaccinevaccine generating
valent FluBlok vaccinedeveloped
developed
developedby by
bySanofi
Sanofi
Sanofi the
the
teins.
teins.
teins.AAAvacuumvacuum
vacuumforces forces
required
required
requiredto
forces to
toturn
turn
turnvaccines
vaccines
vaccinesinto into
intocommercial
commercial
commercial
Pasteur
Pasteur in
Pasteur in Lyon,
in Lyon,
Lyon, France,
France,
France,isis ismanufactured
manufactured
manufactured
thevaccine
vaccine
vaccine the
the
the bacteria
bacteria
bacteria into
into
into the
the
products
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the for
forseasonal
seasonal
seasonalflu, flu,
flu,newnew
newmanufactur-
manufactur-
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in
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thiswayway...To To inside
inside
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the
in this way Togenerate
generate
generateFluBlok,
FluBlok,
FluBlok,genetically
genetically
genetically body.”
body.”
leaves.
leaves.
leaves. The
The
The recombinant
recombinant
recombinant ing
ingingplatforms
platforms
platformssuch such
suchas asasmRNA
mRNA
mRNAmust must
mustdeliver
deliver
deliver
modified
modified baculoviruses
modified baculoviruses
baculovirusesare are
areused
used
usedto to
toinsert
insert
insert body.” DNA
DNA
DNAenters enters
entersthe the
thenucleus
nucleus
improvements
improvements
nucleusimprovementsin ininthe
the
theefficacy
efficacy
efficacyof ofofvaccines.
vaccines.
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tail
tailored
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ored RNA into
RNA into
into insect
insect
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cells,
cells,where
where
wherethe the
the of
of
ofleaf
leaf
leafcells,
cells,
cells,where
where
wherethe theThe
theThe
Thethreat
threat
threatposed posed
posedby bybypandemics
pandemics
pandemicsisisisso so
sogreat
great
great
vaccine
vaccine proteins
proteins are
are subsequently
subsequently
vaccine proteins are subsequently grown. grown.
grown. protein
protein is
is transcribed
transcribed for
for aa
protein is transcribed for a period of days. period
period of
of days.
days. that
that government
government agencies
agencies
that government agencies such as BARDA such
such as
as BARDA
BARDA
In
Inaaapivotal
In pivotalclinical
pivotal clinical
clinicalstudy
study
study(L.(L.
(L.M.M. Dunkleetet
M.Dunkle
Dunkle etal.
al.
al. “This
“This
“Thisisisisaaavery
very
veryquickquick
quickprocess,
process,
process, ”””says
says
saysLandry.
Landry.
might
might
Landry.mightprovide
provide
provideassistance
assistance
assistancefor for
foremerging
emerging
emergingvaccine vaccine
vaccine
N.
N.Engl.
N. Engl.J.J.
Engl. J.Med.
Med.
Med.376, 376,
376,2427–2436;
2427–2436;
2427–2436;2017) 2017)
2017)that that
that Getting
Getting
Gettingthe the
therecombinant
recombinant
recombinantDNA DNA
DNAinto into
intothe
the
theleaves
leaves
platforms.
platforms.
platforms.“We’ve
leaves “We’ve
“We’vespent spent
spentover over
overUS$6 US$6
US$6billionbillion
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led
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to itsapproval
its approvalby
approval by
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the
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USFood
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andDrug Drug
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takes
takesjust
just
justthree
three
threeto to
tofour
four
fourminutes,
minutes,
minutes,and and
andthenthen
thenthethe
optimizing
optimizing
optimizinginfluenza
the influenza
influenzavaccines, vaccines,
vaccines,diversifying
diversifying
diversifyingand and
and
Administration
Administrationin
Administration in
in2016,
2016,
2016,FluBlok
FluBlok
FluBlokwas was
wasatat atleast
least
least plants
plants
plantsare are
areincubated
incubated
incubatedfor for
forfive
five
fiveto to
toseven
seven
sevendays.
days.
days.“If “If
augmenting
augmenting
augmentingthe
“If thethenational
national
nationalsupply supply
supplychain, chain,
chain, ””says
”says
says
30%
30% more efficacious than a standard flu vac-
30% more
more efficacious
efficacious than
than aa standard
standard flu
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we know
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which virus
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strain
we know which virus strain we need, we could we
we need,
need, we
we could
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Bright.
Bright. “We
“We don’t
don’t think
think
Bright. “We don’t think there is any pathogen there
there is
is any
any pathogen
pathogen
cine
cinein
cine inadults
in adultsover
adults over
overthethe
theageage
ageofof
of50,
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gener- start
start
startproducing
producing
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materialfive five
fivetoto
tosix
six
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on
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after the
theplanet
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thatcan can
candevastate
devastate
devastatepublic public
publichealth,
health,
health,
ally
allymore
ally morevulnerable
more vulnerablethan
vulnerable than
thanyounger
younger
youngerpeople,
people,
people,says says
says aaadeclaration
declaration of
of aa pandemic,
pandemic,
declaration of a pandemic,” Landry says. ”” Landry
Landry says.
says.lives,
lives,
lives, national security and our economicsitu-
national
national security
security and
and our
our economic
economic situ-
situ-
John
JohnShiver,
John Shiver,senior
Shiver, senior
seniorvice-president
vice-president
vice-presidentof of
ofglobal
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results
resultsof of
ofphase
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trials
trialswere
were
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positive
ation
ation
positiveationfaster
faster
fasterthan than
thanaaapandemic
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influenzavirus. virus.
virus. ””■”■■
vaccine
vaccineresearch
vaccine researchand
research and
anddevelopment
development
developmentat at
atSanofi
Sanofi
Sanofi and
and
andMedicago
Medicago
Medicagoexpects expects
expectsto to
tocomplete
complete
completeits its
itsthird
third
third
Pasteur
Pasteur in
in Swiftwater,
Swiftwater, Pennsylvania
Pennsylvania
Pasteur in Swiftwater, Pennsylvania. . . phase
phase III
III trial
trial for
for flu
flu this
this
phase III trial for flu this year. The com- Ericyear.
year. The
The com-
com- Eric Benderisisisaaascience
EricBender
Bender science
sciencewriter
writer
writerin
ininNewton,
Newton,
Newton,
Because
Becauserecombinant-protein
Because recombinant-protein
recombinant-proteinplatforms platforms
platformsdo do
do pany
pany
panyisisispreparing
preparing
preparingapplications
applications
applicationsfor for regulatory Massachusetts.
forregulatory
regulatory Massachusetts.
Massachusetts.
SS1155
1 9 S E P T E M B E R 2 0 1 9 | VO L 5 7 3 | NAT U R E | S 6 1

S60-S61 Outlook Influenza Bender DM.indd 61 9/24/19 12:03 PM
OUTLOOK
OUTLOOK INFLUENZA
INFLUENZA
Pigs
Pigswere
werethe
thesource
source
of
ofthe
the2009
2009H1N1
H1N1
influenza
influenzapandemic.
pandemic.
AGRICULTURE
AGRICULTURE production,
production,andandthis
thiscreates
createsan
anopportunity
opportunityfor for
AGNORMARK/GETTY
AGNORMARK/GETTY
Flu on the farm
viruses
virusessuch
suchasasinfluenza
influenzato tomutate
mutateand andspread.
spread.
But
Butthere
thereisisan
aneven
evengreater
greaterfear:
fear:that
thatthese
these
ever-changing
ever-changingviruses
viruseswill
willgive
giverise
riseto
tothe
thenext
next
human
humanpandemic.
pandemic.LastLastyear
yearmarked
markedthe the100-
100-
year
yearanniversary
anniversaryof ofaapandemic
pandemicthat thatkilled
killedas as
many
manyas as50
50million
millionpeople
peopleworldwide.
worldwide.“We’re“We’re
Farms
Farmshelp
helpto
tospread
spreadinfluenza
influenzabut
butthey
theymight
mightbe
bean
anearly
early worried,
worried,””says
saysIp,
Ip,“about
“aboutanother
anotherSpanish
Spanishflu.flu.””
warning
warningsystem
systemfor
forthe
thenext
nexthuman
humanpandemic.
pandemic. To
Toprevent
preventthat
thatfrom
fromhappening,
happening,researchers
researchers
need
needtotobolster
bolstersurveillance
surveillanceefforts
effortsandandcurb
curb
the
thespread
spreadofofflu
fluin
inanimals.
animals.
BBYY CCAASSSSAANNDDRRAA WWI ILLLYA
LYARRDD differed
differedfrom
fromall allthose
thosethat
thathad
hadbeenbeendetected
detected
previously:
previously:ititcamecamefrom
fromAsia.
Asia. THE
THEBIRD
BIRDFLU
FLU
I
nn December
December 2014, 2014, virologist
virologist Hon Hon Ip Ip For
Formore
morethan thanaadecade,
decade,Ip Iphad
hadbeenbeenmoni-
moni- There
Thereare arefour
fourtypes
typesof ofinfluenza.
influenza.TheThemost most
received
receivedaashipment
shipmentfrom fromaabiologist
biologistin in toring
toringwild
wildbirds
birdsfor
forsigns
signsofofAsian
Asianbirdbirdflu
flubut
but common,
common,influenza
influenzaA, A,can
caninfect
infectboth
bothhumans
humans
Washington
Washingtonstate.state.ItItwas
wasaapackage
packagecontain-
contain- had
hadnever
neverfound
foundthe thevirus.
virus.Now,
Now,lesslessthan
thanaayear
year and
andanimals.
animals.Virologists
Virologistsclassify
classifythese
theseviruses
viruses
ing
ingnine
ninedead
deadbirds.
birds. after
afterthe
thevirus
virusemerged
emergedin inChina
Chinaand andSouth
South into
intosubtypes
subtypesbasedbasedon ontwo
twoproteins
proteinson ontheir
their
Ip’s
Ip’s job
job at the US
at the US Geological
Geological Survey’s
Survey’s Korea,
Korea,itithad
hadmademadethetheleap
leapacross
acrossthe theBering
Bering surface,
surface,haemagglutinin
haemagglutinin(H) (H)and
andneuramini-
neuramini-
National
NationalWildlife
WildlifeHealth
HealthCenter
Centerin inMadison,
Madison, Strait
Straitinto
intothetheUnited
UnitedStates.
States.“It
“Itisisthe
thescenario
scenario dase
dase(N).
(N).There
Thereare are1818recognized
recognizedhaemagglu-
haemagglu-
Wisconsin,
Wisconsin,was wasto towork
workout outwhat
whathadhadkilled
killed we’d
we’dbeen
beenwatching
watchingfor forsince
since2005,
2005,””Ip Ipsays.
says. tinin
tinintypes
typesandand11 11neuraminidase
neuraminidasetypes. types.The The
the
thebirds.
birds.He
Hewas
wasworried
worriedthatthatititmight
mightbebeavian
avian Over
Overthethenext
nextsix
sixmonths,
months,the thevirus
virusevolved
evolved dead
deadbirds
birdsthat
thatIpIpexamined
examinedwere wereinfected
infectedwithwith
influenza.
influenza.There
Therehad hadbeen
beenan anoutbreak
outbreakin inSouth
South in
inaavariety
varietyof ofways,
ways,jumped
jumpedfrom fromwild wildbirds
birds the
theH5N8
H5N8virus.
virus.
Korea
Korea earlier
earlier that
that year,
year, and
and in in December
December aa to
toturkeys
turkeysand andchickens,
chickens,andandwreaked
wreakedunprec-
unprec- But
But viruses
viruses do do not
not stay
stay neatly
neatly inin their
their
novel
novelversion
versionof ofavian
avianinfluenza
influenzawas wasdetected
detected edented
edentedhavochavocon onthe
theUSUSpoultry
poultryindustry.
industry. assigned
assignedcategories.
categories.“Flu“Fluviruses
viruseshave
havean aninfi-
infi-
in
inCanada,
Canada,justjust70 70kilometres
kilometresnorth northofofwhere
where More
Morethanthan50 50million
millionchickens
chickensand andturkeys
turkeys nite
nitecapacity
capacityto tomutate,
mutate,””IpIpsays.
says.“They
“Theymutate
mutate
the
the birds
birds now
now in in Ip’s
Ip’s possession
possession had had been
been in
inthe
theUnited
UnitedStatesStateswere
werekilled,
killed,either
eitherbybythe
the atatsome
someof ofthe
thefastest
fastestknown
knownrates”
rates”of
ofany
anyvirus.
virus.
found.
found.He Hefeared
fearedthat thatthese
thesewaterfowl
waterfowlmightmight virus
virusororbybyefforts
effortstotostop
stopits
itsspread,
spread,making
making They
Theyalso alsochange
changethrough
throughaaprocess
processcalled
called
also
alsohave
havebeen
beeninfected.
infected. this
thisthe
thelargest
largestand andmost
mostexpensive
expensiveavian avianinflu-
influ- reassortment.
reassortment.The Theinfluenza
influenzaAAvirusvirushas
haseight
eight
The
Thecause
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indeedavianavianflu.
flu. enza
enzaoutbreak
outbreakin inthe
theUnited
UnitedStates.
States. RNA
RNAsegments,
segments,and andififmore
morethanthanone
onevirusvirus
Whole-genome
Whole-genome sequencing sequencing revealedrevealed11 the
the Modern
Modernfarms farmsareareparticularly
particularlyvulnerable
vulnerableto to infects
infectsaasingle
singlecell,
cell,the
theviruses
virusescancanswap
swapsome some
presence
presenceof ofaahighly
highlypathogenic
pathogenicstrain strainof
ofthe
the devastation
devastationfrom frominfluenza.
influenza.AAlarge
largefarm
farmmight
might of
ofthose
thoseRNARNAsegments.
segments.This Thiscould
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giveriserise
influenza
influenza virus.
virus. Such
Suchviruses
viruses do do occasion-
occasion- hold
holdtens
tensof ofthousands
thousandsof ofchickens
chickensor orthou-
thou- to
toananentirely
entirelynewnewvirus
virusforforwhich
whichnonohuman
human
ally
allyarise
arisein
inthe
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thisstrain
strain sands
sandsof ofpigs
pigsin inthe
thename
nameof ofefficient
efficientprotein
protein or
oranimal
animalhashasimmunity,
immunity,Ip Ipsays,
says,and
andititisisthis
this
SS1166

INFLUENZA
INFLUENZA OUTLOOK
OUTLOOK
constant
constantshuffling
shufflingthat thatmakes
makesinfluenza
influenzaso sodif-
dif- that
thatpoultry
poultryproducers
producersimmunize
immunizetheirtheirbirds
birds improvements
improvementsin intechnology
technologywill
willallow
allowthem
them
ficult
ficultto totreat
treat— —andandso sodangerous.
dangerous. with
withaavaccine
vaccinetargeting
targetingboth
boththetheH5
H5and
andH7H7 to
tokeep
keepbetter
bettertabs
tabsononinfluenza
influenzain
inanimals
animalsand
and
The
Theconcern
concernaroundaroundavian avianinfluenza
influenzabegan began strains.
strains.The
Thestrategy
strategyworked.
worked.By ByJune
June2018,
2018,the
the curb
curbthe
thespread
spreadofofthe
thevirus.
virus.
in
inthethelate
late1990s
1990swhen whenaahighly highlypathogenic
pathogenic vaccine
vaccinehad
hadbeen linked33to
beenlinked toaa92%
92%decrease
decreasein
in
strain
strain of of H5N1
H5N1 began began infecting
infecting people people in in H7
H7detection
detectionrates
ratesin
inpoultry
poultryand
andaa98%
98%reduc-
reduc- STOPPING
STOPPINGTHE
THESPREAD
SPREAD
Hong
HongKong. Kong.Until Untilthen,then,avian avianinfluenza
influenzahad had tion
tionin
inhuman
humancases.
cases. China
Chinahas hasbeen beenvaccinating
vaccinatingpoultrypoultryagainst
against
caused
causedonly onlymildmilddisease
diseasein inhumans.
humans.But ButH5N1H5N1 avian
avianinfluenza
influenzabut butthethepractice
practiceisisnot notcommon
common
was
wasdifferent.
different.The Thefirst
first18 18cases
casesin inHong
HongKong Kong AACAULDRON
CAULDRONOF
OFVIRUSES
VIRUSES in
inthetheUnited
UnitedStates.
States.No Nobirds
birdsatatallallwere
werevac-vac-
resulted
resultedin in66deaths.
deaths.On Onthat thatoccasion,
occasion,there there Some
Someresearchers
researchersare aremore
moreworried
worriedabout aboutpigs pigs cinated
cinatedduringduringthe the2014–15
2014–15outbreak.
outbreak.Accord-Accord-
was
wasno nopandemic
pandemic— —no nomore morehuman humancases cases than
thanpoultry.
poultry.Gregory
GregoryGray, Gray,an anepidemiologist
epidemiologist ing
ingto toJoelle
JoelleHayden,
Hayden,aaspokesperson
spokespersonfor forthe
the
emerged.
emerged. But But in in 2004,
2004, the the World
World Health Health at
atDuke
DukeUniversity
Universityin inDurham,
Durham,North NorthCaro- Caro- USDA’s
USDA’sAnimal Animaland andPlant
PlantHealth
HealthInspection
Inspection
Organization
Organization(WHO) (WHO)warned warnedthat thatthe thenext
next lina,
lina,considers
considerspigs pigsto tobebeideal
idealmixing
mixingvessels vessels Service,
Service,vaccination
vaccinationwould wouldbe beused
usedonlyonlyas aspart
part
pandemic
pandemiccould couldresult
resultin inthethedeaths
deathsof ofupuptoto for
forinfluenza
influenzaviruses virusesbecause
becausethe theanimals
animalsare are of
ofan aneradication
eradicationeffort effortforforhighly
highlypathogenic
pathogenic
7 million
7 millionpeople peopleworldwide.
worldwide. susceptible
susceptibleto tonotnotonly
onlyswine
swineflu, flu,butbutalso
alsoavian
avian strains
strainsof ofavian
avianinfluenza,
influenza,not notasasaareplacement
replacement
Health
Healthofficials
officialsfeared
fearedthat thatdeadly
deadlyAsian Asian and
andhuman
humaninfluenza.
influenza.Even Evenso, so,flu fluviruses
virusesin in for
foreradication.
eradication.
viruses
virusessuch suchas asH5N1
H5N1might mightmake makethe theleapleaptoto swine
swineoften
oftengo goundetected
undetectedand andunreported.
unreported. But
Butvaccination
vaccinationcan canbebeproblematic.
problematic.Any Any
North
NorthAmerica,
America,so soIp Ipand
andothers
othersbeganbeganmoni- moni- “Influenza
“Influenza AA viruses viruses are are largely
largely tolerated
tolerated virus
virusthat thatisisnot notwholly
whollyeradicated
eradicatedcould couldstillstill
toring
toringwild wildbirds
birdsforforsigns
signsof ofsuch
suchviruses.
viruses.For For because
becausethey theydon’t
don’tcausecauseaabig bigproblem,
problem,atatleast least mutate
mutateenough enoughto torender
renderthe thevaccine
vaccineagainst
against
nearly
nearlyaadecade,
decade,every everysearch
searchcame cameup upclean.
clean. not
notininthe
thepigs,
pigs,””Gray
Graysays.says. ititineffective.
ineffective.Even Evenwhen whenan aneffective
effectivevaccine
vaccine
Then,
Then,in in2014,
2014,those
thosenine ninedead deadbirds
birdsarrived
arrived The
TheWorld
WorldOrganisation
Organisationfor forAnimal
AnimalHealth, Health, isisavailable,
available,its itsuse
useisisnotnotguaranteed.
guaranteed.AA2018 2018
atatIp’s
Ip’slab.
lab.TheThemoment
momentthe theH5N8
H5N8virus viruscrossed
crossed the
theParis-based
Paris-basedintergovernmental
intergovernmentalbody bodythat that study55 found
study found that that somesome H7N9
H7N9 viruses
viruses had had
the
theBering
BeringStraitStraitandandentered
enteredNorth NorthAmerica
America sets
setsstandards
standardsfor forreporting
reportinganimal animaldisease,disease, become
becomelethal lethalin inducks,
ducks,yet yetonly
onlyabout
about30% 30%of of
represented
representedthe thedawn
dawnof ofaanew newreality.
reality.“Not “Not requires
requiresthat thatcertain
certainstrains
strainsof ofavian
avianinfluenza
influenza China’s
China’sduck duckpopulation
populationhad hadbeen
beenvaccinated.
vaccinated.
only
onlywas wasititan anexchange
exchangeof ofan anavian
avianinfluenza
influenza be
bedeclared.
declared.But Butporkporkproducers
producersdo donotnotneed
need Jürgen
JürgenRicht,Richt,aaveterinary
veterinarymicrobiologist
microbiologist
virus,
virus,ititwas
wasan anexchange
exchangeof ofaadeadly
deadlyform form— —aa to
toreport
reportswineswineflu fluto tothe
theauthorities.
authorities. atatKansas
KansasState StateUniversity
Universityin inManhattan,
Manhattan,says says
highly
highlypathogenic
pathogenicvirus, virus,””says saysDavid
DavidSwayne,
Swayne, In
InApril
April2009,2009,officials
officialsin inthe
theUnited
UnitedStatesStates that
thatproducers
producersneed needsomething
somethingthey theycancaneas-eas-
laboratory
laboratorydirectordirectorof ofthetheSoutheast
SoutheastPoultry Poultry detected
detectedaanew newstrain
strainof ofinfluenza
influenzain inhumans
humans ily applyen
ilyapply enmasse,
masse,rather
ratherthan
thaninjecting
injectingeach each
Research
ResearchLaboratory
Laboratoryof ofthetheUS USDepartment
Departmentof of known
known as as H1N1.
H1N1. The The bird
birdindividually.
individually.Richt Richtandandhishiscolleagues
colleaguesare are
Agriculture
Agriculture(USDA) (USDA)in inAthens,
Athens,Georgia.
Georgia. virus
virusbecame
becameknown knownas as “The “Thepicture picture developing
developingaasprayable sprayablelive livevaccine
vaccinethat thatpro-
pro-
Another
Another concernconcern isis that that avian
avian influenza
influenza swine
swine flu flu and
and seemed
seemed we wehave haveof of tects
tectsagainst
againstboth bothavian
avianinfluenza
influenzaand andthethevirus
virus
viruses
virusesof ofAsian
Asianorigin
originoften oftenhave havehigher
highermor- mor- to
to be
be the
the product
product of of aa the thetypes typesof of that
thatcauses
causesNewcastle
Newcastlediseasedisease— —another
anotherseri- seri-
bidity
bidityand andmortality
mortalityrates ratesin inhumans
humansthan thanother
other re
reassortment
assortmentbetween between viruses virusesthat that ous
ousinfection
infectionthat thataffects
affectspoultry.
poultry.So Sofar,
far,they
they
avian
avianflu flustrains,
strains,sayssaysJames
JamesKile, Kile,an aninfluenza
influenza three
three viruses
viruses circulat-
circulat- are arecirculating
circulating have
havetested
testedversions
versionsaimedaimedatateradicating
eradicatingthe the
specialist
specialistatatthe theUS
USCenters
DiseaseControl
Control ing
ing inin pigs.
pigs. The The virus
virus H5,
H5,H7 H7and andH9 H9strains
strainsof ofinfluenza.
influenza.RichtRichtisisalso
also
is
isvery
very
and
andPrevention
Prevention(CDC) (CDC)in inAtlanta,
Atlanta,Georgia.
Georgia. spread
spreadquickly
quicklyaround around working
workingon onaauniversal
universalvaccinevaccinefor forhumans
humans
superficial.”
superficial.”
AGNORMARK/GETTY
The
TheH5N8H5N8strainstrainhas hasnot notyet yetcaused
causeddis- dis- the
the world,
world, and and two two that
thatmight
mighteventually
eventuallybe beused
usedforforanimals
animalstoo. too.
ease
easein inhumans
humansbut butother
otheravian avianvirusvirusstrains
strains months
monthslater laterthe theWHOWHO Richt
Richtand andhis hiscolleagues
colleagueshave havealsoalsocreated
created
have.
have.In In2013,
2013,aanew newstrainstrainof ofavian
avianinfluenza
influenza declared
declaredthat thatthe theoutbreak
outbreakhad hadreached
reachedpan- pan- aapigpigthat
thatisisgenetically
geneticallyresistant
resistantto toswine
swineflu. flu.
emerged
emergedin inChina:
China:H7N9.H7N9.Unlike Unlikethe thevirus
virusthatthat demic
demicstatus.
status.In Inthe
thewakewakeof ofthis
thispandemic,
pandemic,the the This
Thismightmightprotect
protectnot notonly
onlythethepigs,
pigs,butbutalso
also
caused
causedthe theUS USoutbreak,
outbreak,H7N9 H7N9did didnot nottypi-
typi- USDA
USDAlaunched
launchedaaprogrammeprogrammein inconcert
concertwith with humans.
humans.Even Evenififthe thepig
pigcancanstill
stillbebeinfected,
infected,
cally
callykill
killpoultry,
poultry,atatleastleastnot notinitially.
initially.Indeed,
Indeed, industry
industryand andthe theCDCCDCto toconduct
conductvoluntaryvoluntary its
itsresistance
resistanceto toinfluenza
influenzacould couldmean meanthat that
itit caused
caused such such mildmild illness
illness that that itit waswas notnot surveillance
surveillancefor forswine
swineflu. flu.The
Thegoal goalisisto tokeep
keep itit spreads
spreads less less readily.
readily. But But whether
whether the the US US
detected
detecteduntil untilititbegan
beganinfecting
infectingpeople.people. tabs
tabsononthetheviruses
virusesthat thatare
arecirculating
circulatingin inpigs.
pigs. Food
Foodand andDrug DrugAdministration
Administration(FDA) (FDA)will will
To
To combat
combat the the spread
spread of of the
the virus,
virus, the the Despite
Despite this, this, “the
“the picture
picture we we have have of of the
the allow
allowsuch suchpigs pigsinto
intothethefood
foodsupply
supplychain chainisis
authorities
authoritiesin inChina
Chinabegan beganclosing
closinglive livepoultry
poultry types
typesof ofviruses
virusesthat thatare arecirculating
circulatingisisvery very not
notyet yetclear.
clear.“This
“Thisisisthe thebiggest
biggestquestion
questionat at
markets
marketsin inprovinces
provinceswhere wherehuman humaninfections
infections superficial,
superficial,””says saysGray.Gray.ThatThatisistrue truenot notonly
only the
themoment,
moment,””Richt Richtsays.says.So Sofar
farthe
theFDAFDAhas has
had
hadoccurred.
occurred.But Butthese
thesemeasures
measuresto tocurb
curbthe the for
forthe
theUnited
UnitedStates Statesbut butalso
alsoChina,
China,which whichisis approved
approved only only oneone genetically
genetically engineered
engineered
spread
spreadof ofinfluenza
influenzamay maynot notalways
alwayshave havehad had the
theworld’s
world’slargest
largestproducer
producerof ofpork.
pork. animal
animalfor forfood
fooduse:use:aasalmon
salmonthat thathashasbeen
been
the
theintended
intendedeffecteffect22..Rather
Ratherthan thanshutting
shuttingall allthe
the “There’s
“There’saamassive
massivetransition
transitionin inChina
Chinafrom from modified
modifiedto togrow
growfaster.
faster.
markets
marketsatatonce, once,thetheclosures
closureshappened
happenedatatdif- dif- small
smallandandmedium-sized
medium-sizedfarms farmstowardstowardslarge large Even
Evenififthese
thesestrategies
strategiesare arewidely
widelyadopted,
adopted,
ferent
ferenttimes
timesin indifferent
differentprovinces.
provinces.In InJiangsu,
Jiangsu, industrialized
industrializedfarms, farms,but butwe westillstillseeseerather
rather Ip
Ip emphasizes
emphasizes that that we we must
must stay
stay vigilant.
vigilant.
for
forexample,
example,the thepolicy
policytook tookeffect
effectin inDecem-
Decem- poor
poorbiosecurity,”
biosecurity,”Gray Graysays.
says.When Whenhe heandand Another
Anotherinfluenzainfluenzapandemic
pandemicisisinevitable
inevitableand and
ber
ber2013,
2013,whereas
whereasthe theneighbouring
neighbouringprovince province his
hiscolleagues
colleaguestoured touredfarms farmsin inChina,
China,they they no
noone oneknows
knowsexactly
exactlywhat whatititwill
willlook
looklike.
like.
of
ofAnhui
Anhuitook tookno noaction
actionuntil untilFebruary
February2014. 2014. noticed
noticedthat thatpersonal
personalprotective
protectiveequipmentequipmentisis “We
“Wealways
alwayshone honeaastrategy
strategytowards
towardsthe thelast
last
This
Thismeant
meantthat thatalthough
althoughthe themeasure
measureseemed seemed used
usedonly
onlysporadically,
sporadically,barriersbarriersto tostop
stoprodents
rodents outbreak
outbreakthat thatwe weexperienced,”
experienced,”Ip Ipsays.
says.But But
to
towork
workinitially,
initially,poultry
poultryfarmers farmersin ininfected
infected entering
entering are are rare,
rare, and and pigs
pigs are are sometimes
sometimes strategies
strategiesused usedduring
duringthe thelast
lastoutbreak
outbreakmay may
areas
areaswerewereableabletotosend
sendtheirtheirbirds
birdsto tomarkets
marketsin in housed
housednear nearducks,
ducks,geese geeseor orchickens.
chickens.“It’s “It’saa not
notworkworknext nexttime.
time.“Never
“Neverbe bedogmatic,
dogmatic,””he he
neighbouring
neighbouringprovinces provincesthat thathadhadnot notyet yetbeen
been cauldron
cauldronof ofvirus
virusmixing,
mixing,””Gray Graysays. says. says.
says.“The“Theflu fluvirus
viruschanges
changesall allthe
thetime.
time.””■■
affected,
affected,thereby
therebyspreading
spreadingthe thevirus.
virus. In
In2015,
2015,Gray Grayand andhis hiscolleagues
colleagueslaunched launched
The
TheCDCCDCcurrently
currentlyranks ranksH7N9 H7N9as asthetheinflu-
influ- aafive-year
five-yearstudy studyto toexamine
examinethe thetransmission
transmission Cassandra
CassandraWillyard Willyardisisaasciencesciencejournalist
journalistin in
enza
enzavirus
viruswithwiththethehighest
highestpotential
potentialpandemic
pandemic of
ofswine
swineinfluenza
influenzain inlarge
largepigpigfarms
farmsin China. Madison,
inChina. Madison,Wisconsin. Wisconsin.
risk.
risk.TheThevirus
virushashasmade
mademore morethan than1,500
1,500peo- peo- Results
Resultsfromfromthe thefirst
firstyear
yearof ofthat
thatstudystudy44suggest
suggest
1.1. Ip,
Ip,H.H.S.S.etetal.al.Emerg.
Emerg.Infect. Dis.21,
Infect.Dis. 21,886–890
886–890
ple
pleillilland
andkilled
killedat atleast
least615 615since
since2013.2013.But But that
thatswine
swineflu fluisisfairly
fairlycommon
commonin inpigs
pigsandandthat
that (2015).
(2015).
the
thethreat
threatseemsseemsto tohave
haveabated,
abated,atatleastleastfor forthe
the farm
farmworkers
workersare arealso
alsobeing
beinginfected.
infected.The Theteam
team 2.2. Li,Li,Y.Y.etetal.al.PLoS ONE13,
PLoSONE 13,e0208884
e0208884(2018).
(2018).
moment.
moment.During Duringthe thewinter
winterof of2016–17,
2016–17,H7N9 H7N9 found
foundsimilar
similarH1N1 H1N1viruses virusesin inpigs, workers 3.3. Wu,
pigs,workers Wu,J.J.etetal. al.Emerg.
Emerg.Infect. Dis.25,
Infect.Dis. 25,116–118
116–118(2019).
(2019).
4.4. Anderson,
Anderson,B. B.D.
D.etetal.
al.Emerg.
Emerg.Microbes Infect.7,7,87
MicrobesInfect. 87
evolved
evolvedinto intoaahighly
highlypathogenic
pathogenicstrain. strain.The The and
andon onsurfaces
surfacesin inthethebarns.
barns. (2018).
(2018).
Chinese
Chinesegovernment
governmentresponded respondedby bymandating
mandating Gray
Grayand andother
otherresearchers
researchersare arehopeful
hopefulthat that 5.5. Shi,
Shi,J.J.etetal. al.Cell
CellHost Microbe24,
HostMicrobe 24,558–568
558–568(2018).
(2018).
SS1177

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