Genetic Privacy

Genetic Information and Privacy

GINA is essentially an anti-discrimination law that has nothing to do with privacy. It prevents
group health and Medicare supplemental plans—but not life, disability, or long-term care plans
—from using genetic information to discriminate against you when it comes to insurance.

Genetic Privacy
Annual Review of Medicine
Vol. 54:393-407 (Volume publication date February 2003)
https://doi.org/10.1146/annurev.med.54.101601.152131
Abstract

During the past 10 years, the number of genetic tests performed more than tripled, and
public concern about genetic privacy emerged. The majority of states and the U.S.
government have passed regulations protecting genetic information. However, research
has shown that concerns about genetic privacy are disproportionate to known instances
of information misuse. Beliefs in genetic determinacy explain some of the heightened
concern about genetic privacy. Discussion of the debate over genetic testing within
families illustrates the most recent response to genetic privacy concerns.

Global resource shortages during COVID-19: Bad

news for low-income countries
 Devon E. McMahon,
 Gregory A. Peters,
 Louise C. Ivers,
 Esther E. Freeman 

 Published: July 6, 2020

 https://doi.org/10.1371/journal.pntd.0008412

The world’s wealthiest countries have been gripped by resource shortages, including shortages of personal
protective equipment (PPE) and ventilators, during the coronavirus disease 2019 (COVID-19) pandemic [1, 2]. In
order to guarantee these resources for their own nation’s health workers, governments around the world are
bargaining for their share in a strangled global supply chain. For example, countries such as Taiwan, Thailand,
Russia, Germany, the Czech Republic, and Kenya have blocked the export of all face masks [3]. There have
additionally been reports of PPE and ventilator exports being intercepted and delivered to the country with the
highest bid, aptly referred to as acts of “modern piracy” [3].

Undeniably, securing PPE for health workers and respiratory devices for patients is a critical part of overcoming the
COVID-19 pandemic. However, we must not forget that for many hospitals, these resources have never been in
abundant supply. Instead, PPE and respiratory devices are scarce commodities for many hospitals in low-income
countries (gross national income per capita ≤US$1,025) under the best of circumstances, with health crises such as
the 2014–2016 West African Ebola epidemic highlighting gaps in the global PPE supply [4]. Indeed, deaths from
Ebola were concentrated among healthcare providers, with 8.1% of the total health workforce in Liberia and 6.9% in
Sierra Leone dying from Ebola [5]. Hospitals in low-income countries rely on the same supply chains as hospitals in
wealthy countries to import medical supplies but have significantly less bargaining power to secure resources [6].
Therefore, resource grabs by high-income countries will likely have devastating effects on low-income countries as
COVID-19 continues to spread globally [6, 7]. Already, UNICEF reports that the organization has only been able to
acquire one-tenth of the 240 million masks requested by low-income countries [6].

To better elucidate COVID preparedness in low-income countries, we combined data from all service provision
assessments (SPAs) conducted in nationally representative surveys of hospitals within the past 5 years in low-
income countries, which included Afghanistan, Democratic Republic of the Congo (DRC), Haiti, Nepal, and
Tanzania [8]. Our analysis of hospital general clinics confirms limited quantities of PPE, with only 24% to 51% of
hospitals reporting any type of face mask, 22% to 92% medical gowns, and 3% to 22% eye protection (Fig 1).
Sanitation supplies were also scarce, with 52% to 87% of hospitals recording soap plus running water and 38% to
56% alcohol-based hand sanitizer. We found further gaps in ability to provide care for respiratory conditions, again
demonstrating under-investment in hospital-based services [9]. The hospitals analyzed lacked pulse oximeters
(12%–48% available), oxygen tanks (10%–82%), and bag-masks necessary for basic resuscitation (28%–45%). As
has been noted by prior studies, more advanced respiratory support such as intensive care unit (ICU) care and
ventilators are even scarcer [10].

Download:

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Fig 1. Availability of hospital clinic PPE, sanitation, and functional diagnostics and therapeutics
across nationally representative samples of hospitals in 5 low-income countries.

PPE, personal protective equipment.

https://doi.org/10.1371/journal.pntd.0008412.g001
An important part of addressing the COVID-19 pandemic is adequate testing at the community level. In addition to
current shortages of COVID-19 testing globally [2, 11], the ability to offer COVID-19 testing will likely be further
constrained in low-income countries due to already limited diagnostic capacity. For example, SPA data show that
fewer than 20% of hospitals, besides those in Tanzania, were able to measure CD4 count for HIV monitoring.
Additionally, there is limited ability to provide routine childhood vaccination in hospitals in Afghanistan (35%),
DRC (14%), Haiti (57%), and Nepal (60%), underscoring the potential for gaps in the ability to transport, store, and
deliver vaccines if eventually available for COVID-19.

With COVID-19 causing unprecedented resource shortages in the world’s wealthiest countries, already limited
healthcare commodities will likely become even scarcer in low-income countries. There have been some rapid
adjustments in the global supply chain, with China increasing its output of medical masks to 12 times previous
levels [3]. But with prices for PPE and respiratory devices soaring, which hospitals will be able to afford them?

In the West African Ebola epidemic, investment in high-quality PPE and infection control training were important
components of halting the spread of disease [12], and where this was lacking, nosocomial spread was clearly worse
[13]. In response to the current COVID-19 challenge, countries such as Afghanistan and Nepal have started
manufacturing their own supplies of PPE and basic life support equipment, but this is not likely to be a feasible
approach for all countries [14, 15].

Continued local as well as international action is needed to ensure access to PPE for all health workers and
respiratory support for all patients, not just for those living in resource-abundant countries. As COVID-19
therapeutics and vaccines emerge, additional international commitment will be necessary to ensure global access.
Equity requires no less.

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Genetic privacy involves the concept of personal privacy concerning the storing,
repurposing, provision to third parties, and displaying of information pertaining to one's
genetic information. ... Due to the shared nature of genetic information between family
members, this raises privacy concerns of relatives as well.

Why is genetic privacy important?

Any DNA sample contains the entirety of the donating individual's genome. ... In 2008,
Congress passed the Genetic Information Nondiscrimination Act (GINA) which, at a
high level, protects against health insurance and employment
discrimination based on what is revealed by an individual's genetic information.

Genetic Privacy for Suspects?

In an upcoming hearing, the US Supreme Court will decide on whether
police can take DNA samples from suspects who have not been convicted.
Dan Cossins
Feb 12, 2013

Later this month the US Supreme Court will address the question of whether authorities have the
right to take DNA samples from people arrested for serious crimes, Wired reported.

During the hearing, scheduled for February 26, the justices will uphold or reject a 2012 decision
by the Maryland Court of Appeals, which ruled that taking DNA without warrants from suspects
who have not been convicted is a breach of the Fourth Amendment right against unreasonable
search and seizure.

The Obama administration filed in support of the practice, however, stating that “DNA
fingerprinting is a minimal incursion of an arrestee’s privacy interests.” The Electronic Privacy
Information Center countered that DNA sampling exposes people to unforeseen privacy issues as
our knowledge of genetics increases. “Once an individual’s DNA sample is in a government
database, protecting that information from future exploitation becomes more difficult,” said the
group in a filing.

But the justices have likely already made up their minds. Last July, Chief Justice John Roberts
said there was a “fair prospect” that the Supreme Court would reverse the lower court’s decision.

Meanwhile, French police investigating a series of sexual assaults in Marseille have used DNA
evidence to arrest identical twins brothers—but they cannot establish which brother committed
the crimes, or if they both did, because standard tests cannot differentiate between their DNA. A
more sophisticated test would be too expensive.

Keywords:

crime
DNA evidence

DNA sequencing

ethics

genetics & genomics

US Supreme Court

The US Supreme Court may consider whether authorities have the ability to take DNA samples from
persons arrested for severe crimes later this month, according to Wired.
The justices will decide whether it should uphold or dismiss a 2012 finding by the Maryland Court of
Appeals, which held that gathering DNA from suspects who have not been convicted without warrants is
a violation of the Fourth Amendment right against unjustified seizure of property.
However, the Obama administration defended the practice, claiming that “DNA fingerprinting is a minor
violation of an arrestee's private interests.” The Electronic Privacy Information Center stated that as our
understanding of biology grows, DNA sample exposes individuals to unknown privacy risks. In a
statement, the group stated that “once an individual's DNA sample is in a government database, securing
that information from future abuse becomes more difficult.”
The justices, on the other hand, are likely to have made up their minds. Last July, Chief Justice John
Roberts stated that the Supreme Court had a "fair shot" of rejecting the lower court's decision.
Meanwhile, French police investigating a series of sexual assaults in Marseille have used DNA evidence
to apprehend identical twin brothers—but they can't tell which brother committed the crimes, or whether
both did, because normal testing can't tell them apart. A more complex test would be too expensive.

The law of genetic privacy: applications,

implications, and limitations 
Ellen Wright Clayton, Barbara J Evans, James W Hazel, Mark A Rothstein
Abstract
Recent advances in technology have significantly improved the accuracy of genetic testing and
analysis, and substantially reduced its cost, resulting in a dramatic increase in the amount of genetic
information generated, analysed, shared, and stored by diverse individuals and entities. Given the
diversity of actors and their interests, coupled with the wide variety of ways genetic data are held, it
has been difficult to develop broadly applicable legal principles for genetic privacy. This article
examines the current landscape of genetic privacy to identify the roles that the law does or should
play, with a focus on federal statutes and regulations, including the Health Insurance Portability and
Accountability Act (HIPAA) and the Genetic Information Nondiscrimination Act (GINA). After
considering the many contexts in which issues of genetic privacy arise, the article concludes that few,
if any, applicable legal doctrines or enactments provide adequate protection or meaningful control to
individuals over disclosures that may affect them. The article describes why it may be time to shift
attention from attempting to control access to genetic information to considering the more
challenging question of how these data can be used and under what conditions, explicitly addressing
trade-offs between individual and social goods in numerous applications.

Technical advances have greatly increased the accuracy and reduced the cost of genetic testing and
analysis, resulting in a huge rise in the volume of genetic data created, analyzed, exchanged, and stored
by different individuals and entities. It has been challenging to define generally applicable legal
standards for genetic privacy due to the diversity of parties and their interests, as well as the wide
variety of methods genetic data is maintained. The current landscape of genetic privacy is examined in
this article to determine the roles that the law plays or should play, with a focus on federal statutes and
regulations, such as the Health Insurance Portability and Accountability Act (HIPAA) and the Genetic
Information Nondiscrimination Act (GINA) (GINA). The paper concludes that few, if any, applicable legal
concepts or enactments provide enough protection or meaningful control to individuals over disclosures
that may impact them after evaluating the different situations in which genetic privacy issues emerge.

GENETIC ENGINEERING OF HUMANS

Humans Inoculated with Genetically

Modified Malaria Parasites
Engineered Plasmodium parasites form the basis of two experimental
malaria vaccines that showed safety and encouraging immune responses
in clinical trials.

Ruth Williams
May 20, 2020
103

ABOVE: Administration of attenuated P. berghei vaccine via bites to the forearms from

mosquitoes (in the box)
ANTONIO MENDES

T wo clinical trials, in which subjects were vaccinated with genetically

engineered Plasmodium parasites and later exposed to the malaria-causing microbe, showed the
vaccines to be safe with promising, but not ideal, efficacy. Results of the trials are published
in two papers in Science Translational Medicine today (May 20).

“Within the malaria control and elimination space, we do need additional tools, so . . . these are
very welcome results,” says malaria and public health expert James Tibenderana of the Malaria
Consortium, a nonprofit organization that carries out research, develops policies, and advocates
for the prevention, control, and treatment of malaria. Tibenderana, who was not involved in
either study, adds, “They are cutting-edge innovations to attempt to customize a vaccine.”
Certain parasites of the Plasmodium genus, including P. falciparum and P. vivax, cause malaria
when transmitted to humans via mosquito bites. These parasites have “impacted human health
throughout history,” says malaria researcher Stefan Kappe of the University of Washington and
Seattle Children’s Research Institute who is developing his own engineered parasite vaccine but
was not involved in the studies. With more than 200 million cases of malaria causing more than
400,000 deaths per year, the majority of which are children, “we urgently need a vaccine,”
Kappe adds.

Developing one has been a decades-long challenge, and while candidates exist, none are ideal,
says Miguel Prudêncio of the Institute of Molecular Medicine in Portugal, author of one of the
papers. The vaccine furthest along in clinical development is RTS,S, which is composed of a
viral vector carrying a highly immunogenic Plasmodium antigen called circumsporozoite protein
(CSP). A pilot study of RTS,S is currently underway in Malawi, but the vaccine protects only
about 40 percent of recipients and has some safety concerns.

An alternative vaccination approach is to use the whole attenuated parasite, Prudêncio says, the
idea being that the live but weakened bug will activate the immune system more potently than
non-living protein vaccines. One strategy for attenuation is to blast the parasites with radiation.
Injection of irradiated P. falciparum has been shown to protect more than 80 percent of
recipients from subsequent challenge with infectious parasites. But, because irradiation doesn’t
affect each parasite equally—some are mildly affected, others killed—and because dead
parasites “probably don’t contribute” as much to immunization, “it is a very inefficient
production process,” says Robert Sauerwein of Radboud University in the Netherlands who
coauthored both papers. “You need many, many parasites and that means many, many
mosquitoes” to get a dose of vaccine.

Sauerwein and colleagues have instead developed genetically attenuated parasites that should be
“cheaper and safer,” he says. Cheaper because all the parasites are identical so fewer should be
needed to elicit the same effect as that seen with irradiated bugs. And safer because there is
practically no chance of the parasites reverting to infectious forms (a slim but not zero chance in
the case of irradiation), and there is no need for handling the infectious form whatsoever. The
rearing of thousands of mosquitoes carrying disease-causing P. falciparum is necessary in the
case of irradiation, but Sauerwein’s mosquitoes carry only the engineered, and therefore safe,
version.

Sauerwein’s engineered P. falciparum is missing two genes essential for the parasite’s
maturation in the human liver—the first stage of infection following a mosquito bite. This
prevents its subsequent infection of red blood cells—the second stage of infection in which the
parasite replicates wildly and the disease becomes symptomatic.

In the trial, 25 volunteers were injected with the modified parasites three times, at eight-week
intervals. The vaccinations were well tolerated and the subjects developed anti-
Plasmodium antibodies. They also had increased resistance to challenge with wildtype P.
falciparum. Three of the 25 vaccine recipients were protected from disease while the remaining
22 showed a significant delay in parasite detection in the blood compared with unvaccinated
controls, indicating the vaccine-induced immunity helped slow disease progression. Once
parasites were detected in a participant’s blood, they were given anti-malarial drugs to stop the
symptoms. A group of 13 volunteers vaccinated with irradiated P. falciparum as a positive
control all showed delayed parasite detection, but none were protected. Why the positive control
failed to protect to the degree previously reported (approximately 50 percent protection at the
dose given, or 80–90 percent had it been a full dose) is unclear, says Sauerwein.

With the positive control and the test vaccines performing more poorly than anticipated, “we
could have been happier,” says Sauerwein, “but we’re moderately happy with the results.”

“They’ve shown that the organism is fully attenuated by their particular gene deletion and that it
is safe in humans so far, and can produce low levels of protective immunity . . . but is still not
quite optimal,” says Kappe.

In the second paper, Sauerwein, in collaboration with Prudêncio and colleagues, report the
results of a trial with a different genetically modified Plasmodium. Instead of attenuating P.
falciparum, the team used a strain that infects mice but is naturally harmless to humans—P.
berghei—and introduced into its genome the code for P. falciparum’s CSP protein.
Plasmodia (green) growing in liver cells
ANTONIO MENDES

While Sauerwein collaborated with Sanaria Inc—a biotech company with technology for
creating injectable parasite vaccines—in the P. falciparum study, the company was not involved
in the P. berghei study. So, twenty-four volunteers were inoculated the old fashioned way, with
75 bites from mosquitoes infected with the modified parasite. The dose was repeated a further
three times for a total of 300 bites. “Believe it or not there were no drop outs,” says Prudêncio,
explaining that all the volunteers braved the itching through to the end of the trial.

Again, the vaccinations were well tolerated and induced anti-CSP antibodies. While none of the
subjects were fully protected from subsequent infection with wildtype P. falciparum, the
vaccinations did significantly delay the detection of live parasites in the blood, says Prudêncio.
He says he thinks that increasing the dose of the vaccine (via injection of parasites in
collaboration with Sanaria, rather than more bites) and tweaking the parasite to enhance
immunogenicity, are likely to improve the vaccine’s performance.

These trials are proof-of-principle studies and genetically engineered parasites “are still a long
way away” from prime time, says Tibenderana. Nevertheless, the results are “important,” he
adds.

“I think we’re seeing the light at the end of the tunnel with malaria vaccines,” says Kappe.
“Overall, it’s super promising, super exciting.”

M. Roestenberg et al., “A double-blind, placebo-controlled phase 1/2a trial of the

genetically attenuated malaria vaccine PfSPZ-GA1,” Sci Transl Med, 12:eaaz5629, 2020.

I.J. Reuling et al., “An open-label phase 1/2a trial of a genetically modified rodent malaria
parasite for immunization against Plasmodium falciparum malaria,” Sci Transl Med,
12:eaay2578, 2020.

Keywords:

disease & medicine

genetic engineering

malaria

malaria prevention

mosquito-borne disease
plasmodium

plasmodium falciparum

vaccination

vaccine

vaccine trials

Monkeys Genetically Edited to Mimic

Human Brain Development
Rhesus monkeys engineered to express a human gene reportedly show
delayed brain development and better short-term memory. Fellow
scientists are raising ethical red flags.
Chia-Yi Hou
Apr 10, 2019
204

ABOVE: © ISTOCK.COM
YOYOCHOW23

R esearchers from Kunming Institute of Zoology, Chinese Academy of Sciences, and the University of
North Carolina have reported successfully editing a human gene into rhesus monkeys in a study
published on March 27 in National Science Review. The gene is said to be important for human brain
development and the treated monkeys subsequently showed human-like brain development,
reports China Daily.

The human gene, microcephalin or MCPH1, is expressed during the fetal stage of brain development and
is linked to brain size, according to the study. Researchers exposed monkey embryos to viruses
containing the gene, which led to the differentiation of neural cells that resembled human development,
they described in their study.

Human brains take much longer to develop in comparison to other primates in a process called neoteny,
where the period of neural plasticity is extended through childhood. The researchers report that their
study may be evidence that engineeredprimates can develop in a similar pattern.

The monkeys in the study also showed signs of better short-term memory, report the authors.
A number of scientists, even one involved with the study, have criticized the experiments. Unnamed
scientists called the experiments “reckless” and “questioned the ethics of genetically modifying primates,”
reports MIT Technology Review. “The use of transgenic monkeys to study human genes linked to brain
evolution is a very risky road to take,” James Sikela of the University of Colorado who was not involved
with the study tells MIT Technology Review. “It is a classic slippery slope issue and one that we can
expect to recur as this type of research is pursued.”

Research using genetic modification of primates is active at Chinese institutions. A research group at the
Institute of Neuroscience in Shanghai published results in January 2019 on disabling a gene necessary
for the sleep-wake cycle, reports Nature.

Keywords:

brain development

developmental biology

gene editing

genetics & genomics

monkeys

nutshell

primate research

rhesus macaque

ORGANIISM HARMFUL

How Environmental Noise Harms the

Cardiovascular System
Sound from cars, aircraft, trains, and other man-made machines is more
than just annoying. It increases the risk of cardiovascular disease.
Thomas Münzel and Omar Hahad
Jun 1, 2021
331
ABOVE: MODIFIED FROM © ISTOCK.COM, OLLYKAVA; ©
SHUTTERSTOCK.COM, IVECTOR

M ore than 100 years ago, the German physician and Nobel Prize winner Robert Koch
predicted that “one day mankind will have to fight the burden of noise as fiercely as plague and
cholera.” He was right. While many sounds in our environments are quite pleasant, noise,
defined as unwanted sound, has the potential to cause real damage to our bodies and minds.

The principal sources of environmental noise are transportation and industrial operations. Since
Koch’s time, researchers have come to recognize that such noise can cause sleep disturbances,
elicit anger, and trigger conditions such as tinnitus and coronary heart disease caused by reduced
blood flow to the organ. Noise can also lead to memory and learning impairments in children. In
2011, the World Health Organization (WHO) concluded that exposure to transportation-related
noise—specifically from aircraft, vehicles, and trains—is responsible for the annual loss of up to
1.6 million cumulative years of healthy life among people in Western Europe. 

The cardiovascular burden of traffic noise is particularly insidious, with annoyance reactions and
sleep disturbances leading to an increased risk of heart disease. A 2015 report from the European
Environment Agency linked exposure to car, truck, plane, and train sounds with nearly 1.7
million additional cases of hypertension, 80,000 additional hospital admissions, and 18,000
premature deaths due to coronary heart disease and stroke in Europe each year. A few years later,
a metaanalysis conducted on behalf of the WHO supported these conclusions, with seven high-
quality longitudinal studies collectively establishing that road traffic noise exposure was
associated with an 8 percent increased risk of coronary heart disease.

Exposure to transportation-related noise is related to the annual loss of up to 1.6

million cumulative years of healthy life among people in Western Europe.
—World Health Organization, data from 2011

In addition to being associated with an increased incidence of coronary heart disease, noise may
serve as an acute trigger of cardiovascular problems. For example, a study published earlier this
year established that for nighttime deaths, noise exposure levels two hours preceding death were
significantly associated with heart-related mortality.

Despite these indications of the hazards of noise, research concerning adverse health effects of
noise pollution is not well supported financially or politically, and the underlying mechanisms by
which noise increases the risk of cardiovascular disease are not well understood. Our research
group in the Department of Cardiology at the University Medical Center of the Johannes
Gutenberg University of Mainz in Germany and others aim to uncover these pathophysiological
processes. This will not only provide a method for quantifying the degree of physiological stress
triggered by noise, but also help to identify novel pharmacological agents or noise mitigation
measures that could be used to prevent, manage, or treat noise-induced disease. 
Indirect harm takes a serious toll

In 1950, Karl Kryter, then the director of the Operational Applications Laboratory at the Air
Force’s Air Research and Development Command in Washington, DC, emphasized the potential
health effects of the so-called nonauditory effects of noise. He proposed that such effects are the
result of the stimulation of the body’s neural systems that are not exclusively linked to audition,
including the autonomic nervous system, which controls systemic responses and arousal
reactions of an organism,  and the cortical and subcortical brain centers responsible for cognitive
performance. 

In 1968, Gerd Jansen from the Max Planck Institute of Molecular Physiology in Dortmund,
Germany, provided evidence linking noise to cardiovascular problems. Examining 1,005 German
industrial workers, Jansen reported the occurrence of physiological changes such as peripheral
circulation issues, heart problems, and equilibrium disturbances, which were more pronounced in
very noisy industries compared with less noisy industries. These early observations hinted that
chronic noise exposure may cause cardiovascular disease, but it was unclear how.

In 2003, Wolfgang Babisch, a senior research officer at the German Federal Environmental
Agency, developed the noise reaction model, which describes two pathways for determining the
adverse health effects induced by noise. In the first, known as the auditory/direct pathway,
exposure to noise louder than 90–100 decibels (such as a jackhammer) causes inner-ear damage
that can lead to hearing loss and tinnitus. In the second, the nonauditory or indirect pathway,
low-level noise exposure of 50–60 decibels (such as a conversation) interferes with
communication, concentration, daily activities, and sleep, resulting in annoyance, mental stress,
and subsequent sympathetic and endocrine activation. It was the latter pathway that Babisch
suspected was the central player for noise-induced cardiovascular effects.  
© SHUTTERSTOCK.COM, IVECTOR

Specifically, he hypothesized that if the exposure is persistent and chronic, noise contributes to a
pathophysiological phenotype that is characterized by increased stress hormone levels, high
blood pressure, and accelerated heart rate. As a consequence, the body generates its own
cardiovascular risk factors, including high cholesterol and glucose levels, increased blood
viscosity, and activation of blood coagulation. If stress persists for years, cardiovascular diseases
such as hypertension, coronary heart disease, heart failure, arrhythmia, and stroke can begin to
manifest, along with mental stress or related disorders such as depression and anxiety, which are
themselves known to negatively affect cardiovascular health. 

Translational aircraft studies in people 

In 2013, to take a more controlled look at the effects of traffic noise, we and our colleagues
conducted our first field study involving the exposure of healthy subjects to simulated aircraft
noise overnight in their homes. On control nights, we simply had participants play a recording of
normal background noise in their home on a standard portable audio system placed on their
nightstands. On other nights, we had them play a looped recording of aircraft noise taken in the
bedroom of a resident living in the vicinity of Düsseldorf airport in Germany with a window
tilted open.

Using questionnaires, blood analyses, and physiological tests of endothelial function, we

established that one night of simulated aircraft noise exposure reduced self-reported sleep
quality, elevated circulating levels of stress hormones such as adrenaline, stiffened blood vessels,
and caused vascular endothelial dysfunction, the latter two reflecting early subclinical signs of
atherosclerosis and being independent predictors of future cardiovascular events and disorders.
Importantly, comparing participants exposed to 30 versus 60 aircraft noise events per night
revealed a dose-dependent worsening of endothelial function. Moreover, previous exposure to 30
aircraft noise events caused 60 events to have larger adverse effects on endothelial function.
Thus, rather than any sort of habituation to the noise, there appeared to be a priming effect: prior
exposure amplified the negative effect of noise on endothelial function.

More recently, we exposed healthy subjects to simulated nighttime train noise and similarly
found that one night of exposure greatly impaired sleep quality and endothelial function. In
addition, proteomic analysis of participant blood samples revealed substantial changes in
circulating proteins that pointed to a higher susceptibility to inflammation and blood clotting. 

Only a few other studies have provided mechanistic insight into the relationship between traffic
noise exposure and cardiovascular disease. In 2017, Maria Foraster and her colleagues at the
Swiss Tropical and Public Health Institute found, much as we did, that a decade of exposure to
nighttime noise events, mainly related to road traffic noise, was associated with increased arterial
stiffness in a cohort of 2,775 Swiss participants. That same year, a pooled analysis of more than
144,000 people in two large European cohorts from Norway and the Netherlands indicated that
long-term exposure to road traffic noise was associated with higher levels of inflammation, blood
lipids, and fasting glucose.

Babisch proposed that annoyance reactions to noise may play an important role in the extent to
which noise-exposed subjects develop cardiovascular disease. That is, it’s not the noise itself
that’s a problem, but one’s emotional reaction to it. In 2019, Michael Osborne of Massachusetts
General Hospital and colleagues demonstrated that, after five years of exposure to transportation
noise such as that caused by road and aircraft traffic, higher activity in the amygdala, a brain
region involved in emotional processing, stress perception, and emotional reactions, is linked
with an increased risk of heart attack, stroke, heart failure, and death through mechanisms
involving heightened arterial inflammation. Noise annoyance, it seems, is a so-called effect
modifier, meaning that the cardiovascular side effects of noise are greater in people who are
getting annoyed and therefore experiencing increased stress responses compared with those who
are not. 

Whatever the cause, evidence is now accumulating to demonstrate that noise pollution is

resulting in endothelial dysfunction, ultimately leading to high blood pressure, arrhythmia, heart
attack, heart failure, and stroke.
Noise Damage Pathways

Epidemiological data have long linked exposure to noise such as aircraft, railway, or traffic sounds to
increased risks of cardiovascular disease. And in recent years, experimental work has been revealing the
biological mechanisms underlying that link. Specifically, researchers are finding that noise activates the
brain’s limbic system, which plays a role in emotional regulation, the release of stress hormones into the
blood, and controlling of the sympathetic nervous system. These stress responses can lead to cerebral and
vascular inflammation, oxidative stress, and altered gene expression, sometimes culminating in endothelial
dysfunction and cardiovascular disease.

© LAURIE O’KEEFE
 Nightti
me
noise
can
disrupt
sleep
and
cause
cogniti
ve and
emotio
nal
respons
es via
activati
on of
the
amygd
ala.

© LAURIE O’KEEFE
Noise
stress
reacti
ons

Disrupt
ed
sleep
can
also
activat
e the
autono
mic
nervou
s
system
and the
endocri
ne
system,
leading
to
increas
es in
circulat
ing
levels
of
stress
hormo
nes
such as
Endot
helial
dysfu
nction

Such
chronic
stress
can
cause
high
cholest
erol,
high
blood
glucose
, high
blood
pressur
e,
increas
ed
blood
viscosit
y, and
the
activati
on of
blood
coagul
ation—
all
cardiov
ascular
risk
factors.
Stress
can
also
increas
e the
permea
bility
of the
endoth
Plaqu
e
buildu
p

If
stress
persists
,a
buildup
of
cholest
erol
and
immun
e cells
below
the
endoth
elium
leads to
plaque
formati
on and
eventu
ally
smooth
muscle
cells
and
lipids
accum
Noise
-
trigger
ed
plaqu
e
ruptur
e

Acute
noise
stress
can
cause a
physica
l
disrupti
on of
the
plaque,
leading
to
cardiov
ascular
disease
,
includi
ng
acute
and
chronic
coronar
y
syndro
me,
stroke,
arrhyth
mia,
arterial
hyperte
nsion,
and
Molecular mechanisms of noise-induced harm

A surprising result to come out of our first field study was that the adverse effects of nighttime
noise on endothelial function were ameliorated by the administration of vitamin C, which we
gave to some participants after noise exposure. Vitamin C is an antioxidant, a scavenger of
oxygen-derived free radicals. Thus, this finding hinted that increased oxidative stress within the
vasculature may be responsible for noise-induced endothelial dysfunction.  

To further elucidate the molecular mechanisms responsible for nonauditory noise-induced

cardiovascular side effects, we established a novel mouse model and employed various noise
pollution protocols. In the first study, we exposed mice to simulated aircraft noise around the
clock for four days and observed increased blood pressure and elevated concentrations of stress
hormones such as cortisol, noradrenaline, angiotensin II, and dopamine, along with raised blood
pressure, suggesting the animals were stressed. This was accompanied by endothelial
dysfunction and increased production of reactive oxygen species (ROS) within the vascular wall.

Blood vessels are lined with endothelial cells that produce powerful vasoconstricting and
vasodilating substances such as the radical nitric oxide (NO.). But ROS—which are produced in
cases of hypertension, high cholesterol, diabetes, chronic smoking, and other conditions that are
risk factors for cardiovascular disease—attack and degrade NO., thus limiting its bioavailability.
This leads to stiffer vessels, higher blood pressure, and the initiation of plaque buildup in
arteries. It appeared that this might be the initial pathway by which noise causes cardiovascular
damage.

Unlike other major cardiovascular risk factors, noise pollution cannot be treated
by doctors and patients but rather by politicians.

In addition to the increased production of ROS in the vasculature, our mouse study revealed that
noise could trigger oxidative stress in the brain. In a subsequent study, which followed the same
noise exposure protocols as the first mouse study, we confirmed high ROS levels in the frontal
brain region of mice and documented significant neuroinflammation in that area. This
observation is particularly interesting because these cerebral effects may explain, at least in part,
the impaired cognitive development seen in children exposed to noise.

We identified two radical-forming enzymes, the phagocytic nicotinamide adenine dinucleotide

phosphate oxidase isoform 2 (Nox2) and endothelial nitric oxide synthase (eNOS), as sources for
increased ROS production in our noise-exposed mice. Nox2 is mainly found in inflammatory
cells such as macrophages and monocytes, and the eNOS we detected tended not to be coupled
with its cofactor or substrate. Under normal conditions, eNOS produces NO, which has
important vasodilating and anti-atherosclerotic effects, but after noise, the enzyme becomes
“uncoupled”—it switches to a pro-atherosclerotic state, producing the reactive oxygen species
superoxide (O2.-) instead of NO.

Indeed, mice lacking the Nox2 gene suffered almost no ill effects from noise exposure,
confirming oxidative stress as a key player in noise-induced cerebral and cardiovascular damage.
We also detected a downregulation of genes encoding antioxidant pathways as well as evidence
for more inflammation of the vasculature, which may further increase oxidative stress and thus
may aggravate endothelial dysfunction and arterial hypertension. 

Importantly, we did not observe these outcomes in a control group of mice, which was exposed
to white noise at the same volume as the animals in the aircraft-exposure group. This indicates
that the sound pressure level per se is not causing the damage. Moreover, the effects were only
seen when the mice were exposed to noise during the day, when the animals are normally
sleeping, suggesting that impaired sleep quality, including frequent fragmentation of sleep and/or
too-short sleep, is a driver of noise-induced adverse health effects. 

In all, the findings in humans and mice indicate that noise activates inflammatory and oxidative
stress pathways in the vasculature and the brain, leading to endothelial and cerebral dysfunction.
(See illustration.) This aligns with the pathophysiological pathways at play in traditional
cardiovascular risk factors such as smoking, obesity, diabetes mellitus, and hypertension. These
and the novel risk factor of noise appear to work similarly to increase cardiovascular risk.

Planning for a less noisy future

While the mechanisms underlying the cardiovascular side effects of environmental noise remain
an active area of investigation, experimental and epidemiological studies from the last several
years clearly demonstrate that exposure increases the risk of disease. Unlike other major
cardiovascular risk factors, however, noise pollution cannot be treated by doctors and patients
but rather by politicians.  

Policies should work to bring noise exposure levels in line with the new guidelines developed by
the WHO, which lowered the recommendations for mean daily noise sound pressure levels to 45
decibels for aircraft noise, 53 decibels for road traffic noise, and 54 decibels for railway noise,
with even stricter limits for nighttime hours, in order to reduce the burden of disease from noise. 
© SHUTTERSTOCK.COM, IVECTOR

Importantly, noise and air pollution have many of the same sources—aircraft, trains, and road
vehicles. Research suggests that the direct and indirect social costs of noise and air pollution in
the European Union could be nearly €1 trillion, accounting for premature death and disease. That
far exceeds the costs caused by alcohol and smoking, which have been estimated to cost €50
billion– €120 billion and €540 billion, respectively. We must better understand the response to
co-exposure to noise and air pollution, as well as the synergistic effects of both exposures on
surrogate measures such as blood pressure and diabetes. Other open questions include the effects
of cardiovascular therapy on noise- and air pollution–related cardiovascular risks and the
influence of noise on circadian rhythms. Finally, we will need to address the combined effects of
noise and lifestyle factors such as diet, stress, and exercise to fully tackle the noise problem. 

Thomas Münzel is the chief of the Department of Cardiology at the University Medical Center of
the Johannes Gutenberg University Mainz in Germany. Omar Hahad is a postdoctoral
researcher in the same department. Both are members of the German Center for Cardiovascular
Research partner site in Rhine-Main, Mainz, Germany. They can be reached at tmuenzel@uni-
mainz.de  and omar.hahad@unimedizin-mainz.de. 

Keywords:

autonomic nervous system

blood clot

cardiovascular disease

cardiovascular system

cholesterol

coronary heart disease

disease & medicine

heart attack

heart disease

macrophages

neuroscience

noise

noise pollution
physiology

plaque

public health

stress

stress response

GENETIC DIVERSITY

Hybrid Animals Are Not Nature’s Misfits

In the 20th century, animals such as mules and ligers that had parents of
different species were considered biological flukes, but genetic sequencing
is beginning to unravel the critical role of hybridization in evolution.

Ashley Yeager
May 1, 2021
249
This liger cub and other hybrid animals were thought to be biological rarities, but recent
studies have revealed cross-species animals are more common than once thought.
ABOVE: FROM © ISTOCK.COM, W1ZZARD

T he whale’s teeth were what had caught molecular ecologist Eline Lorenzen’s attention. Of
the 18 chompers lining the front of the skull’s mouth, some were twisted, not unlike a narwhal’s
tusk. But the 30-year-old specimen, hidden away in the basement of the Natural History Museum
of Denmark at the University of Copenhagen, didn’t have a tusk at all. When Lorenzen became
director of the museum in 2015, she decided to examine the skull more closely. Working with a
team of collaborators, she extracted genetic material and compared it with DNA from the teeth of
narwhal and beluga specimens in the museum. The skull, it turned out, was the first-ever
confirmed narluga, the son of a beluga dad and a narwhal mom.

A deeper dive into the history of the skull (it had been found fixed atop a hunter’s home)
revealed that this animal may not have been the only one of its kind. The hunter said he’d seen it
with two other similar-looking whale creatures, and he, apparently, isn’t the only one to have
seen a narluga. In fact, they are common enough that natives of western Greenland have a word
for the narwhal-beluga hybrid, itorsaq. 

Because several narlugas have been spotted before, researchers suspect that the creatures may be
fertile, and that some narlugas may be the product of two narluga parents rather than one beluga
and one narwhal. That notion challenges naturalists’ traditional view of hybrids as the result of
maladaptive crossings, such as when a female horse mates with a male donkey and gives birth to
a sterile mule. If the hybrids can’t reproduce, they would seem to be irrelevant evolutionarily, but
studies of the narluga and other naturally occurring hybrids have begun to hint that such
offspring may not be the biological misfits they were once thought to be. They are not
evolutionary dead-ends, and in some cases, may serve as evolutionary accelerators.

“We’re beginning to realize that hybridization exists in the evolutionary history of many
organisms we didn’t expect it to, including Homo sapiens,” Scott Taylor, an evolutionary
ecologist at the University of Colorado Boulder, tells The Scientist. 
Snowshoe Hares Borrow from Black-Tailed Jackrabbits
Hybridization’s benefits are not a new idea

As far back as the 1930s, botanists realized that hybridization plays a role in the evolution of
plant species. In 1938, Edgar Anderson and Leslie Hubricht laid out the idea of introgression to
describe the hybridization of species of herbaceous perennial wildflowers of
the Tradescantia  genus. The crosses led to offspring with an even split of parental genetic
material, and typically those offspring then repeatedly bred with one of the original parent
species, while still retaining genetic material from the other parent species. Alternatively, hybrids
bred with other hybrids, and, eventually, entirely new plant species would emerge. 

Zoologists knew about these and other examples of hybridization in the plant world, but there
was a perception, Taylor says, that cross-species breeding was much less common in animals.
That idea stemmed from biologist Ernst Mayr’s description in the 1940s of the biological
characteristics that defined species—essentially, any animal population that could not or did not
breed with other, similar populations. For more than two decades, including in his 1963
book Animal Species and Evolution, Mayr argued that “the evolutionary importance of
hybridization seems small in the better-known groups of animals.” But the idea is not universally
accepted, Taylor says. “I don’t know a lot of evolutionary biologists who study hybridization
who adhere strictly to that concept.” 

Despite the dogma that hybrid animals in nature were rare and therefore not catalysts of
evolutionary innovation, some biologists continued to study them, curious to uncover the barriers
that prevented them from becoming new species, identify the new gene combinations created by
hybridization, and understand how natural selection acted upon them. Focusing on animals in
what scientists call hybrid zones—geographical regions in which two species interbreed to
produce offspring of mixed ancestry—researchers in the late 1980s and early 1990s began to
show that, contrary to the prevailing viewpoint, hybridization was a valid mechanism of
evolutionary change—one that could radically influence an animal’s ability to adapt to its
environment.
A Narwhal Tries Beluga’s Teeth
The thousands of cichlids in Africa’s lakes

Evidence for hybrid-driven adaptation is perhaps nowhere more profound than in the warm,
tropical waters of Lake Victoria in Africa. There, more than 500 species of bony fishes called
cichlids that sport brilliant orange, yellow, and blue hues, roam the lake’s 2,400 cubic
kilometers. Some species eat only plants, others eat invertebrates, the bigger species eat other
fish, and still more feed on Lake Victoria’s detritus. “There’s incredible diversity of species that
live together in the same ecosystem,” evolutionary ecologist Ole Seehausen of the University of
Bern tells The Scientist. “This struck me as a beautiful system, the interaction between ecology
and evolution . . . to study speciation.”

When Seehausen began to study the lake’s cichlids roughly 30 years ago, it wasn’t clear how the
hundreds of species there had evolved. They weren’t geographically isolated, a common driver
of speciation. Rather, the fish were all living in the same lake and could interact, yet there was
still incredible cichlid diversity. Something else appeared to be driving their speciation. 

With continued observation, Seehausen and others found that the barriers preventing the species
in the lakes from mating were rather “shallow,” with some of the major ones being behavioral in
nature. Males, for example, were defending their territories from males of both the same and
other species, or females were choosing flashing mates of only their own species. That last
barrier, based on color signaling, began to break down, Seehausen says, when the clarity of the
water diminished in the 1990s, a result of wastewater from farms and other human activities
polluting the lake. “It turns out that when you change the visual signaling, and the perception of
those signals, then not much more is needed to break down reproductive isolation, so many
species then hybridize,” Seehausen says.  

Something similar appears to have happened thousands of years ago in Lake Victoria. Genetic
analyses of the cichlids have revealed that their vast diversity can be traced back to
a hybridization of two divergent lineages around 150,000 years ago. And Lake Victoria wasn’t
the only body of water in the region where hybridization appeared to play an important role in
speciation. Further investigation revealed that cross-species mating had happened and continued
to occur in nearby lakes, where it was driving cichlid diversity. “This was replicated in several
different lakes across Africa,” Seehausen says. 

As scientists began to look for other examples of hybridization in the wild, both past and present,
they were not disappointed. Genetic analyses have revealed crosses between coyotes and gray
wolves, polar bears and brown bears, chimpanzees and bonobos, finches in the Galapagos
Islands, fish called sculpin, and even modern humans and Neanderthals. 

See “Neanderthal DNA in Modern Human Genomes Is Not Silent”

Researchers suspect that hybridization events are perhaps becoming more common, as human
disturbances shift species ranges in ways that promote breeding across similar species. In
Colorado, for example, two varieties of small, nonmigratory birds—black-capped chickadees
and mountain chickadees—have recently hybridized in areas being heavily developed by
humans. “If you look at the map and squint, the places they’re hybridizing seems to correlate
nicely with places that humans have modified, whether that’s the front range of the Rocky
Mountains or Albuquerque, New Mexico,” he says. His team hypothesizes that the species,
which split some 1.5 million years ago, breed with each other in modified habitats because a
resource needed by both, either breeding grounds or certain food sources, is bringing the birds
together.
On occasion, a mountain chickadee (above) may mate with a black-capped chickadee.
ROBERT TAYLOR

Climate change may also be driving hybridization between species. Evolutionary biologists have
seen pulses of cross-breeding as species shift where they live to higher or lower latitudes or
altitudes to find cooler temperatures. When they move into those regions, the barriers to
hybridization, such as differences in mate choice or other factors, might disappear. “There are
definitely compelling examples” of climate change or environmental shifts influencing
hybridization, says Molly Schumer, an evolutionary biologist at Stanford University, “and my
suspicion is it’s pretty widespread.”

Obviously not all cases of hybridization involved the equal swapping of genes to form a
completely new creature, as appeared to often happen with the cichlids, but in just the last few
years, “the consensus has been that hybridization in animals in particular is hugely widespread
and much more common than was appreciated,” Schumer says. The question in the field now,
she says, is if this gene swapping is common, “what is it doing?”
Fish in Troubled Waters
Cross-breeding’s advantages and disadvantages

In the case of cichlid hybrids, Seehausen found that not only did the hybrids have similar
developmental and reproductive rates to non-hybrids, in some ways individuals with a genetic
mishmash of two distinct species created were actually more suited to a particular environment
or food source than their parents were.

A few years ago, Joana Meier, an evolutionary genomicist at the University of Cambridge who
did her graduate work and a postdoctoral stint with Seehausen, delved into the genetics of the
cichlids and spotted one type of hybrid that caught her attention: dwarf species that combine the
body shape of a plant-eating species with the predatory habits of a bigger species that dines on
other fish. “Genetically, they’re like a mix of both,” she says. “In some cases, they have higher
fitness [than either parent species] in different ecological niches.” Seehausen has also shown this
in the lab, creating hybrids that don’t thrive on the food the parent species ate, but gobble down a
new type of food and begin to flourish.

Schumer is seeing something similar in the hybridization of two related species of swordtail
fish, Xiphophorus malinche and X. birchmanni. The fish live in the rivers of the Mexican state of
Hidalgo and have begun hybridizing within the last 50 to 100 generations, probably as a result of
some human disturbance to the river, she explains. The fish rely on their sense of smell and the
signals in those scents to choose mates, but the contaminants in the rivers appear to be blocking
the fish from picking out their own species, Schumer says, so they’ve ended up mating across
species boundaries. It turns out, that the mix-up could be helping both species survive by
boosting genetic diversity.
Different species of swordtail fish, including Xiphophorus birchmanni (left) and X. malinche (top),
can interbreed to form hybrid offspring (bottom).
DAN POWELL

Swordtail cross-breeding is “really, really recent and gives us a good snapshot to [see] what’s
happening right after hybridization,” Schumer says. Her genetic studies, along with those from
other researchers investigating recent hybridization events, seem to show that right after these
crosses occur, the genome of the hybrid undergoes incredible reorganization. “There’s a lot of
purging of deleterious alleles and rapid evolution happening right after you collide these two
divergent genomes.” The original swordtail parent species are closely related, differing by only
0.5 percent in their genetic makeup, Schumer’s studies show. Still, that small bit of genetic
variation leads to substantial shifts in the species’ tolerances to cold, adaptation to elevation, and
even an extra-long fin extension, called the sword, seen on X. birchmanni but not on X.
malinche. 

On the flip side, mushing together the two swordtail species’ genomes can cause issues in the
offspring, with many not being able to reproduce. The combination of genes can even cause the
hybrids to develop tumorous melanoma, which the parents don’t. “One of the biggest questions
in the field,” Schumer says, “is: In this really rapid genome evolution happening after
hybridization, how are all of these mechanisms—positive effects of hybridization, negative
effects of hybridization, interactions with the environment, social interactions—playing out?” 

Keywords:

evolution

evolutionary biology

evolutionary development

genetics & genomics

hybridization

natural selection

speciation

sympatric speciation
zoology

QUEST QUEST FOR PROFIT UNDERMINES FREE EXCHANGE OF KNOWLEDGE

The Costs of Commercializing Academic

Research
Tom Schierlitz/Stone The Bayh-Dole Act of 1980, which allows US
universities and research institutes to patent and commercialize
discoveries financed with federal funds, may inadvertently hinder scientific
research and impede innovation, scientists and legal experts say. The law
(PL 96-517), the envy of many European universities, has been a powerful
catalyst to spur product development from laboratory research. In FY2001
alone, more than 4,000 new licenses and options from 198 US universiti
Ted Agres
Aug 24, 2003
1

Tom Schierlitz/Stone

The Bayh-Dole Act of 1980, which allows US universities and research institutes to patent and
commercialize discoveries financed with federal funds, may inadvertently hinder scientific
research and impede innovation, scientists and legal experts say.
The law (PL 96-517), the envy of many European universities, has been a powerful catalyst to
spur product development from laboratory research. In FY2001 alone, more than 4,000 new
licenses and options from 198 US universities, hospitals, and research institutes were issued.
These licenses brought in nearly $1.1 billion (US) in royalties, with life science patents
generating the lion's share of revenues for universities and research centers.1

University and government officials have been concerned for some time over how best to patent
and commercialize discoveries while keeping research tools and information flowing freely.2 But
now researchers and legal experts are raising new concerns as legal disputes, and the potential
for vast monetary rewards, mushroom. Some legal experts contend that Bayh-Dole actually
blocks scientific research when institutions claim ownership of fundamental discoveries and
processes, such as new DNA sequences, protein structures, and disease pathways.

In biopharmaceutical research particularly, Bayh-Dole thwarts dissemination of federally

sponsored science and allows the patent system to encroach on basic research formerly in the
domain of open scholarly exchange, says Arti K. Rai, a law professor at Duke University.

In studying life science patents, Rai and colleague Rebecca S. Eisenberg, a University of
Michigan law professor, found that Bayh-Dole draws no distinction between inventions that lead
directly to commercial products and those that provide fundamental advances enabling further
scientific studies. As a result, some institutions have decided to patent research tools in order to
preserve the possibility of future profits. "In the long run, [Bayh-Dole] may hinder rather than
accelerate biomedical research," Rai and Eisenberg conclude.3

Paul Berg, Nobel Prize-winning biochemist and director emeritus of the Beckman Center for
Molecular and Genetic Medicine at Stanford University, puts it more bluntly. Bayh-Dole "is
likely to damage the health of the scientific enterprise in the long term, notwithstanding the
financial benefits in the short term," he told a seminar at the Howard Hughes Medical Institute in
May.

LIMITING EXCHANGES Commercial and proprietary interests encouraged by Bayh-Dole are

driving universities to restrict the transfer of research tools to other scientists through material
transfer agreements (MTAs), Rai says. "There might be royalties on any particular product that
might come out of the usage of the research tool," she says. "Or they might want to preview any
manuscripts that are written to make sure they can claim any patent rights."

One of Bayh-Dole's "unintended effects" is to restrict dissemination of faculty research by

delaying publication and deleting information having commercial potential, says Marie Thursby,
director of the Technology and Innovation Program at the Georgia Institute of Technology's
Dupree College of Management. "I think there are cases where ties to industry may have
restricted access to knowledge and I think that is something that needs to be watched," she told
this year's Colloquium on Science and Technology Policy sponsored by the American
Association for the Advancement of Science (AAAS).

For example, Mildred K. Cho, codirector of Stanford University's Center for Biomedical Ethics,
and colleagues surveyed 121 US laboratories involved in developing or performing clinical
genetic tests. More than half of the labs (54%) had decided not to develop or perform one or
more tests because of concerns over patent infringement.4 "Information sharing and the ability to
do research... has been negatively impacted by patenting," Cho told the AAAS symposium.

In another problem area, universities and their licensees are wielding broad patent claims derived
from Bayh-Dole to prevent other companies from developing useful therapies or to win
substantial judgments after a product has been developed and marketed. "There are fundamental
technologies that serve as the basis for many different types of end products that are being
licensed exclusively to one company rather than not being patented at all, or being licensed
nonexclusively," Rai says.

A prime the example of this, she says, is the legal dispute surrounding the patent on the NF-B
cell-signaling pathway, a key biological trigger described in more than 5,000 scholarly papers.
The patent was issued June 25, 2002 to the Massachusetts Institute of Technology, Whitehead
Institute of Biomedical Research, and Harvard University.5 Because the research received federal
funding, it triggered the licensing provisions of Bayh-Dole.

While the patent application was pending, the research institutions licensed the technology
exclusively to Ariad Pharmaceuticals, a biopharmaceutical company in Cambridge, MA. When
the patent issued, Ariad immediately filed suit against Eli Lilly and Co. claiming two Lilly
drugs--Evista to treat osteoporosis and Xigris to treat septic shock--infringed on the patent.6

Ariad's lawsuit "is problematic because they had really not made any effort to do research on that
pathway itself," Rai says. "This is a case of a very broad patent on a fundamental technology
being asserted against companies that actually developed the technology and produced a product
without the benefit of a patent," she says. "The economist's term for it is 'rent seeking' - trying to
get a cut of the action."

"We will permit broad use of our NF-B intellectual property at no cost by investigators at
academic and not-for-profit institutions to conduct non-commercial research,"7 says a statement
posted on Ariad's corporate Internet site. Ariad spokesman Thomas Pearson declined to say
whether research licenses contain "reach-through" provisions allowing Ariad to share the fruit of
any subsequent discoveries.

Pearson declined to discuss the matter, as did Lita Nelson, director of MIT's technology licensing
office. Asia Martin, a Lilly spokesperson, says her company believes Ariad's patent is invalid
and was not infringed. "Lilly's original work on the discovery and identification of Evista and
Xigris goes back to the early 1980s," she says. "And we are prepared to vigorously defend our
interests."

Since the lawsuit against Lilly was filed, Ariad has licensed the NF-B technology to other
pharmaceutical companies, including Bristol-Myers Squibb In May, the US District Court in
Massachusetts declined Lilly's bid to dismiss the case. Trial is expected to begin later this year.
The NF-B cell-signaling pathway it "is the sort of [broad] technology that probably would have
been best left unpatented, Rai says, "even if it was patented by the universities, it might have
been licensed nonexclusively."

EXCLUSIVITY AND RISK But companies often demand exclusive licenses to compensate for
the risks and expenses in commercializing discoveries, especially those emerging from early-
stage research. Exclusive licenses give the licensee legal benefits not otherwise available, says
Kevin Noonan, a patent attorney with McDonnell Boehnen Hulbert & Berghoff in Chicago.

"Anybody who is bemoaning the impact of Bayh-Dole on the free flow of information among
research scientists is not a research scientist," Noonan says. Scientists prefer to keep their
discoveries to themselves as a matter of human nature, he says. "You keep that stuff close to
your chest because you don't want to get scooped."

Noonan praised the National Institutes of Health for helping universities and research institutions
find an appropriate balance between disseminating research tools and commercializing the
results of their discoveries. "They've been a pretty good broker to not let the commercial intent
overtake the research intent," he says.

In December 1999, NIH issued guidelines for disseminating and acquiring research tools in
projects that fall under Bayh-Dole.8 The policy also has teeth: since 2000 it has become a
condition that must be followed to qualify for NIH grants and contracts. It requires recipients to
preserve research freedom while allowing "reasonable restrictions" from an industrial partner.
But it also cautions against "inappropriate licensing practices" when a discovery "is useful
primarily as a research tool."

NIH defines research tools broadly. In general, a resource is a tool if it is primarily used for
discovery rather than for an FDA-approved product, or if it is a broad enabling invention useful
for many scientists or for multiple companies to develop multiple products. Examples of
inappropriate licensing include commercialization option rights, royalty reach-through rights,
and product reach-through rights back to the provider. In general, NIH wants research
"transferred with the fewest encumbrances possible."

Navigating the dual imperatives of commercialization and research freedom is a challenge. Mark
L. Rohrbaugh, director of NIH's Office of Technology Transfer, says his agency's "internal
policies and practices serve to find that balance as best we can and also serve as a model on how
to have a large successful tech transfer program while adhering to those goals."

Ted Agres (tedagres@lycos.com) is a freelance writer in Washington, DC.

References
1. T. Agres, "The fruits of university research," The Scientist, 17[14]:55-6, Jul. 14, 2003.

2. E. Russo, "Regulating researchers' 'picks and shovels,'" The Scientist, 14[9]:8, May 1, 2000.

3. A.K. Rai and R.S. Eisenberg, "Bayh-Dole reform and the progress of biomedicine," Law Contemp Probl,
66:289, 2003.

4. M.K. Cho, etal, "Efects of gene patents and licenses on the provision of clinical genetic testing
services," J of Mol Diagn, 5:3, 2003.

5. D. Baltimore et al., "Nuclear factors associated with transcriptional regulation," US Patent No.
6,410,516 issued June 25, 2002.

6. P. Brickley, "New patent worries professors," The Scientist, 16[15]:19, July 22, 2002.

7. www.ariad.com/about/about_nfkb.html

8. "Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and
Disseminating Biomedical Research Resources: Final Notice," National Institutes of Health, December 23,
1999.