[Talk of ‘gain-of-function’
research, a muddy category at best, brings up deep questions about how
scientists should study viruses and other pathogens.]
By Carl Zimmer and James Gorman
“Gain-of-function research, as you
know, is juicing up naturally occurring animal viruses to infect humans,” the
senator said.
Dr. Fauci, the nation’s top
infectious disease expert, flatly rejected the claim: “Senator Paul, with all
due respect, you are entirely and completely incorrect, that the N.I.H. has not
ever and does not now fund gain-of-function research in the Wuhan Institute.”
This exchange, and the bit of
scientific jargon at the heart of it, has gained traction in recent weeks,
usually by people suggesting that the coronavirus was engineered, rather than
having jumped from animals to humans, the explanation favored by
most experts on coronaviruses. The uproar has also drawn attention back to a
decade-long debate among scientists over whether certain gain-of-function
research is too risky to allow.
Spurred by some contested bird flu
experiments in 2012, the U.S. government adjusted its policies for oversight of
certain types of pathogen studies. But some critics in the scientific community
say that the policy is overly restrictive and that its enforcement has been far
from transparent.
The stakes of the debate could not
be higher. Too little research on emerging viruses will leave us unprepared for
future pandemics. But too little attention to the safety risks will increase
the chances that an experimental pathogen may escape a lab through an accident
and cause an outbreak of its own.
Sorting out the balance of risks
and benefits of the research has proved over the years to be immensely
challenging. And now, the intensity of the politics and rhetoric over the lab
leak theory threatens to push detailed science policy discussions to the
sidelines.
“It’s just going to make it harder
to get back to a serious debate,” said Marc Lipsitch, an epidemiologist at the
Harvard T.H. Chan School of Public Health who has urged the government to be more transparent about its
support of gain-of-function research.
In the 1970s, researchers were
learning for the first time to move genes from one organism to another to make bacteria produce human insulin. From the start,
critics worried that such experiments could accidentally create deadly
pathogens if they escaped from labs.
Tinkering with genes isn’t the only
way that a scientist can give an organism new abilities. Researchers can also
stage evolutionary experiments, in which pathogens are grown in the cells of an
unfamiliar host species. At first, they don’t replicate well. But new mutations
can help them adapt, gradually improving their performance.
A decade ago, researchers used
serial passage, as this procedure is known, to learn how new strains of
influenza evolve. Flu strains start off in the guts of birds, and sometimes
manage to mutate into a form that can spread among people.
Two teams of researchers — one from
the University of Wisconsin in Madison and the other at Erasmus Medical Center
in Rotterdam, the Netherlands — designed experiments to identify which genetic
mutations were essential for a successful jump from birds to people. They
injected bird flu viruses into the noses of ferrets, waited for the viruses to
replicate, and then transferred the new viruses to new ferrets. Soon the
viruses evolved to become better at replicating in the ferrets.
When news of the experiments broke
in late 2011, a controversy exploded.
Some critics said the research was reckless and shouldn’t be published, for
fear that other researchers would copy the work and accidentally release a new
pandemic strain of flu.
A year later, the U.S. Department
of Health and Human Services held a meeting to consider what it called
“gain-of-function research.” The name took hold, but scientific experts have
grown increasingly frustrated with it ever since.
“It’s a horribly imprecise term,”
said Gigi Gronvall, a senior scholar at the Johns Hopkins Center for Health
Security.
Many gain-of-function experiments
could never pose an existential threat; instead, they have provided huge
benefits to humanity. In 1937, researchers found that when they passed the
yellow fever virus through chicken cells, it lost the ability to cause disease
in humans — a discovery that
led to a vaccine for yellow fever. Likewise, herpes viruses have been engineered
to gain a new function of their own: attacking cancer cells. They’re now an
approved treatment for melanoma.
But the bird flu experiments raised
concerns that certain gain-of-function studies could pose a tiny but real risk
of dangerous outbreaks. In 2014, U.S. officials announced that 18 such studies
would be paused. The experiments were not just on influenza viruses, but on the
coronaviruses that caused SARS and MERS.
Three years later, the
government rolled out a new policy — the “P3CO framework” — for
research on “enhanced potential pandemic pathogens.” The rule requires the
agencies under the H.H.S. umbrella, like N.I.H. and its several institutes, to
carry out a special review of grant applications for any research on “a
credible source of a potential future human pandemic.” In 2019, after
conducting such a scientific review, the agency gave the green light for two
influenza projects to restart, triggering more debate about whether its policy
was thorough enough.
When questioning Dr. Fauci last
month, Senator Paul brought up one of the most cited examples of
gain-of-function research, a study of coronaviruses done by Ralph Baric at the
University of North Carolina published in Nature Medicine
in 2015. Working with data sent from Shi Zhengli, the director of the Wuhan
Institute of Virology, Dr. Baric and his colleagues built a new coronavirus
from an existing one. All of the work was done in the North Carolina lab, and
neither Dr. Zhengli nor members of her lab participated.
The so-called chimeric virus that
resulted was not more pathogenic than the parental virus, Dr. Baric said. “This
work was approved by the N.I.H.., was peer-reviewed, P3CO reviewed and
approved,” Dr. Baric wrote in an email last month. The work also “involved a
very different strain of beta coronavirus than the one that causes Covid-19,” he
said, and was considered low risk because of the particular strain in question.
In the paper, he and his colleagues
cautioned others about similar research. “The potential to prepare for and
mitigate future outbreaks must be weighed against the risk of creating more
dangerous pathogens,” they wrote.
The P3CO policy has a significant
shortcoming, according to David Relman, a member of the U.S. National Science
Advisory Board for Biosecurity and a microbiologist at Stanford University: It
only applies to the grant process in agencies that are part of H.H.S. Grants
from the National Science Foundation, the Pentagon or other agencies could
include dangerous research and also need oversight, he said. Then there is the
even thornier question of private research, not funded by the government.
Dr. Relman has also criticized the
government’s process for screening and approving gain-of-function research. At
a January 2020 meeting of the advisory board, he objected to the lack of
information released about how two research proposals were approved.
Rozanne Sandri-Golin, editor in
chief of the Journal of Virology, a scientist who works on the herpes virus and
a fellow member of the board, said Dr. Relman made a strong case about the lack
of transparency in the grant-screening process. The board was told that a
committee made the decision but “their names weren’t published, their
backgrounds weren’t published and the process that they used for deciding
whether or not it was going to be all right to now proceed with this research
was not clearly defined,” she said.
The secrecy of the screening
process was the most worrisome part of government oversight of potentially
dangerous research, according to Angela Rasmussen, a virologist at University
of Saskatchewan’s Vaccine and Infectious Disease Organization, who was doing
research in the United States at that time. “It’s not clear how they decide
what’s acceptable gain of function and what’s not,” she said.
However, the “star chamber” nature
of the process was not its biggest problem, said Richard Ebright, a molecular
biologist at Rutgers who has also been one of the most vocal proponents of the
lab leak theory, and a longtime advocate of stricter control of research on
dangerous pathogens. An even bigger issue, he said, was that gain-of-function
research was simply not being screened in accordance with the policy
established by H.H.S., which includes the National Institute of Allergy and Infectious
Diseases, run by Dr. Fauci.
The ideal solution, he said, would
be the creation of an independent body to provide the oversight of dangerous
pathogen research, similar to what the Nuclear Regulatory Commission does for
studies of radioactive materials.
In the United States, “there are no
biosafety rules or regulations that have the force of law,” he said. “And this
is in contrast to every other aspect of biomedical research.” There are
enforceable rules, for example, for experiments with human subjects, vertebrate
animals, radioactive materials and lasers, but none for research with
disease-causing organisms.
Dr. Relman, who also supports the
need for independent regulation, cautioned that legal restrictions, as opposed
to guidelines or more flexible regulations, could also pose problems. “The law
is cumbersome and slow,” he said. At one point in the evolution of laws
relating to biological warfare, for example, Congress prohibited the possession
of smallpox. But the rule’s language, Dr. Relman said, also seemed to ban
possession of the vaccine because of its genetic similarity to the virus
itself. “To try to fix it took forever,” he said.
The current H.H.S. policy also
doesn’t offer much guidance about working with scientists in other countries.
Some have different policies about gain-of-function research, while others have
none at all.
Dr. Gronvall of Johns Hopkins
argued that the U.S. government cannot dictate what scientists do in other
parts of the world. “You have to embrace self-governance,” she said. “You’re
not able to sit on everyone’s shoulder.”
Even if other countries fall short
on gain-of-function research policies, Dr. Lipsitch said that shouldn’t stop
the United States from developing better ones. As the world’s leader in
biomedical research, the country could set an example. “The United States is
sufficiently central,” Dr. Lipsitch said. “What we do really does matter.”
Ironically, the pandemic put
deliberations over such issues on hold. But there’s no question the coronavirus
will influence the shape of the debate. Jesse Bloom, a virologist at the Fred
Hutchinson Cancer Research Center, said that before the pandemic, the idea of a
new virus sweeping the world and causing millions of deaths felt hypothetically
plausible. Now he has seen what such a virus can do.
“You have to think really carefully
about any kind of research that could lead to that sort of mishap in the
future,” Dr. Bloom said.
