by Anthony S. Fauci
DOI: 10.1128/mBio.00359-12
Copyright © 2012 Fauci
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ABSTRACT
The voluntary moratorium on gain-of-function research related to the transmissibility of highly pathogenic H5N1 influenza virus should continue, pending the resolution of critical policy questions concerning the rationale for performing such experiments and how best to report their results. The potential benefits and risks of these experiments must be discussed and understood by multiple stakeholders, including the general public, and all decisions regarding such research must be made in a transparent manner.
The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.
Commentary
The influenza virus research community is to be commended for implementing a voluntary moratorium on “gain-of-function” experiments related to the transmissibility of highly pathogenic H5N1 influenza virus (1). As a key funder of influenza virus research, the National Institute of Allergy and Infectious Diseases, a component of the U.S. National Institutes of Health, strongly supports the continuation of this moratorium pending the resolution of critical policy issues related to the rationale for performing and reporting such experiments. We need to be certain that the fundamental purposes of this work, together with its risks and benefits, are understood by multiple stakeholders, including the general public, and that decisions are made in a transparent manner.
It is clear that the scientists who conducted the experiments that triggered this debate (2, 3), and who are among those who voluntarily signed onto the moratorium, have conducted their research properly and under the safest and most secure conditions. However, the issue that has been intensely debated is whether knowledge obtained from these experiments could inadvertently affect public health in an adverse way, even in nations multiple time zones away. Putting aside the specter of bioterrorism for the moment, consider this hypothetical scenario: an important gain-of-function experiment involving a virus with serious pandemic potential is performed in a well-regulated, world-class laboratory by experienced investigators, but the information from the experiment is then used by another scientist who does not have the same training and facilities and is not subject to the same regulations. In an unlikely but conceivable turn of events, what if that scientist becomes infected with the virus, which leads to an outbreak and ultimately triggers a pandemic? Many ask reasonable questions: given the possibility of such a scenario—however remote—should the initial experiments have been performed and/or published in the first place, and what were the processes involved in this decision?
Scientists working in this field might say—as indeed I have said—that the benefits of such experiments and the resulting knowledge outweigh the risks. It is more likely that a pandemic would occur in nature, and the need to stay ahead of such a threat is a primary reason for performing an experiment that might appear to be risky. However, we must respect that there are genuine and legitimate concerns about this type of research, both domestically and globally. We cannot expect those who have these concerns to simply take us, the scientific community, at our word that the benefits of this work outweigh the risks, nor can we ignore their calls for greater transparency, their concerns about conflicts of interest, and their efforts to engage in a dialog about whether these experiments should have been performed in the first place. Those of us in the scientific community who believe in the merits of this work have the responsibility to address these concerns thoughtfully and respectfully.
Granted, the time it takes to engage in such a dialog could potentially delay or even immobilize the conduct of certain important experiments and the publication of valuable information that could move the field forward for the good of public health. Within the research community, many have expressed concern that important research progress could come to a halt just because of the fear that someone, somewhere, might attempt to replicate these experiments sloppily. This is a valid concern. However, although influenza virus scientists are the best-informed individuals about influenza virus science, and possibly even about the true level of risk to public health, the influenza virus research community can no longer be the only player in the discussion of whether certain experiments should be done. Public opinion (domestic and global) and the judgments of independent biosafety and biosecurity experts are also critical. If we want to continue this important work, we collectively need to do a better job of articulating the scientific rationale for such experiments well before they are performed and provide discussion about the potential risk to public health, however remote. We must also not rule out the possibility that in the course of these discussions, a broad consensus might be reached that certain experiments actually should not be conducted or reported.
In this regard, as part of an interagency process, the U.S. Government is planning to augment current policy guidance related to life sciences dual-use research of concern (DURC) (4) by developing a framework for strengthening regular institutional review and oversight of certain life sciences research with high-consequence pathogens and toxins in order to identify potential DURC and mitigate risks where appropriate. This policy implementation proposal will go well beyond H5N1 influenza virus to include 15 pathogens and likely will be modified to include additional examples of DURC. It will delineate the procedures for the oversight of DURC and the responsibilities of investigators, research institutions, and the U.S. Government. Ultimately, there will also be a companion guide to help institutions identify, assess, manage, and responsibly communicate to the public about DURC.
With regard to the specific question of whether certain gain-of-function experiments related to the transmissibility of highly pathogenic H5N1 influenza virus should be conducted at all, which addresses directly the issue of the moratorium, the U.S. Government is planning to host an international workshop before the end of 2012 with important input from the National Science Advisory Board for Biosecurity and with global representation, including those with biosafety and biosecurity expertise, influenza virus and non-influenza virus scientists, and representatives of the domestic and global public. The meeting participants will consider general principles concerning the rationale for and risks and benefits of such experiments and what lines might be drawn in their conduct and/or reporting.
The game has changed for influenza virus scientists and the agencies that support them. As researchers, we must realize that we are critical players in the process of policy and decision making related to DURC, but we are not the only players. Before embarking on certain types of research, we must ask ourselves critical questions about whether there are alternative ways to answer the research questions at hand. When no reasonable alternatives exist, we must take the scientific approach to making the argument for conducting such experiments before they are performed. The voluntary moratorium on the controversial issue of gain-of-function research related to the transmissibility of highly pathogenic H5N1 influenza virus is providing us the time and space we all need to work together and get this right, and it should be continued until we do so (5).
REFERENCES
1. Fouchier RA, et al. 2012. Pause on avian flu transmission research. Science 335:400–401. doi: 10.1126/science.1219412.FREE Full TextGoogle Scholar
2. Herfst S, et al. 2012. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336:1534–1541. Abstract/FREE Full TextGoogle Scholar
3. Imai M, et al. 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420–428.CrossRefPubMedWeb of ScienceGoogle Scholar
4. NIH. 2012. United States Government policy for oversight of life sciences dual use research of concern. NIH, Bethesda, MD. http://oba.od.nih.gov/oba/biosecurity/P ... pdf.Google Scholar
5. Fauci A. S. 31 July 2012. The way forward in influenza research: a dialogue with the NIAID Director. Audio of presentation from the Sixth Annual Meeting of the Centers for Excellence for Influenza Research and Surveillance (CEIRS), New York, NY. http://www.niaid.nih.gov/about/director ... mp3.Google Scholar
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Statement of Drs. Collins and Fauci concerning intention to lift moratorium
Nih.gov
January 24, 2013
Colorized transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green).CDC/Cynthia Goldsmith
One year ago, scientists in the H5N1 influenza research community announced that they would voluntarily suspend certain “gain-of-function” experiments involving highly pathogenic avian influenza (HPAI) H5N1 viruses pending a broad international dialogue about the future direction of this research.
That dialogue — which has included experts in the life sciences, public health, biosecurity, biosafety, law, and science policy communities — has been highly productive, with numerous meetings and publications helping to clarify the most critical issues associated with this type of research.
Countries where this research is (or might be) conducted have had the opportunity to review their policies and parameters for funding, conducting, and communicating about this research. In this context, the H5N1 influenza research community has announced their intention and support for resuming their research in those countries with final guidelines in place.
The Department of Health and Human Services (HHS) has worked in a transparent and collaborative fashion to develop a framework for reviewing funding decisions regarding research that might increase mammalian transmission of HPAI H5N1 viruses by respiratory droplets. We anticipate that the final framework for HHS funding decisions regarding HPAI H5N1 gain-of-function experiments will be complete in the next several weeks. In the meantime, U.S.-funded researchers (both those working in the United States, including those in government laboratories, as well as those working overseas) have agreed not to resume these types of HPAI H5N1 gain-of-function experiments pending finalization of the HHS Framework.
Understanding how influenza viruses become human pandemic threats is vitally important to global health preparedness. We applaud the international H5N1 influenza research community for the spirit in which they instituted this extended “pause” on their work, which has provided time for thoughtful consideration of its implications.
Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health
Anthony S. Fauci, M.D.
Director, National Institute of Allergy and Infectious Diseases
National Institutes of Health
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Dr. Fauci Backed Controversial Wuhan Lab with U.S. Dollars for Risky Coronavirus Research
by Fred Guterl
Newsweek
4/28/20 AT 2:57 PM EDT
Dr. Anthony Fauci is an adviser to President Donald Trump and something of an American folk hero for his steady, calm leadership during the pandemic crisis. At least one poll shows that Americans trust Fauci more than Trump on the coronavirus pandemic—and few scientists are portrayed on TV by Brad Pitt.
But just last year, the National Institute for Allergy and Infectious Diseases, the organization led by Dr. Fauci, funded scientists at the Wuhan Institute of Virology and other institutions for work on gain-of-function research on bat coronaviruses.
In 2019, with the backing of NIAID, the National Institutes of Health committed $3.7 million over six years for research that included some gain-of-function work. The program followed another $3.7 million, 5-year project for collecting and studying bat coronaviruses, which ended in 2019, bringing the total to $7.4 million.
Many scientists have criticized gain of function research, which involves manipulating viruses in the lab to explore their potential for infecting humans, because it creates a risk of starting a pandemic from accidental release.
SARS-CoV-2, the virus now causing a global pandemic, is believed to have originated in bats. U.S. intelligence, after originally asserting that the coronavirus had occurred naturally, conceded last month that the pandemic may have originated in a leak from the Wuhan lab. (At this point most scientists say it's possible—but not likely—that the pandemic virus was engineered or manipulated.)
Dr. Fauci did not respond to Newsweek's requests for comment. NIH responded with a statement that said in part: "Most emerging human viruses come from wildlife, and these represent a significant threat to public health and biosecurity in the US and globally, as demonstrated by the SARS epidemic of 2002-03, and the current COVID-19 pandemic.... scientific research indicates that there is no evidence that suggests the virus was created in a laboratory."
The NIH research consisted of two parts. The first part began in 2014 and involved surveillance of bat coronaviruses, and had a budget of $3.7 million. The program funded Shi Zheng-Li, a virologist at the Wuhan lab, and other researchers to investigate and catalogue bat coronaviruses in the wild. This part of the project was completed in 2019.
A second phase of the project, beginning that year, included additional surveillance work but also gain-of-function research for the purpose of understanding how bat coronaviruses could mutate to attack humans. The project was run by EcoHealth Alliance, a non-profit research group, under the direction of President Peter Daszak, an expert on disease ecology. NIH canceled the project just this past Friday, April 24th, Politico reported. Daszak did not immediately respond to Newsweek requests for comment.
The project proposal states: "We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential."
In layman's terms, "spillover potential" refers to the ability of a virus to jump from animals to humans, which requires that the virus be able to attach to receptors in the cells of humans. SARS-CoV-2, for instance, is adept at binding to the ACE2 receptor in human lungs and other organs.
According to Richard Ebright, an infectious disease expert at Rutgers University, the project description refers to experiments that would enhance the ability of bat coronavirus to infect human cells and laboratory animals using techniques of genetic engineering. In the wake of the pandemic, that is a noteworthy detail.
Ebright, along with many other scientists, has been a vocal opponent of gain-of-function research because of the risk it presents of creating a pandemic through accidental release from a lab.
Dr. Fauci is renowned for his work on the HIV/AIDS crisis in the 1990s. Born in Brooklyn, he graduated first in his class from Cornell University Medical College in 1966. As head of NIAID since 1984, he has served as an adviser to every U.S. president since Ronald Reagan.
A decade ago, during a controversy over gain-of-function research on bird-flu viruses, Dr. Fauci played an important role in promoting the work. He argued that the research was worth the risk it entailed because it enables scientists to make preparations, such as investigating possible anti-viral medications, that could be useful if and when a pandemic occurred.
The work in question was a type of gain-of-function research that involved taking wild viruses and passing them through live animals until they mutate into a form that could pose a pandemic threat. Scientists used it to take a virus that was poorly transmitted among humans and make it into one that was highly transmissible—a hallmark of a pandemic virus. This work was done by infecting a series of ferrets, allowing the virus to mutate until a ferret that hadn't been deliberately infected contracted the disease.
The work entailed risks that worried even seasoned researchers. More than 200 scientists called for the work to be halted. The problem, they said, is that it increased the likelihood that a pandemic would occur through a laboratory accident.
H5N1 is a type of influenza virus that causes a highly infectious, severe respiratory disease in birds called avian influenza (or "bird flu"). Human cases of H5N1 avian influenza occur occasionally, but it is difficult to transmit the infection from person to person. When people do become infected, the mortality rate is about 60%.
-- FAQs: H5N1 influenza, by World Health Organization
Dr. Fauci defended the work. "[D]etermining the molecular Achilles' heel of these viruses can allow scientists to identify novel antiviral drug targets that could be used to prevent infection in those at risk or to better treat those who become infected," wrote Fauci and two co-authors in the Washington Post on December 30, 2011. "Decades of experience tells us that disseminating information gained through biomedical research to legitimate scientists and health officials provides a critical foundation for generating appropriate countermeasures and, ultimately, protecting the public health."
Nevertheless, in 2014, under pressure from the Obama administration, the National of Institutes of Health instituted a moratorium on the work, suspending 21 studies.
Three years later, though—in December 2017—the NIH ended the moratorium and the second phase of the NIAID project, which included the gain-of-function research, began. The NIH established a framework for determining how the research would go forward: scientists have to get approval from a panel of experts, who would decide whether the risks were justified.
The reviews were indeed conducted—but in secret, for which the NIH has drawn criticism. In early 2019, after a reporter for Science magazine discovered that the NIH had approved two influenza research projects that used gain of function methods, scientists who oppose this kind of research excoriated the NIH in an editorial in the Washington Post.
"We have serious doubts about whether these experiments should be conducted at all," wrote Tom Inglesby of Johns Hopkins University and Marc Lipsitch of Harvard. "[W]ith deliberations kept behind closed doors, none of us will have the opportunity to understand how the government arrived at these decisions or to judge the rigor and integrity of that process."
Correction 5/5, 6:20 p.m.: The headline of this story has been corrected to reflect that the Wuhan lab received only a part of the millions of U.S. dollars allocated for virus research.