The Debate Over Gain Of Function Studies Continues

BSL-4 Lab Worker - Photo Credit –USAMRIID

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`Gain of Function’ research (aka GOF) seeks to enhance the virulence, transmissibility, or host range of potentially deadly microorganisms. Proponents believe this could give us an early warning system for the next pandemic, and could aid in the timely creation of a vaccine.  

 

Opponents say those benefits are likely overstated, and there is a small - but genuine - risk that one of these `engineered’ pathogens could escape the lab, and actually cause the pandemic it was supposed to mitigate.

 

While GOF research isn’t new, the bioengineering tools we have today make possible tasks that would have been considered literally impossible a couple of decades ago.

 

All of this really came to a head about three years ago, when Dutch Virologist and flu researcher Dr. Ron Fouchier announced, at the 2011 ESWI Influenza Conference in Malta, that he’d created a `more transmissible’ form of the H5N1 virus (see Debra MacKenzie’s New Scientist: Five Easy Mutations).

 

At roughly the same time we saw a similar announcement from Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine, that together set alarm bells ringing in the world of biosecurity.

 

The early reaction outside of academia was fairly negative, with scathing editorials like An Engineered Doomsday  appearing in the New York Times. There was a year-long self imposed moratorium by a group of major researchers, to allow time for `public discussion and scientific debate’ of the issue, but in the end, very little of that actually took place. 

 

Instead, the moratorium was quietly lifted in early 2013, and research resumed, often in Biosafety level 3+ (Ag) facilities – not – as some have recommended, restricted to the highest containment Biosafety level 4 facilities. 

The revelation two weeks ago of a major breach in biosafety at a CDC lab in Atlanta (see CDC Statement On Possible Lab Exposure To Anthrax), along with the announcement earlier this month that Dr. Kawaoka had recreated viruses similar to the 1918 pandemic strain in his lab (see Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential) has helped to reignite the debate.

 

Today the Wisconsin State Journal carries a long article on concerns raised by University of Wisconsin biosafety expert.

 

UW-Madison flu studies raise risk more than prevent it, biosafety panelist says

By David Wahlberg | Wisconsin State Journal

UW-Madison scientist Yoshihiro Kawaoka says he’s creating potentially deadly flu viruses to help prevent a pandemic, but a campus biosafety panel member says the research could cause more harm than good because the viruses could escape from the lab.

“You’re increasing the probability of having a pandemic rather than decreasing the probability,” said Tom Jeffries, a member of the university’s Institutional Biosafety Committee, which reviews sensitive research.

Jeffries said the flu viruses Kawaoka creates in his lab at University Research Park on Madison’s West Side should be genetically modified to minimize the risk to humans. Kawaoka said doing that would undermine his studies, aimed at identifying troublesome flu viruses that could arise in nature.

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Late last week, the Journal Nature – which published Dr. Kawaoka’s H5N1 study in 2012 – published a cautionary opinion piece on the risks of doing this type of research.  Follow the link to read it in its entirety.

Nature | Editorial

Biosafety in the balance

An accident with anthrax demonstrates that pathogen research always carries a risk of release — and highlights the need for rigorous scrutiny of gain-of-function flu studies.

25 June 2014

The news last week of an accident involving live anthrax bacteria at the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is troubling. Some 84 workers were potentially exposed to the deadly Ames strain at three CDC labs. But the incident will cause much wider ripples: it highlights the risks of the current proliferation of biocontainment labs and work on dangerous pathogens. If an accident can happen at the CDC, then it can happen anywhere.

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As you might imagine, speaking out against this sort of research isn’t exactly popular in academia, as these research projects can bring in large government grants, along with substantial publicity and prestige to Universities.

 

Suggestions that this sort of research be confined to biosafety level 4 facilities are often met with stiff resistance, since that would exclude most of the University based labs in this country.

 

Last November, in BMC Medicine: Containing Laboratory Escape Of Pandemic Viruses, we looked at a report that found the risks of seeing an accidental release from one of these labs is far from zero.

 

They calculated a .3% chance of release from any given lab each year, which works out to be roughly one every 100 years of lab operation.  With hundreds of of BSL-3 and BSL-4 labs around the world, the odds of seeing an accident in any given year somewhere in the world go up substantially.

While one can certainly argue with the methodologies used to come up with estimates for future events, we do know that between 2003 and 2009, US government laboratories had 395 incidents that involved the potential release of select agents  (see CIDRAP News  report Report: 395 mishaps at US labs risked releasing select agents).

 

While only 7 related infections were reported, this does add weight to the concerns being expressed by GOF research critics.   As does the most recent breach at the CDC lab in Atlanta.

 

For more background on all of this, you may wish to revisit a presentation by Dr. Marc Lipsitch on the the risks of these types of experiments from last September, while last December (see The Call For Urgent Talks On `GOF’ Research Projects), we saw  a letter – signed by 56 scientists – and published both in SciAm and the journal Nature - calling for `urgent talks’ over the future course of GOF research on influenza viruses, and other pathogens.

 

And more recently, we’ve seen the debate renewed, first in the pages of PLoS Medicine last month:

 

Lipsitch & Galvani: GOF Research Concerns

 

The debate then moved to CIDRAP News, where Kawaoka & Fouchier responded to this paper:

Experts call for alternatives to 'gain-of-function' flu studies

 

And most recently, a response back by Lipsitch & Galvani, again at CIDRAP.

 

COMMENTARY: The case against 'gain-of-function' experiments: A reply to Fouchier & Kawaoka

Marc Lipsitch, DPhil, and Alison P. Galvani, PhD

 

Unfortunately, despite the ongoing debate, this issue doesn’t seem to be any closer to resolution than it was two and half years ago when the fate of the Fouchier & Kawaoka H5N1 papers was still in doubt.

Fouchier Loses Court Decision Over `Export Permit’

BSL-4 Lab Worker - Photo Credit –USAMRIID  

 

 

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Last year, during the months-long debate over the publication of  Ron Fouchier’s controversial H5N1 GOF (Gain of Function) studies (see Science Publishes The Fouchier Ferret Study), the Dutch government announced that they had jurisdiction over what scientific papers could be `exported’ from the Netherlands, sparking a heated side-debate over government censorship of science (see Fouchier Research To be Debated In The Netherlands This Week).

 

Finally, in April of 2012 the Dutch Govt. Granted Fouchier Export License For H5N1 Research, paving the way for its publication.  But the debate over how much control the Dutch government legally has over the dissemination of scientific publications then moved to the courts.

 

Yesterday, Martin Enserink writing for Science Insider, broke the details of a Dutch court decision, which ruled against Fouchier, and for the government. Follow the link to read it in its entirety.

 

Flu Researcher Ron Fouchier Loses Legal Fight Over H5N1 Studies

25 September 2013 2:45 pm

 

National Institutes of Health

Dismissed. A Dutch court has rejected a challenge to rules that required researchers to get an export permit before sending papers on the H5N1 avian influenza virus (above) to the U.S.-based journal Science.

 

Virologist Ron Fouchier has suffered a loss in a legal battle with the Dutch government over the publication of his controversial H5N1 influenza research. On Friday, a Dutch district court ruled that the government was right to ask Fouchier to obtain an export license before sending two hotly debated papers out for publication. The ruling, published yesterday (Dutch), could provide new roadblocks for Fouchier’s research in the future.

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H7N9: Reigniting The `Gain Of Function’ Research Debate

 

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

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Most readers will recall that, beginning in the fall of 2011 and extending well into the summer of 2012, the global scientific community was roiled by controversy over the wisdom of conducting – and publishing – Gain of Function (GOF) research on the avian H5N1 virus.

 

Objections were raised initially after the 2011 ESWI Influenza Conference in Malta, where Dutch researcher Ron Fouchier revealed that he’d created a more `transmissible’ form of the H5N1 virus (see Debra MacKenzie’s New Scientist: Five Easy Mutations).

 

That discovery, along with similar news coming from Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine, set alarm bells ringing in the biosecurity community.

 

By December of 2011 The Biosecurity Debate On H5N1 Research reached fevered pitch, which led to a group of internationally renowned Scientists to Announce a 60 Day Moratorium On Some H5N1 Research in January, 2012. That moratorium was subsequently extended until January of 2013 (see NIH Statement On Lifting Of The H5N1 Research Moratorium).

 

In the meantime, after much heated debate, last summer Science Published The Fouchier Ferret Study and Nature Published The Kawaoka H5N1 Study. 

 

In March of 2012 the NIH - which funds many of these research projects - promulgated new DURC Oversight Rules (Dual Use Research of Concern), which also includes some types of GOF research.

 

For those unfamiliar with the lexicon of biomedical research, DURC in this new policy is defined as:

. . . life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment,

 

Since then the debate has continued, mostly in academia, over what restrictions (if any) should be placed on potentially dangerous gain of function research.

 

  A couple of recent examples include:

 

Nature: H5N1 viral-engineering dangers will not go away

Morens & Taubenberger - Influenza Viruses: Breaking All the Rules

 

Today, in a bid to head off the kind of controversy they encountered with the surprise announcement of H5N1 GOF studies in 2011, 22 respected international scientists have published a pre-emptive letter (in the Journal Science and the Journal Nature) calling for gain of function research using the H7N9 virus.

 

In this letter they outline the benefits they believe such studies will provide along with the biosecurity measures they will work under.

 

Many of the signatories to this letter are well known to the readers of this blog.

 

RON A. M. FOUCHIER, YOSHIHIRO KAWAOKA, CAROL CARDONA,  RICHARD W. COMPANS, ADOLFO GARCÍA-SASTRE,  ELENA A. GOVORKOVA, YI GUAN, SANDER HERFST, WALTER A. ORENSTEIN, J. S. MALIK PEIRIS, DANIEL R. PEREZ,  JUERGEN A. RICHT, CHARLES RUSSELL, STACEY L. SCHULTZ-CHERRY, DEREK J. SMITH, JOHN STEEL,  S. MARK TOMPKINS, DAVID J. TOPHAM, JOHN J. TREANOR, RALPH A. TRIPP, RICHARD J. WEBBY,  ROBERT G. WEBSTER

 

You can read the full letter here or at the following link:

 

Published Online August 7 2013

Science DOI: 10.1126/science.1243325

Letters

Gain-of-Function Experiments on H7N9

*Corresponding author. E-mail: r.fouchier@erasmusmc.nl (R.A.M.F.); kawaokay@svm.vetmed.wisc.edu (Y.K.)

• Abstract

Since the end of March 2013, avian a influenza viruses of the H7N9 subtype have caused more than 130 human cases of infection in China, many of which were severe, resulting in 43 fatalities. Although this A(H7N9) virus outbreak is now under control, the virus (or one with similar properties) could reemerge as winter approaches. To better assess the pandemic threat posed by A(H7N9) viruses, NIAID/NIH Centers of Excellence in Influenza Research and Surveillance (CEIRS) investigators and other expert laboratories in China and elsewhere have characterized the wild-type avian A(H7N9) viruses in terms of host range, virulence, and transmission, and are evaluating the effectiveness of antiviral drugs and vaccine candidates. However, to fully assess the potential risk associated with these novel viruses, there is a need for additional research including experiments that may be classified as “gain-of-function” (GOF). Here, we outline the aspects of the current situation that most urgently require additional research, our proposed studies, and risk-mitigation strategies.

 

 

But as you might expect, not everyone is in agreement on the value, or the safety, of doing these studies.  In an accompanying news and analysis article in Science Magazine, David Malakoff writes:

 

Avian Influenza

Critics Skeptical as Flu Scientists Argue for Controversial H7N9 Studies

David Malakoff

<EXCERPT>

The openness offensive isn't quieting critics. “The scientific justification presented for doing this work is very flimsy, to put it mildly, and the claims that it will lead to anything useful are lightweight,” says Adel A. F. Mahmoud, an infectious disease specialist at Princeton University and the former president of Merck Vaccines. And the security precautions are “insufficient and amazingly lame,” says molecular biologist Richard Ebright of Rutgers University in Piscataway, New Jersey.

 

(Continue . . . )

 

The NIH, responding to today’s letter, has published their position regarding additional oversight they will require for H7N9 influenza virus gain-of-function research.

 

Extra Oversight for H7N9 Experiments

Harold Jaffe, Amy P. Patterson, Nicole Lurie

The U.S. Department of Health and Human Services (HHS) announces a new review process for certain gain-of-function (GOF) experiments with the avian influenza A (H7N9) virus, some of which are proposed this week by influenza scientists (1). Specifically, before being undertaken using funds from the HHS, proposed studies that are reasonably anticipated to generate H7N9 viruses with increased transmissibility between mammals by respiratory droplets will undergo an additional level of review by the HHS.

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Ed Yong – writing for The Scientist – has penned an excellent overview of this controversy, including extended remarks from a number of experts, including CIDRAP director Michael Osterholm.

 

 

Bird Flu Experiments Proposed

In a bid to avoid the controversy that dogged H5N1 research last year, flu researchers have published a letter proposing how to approach potentially dangerous research on H7N9.

By Ed Yong | August 7, 2013

 

And for a last stop, we have the always reliable Helen Branswell, who writes:

 

Flu researchers propose controversial 'gain-of-function' studies for H7N9 virus

By Helen Branswell, The Canadian Press August 7, 2013 10:30 AM

 

 

Whether this controversy will reach the contentious levels we saw last year with H5N1 research is difficult to predict, but there are strong feelings on both sides of this issue.

 

Stay tuned.

mBio: Should The H5N1 Research Moratorium End?

 

BSL-4 Lab Worker - Photo Credit –USAMRIID  

 

 

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Ten months ago, during the prolonged debate over the publication of a pair of controversial research papers (see The Furor Over H5N1 Research Continues), a group of the world’s leading researchers announced a 60 day moratorium on specific types of bird flu research (see Scientists Announce 60 Day Moratorium On Some H5N1 Research).

 

While the research papers by Fouchier and Kawaoka on the genetic changes needed to provide H5N1 with enhanced transmissibility have now been published, the self-imposed moratorium remains in place.

 

Scientists, biosecurity experts, and policy makers continue to struggle with how to proceed with H5N1 research that potentially falls under the category of DURC -  Dual Use Research of Concern.

 

For those unfamiliar with the lexicon of biomedical research, DURC is defined as:

 

. . . life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.

 

Last March the Office of Science Policy at the NIH released a 4 page set of guidelines for DURC projects, and ordered a review of all current life sciences projects (U.S. Issues New DURC Oversight Rules).

 

Later today the journal mBio will publish a series of opinion pieces regarding H5N1 research by some of the most influential researchers in influenza virology and biosecurity.

We’ve got a preview from a press release, which ought to whet or appetites until the new issue goes live later today (LINK).    Some excerpts follow:

 

202-942-9297
American Society for Microbiology

Research on enhanced transmissibility in H5N1 influenza: Should the moratorium end?

How can scientists safely conduct avian flu research if the results could potentially threaten, as well as save, millions of lives? In a series of commentaries appearing on Tuesday, October 9 in mBio®, the online open-access journal of the American Society for Microbiology, prominent microbiologists and physicians argue the cases both for and against lifting a voluntary moratorium on experiments to enhance the ability of the H5N1 virus to move from mammal to mammal, so-called "gain-of-function" research, and discuss the level of biosecurity that would be appropriate for moving that research forward.

 

<SNIP>

 

Enhancing and analyzing the transmissibility of the H5N1 virus could, on the one hand, provide insights that could help prevent or treat a future outbreak of H5N1 , or, on the other hand, it may provide a roadmap for a "bad actor" to deliberately bring about an influenza pandemic or lead to an inadvertent release of a virus with enhanced transmissibility.

Authors of the commentaries are prominent scientists, including:

• Ron Fouchier of Erasmus MC Rotterdam in The Netherlands, Adolfo García-Sastre of the Mount Sinai School of Medicine, and Yoshihiro Kawaoka of the University of Wisconsin-Madison, lead authors of the two papers that began the controversy, argue that in the eight months since the moratorium was agreed upon, the international research community has had sufficient time to review biosafety and biosecurity measures and that H5N1 transmission studies ought to proceed.
• Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases contributes his voice as a representative of an organization that is a key funder of influenza research. Although Fauci acknowledges that the benefits of gain-of-function research outweigh the risks, he argues that scientists have yet to fully meet their responsibility for engaging the public in weighing these matters and making the case for proceeding. He outlines how the U.S. government plans to augment policy guidelines related to "dual use research of concern" like the experiments on enhanced influenza transmission.
• Marc Lipsitch and Barry R. Bloom of the Harvard School of Public Health explain why they view H5N1 with enhanced transmissibility as a "potential pandemic pathogen," representing an even greater threat to global health than Ebola and other biosafety level 4 (BSL-4) pathogens. They argue that research on enhanced H5N1 and other potential pandemic pathogens requires a new, more stringent set of guidelines for safety, thorough public discussion of the risks and benefits involved, and global guidelines for laboratory procedures, among other measures to minimize the risk of laboratory-released infections or epidemics.
• Ian Lipkin of Columbia University argues that once research on enhanced strains of H5N1 continues it may be advisable to conduct the work only in BSL-3 Ag laboratories that meet additional, enhanced guidelines for handling agents with pandemic potential. Lipkin proposes that any course should be charted in consultation with and oversight from the global scientific and regulatory community.
• Stanley Falkow of Stanford University provides perspective on the H5N1 research moratorium based on his own experiences with a similar situation in the 1970s, when research in recombinant DNA techniques was halted while a committee of scientists and non-scientists could establish a set of guidelines for conducting the work safely. Falkow argues that research on H5N1 viruses with enhanced transmissibility should move forward once scientists work with the public to establish standardized guidelines using common sense and scientific creativity.

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While the papers of Fouchier and Kawaoka sparked this vigorous (and at times heated) debate over the risks of creating a better bird flu virus, many of the same issues apply to other areas of biological research.

 

Among them:

• How are we to handle this brave new world of life sciences, where new viruses and other life forms can be created in the laboratory?
• Who is to decide on what is appropriate, or safe research?
• Who decides what should be published, and who should have access to redacted information?
• What laboratory protocols and protections are necessary for working the the H5N1 virus, and other virulent pathogens?

 

We are entering a new era of scientific discovery, one where great things are possible. But those advances will be for naught if the public loses faith in the science, or the scientists.

 

You can create a genetically modified dengue-resistant mosquito, but if the public fears it more than the disease, all you have is an expensive laboratory curiosity.

 

And a universal flu vaccine – one that could forever stave off the global threat of influenza pandemics -only works if it is accepted by the vast majority of the public as being safe, effective, and necessary.

 

As I wrote in Science At The Crossroads, the public’s faith in science and technology is teetering. 

 

According to a UK poll (Public Attitudes To Science, May 2011), while the majority of respondents (79%) believe science has, on the whole, made our lives easier . . .  astonishingly, just 54% believe that the benefits of science are greater than any harmful effect.

 

One only has to look at the deep divisions over climate change, evolution, vaccine safety, nuclear power, and genetically modified food crops to realize just how wide this rift between the public, and scientists, has become.

 

Which makes getting policy on H5N1 research (and other DURC projects) right, and as safe as possible, absolutely imperative.

 

Given the public’s sentiment, the burgeoning field of Life Sciences (which includes bio-engineering) can ill afford a misstep if they hope to gain and hold the public’s acceptance.