CIDRAP On The GOF Research Pause Debate

Credit CDC PHIL

 

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One of the topics we’ve revisited frequently over the past several years has centered around  the wisdom and safety of creating new and/or enhanced viruses in the laboratory.  Areas of research commonly called either  `Gain of Function’ (GOF) or DURC (Dual Use Research of Concern). 

 

Some earlier blogs on this topic include:

 

mBio: The Risks & Benefits Of `GOF’ Experimentation On Pathogens With Pandemic Potential

The Laboratory Bio-Safety Backlash Continues

ECDC Comment On Gain Of Function Research

Lipsitch & Galvani: GOF Research Concerns

 

While scientists engaged in this type of work insist that the risks are negligible (see Scientists For Science: GOF Research `Essential’ & Can be Done `Safely’), many others (see Updating The Cambridge Working Group) are not convinced.

 

After several years of public and internal debate, two months ago the Obama administration ordered a temporary moratorium on Federally funded GOF research involving influenza, MERS, and SARS while new rules and regulations could be devised. 

 

This policy change came after a summer which saw repeated high-profile stories of lab accidents and violations of biosafety protocols (see The Journal Nature Weighs In On Lab Accidents & Biosafety).

 

Last night Jim Wappes, Editorial Director of  CIDRAP, wrote a long piece looking at both sides of this complicated and growing debate. Follow the link below to read:

 

Experts debate research pause, gain-of-function issues

Dual-Use Research

Jim Wappes | Editorial Director | CIDRAP News

Dec 15, 2014

 In anticipation of today's debate at the National Academy of Sciences (NAS) in Washington, DC, on "gain-of-function" (GOF) research, two recent editorials and three other opinion pieces in mBio discussed the US government's decision earlier this fall to pause controversial GOF research that might elevate the risks of a pandemic as a result of a bioterror attack or accidental pathogen release.

"GOF" typically refers to experiments that involve enhancing the pathogenicity, transmissibility, or host range of a pathogen, with the aim of better understanding disease pathways and developing vaccines and drugs.

One editorial, by Marc Lipsitch, PhD, director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health, and Thomas V. Inglesby, MD, director of the Center for Health Security at the University of Pittsburgh Medical Center, supports the research pause and offers approaches for assessing risk. The second editorial, by mBio editor Michael J. Imperiale, PhD, and mBio founding editor-in-chief Arturo Casadevall, MD, PhD, questions the value of the GOF pause and asks for clarification of key elements in the policy.

The Obama administration announced the moratorium on Oct 17 to assess the risks and benefits of federally funded GOF research involving influenza, MERS (Middle East respiratory syndrome), and SARS (severe acute respiratory syndrome) viruses and to develop federal policies. The National Science Advisory Board for Biosecurity (NSABB) is playing a lead role in the review, which is expected to last almost a year. On Nov 25 the NSABB expressed concerns over the pause.

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Thebulletin.org: Making Viruses Deadlier – An Accident Waiting To Happen

The Doomsday Clock from TheBulletin.org

 

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The Bulletin of the Atomic Scientists – founded by former Manhattan Project scientists after the end of WWII -  covers a variety of global security issues ranging from nuclear technology, to climate change, to new emerging technologies.

 

It is perhaps best known for its Doomsday Clock, which represents how close they believe we are to seeing a technologically induced disaster.

 

Currently that clock sits at 5 minutes to Midnight, having made its closest approach in 1953 (2 minutes to midnight) after the US and the Soviet Union had both tested thermonuclear devices in the same year and its furthest in 1991 (17 minutes) after the signing of the START treaty and the dissolution of the Soviet Union. 

The Doomsday clock has sat at its present position since 2012.

 

While the risks from nuclear threats may seem lower today than during the 1980s when the Doomsday clock last sat at 5 Minutes till Midnight, other threats – including climate change, emerging biotechnologies, and cybertechnologies are now part of the doomsday equation.

 

One of the topics we’ve seen hotly debated over the past several years has centered around  the wisdom and safety of creating new and/or enhanced viruses in the laboratory.  Areas of research commonly called either  `Gain of Function’ (GOF) or DURC (Dual Use Research of Concern).

 

While scientists engaged in this type of work insist that the risks are negligible (see Scientists For Science: GOF Research `Essential’ & Can be Done `Safely’) and are resisting additional additional oversight and regulation, many others (see Updating The Cambridge Working Group) are not convinced.

 

Yesterday the Bulletin of Atomic Scientists published a long analysis/opinion piece (see link below) warning of the perils of this type of research on potentially deadly viruses.  It’s a long read, but very much worth the time.

When you return, I’ll have a bit more:

 

Analysis

08/13/2014 - 21:42

Making viruses in the lab deadlier and more able to spread: an accident waiting to happen

Tatyana Novossiolova Malcolm Dando

 

Although a number of biosafety experts have warned about the risks of these types of experiments for several years - since the revelations of several serious lapses in biosafety at CDC and FDA labs this summer involving anthrax, smallpox, and H5N1 avian flu - we are seeing a growing chorus of concerned voices.

 

A few recent examples include:

 

mBio: The Risks & Benefits Of `GOF’ Experimentation On Pathogens With Pandemic Potential

The Laboratory Bio-Safety Backlash Continues

ECDC Comment On Gain Of Function Research

The Journal Nature Weighs In On Lab Accidents & Biosafety

Lipsitch & Galvani: GOF Research Concerns

 

 

Sixty years ago, during the height of the cold war, the scientific debate of that age was over the safety and wisdom of continuing to conduct above-ground  thermonuclear detonations.  

 

Between 1945 and 1962, hundreds of atmospheric nuclear tests were conducted by the United States, The Soviet Union, France, and the UK, releasing significant quantities of radioactive isotopes into the environment - including (americium-241, cesium-137, iodine-131, strontium-90).

While many scientists and government officials of the day claimed these tests were both safe and necessary for national security, it became apparent by the mid-1950s that the dangers had been downplayed. 

 

Strontium-90 - which acts much like calcium in the human body -  was of great concern as it ended up deposited in bones and teeth of small children, raising serious concerns over future cancer risks.

 

But it would not be until 1963 when the world came to its collective senses and a global nuclear test ban treaty would be adopted, limiting all testing to underground.

 

The debate then over atomic testing - like the debate today over `life sciences’ and GOF work - and the debate we will soon need to have over Artificial Intelligence and nanotechnologies, pits the tantalizing promise of scientific discovery against the sobering reality that emerging technologies can often be a double-edged sword.

 

While some researchers may resist the idea and call it scientific censorship, the time has come to have a thorough and public debate over the risks and benefits of Gain of Function research.   

 

Faith in science and scientists has eroded badly over the past 50 years (see Science At The Crossroads).  Public skepticisms over climate change, the safety of GMO foods and vaccines, or nuclear power are only rising with each passing year.

 

While some of this erosion of trust can be traced to tabloid journalism and conspiracy websites, some of it has been well earned ( see When Scientists Behave Badly & Dysfunctional Science).  

 

With the world facing a growing list of threats – both natural and man made – we need to restore the public’s faith both in science, and its scientists.   But for that to happen, we need its representatives to do more than to wave their hands and say:

 

`Trust us . . . we’re scientists’.

The Laboratory Bio-Safety Backlash Continues

Credit CDC

 

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The groundswell of concern over controversial `gain of function’ laboratory experiments, and recent high-profile lapses in biosecurity at the nation’s top labs, continues to grow with a scathing editorial appearing yesterday in the Annals of Internal Medicine penned by Deputy Editor Deborah Cotton, MD, MPH.

 

While much of the editorial is behind a pay wall, you can find a readable scan of the first page at the link below.  Fortunately, Medscape Medical News  published a detailed summary, and interview with the author, yesterday (more on that after you return).

 

Editorials | 29 July 2014

Biocontainment Laboratories: Addressing the Terror Within 

Deborah Cotton, MD, MPH, Deputy Editor

Ann Intern Med. Published online 29 July 2014 doi:10.7326/M14-1668

Recently revealed safety lapses in U.S. government facilities that work with deadly pathogens suggest that, despite efforts to protect us from bioterrorism as well as naturally occurring infectious diseases, there is another grave bioterror threat: the risk emanating from biocontainment laboratories themselves. This commentary discusses possible factors contributing to the safety lapses and strategies to prevent future incidents.

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The following lengthy report from Medscape provides more detail on the above editorial, along with comments from the author, and additional input from by Nancy Kingsbury, PhD, of the Government Accountability Office and  by Richard H. Ebright, PhD, professor of chemistry and chemical biology at Rutgers University  (see House Subcommittee Hearing on Biosafety  for their recent testimony). .

 

Suspend Work, Close Most High-Level Biosafety Labs, Experts Say

Janis C. Kelly

July 29, 2014

( UPDATED July 29, 2014 ) Management of US government bioterrorism research facilities is so lax that work in biosafety level (BSL) 4 laboratories (which house deadly organisms for which there are no effective treatments or vaccines) should be suspended pending a complete safety overhaul, Annals of Internal Medicine deputy editor Deborah Cotton, MD, MPH, writes in an editorial published online July 28 in the journal

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Beyond suspension of work pending a a safety overhaul, experts are calling for a dramatic scale back in the number of BSL-3 and BSL-4 labs in the county that are allowed to work on the most dangerous pathogens.  Currently, there isn’t even a good count on the number of BSL-3 labs in operation, and there is no one single regulatory agency in charge of monitoring their operations.

 

While we continue to get bland assurances from researchers that their work is both safe and essential (“We’re scientists . . . trust us” )  we are also hearing from others – like the Director of the CDC - that there  remains an insufficient `culture of safety’ among research scientists.  

 

We are also seeing reports  that the number of laboratory `incidents’ may be far higher than is reported.

 

While many researchers will be justifiably dismayed by the draconian recommendations made in the above editorial, and I doubt that we’ll see anything close to the reduction in BSL-3 labs they are calling for, it is obvious that serious changes are needed.  

 

For the past ten years – spurred on in part by national security concerns – there’s been an `anything goes’ attitude when it comes to biomedical research.  Since the 9/11 attack, the number of BSL-4 labs in the United States has jumped from 2 to 14, and the number of BSL-3 labs has grown from around 400 to over 1400 (although the exact number is murky).

 

Although BSL-3 and BSL-4 labs are essential parts of national security, biomedical research, and the testing of pathogens - the more of them that are in operation - the better the chance of a seeing a serious accident.

 

How many are too many, will be one of the major decisions facing regulators.

 

Given the money, power, and prestige at stake, I don’t expect to see many BSL-3 labs voluntarily sacrifice themselves on the altar of public safety.  So we should expect more than a little resistance to any reductions.

 

For more on this growing debate, you may wish to revisit:

 

Scientists For Science: GOF Research `Essential’ & Can be Done `Safely’

Updating The Cambridge Working Group

ECDC Comment On Gain Of Function Research

CDC: Press Conference Transcript, Audio & Timelines For Lab Incidents

Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential

Lipsitch & Galvani: GOF Research Concerns

Updating The Cambridge Working Group

Credit CDC PHIL

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Two weeks ago in Reshuffling The NSABB & A New Biosecurity Working Group Emerges, we learned that the NIH had notified 11 of the 23 original members of the NSABB (or National Science Advisory Board for Biosecurity) - an under-utilized biosafety advisory committee, formed in 2005 - that their services are no longer required.

 

Gone were such well known (and frequently outspoken) experts as Paul Keim from Northern Arizona University, Arturo Casadevall from Albert Einstein College of Medicine, Michael Imperiale of the University of Michigan, and Michael Osterholm from CIDRAP.

 

Given the recent serious lapses in lab biosecurity at both the CDC and FDA, and continued work on `Gain of Function’ research (designed to enhance the virulence, transmissibility, or host range) of highly dangerous pathogens (see The Debate Over Gain Of Function Studies Continues), one might easily have assumed that the NSABB would have their plates full.

 

Although they made headlines in 2011-2012 over their cautionary stance regarding the publication of the Fouchier H5N1 ferret study (see The Furor Over H5N1 Research Continues), the NSABB been idle for the past two years, with no requests from the NIH to reconvene.

 

The day following the NIH’s decision to release 11 of their members, a new initiative appeared online called the Cambridge Working Group, with a consensus statement supported by 18 internationally known experts and researchers (including several former NSABB members).

 

Cambridge Working Group Consensus Statement on the Creation of Potential Pandemic Pathogens (PPPs)

Recent incidents involving smallpox, anthrax and bird flu in some of the top US laboratories remind us of the fallibility of even the most secure laboratories, reinforcing the urgent need for a thorough reassessment of biosafety. Such incidents have been accelerating and have been occurring on average over twice a week with regulated pathogens in academic and government labs across the country. An accidental infection with any pathogen is concerning. But accident risks with newly created “potential pandemic pathogens” raise grave new concerns. Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control. Historically, new strains of influenza, once they establish transmission in the human population, have infected a quarter or more of the world’s population within two years.

For any experiment, the expected net benefits should outweigh the risks. Experiments involving the creation of potential pandemic pathogens should be curtailed until there has been a quantitative, objective and credible assessment of the risks, potential benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches. A modern version of the Asilomar process, which engaged scientists in proposing rules to manage research on recombinant DNA, could be a starting point to identify the best approaches to achieve the global public health goals of defeating pandemic disease and assuring the highest level of safety. Whenever possible, safer approaches should be pursued in preference to any approach that risks an accidental pandemic.

Original Signatories & Founding Members:

(Founding Members met in Cambridge on July 14 and crafted the statement)

• Amir Attaran, University of Ottawa
• Barry Bloom, Harvard School of Public Health
• Arturo Casadevall, Albert Einstein College of Medicine
• Richard Ebright, Rutgers University
• Nicholas G. Evans, University of Pennsylvania
• David Fisman, University of Toronto Dalla Lana School of Public Health
• Alison Galvani, Yale School of Public Health
• Peter Hale, Foundation for Vaccine Research
• Edward Hammond, Third World Network
• Michael Imperiale, University of Michigan
• Thomas Inglesby, UPMC Center for Health Security
• Marc Lipsitch, Harvard School of Public Health
• Michael Osterholm, University of Minnesota/CIDRAP
• David Relman, Stanford University
• Richard Roberts (Nobel Laureate '93), New England Biolabs
• Marcel Salathé, Pennsylvania State University
• Lone Simonsen, George Washington University
• Silja Vöneky, University of Freiburg Institute of Public Law, Deutscher Ethikrat

In the two weeks since that initiative appeared only, more than 50 more Charter Members have also signed, including such familiar names as John S. Brownstein from Harvard Medical School, Neil M. Ferguson of Imperial College, W. Ian Lipkin of Columbia University, Andrew Rambaut of the University of Edinburgh, UK, and Klaus Stöhr, Novartis Vaccines and Diagnostics.

Follow this link to review this expanding roster of supporters.

 

As you might imagine, urging caution over this sort of research won’t win popularity contests in some circles of academia, as these (often government funded) research projects can bring in large grants, along with substantial publicity and prestige to labs, universities, and researchers.

 

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

 

The debate up until now over this type of research has been largely limited to academia, and has often been acrimonious.

 

The often promised  `thorough public discussion of the risks and benefits involved; never materialized as the issue exited the headlines, and GOF research resumed in early 2013 after Scientists Declare End To H5N1 Research Moratorium.

 

While undeniably bad timing for proponents of unfettered GOF research, three high profile lab incidents this summer involving anthrax, smallpox, and avian flu  have reawakened the public’s (and congressional) concern over lab safety and the wisdom of conducting certain types of research.

 

Despite the assurances from researchers on the relatively low risk of an accidental biological release, if we’ve learned nothing else this summer, it’s that accidents can happen even the best labs in the country.

 

And when dealing with Potential Pandemic Pathogens (PPPs), even a small mistake could have serious public health ramifications.

 

The stated goal here isn’t to ban GOF or DURC (Dual Use Research of Concern) studies, but rather to ensure they are only conducted in an appropriate high containment lab, are done in the safest and most responsible way possible, and only conducted when their benefits clearly outweigh the risks. 

 

While additional regulation is unlikely to be popular among many engaged in GOF research, these are all issues that need to be discussed, mapped out, and agreed upon.

 

And preferably before next high profile lab accident makes the headlines . . . or worse.

 

For more on the issue of Lab Safety,  GOF,  and DURC research, you may wish to revisit:

 

ECDC Comment On Gain Of Function Research

CDC: Press Conference Transcript, Audio & Timelines For Lab Incidents

Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential

Lipsitch & Galvani: GOF Research Concerns

SciAm: Branswell On Lab Biosafety

 

 

 

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I’ve been away from my desk for most of the day, but I wanted to recommend (very highly) the following Scientific American piece by Helen Branswell on the fallout from the recent laboratory incidents involving select agents at the CDC and FDA.

 

 

Bio-Unsafety Level 3: Could the Next Lab Accident Result in a Pandemic?

So-called gain-of-function pathogen research will likely receive closer scrutiny after three U.S. biolab incidents

Jul 14, 2014 |By Helen Branswell

A CDC scientist inoculates a chicken egg with H5N1 in a biosafety level 3 lab. 
Credit: CDC/Greg Knobloch

There had to be a sinking feeling in the chest of every researcher who works in a high-containment research laboratory last Friday when the U.S. Centers for Disease Control and Prevention (CDC) released its report on three worrisome incidents that raised safety questions at two well-respected government facilities. But it is likely the sensation was most acute for the influenza scientists who work in a controversial field known as gain-of-function research.

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Upcoming House Sub-Committee Hearing On Lab Safety

CDC Anthrax Timeline – Credit CDC

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Even before Friday’s announcement by the CDC that one of their labs had accidentally shipped H5N1 contaminated virus samples to a USDA lab, the House Energy and Commerce Oversight and Investigations Subcommittee had scheduled a hearing on last month’s CDC Anthrax incident (see CDC Statement On Possible Lab Exposure To Anthrax).

 

Hearing Notice: Subcommittee on Oversight and Investigations to Examine Anthrax Incident

July 8, 2014

Director of the Centers for Disease Control and Prevention to Testify on Recent Anthrax Exposure

The Subcommittee on Oversight and Investigations, chaired by Rep. Tim Murphy (R-PA), has scheduled a hearing for Wednesday, July 16, 2014, at 10 a.m. in room 2123 of the Rayburn House Office Building. The hearing is entitled “Review of CDC Anthrax Lab Incident.” Dr. Tom Frieden, Director of the Centers for Disease Control and Prevention (CDC), will be among the witnesses testifying.

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An incident which was closely followed by the equally disturbing discovery of six vials of unsecured smallpox at an FDA lab in Bethesda, Md. (see CDC Media Statement on Newly Discovered Smallpox Specimens).

Despite their age (vials dated 1954), and a sub-optimal storage environment for decades, on Friday we learned that samples taken from two of the vials were still viable, and growing in a CDC Lab (see CDC Announces Another Serious Biosecurity Incident).

 

The third - and arguably most serious incident – involved the cross contamination of H9N2 samples with highly pathogenic H5N1, and then shipping them to an unsuspecting USDA lab in Georgia.   Worse, once the discovery was made by the USDA lab, the incident went `unreported’ to upper management at the CDC for another six weeks.

 

March 12

• CDC Influenza Division (ID) shipped low pathogenic avian influenza H9N2 to USDA SEPRL in Athens, Ga
  Genetic analysis confirmed identity of H9N2
• Shipment delivered on March 13 to USDA Southeast Poultry Research Laboratories (SEPRL) (Athens GA)
  SEPRL observed pathogenicity in chickens inconsistent with H9N2 virus
  SEPRL performed molecular analyses on SEPRL virus stock and material sent by CDC
  SEPRL confirmed highly pathogenic H5N1 contamination and destroyed all SEPRL virus stocks in biosafety level 3 (BSL-3) enhanced

May 23

• SEPRL notified CDC ID that SEPRL virus stock was contaminated and destroyed

May 23

• CDC ID confirmed H9N2 virus was contaminated by H5N1 virus

July 9

• CDC Responsible Official was notified; investigation is ongoing

 

A revelation that led to another press release from the House Sub-Committee on Friday, which indicates a widening of the scope of the hearing scheduled for Wednesday.

 

Upton, Murphy Comment On Additional CDC Safety Failures

July 11, 2014

CDC Head Will Testify on Recent Anthrax Incident WEDNESDAY

WASHINGTON, DC – House Energy and Commerce Committee Chairman Fred Upton (R-MI) and Oversight and Investigations Subcommittee Chairman Tim Murphy (R-PA) responded to the latest announcement by the Centers for Disease Control and Prevention (CDC) on additional safety breaches. As part of the ongoing investigation into the potential exposure of more than 80 workers at a CDC lab in Atlanta to live anthrax, committee leaders earlier this week sent letters to the CDC and HHS Inspector General seeking documents and information. CDC Director Dr. Tom Frieden is scheduled to testify before the Oversight and Investigations Subcommittee next Wednesday, July 16, at 10 a.m.

Chairman Upton commented, “The repeated breakdown in protocols and safety failures involving the world’s deadliest germs and pathogens is wholly unacceptable. The consequences of such carelessness could not be more dire. This latest revelation underscores the need for our investigation and the importance of next week's hearing to review the safety measures and practices at the CDC. Past fixes by CDC several years ago apparently were not followed and not adequately implemented. We will seek to find out why CDC thinks its latest actions will prove more effective than past efforts, and whether congressional intervention may be necessary. We look forward to hearing directly from Dr. Frieden next Wednesday and will seek his firm commitment that such safety lapses are over.”

Subcommittee Chairman Murphy added, “With the release of today’s report, we’ve learned the dangerous transfer of possible live anthrax bacteria by the CDC’s Atlanta lab was not an isolated incident by a rogue scientist, but rather one of multiple mishaps over the last several years that were violations, or apparent violations, of federal regulations for handling deadly biological material. These repeated safety failures raise grave concerns about the CDC’s ability to ensure strict procedures, protocols, and training are followed and an area we will examine further at Wednesday’s Oversight and Investigations Subcommittee hearing.”

 

House E&C Subcommittee hearings are usually broadcast live at this link:

 

 http://energycommerce.house.gov/studio/webcasts

 

All of this comes after several years of debate over the safety of government and university laboratories, and concerns over potentially dangerous work on DURC (Dual Use of Concern) and GOF (Gain of Function) research projects.

 

For those unfamiliar with the lexicon of biomedical research, GOF research involves the creation of viruses and/or bacteria with enhanced virulence, transmissibility, or host range  while 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

 

Proponents of these types of research projects argue that the risks of an accidental release are small, that they can open up new avenues of knowledge in the world of bioengineering, and perhaps tip us off as to the what pathogens have the most pandemic potential, and even help in the early development of a vaccine. 

 

Opponents argue that these potential benefits are overstated, and the risks of an accidental release from one of the hundreds of labs doing this type of work are underappreciated (see The Debate Over Gain Of Function Studies Continues).

 

While we don’t know what Dr. Frieden will say before the subcommittee on Wednesday, on Friday he did say:

 

“And fundamentally, and this is relation to the previous question from the wall street journal as well, one of the things that we want to do is reduce the number of laboratories that work with dangerous agents to the absolute minimum necessary.  Reduce the number of people who have access to those laboratories to the absolute minimum necessary.  Reduce the number of dangerous pathogens we work with in those laboratories.”

 

This week, you can expect to see a good deal of media coverage of this topic, but a good one to start your week with is this from Reuters:

 

 

ANALYSIS-How to fix U.S. biosecurity leaks? Close some labs

Source: Reuters - Mon, 14 Jul 2014 05:00 GMT

By Sharon Begley and Julie Steenhuysen

July 14 - In the wake of disclosures that top government labs mishandled anthrax, smallpox and avian flu, U.S. health authorities are considering the once unthinkable: cutting the burgeoning number of labs working with the planet's most dangerous microbes.

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In 2012 we saw a year-long self imposed moratorium on controversial GOF research 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 – except for the occasional scathing newspaper editorial (see NYTs  An Engineered Doomsday) – this debate has been largely conducted in academic circles or in research journals.

 

Now, the debate finds itself once again on the front page, and this time it will be conducted under the formidable shadow of three very high-profile biosecurity lapses in what are assumed to be the best, and safest, labs in the country. 

 

Which means that advocates of  GOF & DURC research have a big job ahead of them to convince an increasingly skeptical public, and traditionally risk adverse politicians, of the wisdom and safety of continuing – particularly in anything less than the highest biosecurity settings.

Stay tuned.

Lipsitch & Galvani: GOF Research Concerns

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

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In September it will have been three years since 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.

 

While the media furor (see New York Times An Engineered Doomsday) has since quieted, the debate over the wisdom and safety of conducting certain types of Gain of Function (GOF) experiments – designed to enhance the transmissibility, virulence, or host range of potentially deadly microorganisms - has not gone away.

I’ve covered both sides of this debate previously, in:

Laurie Garrett On Biosecurity Reforms

H7N9: Reigniting The `Gain Of Function’ Research Debate 

Nature: H5N1 viral-engineering dangers will not go away

Morens & Taubenberger - Influenza Viruses: Breaking All the Rules

mbio Science Should Be in the Public Domain

Last September we looked at a presentation by Dr. Marc Lipsitch on the the risks of these types of experiments, while last December (see The Call For Urgent Talks On `GOF’ Research Projects), we saw a 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.

 

Yesterday Dr. Lipsitch - Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health – along with Yale's Alison Galvani, published an opinion piece in PLoS Medicine  on the risks involved in experimenting on potential pandemic pathogens (PPPs).

 

Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens

Marc Lipsitch mail, Alison P. Galvani

Published: May 20, 2014  DOI: 10.1371/journal.pmed.1001646

Summary Points

• “Gain of function” experiments involving the creation and manipulation of novel potential pandemic pathogens (PPPs) deserve ethical scrutiny regarding the acceptability of the risks of accidental or deliberate release and global spread.
• The Nuremberg Code, a seminal statement of clinical research ethics, mandates that experiments that pose a risk to human life should be undertaken only if they provide humanitarian benefits that sufficiently offset the risks and if these benefits are unachievable by safer means.
• A novel PPP research program of moderate size would pose substantial risks to human life, even optimistically assuming a low probability that a pandemic would ensue from a laboratory accident.
• Alternative approaches would not only be safer but would also be more effective at improving surveillance and vaccine design, the two purported benefits of gain-of-function experiments to create novel, mammalian-transmissible influenza strains.
• A rigorous, quantitative, impartial risk–benefit assessment should precede further novel PPP experimentation. In the case of influenza, we anticipate that such a risk assessment will show that the risks are unjustifiable. Given the risk of a global pandemic posed by such experiments, this risk assessment should be part of a broader international discussion involving multiple stakeholders and not dominated by those with an interest in performing or funding such research.

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Although you’ll want to read the whole article, the Harvard School of Public Health has published a press release with a summation of their findings.  A few excerpts follow:

 

Experiments using virulent avian flu strains pose risk of accidental release

Research in mammals that aims to prevent future influenza pandemics raises ethical, public health concerns

Boston, MA — Experiments creating dangerous flu strains that are transmissible between mammals pose too great a risk to human life from potential release, according to an editorial by researchers from Harvard School of Public Health (HSPH) and Yale School of Public Health. The researchers are calling for greater scrutiny of experiments that make virulent influenza strains transmissible, and for future studies on flu transmission to use safer and more effective alternative approaches.

<SNIP>

The authors call for the U.S. government and other funders to conduct a comprehensive risk-benefit analysis before backing further PPP studies. They estimate that if 10 high-containment laboratories in the United States were running such experiments for a decade, there would be a nearly 20% risk of at least one laboratory-acquired flu infection with the potential to spread. In countries operating under less-stringent conditions than the United States, the risk is much greater.

If a PPP were released, it could lead to widespread human-to-human transmission of a highly virulent virus. It is believed that the H1N1 flu strain that caused a pandemic in 1977 and continued to circulate for 20 years was accidently released from a lab in Russia or China.

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While accidents in well regulated Bio-level 4 labs are rare, they are not unheard of.  And many researchers doing GOF studies only have access to Bio-level 3 or 3+ labs, where safety standards are not as rigorous. 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.

 

Between 2003 and 2009, US government laboratories had 395 incidents that involved the potential release of select agents, according to this report from CIDRAP NEWS.  While only 7 related infections were reported, this does add weight to the concerns being expressed by GOF research critics.  

While there is often a tendency of the public (and the press) to overreact to new fields of scientific research  – imagining the worst possible outcome – over the past three years we’ve seen a growing number of sober, rational, and highly skilled scientists who see a genuine and unacceptable risk in certain types of GOF research, and are concerned enough to take an unpopular  position in academia.

 

Something that ought to give us serious pause, regardless of how we might feel about the benefits that this type of research might someday yield. 

The Call For Urgent Talks On `GOF’ Research Projects

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

# 8101

 

It’s been more than two years since 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).

 

That, combined with a similar announcement 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. 

 

In the months that followed we saw a protracted, and at times rancorous, debate over the merits and safety of so-called `Gain of Function’  (GOF) research on dangerous pathogens. GOF research involves the creation of viruses and/or  bacteria with enhanced virulence, transmissibility, or host range. 

 

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 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,

 

After much heated debate, during the summer of 2012 Science Published The Fouchier Ferret Study and Nature Published The Kawaoka H5N1 Study.  But the debate over the safety, merits, and wisdom of conducting these sorts of experiments has continued.

 

Researchers in favor of GOF studies argue against undue restrictions and `censorship’ of science (see mbio Science Should Be in the Public Domain by Vincent R. Racaniello), while critics point out that the benefits of such research have been overstated (see Options VIII: Dr. Marc Lipsitch Argues Against HPAI GOF Experiments) and the risks have been downplayed.

 

All of which serves as prelude to an article over the weekend in in the Journal Nature (and SciAm) regarding a letter – signed by 56 scientists – sent to the European Commission, calling for `urgent talks’ over the future course of GOF research on influenza viruses, and other pathogens.

 

Scientists call for urgent talks on mutant-flu research in Europe

Benefits and risks of ‘gain-of-function’ work must be evaluated, they say.

Heidi Ledford

20 December 2013

A group of over 50 researchers has called on the European Commission to hold a scientific briefing on research that involves engineering microbes to make them more deadly.

In an 18 December letter to European Commission president José Manuel Barroso, the scientists — including representatives from the non-profit Foundation for Vaccine Research in Washington DC — urged the commission to organize the briefing, and to formally evaluate the risks and benefits of such 'gain-of-function' research.

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Although initial concerns were that the publication of the Fouchier or Kawaoka papers could serve as a blueprint for `bad actors’ to create a bio weapon, of even greater concern is the possibility of a laboratory accident that could result in the release of an `enhanced pathogen’.    

 

While accidents in well regulated Bio-level 4 labs are rare, they are not unheard of.  And many researchers doing GOF studies only have access to Bio-level 3 or 3+ labs, where safety standards are not as rigorous.

 

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.

 

Between 2003 and 2009, US government laboratories had 395 incidents that involved the potential release of select agents, according to this report from CIDRAP NEWS.  While only 7 related infections were reported, this does add weight to some of the concerns being expressed by GOF research critics.  

 

Whether `an urgent meeting’  will help resolve  this controversy is difficult to predict, as there are strong feelings on both sides of this issue.  But as I wrote nearly 2 years ago, in Science At The Crossroads, one need only look at the public’s reaction to vaccines, GMO foods, and nuclear power to see that their trust in science, and scientists, continues to ebb badly.  

 

While seemingly a debate for Academia, how this debate is conducted, and how this issue is resolved, has to potential  to greatly affect the public’s perception – for better or worse – of the entire scientific community.

 

Stay tuned.

Laurie Garrett On Biosecurity Reforms

BSL-4 Lab Worker - Photo Credit –USAMRIID  

 

# 7992

 

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 (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 a creshendo, which resulted in 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, often contentiously, over what restrictions (if any) should be placed on potentially dangerous gain of function research.  A few recent blogs on those debates include:

 

H7N9: Reigniting The `Gain Of Function’ Research Debate

Nature: H5N1 viral-engineering dangers will not go away

Morens & Taubenberger - Influenza Viruses: Breaking All the Rules

 

While we’ve been primarily concerned over GOF (Gain of Function) influenza research, the implications of this revolution in biology go far beyond influenza research.  It is now possible for even small laboratories to genetically engineer new (albeit, simple) life forms.

 

Today, Laurie Garrett - Pulitzer-prize winning journalist (1996 for her series on Ebola) and  author of 3 books (including The Coming Plague: Newly Emerging Diseases in a World Out of Balance), and Senior Fellow at the Council on Foreign Relations - has published a  Policy Innovation Memorandum on this revolution in the emerging  `life sciences’ field,  and the biosecurity controls she believes are needed.

Follow the link to read:

 

Making the New Revolutions in Biology Safe

Author: Laurie Garrett
October 2013

Two new revolutions in biology—gain-of-function research and synthetic biology—are forcing policymakers to rethink current national and international surveillance and regulatory systems, and any resolution will require international buy-in since the threat entails all living organisms.

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I suspect few would argue against the call to  restore disease surveillance and response funding to the CDC and USDA, or the need to `harmonize global laboratory and biosecurity standards’ .  A biosecurity Level 3+ lab in India or China really ought to have the same safety standards as one operating in Japan, or Australia, or the United States. 

 

The tougher nut to crack will be developing a suitable `regulatory framework appropriate to the DURC conundrum’ .  

 

While I expect there will be opposition to additional governmental oversight, a failure to come up with clear, concise, and workable rules will (at the very least) leave the scientific community open to continual criticism (like this Editorial in the New York Times called An Engineered Doomsday) every time a new DURC or GOF research project is proposed or published.   And in a worse-case scenario, could lead to dangerous a biological release.

 

Given the stakes, it will be interesting to see how researchers, and regulators, will respond to Ms. Garrett’s proposals.

Options VIII: Dr. Marc Lipsitch Argues Against HPAI GOF Experiments

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BSL-4 Lab Worker - Photo Credit –USAMRIID

 

# 7754

 

While the media furor has died down, the debate over the wisdom and safety of conducting Gain of Function (GOF) experiments on highly pathogenic avian influenza strains has not gone away. 

 

These experiments involve laboratory manipulation of the virus’s genetics in order to enhance its transmissibility, virulence, or host range. 

 

Proponents argue that these experiments can help us discover what strains have the most pandemic potential, and could help in the early development of a vaccine.  Opponents argue that these potential benefits are overstated, and the risks of an accidental release from the lab are too great.

 

Over the summer we’ve revisited this issue several times, including Proposed MicroRNA-based Strategy to Mitigate Risks Of GOF Influenza Studies, H7N9: Reigniting The `Gain Of Function’ Research Debate, and Nature: H5N1 viral-engineering dangers will not go away.

 

This past week, Cape Town, South Africa hosted Options for the Control of Influenza VIII – which every three years convenes the largest international scientific conference devoted soley to influenza. The topic of GOF research was, as you might expect,  a hot topic.

 

During this conference Dr. Marc Lipsitch - Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health, gave a 30 minute presentation on why he feels the risks of this type of work exceed the benefits. 

 

Links to  access the video, and his slides, are provided on the CCDD website below:

 

 

Marc Lipsitch opposes flu gain-of-function experiments

September 10, 2013

CCDD Director Marc Lipsitch participated in a panel discussion at Options for the Control of Influenza VIII on September 9, 2013, on the risks and benefits of "gain of function" research to make avian influenza viruses transmissible by mammals via an airborne route. His talk was entitled "Transmissibility Gain-of-Function Experiments with High-Pathogenicity Avian Influenza: Interesting Science, but Not Worth the Risk of An Accidental Pandemic."

A video of him giving the talk is here and a pdf of the slides can be found here.

 

Not that I expect this video to settle anything, but at least it puts into perspective the concerns that Dr. Lipsitch (and many others) hold in regards to these types of genetic experiments. 

Highly recommended.

Proposed MicroRNA-based Strategy to Mitigate Risks Of GOF Influenza Studies

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

# 7564

 

An interesting report appeared yesterday in the journal Nature Biotechnology that describes a potential method to help mitigate the risks of influenza GOF (Gain of Function) research.

 

Gain of function influenza research involves the creation (in the lab) of flu strains that have increased transmissibility, pathogenicity, or altered host range.

 

We looked at some of the issues (and controversies) surrounding this type of research last week in H7N9: Reigniting The `Gain Of Function’ Research Debate.

 

While there are multiple concerns over this type of research, one that has been cited often is the fear an `engineered’ virus could escape the lab and spark an epidemic.

 

Accidents and serious breaches in laboratory protocols and integrity, while rare, have occurred in the past.

 

One group of researchers believes that by genetically altering the influenza virus - it can be made less infectious to humans, but still transmit and infect ferrets – allowing for GOF research while reducing the risk of accidental human infection or release.

 

 

MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies

Ryan A Langlois, Randy A Albrecht, Brian Kimble, Troy Sutton, Jillian S Shapiro, Courtney Finch, Matthew Angel, Mark A Chua, Ana Silvia Gonzalez-Reiche, Kemin Xu, Daniel Perez, Adolfo García-Sastre & Benjamin R tenOever

Nature Biotechnology (2013) doi:10.1038/nbt.2666

Recent gain-of-function studies in influenza A virus H5N1 strains revealed that as few as three-amino-acid changes in the hemagglutinin protein confer the capacity for viral transmission between ferrets .

 

As transmission between ferrets is considered a surrogate indicator of transmissibility between humans, these studies raised concerns about the risks of gain-of-function influenza A virus research.

 

Here we present an approach to strengthen the biosafety of gain-of-function influenza experiments. We exploit species-specific endogenous small RNAs to restrict influenza A virus tropism. In particular, we found that the microRNA miR-192 was expressed in primary human respiratory tract epithelial cells as well as in mouse lungs but absent from the ferret respiratory tract. Incorporation of miR-192 target sites into influenza A virus did not prevent influenza replication and transmissibility in ferrets, but did attenuate influenza pathogenicity in mice.

This molecular biocontainment approach should be applicable beyond influenza A virus to minimize the risk of experiments involving other pathogenic viruses.

 

For more on this, The Scientist has a report describing this strategy.

 

Safe Flu Research Strategy

Researchers develop a new “molecular biocontainment” strategy for safely studying deadly flu viruses.

By Chris Palmer | August 12, 2013

Following a year-long, worldwide moratorium on H5N1 research stemming from fears of a global pandemic after researchers showed that the avian flu virus could be spread among ferrets, scientists have released a new “molecular biocontainment” strategy for the safe study of deadly viruses. The protocol, detailed in a paper published Sunday (August 11) in Nature Biotechnology, involves introducing viruses to be studied to human lung cells, which inactivate the viruses. 

 

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All of this is – quite frankly – well above my pay grade, so I pass it on without comment, and will leave it those more qualified to discuss the the merits and feasibility of this approach.