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’.

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

Credit CDC PHIL

 

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Somehow, between the Ebola news, and the fact that it was published on Wednesday (instead of mBio’s normal Tuesday publication date), I missed the following editorial by Arturo Casadevall  and Michael J. Imperiale in the open-access journal mBio.

 

It is a long, thoughtful look at the complex issues at hand.   Follow the link to read it in its entirety.

 

1 August 2014

Risks and Benefits of Gain-of-Function Experiments with Pathogens of Pandemic Potential, Such as Influenza Virus: a Call for a Science-Based Discussion

Arturo Casadevall and Michael J. Imperiale

doi:10.1128/mBio.01730-14

Editorial

Influenza virus is one of a handful of infectious disease agents that can cause devastating pandemics with high mortality and morbidity in human populations. The human species is vulnerable to zoonotic infection with new influenza viruses, with the last occurring as recently as 2009. Influenza kills thousands of people each year, and the world is continuously confronting new epidemics. Today the complexity and interconnectivity of our society create vulnerabilities, such that pandemics with even low mortality have the potential to cause widespread suffering and economic disruption. Epidemics can have catastrophic effects on the social order and result in the disruption of benefits that we associate with current society, such as law and order and reliable food distribution (for a vivid and dramatic representation of the effect of epidemics on society, readers are invited to see the movie Contagion, where an outbreak with a new fictional virus leads to the breakdown of the social order). Hence, epidemics pose existential threats to civil society even when morbidity and mortality occur in a fraction of those infected. Given the biological characteristics of the influenza virus that ensure the continuous generation of antigenic variability, this virus poses a continuous extant threat, with the likelihood of new pandemics being determined by variables that remain poorly understood. In this environment, the influenza virus research community is humanity’s best defense against influenza virus. Consequently, anything that impacts influenza virus research is of utmost importance to societal well-being.

(Continue . . . )

 

For more on this controversial 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

The Debate Over Gain Of Function Studies Continues

Lipsitch & Galvani: GOF Research Concerns

The Call For Urgent Talks On `GOF’ Research Projects

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

(Continue . . .)

 

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

The Journal Nature Weighs In On Lab Accidents & Biosafety

 

 

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In the wake of revelations regarding laboratory safety lapses both at the FDA and the CDC involving `select agents’ including anthrax, smallpox, and H5N1 avian influenza, and the ongoing Debate Over Gain Of Function research, we are seeing agencies, scientific journals, universities, politicians, consultants, newspaper editorial boards, scientific working groups, and individual scientists all publicly staking out their positions on these issues.

 

A little over two weeks ago, the Cambridge Working Group produced a consensus statement, which urges caution, and better regulation and oversight of laboratory research seeking to enhance the virulence, transmissibility, or host range of pathogens with pandemic potential (PPPs).

 

While just yesterday, the newly formed coalition Scientists for Science, posted a statement of their own, that called their work `essential’ and dismissed many of the concerns being raised over GOF research as being overstated.

 

Not everyone is convinced, however, as evidenced by last week’s ECDC Comment On Gain Of Function Research, which acknowledged the potential public health risks that these types of experiments can pose, and proposed that the overriding concern of researchers should be first, and foremost  `to do no harm.’

 

Today the Journal Nature has two articles on Laboratory safety standards (or the lack thereof).  First an article by Declan Butler, on the lack of universal, and consistent standards for laboratories conducting work on potentially dangerous pathogens.

 

Biosafety controls come under fire

Experts call for a stronger safety culture at secure sites after incidents involving anthrax and flu in a US laboratory.

Declan Butler

29 July 2014

Recent accidents involving deadly pathogens at a leading laboratory in the United States highlight the need for a major global rethink of biosafety controls, experts say.

The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, reported two accidents involving anthrax and the deadly H5N1 influenza virus. Biosafety professionals argue that such incidents show that without a strong culture of biosafety, even highly secure facilities are susceptible to errors that could place workers and the public at risk.

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A second report, this time an editorial, suggests that lab accidents such as the ones making headlines this summer happen far more often than are ever reported, and calls for full transparency.

 

Safety doesn’t happen by accident

To create a strong biosafety culture, information on mishaps involving deadly pathogens must be reported and shared fully and transparently.

(Continue . . .)

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

ECDC Comment On Gain Of Function Research

Credit CDC PHIL

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My thanks to Dr. Marc Lipsitch for tweeting the link to the ECDC’s comment on recent GOF (Gain of Function) work being performed on 1918-like influenza viruses.  I blogged about this particular study last month in Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential, where I wrote about the ongoing concerns over this type of research.

 

Simply put, GOF research involves laboratory manipulation of a virus’s genetics in order to enhance its transmissibility, virulence, or host range.

 

While 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.

 

And despite bland reassurances from many researchers on the safety of high containment labs, recent serious biosafety lapses at CDC and FDA labs involving anthrax, H5N1 bird flu, and smallpox all point out that accidents happen even in the best of labs.

Here then is an ECDC_EU review of the Cell Host & Microbe paper, along with a cautionary comment.

 

Circulating Avian Influenza Viruses Closely Related to the 1918 Virus Have Pandemic Potential

 16 Jul 2014

​A recent article by Watanabe et al. in the Cell Host & Microbe journal describes an attempt to assess the risk of emergence of pandemic influenza viruses closely related to the 1918 influenza virus.

Reverse genetics methods were used to generate an avian influenza virus closely related to the 1918 influenza virus, based on sequence information reported from various avian influenza viruses. Further experiments were done to demonstrate what mutations are required for this virus to become easily transmissible between mammals. Effectiveness of the current influenza vaccine and the antiviral drug oseltamivir against the 1918-like influenza virus was also assessed.

It was experimentally demonstrated that a 1918-like avian influenza virus with a limited number of additional mutations exhibits relatively high pathogenicity in mammals, although lower than the original 1918 influenza virus strain that was also recreated with reverse genetics technology in the laboratory. In the transmissibility studies, only some constellations of the virus genes allowed transmissibility between ferrets, suggesting roles for RNA replication complex, HA and NA in virus transmission.

To further assess the risk of the emergence of such avian influenza viruses that could infect humans, the team examined the prevalence of avian influenza viruses that are similar to the 1918 influenza virus, and looked for avian influenza viruses possessing human-type amino acid residues.

The study thus demonstrated the continued circulation of such avian influenza viruses that possess 1918 virus-like proteins and viruses that may acquire 1918 virus-like properties. This would suggest that a potential exists for a 1918-like pandemic virus to emerge from the avian virus gene pool.

ECDC comment

The study by Watanabe et al. is the latest in a series of genetic engineering experiments where research groups have created influenza viruses of pandemic potential. The new study discussed here further confirms the power of recombinant technology to create pathogenic viruses that are not currently circulating in nature. From the public health perspective, this poses a risk both for the laboratory personnel working with these viruses, even in very secure biosafety conditions, and to the general public in case of a laboratory escape. Recent incidents remind us that laboratory accidents and laboratory escapes can happen with dangerous pathogens, even if the highest security standards are applied [1,2,3]. The developments in technology should not and cannot be stopped and research laboratories should have the freedom to apply the latest technologies for science purposes as long as this is done with full adherence to good ethical and biosafety practices. However, the decision to fund this type of gain of pathogenic function studies in influenza viruses and other human pathogens has stirred scientific controversy about the mechanisms currently in place to ensure sound assessment of risk and benefits by independent reviewers [4].

The public health perspective to the critical review of funding such dual-use research of concern including studies aiming at the creation of potential pandemic pathogens has been so far limited. Very often the research groups justify their research agenda with pandemic preparedness and better understanding of the avian influenza viruses without further specifying how exactly the results may improve the preparedness plans. It is important to ask what this type of result adds to the field of pandemic influenza preparedness and how the prediction of efficacy of influenza vaccines or antivirals against influenza viruses is improved based on these results. Furthermore, it is pertinent to ask for justification of the methods, and if any of those could be replaced by safer experiments. It is of utmost importance that the biosafety practices and controls in the laboratories undertaking such research are kept to a high standard. A forum for public health discussion around dual-use research of concern topics is not yet available at European level. ECDC advocates for open discussion about studies where potential pandemic threats are created. The research community should in all their work apply the medical ethical principle of “first do no harm”.

References:

1: Normile D. Mounting Lab Accidents Raise SARS Fears. Science. 2004;304(5671):659-61.
2: CDC Lab Determines Possible Anthrax Exposures, CDC Media Statement, 19 June 2014
3: CDC Director Releases After-Action Report on Recent Anthrax Incident; Highlights Steps to Improve Laboratory Quality and Safety, CDC Press Release, 11 July 2014
4: Gigi Kwik Gronvall. National-level biosafety norms needed for dual-use research .Front. Public Health, 14 July 2014 | doi: 10.3389/fpubh.2014.00084

 

Over the past three years we’ve touched on these issues dozens of times, but a partial list of blogs on this topic you might wish to revisit include:

 

The Debate Over Gain Of Function Studies Continues

Lipsitch & Galvani: GOF Research Concerns

The Call For Urgent Talks On `GOF’ Research Projects

Laurie Garrett On Biosecurity Reforms

H7N9: Reigniting The `Gain Of Function’ Research Debate

Nature: H5N1 viral-engineering dangers will not go away

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.

(Continue . . . )

 

Upcoming House Sub-Committee Hearing On Lab Safety

CDC Anthrax Timeline – Credit CDC

# 8830

 

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.

(Continue . . .)

 

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.

(Continue . . . )

 

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.

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.

(Continue . . .)

 

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.

(Continue . . . )

 

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.

CIDRAP: Lipstich & Galvani Respond To Fouchier & Kawaoka On GOF Studies

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

 

# 8764

 

They say `Timing is everything’.

 

And given the timing of today’s announcement of a lab accident last week in Atlanta (see CDC Statement On Possible Lab Exposure To Anthrax) and the publication of lengthy reply by Marc Lipsitch & Alison P. Galvani to Fouchier & Kawaoka on the risks of GOF (Gain of Function) lab research – including accidental release -  I would have to agree.

 

This controversy has been brewing for several years, but took off again last month when  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

 

This led to response from researchers Fouchier & Kawaoka, defending their work,  published in a CIDRAP NEWS report on May 22th.   What follows is a reply to that response.

 

There’s far too much here to synopsize, so I’ll simply post the link and CIDRAP’s preface, and invite you to read it in its entirety.  After which, I’ll have a little more.

 

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

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

Henrik5000 / iStock

Editor's note: Today's commentary was submitted to CIDRAP by the authors. They respond to critiques of their recent journal article in which they argued that there are safer and better ways to investigate influenza virus transmissibility, prevention and control than to conduct experiments that lead to the creation of more-contagious viruses.

Dr Lipsitch (mlipsitch@hsph.harvard.edu) is a professor of epidemiology and director of the Center for Communicable Disease Dynamics, Harvard School of Public Health, Boston. Dr. Galvani (alison.galvani@yale.edu) is a professor of epidemiology (microbial diseases) and of ecology and evolutionary biology and director of the Center for Infectious Disease Modeling, Yale School of Public Health, New Haven, Conn.

(Continue . . . .)

 

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.

CDC Statement On Possible Lab Exposure To Anthrax

Electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria. – Credit CDC

 

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Based on the reports thus far, it appears that the risks to those who were potentially exposed to anthrax at a CDC lab facility in Atlanta last week are pretty low.   It has been a week since the likely exposure took place, and thus far, no employees have developed symptoms.

 

First the statement, then I’ll have a bit more.

 

 

Media Statement

For Immediate Release: Thursday, June 19, 2014
Contact: CDC Media Relations
(404) 639-3286

CDC Lab Determines Possible Anthrax Exposures: Staff Provided Antibiotics/Monitoring

CDC announced today that approximately 75 Atlanta-based staff are being monitored or provided antibiotics because they may have been unintentionally exposed to live Bacillus anthracis (anthrax) after established safety practices were not followed.

Out of an abundance of caution, CDC is taking aggressive steps to protect the health of all involved, including providing protective courses of antibiotics for potentially exposed staff. Based on most of the potential exposure scenarios, the risk of infection is very low. Based on the review to date, CDC believes that other CDC staff, family members, and the general public are not at risk of exposure and do not need to take any protective action.  Although the investigation continues, early reports show that one of its Roybal campus biosafety level 3 (BSL3) labs was preparing B. anthracis samples for research in other CDC labs at lower biosafety levels to yield new means of detecting dangerous pathogens in environmental samples. However, the lab used a procedure that did not adequately inactivate the samples.

The potentially infectious samples were moved and used for experimentation in three CDC Roybal campus laboratories not equipped to handle live B. anthracis.  Workers, believing the samples were inactivated, were not wearing adequate personal protective equipment while handling the material.

Lab safety investigators also determined that, sometime between June 6 and June 13, procedures used in two of the three labs may have aerosolized the spores.  Environmental sampling was done, lab and hallway areas were decontaminated and laboratories will be re-opened when safe to operate.

The unintentional exposure was discovered June 13 when the original bacterial plates were gathered for disposal and B. anthracis colonies (live bacteria) were found on the plates. These plates had appeared negative for B. anthracis at the time samples were distributed to the other CDC laboratories.  The review began immediately to assess the health risk, and those workers handling the plates were immediately notified.

CDC’s guiding principles for laboratory work are to ensure the safety of all staff and the community and be as transparent as possible about our work as we conduct high-quality scientific research to protect people in this country and around the world.

CDC continues its internal review to determine why validated procedures were not used by the lab. Also, CDC has reported the incident to the Federal Select Agent Program.  Given that CDC expert protocols were not followed, disciplinary action(s) will be taken as necessary.  In addition, CDC will review the safety protocol again with all employees who work in this area.

It is CDC’s obligation to ensure that people feel safe and are safe in the workplace and the community as we conduct our life-saving laboratory work. We will report findings of this review and all steps we take to improve lab-safety processes as a result of this incident. 

 

 

Mistakes or accidents at high biosecurity-level laboratories are admittedly rare events, but they are not completely unheard of, even at the CDC.  Between 2003 and 2009, US government laboratories reported 395 incidents that involved the potential release of select agents, according to this report from CIDRAP NEWS.

 

Although it seems likely that this latest incident is contained, it will likely fuel existing biosecurity concerns over controversial Gain of Function (GOF) experiments; those designed to enhance the transmissibility or virulence of dangerous pathogens – including the H5N1 virus (and most recently the 1918 pandemic virus).

 

While most researchers offer broad assurances on the safety of high security laboratories - as today’s incident shows –even the most professionally run high security lab is vulnerable to human error. 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.

 

For more on the contentious debate over the risk of accidental releases from labs, and the pursuit of GOF research, you may wish to revisit:

 

Lipsitch & Galvani: GOF Research Concerns.

Laurie Garrett On Biosecurity Reforms

H7N9: Reigniting The `Gain Of Function’ Research Debate