December 14, 2014

VolkswagenStiftung conference on
Dual use research on microbes – biosafety, biosecurity and responsibility
December 10-12, 2014
Herrenhausen Palace, Hanover, Germany


Overview
There was little common ground concerning the GOF influenza transmission work. The flu virologists wanted to continue without any additional regulations, which was the negative buzzword for them. Other scientists pointed out the weakness of the virology and the inability to deliver on the benefits originally touted, notably pro-active vaccines.

The flu people said that these viruses were a first step in that direction and that it would take time, like so much in science. Indeed, it may take so much experimental and ferret model time to refine the studies and converge on a constellation of mutations that transforms an avian virus into something as powerful as a human pandemic virus, that it may not be worth pursuing to the end.

There is clearly a legal liability issue if ever there was an accident involving avian influenza virus GOF transmission research. For the risk experts the most likely danger comes from copying this work in less secure environments. As the methods are not too demanding, while the papers are in the public domain, comparable work can be performed. Furthermore, what is tough today will be much easier to accomplish in five years.

It is an issue of public trust. The public is primarily concerned in trusting science, rather than the scientists. Scientists have to work to build outfits that are productive and transparent. The meeting showed more clearly than ever before that there are really important issues that go way beyond the virology. Indeed they are not the remit of bench virologists who do not have the knowledge to handle them. These will have to be addressed, like it or not.


Pros and cons of the virology
The ins and outs of the influenza experiments were addressed. Dr. Kawaoka (University of Wisconsin, Madison) in particular addressed the concerns of the critics. Yet the flu virologists felt that GOF transmission research was the only way to get answers to certain questions concerning cross species transmission from birds to mammals, the ferret being the model for humans.

Nonetheless, Peter Palese (Mount Sinai Medical Centet, New York) wasn’t of the opinion that avian H5N1 influenza virus was a real threat to man, which highlights the difficulty of looking into the future of influenza infections. He spoke about “influenza viruses - facts not fear”.

Yet fear is intrinsic to influenza for three viruses have generated five human pandemics (1918 H1N1, 1957 H2N2, 1968 H3N2, 1977 H1N1 & 2009 H1N1) of varying severity taking a death toll of between 250,000 to 50 million deaths. Fear is far less associated with bunyavirus or a metapneumovirus infections, although both can kill. To quote Rob Webster as “prediction is the name of the game in the influenza field”, inevitably they are trying to predict fear.

H5N1 virus infections in man represent spillovers from animals, and they occur regularly - witness the H7N9, H6N1 and H10N8 viruses in the last couple of years.

Since March 2014 a H10N7 influenza A virus or avian origin is killing harbor seals (Phoca vitulina) in Sweden, Denmark, Germany and the Netherlands. It is the first influenza epidemic in seals recorded in Europe. The amino acid sequence at the cleavage site in the hemagglutinin molecule was PELVQGR/GLF, characteristic of low-pathogenicity avian influenza virus (LPAI). The avian H5N1 high pathogenicity avian influenza virus (HPAI) on which GOF experiments has a highly basic cleavage site.

Ron Fouchier (Erasmus Medical Center, Rotterdam) considered this new seal virus to be more dangerous than avian H5N1 primarily because it is being passaged between seals and causing death. This comment shows how priorities shift even over a short space of time - in 2010 H5N1 was the virus to beat. He considered that endless transmission of the H10N7 virus between seals was no different to passaging the virus in a GOF setting between ferrets in the lab.

In nature there is no observer bias while in the lab the experimenter introduces bias by selecting the infected animal – if the animals with low viremia (the amount of virus in the animal) are consistently chosen the end result will be a highly transmissible virus that will produce mild symptoms. By contrast if animals that have respiratory distress and high viremia are consistently selected, the experimenter will ultimately recover a highly transmissible highly, pathogenic virus. As humans are afraid of the latter, the researcher will focus on that scenario or trajectory. The question is will nature do the same?

In this context SWH (Institut Pasteur, Paris)made the comparison with dog breeding. Starting from the wolf, selection over 10,000 years ensued and then want haywire in the last few hundred years ending up with Great Danes, salukis and dachshunds, to name a few. Would nature have selected the dachshund? Given its short legs it would have fallen prey to any number of predators including their ancestor, the wolf. Lest it be said that 10,000 is a long time, Dmitri Belayev was able to select for reduced fear of humans in Siberian silver foxes over a period of 50 years. Interestingly a genetic component has been revealed (Trut et al., 2009). Observer bias is real.

RF noted that his H5N1 virus was nothing like as powerful as a human pandemic flu virus and didn’t grow as well in the ferret model. Larger amounts of virus are needed to inoculate ferrets. This contrasts with the Malta statement that his H5N1 virus “is a very dangerous virus” but in keeping with subsequent statements.

When asked why this should be and what could be done experimentally to close the gap, RF remarked that far more passaging would be necessary which would probably reveal more mutations that would ultimately transform his present GOF enhanced H5N1 virus into one of fully pandemic potential. This would take quite some time and he was more inclined to go for the major mutations rather than take the experiment to the very end.

Of course in terms of the claimed benefits this changes a lot. Since we cannot predict where these extra mutations will lie – it needs more experimentation – identifying a pro-active vaccine strain is not going to come quickly. Hence in terms of pandemic preparedness, the approach is not going to deliver fast. As drug design requires the pandemic strain this claim falls. Perhaps the data could be of use for interpreting mutations in the wild, but as the mutation constellation is incomplete, interpretation can only be partial. Once again this assumes that epistasis is not a problem.

Note also that taking the experiment to the end through repeated passaging will take it further and further on an experimental trajectory, so reducing the probability that nature will follow it among the possible trajectories open to a rapidly evolving virus.

Adel Mahmoud (Princeton University), former president of Merck Vaccines, said that flu vaccines are made according to a formula that hasn’t changed for roughly 70 years. He considered the manufacture of pre-pandemic vaccine stocks, involving manufacture of millions of doses as “wishful thinking”. In short, nothing short of THE virus or something exceptionally close to it, will work vaccine wise.

He pointed to the upcoming 2014-2015 flu season: “Increasing the risk of a severe flu season is the finding that roughly half of the H3N2 viruses analyzed are drift variants: viruses with antigenic or genetic changes that make them different from that season’s vaccine virus. This means the vaccine’s ability to protect against those viruses may be reduced, although vaccinated people may have a milder illness if they do become infected. During the 2007-2008 flu season, the predominant H3N2 virus was a drift variant yet the vaccine had an overall efficacy of 37 percent and 42 percent against H3N2 viruses.”

“The drifted H3N2 viruses were first detected in late March 2014, after World Health Organization (WHO) recommendations for the 2014-2015 Northern Hemisphere vaccine had been made in mid-February. At that time, a very small number of these viruses had been found among the thousands of specimens that had been collected and tested.”

Pre-pandemic vaccines are made in the same way and according to the same logic as seasonal human flu vaccines. This puts RF’s comment about not going to the end of his avian influenza H5N1 virus experiment in perspective – if he doesn’t go to the end then how can his virus help us?

Marc Lipstich (Harvard University) calculated the loss of life in the event of an accident. Using published data from the CDC and elsewhere, he computed that for every year in a lab working on GOF influenza transmission research the equivalent of 12,000 to 1,400,000 lives could be lost. These numbers are huge but how are these numbers to be understood.

Very simply, it supposes that several labs will be doing this work. It is impossible to predict in which lab and when a leak will occur. Given the sands of time, an accident and a lab acquired infection is inevitable (all agree that zero risk is fiction). When the accident occurs, ML’s numbers suggest that hundreds of thousands to scores of millions of people will be involved. The numbers do not mean that every year 12,000 to 1,400,000 lives will be lost. They mean that if an accident occurs in one such lab after 10 years, 10x 12,000 to 1,400,000 lives (120,000 to 14,000,000) could be lost; the risk accumulates with time and the figures add up. Obviously the more labs doing such GOF influenza transmission work the sooner the probability of a serious accident.

Again, this doesn’t indicate that any one lab will have serious accident at all. It is a collective, or overall risk. In the nuclear arena where the cat has been out of the bag for 70 years, the effort is to reduce proliferation. The same is true given the eradication of rinderpest and smallpox viruses. Efforts are made to reduce the number of labs holding and working with these viruses.

Note that even if ML is out by a factor of 100, the numbers go down to a potential of 12 to 14,000 lives lost per year of GOF research, which is still huge. For people to feel calmer, it behooves the research community as a whole to perform more risk analyses, check the assumptions and weaknesses and refine the risk estimates. Fact checking, challenging and reproducibility are essential and fast.

It is unfortunate, sad, stunning or odd that no independent risk analysis has been performed in three years of controversy. Virology shouldn’t be in this vulnerable; indeed, it is in very uncomfortable and embarrassing position. Leadership is now warranted for it has been lacking.


Biosecurity was covered by two experts: some of their comments were telling. For example, those of Paul Huntly (Risken, Singapore). “BSL3+, BSL3++, BSL4- biosafety levels are not standardized and meaningful”, “there is lots of guidance, not enough standards”, “Vast majority of accidents are caused by unsafe acts as opposed to unsafe conditions” and “the greatest risk is insiders not well controlled”.

Paul Clevestig (Stockholm International Peace Research Institute) considered that the greatest risk came from reproducing or conducting GOF flu transmission experiments in research in less stringently controlled settings compared to those performed by Drs. Kawaoka and Fouchier. The human factor is the Achilles heel.

This ties in with the immaterial nature of the genetic code. Our technology is so powerful a researcher doesn’t need to get hold of the virus itself. All you need is the published sequence: have sequence, make virus to quote David Relman (University of Stanford). Where does the scientist’s responsibility lie and/or stop?

The dilemma was illustrated by Ray Zilinskas (Monterey Institute of International Studies) who spoke about the Soviet biological weapons, circa 1972-2000, which he has followed for many years. On one slide he juxtaposed a précis of Russian bioweapons experiments enhancing bacterial and viral pathogenesis and virulence and that of GOF avian influenza research:

“1972 – Ferment’s top secret objectives were to enhance pathogens’ abilities for infection and virulence, and endow them with new capabilities to circumvent or defeat enemies’ defenses; e.g. vaccines, antibiotics, and detection techniques. Malevolent intent.

2014 – Open objectives of gain-of-function research are to increase the ability of pathogens to cause disease by enhancing their pathogenicity or increasing their transmissibility. Intent – ultimate benefit for biomedicine and public health.”

The two are remarkably similar in aims. The big difference of course lies in the intent of the two groups.

However, it shows brutally – perhaps painfully for civilian scientists – that their work can be misused by others as soon as it is published. This juxtaposition shouldn’t be taken personally and was in no way meant personally. It is just a tough reality check.

Collating a number of sentences used during the meeting leads to:
• Have sequence, make virus.
• Copying is easier than doing the original experiment.
• What is a tough experiment today will be much easier tomorrow.
• Experiments can be done by others faster than you think and in environments and countries that are beholden to their own regulations and values.
• New technologies have always been tried out for offensive purposes.

The IAP statement on biosecurity says that scientists cannot simply respond by saying that once their paper is published, they are not responsible for what others do with their findings. Yet nothing has been done by the IAP or national academies to help microbiologists come to terms with this painful dilemma. Nor was any effort made to get this message down to PIs and post docs. Microbiologists need guidance badly.

Three lawyers addressed the conference. Rudiger Wolfram (Max Planck Institute, Heidelberg) noted that freedom of scientific inquiry questions were usually provoked by the scientists. Like other freedoms, limitations arise when other freedoms are impinged upon. For example working in BSL3 or BSL4 confinement is anti-freedom, yet it allows protection of others and hence protects their freedom. He said that it was the German Government who decides the risk levels, not the scientists who provide the data allowing the decision. His simple conclusion was that is you follow the regulations you will be covered. However, the problem is that accidents generally or often arise when protocols are not fully respected.

From experience Ulrich Sieber (Max Planck Institute, Freiburg) noted that scientists accept peer review more easily than outside rules. Hence, a carrot and stick approach is necessary. He found that private/public partnerships were easier to put into place than legislation. In considering the effectiveness of self-governance he took his experience with corporate crime compliance. Studies showed that the “tone from the top” and good moral corporate standards were both effective and appreciated.

Silja Voneky (University of Freiburg) noted that in this area there were gaps in legislation that needed to be plugged. This was particularly so for low probability events of high consequence. The European Union code of human rights has an obligation to protect the individual. The gaps could be filled by codes of conduct. She recommended five levels of action that came from the German Ethics Council report – Biosecurity – freedom and responsibility of research, an excellent English version is available on the web.

• Increase awareness for biosecurity among scientists and the scientific community
• Elaboration of a biosecurity code of conduct, with a special burden of proof when undertaking such work
• Elaborate rules concerning research funding with a call for a national DURC committee
• A legal framework such that a DURC committee is consulted before undertaking such work
• International EU coordination

Volker Stollorz, a German science journalist who started life as a cell biologist, recognized the hubris in the present climate and noted that hubris is the very antithesis of prudence. He felt that society has a need to know what GOF experiments are allowed. He thought these “ruin/risk” experiments were akin to black swans and a asked what should be done. What benefits would society miss? He felt we had a serious collective action problem without any obvious solutions for the moment.

Dave Relman reminded the meeting of the moral responsibilities facing us all especially with a technology that can be outsourced more and more. What he called the packaging of recombinant DNA technology – designer genes, outsourcing of experiments to companies. Among his conclusions for the coming biological century
• Issues of risk are here to stay, and will increase in frequency, magnitude
• We must commit to ongoing conversations, relationship-building
• Scientists have social, moral obligations
• Not all “interesting” experiments should be undertaken; risks must be considered
• Mitigating the risks: raise awareness, educate, communicate, norms, guidelines, anticipate, promote flexible/agile/rapid/generic responses

The last talk was from a bioethicist. Mark Yarborough (University of California at Davis) felt the debate was about trust in scientists and about hubris. Contemporary societies have great trust in science, not the scientists. Their primary concern is the process and the benefits, not the individuals conducting the research. Trust requires transparency in the way science is performed which is why the GOF issue needs to be aired.

December 4, 2014

Revealed: 100 safety breaches at UK labs handling potentially deadly diseases
Ian Sample
The Guardian, London

A longish article detailing numerous failures in biosafety containment in UK labs in recent history, aka since 2012. They range from simple to complex failures in systems surrounding the manipulation of agents such as virulent Bascillus anthracis and Ebola virus.

Richard Ebright (Rutgers University, USA), Brian Spratt (Imperial, UK) and Tom Inglesby (U Pennsylvania, USA) provide no nonsense comments. The article is easy and worthwhile reading. 

While no system is failsafe, the simplicity of some of the "failures" reminds us that working with dangerous microbes is a more than normal risky business, and some people put their lives on the line. This is admirable. Because of this, if making microbes more dangerous is considered necessary, some sort of consensus as to the scientific merits should be forthcoming, or failing that solid reasons should be articulated that hold up to outside scrutiny. This is only fair to the researchers involved.

November 20, 2014

Openness in science is key to keeping public trust

Silence stifles progress. The scientific enterprise needs a transparent culture that actively finds and fixes problems.

Yarborough M.

Nature. 2014 Nov 20;515(7527):313. doi: 10.1038/515313a.

A must. Nothing else to be said. 

November 17, 2014

Moratorium on risky virology studies leaves work at 14 institutions in limbo
Jocelyn Kaiser
ScienceInsider

Under the Freedom of Information Act Jocelyn Kaiser obtained so-called stop orders issued by the NIAID. Dated October 21, 18 such orders affecting 14 institutions were issued covering influenza, MERS and SARS viruses. Somewhat surprisingly, a MERS coronavirus project with the aim to adapt it to mice was put on hold. The details of the project are unknown. Nonetheless it is plausible that this would involve physical inoculation of mice.

Personal opinion
This MERS virus experiment is not the GOF research most people have in mind. A small animal model of the MERS virus would be useful for testing of small molecule inhibitors and learning something of the physiopathology of the infection. Put it another way, we don’t have too many reagents for camels, which are rather large. The benefits are fairly easy to articulate.

Adapting a virus to the mouse is a goal for many researchers because there are huge numbers of markers, reagents and knock out mice that unquestionably help the scientist. Of course human and mouse genomes and physiology are different and so the mouse is “only” a model. But mouse model work invariably advances the field.

An experiment of concern is one that adapts a virus to humans and agriculturally important animals and crops. Equally increasing the virulence of an extant virus that infects humans, agriculturally important animals and crops would be of concern. Experiments of concern were first listed in the so called Fink report 2003.

November 6, 2014

Stockholm ESCAIDE 2014

Plenary session D:
Primum non nocere – Why engineer microbes to be more dangerous to humankind?

Audience survey - electronic voting via smart phones after the session

Q1: Should ‘Gain of Function’ (GOF) research be paused in the EU until clearer policies are in place for researchers?
101 yes - 43 no (70% yes)

Q2: should the public health sector be more involved in the risk-benefit analysis of GOF research?
139 yes - 7 no (95% yes)

Q3: Should the EU have a “dedicated body” to manage biosafety and biosecurity issues around dual-use ‘research of concern”?
114 yes - 29 no (80% yes)

November 5, 2014

Guest post from Prof. Mike Imperiale of the University of Michigan.

The post is on the UK Society of Biology blog ahead of their “Policy Lates” session at the Charles Darwin House, November 20, 2014.

Prof. Imperiale comments on the recent US pause in GOF virus research. He is worried by it being open ended and is concerned about collateral damage in virology.

October 23, 2014

Nature editorial – A ripe time for gaining ground

After three years of heated debate, the advocates and critics of gain-of-function research must work to agree on how best to regulate work.

Nature. 2014 Oct 23;514(7523):403. doi: 10.1038/514403a.

“And the revelations over the past few months of serious violations and accidents at some of the leading biosafety containment labs in the United States has burst the hubris that some scientists, and their institutions, have in their perceived ability to work safely with dangerous pathogens.”

October 22, 2014

Meeting of new NSABB. For agenda see here.

Two news reports in Science and Nature written within hours of the meeting.

We learn that “Such GOF studies are "crucial" for the selection of each year's candidate vaccine strain because they help WHO identify the riskiest strains in the wild, Schultz-Cherry said.”

Consultation with two senior flu researchers familiar with the selection process of strains for the annual flu vaccine revealed that they disagree with this statement.

October 17, 2014

The US National Academies announced that they would be holding a workshop on GOF research. 
It will take place at the National Academies of Science building in Washington DC on December 15-16.

October 17, 2014 (Bis)

White House statement on funding new GOF research:
Doing diligence to assess the risks and benefits of life sciences gain-of-function research

A pause in new funding of GOF virus research is implemented. It concerns influenza, SARS and MERS viruses. The document clearly excludes work on natural influenza SARS and MERS viruses. During the time, a review and discussion process is to be initiated so that a considered opinion as to the risks and benefits of GOF virus research can be forged.

It “encourages those currently conducting this type of work – whether federally funded or not – to voluntarily pause their research while risks and benefits are being reassessed.”

October 16, 2014

Improving pandemic influenza risk assessment.
Russell CA, Kasson PM, Donis RO, Riley S, Dunbar J, Rambaut A, Asher J, Burke S, Davis CT, Garten RJ, Gnanakaran S, Hay SI, Herfst S, Lewis NS, Lloyd-Smith JO, Macken CA, Maurer-Stroh S, Neuhaus E, Parrish CR, Pepin KM, Shepard SS, Smith DL, Suarez DL, Trock SC, Widdowson MA, George DB, Lipsitch M, Bloom JD.
Elife. 2014 Oct 16;3:e03883. doi: 10.7554/eLife.03883.

“Abstract 
Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.”

Predictions are extremely difficult while the genotype-phenotype relationship (how to understand biological potential from genetic data) is a very tough call.

The conclusion starts with:
“It is currently not possible to predict which non-human influenza A virus will cause the next pandemic. Reducing the impact of the next pandemic will rely on early detection and mitigation strategies that slow the early spread to allow more preparatory work to be done.”

The first sentence is in keeping with what others have said (Morse et al., 2012; Morens et al., 2013; Wain-Hobson 2013). It undermines the claims that GOF research would help with pandemic preparedness. If the next pandemic cannot be predicted, this means that the strain cannot be identified. In turn this means that preventive vaccines and drugs cannot be made. The second sentence is more pragmatic and can be readily adhered to.

The paper is interesting for three authors of this eLife paper have been proponents of GOF influenza research while one has been against.

References
Prediction and prevention of the next pandemic zoonosis.
Morse SS, Mazet JA, Woolhouse M, Parrish CR, Carroll D, Karesh WB, Zambrana-Torrelio C, Lipkin WI, Daszak P.
Lancet. 2012 Dec 1;380(9857):1956-65. doi: 10.1016/S0140-6736(12)61684-5.
http://www.sciencedirect.com/science/article/pii/S0140673612616845

Pandemic influenza viruses--hoping for the road not taken.
Morens DM, Taubenberger JK, Fauci AS.
N Engl J Med. 2013 Jun 20;368(25):2345-8. doi: 10.1056/NEJMp1307009. Epub 2013 Jun 5. 
http://www.nejm.org/doi/full/10.1056/NEJMp1307009

Pandemic influenza viruses: time to recognize our inability to predict the unpredictable and stop dangerous gain-of-function experiments.
Wain-Hobson S.
EMBO Mol Med. 2013 Nov;5(11):1637-41. doi: 10.1002/emmm.201303475. Epub 2013 Oct 24. 
http://embomolmed.embopress.org/content/5/11/1637.long

October 14, 2014

Rules of engagement
Johannes Rath
EMBO Reports doi 10.15252/embr.201439281

A discussion of problems associated with risk-benefit analyses. It is interesting for alternatives to risk-benefit analyses have never been mentioned by scientists familiar with the GOF controversy. It refers to the precautionary and proportionality principles that are widely known and used in other fields.

October 14, 2014 (bis)

A cluster of seven papers on GOF research in the scientific journal mBio came on line. There are three contributions and three replies from the mBio editors and ASM representatives, the publisher of mBio. The ensemble is covered by an overarching editorial:

The apocalypse as a rhetorical device in the influenza virus gain-of-function debate
Arturo Casadevall, Don Howard, Michael J. Imperiale

The authors note that the “central nugget in the controversy is a disagreement on the risks and benefits of such experiments”. It is fair to say that nobody has squarely addressed this duo, so there is agreement. This is quickly morphed into a dichotomy whereby pro-GOF proponents stress the benefits and the anti-GOF group concentrate on the risks. While risk is an important issue it is not the only one. Some opponents of the work have focused on the virology and concluded that the touted benefits were overblown. Others who have not taken explicit stands, or who cannot be considered opponents have argued that predicting a pandemic is extremely difficult, if not possible. For such a discussion, see:

• http://www.nejm.org/doi/full/10.1056/NEJMp1307009
• http://www.sciencemag.org/content/342/6156/310.2.long
• http://www.atsjournals.org/doi/abs/10.1164/rccm.201305-0914ED?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&#.VEQ1I4dAyTc
• http://embomolmed.embopress.org/content/5/11/1637.long

September 23, 2014

A brain drain to increased regulation of influenza virus research is highly speculative
Derrin Culp
mBio 5: e01814-14 (2014). doi: 10.1128/mBio.01814-14

DC comments on an earlier commentary in mBio from Arturo Casadevall and Mike Imperiale. Risks and benefits of gain-of-function experiments with pathogens of pandemic potential, such as influenza virus: a call for a science-based discussion. MBio. 2014 Aug 1;5(4):e01730-14. doi: 10.1128/mBio.01730-14.

DC is concerned that virtually no evidence has been offered to substantiate the claims “that up-and-coming young virologists might eschew virology careers” or “may drive select agent research out of academia”. He offers some very interesting perspectives from US federal nuclear facilities, and concludes that elevating this brain drain issue “to a potentially existential threat is totally unjustified”.

Scientists are not fans of regulations. One follows the logic that people will avoid working with select agents, although people continue do so when they could work on important human microbes with far fewer restrictions – HIV, HPV, HBV and HCV to name but four viruses.

In the same issue Casadevall and Imperiale reply to Derrin Culp’s letter.
mBio 5(5):e01860-14 (2014). doi:10.1128/mBio.01860-14.

“Although we do not have any data at this time to support our belief that increased regulations in influenza research will drive some young scientists to look for less-restrictive pastures, it is reasonable to suspect that changes that affect their work environment will have some effect on career choices.”


DC wrote a singular and very interesting piece entitled:
Lessons not learned: insider threats in pathogen research.
Bulletin of the Atomic Scientists, April 3, 2013

September

USG clarifications on GOF.

September 12, 2014

CDC post on Avian Influenza (Bird Flu) Research

It discusses previous GOF work performed at the CDC which consisted of making reassortants between H5N1 and human flu viruses (published 2006) and between H5N1 and H3N2 (published 2009) “as part of pandemic preparedness efforts”. Some 5-8 years on and one pandemic later we see that such reassortants haven’t yet emerged. This is not a criticism of the work, just another observation as to the difficulties of predicting influenza virus evolution.

Mutations around the H5 receptor binding site tended to attenuate the virus which would require compensating mutations to acquire pathogenicity. They suggested that “extensive evolution of H5N1 viruses would be need to occur before these H5N1 viruses could become fully transmissible in humans”. As we know Fouchier and Kawaoka succeeded with a handful of mutations.

Under the heading “…what is the purpose of this research?” two paragraphs are worth noting:

“Typically, the purpose of this research is to identify dangerous mutations in existing viruses so that global surveillance efforts can monitor for these mutations in circulating flu viruses. These studies also have the potential to predict what dangerous viruses might emerge in nature before they actually emerge, which allows interventions such as vaccines and drugs to be developed before nature produces the next pandemic virus.

One of the biggest challenges of current flu vaccine development is the lag time between when a virus is first identified and when a vaccine can be manufactured and distributed to the public to protect against that virus. In the United States, the composition of the flu vaccine is decided in February, but due to technological and other limitations, the manufactured vaccine typically does not become available until July or later. Proponents of gain of function research hope to overcome the time constraints of vaccine production by preparing and manufacturing vaccines in advance to protect against flu viruses before they emerge in nature.”

The utility of this work in terms of developing proactive drugs and vaccines has been challenged, at least given present approaches (Mahmoud, 2013; Wain-Hobson, 2014).

For the moment, industry needs to know the strain to beat.

The interpretation of mutations in field isolates is complicated by the genetic background of the strain. The surest way to ascertain the impact of a mutation of concern is to first isolate the virus and test it in a ferret aerosol transmission assay. “CDC does conduct transmissibility studies using naturally occurring (not altered) HPAI viruses in animal models to assess their transmissibility. This research informs CDC’s risk assessments of novel flu viruses.”


Small point
The document lists the 15 select agents that fall under DURC umbrella. They include the eradicated variola and rinderpest viruses. It does not include human influenza H2H2 which caused the Asian flu pandemic in 1957. This virus is no longer circulating and given that the majority of the world’s population is <50 years old there is no herd immunity (Nabel et al., 2011).

H2N2 viruses are circulating in pigs and birds. In the UK, the H2N2 pandemic virus is handled in a BSL4 lab.

References
Mahmoud, A. Gain-of-function research: unproven technique. Science. 2013 Oct 18;342(6156):310-1. doi: 10.1126/science.342.6156.310-b.

Nabel GJ, Wei CJ, Ledgerwood JE. Vaccinate for the next H2N2 pandemic now. Nature. 2011 Mar 10;471(7337):157-8. doi: 10.1038/471157a.

Wain-Hobson, S. The irrationality of GOF avian influenza research. Frontiers in Public Health 2, 77 2014 doi: 10.3389/fpubh.2014.00077


An interesting comment on preventive flu vaccination is to be found on the NHS website (10 March 2011)

September 5, 2014

Editorial - Culture of responsibility
Berkelman RL and Le Duc JW.
Science. 2014 Sep 5;345(6201):1101. doi: 10.1126/science.1260424.url


This one page editorial is packed with lucid sentences. A must.

“Achieving a “culture of safety,” so often alluded to after recent lapses in biosafety procedures, demands adopting a “culture of responsibility” as well.”

“No single meeting or organization is likely to grapple successfully with the conundrum of weighing the risks and benefits of certain lines of research.”

“Why are scientists required to understand the individual risks to participants in a clinical trial but not required to have ethical training related to the potential risks of research to the public? This is a fundamental disconnect in the ethics education of scientists and in the review process of protocols.”

“Scientists conduct work for the benefit of humanity. When the balance is unclear as to risks and benefits, as it currently is, should we not adhere to the principle of “first do no harm?”

Le Duc was recently appointed to the NSABB.

September 3, 2014

PB2-E627K and PA-T97I substitutions enhance polymerase activity and confer a virulent phenotype to an H6N1 avian influenza virus in mice.
Cheng K, Yu Z, Chai H, Sun W, Xin Y, Zhang Q, Huang J, Zhang K, Li X, Yang S, Wang T, Zheng X, Wang H, Qin C, Qian J, Chen H, Hua Y, Gao Y, Xia X.
Virology. 2014 Sep 3;468-470C:207-213. doi: 10.1016/j.virol.2014.08.010.

This illustrates the difficulties in interpreting viral mutations. The work does not involve airborne transmission but the authors had previously serially adapted the avian H6N1 virus to mice. Adaptation was accompanied by three mutations two of which render the virus more pathogenic than the initial virus and are the subject of the study. To date there has only been one symptomatic case of H6N1 infection in humans so the potential of such avian viruses is totally unclear. It is yet another example of the adaptability of influenza and other RNA viruses to a new experimental environment.

September 1, 2014

All-in-one bacmids: an efficient reverse genetics strategy for influenza A virus vaccines.
Chen H, Angel M, Li W, Finch C, Gonzalez AS, Sutton T, Santos J, Perez DR.
J Virol. 2014; 88:10013-25. doi: 10.1128/JVI.01468-14. Epub 2014 Jun 18.

This is a neat variant to classical influenza reverse genetics. All segments are on a single large plasmid – a bacmid (a larger than usual circular DNA molecule) – that results in more rapid recovery of virus.

August 15, 2014

PB2 mutations D701N and S714R promote adaptation of an influenza H5N1 virus to a mammalian host
Czudai-Matwich V, Otte A, Matrosovich M, Gabriel G, Klenk HD.
J Virol. 2014; 88:8735-42. doi: 10.1128/JVI.00422-14; epub Jun 4, 2014.