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.
Monday, December 22, 2014
Friday, December 5, 2014
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.
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.
Thursday, November 20, 2014
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.
Monday, November 17, 2014
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.
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.
Thursday, November 6, 2014
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)
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)
Wednesday, November 5, 2014
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.
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.
Thursday, October 23, 2014
October 23, 2014
Nature editorial – A ripe time for gaining ground
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.”
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.
“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.”
Wednesday, October 22, 2014
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.
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.
Friday, October 17, 2014
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.
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.”
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.”
Thursday, October 16, 2014
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
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
Tuesday, October 14, 2014
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.
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:
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
Tuesday, September 23, 2014
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
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
Saturday, September 20, 2014
Friday, September 12, 2014
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)
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)
Friday, September 5, 2014
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.
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.
Wednesday, September 3, 2014
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.
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.
Monday, September 1, 2014
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.
Friday, August 15, 2014
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.
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.
Wednesday, August 13, 2014
August 13, 2014
Making viruses in the lab deadlier and more able to spread: an accident waiting to happen
Tatyana Novossiolova and Malcolm Dando.
Bulletin of the Atomic Scientists
This is a short article from a veteran of the Biological Weapons Convention (BWC) discussions that occur mainly in Geneva. Malcolm Dando is at the University of Bradford’s Department of Peace Studies and is author of a widely known book in the field “Bioterror and biowarfare: A beginner’s guide”. Tatyana Novossiolova is a Wellcome Trust Doctoral Researcher at the Bradford Disarmament Research Centre at the University of Bradford, UK. The piece is interesting precisely because the authors offer a different perspective while being highly versed in the vocabulary of microbiology. It is written in reaction to the publication of Kawaoka’s paper on a 1918-like virus.
The opening statement is worth citing in full “All rights come with limits and responsibilities. For example, US Supreme Court Justice Oliver Wendell Holmes famously noted that the right to free speech does not mean that one can falsely shout "fire" in a crowded theatre.”
They make the analogy with the nuclear industry and cite Charles Perrow’s classic account of the Three Mile Island disaster, not the sort of reading that comes across the screen of most virologists. The conclusion was that the very structure and organization of nuclear power plants made them accident-prone. Perrow considered it a “normal” accident, which is a variant of an accident waiting to happen. He has a far more recent piece on the Fukushima accident. Dando writes “Gain-of-function research in the life sciences is another example of the inevitable failure of overly complex, human-designed systems with multiple variables.”
For the record, Malcolm Dando signed the FVR sponsored letter to Manuel Barroso and the CWG statement.
References
Malcolm R. Dando (2006), Bioterror and Biowarfare: A beginner’s guide, Oneworld Publications. ISBN-10: 1851684476
A very sobering and pertinent paragraph from this book is:
“unlike the international community of physical scientists, biologists have little tradition of taking an interest in security issues. Therefore the people who should really be able to give the best advice to the public and to politicians are still hardly aware of their grave responsibilities. A key issue for civil society is how to make the whole life sciences community around the world more aware and willing to bring their expertise to bear on the issue of preventing the misuse of their science.”
Charles Perrow (1982), "The President’s Commission and the Normal Accident", in Sils, D., Wolf, C. and Shelanski, V. (Eds), Accident at Three Mile Island: The Human Dimensions, Westview, Boulder, pp.173–184.
Charles Perrow (November/December 2011 vol. 67 no. 6). "Fukushima and the inevitability of accidents". Bulletin of the Atomic Scientists. pp. 44–52.
Tatyana Novossiolova and Malcolm Dando.
Bulletin of the Atomic Scientists
This is a short article from a veteran of the Biological Weapons Convention (BWC) discussions that occur mainly in Geneva. Malcolm Dando is at the University of Bradford’s Department of Peace Studies and is author of a widely known book in the field “Bioterror and biowarfare: A beginner’s guide”. Tatyana Novossiolova is a Wellcome Trust Doctoral Researcher at the Bradford Disarmament Research Centre at the University of Bradford, UK. The piece is interesting precisely because the authors offer a different perspective while being highly versed in the vocabulary of microbiology. It is written in reaction to the publication of Kawaoka’s paper on a 1918-like virus.
The opening statement is worth citing in full “All rights come with limits and responsibilities. For example, US Supreme Court Justice Oliver Wendell Holmes famously noted that the right to free speech does not mean that one can falsely shout "fire" in a crowded theatre.”
They make the analogy with the nuclear industry and cite Charles Perrow’s classic account of the Three Mile Island disaster, not the sort of reading that comes across the screen of most virologists. The conclusion was that the very structure and organization of nuclear power plants made them accident-prone. Perrow considered it a “normal” accident, which is a variant of an accident waiting to happen. He has a far more recent piece on the Fukushima accident. Dando writes “Gain-of-function research in the life sciences is another example of the inevitable failure of overly complex, human-designed systems with multiple variables.”
For the record, Malcolm Dando signed the FVR sponsored letter to Manuel Barroso and the CWG statement.
References
Malcolm R. Dando (2006), Bioterror and Biowarfare: A beginner’s guide, Oneworld Publications. ISBN-10: 1851684476
A very sobering and pertinent paragraph from this book is:
“unlike the international community of physical scientists, biologists have little tradition of taking an interest in security issues. Therefore the people who should really be able to give the best advice to the public and to politicians are still hardly aware of their grave responsibilities. A key issue for civil society is how to make the whole life sciences community around the world more aware and willing to bring their expertise to bear on the issue of preventing the misuse of their science.”
Charles Perrow (1982), "The President’s Commission and the Normal Accident", in Sils, D., Wolf, C. and Shelanski, V. (Eds), Accident at Three Mile Island: The Human Dimensions, Westview, Boulder, pp.173–184.
Charles Perrow (November/December 2011 vol. 67 no. 6). "Fukushima and the inevitability of accidents". Bulletin of the Atomic Scientists. pp. 44–52.
Monday, August 11, 2014
August 11, 2014
The consequences of a lab escape of a potential pandemic pathogen
Lynn Klotz & Edward J Sylvester
Front. Public Health, 11 August 2014 doi: 10.3389/fpubh.2014.00116
This constitutes the first risk analysis made in the filed of GOF influenza research. “what is the likelihood that one of these viruses will escape from a lab and seed the very pandemic the researchers claim they are trying to prevent? As we shall estimate, that probability could be as high as 27%, a risk too dangerous to live with.”
If they are right the probability is unacceptable high. If they are wrong, then we need to know where for the probability is too high for comfort. Risk analyses are urgently needed.
Lynn Klotz & Edward J Sylvester
Front. Public Health, 11 August 2014 doi: 10.3389/fpubh.2014.00116
This constitutes the first risk analysis made in the filed of GOF influenza research. “what is the likelihood that one of these viruses will escape from a lab and seed the very pandemic the researchers claim they are trying to prevent? As we shall estimate, that probability could be as high as 27%, a risk too dangerous to live with.”
If they are right the probability is unacceptable high. If they are wrong, then we need to know where for the probability is too high for comfort. Risk analyses are urgently needed.
Wednesday, August 6, 2014
August 6, 2014
The Society for General Microbiology’s position on biosecurity and DURC
It urges all parties to get together and discuss.
It urges all parties to get together and discuss.
Thursday, July 31, 2014
Juy 31, 2014
ASM Statement on Dual Use Research of Concern and Biosafety
This document emphasizes two chains of thought. First, scientists must respect the rules and regulations in force. Secondly, scientific freedom must be maintained as much as is possible. Nobody can quibble.
Highly pathogenic avian influenza (HPAI) H5N1 GOF research is specifically mentioned and the HHS/NIH is clearly in charge. They should consult with the scientists and if changes to existing guidelines are necessary, so be it. With its diverse membership that goes beyond the US, the ASM is in a unique position to provide a broad and informed source of opinion second to none. Yet it calls on the NAS “…to consider whether the current scope of GOF research offers the benefits that merit taking the risks inherent in performing that research…”.
The ASM pushes up and away the problem as to the risks and benefits of such work despite having a large membership, many coming from virology. The benefits of GOF influenza virus research have been shown to be wanting by several commentators. The risks are there, small we do agree but not zero, while the compound risk will increase as more and more microbiologists get into GOF/DURC research.
Time and time again the piece repeats the importance unencumbered scientific enquiry. Safety must be balanced “with the need to conduct legitimate research and diagnostic testing that is vital to making new scientific discoveries and combatting infectious diseases”. Yet this is standard policy around the globe.
This document emphasizes two chains of thought. First, scientists must respect the rules and regulations in force. Secondly, scientific freedom must be maintained as much as is possible. Nobody can quibble.
Highly pathogenic avian influenza (HPAI) H5N1 GOF research is specifically mentioned and the HHS/NIH is clearly in charge. They should consult with the scientists and if changes to existing guidelines are necessary, so be it. With its diverse membership that goes beyond the US, the ASM is in a unique position to provide a broad and informed source of opinion second to none. Yet it calls on the NAS “…to consider whether the current scope of GOF research offers the benefits that merit taking the risks inherent in performing that research…”.
The ASM pushes up and away the problem as to the risks and benefits of such work despite having a large membership, many coming from virology. The benefits of GOF influenza virus research have been shown to be wanting by several commentators. The risks are there, small we do agree but not zero, while the compound risk will increase as more and more microbiologists get into GOF/DURC research.
Time and time again the piece repeats the importance unencumbered scientific enquiry. Safety must be balanced “with the need to conduct legitimate research and diagnostic testing that is vital to making new scientific discoveries and combatting infectious diseases”. Yet this is standard policy around the globe.
Monday, July 28, 2014
July 28, 2014
Scientists for Science
The statement supports ongoing GOF research and “Most importantly, we are united as experts committed to ensuring public health is not compromised and the reputation of science in general, and microbiology in particular, is defended.”
Agreed.
The statement supports ongoing GOF research and “Most importantly, we are united as experts committed to ensuring public health is not compromised and the reputation of science in general, and microbiology in particular, is defended.”
Agreed.
Sunday, July 20, 2014
July 20, 2014
TWIV294
The opinions of the Cambridge Working Group (CWG) are sidelined without ceremony and are considered to represent an extremist view. Not once were arguments given as to why these people, that include eminent microbiologists such Barry Bloom of Harvard and David Relman from UCSF and President of the Infectious Disease Physicians of America, to mention just two, are barking up the wrong street. Paul Berg and Stanley Falkow, architects of the 1975 Asilomar meeting have signed on as well as highly respected virologists, bacteriologists and international lawyers.
Vincent Racaniello maintains that sufficient procedures are in place and that GOF researchers followed them. He considers that the CWG has not listened to the other sides’ arguments. Dickson Despommiers, who is a parasitologist, said that the CWG is unhappy because they haven’t been agreed with.
“The CWG is damaging science irreparably”. Lipsitch (an organizer of CWG, “doesn’t understand the amount of collateral damage” he is creating, and is simply “increasing public distrust in science”.
We learn that risk-benefit analyses are absurd as it is very difficult to quantify risk and benefits of most research. This is very revealing comment for there is huge field in risk assessment and risk management. Insurance companies and re-assurers compute risk out to 20 years or more, meaning that they take a long view. It is so mature a field that there are even risk communication consultants. See October 14, 2014.
We learn that any Asilomar type meeting must not be organized by members of the CWG. They may attend. Alan Condit, perhaps, goes on to say that the same applies to members of Scientists For Science, a web page set up by Racaniello in response to the CWG, which is accepted and leads on to a discussion of which neutral third party might play the go between.
Marc Lipsitch from Harvard Medical School is dismissed out of hand because he is an epidemiologist and presumably cannot understand virology. Yet it was the US epidemiologist Palmer Beasley who established beyond a shadow of doubt that prior hepatitis B virus (HBV) infection was linked to the onset of hepatocellular carcinoma (Beasley et al., 1981). Beasley then went on to push for extremely early vaccination of babies in Taiwan which is now the standard of care in endemic areas. He became the author of HBV immunization policies for the World Health Organization.
A parasitologist with one PubMed reference including the word “virus” is more qualified to comment on GOF virology than an epidemiologist who has 56 such references.
Dickson Despommier makes a parallel with the decommissioning nuclear plants and considers it a more important issue than the GOF. Suffice to say that in the nuclear arena, for decades the pressure has been to reduce proliferation based on the idea that the more structures there are the greater the risk of an accident. Undoubtedly there are other political motivations in this field but anti-proliferation has been a buzz word for ages. For an alternative view see Rath, 2014.
The parallel with the control of rinderpest viral stocks is revealing. Rinderpest was/is the measles virus of cattle and is only the second virus to be eradicated since 2001.
To reduce the risk of a lab accident, the FAO-OIE are calling to reduce the number of labs holding rinderpest viral stocks from 30 to around 10, which is the equivalent to reducing the number of centers handling nuclear material.
Despommier continues with the opponents of GOF research in no uncertain terms. It starts with a form of questioning: “are they some right wing group” which reminds him of the McCarthy era in that they have a jaundiced view of science…
References
Beasley RP, Hwang LY, Lin CC, Chien CS. (1981). Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 2:1129-33.
The opinions of the Cambridge Working Group (CWG) are sidelined without ceremony and are considered to represent an extremist view. Not once were arguments given as to why these people, that include eminent microbiologists such Barry Bloom of Harvard and David Relman from UCSF and President of the Infectious Disease Physicians of America, to mention just two, are barking up the wrong street. Paul Berg and Stanley Falkow, architects of the 1975 Asilomar meeting have signed on as well as highly respected virologists, bacteriologists and international lawyers.
Vincent Racaniello maintains that sufficient procedures are in place and that GOF researchers followed them. He considers that the CWG has not listened to the other sides’ arguments. Dickson Despommiers, who is a parasitologist, said that the CWG is unhappy because they haven’t been agreed with.
“The CWG is damaging science irreparably”. Lipsitch (an organizer of CWG, “doesn’t understand the amount of collateral damage” he is creating, and is simply “increasing public distrust in science”.
We learn that risk-benefit analyses are absurd as it is very difficult to quantify risk and benefits of most research. This is very revealing comment for there is huge field in risk assessment and risk management. Insurance companies and re-assurers compute risk out to 20 years or more, meaning that they take a long view. It is so mature a field that there are even risk communication consultants. See October 14, 2014.
We learn that any Asilomar type meeting must not be organized by members of the CWG. They may attend. Alan Condit, perhaps, goes on to say that the same applies to members of Scientists For Science, a web page set up by Racaniello in response to the CWG, which is accepted and leads on to a discussion of which neutral third party might play the go between.
Marc Lipsitch from Harvard Medical School is dismissed out of hand because he is an epidemiologist and presumably cannot understand virology. Yet it was the US epidemiologist Palmer Beasley who established beyond a shadow of doubt that prior hepatitis B virus (HBV) infection was linked to the onset of hepatocellular carcinoma (Beasley et al., 1981). Beasley then went on to push for extremely early vaccination of babies in Taiwan which is now the standard of care in endemic areas. He became the author of HBV immunization policies for the World Health Organization.
A parasitologist with one PubMed reference including the word “virus” is more qualified to comment on GOF virology than an epidemiologist who has 56 such references.
Dickson Despommier makes a parallel with the decommissioning nuclear plants and considers it a more important issue than the GOF. Suffice to say that in the nuclear arena, for decades the pressure has been to reduce proliferation based on the idea that the more structures there are the greater the risk of an accident. Undoubtedly there are other political motivations in this field but anti-proliferation has been a buzz word for ages. For an alternative view see Rath, 2014.
The parallel with the control of rinderpest viral stocks is revealing. Rinderpest was/is the measles virus of cattle and is only the second virus to be eradicated since 2001.
To reduce the risk of a lab accident, the FAO-OIE are calling to reduce the number of labs holding rinderpest viral stocks from 30 to around 10, which is the equivalent to reducing the number of centers handling nuclear material.
Despommier continues with the opponents of GOF research in no uncertain terms. It starts with a form of questioning: “are they some right wing group” which reminds him of the McCarthy era in that they have a jaundiced view of science…
References
Beasley RP, Hwang LY, Lin CC, Chien CS. (1981). Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 2:1129-33.
Wednesday, July 16, 2014
July 16, 2014
The irrationality of GOF avian influenza virus research
Wain-Hobson S.
Front Public Health. 2014 Jul 16;2:77. doi: 10.3389/fpubh.2014.00077. eCollection 2014.
The paper takes a detailed look at the claims put forward by the GOF influenza researchers to justify their work. The vaccine claim in particular doesn’t hold up to scrutiny.
Wain-Hobson S.
Front Public Health. 2014 Jul 16;2:77. doi: 10.3389/fpubh.2014.00077. eCollection 2014.
The paper takes a detailed look at the claims put forward by the GOF influenza researchers to justify their work. The vaccine claim in particular doesn’t hold up to scrutiny.
Monday, July 14, 2014
July 14, 2014
Cambridge Working Group Consensus Statement on the Creation of Potential Pandemic Pathogens (PPPs)
This is a statement resulting from the discussion of 18 researchers and concerned individuals in Boston. It expresses concern about the ongoing GOF research and calls for it to be curbed. It was ultimately signed by 295 individuals including Paul Berg and Stanley Falkow, architects of the 1975 Asilomar conference.
This is a statement resulting from the discussion of 18 researchers and concerned individuals in Boston. It expresses concern about the ongoing GOF research and calls for it to be curbed. It was ultimately signed by 295 individuals including Paul Berg and Stanley Falkow, architects of the 1975 Asilomar conference.
Sunday, June 29, 2014
June 29, 2014
TWIV291 from 33rd annual meeting of the American Society for Virology (ASV) in Fort Collins, Colorado.
Ron Fouchier was a guest.
Ron Fouchier was a guest.
Thursday, June 26, 2014
June 26, 2014
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.
Nature. 2014 Jun 26;510(7506):443.
“The fewer the labs that perform experiments, the smaller is the risk of an accidental release. But as the CDC accident reminds us, should gain-of-function flu research proliferate, in particular at facilities with less than exemplary biosafety standards, the risks of an accidental release of a potentially pandemic flu virus will be multiplied.”
Nature. 2014 Jun 26;510(7506):443.
“The fewer the labs that perform experiments, the smaller is the risk of an accidental release. But as the CDC accident reminds us, should gain-of-function flu research proliferate, in particular at facilities with less than exemplary biosafety standards, the risks of an accidental release of a potentially pandemic flu virus will be multiplied.”
Saturday, June 14, 2014
June 11, 2014
Circulating avian influenza viruses closely related to the 1918 virus have pandemic potential.
Watanabe T, Zhong G, Russell CA, Nakajima N, Hatta M, Hanson A, McBride R, Burke DF, Takahashi K, Fukuyama S, Tomita Y, Maher EA, Watanabe S, Imai M, Neumann G, Hasegawa H, Paulson JC, Smith DJ, Kawaoka Y.
Cell Host Microbe. 2014 Jun 11;15(6):692-705. doi: 10.1016/j.chom.2014.05.006.
Comment to be posted.
Watanabe T, Zhong G, Russell CA, Nakajima N, Hatta M, Hanson A, McBride R, Burke DF, Takahashi K, Fukuyama S, Tomita Y, Maher EA, Watanabe S, Imai M, Neumann G, Hasegawa H, Paulson JC, Smith DJ, Kawaoka Y.
Cell Host Microbe. 2014 Jun 11;15(6):692-705. doi: 10.1016/j.chom.2014.05.006.
Comment to be posted.
Sunday, June 1, 2014
June 2014
Airborne transmission of highly pathogenic H7N1 influenza virus in ferrets.
Sutton TC, Finch C, Shao H, Angel M, Chen H, Capua I, Cattoli G, Monne I, Perez DR.
J Virol. 2014 Jun;88(12):6623-35. doi: 10.1128/JVI.02765-13. Epub 2014 Apr 2.
Sequence changes associated with respiratory transmission of H7N1 influenza virus in mammals.
Dermody TS, Sandri-Goldin RM, Shenk T.
J Virol. 2014 Jun;88(12):6533-4. doi: 10.1128/JVI.00886-14. Epub 2014 Apr 2.
Sutton TC, Finch C, Shao H, Angel M, Chen H, Capua I, Cattoli G, Monne I, Perez DR.
J Virol. 2014 Jun;88(12):6623-35. doi: 10.1128/JVI.02765-13. Epub 2014 Apr 2.
Sequence changes associated with respiratory transmission of H7N1 influenza virus in mammals.
Dermody TS, Sandri-Goldin RM, Shenk T.
J Virol. 2014 Jun;88(12):6533-4. doi: 10.1128/JVI.00886-14. Epub 2014 Apr 2.
Monday, May 12, 2014
May 12, 2014
Little evidence of subclinical avian influenza virus infections among rural villagers in Cambodia.
Gray GC, Krueger WS, Chum C, Putnam SD, Wierzba TF, Heil GL, Anderson BD, Yasuda CY, Williams M, Kasper MR, Saphonn V, Blair PJ.
PLoS One. 2014 May 12;9(5):e97097. doi: 10.1371/journal.pone.0097097. eCollection 2014.
In 2008, 800 adults living within rural Kampong Cham Province, Cambodia were enrolled in a 2 year prospective cohort study of zoonotic influenza transmission. Apart from symptomatic human influenza infections a single symptomatic H5N1 infection of avian origin was identified.
Interestingly a handful of symptomatic avian influenza infections were identified using patient sera. Using a conservative WHO accepted cut off for serum titers one individual scored positive using a H9N2 test virus and two others for a H12N5 virus. As the titer of human H5N1 convalescent sera wanes within one year these numbers are probably underestimates.
The paper shows that more strains of avian influenza viruses infect man than judged by symptomatic infections. Spill over resulting in asymptomatic infection could well be relatively common with symptomatic infections being a subset.
Gray GC, Krueger WS, Chum C, Putnam SD, Wierzba TF, Heil GL, Anderson BD, Yasuda CY, Williams M, Kasper MR, Saphonn V, Blair PJ.
PLoS One. 2014 May 12;9(5):e97097. doi: 10.1371/journal.pone.0097097. eCollection 2014.
In 2008, 800 adults living within rural Kampong Cham Province, Cambodia were enrolled in a 2 year prospective cohort study of zoonotic influenza transmission. Apart from symptomatic human influenza infections a single symptomatic H5N1 infection of avian origin was identified.
Interestingly a handful of symptomatic avian influenza infections were identified using patient sera. Using a conservative WHO accepted cut off for serum titers one individual scored positive using a H9N2 test virus and two others for a H12N5 virus. As the titer of human H5N1 convalescent sera wanes within one year these numbers are probably underestimates.
The paper shows that more strains of avian influenza viruses infect man than judged by symptomatic infections. Spill over resulting in asymptomatic infection could well be relatively common with symptomatic infections being a subset.
Thursday, May 8, 2014
May 8, 2014
Time to settle the synthetic biology controversy
Nature. 2014 May 8;509(7499):135. doi: 10.1038/509135a.
Two comments were prompted by this piece from ter Meulen.
Synthetic biology: Missing the point.
Evans SW and others.
Nature. 2014 Jun 12;510(7504):218. doi: 10.1038/510218b.
Synthetic biology: A global approach
Keasling JD and others
Nature 2014 Jun 12;510(7504):218. doi: 10.1038/510218c.
The first contains two sentences that are relevant to GOF-discussed.
“…supporting synthetic biology is not about making sure that science can go wherever it wants: it is about making the type of society people want to live in.”
“It is not unknown for scientists themselves to foster exaggeration and uncritical acceptance of claims, or to focus on anticipated benefits rather than on risks.”
Personal opinion
Synthetic biologists do not intend to make microbes that threaten humankind. If ever such an organism arose they may well be horrified. The intent of avian GOF influenza A virus research is to make novel viruses that are dangerous for humans with the idea of using them to develop vaccines and drugs, claims that do not hold water.
Nature. 2014 May 8;509(7499):135. doi: 10.1038/509135a.
Two comments were prompted by this piece from ter Meulen.
Synthetic biology: Missing the point.
Evans SW and others.
Nature. 2014 Jun 12;510(7504):218. doi: 10.1038/510218b.
Synthetic biology: A global approach
Keasling JD and others
Nature 2014 Jun 12;510(7504):218. doi: 10.1038/510218c.
The first contains two sentences that are relevant to GOF-discussed.
“…supporting synthetic biology is not about making sure that science can go wherever it wants: it is about making the type of society people want to live in.”
“It is not unknown for scientists themselves to foster exaggeration and uncritical acceptance of claims, or to focus on anticipated benefits rather than on risks.”
Personal opinion
Synthetic biologists do not intend to make microbes that threaten humankind. If ever such an organism arose they may well be horrified. The intent of avian GOF influenza A virus research is to make novel viruses that are dangerous for humans with the idea of using them to develop vaccines and drugs, claims that do not hold water.
Thursday, May 1, 2014
May, 2014
The Soviet biological warfare program and its uncertain legacy.
Past Soviet secrecy when linked with a promise by Putin raise nagging questions about Russian BW-related intentionsRaymond A. Zilinskas
Microbe, 2014. 9, 191-197.
RZ is Director of Chemical & Biological Weapons Nonproliferation Program at the Monterey Institute of International Studies, Monterey, California
The paper is interesting and relevant for two reasons. The first is that some of the work undertaken during the second generation of Russian biological warfare (1972-94) is the equivalent of gain of function virus research.
“The Soviet second-generation BW program had two components, codenamed Ferment and Ekology. Ferment was mandated to weaponize pathogens for use against humans, while Ekology weaponized animal and plant pathogens. Both components were set up to apply genetic engineering techniques to enhance the ability of pathogens to cause infections, to increase the virulence of pathogens, to endow them with new capabilities for circumventing or defeating defenses against them, including vaccines, antibiotics, and detection techniques, and to develop new genetic constructs that caused unique symptoms. It bears noting that in today’s parlance these kinds of experiments are termed “gain of function” experiments.”
Reversing the argument based on cold war logic leads to the conclusion that contemporary GOF influenza virus experiments are de facto the equivalent of biological warfare research. Accordingly, if this work had been performed in some military lab in the West and had been leaked to the press, it is probable that there would have been uproar with headlines like “Weaponizing avian flu”.
The second reason why this article is worth reading is the suggestion that Russia might engage on a new round of biological warfare research.
Past Soviet secrecy when linked with a promise by Putin raise nagging questions about Russian BW-related intentionsRaymond A. Zilinskas
Microbe, 2014. 9, 191-197.
RZ is Director of Chemical & Biological Weapons Nonproliferation Program at the Monterey Institute of International Studies, Monterey, California
The paper is interesting and relevant for two reasons. The first is that some of the work undertaken during the second generation of Russian biological warfare (1972-94) is the equivalent of gain of function virus research.
“The Soviet second-generation BW program had two components, codenamed Ferment and Ekology. Ferment was mandated to weaponize pathogens for use against humans, while Ekology weaponized animal and plant pathogens. Both components were set up to apply genetic engineering techniques to enhance the ability of pathogens to cause infections, to increase the virulence of pathogens, to endow them with new capabilities for circumventing or defeating defenses against them, including vaccines, antibiotics, and detection techniques, and to develop new genetic constructs that caused unique symptoms. It bears noting that in today’s parlance these kinds of experiments are termed “gain of function” experiments.”
Reversing the argument based on cold war logic leads to the conclusion that contemporary GOF influenza virus experiments are de facto the equivalent of biological warfare research. Accordingly, if this work had been performed in some military lab in the West and had been leaked to the press, it is probable that there would have been uproar with headlines like “Weaponizing avian flu”.
The second reason why this article is worth reading is the suggestion that Russia might engage on a new round of biological warfare research.
Friday, April 11, 2014
April 11, 2014
Dr. Kawaoka gave a talk at the Institut Pasteur as part of the 9th Louis Pasteur conference on Emerging Infectious Diseases. No title or abstract were provided. Lots of data were flashed up; not easy to keep up with the tempo.
• Started with pandemic 2009 influenza A virus (pH1N1) and selected escape mutants with polyclonal sera. Classic. There was little diversity and was disappointed.
• Took gene segment corresponding to amino acid residues 71-270 of the hemagglutinin (HA), performed error prone PCR, re-expressed as mutant library in H1N1 backbone by reverse genetics.
• Took 14 convalescent sera and isolated 50 escape mutants. Found 9 amino acid sites of variation.
• Factored in a few other sites (didn’t catch how) and ended up with 15 key sites in the HA sequence
• Performed saturation codon mutagenesis on these sites in the gene and ended up with 2 amino acid site, 3 site, 4 site and 5 site virus variants that were further refined by mutagenesis. 4 and 5 site mutants completely escaped vaccine-induced antibodies.
They worked hard to get a vaccine resistant virus. Apparently the work was performed at biosafety level 2 (BSL2).
• Started with pandemic 2009 influenza A virus (pH1N1) and selected escape mutants with polyclonal sera. Classic. There was little diversity and was disappointed.
• Took gene segment corresponding to amino acid residues 71-270 of the hemagglutinin (HA), performed error prone PCR, re-expressed as mutant library in H1N1 backbone by reverse genetics.
• Took 14 convalescent sera and isolated 50 escape mutants. Found 9 amino acid sites of variation.
• Factored in a few other sites (didn’t catch how) and ended up with 15 key sites in the HA sequence
• Performed saturation codon mutagenesis on these sites in the gene and ended up with 2 amino acid site, 3 site, 4 site and 5 site virus variants that were further refined by mutagenesis. 4 and 5 site mutants completely escaped vaccine-induced antibodies.
They worked hard to get a vaccine resistant virus. Apparently the work was performed at biosafety level 2 (BSL2).
Thursday, April 10, 2014
April 10, 2014
Linster M, van Boheemen S, de Graaf M, Schrauwen EJ, Lexmond P, Mänz B, Bestebroer TM, Baumann J, van Riel D, Rimmelzwaan GF, Osterhaus AD, Matrosovich M, Fouchier RA, Herfst S.
Identification, characterization, and natural selection of mutations driving airborne transmission of A/H5N1 virus.
Cell. 2014 Apr 10;157(2):329-39. doi: 10.1016/j.cell.2014.02.040.
Identification, characterization, and natural selection of mutations driving airborne transmission of A/H5N1 virus.
Cell. 2014 Apr 10;157(2):329-39. doi: 10.1016/j.cell.2014.02.040.
Wednesday, January 15, 2014
January 15, 2014
A new strain of Clostridium botulinum encoding a novel toxin, BoNT/H the eight such toxin, has been described, the first such toxin to be described in >40 years (Barash et al., 2014; Dover et al., 2014).
The authors referred their concerns up the line. Journal editors and US security agencies were involved resulting in the publication of the work without description of the toxin itself. The original paper was published accompanied by a letter from the editors describing the review process and decision (Hooper & Hirsch, 2014), a historical overview of botulinum toxins (Popoff, 2014) and a comment from David Relman, former member of the NSABB and one who handled the original Kawaoka and Fouchier papers (Relman, 2014).
While the efficiency and merits of redacting essential data from a paper can be debated, the example is well worth reading for the authors flagged up their concerns and shared their observations and difficulties with other stakeholders. It shows that complex and worrying biological issues can be shared and acted upon. The accompanying review papers make for good reading.
A note at the end of the editor’s letter (Hooper & Hirsch, 2014) lists the large number of committees that were involved in commenting on the larger dimensions of theses findings.
“A committee representing various branches of the US government reviewed and approved submission of the manuscripts. Represented on this committee were the Drug Development Section, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); the Enteric and Hepatic Diseases Branch, NIAID, NIH; the Bacteriology and Mycology Branch, NIAID, NIH; the Office of Biotechnology Activities, Office of Science Policy, NIH; the National Counterproliferation Center, Office of the Director of National Intelligence; the Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services (DHHS); the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, DHHS; the Threat Characterization and Attribution Branch, Chemical and Biological Defense Division, Science and Technology Directorate, Department of Homeland Security; the US Army Medical Research Institute of Infectious Diseases; the Division of Select Agents and Toxins, Office of Public Health Preparedness and Response, Centers for Disease Control and Prevention, DHHS; and the Biological Countermeasures Unit, Federal Bureau of Investigation Weapons of Mass Destruction Directorate, Department of Justice.”
The last paragraph from Relman’s letter is worth reading.
“Finally, for voluntary controls to play a useful role in the management of problematic information in the “gray area,” scientists will first need to recognize their ethical and moral responsibilities to society in the pursuit of knowledge. Scientists have obligations to society that involve more than blind pursuit of information. Like clinicians, scientists have an obligation to do no harm.”
References
A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins.
Barash JR, Arnon SS.
J Infect Dis. 2014 Jan 15;209(2):183-91. doi: 10.1093/infdis/jit449. Epub 2013 Oct 7.
Molecular characterization of a novel botulinum neurotoxin type H gene.
Dover N, Barash JR, Hill KK, Xie G, Arnon SS.
J Infect Dis. 2014 Jan 15;209(2):192-202. doi: 10.1093/infdis/jit450. Epub 2013 Oct 7.
Novel clostridium botulinum toxin and dual use research of concern issues.
Hooper DC, Hirsch MS.
J Infect Dis. 2014 Jan 15;209(2):167. doi: 10.1093/infdis/jit528. Epub 2013 Oct 7.
Botulinum neurotoxins: more and more diverse and fascinating toxic proteins.
Popoff MR.
J Infect Dis. 2014 Jan 15;209(2):168-9. doi: 10.1093/infdis/jit505. Epub 2013 Oct 7.
"Inconvenient truths" in the pursuit of scientific knowledge and public health.
Relman DA.
J Infect Dis. 2014 Jan 15;209(2):170-2. doi: 10.1093/infdis/jit529. Epub 2013 Oct 7.
The authors referred their concerns up the line. Journal editors and US security agencies were involved resulting in the publication of the work without description of the toxin itself. The original paper was published accompanied by a letter from the editors describing the review process and decision (Hooper & Hirsch, 2014), a historical overview of botulinum toxins (Popoff, 2014) and a comment from David Relman, former member of the NSABB and one who handled the original Kawaoka and Fouchier papers (Relman, 2014).
While the efficiency and merits of redacting essential data from a paper can be debated, the example is well worth reading for the authors flagged up their concerns and shared their observations and difficulties with other stakeholders. It shows that complex and worrying biological issues can be shared and acted upon. The accompanying review papers make for good reading.
A note at the end of the editor’s letter (Hooper & Hirsch, 2014) lists the large number of committees that were involved in commenting on the larger dimensions of theses findings.
“A committee representing various branches of the US government reviewed and approved submission of the manuscripts. Represented on this committee were the Drug Development Section, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); the Enteric and Hepatic Diseases Branch, NIAID, NIH; the Bacteriology and Mycology Branch, NIAID, NIH; the Office of Biotechnology Activities, Office of Science Policy, NIH; the National Counterproliferation Center, Office of the Director of National Intelligence; the Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services (DHHS); the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, DHHS; the Threat Characterization and Attribution Branch, Chemical and Biological Defense Division, Science and Technology Directorate, Department of Homeland Security; the US Army Medical Research Institute of Infectious Diseases; the Division of Select Agents and Toxins, Office of Public Health Preparedness and Response, Centers for Disease Control and Prevention, DHHS; and the Biological Countermeasures Unit, Federal Bureau of Investigation Weapons of Mass Destruction Directorate, Department of Justice.”
The last paragraph from Relman’s letter is worth reading.
“Finally, for voluntary controls to play a useful role in the management of problematic information in the “gray area,” scientists will first need to recognize their ethical and moral responsibilities to society in the pursuit of knowledge. Scientists have obligations to society that involve more than blind pursuit of information. Like clinicians, scientists have an obligation to do no harm.”
References
A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins.
Barash JR, Arnon SS.
J Infect Dis. 2014 Jan 15;209(2):183-91. doi: 10.1093/infdis/jit449. Epub 2013 Oct 7.
Molecular characterization of a novel botulinum neurotoxin type H gene.
Dover N, Barash JR, Hill KK, Xie G, Arnon SS.
J Infect Dis. 2014 Jan 15;209(2):192-202. doi: 10.1093/infdis/jit450. Epub 2013 Oct 7.
Novel clostridium botulinum toxin and dual use research of concern issues.
Hooper DC, Hirsch MS.
J Infect Dis. 2014 Jan 15;209(2):167. doi: 10.1093/infdis/jit528. Epub 2013 Oct 7.
Botulinum neurotoxins: more and more diverse and fascinating toxic proteins.
Popoff MR.
J Infect Dis. 2014 Jan 15;209(2):168-9. doi: 10.1093/infdis/jit505. Epub 2013 Oct 7.
"Inconvenient truths" in the pursuit of scientific knowledge and public health.
Relman DA.
J Infect Dis. 2014 Jan 15;209(2):170-2. doi: 10.1093/infdis/jit529. Epub 2013 Oct 7.
Wednesday, January 1, 2014
January 2014
Alternative reassortment events leading to transmissible H9N1 influenza viruses in the ferret model.
Kimble JB, Angel M, Wan H, Sutton TC, Finch C, Perez DR.
J Virol. 2014 Jan;88(1):66-71. doi: 10.1128/JVI.02677-13. Epub 2013 Oct 16.
Kimble et al., describe inoculation of ferrets with MDCK (dog) cells transfected by 15 plasmids for avian H9N2 flu strain and human pandemic 2009 H1N1 (minus the H1 hemagglutinin). Theoretically 128 reassortant viruses can be made. Two of three animals so inoculated became infected giving rise to what were called lineage A and B viruses. Within 4 days of transfection, the dye was cast and one combination quickly dominated in each infected animal. This contrasts to the findings for tissue culture that once again highlights the need for animal studies.
At the end of 4 manual passages (P1-P4 virus) a fifth passage by aerosol transmission with P4 virus was attempted for three infected animals and it worked (RCP5 virus, RC=respiratory contact). P1 and RCP5 viruses were sequenced. There were 4 non-synonymous nucleotide changes (i.e. resulting in amino acid changes) for lineage A virus and 6 (5 non-synonymous, 1 synonymous, or silent change) for lineage B virus. None of the mutations overlapped. None were in the HA receptor binding pocket. This shows that there are many constellations that compatible with aerosol transmission using 6 common genes (PB2, PA, HA, NP, NA, and NS, Table 1). 2/4 and 5/5 mutations were of unknown phenotype indicating once again the wide gap in correlating genotype and phenotype.
The authors did not sequence the P4 virus used to initiate the aerosol transmission experiment hence we cannot work out which mutations arose during serial mechanical passage and which resulted from selection via transmission. It is unlikely that all 4 and 6 mutations arose during the single aerosol transmission passage, hence the numbers so acquired must be <4 and <5 for lineage A and B. Sequencing the P4 virus would have established the precise number involved.
Their interest in GOF is shown by the last sentence: “A similar approach can be implemented to ascertain the gene constellation that would most likely lead to more effective respiratory-droplet transmission of other avian influenza viruses in mammals.” Sequencing the P4 virus would have helped.
Kimble JB, Angel M, Wan H, Sutton TC, Finch C, Perez DR.
J Virol. 2014 Jan;88(1):66-71. doi: 10.1128/JVI.02677-13. Epub 2013 Oct 16.
Kimble et al., describe inoculation of ferrets with MDCK (dog) cells transfected by 15 plasmids for avian H9N2 flu strain and human pandemic 2009 H1N1 (minus the H1 hemagglutinin). Theoretically 128 reassortant viruses can be made. Two of three animals so inoculated became infected giving rise to what were called lineage A and B viruses. Within 4 days of transfection, the dye was cast and one combination quickly dominated in each infected animal. This contrasts to the findings for tissue culture that once again highlights the need for animal studies.
At the end of 4 manual passages (P1-P4 virus) a fifth passage by aerosol transmission with P4 virus was attempted for three infected animals and it worked (RCP5 virus, RC=respiratory contact). P1 and RCP5 viruses were sequenced. There were 4 non-synonymous nucleotide changes (i.e. resulting in amino acid changes) for lineage A virus and 6 (5 non-synonymous, 1 synonymous, or silent change) for lineage B virus. None of the mutations overlapped. None were in the HA receptor binding pocket. This shows that there are many constellations that compatible with aerosol transmission using 6 common genes (PB2, PA, HA, NP, NA, and NS, Table 1). 2/4 and 5/5 mutations were of unknown phenotype indicating once again the wide gap in correlating genotype and phenotype.
The authors did not sequence the P4 virus used to initiate the aerosol transmission experiment hence we cannot work out which mutations arose during serial mechanical passage and which resulted from selection via transmission. It is unlikely that all 4 and 6 mutations arose during the single aerosol transmission passage, hence the numbers so acquired must be <4 and <5 for lineage A and B. Sequencing the P4 virus would have established the precise number involved.
Their interest in GOF is shown by the last sentence: “A similar approach can be implemented to ascertain the gene constellation that would most likely lead to more effective respiratory-droplet transmission of other avian influenza viruses in mammals.” Sequencing the P4 virus would have helped.
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