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
Tuesday, September 23, 2014
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.
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