Dr. Marc Lipsitch | mlipsitc@hsph.harvard Center for Communicable Disease Dynamics

1. Here is a partial, incomplete, draft timeline of the controversy over experiments to make H5N1 (and subsequently H7N9) more transmissible. Rather than “gain-of-function” (GOF), a broad, nonspecific term, I prefer to call this class of experiments “creation of potential pandemic pathogens” (PPP), to emphasize the aspect that is controversial. This term is due to Klotz and Sylvester.Disclaimers: It is not a scientific timeline so much as a timeline of the criticism of the experiments. This timeline is certainly not comprehensive, and is obviously more detailed about things I was involved in than about those I was not, and it includes links to my own (and some other) contributions to the discussion. It was constructed in response to a Twitter discussion that got too complicated for 140 characters at a time. Dr. Marc Lipsitch | mlipsitc@hsph.harvard.edu Center for Communicable Disease Dynamics and Department of Epidemiology Harvard School of Public Health January 2014 @CCDD_HSPH | @mlipsitch Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses

2. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses 2011 2012 SEP OCT NOV DEC JAN FEB Sep 2011 through Summer 2012: Debate about publication, and some debate on the merit of the research. Science and Nature, among others, extensively covered the debate on publication. Moratorium declared on future H5N1 GOF studies. First public announcement of PPP-creation experimentsin Malta by Fouchier Among the few public discussions of the merits (remember, of not-yet-published articles for which most had not seen the data) took place on PBS & Nature. Ebright in PBS documentary voices concerns In Nature News, Capua & Webby deny value of PPP experiments for vaccine development, note the need for other approaches

3. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses 2012 MAY MAR APR Sep 2011 through Summer 2012: Debate about publication, and some debate on the merit of the research. Science and Nature, among others, extensively covered the debate on publication. Kawaoka PPP H5N1 paper published in Nature. Now the debate about the merits of the experiments themselves begins in earnest NSABB gives permission to publish revised MSS from Fouchier and Kawaoka labs, in a split decision. Ebright criticizes publication decision in NYT Brandon Keim writes twoarticles in Wired about the risks of doing the experiments Roberts, Ebright, Osterholm, Klotz , Morse and Salzberg Royal Society meeting chaired by Wain-Hobson & Skehel to air critical debate

4. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses 2012 JUN JUL Sep 2011 through Summer 2012: Debate about publication, and some debate on the merit of the research. Science and Nature, among others, extensively covered the debate on publication. Fouchier paper published in Science, withPolicy Forum in same issue by Lipsitch, Plotkin, Simonsen, Bloom questioning the interpretability of the results Relman, Lipsitch, Roberts, and Capua raise safety concerns on NPR with Nell Greenfieldboyce US Rep. Sensenbrenner publicly criticizes NIH handling of the papers

5. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses 2012 AUG SEP OCT NOV DEC August to Fall 2012, Lead up to lifting of the pause. Critique by Hale, May and Wain-Hobson in the Financial Times , “The folly of resuming avian flu research” Publishing of debate in mBio on the merits of the research, including Lipsitch and Bloom’s criticisms December 2012 NIH meeting and request for guidance about framework. Critical written comments from Lipsitch and no doubt others. At the meeting, speakers include Wooley, Capua, Mahmoud Klotz & Sylvester in Bulletin of the Atomic Scientists, “The unacceptable risks of a man-made pandemic” Taubenberger et al. assert that the reconstruction of 1918 H1N1 created “unexpected public health rewards,”a claim that could be debated

6. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses, Dr. Marc Lipsitch @CCDD_HSPH | @mlipsitch 2013 JAN FEB MAR APR MAY JUN H5N1 moratorium on H5N1 GOF lifted Lipsitch criticizes experiments in Harvard Magazine Recombinant DNA Advisory Committee discussion including concerns from Wooley, member HHS framework for funding H5N1 HPAI GOF announced

7. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses, Dr. Marc Lipsitch @CCDD_HSPH | @mlipsitch 2013 JUL AUG/SEP H7N9 framework for funding similar to H5N1 announced by US HHS. Simultaneously, flu researchers announce plans to do H7N9 GOF and Fouchier lab publishes a 2-generation ferret passage study of H7N9 which is criticized as being 1) scientifically limited due to sample size, variation in dose and the limits of the ferret model, 2) a gain-of-function study by the definition of HHS "reasonably expected to produce an increase in transmissibility."

8. Partial Timeline of Critical Discussion of Experiments to Increase Transmissibility of Avian Influenza Viruses, Dr. Marc Lipsitch @CCDD_HSPH | @mlipsitch 2013 2014 SEP OCT NOV DEC JAN Debate on the topic at Options for the Control of Influenza, Cape Town. Lipsitch slides available here Lipsitch talk at Epidemics4 highlighting ethical problems and availability of alternatives Center for Arms Control and Non-Proliferation publishes “Risk Assessment: The Human Fatality and Economic Burden of a Man-made Influenza Pandemic” Wain-Hobson questions rationale for experiments in EMBO Molecular Medicine Foundation for Vaccine Research and 50+ scientists, write letter of concern to President of the European Commission Science publishes critical correspondence by Mahmoud and Rey et al Lipsitch criticizes experiments in The European