Biodefense and the case of H5N1
I’m very pleased to be able to feature Willard Applefeld for a guest post today on the flu, biodefense, and scientific ethics. We are all very lucky he has chosen to use his powers for good, and not for evil.
Willard Applefeld is currently a first year medical student at the University of Maryland School of Medicine. He is interested in newly emerging and re-emerging infectious diseases, biodefense, security issues, and biotechnology in general. He has done both bench-top research in the life sciences as well as policy planning. He His views and opinions are his own and do not reflect, nor should be attributed to, those of the University of Maryland, his friends, family, previous employers, or any other organizations he currently is or previously was affiliated with.
It can be thought that radium could become very dangerous in criminal hands, and here the one question can be raised whether mankind benefits from knowing the secrets of Nature, whether it is ready to profit from it, or whether this knowledge will not be harmful for it. The example of the discoveries of Nobel is characteristic, as powerful explosives have enabled man to do wonderful work. They are also a terrible means of destruction in the hands of great criminals who lead the peoples towards war. I am one of those who believe with Nobel that mankind will derive more good than harm from new discoveries. –Pierre Curie Nobel Lecture on 6th June 1905.
Last month, the National Science Advisory Board for Biosecurity (NSABB) had the unenviable job of making a recommendation to the scientific community on matters of national security. Scientists, as a whole, tend to be purists — their professional development has instilled in them the belief that if something was worth doing, it is worth publishing. Therefore, most scientific information is widely disseminated and easily found, provided one has a way of getting passed the pay-walls set up by scientific journals. Advancement in one’s field, and prestige within the scientific community as a whole, is closely tied to the number and quality of one’s publications. The old adage of “publish or perish” spans not just scientific disciplines, but other fields as well. Indeed, the entirety of the academic system relies upon a hierarchy established by one’s publications. In almost all fields this is the case, save for one notable exception: National Security. In this arena, previous publications might get one a job, but it is the work that goes on “behind closed doors” that matters. This notion, for scientists, is somewhat difficult to reconcile with their normal experience.
But this is not a historically novel problem. Indeed, there is a large branch of research concerned with military applications of science. This is because prudent use of technology serves as an effective and powerful force multiplier. Nuclear Physics, which was previously only theoretical, was brought to bear against Imperial Japan during the Second World War and was instrumental in securing American victory in the conflict. The concept of Mutually Assured Destruction created a bipolar geopolitical system that was uniquely stable. This stability brought about an era of uncommon peace where great power conflict was confined to proxy-wars between superpowers. Even today, American military grand strategy fundamentally relies on using an asymmetric advantage in technology to secure victory in conflicts. The proliferation of drones in theater reveals the extent to which the Armed Forces rely on technology to achieve objectives, both strategic and tactical.
It is important to note that past syntheses of science and military matters have all been conducted under the watchful eye of Pentagon. This has previously been accomplished by doing all the science “in house” or by contracting it out to carefully monitored (and controlled) corporate partners. This model has been quite successful. Both DARPA and Skunk Works represent a triumph of applying novel aerospace solutions to meet strategic needs, despite the fact that one is public sector and the other is private. Academia composes the third piece of the defense-research trinity, with useful advancements and discoveries proceeding in university labs before they are channeled into the industrial pipeline for further development. In all aspects, this development pathway in tightly controlled.
Biology presents a unique situation. First, all research is purely defensive in nature. The United States’ offensive bioweapon program ceased in 1969, when it was disestablished by an executive order of Richard Nixon. Since that time, the United States government has devoted considerable resources to develop a biodefense program. This effort has historically been spearheaded by the US Army, CDC, and academic research labs, though in the post-9/11 years the number of parties working on biodefense has increased dramatically. A focus on the basics of benchtop biology has meant that research efforts have proceeded in a more decentralized fashion. As of 2007, there were upwards of 1,300 Biosafety Level 3 laboratories in the United States alone. These labs, both federal and academic, focus on research of newly emerging or re-emerging pathogens, many of which pose as significant threat to US national security. Elucidating the nuances of these pathogens, of which there are many, could be done in academic centers. The fact that many of these pathogens were microbial threats to both health and national security was not an issue of great concern, since these investigators were forbidden by both law and morality from weaponizing the organisms they worked with. But as science is prone to do, the circumstances and the research as changed.
Two laboratories, one at Erasmus University in Rotterdam and the other at the University of Wisconsin in Madison, have modified the H5N1 flu virus to make it much more virulent and, more worrisome, able to transmit between humans easily. The implications of this are numerous. Understanding flu virulence, transmission, and pathology will no doubt aid future investigators in the discovery of new vaccines and therapeutics. Yet unscrupulous individuals exist who would use such knowledge to construct a terrifying and effective biological weapon. It should be noted that the efforts of the Netherlands and Wisconsin teams were purely peaceful in nature – no one set out to make a bioweapon. And this is certainly not the first time research on emerging and hyper-virulent pathogens has been conducted; nearly every country maintains dedicated government labs to research such pathogens and numerous universities have an active role in creating biodefense solutions. But just like advancements in any technology, there are dual-use applications. Biowarfare is a tragic trend that permeates history –The Black Death spread in large part due to the use of plague-laden carcasses during the siege of Caffa, Amherst gave smallpox blankets to Chief Pontiac’s Ottawa Indians, Aum Shinrikyo tried extensively to develop and deploy bioweapons like Botulism toxin, and Al Qaeda has actively sought a biological weapon. Therefore, the scientific community is at a unique juncture with the national security community with regards to the dissemination of the information on this new flu strain. This will be the first time that research on how to make a natural pathogen more virulent will be made available in a public journal.
This is not to say that research like this hasn’t been done before. The USSR maintained a multi-billion ruble biowarfare-industrial complex which focused on enhancing the virulence of natural pathogens and also developing chimeric organisms more deadly than any found in nature. But this research, labeled with sinister titles like “Project Bonfire” and the “Hunter Program”, were ensconced in multiple labyrinthine layers of secrecy. After the collapse of the USSR, the United States sunk millions of dollars into programs that would prevent Soviet bioweapons scientists from using their knowledge and skills to develop and disseminate bioweapons to this century’s security threats.
Understandably, many view the publication of the Rotterdam and Madison research as a how-to manual for prospective bioterrorists. To some extent this is true, publication of the techniques as to how to increase the virulence of an already virulent pathogen could aid unscrupulous individuals. But this is a relatively simplistic view. As Laurie Garrett argued earlier this month, publications were faced with three options:
1) Advise all credible scientific publications to decline release of the papers, essentially censoring the work;
2) Allow full and free publication of both papers;
3) Advise publication, but with key passages related to how the feats were performed, deleted.
The NSABB essentially went with option 3 and in doing so attempted to walk a fine line between “censorship” and publication of potentially dangerous information. Although I eagerly await reading whatever is eventually published, I suspect that their efforts to contain harmful information while avoiding outright censorship will be futile at best. Even if the publishing journals do censor the “materials and methods” sections of the papers (where techniques used to do the experiments are described), the end result itself will appear in print. The “Results” and/or “Discussion” sections will no doubt describe the particular mechanism through which viral transmission and virulence were increased. This is to say, there will be a description of the new virus and how it differs from its less virulent progenitor strain. I personally suspect it is due to enhanced affinity of a viral protein for a cell surface binding receptor that is responsible for the human-to-human transmission and increased virulence (perhaps a different isoform of Hemagglutinin); though at this point it is just idle speculation. Still, once the features that account for increased viral virulence are described, the mystery of why this particular strain is more lethal will be removed. When that happens, the “materials and methods” section is largely irrelevant. Any budding virologist (pardon the pun) with sufficient laboratory experience and knowledge of molecular biology techniques would be able to construct a virus similar to the one described by the Rotterdam and Madison teams. Censoring only the “materials and methods” section will only slightly delay a prospective bioterrorist and certainly not discourage one in the slightest.
After all, every student of history and biology already knows that a flu virus has the potential to be much more virulent than the ones currently circulating the globe – just not the how of the matter. Although the teleology of the virus is known, the pathway of getting there is still unclear to most students. Simply put, most scientists know that a more virulent flu can exist and has existed in the past, just not what exactly makes it that virulent. Once the je ne sais quoi of the virus is known, it can be produced in a well-stocked molecular biology lab by an individual with sufficient expertise and animus.
Ms. Garrett is correct when she argues that
The NSABB decision will satisfy almost nobody. Advocates for scientific openness will bristle at any censorship, whether it involves a few sentences or an entire article. Conversely, those that fear bioterrorist use of such information will scoff at the notion that deleting a few paragraphs of methodology will in any way deter dedicated miscreants.
On one hand, open disclosure of the material would allow for a more open discussion within the scientific community. It would also avoid a situation where the government requested that a given publication censor data, only to have that journal refuse. This still is a very real possibility as Nature is a British publication which may not comply with the extent of censorship recommended by the NSABB. If this happens, it will become incredibly apparent how little authority the NSABB has to actually censor data. Yet a recommendation of full censorship would prevent a “nudge-nudge, wink-wink” type of publication which does nothing to substantively discourage bioterrorists.
The best course of action to balance scientific with national security concerns would be to make the data only available to reputable investigators. The NSABB should mandate that all future work on this new virus be done only in Biosafety Level 4 Laboratories. This would accomplish multiple objectives. First, it would alleviate many safety and security concerns about working with a virus that has a 60% mortality rate (for reference in the Kikwit outbreak of Ebola Zaire the case fatality rate was 77%). Second, it would allow the consolidation of research into closely monitored facilities and groups. The majority of BSL-4 suites are owned and operated by the United States government or the governments of other nations with strong diplomatic and scientific ties to the U.S. Investigators who work in BSL-4 suites must undergo rigorous background checks and obtain security clearance. Mandating that all future work on this virus be done in a BSL-4 would help the proper regulatory authorities closely monitor this research all the while not occluding the process of scientific discovery.
Lastly, confining this research to a BSL-4 suite would actively fast-track influenza virus research as an area of biodefense. This would be advantageous for public health as well as national security infrastructure. All things being equal, a bioterrorist would more likely select a pathogen other than the flu. This is because bioterrorists are terrorists with a bit of a biology background. Terrorists want to inflict terror as efficiently as possible and, because of this, will choose agents that exist in the collective nightmares of society. While the flu is incredibly destructive and has the potential to shake society’s foundations to its core; it is not pathogen that everyone fears the most, and thus may not best suit the organization’s strategy. Anthrax, Plague, Ebola, and Smallpox are diseases that would cause abject terror – and be more readily associated with terrorism – if even a single case was identified in the United States. Yet millions of people get the flu every year. A bioterrorist would select an organism that people know and, more importantly, fear – an organism where even the rumor of a single case, no matter how well contained, would frighten every member of society. This is because such diseases bear the signature of a terrorist. Of course, if a bioterrorist could easily develop a flu virus which had mammalian transmission and a 60% mortality rate, it would obviously be utilized. But if all diseases were equally difficult to acquire and produce, the flu would not be at the top of the list for a bioterrorist. But nature doesn’t work that way. Nature bears a special place in her cold, capricious, and uncaring heart for the flu virus. It is an old adage in the virology community that a massive flu outbreak hits every 20 years or so. We are currently 80 years overdue. The absence of “the big one” is due to a combination of clever public health measures but also a great deal of dumb luck on our part. If research on hyper-virulent flu were included as part of biodefense research portfolio, we all will be much better prepared for when the inevitable naturally occurring hyper-virulent flu does hit.
The decisions and actions taken by regulatory and advisory agencies now will shape the future of research on not just biodefense, but also on the more broad class of hyper-virulent pathogens. It is important to note that neither safety nor an act by a bioterrorist is a fait accompli. It is crucial that we strike the right balance between safety and discovery, censorship and openness now while we still have the luxury of doing so.