"The Making of the Atomic Bomb", andrew shulman, dual-use controversy, Fouchier, H5N1 flu research, influenza publication debate, Kawaoka flu research, left on longwood, Manhattan Project, responsible use of scientific research, Richard Rhodes, Roy Glauber
The debate regarding the publication of research describing the transmission of strains of the H5N1 avian influenza virus in laboratory ferrets is the latest episode in the controversy regarding “dual-use” science. How should governments, agencies and society approach scientific research that has the potential for public good but could be harmful if used inappropriately?
It is hardly a new question. The history of 20th century science is dominated by how discoveries in nuclear physics led the way to transformative technologies, groundbreaking advancements in understanding the universe and the development of devastating weapons on a scale not previously imagined. Fukushima and the lingering fear of nuclear terrorism by rouge states or border-less terror networks remind us that harm can potentially result from the legitimate or illegitimate use of nuclear technology.
In the months after 9/11, my med school buddy was boarding a domestic flight. D. is a brilliant physician-scientist, at the time he was deeply immersed in his PhD research in the field of apoptosis (the process of “programmed cell death”). He looked the part of a graduate student (and still does): goatee, specs, fleece, jeans, trail-worthy footwear, bike messenger bag. I should also mention that he is a Southeast Asian American, a self-described “brown guy.” D. was already very much accustomed to extra attention at the airport, long before the advent of TSA and that machine that we stand in with our hands held above our heads. He pretty much expected to be pulled out of the security line for a manual bag check and wand pat-down.
As he approached the metal detector, D. had a moment of panic. Tucked away in his carry-on was “The Making of the Atomic Bomb,” Richard Rhodes’ definitive history of the Manhattan Project. As proof that it is an amazing book, Professor Roy Glauber, who worked on the Manhattan project as an 18-year old and went on to share the 2005 Nobel Prize in Physics, used it and its sequel on the hydrogen bomb project as the only texts for his freshman seminar that I was fortunate to take (his great autobiographical piece is here). Being enthralled by a tale of scientific discovery and engaged with the relationship of science and society, D. couldn’t wait to get to his in-flight reading. Now he realized that with the glossy insert photographs and diagrams, the “Making of…” could potentially be misinterpreted as “How to make an atomic bomb.”
Moments later, the contents of his carry-on dumped out on the table, D is trying to explain the difference between historical study and assembly manual to the wide-eyed security agent flipping through the pages. A supervisor was summoned. He ended up being allowed to board just in time. I’m trying to remember from D.’s most recent dramatic telling (he tells it well) whether or not the suspicious book was confiscated.
“Dual-use” and Biomedical Science
Long before the debate over stem cell research, molecular biology ran into its own crucial “dual-use” decision point. With the deciphering of the genetic code and the development of the techniques needed to work with DNA, biology was perched on the edge of revolutionary change in the mid ‘70s. With the fall of Saigon approaching and in the aftermath of Watergate, the national moment was one of unprecedented distrust of government and authority. A group of far-sighted pioneers of molecular biology, Paul Berg in the lead, voluntarily pledged to halt their laboratory manipulation of DNA in 1974 and planned an international conference to discuss the potential dangers of their work. The conference was held at the Asilomar Conference Center on the Monterrey Peninsula in February of 1975. The assembled effectively laid out the safety considerations for biomedical research that are still used as guidelines today: 1) containment of engineered biologics should be part of experimental design 2) barriers for containment should reflect the degree of potential risk 3) DNA of microbes highly pathogenic to humans would not be manipulated because the available safety measures of the day could not off-set the risk. The scientists lifted their self-imposed ban and biology moved forward.
Without this clever, preemptive action, would the development of recombinant DNA technology have been hampered by ill-informed, reactionary legislators? A few months later, the Cambridge City Council banned recombinant DNA research in July 1975 when Harvard announced plans to build a high-security laboratory. Fears of a mass-exodus of Harvard biologists did not materialize (David Baltimore raises the alarm to the Harvard Crimson circa December, 1975 here). Needless to say, the ban was lifted and Cambridge became one of the international centers of the biotechnology industry.
Flu, Ferrets and Fear
In late March, Dr. Paul Keim of the National Science Advisory Board for Biosecurity announced that the panel had reversed its prior decision and would allow two manuscripts describing laboratory transmission of H5N1 avian influenza virus to be published in Science and Nature. For several months prior, editors at Nature and Science, Drs. Ron Fouchier and Yoshihiro Kawaoka, the lead investigators of the two research groups, members of the advisory board and bioethicists-at-large debated the decision to redact publication in hearings, interviews and editorials. Opinions ranged from calls to permanently shut down the research programs to demands for full, immediate publication.
H5N1 is a flu strain that appeared naturally in bird populations, is transmissible via respiratory droplets and appears to be highly pathogenic in birds. Although it has led to the death and culling of hundreds of millions of birds, it was first found to cause a lethal human infection in Hong Kong in 1997. Since 2003, 578 confirmed human infections have resulted in 340 deaths. Many questions must be answered to understand the virus and prevent a potential public health threat: why is the virus not easily transmitted from birds to humans? Is the virus highly communicable between infected humans? What makes the viral infection so severe?
Dr. Fouchier and Kawaoka, working independently, attempted to move towards answers using ferrets, the lab rodents most similar to humans in terms of susceptibility to influenza infection. The researchers took the hemagglutinin protein (shorthanded as “H5”) from the avian virus and genetically combined it with remaining genes from other flu strains. In Kawaoka’s experiment, avian flu H5 was combined with the H1N1 strain that caused pandemic human infection rates in 2009 but had low lethality. The result is a virus can be transmitted via air droplets between ferrets. Importantly, the virus is not more lethal that H1N1 and responded to vaccines and treatment with drugs. Dr. Fouchier’s group mutated the H5 protein in the context of the avian H5N1 background. This virus could also be transmitted but did kill infected ferrets.
These experiments clearly have moved the influenza field forward in determining the genetic basis of transmission and lethality in infected mammals. The work has immediate implications in aiding surveillance of flu strains in birds and humans. It could provide seminal in developing vaccination and treatment strategies to block flu transmission or lessen the severity of infection. The experiments also raised fears that a laboratory strain of the virus could be released and cause and epidemic. More sinister, some worried that would-be bioterrorists could pick up Science or Nature and learn how to engineer a global pandemic.
The decision to publish the findings after careful review represents a victory for responsible use of biomedical science and for the public health. It also highlights continuing challenges for the scientific community: clearly communicating the importance of research in serving the public good and inspiring confidence that scientists can play the primary role in responsible self-governance. Remarkably, this was exactly what brought the luminaries of molecular biology to Asilomar more than 35 years ago.
In the case of the influenza controversy, the real and present danger is a flu pandemic resulting from genetic exchange between avian and human strains brought about through overcrowding, alteration of natural ecosystems, improper animal handling techniques and inadequate public health safeguards. Through the lens of fear, a seminal study can look like a field guide for terrorists. One of the key roles of science in our society must be to expose fear to knowledge.