On the Threat of the 1918 Flu

What do you do when a vanquished but still quite deadly foe reappears?  To further complicate the situation, what if the only way to combat not just that particular foe, but also fearsome cousins who show up every once in a while, is to invite them into your house so as to get to know them better?  Chat.  Suss out their strengths and weaknesses.  Sort out the best way to survive an inevitable onslaught.  This is our situation with the 1918 Influenza virus and and its contemporary Avian relatives

Over the last couple of weeks, several academic papers have been published containing the genomic sequence of the 1918 "Spanish" Flu.  These reports also contained some description of the mechanism behind that flu's remarkable pathogenicity.  (Here is the 1918 Influenza Pandemic focus site at Nature, and here is the Tumpey, et al., paper in Science.)  In response, several high visibility editorials and Op-Ed pieces have questioned the wisdom of releasing the sequence into the public domain.

Notably, Charles Krauthammer's 14 October column in The Washington Post, entitled "A Flu Hope, Or Horror?", suggests:

Biological knowledge is far easier to acquire for Osama bin Laden and friends than nuclear knowledge. And if you can't make this stuff yourself, you can simply order up DNA sequences from commercial laboratories around the world that will make it and ship it to you on demand. Taubenberger himself admits that "the technology is available."

I certainly won't debate the point that biological skills and knowledge are highly distributed (PDF), nor that access to DNA fabrication is widely distributed.  However, while I am sure that Dr. Taubenberger is familiar with the ubiquity of DNA synthesis, I seriously doubt he suggested to anyone that it is easy to take synthetic DNA and from it create live, infectious negative strand RNA viruses such as influenza.  I've written to him, and others, for clarification, just to make sure I've got that part of the story correct.

Krauthammer also asserts that, "Anybody, bad guys included, can now create it," and that, "We might have just given it to our enemies."  These statements border on being inflammatory.  They are certainly inaccurate.  The technology to manipulate flu viruses in the lab has been around for quite a few years, but not many research groups have managed to pull it off, which suggests there is considerable technical expertise required.  (I will clarify this point in my blog as I hear back from those involved in the work.)

The other commentary of note appeared in the 17 October New York Times, "Recipe for Destruction", an Op-Ed written by Ray Kurzweil and Bill Joy.  They call publication of the sequence "extremely foolish":

The genome is essentially the design of a weapon of mass destruction. No responsible scientist would advocate publishing precise designs for an atomic bomb, and in two ways revealing the sequence for the flu virus is even more dangerous.

First, it would be easier to create and release this highly destructive virus from the genetic data than it would be to build and detonate an atomic bomb given only its design, as you don't need rare raw materials like plutonium or enriched uranium. Synthesizing the virus from scratch would be difficult, but far from impossible. An easier approach would be to modify a conventional flu virus with the eight unique and now published genes of the 1918 killer virus.

Second, release of the virus would be far worse than an atomic bomb. Analyses have shown that the detonation of an atomic bomb in an American city could kill as many as one million people. Release of a highly communicable and deadly biological virus could kill tens of millions, with some estimates in the hundreds of millions.

These passages are rife with technical misunderstanding and overheated rhetoric.  My response to Joy and Kurzweil arrived late at the Times, but on the same day a number of other letters made points similar to mine.  For the record, here is my letter:

The Op-Ed by Ray Kurzweil and Bill Joy, celebrated inventors and commentators, is misleading and alarmist.
    The authors overstate the ease of producing a live RNA virus, such as influenza, based on genomic information.  Moreover, their assertion that publishing the viral genome is potentially more dangerous than publishing instructions to build nuclear weapons is simply melodramatic.
    The technology to manipulate and synthesize influenza has been in the public domain for many years.  Yet despite copious U.S. government funds available for such work, only a few highly skilled research groups have demonstrated the capability.  Restricting access to information will only impede progress towards understanding and combating the flu.  Obscuring information to achieve security makes even less sense in biology than in software development or telecommunications, fields Kurzweil and Joy are more familiar with.
    Dealing with emerging biological threats will require better communication and technical ability than we now possess.  Open discussion and research are crucial tools to create a safer world.

Dr. Rob Carlson, Senior Scientist, Department of Electrical Engineering, University of Washington, and Senior Associate, Bio-Economic Research Associates

I was, of course, tempted to go on, but alas the Times limits letters to 150 words.  ("Alas" or "fortunately", depending on your perspective.  Of course, I've no such restriction here.)  Kurzweil and Joy commit the same error as Krauthammer of confounding access to DNA synthesis with producing live RNA virus in the lab.  Fundamentally, however, both the opinion pieces are confused about the threat from a modern release of the 1918 Flu virus.  In a Special Report, Nature described the work by Terrence Tumpey at the CDC to recreate and test the virus:

[Terrence Tumpey] adds that even if the virus did escape, it wouldn't have the same consequences as the 1918 pandemic. Most people now have some immunity to the 1918 virus because subsequent human flu viruses are in part derived from it. And, in mice, regular flu vaccines and drugs are at least partly effective against an infection with reconstructed viruses that contain some of the genes from 1918 flu.

Thus, without minimizing any illness that would inevitably result from release of the original flu virus, the suggestion that any such event would be as deadly as the first go round is inaccurate.  To further clarify the threat, I asked Brad Smith, at the Center for Biosecurity and the University of Pittsburgh Medical Center for some assistance.  He returned, via email, with a story less comforting than that in Nature:

After speaking with my colleagues DA Henderson and Eric Toner, here are my thoughts on this:
The 1918 flu was an H1N1 strain.  The most prevalent seasonal flu strain for the last several decades has been based on H3N2.  Note that there are many flavors of any given H and N type, the hemaglutinin and neauraminidase are constantly mutating and each has a series of antigenic sites.  For example, while the recent predominant seasonal flu has been H3N2, each season it is a slightly different H3N2.  We do retain some residual immunity from last year's H3N2, so we do get sick, but only the weakest that are infected die.  This is the difference between common antigenic drift, and the less common antigenic shift to an entirely new H and N that results in a new pandemic flu strain. (You already know this, but I'm just trying to lay it all out.)
H1N1 variants had been major annual strains until the 1957 H2N2 pandemic strain emerged, and has continued as a minor annual strain.  (The H3N2 strain emerged as the 1968 pandemic strain.)  It is accurate that a version of H1N1 is a component of the annual trivalent flu vaccine that we use today and some of the internal proteins of H3N2 strains are derived from H1N1 through reassortment.
However, most people in the US born after 1957 have never been exposed to H1N1 in the "wild" and most people do not get flu shots either (in the US or worldwide) - so they would not have been exposed to the H1N1 variant in the vaccine.
So, I am not completely sanguine that a reintroduction of the 1918 flu virus into today's relatively naive population would be tempered by some degree of residual immunity.  If there is residual immunity, or some effectiveness of today's vaccine and anti-virals, what would that translate into with respect to a decrease in the numbers of people sick and dying?  1918 flu caused 500,000 deaths in the US and perhaps 50 million deaths worldwide over an amazingly short 18 months.  So, even if only a few percent (relative to what happened in 1918) of the people who are infected by an escaped 1918 flu virus died, the toll would be in the millions.
This does not mean that the cost/benefit of studying 1918 flu means it shouldn't be studied, but it certainly isn't as de-fanged as one might hope.


Truth be told, the diversity of opinions amongst people well educated on the details means we can't really estimate what would happen if the original virus were released.  So what do we do about the this and other threats?  One answer is to spin up a well-funded effort to improve our technical capabilities.

Echoing Senate Majority Leader Bill Frist, Joy and Kurzweil go on call in their Op-Ed for "a new Manhattan Project to develop specific defenses against new biological viral threats, natural or human made."  This is fine and all, but the Manhattan Project is decidedly the wrong model for an effort to increase biological security.  Far better as a metaphor is the Apollo Program; massive and effective but relatively open to public scrutiny.  Quoting briefly from my 2003 paper on how to improve security amidst the proliferation of biological technologies:

Previous governmental efforts to rapidly develop technology, such as the Manhattan and Apollo Projects, were predominantly closed, arguably with good reason at the time. But we live in a different era and should consider an open effort that takes advantage of preexisting research and development networks. This strategy may result in more robust, sustainable, distributed security and economic benefits.  Note also that though both were closed and centrally coordinated, the Manhattan and Apollo Projects were very different in structure. The Apollo Project took place in the public eye, with failures plainly writ in smoke and debris in the sky. The Manhattan Project, on the other hand, took place behind barbed wire and was so secret that very few people within the US government and military knew of its existence. This is not the ideal model for research that is explicitly aimed at understanding how to modify biological systems. Above all else, let us insist that this work happens in the light, subject to the scrutiny of all who choose to examine it.

Which, I think, is quite enough said on this issue (for now).