Is Annual Influenza a Bigger Killer Than We Think?

In a short paper in the Journal of the Royal Society of Medicine in July, 2003, Madjid et al., note that influenza immunization significantly reduces the risk of recurrent myocardial infarction, sudden cardiac death, and stroke.  They suggest that rather than the oft quoted figure of 20,000 deaths per year in the U.S., influenza should probably be credited with more like 90,000 deaths per year.

Madjid et al., go on to question whether influenza should be considered a bioweapon risk, particularly in light of the project (now completed) to sequence the 1918 flu strain.  As I wrote last week, I think publishing the 1918 sequence is critical to scientific progress and that the risks are overstated.  Still, the notion that flu accounts for many more annual deaths than is typically acknowledged is interesting.

More on Henry Niman's claims about the H5N1 Avian Flu

Here is an article in the 30 October Pittsburgh Tribune-Review by Jennifer Bails profiling Henry Niman and his ideas; "Fox Chapel researcher says bird flu coming faster than expected."  I'm quoted towards the end of the article, once again pointing out the lack of peer-reviewed anything from Niman.  I find it increasingly odd that Niman claims the H5N1 strain currently circulating carries portions of genes imported from mammalian flu strains, particularly since recent sequence analysis indicates the virus is entirely avian in origin.

Specifically, the WHO Global Influenza Program published a paper in the journal Emerging Infectious Disease in October, "Evolution of H5N1 Avian Influenza Viruses in Asia", which states quite explicitly that:

Genomic analyses of H5N1 isolates from birds and humans showed 2 distinct clades with a nonoverlapping geographic distribution. All the viral genes were of avian influenza origin, which indicates absence of reassortment with human influenza viruses.

So, Dr. Niman, what gives?

By the way, even after no less a figure than Sydney Brenner explained cladistics to me, I still don't understand.  Anyone care to enlighten me in, say, 30 words or less?

I'll have another post on the evolution of flu viruses by tomorrow.

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:

Rob,
       
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.

-Brad

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).

Beamed Power

Wired News has a story today mentioning a fresh examination of beamed power.  Most of the piece is about a $500 billion project to generate power on the moon and then beam it back to Earth (oy), though it does mention the space elevator eventually.  NASA is partnering in set of Centennial Challenges aimed to promote development of technologies such as beamed power, strong tethers, and climber robots.

The Rise of Chinese Biotech

On the theme of increased participation of developing countries in biological technology, Rik Wehbring pointed me to a Reuters story, "Low Cost Spearheads China Drive Into Biotech".  As I have written previously here, in addition to investment by Western companies China is putting considerable effort into developing both domestic R&D and domestic clinical expertise.

The Reuters story notes that

China already boasts more than 20 biotech parks dotted around the country and 500 biotech enterprises.  Some 300 of these companies are focused on medicine, with the balance mainly targeting agriculture.  The Chinese government and local governments have both been active in supporting the sector, with total state funding last year reaching the equivalent of 270 million euros ($325 million).

Because "the cost of biomedical research in China is only about 20 percent of the cost in Western countries", that $325 million goes quite a long ways.

We can expect drug development and biomedical research to take off in India as well.  A friend of mine with investments in the U.S., Europe, and in India cites cost figures for India identical to those for China.

So I ask you, without considerably greater investment in education and domestic R&D, how are either the U.S. or Europe going to compete?  What is it going to take for policy (politicians) to catch up to reality?

Progress on Cell-Based Therapies

Spinal cord injury and HIV are the targets of two innovative cell-based therapies, with the planned HIV treatment relying on gene-therapy to produce in vivo RNA interference (RNAi).  In a very short news piece in Nature (subscription required), "Pioneering HIV treatment would use interference and gene therapy", Erika Check writes that;

If the FDA says yes, [John Rossi and his team at  at City of Hope's Beckman Research Institute] will test the therapy on five HIV patients who have a blood cancer called lymphoma. They will treat the patients' lymphoma with aggressive chemotherapy and a bone-marrow transplant — a normal procedure. But before the transplant, they will use gene therapy to add stretches of DNA to stem cells in the bone marrow. It is hoped that molecules encoded by the added genes will trigger the cells' RNAi defences against HIV.

The trial is different from the RNAi trials already under way, because the molecules used in those studies remain in the body for only a short time. The City of Hope researchers will deliver DNA packaged into a gene-therapy vector that could persist in patients for months or even years.

The Recombinant DNA Advisory Committee is having Rossi perform additional safety tests before giving the OK for the trial.  If this works out, it will demonstrate a remarkably powerful way to alter human physiology through the permanent (?) addition of a new RNAi pathway.  The strategy pursued by Rossi, et al., would provide a pool of stem cells that produce lymphocytes immune to HIV.  Since HIV shows some tropism for neural and other tissues, the treatment may not completely rid patients of the virus, but as lymphocytes carrying HIV die out at least the patient would have a source of healthy immune cells.  As this research goes forward, we can expect significant press coverage because the technique will probably find immediate use in treating many other chronic diseases.

The work on repairing spinal cord injury through cord blood cell transplantation has received surprisingly little press.  In an article in Cytotherapy, K-S Kang et al., demonstrate that multipotent stem cells (MSC) derived from umbilical cord blood colonized the site of a spinal cord injury in a 37-year old women who had been a paraplegic for almost 20 years.  The MSCs were amplified in vitro and then surgically transplanted to the site of the injury.

Prior to treatment, the patient showed no somatosensory or motor activity in her lower body, and nerve conduction studies confirmed the extent of the damage.  After transplantation, the patient regained significant sensation within 2 weeks and could maintain an upright posture.  She was able to move her lower legs shortly thereafter.  Nerve conduction studies were used to confirm the extent of recovered electrical activity.  CT and MRI demonstrated regeneration of the spinal cord.

My neurophysiology is more than a tad rusty, which means the import of some specific things reported in the paper isn't immediately clear to me, but the overall results are enough to make anyone take notice; a previously paralyzed patient is now able to at least feel stimulation in her lower limbs, maintain an upright posture unassisted, and has regained some motion in her lower legs.

The specific mechanisms behind the recovery must now be determined, including how the MSCs produce such dramatic improvement.  The authors also note that they cannot rule out the surgery as effecting some recovery.  But the demonstrated increase in electrical activity and motion is extraordinary.  And you have to imagine that the ability to maintain an upright position unassisted for the first time in 20 years is by itself an enormous gift.

This is just one patient, and just one paper, so lots of work is required before anything like this becomes standard treatment.  It is also unclear what the long term effects of the procedure and the new cells will be.  Then there is the little problem that in the U.S. working with stem cells is a tad problematic, regardless of their source.  This study notably, took place in Korea.

Nonetheless, what fantastic news.

Big Day for Bird Flu News

Today brings news that a live, infectious strain of the 1918 flu has been reconstructed in the lab.  The press has responded smartly this time (New York Times, AP via Wired News, CNN, The New Scientist) -- with fairly decent reporting -- no doubt in part because President Bush addressed the situation in a press conference, suggesting that the U.S. military might be involved in managing a pandemic.  There is quite the political hullabaloo in Washington DC, too boot, with the New York Times reporting that in response to closed door briefing last week a Pentagon appropriations bill has been boosted by USD 3.9 Billion solely for dealing with the flu (it's unclear from the story whether that money is intended for use by the Pentagon or by the NIH).  Politicians, and political parties, are evidently trying to outdo one another in being out front on this issue, despite the fact that we are hopelessly behind.  No surprise there.

As far as the biology goes, for those who have been paying attention, or even just reading this blog, there isn't that much new in today's reports.  As related by the Times, papers in Science and Nature basically confirm at least part of the molecular detective story told by Oxford et al., namely that the 1918 flu jumped directly from birds to humans.  Thus, "The Swine Flu" is a misnomer for the disease caused by this particular bug.  There is no further progress on figuring out when and where the bug evolved, as far as I can tell.

The Nature paper, from Jeffrey Taubenberger's group, describes his work in extracting flu sequences from preserved lung tissue and from a corpse frozen in permafrost.  This paper is a bioinformatic comparison (i.e. no experiments) that characterizes the 1918 flu polymerase genes.  The Science article describes infecting mice with a reconstructed virus, which turned out to be considerably more lethal than expected.  The article will be out on 7 October.  I will write more when I've had a chance to carefully ready both papers.

The publication of the viral sequence, with accompanying descriptions of how to reconstruct live virus, obviously raise questions about safety.  Every story above mentions that the investigators and journal editors balanced the benefits and threats, and asked for a review from the National Science Advisory Board for Biosecurity (NSABB), before going to press.  Fortunately, everyone came to a conclusion in favor of publishing.  Press reports, including one in Nature, give voice to critics of publishing the sequence and construction methods.  In particular, there are complaints that the 1918 strain could be reconstituted for use as a weapon or that it could simply escape back into the wild.  I am obviously not the only one not much convinced by these arguments.  While very few people alive today have been exposed to the 1918 strain, related strains are often included in annual flu vaccines.  So humans is no longer immune naive for that set of bugs.  As for the use of 1918 as a weapon, the reverse genetics required to produce a live RNA virus from DNA plasmids are decidedly non trivial at the time being.  No doubt, this process will get simpler, but this isn't something you are going to do in your garage.

 

Tamiflu Resistant H5N1?

CNN is reporting that Tamiflu-resistant strains of H5N1 are appearing in Asia, and that "resistance to anti-flu drugs [is] growing worldwide."  It is a typical CNN story, and therefore leaves one wanting more facts, but at least it's enough to start a Google adventure.

In another story, CNN is repeating the forecast by Dr. David Nabarro of up to 150 million deaths from H5N1.