Confusion over genetic origin of Mexican "Swine Flu" and assorted press nonesense.

There appears to be uncertainty over just which genes are in the H1N1 genome now causing illness.

(Update: Must read for anyone interested in the present situation: the CIDRAP Swine Influenza Overview.)

As of the evening of Tuesday, 28 April, CNN is reporting that:

The new virus has genes from North American swine influenza, avian influenza, human influenza and a form of swine influenza normally found in Asia and Europe, said Nancy Cox, chief of the CDC's Influenza Division.

However, today's ProMED mail contained a the following exchange.

From Professor Roger Morris, at Massey University, New Zealand, a whole bunch of really good questions:

For those of us who are involved in international work on influenza epidemiology and control and responding to the many media enquiries, there is a very large information gap in relation to diagnosis and epidemiology of the Mexican influenza. What is known of the genetic structure of this virus? It has been called a swine flu, but no evidence has been put forward to allow this statement to be evaluated. I have received information that it is a reassortant, which has genetic components from 4 different sources, but nothing official has been released on this. Where does it fit phylogenetically? Is there any genetic variation of significance among the isolates investigated? Would this help to explain the difference in severity of disease between Mexico and other countries?

It is also stated that it should be diagnosed by RT-PCR, without clarifying which PCR. I have received information that the standard PCR for H1 does not reliably detect this virus. Is this true? What is an appropriate series of diagnostic steps for samples from suspect cases? Could we have an authoritative statement on these issues from one of the laboratories, which has been working with the virus?

In response, here is Professor Paul Rabadan, of Columbia University College of Physicians and Surgeons, who is digging into the flu genome sequences filed at NCBI and finds that the sequence appears to be solely of swine (swinian?) origin:

In relation to the questions posed by Prof. Morris: My group and I are analyzing the recent sequences from the isolates in Texas and California of swine H1N1 deposited in National Center for Biotechnology Information (NCBI) (A/California/ 04/2009(H1N1), A/California/05/2009(H1N1), A/California/ 06/2009(H1N1), A/California/07/2009(H1N1), A/California/09/2009(H1N1), A/Texas/04/2009(H1N1) and A/Texas/05/2009(H1N1).

The preliminary analysis using all the sequences in public databases (NCBI) suggests that all segments are of swine origin. NA and MP seem related to Asian/European swine and the rest to North American swine (H1N2 and H3N2 swine viruses isolated since 1998). There is also interesting substratification between these groups, suggesting a multiple reassortment.

We are puzzled about sources of information that affirm that the virus is a reassortment of avian, human and swine viruses. It is true that the H3N2 swine virus from 1998 and 1999 is a triple reassortant, but all the related isolates are found since then in swine.

In lay English: the virus is composed of pieces of other viruses found in pigs.  While the structure of the genome is curious, in that it appears the different viruses exchanged chromosomes multiple times, there isn't any sign that the present genome of concern contains elements of avian or human flu viruses.

(Update: I just stumbled over a 21 April CDC briefing that describes the genomes of H1N1 viruses in pediatric cases in California as entirely of swine origin.)

So it isn't at all clear why the press (and government officials) keep repeating the assertion that the new virus is some sort of amazing Frankenstein strain.  The message containing Professor Rabadan's comments also notes that a mess of new sequences from clinical isolates were filed today in the GISAID database.  Analysis of those sequences should help clarify the origin -- or at least the composition of the genome -- of the virus in the coming days.

The press also continues to bray about flies as the vector, when there is no evidence I can find in any literature, anywhere, that suggests flies have ever been associated with transmitting the flu.  If this particular bug did figure out how to hitch a ride of flies, that would be some seriously scary evolutionary juju.  Intelligent design, even.  We would all be in deep trouble.  But, as there is no evidence to support these assertions other than repeating what other reporters are saying, my recommendation to all you in the press would be simply this: STOP.

Similarly, the notion that at this early date anyone could possibly have identified the index case ("Patient 0") as a young boy in some village in Mexico is -- let me choose my words very carefully here -- COMPLETE PIGSHIT.  With so little molecular forensics done on the virus, and no real map of who is actually sick, who has been sick, nor when or where they were sick, publishing the name of an innocent four-year old boy based on cribbing from some other reporter's story is the height of irresponsible journalism.  Where the fuck are the editors?

(Update: The New York Times is still repeating this nonesense: "...The Mexican government has identified a young boy as the first person in the country infected with swine flu...".  Waaay down in the story it acknowledges that the village the boy is from "may not, in the end, be found to be the source of anything" and then goes on to describe earlier potential cases. Oy.)

Perhaps reporters should try a little, oh, I don't know, reporting.  Visit ProMED mail.  Check out CIDRAP and Effect Measure.  Stop reading what other reporters write, and think for yourseves.  We will all be better off.

H1N1 Influenza coverage

Well, it looks like we got surprised.  Just like we, um, expected.  To be surprised, that is.

It's been quite a while since I wrote anything about the flu, but I suppose I should start keeping track of interesting new developments.

We should consider the clock started on vaccine development.  Various reports suggest that Baxter is already at work at the request of the Mexican government.  News outlets are being very careless, throwing around phrases like "vaccines are at least six months away", when it would surprise me if anything became available in less than nine months.  I expect it to be more like 12-18 months, but I really, truly, hope I am wrong about this.  All of a sudden we are doing a real-world test of our preparedness.

There is excellent coverage, as usual, over at EffectMeasure.  Other reporting is sort of spotty.  I keep seeing stories (Wired, CNN, even the NYT) reporting that the CDC says vomiting and diarrhea are symptoms of the flu, when what the CDC says is that "some people report" those symptoms for the flu.  Usually GI tract symptoms like that are due to noroviruses (think cruise ships), not influenza viruses.  But I suppose we could be seeing something new.

I just heard a report from the BBC suggesting that Mexico thinks as many as 2000 people have been infected, with Mexico's health minister putting the death toll at 149.  That would put the fatality rate at 7.5%, which would be extremely high for the flu.  It is too early to say whether those numbers are realistic or not, especially since Mexico will have difficulty making positive molecular diagnoses.  I would expect a retrospective analysis of this outbreak to determine that many, many more people have been exposed and infected than presently reported.  It is certainly confusing why all the deaths have thus far been confined to Mexico.

It seems that cases are already spread across the world.  Here is a Google Maps version of suspected and confirmed cases, which looks to be maintained by Henry Niman.  Good show Dr. Niman, even though I haven't always seen eye to eye with you on your ideas about the flu and SARS.  Niman seems to be maintaining a bunch of other such maps, which are worth checking out, including H5N1 in Egypt and ... "SARS 2009" -- WTF!!!

*shudder*

Back to H1N1: According to this ProMED summary, Israel is taking the most important step it can in preparing:

Israel renames unkosher swine flu.
Israel's health minister updates a nervous public about the swine flu 
epidemic - and starts by renaming it Mexican flu.

Perhaps my slight turn to appreciating black humor here is that I just don't see that things have improved very much since 2005.  In mid-February of this year, I sat around a table in DC with a bunch of people who had been called together to discuss biopreparedness, whether for natural or artificial threats.  The person convening the meeting suggested that basically everyone who deeply cared about the issue in DC was in the room, and it was a disturbingly small group.

Also disturbing was what those people reported about their experiences in trying to prepare the US for the inevitable appearance of biothreats.  The news wasn't encouraging.  Another anecdote for context -- in 2005 I had a conversation with the head of Asian operations for one of the two remaining international express shipping companies.  At that time, his company hadn't given much thought to the flu -- this was before all the hullaballoo -- and he suggested should H5N1 become a problem that the company would simply stop flying.  An executive from a major disposable syringe manufacturer then suggested there would be no way to keep up with demand if that shipping stopped.  I went on to write here, and elsewhere, about what might happen to not just our economy, but also our R&D efforts, if plastic labware and rubber gloves made in Asia were stuck there.  I can report that, as of February this year, there are at least a few stockpiles of critical supplies here in the States, but that the academics, state, and federal officials around that table in DC were far less than sanguine about our state of preparedness.  One professor, who was running an ongoing assessment of his state's preparedness, suggested that they were still having trouble getting the basic data they needed on the available stock of consumables in hospitals.

I have been concentrating on other topics for the last eighteen months or so, and so I raised my hand to express my incredulous dismay that things haven't improved in 4 years.  That generated an interesting response.  About half the room assured me it was okay, and the other half assured me my dismay was entirely warranted.  Great.

Thus my slightly foul mood as a new potential threat is rapidly finding its way around the globe.  That and the fact that I am about to climb into an airplane bound for the UK -- eight hours in a closed environment with hundreds of international travelers at the beginning of a potential epidemic.  Oh, joy.

Where's my Tamiflu?

Tamiflu-resistant Influenza Strains

(Update, 30 April 2009: I see from the server logs that this post is getting a lot of traffic today.  Please note that the contents of the post discuss the annual influenza strains in the US, not the "H1N1 Influenza A" strain, which at this time is susceptible to Tamiflu.)

The IHT is carrying a great article by Donald Mcneil on the sudden emergence of antiviral resistance in this year's circulating influenza viruses.  The title says it all: "Flu in U.S. found resistant to main antiviral drug".

Virtually all the flu in the United States this season is resistant to the leading antiviral drug Tamiflu...  The problem is not yet a public health crisis because this has been a below-average flu season so far and the chief strain circulating is still susceptible to other drugs.

There are two important points in this story.  First, the resistance seems to derive from a spontaneous mutation rather than having emerged from overuse of the drug:

"It's quite shocking," said Dr. Kent Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York. "We've never lost an antimicrobial this fast. It blew me away."

The mutation appears to have arisen in Norway, a country that the article suggests does not even use Tamiflu. Second, while the CDC is recommending that hospitals test all flu cases to find out whether patients are carrying a the resistant subtype, this capability is still not widespread:

"We're a fancy hospital, and we can't even do the ... test in a timely fashion," Sepkowitz said. "I have no idea what a doctor in an unfancy office without that lab backup can do."

I haven't written very much about the flu for a couple of years, but it is clear that the threat is still quite present.

The article ends with this bit of speculation:

And while seasonal flu is relatively mild, the Tamiflu resistance could transfer onto the H5N1 bird flu circulating in Asia and Egypt, which has killed millions of birds and about 250 people since 2003. Although H5N1 has not turned into a pandemic strain, as many experts recently feared it would, it still could -- and Tamiflu resistance in that case would be a disaster.

I'm not so sure that the resistance gene "could easily transfer onto the H5N1 bird flu".  It sounds like Mr. Mcneil may be giving more weight here to Henry Niman (who is quoted extensively in the article on other specific topics) than the rest of the community might.  This is not to say that such a transfer is unlikely -- this is the sort of thing that I fear we know so little about that we could make poor assumptions leading to even worse policy.  The mechanisms for recombination and reassortment of genes in the flu are still disputed in the literature.  But it's damn scary, either way, even if the probability of such a transfer is small.

In the end, if nothing else, what this demonstrates is that our technological base for both detecting and responding to infectious disease is still poorly developed.

iGEM 2008: Surprise -- The Future is Here Already.

I'm back from a weekend at MIT serving as a judge for the International Genetically Engineered Machines Competition.  Here are a few thoughts on the competition.

The "international" flavor continues to strengthen.  Of the six finalists, three were from the U.S., two from Europe, and one from Asia.  There were 85 teams registered, almost all of whom showed up.  I was hoping for more biofuels/energy projects, but perhaps that fad is already past.

The top three teams were (here are the full results): 1) Slovenia 2) Freiburg 3) Caltech.

First, a couple of slightly blurry iPhotos (when the hell is Apple going to upgrade that camera?):

IMG_0138 Tom Knight receives the BioBrick from the 2007 winner, Peking University.

IMG_0140 A collective dance party while the competitors wait for the judges.

IMG_0141 Tom Knight awards the BioBrick to the 2008 winners, Slovenia.

Several of the 2008 projects implement ideas that have appeared in science fiction stories and in my own speculations about the future of biological technologies:

UCSF characterized a fusion protein that enables epigenetic control of gene expression through chromatin silencing.  This, in effect, gives the user (which could be the cell itself) a new control knob for building memory circuits in eukaryotes.  I seem to recall that this is the basic innovation in Greg Bear's Blood Music that brings about the end of the world through Green Goo.  Go UCSF!

Caltech and NYMU-Taipei (check out the killer Wiki) both modified commensal E. coli strains to serve as therapeutics.  Caltech built a bunch of new functionality into the probiotic strain Nissle 1917, including microbicidal circuits, Vitamin B supplements, and lactase production (big kudos to Christina Smolke, here).  Taipei built a "Bactokidney" for people with kidney failure: cells that attach to the lining of the small intestine and absorb nasty substances that would otherwise need to be removed via dialysis.  These are both very cool ideas.

Seeing these projects brought back shades of a scenario published in Bio-era's "Genome Synthesis and Design Futures: Implications for the U.S. Economy".  (I wrote the original story, which was less complicated but slightly more nefarious than the Bio-era version, in 2005 as a short, provocative piece of a larger report for a TLA -- a three letter agency.)  Almost all the technology described below has been published in bits and pieces -- fortunately, it has not yet been put together in one microbe.

In 2008, the North Korean government launches a secret program to develop biological tools that can be used to pacify target populations for crowd control or military purposes. North Korea's research draws on Soviet work on modifying pathogens to express mood-altering peptides, and the demonstration by U.S. scientists at the National Institutes of Health that common commensal strains of E. coli could be modified to secrete specialized peptides in human intestines.  Modifying the same strain used by the NIH, available in an over-the-counter probiotic pill, the North Koreans secretly produce an organism that produces peptide hormones easily absorbed through the intestinal wall.

With further modifications to allow the peptides to enter the brain, the new strain produces a calming, almost sedative, effect on colonized individuals. Combined with a genetic circuit that confers both antibiotic resistance and upregulation of the peptides upon exposure to a chemical that can be dispersed like teargas, these modifications enable the government to pacify crowds in times of crisis. The E. coli can be distributed via food and water to target populations.

To maintain the presence of the genetic circuit within the population, the new strain is equipped with an antibiotic resistance mechanism from V. cholera that causes plasmids containing the entire genetic circuit, including the regulatory genes and the mood modification genes, to be horizontally transferred to other bacteria upon treatment with common antibiotics.

In 2009, Pyongyang uses military forces to suppress a widening political uprising against the regime. Reports of a "pacifying gas" quickly emerge, raising allegations about the use of chemical weapons. U.S. intelligence agencies claim that North Korea has used a novel combination of biological and chemical weapons against rioters, leading the U.S. to declare that Pyongyang has violated the international treaty on bioweapons. Pacifist biohackers undertake to recreate the microbe , or to invent new versions to use as "peace weapons" against armies.

When a U.S.-led coalition attempts to impose an economic embargo against North Korea, the Chinese government uses its military to secure supply lines to North Korea. A military standoff between U.S. and Chinese forces ensues.

Here is the original inspiration: "Toward a live microbial microbicide for HIV: Commensal bacteria secreting an HIV fusion inhibitor peptide". (I'd completely forgotten that I blogged the original paper.)

Slovenia won (again) with "Immunobricks" by engineering new vaccines. The technology they used forms the basis of arguments about rapid, distributed vaccine production we made in Genome Synthesis and Design Futures (Section 4.3, in particular), which I've also written about extensively here on this blog, and which will show up in my book.  Yet all of a sudden it's real, all the more so because it was an iGEM project.

From Slovenia's Wiki abstract:

Using synthetic biology approaches we managed to assemble functional "immunobricks" into a designer vaccine with a goal to activate both innate and acquired immune response to H. pylori. We successfully developed two forms of such designer vaccines. One was based on modifying H. pylori component (flagellin) such that it can now be recognized by the immune system. The other relied upon linking H. pylori components to certain molecules of the innate immune response (so called Toll-like receptors) to activate and guide H. pylori proteins to relevant compartments within the immune cell causing optimal innate and acquired immune response. Both types of vaccines have been thoroughly characterized in vitro (in test tubes or cells) as well as in vivo (laboratory mice) exhibiting substantial antibody response. Our strategy of both vaccines' design is not limited to H. pylori and can be applied to other pathogens. Additionally, our vaccines can be delivered using simple and inexpensive vaccination routes, which could be suitable also in third world countries.

If you've read this far into the post, you should definitely spend some time on Slovenia's Wiki.

Here's the short, pithy version: There is presently no vaccine for H. pylori.  Between June and October this year, seven undergraduates built and tested three kinds of brand new vaccines against H. pylori.  (They also put a whole mess of Biobrick parts into the Registry, which means those parts are all in the public domain.)

Yes, yes -- it's true, getting something to work in a mouse and in mammalian cell culture is a long way from getting it to work in humans, or even in ferrets.  But the skill level and speed of this work should make everyone sit up and take notice.

So it is worth pondering the broader implications of these projects.

The Slovenian team clearly has access to very high quality labs and protocols.  Mammalian cell culture can be very fiddly unless you know what you are doing and have the right equipment (I speak from painful experience, lo those many years ago in grad school).  The Caltech and Taipei teams also clearly have a great deal of support and mentoring.  Yet while bashing DNA and growing E. coli are not particularly hard, the design and testing of the coli projects is very impressive.

Despite all the support and money evident in the projects, there is absolutely no reason this work could not be done in a garage.  And all of the parts for these projects are now available from the Registry.

Over the past couple of years, in various venues, I have tried to point out both the utility and inevitability of proliferating biological technologies.  iGEM 2008 drives home the point yet again.  In particular, the ability to rapidly create vaccines and biological therapeutics points the way to increased participation by "amateurs", whether the professionals (and policy makers...and security types) are ready or not.  I'm also thinking back to "peer reviews" in which I was excoriated for suggesting this kind of work was within the reach of people with minimal formal training.  Because, really, you need a PhD, and an NIH grant, and tenure, to even think of taking on anything like a synthetic vaccine.  Oh, wait...

Although I've predicted in writing that this sort of thing would happen, I frankly expected practical implementation of both the rapid, synthetic vaccines and the modified commensal bacteria to take a few more years. Yet undergraduates are already building these things as summer projects.

It didn't really hit me until I started writing this post earlier this afternoon, but as I ponder the results from this year's iGEM only one thought comes to mind: "Holy crap -- hold on to your knickers."

The world is changing very, very quickly.

Update on Influenza Subtype Activity in 2007-2008

While addressing some comments from Ralph Baric on one chapter my book, I had reason to go find statistics on influenza subtype activity last year.  Those interested in keeping up on recent flu activity should peruse this July, 2008, report from the CDC: Influenza Activity --- United States and Worldwide, 2007--08 Season.

Here is the breakdown on subtype activity:

During September 30, 2007--May 17, 2008, World Health Organization and National Respiratory and Enteric Virus Surveillance System collaborating laboratories in the United States tested 225,329 specimens for influenza viruses; 39,827 (18%) were positive. Of the positive specimens, 28,263 (71%) were influenza A viruses, and 11,564 (29%) were influenza B viruses. Among the influenza A viruses, 8,290 (29%) were subtyped; 2,175 (26%) were influenza A (H1N1), and 6,115 (74%) were influenza A (H3N2) viruses. The proportion of specimens testing positive for influenza first exceeded 10% during the week ending January 12, 2008 (week 2), peaked at 32% during the week ending February 9, 2008 (week 6), and declined to <10% during the week ending April 19, 2008 (week 16). The proportion positive was above 10% for 14 consecutive weeks. The peak percentage of specimens testing positive for influenza during the previous three seasons ranged from 22% to 34% and the peak occurred during mid-February to early March. During the previous three influenza seasons, the number of consecutive weeks during which more than 10% of specimens tested positive for influenza ranged from 13 to 17 weeks.

Of note, 26% of samples positive for influenza were the H1N1 subtype -- the same as the 1918 flu -- which means we all have probably been exposed to it and have some immunity.  That does not mean the particular combination of genes in the 1918 flu would be harmless if it showed up again, but rather than our immune systems should be able to better recognize that bug and thus might defend against it better than the first time around.

Synthetic Biology 4.0 – Not so live blog, part 1

What a difference a few years makes.  SB 1.0 was mostly a bunch of professors and grad students in a relatively small, stuffy lecture hall at MIT.  SB 2.0 in Berkeley expanded a bit to include a few lawyers, sociologists, and venture capitalists.  (I skipped 3.0 in Zurich.)

At just over 600 attendees, SB 4.0 is more than twice as big as even 3.0, with just under half the roster from Asia.  The venue, at the Hong Kong University of Science and Technology, is absurdly nice, with a view over the ocean that beats even UCSB and UCSD.  Kudos also to the organizers here.  They worked very hard to make sure the meeting came off well, and it is clear they are interested in synthetic biology, and biotech in general, as a long term proposition.  The Finance Minister of Hong Kong, John Tsang, spoke one evening, and he was very clear that HK is planning to put quite a lot of money and effort into biology.

Which brings me to a general observation that Hong Kong really cares about the future, and is investing to bring it along that much sooner.  I arrived a day early in order to acclimate a bit and wander around the city, as my previous visit was somewhat hectic.  Even amid the financial crisis, the city feels more optimistic and energetic than most American cities I visit.

I will have to write up the rest of the meeting when I get back to the States later this week.  But here are a few thoughts:

As of the last few days, I have now seen all the pieces necessary to build a desktop gene printer.  I don’t have prediction when such a thing will arrive on the market, but there is no doubt in my mind that it is technically feasible.  With appropriate resources, I think it would take about 8 weeks to build a prototype.  It is that close.

Ralph Baric continues to do work on SARS that completely scares the shit out of me.  And I am really glad it is getting done, and also that he is the one doing it.  His work clearly demonstrates how real the threat from natural pathogens is, and how poorly prepared we are to deal with it.

Jian Xu, who is better known for his efforts to understand the human gut microbiome, spoke on the soup-to-nuts plant engineering and biofuels effort at the Qingdao Institute of Bioenergy and Bioprocess Technology, run by the Chinese Academy of Sciences (QIBEBT).   The Chinese are serious about putting GM plants into the field and deriving massive amounts of energy from biomass.

Daphne Prauss from Chromatin gave a great talk about artificial chromosomes in plants and how they speed up genetic modification.  I’ll have to understand this a bit better before I write about it.

Zach Serber from Amyris spoke about on their biofuels efforts, and Amyris is on schedule to get aviation fuel, diesel, and biogasoline into the market within the next couple of years.  All three fuels have equivalent or better characteristic as petro-fuels when it comes to vapor pressure, cloud point, cetane number, octane, energy density, etc.

More soon.

"Laying the foundations for a bio-economy"

My new commentary, "Laying the foundations for a bio-economy", will be appearing in a upcoming issue of Systems and Synthetic Biology.  The piece is freely available online as both text and PDF.  Thanks to Springer for supporting the Open Access option.  Here are the abstract, the first two paragraphs, and the last two paragraphs:

Abstract  Biologicaltechnologies are becoming an important part of the economy. Biotechnology already contributes at least 1% of US GDP, with revenues growing as much as 20% annually. The introduction of composable biological parts will enable an engineering discipline similar to the ones that resulted in modern aviation and information technology. As the sophistication of biological engineering increases, it will provide new goods and services at lower costs and higher efficiencies. Broad access to foundational engineering technologies is seen by some as a threat to physical and economic security. However, regulation of access will serve to suppress the innovation required to produce new vaccines and other countermeasures as well as limiting general economic growth.          

Welcome to the Paleobiotic Age. Just as today we look back somewhat wistfully on our quaint Paleolithic--literally "old stone"--ancestors, so will our descendants see the present age as that of "old biology", inhabited by Paleobiotic Man. The technologies we use to manipulate biological systems are experiencing dramatic improvement, and as a result are driving change throughout human economies.       

In order to understand the impact of our growing economic dependence on biological technologies it is worth taking a moment to consider the meaning of economy. "Economy" is variously thought of as, "the management of the resources of a country, especially with a view to its productivity" and "the disposition or regulation of the parts or functions of any organic whole; an organized system or method"  Amid a constantly increasing demand for resources, we look to technology to improve the productivity of labor, to improve the efficiency of industrial process and energy production, and to improve the yield of agriculture. Very tritely, we look to technological innovation within our economy to provide more stuff at lower cost. Biological technologies are increasingly playing that role.

...

In this, the Paleobiotic Age, our society is only just beginning to struggle with all the social and technical questions that arise from a fundamental transformation of the economy. History holds many lessons for those of us involved in creating new tools and new organisms and in trying to safely integrate these new technologies into an already complex socio-economic system. Alas, history also fails to provide examples of any technological system as powerful as rational engineering of biology. We have precious little guidance concerning how our socio-economic system might be changed in the Neobiotic Age to come. We can only attempt to minimize our mistakes and rapidly correct those we and others do make.

The coming bio-economy will be based on fundamentally less expensive and more distributed technologies than those that shaped the course of the 20th Century. Our choices about how to structure the system around biological technologies will determine the pace and effectiveness of innovation. As with the rest of the natural and human built world, the development of this system is decidedly in human hands. To paraphrase Stewart Brand: We are as engineers, and we'd better get good at it in a hurry.          

On Indonesia and Distribution of H5N1 Strains

News in the last couple of days that Indonesia has decided not to forward homegrown strains of H5N1 to the WHO and instead is dealing directly with Baxter Healthcare for production of vaccines.  The worst bit of this, of course, is that there does not appear to be much cross reactivity elicited by the Vietnamese and Indonesian isolates, where the international reference vaccine is derived from a strain isolated in Vietnam.  Moreover, while Baxter is supposedly making progress in producing influenza vaccines in cell culture (Baxter's Press Releases, CIDRAP's version), this technology is not yet approved for human use; only research contracts, rather than production contracts, have been let by the U.S. Government for cell culture production.  Finally, despite much noise that cell culture is faster/better/cheaper than eggs for producing vaccines, it appears cell culture only beats eggs by a month or two.  (Baxter does have a very comendably decent Influenza information web page, which is here.) 

Here are a few paragraphs from an AP story, "Experts say Indonesian deal on H5N1 virus jeopardizes race for pandemic vaccine", via the IHT:

Indonesia Wednesday signed a memorandum of understanding with U.S. drug manufacturer Baxter Healthcare Corp. to develop a human bird flu vaccine.

Under the agreement, Indonesia will provide H5N1 virus samples in exchange for Baxter's expertise in vaccine production. Other organizations would have access to Indonesian samples provided they agree not to use the viruses for "commercial" purposes, said Siti Fadilah Supari, Indonesia's health minister.

But that is a major departure from the World Health Organization's existing virus-sharing system, where bird flu viruses are freely shared with the global community for public health purposes, including vaccine and antiviral development. Indonesia has not shared any viruses since the beginning of 2007.

Indonesia defended its decision, arguing the system works against poor countries. "The specimens we send to WHO...are then used by vaccine makers who then sell to us (at a profit)," Supari told reporters Wednesday. "This is unfair, we have the virus, we are getting sick, and then they take the virus from WHO — 'with WHO's permission' they say — and make it themselves," said Supari.

There seems to be a bit of confusion among reporters about whether Indonesia now has an official policy of withholding samples from the WHO, but Baxter is making it clear they don't have anything to do with the decision.  From The New York Times' coverage: "A Baxter spokeswoman said the company had not asked Indonesia to stop cooperating with the W.H.O. She added that the agreement under negotiation would not give it exclusive access to Indonesian strains."

In any event, Indonesians feel bent out of shape that they have previously provided strains to the international community, only to be charged for the vaccine when it becomes available.  News reports portray this as something of an IP spat, akin to controversy over biomining.  From the Reuters coverage:

"The specimens we sent to the WHO have been forwarded to their collaborating center. There it has been used for various reasons such as vaccine development ... or research," Supari said.

"Later they sold the discovery to us. This is not fair. We are the ones who got sick. They took the sample through WHO and with WHO consent and they tried to produce it for their own use," she said at a news conference after the signing of the pact with Baxter.

Supari said Australia was producing a human bird flu vaccine using the Indonesian virus strain, but did not give details.

"I was shocked because I never gave permits to Australia to produce a vaccine using our strain," she said.

"We have been working with Baxter since the beginning and are processing intellectual property rights with them. Baxter protects our intellectual property rights," she said.

...Under the memorandum of understanding, Indonesia would have the right to produce and market the bird flu vaccine domestically. It is negotiating to export it to a number of countries.

Production would be carried out by makers appointed by the Health Ministry.

So, in conclusion, the deal appears to put Indonesian isolates of H5N1 out of the reach of governments and firms with other vaccine technologies, at least for the time being.  Finally, in an interesting twist on the distribution of biological technologies, the deal also appears to put Indonesia in a position to become a leader in cell culture production of vaccines, potentially jumping to the head of the pack in the international vaccine market.

H5N1 is back in the U.K.

The headlines are today loudly announcing the return of H5N1 to the United Kingdom (CNN, New York Times) at a Turkey farm near Lowestoft.  Though nobody can say for sure, the virus probably arrived via migrating birds.  It appears that the likelihood of transmission by migrating bird or smuggled poultry has a geopolitical dependence.

Last month, Kilpatrick, et al., published a paper in PNAS ("Predicting the global spread of H5N1 influenza") that looked at a variety of factors to classify historical outbreaks and predict new ones.  The abstract does a decent job of summarizing the paper, so here it is:

The spread of highly pathogenic H5N1 avian influenza into Asia, Europe, and Africa has resulted in enormous impacts on the poultry industry and presents an important threat to human health. The pathways by which the virus has and will spread between countries have been debated extensively, but have yet to be analyzed comprehensively and quantitatively. We integrated data on phylogenetic relationships of virus isolates, migratory bird movements, and trade in poultry and wild birds to determine the pathway for 52 individual introduction events into countries and predict future spread. We show that 9 of 21 of H5N1 introductions to countries in Asia were most likely through poultry, and 3 of 21 were most likely through migrating birds. In contrast, spread to most (20/23) countries in Europe was most likely through migratory birds. Spread in Africa was likely partly by poultry (2/8 introductions) and partly by migrating birds (3/8). Our analyses predict that H5N1 is more likely to be introduced into the Western Hemisphere through infected poultry and into the mainland United States by subsequent movement of migrating birds from neighboring countries, rather than from eastern Siberia. These results highlight the potential synergism between trade and wild animal movement in the emergence and pandemic spread of pathogens and demonstrate the value of predictive models for disease control.

Of course, the only way to know if the model really works is, alas, to wait for more outbreaks.  Anyway, it seems the U.S. is safe from poultry smuggling, which we have a chance of intercepting, but susceptible to migrating birds, a pathway that almost certainly resists any defensive measures.