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Harry Potter and The Future of Nature

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How will Synthetic Biology and Conservation Shape the Future of Nature?  Last month I was privileged to take part in a meeting organized by The Wildlife Conservation Society to consider that question.  Here is the framing paper (PDF), of which I am a co-author.  There will be a follow-up paper in the coming months.  I am still mulling over what I think happened during the meeting, and below are a few observations that I have managed to settle on so far.  Others have written their own accounts.  Here is a summary from Julie Gould, riffing on an offer that Paul Freemont made to conservation biologists at the close of the meeting, "The Open Door".  Ed Gillespie has a lovely, must-read take on Pandora's Box, cane toads, and Emily Dickenson, "Hope is the thing with feathers".  Cristian Samper, the new head of the Wildlife Conservation Society was ultimately quite enthusiastic: Jim Thomas of ETC, unsurprisingly, not so much.

The meeting venue was movie set-like Cambridge.  My journey took me through King's Cross, with its requisite mock-up of a luggage trolley passing through the wall at platform nine and three-quarters.  So I am tempted to style parts of the meeting as a confrontation between a boyish protagonist trying to save the world and He Who Must Not Be Named.  But my experience at the meeting was that not everyone was able to laugh at a little tension-relieving humor, or even to recognize that humor.  Thus the title of this post is as much as I will give in temptation.

How Can SB and CB Collaborate?

I'll start with an opportunity that emerged during the week, exactly the sort of thing you hope would come from introducing two disciplines to each other.  What if synthetic biology could be used as a tool to aid in conservation efforts, say to buttress biodiversity against threats?  If the ongoing, astonishing loss of species were an insufficient motivation to think about this possibility, now some species that humans explicitly rely upon economically are under threat.    Synthetic biology might - might! - be able to offer help in the form of engineering species to be more robust in the face of a changing environment, such as enabling corals to cope with increases in water temperature and acidity, or it perhaps via intervening in a host-prey relationship, such as that between bats and white-nose disease or between bees and their mites and viruses.

The first thing to say here is that if the plight of various species can be improved through changes in human behavior then we should by all means work toward that end.  The simpler solution is usually the better solution.  For example, it might be a good idea to stop using those pesticides and antibiotics that appear to create more problems than they solve when introduced into the environment.  Moreover, at the level of the environment and the economy, technological fixes are probably best reserved until we try changes in human behavior.  After all, we've mucked up such fixes quite a few times already.  (All together now: "Cane Toad Blues".)  But what if the damage is too far along and cannot be addressed by changes in behavior?  We should at least consider the possibility that a technological fix might be worth a go, if for no other reason that to figure out how to create a back up plan.  Given the time scales involved in manipulating complex organisms, exploring the option of a back-up plan means getting started early.  It also means thoughtfully considering which interventions would be most appropriate and urgent, where part of the evaluation should probably involve asking whether changes in human behavior are likely to have any effect.  In some cases, a technical solution is likely to be our only chance.

First up: corals.

We heard from Stanford's Steve Palumbi on work to understand the effects of climate change on corals in the South Pacific.  Temperature and acidity - two parameters already set on long term changes - are already affecting coral health around the globe.  But it turns out that in the lab some corals can handle remarkably difficult environmental conditions.  What if we could isolate the relevant genetic circuits and, if necessary, transplant them into other species, or turn them on if they are already widespread?  My understanding of Professor Palumbi's talk is that it is not yet clear why some corals have the pathway turned on and some do not.  So, first up, a bunch of genetics, molecular biology, and field biology to figure out why the corals do what they do.  After that, if necessary, it seems that it would be worth exploring whether other coral species can be modified to use the relevant pathways.  Corals are immensely important for the health of both natural ecosystems and human economies; we should have a back-up plan, and synthetic biology could certainly contribute.

Next up: bats.

Bats are unsung partners of human agriculture, and they contribute an estimated $23 billion annually to U.S. farmers by eating insects and pollinating various plants.  Here is nice summary article from The Atlantic by Stephanie Gruner Buckely on the impact upon North American bats of white nose syndrome.  The syndrome, caused by a fungus evidently imported from Europe, has already killed so many bats that we may see an impact on agriculture as soon as this year.  European bats are resistant to the fungus, so one option would be to try to introduce the appropriate genes into North American bats via standard breeding.  However, bats breed very slowly, usually only having one pup a year, and only 5 or so pups in a lifetime.  Given the mortality rate due to white nose syndrome, this suggests breeding is probably too slow to be useful in conservation efforts.  What if synthetic biology could be used to intervene in some way, either to directly attack the non-native fungus or to interfere with its attack on bats.  Obviously this would be a hard problem to take on, but both biodiversity and human welfare would be improved by making progress here.

And now: bees.

If you eat, you rely on honeybees.  Due to a variety of causes, bee populations have fallen to the point where food crops are in jeopardy.  Entomologist Dennis vanEngelstorp, quoted in Wired, warns "We're getting closer and closer to the point where we don't have enough bees in this country to meet pollination demands.  If we want to grow fruits and nuts and berries, this is important.  One in every three bites [of food consumed in the U.S.] is directly or indirectly pollinated by bees."  Have a look at the Wired article for a summary of the constellation of causes of Colony Collapse Disorder, or CCD -- they are multifold and interlocking.  Obviously, the first thing to do is to stop making the problem worse; Europe has banned a class of pesticide that is exceptionally hard on honeybees, though the various sides in this debate continue to argue about whether that will make any difference.  This change in human behavior may have some impact, but most experts agree we need to do more.  Efforts are underway to breed bees that are resistant to both pesticides and to particular mites that prey on bees and that transmit viruses between bees.  Applying synthetic biology here might be the hardest task of all, given the complexity of the problem.  Should synthetic biologists focus on boosting apian immune systems?  Should they focus on the mite?  Apian viruses?  It sounds very difficult.  But with such a large fraction of our food supply dependent upon healthy bees, it also seems pretty clear that we should be working on all fronts to sort out potential solutions.

A Bit of Good News

Finally, a problem synthetic biologists are already working to solve: malaria.  The meeting was fortunate to hear directly from Jay Keasling.  Keasling presented progress on a variety of fronts, but the most striking was his announcement that Sanofi-Aventis has produced substantially more artemisinin this year than planned, marking real progress in producing the best malaria drug extant using synthetic biology rather than by purifying it from plants.  Moreover, he announced that Sanofi and OneWorldHealth are likely to take over the entire world production of artemisinin.  The original funding deal between The Gates Foundation, OneWorldHealth, Amyris, and Sanofi required selling at cost.  The collaboration has worked very hard at bringing the price down, and now it appears that they can simply outcompete the for-profit pricing monopoly.

The stated goal of this effort is to reduce the cost of malaria drugs and provide inexpensive cures to the many millions of people who suffer from malaria annually.  Currently, the global supply fluctuates, as, consequently, do prices, which are often well above what those afflicted can pay.  A stable, high volume source of the drug would reduce prices and also reduce the ability of middle-men to sell doctored, diluted, or mis-formulated artemisinin, all of which are contributing to a rise of resistant pathogens.

There is a potential downside to this project.  If Sanofi and OneWorldHealth do corner the market on artemisinin, then farmers who currently grow artemisia will no longer have that option, at least for supplying the artemisinin market.  That might be a bad thing, so we should at least ask the question of whether the world is a better place with artemisinin production done in vats or derived from plants.  This question can be broken into two pieces: 1) what is best for the farmers? and 2) what is best for malaria sufferers?  It turns out these questions have the same answer.

There is no question that people who suffer from malaria will be better off with artemisinin produced in yeast by Sanofi.  Malaria is a debilitating disease that causes pain, potentially death, and economic hardship.  The best estimates are that countries in which malaria is endemic suffer a hit to GDP growth of 1.3% annually compared to non-malarious countries.  Over just a few years this yearly penalty swamps all the foreign aid those countries receive; I've previously argued that eliminating malaria would be the biggest humanitarian achievement in history and would make the world a much safer place.  Farmers in malarious countries are the worst hit, because the disease prevents them from getting into the fields to work.  I clashed in public over this with Jim Thomas around our respective testimonies in front of the Presidential Bioethics Commission a couple of years ago.  Quoting myself briefly from the relevant blog post,

The human cost of not producing inexpensive artemisinin in vats is astronomical.  If reducing the burden of malaria around the world on almost 2 billion people might harm "a few thousand" farmers, then we should make sure those farmers can make a living growing some other crop.  We can solve both problems.  ...Just one year of 1.3% GDP growth recovered by reducing (eliminating?) the impact of malaria would more than offset paying wormwood farmers to grow something else.  There is really no argument to do anything else.

For a bit more background on artemisinin supply and pricing, and upon the apparent cartel in control of pricing both the drug and the crop, see this piece in Nature last month by Mark Peplow.  I was surprised to learn that that the price of artemisia is set by a small group that controls production of the drug.  This group, unsurprisingly, is unhappy that they may lose control of the market for artemisinin to a non-profit coalition whose goal is to eliminate the disease.  Have a look at the chart titled "The Cost of Progress", which reveals substantial price fluctuations, to which I will return below.

Mr. Thomas responded to Keasling's announcement in Cambridge with a broadside in the Guardian UK against Keasling and synthetic biology more generally.  Mr. Thomas is always quick to shout "What about the farmers?"  Yet he is rather less apt to offer actual analysis of what farmers actually gain, or lose, by planting artemisia.

The core of the problem for farmers is in that chart from Nature, which shows that artemisinin has fluctuated in price by a factor of 3 over the last decade.  Those fluctuations are bad for both farmers and malaria sufferers; farmers have a hard time knowing whether it makes economic sense to plant artemisia, which subsequently means shortages if farmers don't plant enough.  Shortages mean price spikes, which causes more farmers to plant, which results in oversupply, which causes the price to plunge, etc.  You'll notice that Mr. Thomas asserts that farmers know best, but he never himself descends to the level of looking at actual numbers, and whether farmers benefit by growing artemisia.  The numbers are quite revealing.

Eyeballing "The Cost of Progress" chart, it looks like artemisia has been below the $400/kg level for about half the last 10 years.  To be honest, there isn't enough data on the chart to make firm conclusions, but it does look like the most stable price level is around $350/kg, with rapid and large price spikes up to about $1000/kg.  Farmers who time their planting right will probably do well; those who are less lucky will make much less on the crop.  So it goes with all farming, unfortunately, as I am sure Mr. Thomas would agree.

During his talk, Keasling put up a chart I hadn't seen before, which showed predicted farmer revenues for a variety of crops.  The chart is below; it makes clear that farmers will have substantially higher revenues planting crops other than artemisia at prices at or below $400/kg. 
Keasling_Alternate_crops.png
The Strange Arguments Against Microbial Production of Malaria Drugs

Mr. Thomas' response in the Guardian to rational arguments and actual data was a glib accusation that Keasling is dismissing the welfare of farmers with "Let them plant potatoes".  This is actually quite clever and witty, but not funny in the slightest when you look at the numbers.  Thomas worries that farmers in African and Asia will suffer unduly from a shift away from artemisia to yeast.  But here is the problem: those farmers are already suffering -- from malaria.  Digging deeper, it becomes clear that Mr. Thomas is bafflingly joining the pricing cartel in arguing against the farmers' best interests.

A brief examination of the latest world malaria map shows that the most intense malaria hot spots are in Africa and Asia, with South America not far behind (here is the interactive CDC version).  Artemisia is primarily grown in Africa and Asia.  That is, farmers most at risk of contracting malaria only benefit economically when there is a shortage of artemisinin, the risk of which is maintained by leaving artemisia production in the hands of farmers.  Planting sufficient quantities of artemisia to meet demand means prices that are not economically viable for the farmer.  There are some time lags here due to growing and processing the crop into the drug, but the upshot is that the only way farmers make more money planting artemisia than other crops is when there is a shortage.  This is a deadly paradox, and its existence has only one beneficiary: the artemisinin pricing cartel.  But we can now eliminate the paradox.  It is imperative for us to do so.

Once you look at the numbers there is no argument Mr. Thomas, or anyone else, can make that we should do anything but brew artemisinin in vats and bring the price as low as possible.

I had previously made the macro-scale economic arguments about humanitarian impacts economic growth.  Malarious countries, and all the farmers in them, would benefit tremendously by a 1.3% annual increase in GDP.  But I only realized while writing this post that the micro-scale argument gives the same answer: the farmers most at risk from malaria only make money growing artemisia when there is a shortage of the drug, which is when they are most likely to be affected by the disease.

I get along quite well in person with Mr. Thomas, but I have long been baffled by his arguments about artemisinin.  I heartily support his aims of protecting the rights of farmers and taking care of the land.  We should strive to do the right thing, except when analysis reveals it to be the wrong thing.  Since I only just understood the inverse relationship between artemisinin pricing and the availability of the drug to the very farmers growing artemisia, I am certain Mr. Thomas has not had the opportunity to consider the facts and think through the problem so that he might come to the same conclusion.  I invite him to do so.

Censoring Science is Detrimental to Security

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Restricting access to science and technology in the name of security is historically a losing proposition.  Censorship of information that is known to exist incentivizes innovation and rediscovery. 

As most readers of this blog know, there has been quite a furor over new results demonstrating mutations in H5N1 influenza strains that are both deadly and highly contagious in mammals.  Two groups, led by Ron Fouchier in the The Netherlands and Yoshihiro Kawaoka at The University of Wisconsin, have submitted papers to Nature and Science describing the results.  The National Science Advisory Board for Biosecurity (NSABB) has requested that some details, such as sequence information, be omitted from publication.  According to Nature, both journals are "reserving judgement about whether to censor the papers until the US government provides details of how it will allow genuine researchers to obtain redacted information".

For those looking to find more details about what happened, I suggest starting with Dorveen Caraval's interview with Fouchier in the New York Times, "Security in Flu Study Was Paramount, Scientist Says"; Kathleen Harmon's firsthand account of what actually happened when the study was announced; and Heidi Ledford's post at Nature News about the NSABB's concerns.

If you want to go further, there is more good commentary, especially the conversation in the comments (including from a member of the NSABB), in "A bad day for science" by Vincent Racaniello.  See also Michael Eisen's post "Stop the presses! H5N1 Frankenflu is going to kill us all!", keeping in mind that Eisen used to work on the flu.

Writing at Foreign Policy, Laurie Garrett has done some nice reporting on these events in two posts, "The Bioterrorist Next Door" and "Flu Season".  She suggests that attempts to censor the results would be futile: "The genie is out of the bottle: Eager graduate students in virology departments from Boston to Bangkok have convened journal-review debates reckoning exactly how these viral Frankenstein efforts were carried out."

There is much I agree with in Ms. Garrett's posts.  However, I must object to her assertion that the work done by Fouchier and Kawaoka can be repeated easily using the tools of synthetic biology.  She writes "The Fouchier episode laid bare the emptiness of biological-weapons prevention programs on the global, national, and local levels.  Along with several older studies that are now garnering fresh attention, it has revealed that the political world is completely unprepared for the synthetic-biology revolution."   As I have already written a book that discusses this confusion (here is an excerpt about synthetic biology and the influenza virus), it is not actually what I want to write about today.  But I have to get this issue out of the way first.

As far as I understand from reading the press accounts, both groups used various means to create mutations in the flu genome and then selected viruses with properties they wanted to study.  To clarify, from what I have been able to glean from the sparse accounts thus far, DNA synthesis was not used in the work.  And as far as I understand from reading the literature and talking to people who build viruses for a living, it is still very hard to assemble a functioning, infectious influenza virus from scratch.   

If it were easy to write pathogen genomes -- particularly flu genomes -- from scratch, we would quite frankly be in deep shit. But, for the time being, it is hard.  And that is important.  Labs who do use synthetic biology to build influenza viruses, as with those who reconstructed the 1918 H1N1 influenza virus, fail most of the time despite great skill and funding.  Synthesizing flu viruses is simply not a garage activity.  And with that, I'll move on.

Regardless of how the results might be reproduced, many have suggested that the particular experiments described by Fouchier and Kawaoka should not have been allowed.  Fouchier himself acknowledges that selecting for airborne viruses was not the wisest experiment he could have done; it was, he says, "really, really stupid".  But the work is done, and people do know about it.  So the question of whether this work should have been done in the first place is beside the point.  If, as suggested by Michael Eisen, that "any decent molecular biologist" could repeat the work, then it was too late to censor the details as soon as the initial report came out. 

I am more interested in the consequences of trying to contain the results while somehow allowing access to vetted individuals.  Containing the results is as much about information security as it is biological security.  Once such information is created, the challenge is to protect it, to secure it.  Unfortunately, the proposal to allow secure access only by particular individuals is at least a decade (if not three decades) out of date.

Any attempt to secure the data would have to start with an assessment of how widely it is already distributed.  I have yet to meet an academic who regularly encrypts email, and my suspicion is that few avail themselves of the built-in encryption on their laptops.  So, in addition to the university computers and email servers where the science originated, the information is sitting in the computers of reviewers, on servers at Nature and Science, at the NSABB, and, depending on how the papers were distributed and discussed by members of the NSABB, possibly on their various email servers and individual computers as well.  And let's not forget the various unencrypted phones and tablets all of those reviewers now carry around.

But never mind that for a moment.  Let's assume that all these repositories of the relevant data are actually secure.  The next step is to arrange access for selected researchers.  That access would inevitably be electronic, requiring secure networks, passwords, etc.  In the last few days the news has brought word that computer security firms Stratfor and Symantec have evidently been hacked recently.  Such attacks are not uncommon.  Think back over the last couple of years: hacks at Google, various government agencies, universities.  Credit card numbers, identities, and supposedly secret DoD documents are all for sale on the web.  To that valuable information we can now add a certain list of influenza mutations.  If those mutations are truly a critical biosecurity risk -- as asserted publicly by various members of the NSABB -- then that data has value far beyond its utility in virology and vaccinology.

The behavior of various hackers (governments, individuals, other) over the last few years make clear that what the discussion thus far has done is to stick a giant "HACK HERE" sign on the data.  Moreover, if Ms. Garrett is correct that students across the planet are busy reverse engineering the experiments because they don't have access to the original methods and data, then censorship is creating a perverse incentive for innovation.  Given today's widespread communication, restriction of access to data is an invitation, not a proscription.

This same fate awaits any concentration of valuable data.  It obviously isn't a problem limited to collections of sensitive genetic sequences or laboratory methods.  And there is certainly a case to be made for attempting to maintain confidential or secret caches of data, whether in the public or private interest.  In such instances, compartmentalization and encryption must be implemented at the earliest stages of communication in order to have any hope of maintaining security. 

However, in this case, if it true that reverse engineering the results is straightforward, then restriction of access serves only to slow down the general process of science.  Moreover, censorship will slow the development of countermeasures.  It is unlikely that any collection of scientists identified by the NSABB or the government will be sufficient to develop all the technology we need to respond to natural pathogens, let alone any artificial ones.

As with most other examples of prohibition, these restrictions are doomed before they are even implemented.  Censorship of information that is known to exist incentivizes innovation and rediscovery.  As I explored in my book, prohibition in the name of security is historically a losing proposition.  Moreover, science is inherently a networked human activity that is fundamentally incompatible with constraints on communication, particularly of results that are already disclosed.  Any endeavor that relies upon science is, therefore, also fundamentally incompatible with constraints on communication.  Namely developing technologies to defend against natural and artificial pathogens.  Censorship threatens not just science but also our security.
I recently had cause to re-read the National Strategy for Countering Biological Threats (Full PDF), released last fall by the National Security Council and signed by the President.  I think there is a lot to like, and it demonstrates a welcome change in the mindset I encounter in Washington DC.

When the document came out, there was just a little bit of coverage in the press.  Notably, Wired's Threat Level, which usually does a commendable job on security issues, gave the document a haphazard swipe, asserting that "Obama's Biodefense Strategy is a Lot Like Bush's".  As described in that post, various commentators were unhappy with the language that Under Secretary of State Ellen Tauscher used when announcing the Strategy at a BWC meeting in Geneva.  According to Threat Level, "Sources tell this reporter that the National Security Council had some Bush administration holdovers in charge of editing the National Strategy and preparing Ms. Tauscher's script, and these individuals basically bulldozed the final draft through Defense and State officials with very little interagency input and with a very short suspense."  Threat Level also asserts that "Most are disappointed in the language, which doesn't appear to be significantly different than the previous administration."  It is unclear who "Most" are.

In contrast to all of this, in my view the Strategy is a clear departure from the muddled thinking that dominated earlier discussions.  By muddled, I mean security discussions and policy that, paraphrasing just a little, went like this: "Biology Bad!  Hacking Bad!  Must Contain!" 

The new National Strategy document, however takes a very different line.  Sources tell this reporter, if you will, that the document resulted from a careful review that involved multiple agencies, over many months, with an aim to develop the future biosecurity strategy of the United States in a realistic context of rapidly spreading infectious diseases and international technological proliferation driven by economic and technical needs.  To wit, here are the first two paragraphs from the first page (emphasis added, of course):

We are experiencing an unparalleled period of advancement and innovation in the life sciences globally that continues to transform our way of life. Whether augmenting our ability to provide health care and protect the environment, or expanding our capacity for energy and agricultural production towards global sustainability, continued research and development in the life sciences is essential to a brighter future for all people.

The beneficial nature of life science research is reflected in the widespread manner in which it occurs. From cutting-edge academic institutes, to industrial research centers,
to private laboratories in baseĀ­ments and garages, progress is increasingly driven by innovation and open access to the insights and materials needed to advance individual initiatives.
Recall that this document carries the signature of the President of the United States.  I'll pause to let that sink in for a moment.

And now to drive home the point: the new Strategy for Countering Biological Threats explicitly points to garage biotech innovation and open access as crucial components of our physical and economic security.  I will note that this is a definite change in perspective, and one that has not fully permeated all levels of the Federal bureaucracy and contractor-aucracy.  Recently, during a conversation about locked doors, buddy systems, security cameras, and armed guards, I found myself reminding a room full of biosecurity professionals of the phrase emphasized above.  I also found myself reminding them -- with sincere apologies to all who might take offense -- that not all the brains, not all the money, and not all the ideas in the United States are found within Beltway.  Fortunately, the assembled great minds took this as intended and some laughter ensued, because they realized this was the point of including garage labs in the National Strategy, even if not everyone is comfortable with it.  And there are definitely very influential people who are not comfortable with it.  But, hey, the President signed it (forgive me, did I mention that part already?), so everyone is on board, right?

Anyway, I think the new National Strategy is a big step forward in that it also acknowledges that improving public health infrastructure and countering infectious diseases are explicitly part of countering artificial threats.  Additionally, the Strategy is clear on the need to establish networks that both promulgate behavioral norms and that help disseminate information.  And the new document clearly recognizes that these are international challenges (p.3):

Our Strategy is targeted to reduce biological threats by: (1) improving global access to the life sciences to combat infectious disease regardless of its cause; (2) establishing and reinforcing norms against the misuse of the life sciences; and (3) instituting a suite of coordinated activities that collectively will help influence, identify, inhibit, and/or interdict those who seek to misuse the life sciences.

...This Strategy reflects the fact that the challenges presented by biological threats cannot be addressed by the Federal Government alone, and that planning and participation must include the full range of domestic and international partners.
Norms, open biology, better technology, better public health infrastructure, and better intelligence: all are themes I have been pushing for a decade now.  So, 'nuff said on those points, I suppose.

Implementation is, of course, another matter entirely.  The Strategy leaves much up to federal, state, and local agencies, not all of whom have the funding, expertise, or inclination to follow along.  I don't have much to say about that part of the Strategy, for now.  But I am definitely not disappointed with the rest of it.  It is, you might say, the least bad thing I have read out of DC in a long time.

The New Yorker on Synthetic Biology

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Here is Michael Specter's article on synthetic biology "A Life of Its Own".  
A ProMED mail from yesterday (Archive Number 20090430.1636) has some interesting tidbits.

First, following up on the confusion over the genetic origins of "H1N1 Influenza A", the group at Columbia states:

Preliminary analysis of the genome of the new H1N1 influenza A virus responsible for the current pandemic indicates that all genetic segments are related closest to those of common swine influenza viruses.

...Six segments of the virus are related to swine viruses from North America and the
other 2 (NA and M) from swine viruses isolated in Europe/Asia.

The North American ancestors are related to the multiple reassortants, H1N2 and H3N2 swine viruses isolated in North America since 1998 [2,3]. In particular, the swine H3N2 isolates from 1998 were a triple reassortment of human, swine and avian origin.

Therefore, this preliminary analysis suggests at least 2 swine ancestors to the current H1N1, one of them related to the triple reassortant viruses isolated in North America in 1998.
So, it's composed of all recent pig viruses, but displays some inheritance from human and avian strains from a decade ago.  It's a flu potpourri!  And here I intend the original French meaning of the word potpourri -- "rotten pot".

On the vaccine front, there is a mix of efforts.  It is unclear when a traditional vaccine might show up.  However, the ProMED mail does contain an excerpt of a Scientific American story that suggests Novavax is already working on a VLP synthetic vaccine, possibly confirming my earlier speculation.


After working with Bio-era for several years on pandemic preparedness, pathogen surveillance, and synthetic vaccines, a few things jumped out at me from ScienceInsider's interview with CDC Virologist Ruben Donis.

As part of the discussion on the origin of the present "H1N1 Influenza A", as we are now supposed to call it, Donis notes that "The amazing thing is the hemagglutinins we are seeing in this strain are a lonely branch that have been evolving somewhere and we didn't know about it."

Translation: Despite the increased surveillance since 2005, a key set of genes that are important components of the present virus(es) appeared out of nowhere, or, rather, appeared out of somewhere that the surveillance does not reach.  Must fix.  Immediately.

With respect to vaccine development, Donis suggests that "The virus doesn't grow very well in eggs. We hope the virus will improve [the] ability to grow in eggs so we can produce [a] vaccine very quickly so these secondary and tertiary cases can be controlled."  It is unclear at this point in the interview whether he is referring specifically to "H1N1 Influenza A", or to a larger group of viruses, or something else.  Assuming he means the present (almost pandemic) strain, it is interesting that somebody at CDC already knows the bug doesn't grow well in eggs.  It is also unclear what he means by "we hope the virus will improve [the] ablity to grow in eggs" -- perhaps he is referring to an effort to produce a vaccine via reverse genetics for production in eggs.  Either way, it suggests we may have to rely on newer technologies to produce vaccines (see my earlier posts on synthetic vaccines).

I have heard rumors that DARPA has a program up and running to turn out several million doses of synthetic vaccines (VLPs, primarily) in six weeks.  Here's hoping those are more than rumors.

The interview with Donis ends on a rather somber note:  Even though the flu season is ending in North America and Europe, we can't forget the rest of the planet: "The folks in Buenos Aires are in trouble. They're entering winter now."

This is a long, long way from being over.

More on the genetics of the H1N1 virus

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Effect Measure has a nice post on the origin of genes in the present H1N1 strain making the rounds, and it adds some subtlety to the story I relayed a couple of days ago.

In short, the genome appears to be composed of pieces that have all be circulating in pigs for many years, yet some of those genes may have originally come from human and avian viruses.

I took a few minutes last night to add tags to most of my old posts about SARS, H5N1, vaccines, influenza, and infectious disease.  I also fixed a few links still broken from the ISP switch last year, including the SARS outbreak timeline in "Nature is Full of Surprises, and We Are Totally Unprepared".

Update:  Here is another good 2009 H1N1 Flu Outbreak map from Google.
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

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Well, it looks like we got surprised.  Just like we, um, expectedTo 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

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(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.

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