The New Yorker on Synthetic Biology

Here is Michael Specter's article on synthetic biology "A Life of Its Own".  

The Bio-Economist

Last week's Economist has another story on biohacking, "Hacking goes squishy", that contains a nod or two to the economic context and also has a version of my cost curves.  I have a couple of thoughts.

The cost curve figure in the article was finished early August, and since then I have decided to add additional data points.  Just a couple of days ago, an ad from Mr. Gene (a division of GENEART) showed up in my inbox advertising synthesis for $.39/base pair.  I haven't had time to figure out why GENEART itself charges $.44/base, but presumably there is some additional customer service/sequencing/etc. thrown in.  The latest commercial cost for oligos (in low volume) appears to be about $.15/base, which is actually a slight increase compared to prices I found a couple of years ago.  More on this later.

On the sequencing side of things, Illumina has delivered its first commercial human genome at $48,000.  Here is the Bio-IT World summary: "Illumina completed the sequence at its CLIA-certified laboratory, producing more than 110 billion base calls, good for 30X coverage of the genome and the identification of some 300,000 novel single nucleotide polymorphisms."  I'll call it $8x10^(-6) per finished base, even though they actually sequenced many more bases than are in a human genome.

In other sequencing news, Complete Genomics just announced (PDF) the sequencing of 14 individuals for various academic projects.  They claim to be on track to offer $5000 human genomes in the next six months.  Helicos made a lot of noise last month with the publication of Steve Quake's genome at a cost in reagents of ~$48,000.  While all the numbers in the article are impressive, like many observers I still have questions about the actual cost per base in a commercial operation.  Labor?  Cost of capital?  Nonetheless, the technology is impressive.

The cost of sequencing continues to fall rapidly.  The race to the bottom is well under way.  Here is the figure:

It is interesting that the oligo and gene synthesis numbers have the appearance of slowing down.  I don't believe this is evidence of a real trend, but rather that the cost of synthesis is now about labor and finance rather than about raw materials.  And sequencing (proof reading) of synthetic genes now accounts for a good hunk of the cost, depending on what exactly you are synthesizing.  Since I have now seen several different technologies that can be used to reduce costs, I expect prices to continue falling in the years to come.  One technology nearing the marketing stage enables the use of unpurified oligos in gene assembly, including those synthesized on chips, through true error correction rather than error removal.  While the consequent reduction in the cost of raw materials may not add up to much, there should be substantial cost improvements from 1) reducing required sequencing and 2) the ability to automate assembly. 

I can also now update my "genetically modified domestic product" (GMDP) numbers for the US.  My earlier article "Laying the foundations for a bio-economy" (journal link), contained an estimate that genetically modified systems generate revenues that are the equivalent of about 1% of US GDP.  It turns out that is too small.

The reason for the underestimate is that I was overly trusting of reporting by The Financial Times, Nature Biotechnology (upper left panel), and others, who all published stories claiming that 2007/8 revenues from genetically modified crops were about US$ 8 billion worldwide and a bit over $4 billion in the US.  It is interesting to me that all these organizations misreported in exactly the same way a number published by the ISAAA in its report "Global Status of Commercialized Biotech/GM Crops: 2008".  In their defense, the reporters probably just had access to the executive summary, which contains the phrase "the global market value of biotech crops... was US$7.5 billion", and they were probably in a hurry to meet deadlines.  But the very next sentence in the executive summary reads "The value of the global biotech crop market is based on the sale price of biotech seed plus any technology fees that apply." So that ~$8 billion worldwide is just seeds and related fees.  And seeds grow.  Into bigger things.  With greater value.  Like crops. 

A quick visit to the USDA reveals US revenues from GM crops that is in the neighborhood of $100 billion.  Here is a nice figure showing crop adoption since 1996, which gives us the percentage of acres planted in GM seeds.  Then, jumping over to the National Agricultural Statistics Service, you can figure out the revenues per crop.  Put it all together and you find out that in 2007 the value to US farmers of revenues from GM crops was close to $70 billion.

Here is a table from Biology is Technology that lays out some of the global numbers up through 2007:
 

Table 11.1 Revenues from genetically modified systems in 2007
Sector	Worldwide revenues ($ billions)	US revenues ($ billions)	% of US GDP (total of $~14 trillion)	Revenue growth rate in US (%)
Biotech drugs ("biologics")	79	67	.48	15-20
Agbiotech/GMOs	128 (est)	69	.49	10
Industrial	~110	~85	.61	15-20

 
I left out of the book any discussion of what benefit GM crops give compared to non-GM crops because I don't yet trust any of the numbers I have found; estimates range from -30% to +30%.  When I have time to sort it out for myself, I will publish something.  Until then, I would note that it seems unlikely to me that farmers around the world would keep buying GM seeds (that are more expensive than non-GM seeds) -- and buying more GM seeds every year -- if they didn't benefit financially from making that choice.

By the way, for those who have asked or are curious, I just learned that the book comes off the presses in the first week of December, though I don't know when they actually will be available in stores and whatnot.  No news yet on e-versions for the Kindle, etc., but let me know if you are interested.

Anyway, although not all the numbers for 2008-2009 are available (including GDP), at this point I am pretty comfortable with the estimate that revenues from GM systems in 2009 will be the equivalent of about 2% of US GDP.  That is a big number.  As big as mining in the US.  And there is no way mining is growing at ~15% a year.  The future of the economy is biology. 

NYT on Systems Biology, Eric Schadt, and Sage Bionetworks

The Times is running a nice profile piece on Eric Schadt and his work at Rosetta and now Sage Bionetworks.

Biodesic evaluated systems biology investments for a large organization about 18 months ago, and Schadt's approach makes more sense to me -- by far -- than anything else we looked at.  I sat in on the pitch that Schadt and Stephen Friend made to that sameorganization, and it was crystal clear to me that Sage -- now residing at the Hutch here in Seattle -- should be on the receiving end of piles of money.  The stacks of Nature Group publications Schadt is accumulating suggest he is on to something, and it appears that his methods can be used to make predictions about the behaviors of complex networks.  Time and experimentation will tell, of course.  The open source aspect is a huge bonus.

Schadt's move to Pacific Biosciences is interesting because during his talk he suggested that genome sequencing provides enough information about variation to fuel his statistical methods for predicting interactions not just between genes but between tissues -- he is working at the level of describing the behavior of networks of networks.  It seems he will now have access to plenty of data.

And the Innovation Continues...Starting with Shake and Bake Meth!

My first published effort at tracking the pace and proliferation of biological technologies (PDF) was published in 2003.  In that paper, I started following the efforts of the DEA and the DOJ to restrict production and use of methamphetamine, and also started following the response to those efforts as an example of proliferation and innovation driven by proscription.

The story started circa 2002 with 95% of meth production in Mom and Pop operations that made less than 5 kg per year.  Then the US Government decided to restrict access to the precursor chemicals and also to crack down on domestic production.  As I described in 2008, these enforcement actions did sharply reduce the number of "clandestine laboratory incidents" in the US, but those actions also resulted in a proliferation of production across the US border, and a consequently greater flow of drugs across the border.  Domestic consumption continued to increase.  The DEA acknowledged that its efforts contributed to the development of a drug production and distribution infrastructure that is, "[M]ore difficult for local law enforcement agencies to identify, investigate, and dismantle because[it is] typically much more organized and experienced than local independent producers and distributors."  The meth market thus became both bigger and blacker.

Now it turns out that the production infrastructure for meth has been reduced to a 2-liter soda bottle.  As reported by the AP in the last few days, "The do-it-yourself method creates just enough meth for a few hits, allowing users to make their own doses instead of buying mass-produced drugs from a dealer."  The AP reporters found that meth-related busts are on the increase in 2/3 of the states examined.  So we are back to distributed meth production -- using methods that are even harder to track and crack than bathtub labs -- thanks to innovation driven by attempts to restrict/regulate/proscribe access to a technology.

And in Other News...3D Printers for All

Priya Ganapati recently covered the latest in 3D printing for Wired.  The Makerbot looks to cost about a grand, depending on what you order, and how much of it you build yourself.  It prints all sorts of interesting plastics.  According to the wiki, the "plastruder" print head accepts 3mm plastic filament, so presumably the smallest voxel is 3mm on a side.  Alas this is quite macroscopic, but even if I can't yet print microfluidic components I can imagine all sorts of other interesting applications.  The Makerbot is related to the Reprap, which can now (mostly) print itself.  Combine the two, and you can print a pretty impressive -- and always growing -- list of plastic and metal objects (see the Thingiverse and the Reprap Object Library).

How does 3D printing tie into drug proscription?  Oh, just tangentially, I suppose.  I make more of this in the book.  More power to create in more creative people's hands.  Good luck trying to ban anything in the future.

Data and References for Longest Published sDNA

Various hard drive crashes have several times wiped out my records for the longest published synthetic DNA (sDNA).  I find that I once again need the list of references to finish off the edits for the book.  I will post them in the open here so that I, and everyone else, will always have access to them.

Year	Length	Refs
1979	207	Khorana (1979)
1990	2100	Mandecki (1990)
1995	2700	Stemmer (1995)
2002	7500	Cello (2002)
2004.4	14600	Tian (2004)
2004.7	32000	Kodumal (2004)
2008	583000	Gibson (2008)

1979
Total synthesis of a gene
HG Khorana
Science 16 February 1979:
Vol. 203. no. 4381, pp. 614 - 625
http://www.sciencemag.org/cgi/content/abstract/203/4381/614

1990
A totally synthetic plasmid for general cloning, gene expression and mutagenesis in Escherichia coli
Wlodek Mandecki, Mark A. Hayden, Mary Ann Shallcross and Elizabeth Stotland
Gene Volume 94, Issue 1, 28 September 1990, Pages 103-107
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T39-47GH99S-1J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=84ca7779ff1489d5e18082b9ecb80683

1995
Single-step assembly of a gene and entire plasmid from large numbers of oligodeoxyribonucleotides
Willem P. C. Stemmer, Andreas Crameria, Kim D. Hab, Thomas M. Brennanb and Herbert L. Heynekerb
Gene Volume 164, Issue 1, 16 October 1995, Pages 49-53
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T39-3Y6HK7G-66&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=83620e335899881aac712a720396b8f2

2002
Chemical Synthesis of Poliovirus cDNA: Generation of Infectious Virus in the Absence of Natural Template
Jeronimo Cello, Aniko V. Paul, Eckard Wimmer
Science 9 August 2002: Vol. 297. no. 5583, pp. 1016 - 1018
http://www.sciencemag.org/cgi/content/abstract/1072266

2004
Accurate multiplex gene synthesis from programmable DNA microchips
Jingdong Tian, Hui Gong, Nijing Sheng, Xiaochuan Zhou, Erdogan Gulari, Xiaolian Gao & George Church
Nature 432, 1050-1054 (23 December 2004)
http://www.nature.com/nature/journal/v432/n7020/full/nature03151.html

Total synthesis of long DNA sequences: Synthesis of a contiguous 32-kb polyketide synthase gene cluster
Sarah J. Kodumal, Kedar G. Patel, Ralph Reid, Hugo G. Menzella, Mark Welch, and Daniel V. Santi
PNAS November 2, 2004 vol. 101 no. 44 15573-15578
http://www.pnas.org/content/101/44/15573.abstract

2008
Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome
Daniel G. Gibson, Gwynedd A. Benders, Cynthia Andrews-Pfannkoch, Evgeniya A. Denisova, Holly Baden-Tillson, Jayshree Zaveri, Timothy B. Stockwell, Anushka Brownley, David W. Thomas, Mikkel A. Algire, Chuck Merryman, Lei Young, Vladimir N. Noskov, John I. Glass, J. Craig Venter, Clyde A. Hutchison, III, Hamilton O. Smith
Science 29 February 2008: Vol. 319. no. 5867, pp. 1215 - 1220
http://www.sciencemag.org/cgi/content/abstract/1151721

Another Step Toward DIYStemCells

(18 June 2009: Lightly edited for clarity.)

The June 5 issue of Cell Stem Cells has a brief report describing the use of four proteins to reprogram human fibroblasts into induced pluripotent stem cells (iPSCs).  I think this is a pretty important paper, as it dispenses with any sort of genetic manipulation of the target cells or any use of plasmids to insert new "control circuitry", or any chemical manipulation whatsoever.

As expected, it is getting easier to produce iPSCs, and the authors of the paper ("Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins") note that their work demonstrates the elimination of "the potential risks associated with the use of viruses, DNA transfection, and potentially harmful chemicals and in the future could potentially provide a safe source of patient-specific cells for regenerative medicine".

Kim et al used four recombinant human proteins to turn human newborn fibroblast cells (purchased from ATCC -- see the Supplemental Data) into iPSCs, where each of the proteins was fused to a nine amino acid long "cell-penetrating peptide" (CPP) that facilitated the importation of the proteins across the cell membrane.  The procedure was not particularly efficient, but after multiple treatments the authors produced cells that could differentiate into many different kinds of human tissues.

Here are a couple of thoughts about the paper.  Note that in what follows I have only had a few sips of my first cup of coffee today, and my brain is still quite fuzzy, but I think I am mostly coherent.  You can be the judge.

First, the authors did not use mature cells from adults, so don't expect this paper to lead to replacement organs and tissues tomorrow.  The use of cells from newborns makes a great deal of sense for a first go at getting protein-based reprogramming to work, as those cells have already been demonstrated to be relatively easy to reprogram.  The published procedure required many weeks of effort to produce iPSCs, and authors note that they have quite a ways to go before they can produce stem cells at the same efficiency as other techniques.

Nonetheless, it works.

Second, the paper describes PCR-based cloning of human genes to add the CPP sequences, along with a fair amount of bench manipulation to generate cells that made each of the four reprogramming proteins.  All the sequences for those proteins are online, as are the sequences for the CPPs, so generating the corresponding genes by synthesis rather than cloning would now cost less than $10K, with delivery in 2-4 weeks.  In another year, it will probably cost no more than $5K.  (How long will it be before these proteins show up in the Registry of Standard Biology Parts?)

Third, the authors did not use purified reprogramming proteins to generate iPSCs, but rather used whole cell extracts from cells that produced those proteins.  Thus the concentrations of the reprogramming proteins were limited to whatever was in the cell extract.  This might critically affect the efficiency of the reprogramming.  Presumably, the authors are already working on generating cultured cell lines to produced the reprogramming proteins in larger quantities.  But if you wanted to do it yourself, it looks like you might "simply" have to order the appropriate sequences from Blue Heron already cloned into the human expression plasmid pCDNA3.1/myc-His A, which is available from Invitrogen.  This would add a couple of hundred dollars to the cost because Blue Heron would have to play around with a proprietary plasmid instead of the public domain plasmids they usually use to ship genes.  You would then follow the recipe from the Supplementary Data to transform a protein production cell line to make those proteins.  Or perhaps you have a favorite recipe of your own.  Here is something I don't get -- it looks like that particular expression plasmid adds a His tag to the end of the gene, so I don't understand why Kim et al didn't try a purification step, but maybe that is underway.

Fourth, if you wanted to do this at home, you could.  You should expect to fail many times.  And then you should expect to fail some more.  And then, assuming your human cell culture technique is up to snuff, you should expect to eventually succeed.  You might want to wait until the inevitable paper showing how to do this with adult differentiated skin cells is published.

And then what?

You will have an autologous stem cell line that you can use to produce tissues that are, immunologically speaking, identical to those in your body.  What should you do with them?  I would suggest you show them off at cocktail parties, brag about them on Facebook, and then destroy them with bleach and an autoclave.  In lieu of an autoclave a microwave would probably do just fine.

But I expect that at least some of you will try to follow a recipe to generate some sort of human tissue, or even to simply inject those cells in your own bodies, which will result in all kinds of crazy teratomas and other tumors.  To quote Harold Ramus, "that would be bad".  So don't do that.  Just because DIYStemCells are cool doesn't mean you should actually use them yourself.  But I know some of you will anyway.  That is the future of biological technologies, for better or worse.

The Economist Debate on the Fuel of the Future for Cars

Last week The Economist ran an online debate considering the motion "Biofuels, not electricity, will power the car of the future".  I was privileged to be invited as a guest contributor along with Tim Searchinger of Princeton University.  The two primary "speakers" were Alan Shaw of Codexis and Sidney Goodman of Automotive Alliances.  Here is my contribution to the debate, in which I basically rejected the false dichotomy of the motion (the first two 'graphs follow):

The future of transportation power sources will not be restricted to "either/or". Rather, over the coming decades, the nature of transportation fuel will be characterised by a growing diversity. The power sources for the cars of the future will be determined by the needs those cars address.

Those needs will be set for the market by a wide range of factors. Political and economic pressures are likely to require reducing greenhouse gas emissions and overall energy use per trip. Individuals behind the wheel will seek to minimise costs. But there is no single fuel that simultaneously satisfies the requirements of carbon neutrality, rapid refuelling, high-energy density for medium- to long-range driving and low cost.

I find it interesting that the voting came down so heavily in favor of electricity as the "fuel" of the future.  I suppose the feasibility of widespread electric cars depends on what you mean by "future".  Two substantial technology shifts will have to occur before electric cars displace those running on liquid fuels, both of which will require decades and trillions.

First, for the next several decades, no country, including the US, is likely to have sufficient electricity generating resources and power distribution infrustructure to convert large numbers of automobiles to electric power.  We need to install all kinds of new transmission lines around the country to pull this off.  And if we want the electricity to be carbon neutral, we need to install vast amounts of wind and solar generating capacity.  I know Stewart Brand is now arguing for nuclear power as "clean energy", but that still doesn't make sense to me for basic economic reasons. (Aside: at a party a few months ago, I got Lowell Wood to admit that nuclear power can't be economically viable unless the original funders go bankrupt and you can buy the physical plant on the cheap after all the initial investment has been wiped out.  Sweet business model.)

Second, the energy density of batteries is far below that of liquid hydrocarbons.  (See the Ragone chart included in my contribution to The Economist debate.)  Batteries are likely to close the gap over the coming years, but long distance driving will be the domain of liquid fuels for many years to come.  Yes, battery changing stations are an interesting option (as demonstrated by Better Place), but it will take vast investment to build a network of such stations sufficient to replace (or even compete with) liquid fuels.  Plugging in to the existing grid will require many hours to charge the batteries, if only because running sufficient current through most existing wires (and the cars themselves) to recharge car batteries rapidly would melt those wires.  Yes, yes -- nanothis and nanothat promise to enable rapid recharging of batteries.  Someday.  'Til then, don't bother me with science fiction.  And even if those batteries do show up in the proverbial "3 to 5 year" time frame, charging them rapidly would still melt most household power systems.

In the long run, I expect that electric cars will eventually replace those powered by liquid fuels.  But in the mean time, liquid fuels will continue to dominate our economy.

Stem_Cells@Home or DIYStemCells?

I'm in Cambridge, UK, and mostly on local time.  Mostly.  Spring is very pleasant here.

Here are a couple of interesting things that I've come across recently.

The FDA is considering regulating autologous stem cells as prescription drugs.  These cells are removed from a patient, multiplied in culture, and then reintroduced at a site of injury.  The culture step, reportedly, gets the FDA all in a lather with the desire for control.  According to the author of a story at h+ magazine, this could drastically slow down adoption and use, and potentially relegate the the technology to large corporate interests.  The story, and an accompanying interview with a physician, argues that self-regulation of stem cell treatments as a medical practice (which the FDA is not chartered to regulate) is a far better choice.

If the FDA does go the route of asserting (or, rather, attempting to assert) its might, it suggests to me that once again the powers that be are not sufficiently in tune with the progress of technology.  To wit: here is Attila Chordash's homebrew procedure from MAKE for isolating placental stem cells (I met Attila a few years ago at SciFoo and have participated with him in some IFTF activities -- smart fellow).  News this past year has been full of various ways to produce induced pluripotent stem (iPS) cells, ranging from retroviral reprogramming, to drug-controlled lentiviruses, to plasmid-mediated reprogramming. Skin cells were turned into iPSs early in 2008 (here is an earlier summary at Nature Reports Stem Cells).  Last November, a paper in PNAS showed a single synthetic prophage containing 4 genes was sufficient to turn a mouse fibroblast into an iPS cell, and showed that the method could be used to generate human iPS cells from human keratinocytes.  Each of these steps is said to demonstrate an increase the controllability of the reprogramming, increase the uniformity of the resulting population of cells, and decrease the difficulty.

This is not to say that any step in the reprogramming is simple.  From personal experience I can testify that culturing even "stable" human cell lines can be challenging at times.  But, by definition, as published methods to reprogram cells are repeated and refined this will demonstrate a progression from iPS cell production as an art into a technology.  The plasmid-mediated programming, in particular, strikes me as a promising route to a widespread technology because it does not depend upon, or result in, integration of the plasmid into the host chromosome.  Moreover, it will be trivial to synthesize new genes for use in the plasmid as better recipes come along.  So how long before these cells will be used in therapies?

A recent review in Science by Gurdon and Melton identifies some interesting challenges:

The future value of reprogrammed cells is of two kinds. One is to create long-lasting cell lines from patients with genetic diseases, in order to test potentially useful drugs or other treatments. The other is to provide replacement cells for patients. To be therapeutically beneficial, replacement cells will probably need (i) to be provided in sufficient numbers; (ii) to carry out their function, even though they are not normally integrated into host tissues; and (iii) to be able to produce the correct amount of their product.

A human adult has about 10¹⁵ cells, and the liver contains about 10¹⁴ cells. To create this number of cells starting from a 10^-4 success rate of deriving iPS cells from skin would require an enormous number of cell divisions in culture, although the prolonged culture of ES-like cells provides a valuable amplification step. However, many parts of the human body need a far smaller number of cells to improve function. An example is the human eye retina, in which only 10⁵ cells could be of therapeutic benefit.

Will introduced cells be useful even if not "properly" integrated into the host? Most organs consist of a complex arrangement of several different cell types. The pancreas, for example, contains exocrine (acinar) cells, ductal cells, and at least four kinds of hormone-secreting cells in the endocrine islet. Replacement endocrine cells can provide useful therapeutic benefit even if not incorporated into the normal complex pancreas cell configuration. In some cases, introduced cells can have functionally beneficial effects, even if indirectly. It is not yet clear whether introduced cells will be correctly regulated to produce the desired amount of product.

There is obviously a great deal of science to do before iPS cells are used on a regular basis to produce therapies. Nonetheless, therapy is already beginning around the world.  Medical tourism to China for stem cell treatments is increasingly common, even for children.

Clearly, the technology is so promising that families are willing to go to considerable sacrifice to obtain treatment.  Which brings us back to the FDA and regulation.  I have to wonder what the Feds are thinking.  I would certainly agree with anyone who suggests that stem cells are a powerful technology, and that treatments should be safe.  But any regulatory or policy step that reduces access and slows progress in the US is simply going to send people overseas for treatment.  Then, as the technology becomes ever simpler to learn and use, a back-room market will open up in the States.  
 
So, I wonder, as the technology matures, how long before we get DIYStemCells, Stem_Cells@Home, or HomebrewStemCells?  As methods are published to harvest candidate cells and turn them into autologous iPS cells, how long will it be before athletes looking for an edge, the curious, and the truly ill, all start trying this for themselves?  I am by no means arguing that this is a good idea, and I strongly suspect that the better course is to ensure that people have access to the technology through physicians who know what they are doing.  But without that access, a black market, with all of the shadows and horrors envisioned by William Gibson and others, is inevitable.

Wouldn't it be simpler, and vastly safer, to make sure that everyone has access to skills and materials?  This seems like another arena in which pushing for an Open Biology makes a great deal more sense than the alternative.

Visiting Europe in May

I'll be in Europe and the UK for all of May, based in Cambridge.  I'll be making trips to London, Edinburgh, and Paris, and probably The Netherlands, all to give talks and visit with iGEM teams and other students.

Anybody interested in chatting?

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?