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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.

The latest issue of The Hastings Center Report carries an essay of mine, "Staying Sober about Science" (free access after registration), about my thoughts on New Directions: The Ethics of Synthetic Biology and Emerging Technologies (PDF) from The Presidential Commission for the Study of Bioethical Issues.

Here is the first paragraph:

Biology, we are frequently told, is the science of the twenty-first century. Authority informs us that moving genes from one organism to another will provide new drugs, extend both the quantity and quality of life, and feed and fuel the world while reducing water consumption and greenhouse gas emissions. Authority also informs that novel genes will escape from genetically modified crops, thereby leading to herbicide-resistant weeds; that genetically modified crops are an evil privatization of the gene pool that will with certainty lead to the economic ruin of small farmers around the world; and that economic growth derived from biological technologies will cause more harm than good. In other words, we are told that biological technologies will provide benefits and will come with costs--with tales of both costs and benefits occasionally inflated--like every other technology humans have developed and deployed over all of recorded history.

And here are a couple of other selected bits:

Overall, in my opinion, the report is well considered. One must commend President Obama for showing leadership in so rapidly addressing what is seen in some quarters as a highly contentious issue. However, as noted by the commission itself, much of the hubbub is due to hype by both the press and certain parties interested in amplifying the importance of the Venter Institute's accomplishments. Certain scientists want to drive a stake into the heart of vitalism, and perhaps to undermine religious positions concerning the origin of life, while "civil society" groups stoke fears about Frankenstein and want a moratorium on research in synthetic biology. Notably, even when invited to comment by the commission, religious groups had little to say on the matter.

The commission avoided the trap of proscribing from on high the future course of a technology still emerging from the muck. Yet I cannot help the feeling that the report implicitly assumes that the technology can be guided or somehow controlled, as does most of the public discourse on synthetic biology. The broader history of technology, and of its regulation or restriction, suggests that directing its development would be no easy task.8 Often technologies that are encouraged and supported are also stunted, while technologies that face restriction or prohibition become widespread and indispensable.

...The commission's stance favors continued research in synthetic biology precisely because the threats of enormous societal and economic costs are vague and unsubstantiated. Moreover, there are practical implications of continued research that are critical to preparing for future challenges. The commission notes that "undue restriction may not only inhibit the distribution of new benefits, but it may also be counterproductive to security and safety by preventing researchers from developing effective safeguards."12 Continued pursuit of knowledge and capability is critical to our physical and economic security, an argument I have been attempting to inject into the conversation in Washington, D.C., for a decade. The commission firmly embraced a concept woven into the founding fabric of the United States. In the inaugural State of the Union Address in 1790, George Washington told Congress "there is nothing which can better deserve your patronage than the promotion of science and literature. Knowledge is in every country the surest basis of publick happiness."13

The pursuit of knowledge is every bit as important a foundation of the republic as explicit acknowledgment of the unalienable rights of life, liberty, and the pursuit of happiness. Science, literature, art, and technology have played obvious roles in the cultural, economic, and political development of the United States. More broadly, science and engineering are inextricably linked with human progress from a history of living in dirt, disease, and hunger to . . . today. One must of course acknowledge that today's world is imperfect; dirt, disease, and hunger remain part of the human experience. But these ills will always be part of the human experience. Overall, the pursuit of knowledge has vastly improved the human condition. Without scientific inquiry, technological development, and the economic incentive to refine innovations into useful and desirable products, we would still be scrabbling in the dirt, beset by countless diseases, often hungry, slowly losing our teeth.

There's more here.

References:

8. R. Carlson, Biology Is Technology: The Promise, Peril, and New Business of Engineering Life (Cambridge, Mass.: Harvard University Press, 2010).

12. Presidential Commission for the Study of Bioethical Issues, New Directions, 5.

13. G. Washington, "The First State of the Union Address," January 8, 1790, http://ahp.gatech.edu/first_state_union_1790.html.

I've just landed in Washington DC for a biosecurity meeting -- a chat about how not to get caught with our pants down.  Catching up on the news in my hotel room, I notice that over at Danger Room Adam Rawnsley is reporting that the Chinese are talking tough about "crashing" the land bases of pirates in Africa.

With regards to biosecurity, and its extension into other security matters -- food security, in this case -- I've been expecting China to get more aggressive on pirates.  And this is just the beginning.  China's food demand is skyrocketing as incomes rise, and much of that food is going to come from overseas (see my previous post "More on China's Economy, Food Production, and Food Demand").  The Economist recently estimated that of the approximately 80 million hectares of land deals in developing countries in the last decade -- "more than the area of farmland of Britain, France, Germany and Italy combined" -- two-thirds were by Chinese companies.  A very good guess is that a substantial fraction of the other one-third were made by countries or companies who hope to sell to the Chinese.

The motivation for this land rush is simple: despite plans by the Chinese government, it is highly unlikely that the country will be able to maintain "food independence" -- the ability to feed its population with domestic supplies.  So China's critical supply lines for food and other raw materials are going global, and those shipping lines often pass through waters off eastern Africa -- prime pirate waters.  Chinese shipping is also at threat in the Straight of Malacca.

It is thus no surprise that China is getting serious about piracy.  The U.S. should expect the Chinese Navy to be more active around the world, and we should expect more investment by the Chinese government in the ability to protect global supply lines.  We should also not overreact to this situation.  We know that it is coming, and everyone should be paying attention, in part so that there are no misunderstandings.  The U.S. Navy, among others, should get its ducks (and, admirals, and carriers, etc) in a row now in the form of real engagement with the Chinese Navy.  This is an opportunity for more cooperation.

Increasing demand for food will create more situations like this in coming years.  The security of all countries depends on getting this right, and not getting caught with our pants down.

By now everybody has heard that bin Laden is dead.  R.I.H.

When I heard President Obama say last night that bin Laden's identity had been confirmed by DNA analysis (here's a post from Scientific American about how this might be done), I started mulling over what you might put in place to pull off this analysis quickly.

First, you need DNA.  US forces had OBL's, and everyone is reporting they compared his DNA to his sisters.  How?  If I really wanted to be certain, I would sequence some of her DNA and then prepare PCR primers based on that information.

Second, you need to check the suspect sequence.  There is certainly at least one of Idaho Technology's JBAIDS real-time PCR systems in theater.  Could be on the ground in Afghanistan, could be on an aircraft carrier or assault ship.  I doubt they flew one in and did the test in the air, but that is certainly possible.  (Side note, if you click through to the JBAIDS site, the photo totally makes the instrument look smaller than it is.  The box in real life is waaay bigger than a laptop.  "Man-portable RT-PCR" they say.  I say not by me.)

It probably took longer to fly the body out and get a sample to the PCR machine than it did to actually process the DNA and certify identity by RT-PCR.

So I have only one question: Who got the contract for high purity bin Laden-specific DNA primers?

On my head, that is.  Not in, alas, but on.  That's the way it goes, some days.  But at least I am pressing forward.  Or the idea on my head is.  That is what the sign says, anyway. 

Week before last, I spent an enjoyable couple of days at The Economist's Ideas Economy: Human Potential 2010.  I'll post the video when it is available.

Among the most interesting things I heard: Richard Florida says that the "creative sector" has never been above 5% unemployment, and that sector now constitutes 30% of the US workforce.  Here is his presentation:



I also had the chance to meet Vivek Wadhwa (very smart fellow), whose recent fascinating blog post on whether job creation comes from big companies or startups I have been pondering for weeks.  Here is a snippet from the post: "Startups aren't just an important contributor to job growth: they're the only thing. Without startups, there would be no net job growth in the U.S. economy. From 1977 to 2005, existing companies were net job destroyers, losing 1 million net jobs per year. In contrast, new businesses in their first year added an average of 3 million jobs annually."

The Greeks just can't get a break.

Talk about Greecing the wheels.

I'm operating on waaaay too little sleep in Brazil...

The press is all abuzz over the Venter Institute's paper last week demonstrating a functioning synthetic genome.  Here is the Gibson et al paper in Science, and here are takes from the NYT and The Economist (lede, story).  The Economist story has a figure with the cost and productivity data for gene and oligo synthesis, respectively.  Here also are Jamais Cascio and Oliver Morton, who points to this collection of opinions in Nature.

The nuts and bolts (or bases and methylases?) of the story are this: Gibson et al ordered a whole mess of pieces of relatively short, synthetic DNA from Blue Heron and stitched that DNA together into full length genome for Bug B, which they then transplanted into a related microbial species, Bug A.  The transplanted genome B was shown to be fully functional and to change the species from old to new, from A to B.  Cool.

Yet, my general reaction to this is the same as it was the last time the Venter team claimed they were creating artificial life.  (How many times can one make this claim?)  The assembly and boot-up are really fantastic technical achievements.  (If only we all had the reported $40 million to throw at a project like this.)  But creating life, and the even the claim of creating a "synthetic cell"?  Meh.

(See my earlier posts, "Publication of the Venter Institute's synthetic bacterial chromosome", January 2008, and "Updated Longest Synthetic DNA Plot ", December 2007.)

I am going to agree with my friends at The Economist (see main story) that the announcement is "not unexpected", and disagree strongly that "The announcement is momentous."  DNA is DNA.  We have known that for, oh, a long time now.  Synthetic DNA that is biologically indistinguishable from "natural DNA" is, well, biologically indistinguishable from natural DNA.  This result is at least thirty years old, when synthetic DNA was first used to cause an organism to do something new.  There are plenty of other people saying this in print, so I won't belabor the point; see, for example, the comments in the NYT article.

One less-than-interesting outcome of this paper is that we are once again going to read all about the death of vitalism (see the Nature opinion pieces).  Here are the first two paragraphs from Chapter 4 of my book:

"I must tell you that I can prepare urea without requiring a kidney of an animal, either man or dog." With these words, in 1828 Friedrich Wöhler claimed he had irreversibly changed the world. In a letter to his former teacher Joens Jacob Berzelius, Wöhler wrote that he had witnessed "the great tragedy of science, the slaying of a beautiful hypothesis by an ugly fact." The beautiful idea to which he referred was vitalism, the notion that organic matter, exemplified in this case by urea, was animated and created by a vital force and that it could not be synthesized from inorganic components. The ugly fact was a dish of urea crystals on his laboratory bench, produced by heating inorganic salts. Thus, many textbooks announce, was born the field of synthetic organic chemistry.

As is often the case, however, events were somewhat more complicated than the textbook story. Wöhler had used salts prepared from tannery wastes, which adherents to vitalism claimed contaminated his reaction with a vital component. Wöhler's achievement took many years to permeate the mind-set of the day, and nearly two decades passed before a student of his, Hermann Kolbe, first used the word "synthesis" in a paper to describe a set of reactions that produced acetic acid from its inorganic elements.

Care to guess where the nucleotides came from that went into the Gibson et al synthetic genome?  Probably purified and reprocessed from sugarcane.  Less probably salmon sperm.  In other words, the nucleotides came from living systems, and are thus tainted for those who care about such things.  So much for another nail in the vital coffin.

Somewhat more intriguing will be the debate around whether it is the atoms in the genome that are interesting or instead the information conveyed by the arrangement of those atoms that we should care about.  Clearly, if nothing else this paper demonstrates that the informational code determines species.  This isn't really news to anyone who has thought about it (except, perhaps, to IP lawyers -- see my recent post on the breast cancer gene lawsuit) but it might get a broader range of people thinking more about life as information.  What then, does "creating life" mean?  Creating information?  Creating sequence?  And what sort of design tools do we need to truly control these creations?  Are we just talking about much better computer simulations, or is there more physics to learn, or is it all just too complicated?  Will we be forever chasing away ghosts of vitalism?

That's all I have for deep meaning at the moment.  I've hardly just got off one set of airplanes (New York-DC-LA) and have to get on another for Brazil in the morning. 

I would, however, point out that the recent paper describes what may be a species-specific processing hack.  From the paper:

...Initial attempts to extract the M. mycoides genome from yeast and transplant it into M. capricolum failed. We discovered that the donor and recipient mycoplasmas share a common restriction system. The donor genome was methylated in the native M. mycoides cells and was therefore protected against restriction during the transplantation from a native donor cell. However, the bacterial genomes grown in yeast are unmethylated and so are not protected from the single restriction system of the recipient cell. We were able to overcome this restriction barrier by methylating the donor DNA with purified methylases or crude M. mycoides or M. capricolum extracts, or by simply disrupting the recipient cell's restriction system.

This methylation trick will probably -- probably -- work just fine for other microbes, but I just want to point out that it isn't necessarily generalizable and that the JVCI team didn't demonstrate any such thing.  The team got this one bug working, and who knows what surprises wait in store for the next team working on the next bug.

Since Gibson et al have in fact built an impressive bit of DNA, here is an updated "Longest Synthetic DNA Plot" (here is the previous version with refs.); alas, the one I published just a few months ago in Nature Biotech is already obsolete (hmph, they have evidently now stuck it behind a pay wall).

A couple of thoughts:  As I noted in DNA Synthesis "Learning Curve": Thoughts on the Future of Building Genes and Organisms (July 2008), it isn't really clear to me that this game can go on for much longer.  Once you hit a MegaBase (1,000,000 bases, or 1 MB) in length, you are basically at a medium-long microbial genome.  Another order of magnitude or so gets you to eukaryotic chromosomes, and why would anyone bother building a contiguous chuck of DNA longer than that?  Eventually you get into all the same problems that the artificial chromosome community has been dealing with for decades -- namely that chromatin structure is complex and nobody really knows how to build something like it from scratch.  There is progress, yes, and as soon as we get a real mammalian artificial chromosome all sorts of interesting therapies should become possible (note to self: dig into the state of the art here -- it has been a few years since I looked into artificial chromosomes).  But with the 1 MB milestone I suspect people will begin to look elsewhere and the typical technology development S-curve kicks in.  Maybe the curve has already started to roll over, as I predicted (sketched in) with the Learning Curve. 

Finally, I have to point out that the ~1000 genes in the synthetic genome are vastly more than anybody knows how to deal with in a design framework.  I doubt very much that the JCVI team, or the team at Synthetic Genomics, will be using this or any other genome in any economically interesting bug any time soon.  As I note in Chapter 8 of Biology is Technology, Jay Keasling's lab and the folks at Amyris are playing with only about 15 genes.  And getting the isoprenoid pathway working (small by the Gibson et al standard but big by the everyone-else standard) took tens of person years and about as much investment (roughly ~$50 million in total by the Gates Foundation and investors) as Venter spent on synthetic DNA alone.  And then is Synthetic Genomics going to start doing metabolic engineering in a microbe that they only just sequenced and about which relatively little is known (at least compared with E. coli, yeast, and other favorite lab animals)?  Or they are going to redo this same genome synthesis project in a bug that is better understood and will serve as a platform or chassis?  Either way, really?  The company has hundreds of millions of dollars in the bank to spend on this sort of thing, but I simply don't understand what the present publication has to do with making any money.

So, in summary: very cool big chuck of synthetic DNA being used to run a cell.  Not artificial life, and neither artificial cell nor synthetic cell.  Probably not going to show up in a product, or be used to make a product, for many years.  If ever.  Confusing from the standpoint of project management, profit, and economic viability.

But I rather hope somebody proves me wrong about that and surprises me soon with something large, synthetic, and valuable.  That way lies truly world changing biological technologies.

Tomorrow evening, May 19th, I will give a short talk about my recent book Biology is Technology at Reiter's Books  in Washington DC, followed by discussion and refreshments.  Among other issues, I will discuss updated figures for the impact of biotech and bioengineering on the US and world economies, the impact of the recent BRCA 1/2 gene patent decision, garage biotech, biosecurity, and regulation.

I look forward to seeing you there -- please bring hard questions.

Biology is Technology: The Promise, Peril, and New Business of Engineering Life
Robert Carlson
Harvard University Press, 2010
www.biologyistechnology.com

Where:

(Note that Reiter's has recently moved.)
Reiter's Books
1900 G St. NW
Washington DC 20006
www.reiters.com

When:

May 19, 2010
6:30 PM

I've just signed on to The Economist's next event in the Ideas Economy series, "Human Potential".  15-16 September, 2010 in NYC.  See you there.

This morning's biosecurity update from the Partnership for Global Security carried a mess of links I hadn't seen, including a story at the BBC entitled "Tech Know: Life hacking with 3D printing and DIY DNA kits".  The embedded video has an interesting clip on a printed stainless steel Mobius strip with freely moving rings that can run around the perimeter -- interlinked complex shapes.  Neat.  (Not a new thing in plastics, but I hadn't seen it in metal before.)

Cambridge's James Brown gets the honor of introducing the Beeb's audience to synthetic biology, biobricks, and engineering methods for biological systems.  The 3D-printed DremelFuge gets a photo and a significant mention.  I explicitly pointed to this sort of application of 3D printing in my book, though it is happening even faster than I had imagined.  Shapeways is now printing all sorts of interesting materials, though the resolution of most 3D printers and processes still doesn't make them useful for the sorts of objects I want to print.  That said, there is clear improvement over time.

It will be interesting to see how long it takes before you can print mixed media functional objects, say something like a zero-dead volume, positive displacement membrane pump.  Or better yet an entire pump block.  (Which is usually milled from a piece of stainless steel -- see where this is going?)  That gets you the most annoying bit of kit needed for a DNA synthesizer.  At which point you can forget any regulations limiting access to DNA of any sequence.