Comments on Mail Ordering Smallpox Genes

I've been debating whether to respond to James Randerson's recent front page story in The Guardian, "Revealed: the lax laws that could allow assembly of deadly virus DNA", about mail ordering genes for smallpox.  The bottom line is that the story as published is neither well-reported nor a particularly useful contribution to the discussion about emerging biological threats.

Years ago, I was fortunate to take a science writing class from the great science and war correspondent Malcom Browne, who for many years provided exceptional science reporting at The New York Times.  Among his  suggestions for an ideal (!) newspaper story is that it be no longer than a Haiku.  Of course, this makes all articles published in the history of the press less than ideal.  (No news there.)  Here is my version of the Guardian article:

Humans play with fire!
Newspaper sales are lagging!
Set our hair alight!

Alas, I've ignored most of the stylistic requirements for a Haiku (no mention of a season, or of nature), and the exclamation points are unforgivable.  Still, it captures the essence of Mr. Randerson's story.

Although the article does make one, albeit brief, nod to, "Legitimate reasons for researchers to buy lengths of DNA from pathogens, for example in developing treatments or vaccines against them," the majority of the text is simply alarmist and a rehash of arguments that have appeared previously (The New York Times, Wired, Technology Review; the list goes on).

The worst bit, from my perspective, is that Mr. Randerson promulgates the facetious notion that producing a live, infectious 1918 pandemic influenza virus is as easy as ordering out the DNA from a gullible company.  I've written about this before, and refer readers to those posts (here, and here).  This isn't quibbling on my part.  The capabilities of the technology are central to evaluating the immediacy of the threat.

The Guardian article spends many inches (not an Internet concept, those newsprint inches) announcing the need for regulation without even mentioning the potential detrimental effects of limiting access to the technology.  Because the threat is not immenent, instituting regulations would certainly only reduce our capacity to learn who is employing the technology and thus reduce our capacity to respond to any threats that do arise.  Again, arguments I have made extensively elsewhere (in Wired, at Future Brief, and in Biosecurity and Bioterrorism (via Kurzweilai.net), for example).

The short version of why regulation is bad is this: Because it is not physically possible to control access to the reagents or instrumentation used in DNA synthesis, our only defense in this situation is to keep track of, as best we can, who is doing what.  Our sole weapon is information, in other words.  The only thing regulation will do is cause people to be more secretive, whether they have a nefarious or an innocuous intent.  That is, regulation will restrict our ("we" being the good guys, of course) access to information.  Moreover, regulation in the U.K. and/or the U.S. will only limit activity in those countries.  You can order synthetic genes from a large number of convenient countries, these days.

In a companion article, "Lax laws, virus DNA and potential for terror", Mr. Randerson introduces his readers to Synthetic Biology:

Edward Hammond, a biological weapons expert with the Sunshine Project, an NGO that campaigns against the development of biological weapons, said: "The most worrisome thing ... is that [the field of synthetic biology] is going to enable people to create potentially very dangerous diseases that don't otherwise exist or to recreate ones that have been wiped off the face of the earth."

Mr. Randerson makes no effort to explain that you don't need synthetic methods to create new, potentially dangerous organisms.  (Harder to sell newspapers if you don't stoke the fires, after all.)  Breeding and artificial selection can produce pathogens for you, and these tried and true techniques will do a much better job of it.  And if you want a nasty bug ready-made, you just need to visit a poultry farm here in the US, where due to all those fantastic "growth hormones" a soil sample will provide you with Cipro-resistant anthrax. 

I was perplexed through the entire article why no mention was made of Drew Endy's efforts to synthesize novel viruses for the sake of learning how they work.  In other correspondence with Drew, I learned that he had been approached by Mr. Randerson, but was so troubled by the very idea of the article and project that he declined to participate or be interviewed.  Here (PDF warning) is a log of their email exchange.

The most remarkable thing about the email is that it demonstrates Mr. Randerson is hell bent on doing exactly what he warns against, namely letting loose in the world a sequence from a deadly pathogen that has been extinct in the wild for quite some time.  It doesn't matter that he introduced three small changes rendering the gene supposedly incapable of being used to produce a protein.  Those changes would be trivial for any college, and perhaps high school, student to remove (laborious, perhaps, but trivial), thus restoring the functionality of the smallpox gene.

By my reading, Randerson's correspondence with Drew clearly shows The Guardian reporter hasn't thought about the bigger context.  He had his teeth into a story and wedged himself into discussing only his own ill-informed conclusions rather than carefully exploring what it will take to keep us safe from emerging threats.  He simply didn't do his homework.

I hope The Guardian can do better in the future.

Confusion Over Indonesian H5N1 Outbreak

It seems there is a profusion of bad information about the present Indonesian H5N1 outbreak.  Over the last week, The New York Times has reported conflicting statements from the World Health Organization about whether the cluster of cases was caused by human to human transmission.  Somebody needs to make up their mind about when to talk to the press, and who to let speculate about the science when they obviously have no idea what's going on.  How are we supposed to have any confidence if they keep shooting from the hip before solid evidence is in hand?

As important as whether there was confirmed human to human spread is the issue of how the sequence is varying.  I wrote earlier this week about reports that changes in the human sequence appeared to put it closer to a feline sequence, but Wired News is carrying a Reuters story in which the WHO states otherwise:

"Sequencing ... found no evidence of genetic reassortment ... and no evidence of significant mutations," the United Nations health agency said in its statement.

I would note now that I'm not sure what Andrew Jeremijenko means by "the closest match we have to the human virus is from a cat virus."  I was unaware there was any distinction observed in the wild between viruses afflicting humans and felines.  But the point is that one agency is saying the virus is changing and may be related to something killing other mammals, while another says there are no mutations and can't make up its mind whether we already have human to human transmission.

People, get your shit together, please.  Don't talk to the press until you know what's going on.  This thing is scary and complicated enough as it is without having to sort through conflicting information from "official sources".

(Not Quite Live From) Synthetic Biology 2.0, Part V :: Fin

First off, here is the link for Synthetic Biology 3.0, next year's meeting in Switzerland.

This year's meeting was impressive on many counts.  As I have noted already (Part II), there was a distinct change in the flavor of the presentations.  The first day started out with a Nobel Laureate, followed up by a potential (probable?) future Laureate.  There was a significant amount of money in the room, from corporate representatives of synthesis companies to venture capitalist Vinod Khosla.  With respect to the technical presentations, the sheer diversity of systems and applications compared to two years ago was remarkable.  People are playing with more organisms and more parts (here's the meeting agenda).  The number of genes combined in several of the talks was itself remarkable.  Medical applications are clearly coming down the pike.

Yet I found something lacking.  As in 2004, there was no mention this year of a critical set of tools required in any engineering field.  It may not be sexy, but test and measurement gear is what allows rapid comparison of prediction and experimental outcome.  Without sophisticated test gear, you have no Pentium, no 777, no Honda Element, no SpaceShipOne.  At the moment, while each experiment presented at SB 2.0 may be technically beautiful and impressive, they are primarily one-offs.  There is no common signal, and there is no common way to compare experiments in different organisms.  This will eventually be addressed through some sort of standardization, such as is being attempted with Biobricks.  Yet I have always found the common signal in the Biobricks standard to be confusing.  I forget what it was called originally, but now the input and output relationships of the parts are defined in Polymerases Per Second, or POPS, the number of polymerases running into, or out of, a genetic element in a second.

As I write this, I finally realize why I don't like POPS.  As Drew Endy describes it, POPS is a way to allow abstraction from the level of genes and specific proteins up to devices with a common reference.  I understand this story, and it makes sense to me given the constraints of the biological parts we have to work with.  But here's the thing: measuring POPS is presently exceptionally hard.  You can test each part in a framework that allows the measurement of POPS, probably using a fluorescent protein as an output signal, which is only vaguely quantitative.  It is also not a direct measure of POPS, as there is at least one layer of function between the number of RNA polymerases running down DNA and the number of proteins that get translated from RNA.   But it gets worse; how to you troubleshoot the entire circuit?  Where do you stick the multimeter probes on the fly to see why your circuit isn't behaving as expected?  You don't.  Instead, you resort to microarrays to check RNA expression levels or you use protein assays.  Until there is a magic "POPSometer", there won't be any way to examine a circuit in real time.  Fluorescent proteins will never adequately fill this role, 1) because of the time required to fold and produce a fluorescent signal and 2) because you have to build a new circuit every time you want to stick the test probe in a new spot.

Moreover, tools presently in use provide the illusion to the uninitiated that the physical infrastructure of synthetic biology is already well developed.  It is fairly straightforward to get single cell fluorescence or behavior data at this point, but you have to presume the organism is running the program you wrote.  Separately, it is easy to sequence large amounts of DNA, generally purified from many individuals.  But you can't yet sequence a given bug behaving in a given way to make sure it is following the DNA you put into it.  And readily available sequencing technologies average over variation present in a population that may be critical to understanding function.

This technological mismatch extends to discussions of security.  We heard descriptions of various programs to monitor DNA synthesis efforts, which would tie into a surveillance network using a microbial background signal for the environment.  The later would serve as a reference for efforts to detect novel, and perhaps threatening organisms, in real time.  But there isn't yet any technology that can provide that sort of environmental information, nor will one be available in short order from what I have seen.

In summary, we are still at the beginning of a very long road.  Before chemical engineering came synthetic chemistry, and before biological engineering will come synthetic biology.  I just wish the community had better perspective on how far we have to go.

Synthetic Biology 2.0, Part IV :: What's in a name?

The last session at Synthetic Biology 2.0 was full of hand-wringing about the very name of the thing.  "Synthetic" seems to conjure up too many bogeymen for the likes of of many attendees.  The arguments against the name were all centered around the fact that "synthetic" is un-PC these days.  Never mind that we live in a world consisting entirely of synthetic food, clothes, houses, computers, solar panels, windmills, and liquid fuels.  Synthetic is just bad, evidently.

This debate is essentially about politics.  It seems the new field is scaring people just by it's name.  So perhaps we should choose a new name in order to finesse the acceptance of the science and technology?  After all, why fight more battles than you need to?

Okay, fine.  Go ahead and try to rename it.  I'll just watch this time, thanks.  Besides, I think the present name is both appropriate and inevitable, but more on that in a moment.  We started with a different name, once upon a time, and that one didn't go over so very well either.  In 2000, while trying to describe the way biology was about to change (here is the PDF), or at least the way Drew Endy and I were conceiving of a new biological engineering, I floated the phrase "Intentional Biology."  The text on that web page was last modified in late 2000, but the story is basically the same today.   Through predictive design, biological systems should be both easier to understand and more useful.  These engineered systems would behave as intended, rather than displaying random and mystifying behaviors often encountered when genetically modified organisms are introduced into new environments or set loose in the wild; i.e., unintended behaviors.  Roger Brent, Drew, and I, even organized a meeting to figure out how to make this happen.  "After the Genome 6, Achieving an Intentional Biology", was held in Tucson, AZ, in December of 2000.  Alas, that name had unintended consequences, namely that the biologists attending the meeting thought we were asserting that all prior molecular biology had been unintentional.  If rotten vegetables had been available, I'd have been pelted during my talk.

Not the best start.  Can't win them all.  A good lesson, too.

Fast forward to mid 2001 or so, when Drew and I are at a cocktail party in San Fransisco thrown in celebration of the opening of the new local office for Nature.  We wind up in a conversation with Carlos Bustamante, who regales us with the origin of the field of Synthetic Chemistry, and how this gives us the name for Synthetic Biology.  Drew and I are convinced.  But, of course, it wasn't up to Drew and I to name a new field.  We were simply looking for a name to distinguish what we wanted to do from how things had been done previously.  The phrase "Synthetic Biology" certainly isn't new, and was emerging from other sources at the same time (Steven Benner, in particular, if memory serves).

Drew has flirted with other names in the last 5 years, among them "constructive biology" and "natural engineering".  Craig Venter insists on calling it Synthetic Genomics.  Frankly, these aren't any more compelling to me than Synthetic Biology, and they also seem to require even more explanation.  At this point, I don't really care what it is called.  The work is going to happen regardless, and there is no way to turn back.  The name is only a lightening rod for criticism because, as Oliver Morton and others have pointed out, the community keeps drawing attention to itself and all the bad things it might facilitate.  But where is the good news?  I have tried in this space to point out the connections between Synthetic Biology and vaccines, to the possibility that Synthetic Biology might be our best hope to beat a pandemic, but it appears most people want to focus on the negative aspects of rapid and distributed DNA synthesis.  The recent SB 2.0 meeting started with a focus on biological production of energy, another excellent beneficial application, but any subsequent optimism was lost by the third day.

Now onto why the name is inevitable.  What we are doing has been called Synthetic Biology for almost a century.  Here is some text from my book:

Ch 4: The Second Coming of Synthetic Biology

"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 Wohler announced he had irreversibly changed the world.  In a letter to his former teacher Joens Jacob Berzelius, Wohler 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 was born the field of synthetic organic chemistry.

Around the dawn of the 19th century, chemistry was in revolution right along with the rest of the western world.  The study of chemical transformation, then still known as alchemy, was undergoing systematic quantification.  Rather than rely on vague and mysterious incantations, scientists such as Antoine Lavoisier wanted to create what historian of science and technology Bruce Hevly calls an “objective vocabulary” for chemistry.  Through careful measurement, a set of clear rules governing the synthesis of inorganic, non-living materials gradually emerged.

In contrast, in the early 1800s the study of organic molecules was primarily concerned with understanding how molecules already in existence were put together.  It was a study of chemical compositions and reactions.  Unlike the broader field of chemistry taking shape from alchemy, making new organic things was of lesser concern because it was thought by many that organic molecules were beyond synthesis.  Then, in 1828, Wohler synthesized urea.  Suddenly, with one experiment, the way scientists did organic chemistry changed. The ability to assemble organic molecules from inorganic components altered the way people viewed a large fraction of the natural world because they could conceive of building much of it from simpler pieces.  Building something from scratch, or modifying an existing system, requires understanding more details about the system than simply looking at it, poking it, and describing how it behaves.  This new approach to chemistry helped open the door to the world we live in today.  Products of synthetic organic chemistry dominate our environment, and the design of those products is possible only because understanding the process of novel assembly revealed new principles.

It was this step of moving to Synthetic Chemistry, and then to an engineering of chemistry, which radically changed the way people understood chemistry.  Chemists had to learn rules that weren’t apparent before.  In the same way that Chemical Engineering changed our understanding of nature, as we begin engineering biological systems we will learn considerably more about the way biological pieces work together.  Challenges will arise that aren’t obvious just from watching things happen.  With time, we will understand and address those challenges, and our use of biology will change dramatically in the process.  The analogy at this point should be clear; we are well on our way to developing Synthetic Biology. [Auth. note: Clear if you've read the first three chapters of the book, anyway.]

Before going further, it is worth noting that this is not the original incantation of the phrase “synthetic biology”.  Whatever the reception this time around, the first time it was a flop.  In her history of the modern science of biology, Making Sense of Life, Evelyn Fox Keller recounts efforts at the turn of the 20th Century to discover the secret of life through construction of artificial, and synthetic, living systems; “To many authors writing in the early part of the [20th] century, the [path] seemed obvious: the question of what life is was to be answered not by induction but by production, not be analysis but by synthesis.”(Keller, p.18)  This offshoot of experimental biology reached its pinnacle, or nadir, depending on your point of view, in attempts by Stephané Leduc to assemble purely physical and chemical systems that demonstrated behaviors reminiscent of biology.  As part of his program to demonstrate “the essential character of the living being”(ibid, p.28) at both the sub-cellular and cellular level, Leduc constructed chemical systems that he claimed displayed mitotic division, growth, development, and even cellular motility.  He described these patterns and forms in terms of the well-understood physical phenomena of diffusion and osmotic pressure.  It is important to note that these efforts to synthesize life-like forms relied as much on experiment as upon theory developed to describe the relevant physics and chemistry.  That is, this was a specific program to use physical principles to explain biological phenomena.  These efforts were described in a review paper at the time as “La Biologie synthetique”(ibid, p.31-32).

While the initial reception to this work was somewhat favorable, Leduc’s grandiose claims about the implications of his work, and a growing general appreciation for complicated biological mechanisms determined through experiments with living systems, led to something of a backlash against the approach of understanding biology through construction.  By 1913, one reviewer wrote, “The interpretations of M. Leduc are so fantastic…that it is impossible to take them seriously”(ibid, p.31).  Keller chronicles this episode within the broader historical debate over the role of construction and theory in biology.   History regards the folks in the synthetic camp, and related efforts to build mathematical descriptions of biology, particularly in the area of growth and development, as poorly regarded by their peers.  Perhaps inspired by the contemporaneous advances in physics, it seems that the mathematical biologists and the synthetic biologists of the day pushed the interpretation of their work further than was warrented by available data.

In response to what he viewed as theory run rampant, Charles Davenport suggested in 1934 that, “What we require at the present time is more measurement and less theory…There is an unfortunate confusion at the present time bewteen quantitative biology and bio-mathematics…Until quantitative measurement has provided us with more facts of biology, I prefer the former science to the latter”(ibid, p.86).  I think these remarks are still valid today.  Leduc, and the approach he espoused, failed because real biological parts are more complex, and obey different rules, than his simple chemical systems, however beautiful they were.  And it is quite clear that vast forests have been felled to publish theoretical papers that have little to do with the biology we see out the window.  But theory, drawn from physics, chemistry, and engineering, does have a role to play in describing biological systems.  Resistance to the tools of theory has been, in part, cultural.  There has always been a certain tension in biology over the utility of mathematical and physical approaches to the subject;

To put it simply, one could say that biologists do not accept the Kantian view of mathematics (or, rather, mathematization) as the measure of a true science; indeed, they have often actively and vociferously repudiated any such criterion.  Nor have practicing biologists shown much enthusiasm for the use of mathematics as a heuristic guide in their studies of biological problems.(Keller, p. 81)

Fortunately, this appears to be changing. Mathematical approaches are flourishing in biology, particularly in the interpretation of large data sets produced by genomic and proteomic studies.  Physicists and engineers are making fundamental contributions to the quantitative understanding of how individual proteins work in their biological context.  But I think it is important to acknowledge that not all biologists think a synthetic, bottom up, approach will yield truths applicable to complex systems that have evolved over billions of years.  Such concerns are not without merit, because as the quotation from Charles Davenport suggests, biology has traditionally had more success when driven by good data rather than theory.  The challenge today is to build quantitatively predictive design tools based on the measured device physics of real biological parts, and to implement designs within organisms in ways that work in the real world.

Thus the present project is truly different than the biology that has come before.  Synthetic Biology is based on an explicit reliance upon mathematical models.  My own particular bent here is in developing technology that enables better measurement of biological systems so as to test and constrain models and also to provide required capabilities for biological engineering.  Without that, we are stuck with Charles Davenport's criticism of seventy years ago.

"Synthetic Biology" fits, both linguistically and historically.  Why are we stuck on this same damn topic two years after the first meeting?  We have better, and more important, things to worry about.  And lot's of work to do.  Synthetic Biology 3.0 will take place in Zurich, Switzerland, 24-27 June, 2007.

Live from Synthetic Biology 2.0, Part III

Wandering out into the lobby, I found Paul Rabinow and Oliver Morton chatting about the future of DNA synthesis companies.  Oliver is blogging the meeting at his site Mainly Martian.

Earlier I mentioned the new flavor of money at this meeting and the presence of competing DNA synthesis companies.  Oliver is hot onto the story that these companies are already struggling with the fact that large scale synthesis is becoming commoditized, and they may not all be around for long.  (By the way, we are wondering why John Mulligan, founder of Blue Heron and an early entrant into the commercial synthesis game, isn't at the meeting.  His is a conspicuous absence. (UPDATE:  John Mulligan was on a camping trip and is apparently on his way here now.  But we still missed him yesterday.))  It seems like there is already quite a lot of pressure for desktop DNA synthesizers.

David Baltimore is speaking now about engineering the immune system, which I should tune into.

Live from Synthetic Biology 2.0, Part II

This year's meeting has an interesting new flavor, namely that of money.  There are VC's here (yesterday at lunch gave us the interesting sight of Vinod Khosla and Craig Venter sitting off together in a corner, no doubt planning the future of Synthetic Biology); the list of sponsors is heavy with corporate names.  This is all a great change from SB 1.0, which had a very academic feel.

Yesterday's "Synthesis Panel" was in fact a series of tag team marketing pitches from synthesis company executives, presumably in exchange for their sponsorship of the meeting.  The summary of that session, perhaps unintended, was that all four companies essentially gave quotations to the audience for synthesis jobs: "no more than four weeks, perfect synthesis, buck a base."  We also heard that they are expecting the cost curves to keep up the current pace, and that this time next year synthesis of genes will be $.50 a base.  We heard some discussion of changes in technology, but everybody is still essentially using the same chemistry, just different plumbing.  The presentation from Codon Devices included references to a bunch of interesting methods, including something I predicted/hoped would happen, namely the combination of the synthesis strategy published by Tian, et al., with the MutS purification scheme from Peter Carr at MIT.

The commercial (as opposed to governmental or foundation) money here is an indication that biological technologies are achieving recognition as a significant potential influence on the economy.  I still don't understand how to finesse the IP issues -- I've been working on a blog post and book chapter about "The State of Open Source Biology", or perhaps just "Open Biology", which just aren't ready for release yet.

Carolyn Bertozzi (UC Berkeley) is speaking now, which reveals another interesting thread to this meeting.  Prof. Bertozzi is presenting work on modifying extracellular sugar groups to better understand cell signaling and hopefully get at cancer diagnostics and therapeutics.  People are really waking up to the possibilities of combining powerful biochemistry with synthetic methods for building new pathways with exceptional power and flexibility.

Jack Szostak (Harvard) just stepped up to the microphone to speak about a "Model of Synthetic Protocell."  His protocell is a simple replicating vesicle with it's own nucleic acid instruction set, but he doesn't want to use any preexisting biochemical machinery.  "All processes must be spontaneous".  That's ambitious.  He says he doesn't think the work has any particular practical application, but I suspect that is just a matter of time.

Indonesian H5N1 Outbreak Linked to Cats?

(Sitting in the Synthetic Biology 2.0 meeting, so this will be brief.)

Following up on my earlier reports and speculation (here, here and here) about the role of felines in spreading H5N1:

The Australian Broadcast Company is carrying an interview in which Andrew Jeremijenko, Project Leader of the Influenza Surveillance Studies for a US Naval Medical Research Group, suggests the outbreak in Indonesia may be directly related to infection in cats.

The article, entitled "Failed Indonesian bird flu response concerns experts", by Peter Cave, contains the following exchange:

PETER CAVE: Are you seeing mutations in the virus in Indonesia?

ANDREW JEREMIJENKO: Yes, that's a good question. We are seeing mutations in the human virus. We are not seeing that same mutation in the bird virus. And that's of great concern.

Basically, when you do an investigation of a bird flu case, you should try to find the virus from the human and match it up with the virus from the bird and find the cause.

Now, in Indonesia, the investigations have been sub-optimal, and they have not been able to match the human virus to the poultry virus, so we really do not know where that virus is coming from in most of these human cases.

PETER CAVE: Does it suggest it's going through an intermediary before it's infecting humans?

[Andrew Jeremijenko]: It's a possibility that we can't rule out. I think they really need to do a lot more investigations. So far the closest match we have to the human virus is from a cat virus. So the cat could be an intermediate. We really don't know what's happening yet.