Book Talk at Reiter's in Washington DC, May 19

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

A Few Biosecurity Notes

  • Last January, the UPMC Center for Biosecurity published "U.S. Government Judgments on the Threat of Biological Weapons: Official Assessments, 2004-2009".  If you are interested in bioterrorism, you should have a look.
  • Also in January, the Belfer Center for Science and International Affairs at Harvard's Kenney School of Government released "Al Qaeda Weapons of Mass Destruction Threat: Hype or Reality?" (PDF) By Rolf Mowatt-Larssen.  The document gathers together open source information regarding Al Qaeda's interest in WMD.  Mowatt-Larssen is formerly the Director of Intelligence and Counterintelligence at the U.S. Department of Energy, and spent 23 years at the CIA.  The introduction sets out the purpose of the document as dispelling the doubts of those skeptical there is a real threat.
  • Former Senate Intelligence Committee chairman Bob Graham recently told the Washington Post that "India and Pakistan, as well as Syria and Israel, may have manufactured biological weapons."  Graham said: "The extent to which they may have done it is classified, but it is a serious threat. ...A couple of weeks in the Middle East has given me a greater sense of urgency."  Graham called out the lack of progress here at home in establishing "a response capability".  In an update to the story, the Post then pointed to a description of a new "biosecurity" bill introduced in the House, which from the article sounds to be all about securing national labs rather than standing up any sort of real biodefense response capability.

Sweet dreams.

DIYBio and Making at the BBC

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. 

Life Technologies Buys GeneART

Life Technologies today bought 58% of synthetic DNA provider GeneART, with a public tender planned for shares outstanding (Yahoo Finance, GeneART Press Release).  Previously, before changing its name, Invitrogen entered into a strategic agreement to buy the exclusive worldwide rights to distribute Blue Heron Biotechnologies gene synthesis services.

What should we make of this?

First, Life is led by Gregory Lucier, who used to be way high up at GE and is a former protege of Jack Welch.  In my observation, and in my experience, Life is trying to the be the GE of biology.  What does that mean?  GE is obviously a conglomerate, and it operates not so much as a maker and seller of things but as a finance operation that seeks growth through return on capital.  As such, GE buys other companies aggressively -- this is, vastly oversimplified, the Jack Welch strategy.  Life is operating the same way.  The company is aggressively acquiring biotech companies of all sizes. The web was full of rumors earlier in 2010 that GE, seeing something it liked and a familiar strategy, was trying to buy Life Tech.  Who knows -- that may be real and may still happen.  It would be another interesting indication of a certain kind of maturity in the market for biological technologies.

Second, Life obviously sells lots of cloning reagents -- a market that is threatened by synthesis -- so the move could be somewhat defensive in nature.  Life is getting reputation, market share, and expertise in an area that they do not yet dominate.

Third, while GeneART is big, they are a European shop paying German wages to a bunch of people running around with plates and pipetters.  GeneART gets some cash and a big marketing arm, and Life gets ... hummm ... an operation that may have difficulty competing with Chinese labor (Genescript) and automation (Blue Heron).  Presumably, Life looked at the balance sheet and the marketing forecasts and decided the deal makes sense.  But it might be a complex calculation involving not just return on capital, but also access to IP, expertise, and factors that nobody outside Life can do more than guess at, like balancing sales of cloning reagents against sales of synthetic genes.

Now, what might be the implications for the synthetic biology community?  Probably not much.  Prices for synthetic DNA continue to fall.  The $.39 per base price established last autumn as a "special" is now, no surprise, the industry standard.  We will probably see additional consolidation and shifting around as margins get squeezed.  The industry is expecting prices to be at $.05 to $.15 per base within 5 years.  Though even within the same conversation you might hear $.10-$.25 per base, thereby managing consumer expectations, which makes me wonder if people are starting to quail a bit at the exponential and its implications for their business.  You will still have the option to pay more for rush jobs or for genes that are tricky to synthesize.

As I have observed previously (most recently in Nature Biotechnology, here), the maximum profit margin on synthetic genes is evaporating exponentially.  That is not hyperbole, but rather a quantitative observation based on market prices over more than ten years; it is data.  That said, even as prices fall it will still be possible for some companies to increase their revenues as competitors leave the market or go out of business.  But I would be surprised if the market dynamics that enabled Intel to exploit Moore's Law for many decades reemerged in synthetic genes.  Intel knew it could ship exponentially more transistors every quarter -- which meant it could rapidly grow even in the face of falling prices -- but I do not have any evidence that the total market for synthetic genes is expanding much faster than the price is falling.  Conversations with industry executives lead me to believe the total dollar value in the market is continuing to rise, if somewhat slowly.  The rate of increase is hard to pin down, however, given the hiccup that was 2009.  This year's volume and revenues should be bigger, but it isn't clear that one should attribute this to more than the broader economic recovery.

All in all, this seems like business as usual for an industry that is experiencing a rapid transition to commodity status while simultaneously suffering from globalization and lowered barriers to entry.  It probably isn't so different in overall impact from the demise of Codon Devices.  This is just another step towards maturity in an area that will have much more impact on our lives in the future than it has thus far.

"National Strategy for Countering Biological Threats"

I recently had cause to re-read the National Strategy for Countering Biological Threats (Full PDF), released last fall by the National Security Council and signed by the President. I think there is a lot to like, and it demonstrates a welcome change in the mindset I encounter in Washington DC.

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

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

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

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

The beneficial nature of life science research is reflected in the widespread manner in which it occurs. From cutting-edge academic institutes, to industrial research centers, to private laboratories in base­ments and garages, progress is increasingly driven by innovation and open access to the insights and materials needed to advance individual initiatives.

Recall that this document carries the signature of the President of the United States.  I'll pause to let that sink in for a moment.

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

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

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

...This Strategy reflects the fact that the challenges presented by biological threats cannot be addressed by the Federal Government alone, and that planning and participation must include the full range of domestic and international partners.

Norms, open biology, better technology, better public health infrastructure, and better intelligence: all are themes I have been pushing for a decade now. So, 'nuff said on those points, I suppose.

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

Big Gene Patent (Busting) News???

Well now, isn't this an interesting development.  As covered by many news outlets (NYT, Wired, Genomeweb), US District Court Judge Robert Sweet has invalidated several US patents, sometimes referred to as the "BRCA1/2 patents", held by the University of Utah and Myriad Genetics.  From Judge Sweet's decision: "Products of nature do not constitute patentable subject matter absent achange that results in the creation of a fundamentally new product."  Judge Sweet's decision is here (PDF) via Genomics Law Report.  Here is the ACLU's take.

Here is a brief summary of what follows: The ruling is remarkable.  Various commentators and reporters remark upon it.  They get confused.  I try to clarify.  Then we get to a truly revolutionary part of the decision: it's about science!  And a little bit about law.  Finally: so what if a few patents are invalidated?
 

Didn't See That Coming.  But I Can't Complain.

Last month, I noted that I was skeptical that the ACLU and other plaintiffs would be so successful in one go.  So I am surprised, but I am certainly not disappointed.  But I am not surprised, while being somewhat disappointed, that the coverage of the decision is so confused and confusing.  This confusion arises, I suspect, because the wording of Judge Sweet's decision is not entirely straightforward in places, and this has led to analyses that are insufficiently careful.  More on these points below.

DISCLAIMER: Please recall in what follows that I am but a humble physicist by training (oh yes, yes, we're all very humble), not a lawyer.  But I have written some stuff about patents on genes, and at least a few people (some of whom are IP law lawyers) think my analysis doesn't suck a lot.

First, over at Genomics Law Report (GLR), John Conley and Dan Vorhaus have a great analysis with a nice title: "Pigs Fly: Federal Court Invalidates Myriad's Patent Claims".  I won't bother to repeat their discussion.  If you are interested in this issue, please read that post as well as Dan Vorhaus' initial post analyzing the decision.  In particular, the reader might want to attend closely Vorhaus and Conley's observations about the potential for appeals, the likelihood of success in that endeavor, and the applicability of the ruling in other jurisdictions.

The short summary of what's transpired so far in the case is that Judge Sweet has invalidated a small number of claims, in a summary judgement ruling that so far applies only in the Southern District of New York.  Assertions that this is the end of the world for companies that hold gene patents are rather overblown.

There's Too Much Confusion, But Here is Some Relief

But now onto some of the confusing bits alluded to above.  The confusion starts, surprisingly, at GLR.  Here are Conely and Vorhaus:  "In the broader policy debate surrounding gene and biotechnology patents, however, this decision is the latest, unmistakable shot across the bow of gene patent holders, particularly those such as Myriad Genetics that have developed businesses around patent-protected genetic tests supported by exclusive rights in underlying gene patents."  Hummm...  Maybe not so much, actually.  Let me get straight to the point: there is a rather substantial difference between a "gene patent" that claims naturally occurring sequences and one that claims sequences that are not natural. 

Here is one way to think about the issues under discussion: in my one hand, I have a piece of isolated DNA that is identical in sequence to one in your body.  It is the same genetic sequence, so it carries the same information.  Indeed, for it to be useful in a test tube for the purposes of diagnosis, it must have both the same information content and the same function as the sequence in your body.  In fact, it only works as a diagnostic tool because it is the same as what is in your body.  As I noted in my earlier post, this is sort of the opposite of invention, and I have never understood why natural genes can be patented.  (Note: Judge Sweet hits this point quite squarely, but not until p.124 of his ruling.)  In my other hand, I have a piece of isolated DNA that is solely the result of human manipulation -- "human ingenuity" -- consisting of a sequence that does not exist in nature.  Both pieces of DNA are isolated, but they derive from very different sources, and are derived by very different means. Unfortunately, everybody discussing the present decision, including Judge Sweet in the early pages of his decision, seems to be a tad careless about the distinction, which leads many people down a rabbit hole.  (There is an extended discussion of the definition of "isolated DNA" and of the BRCA1/2 genes on p.90-92.)

Here is where it starts: Judge Sweet sets up his decision in the first couple of pages focusing specifically on the BRCA1/2 genes, and slightly more generally on isolated human genes: "Are isolated human genes and the comparison of their sequences patentable?" (p.2)  He continues: "Two complicated areas of science and law are involved: molecular biology and patent law.  The task is to seek the governing principles in each and to determine the essential elements of the claimed biological compositions and processes and their relationships to the laws of nature."

This sounds great.  Judge Sweet is clearly referring specifically to certain human gene sequences named in the patents in question.  Alas, on the next page he switches his language to address the specific assertions of the plaintiffs that ""isolated DNA" containing human BRCA1/2 sequences" are not patentable.  The basic contention here is that because the isolated DNA as described in the patents does the same thing inside the body as outside the body -- it is an information storage medium -- there is no difference between the two forms of DNA and therefore the isolated DNA in question cannot be patented.  Judge Sweet concludes (p.4):

DNA represents the physical embodiment of biological information, distinct in its essential characteristics from any other chemical found in nature. It is concluded that DNA's existence in an 'isolated' form alters neither this fundamental quality as it exists in the body not the information it encodes.  Therefore, the patents at issue directed to "isolated DNA" containing sequences found in nature are unsustainable as a matter of law and are deemed unpatentable subject matter.

The judge thereby switches within a couple of paragraphs very seamlessly from language referring only to human genes to language referring seemingly to all "isolated DNA".  It takes another 100 pages to get to a true clarification, and I'll bet very few people have read that far, or followed all the byways and cross-references (p.100): "...The issue presented by the instant motions with respect to the composition claims is whether or not claims directed to isolated DNA containing naturally-occurring human sequences [emph added] fall within the products nature exception.  ...It is concluded that the composition claims-in-suit are excepted."

In other words, Judge Sweet very specifically ruled that the claims on isolated DNA containing naturally occurring sequences are not valid.  Even more specifically, the ruling only applies to the motion in question by the plaintiffs, namely to invalidate the patents on BRCA1/2 held by Myriad et al.  Judge Sweet pointedly cites Diamond vs. Chakrabarty (p.109) -- a case that affirmed the patentability of "genetically engineered" organisms -- in limiting his ruling to the patentability of naturally occurring genes.  The ruling has no applicability outside that subject matter, and therefore has little applicability to, for example, much of anything that might come out of synthetic biology (unless you are talking about a synthetic DNA version of a naturally occurring gene).  Nor, for that matter, does the ruling have any say about any bit of DNA altered to be different from a natural sequence.  Which means that the ruling has very little to do with most patents on DNA, and therefore has very little to do with most of the industry surrounding those patents -- more on this below.

(Side note, as I read through the decision: Myriad's lawyers didn't do themselves any favors by making generally unpersuasive assertions aimed as broadside attacks against the plaintiffs' arguments.  As noted in my previous post on this case "Whither Genome Patents?", the defendants' assertions that patents serve as necessary incentives for scientific research are complete bunk.  Defense attorney Brian Poissant previously argued that "women would not even know they had BRCA gene if it weren't discovered" under a system that incentivizes patents.  I say again, as calmly as I can, bull pucky.  For example, see the publicly funded Human Genome Project.  See also the fact that BRCA2 was sequenced first in academic labs rather than by Myriad, who somehow managed to patent it anyway.  See also the many  BRCA1/2 assays independently developed in academia, the use of which Myriad repeatedly quashed through cease-and-desist letters, as recounted in detail in the decision.  But here is Judge Sweet himself (p.76): "According to Myriad, its policy and practice has been and still is to allow scientists to conduct research studies on BRCA 1 and BRCA 2 freely, the result of which has been the publication of [over 8600 papers] representing the work of over 18,000 scientists."  (It wasn't clear to me whether Myriad's legal team itself provided these numbers -- but if they did: bad legal tactics, fellas.)  In other words, 18,000 scientists have managed to produce a substantial body of work without any promise whatsoever of remuneration based on a patent for BRCA1/2.  Unless, of course, you count keeping your job through the promise of not being sued by Myriad.)  

It's Science!  And Science Always Wins -- Eventually, But May be Delayed By Appeals.

There is another very interesting angle to Judge Sweet's decision.  Andrew Pollack, writing in the New York Times, suggests that the most revolutionary part of the decision is where Judge Sweet recognizes that DNA carries information.  Pollack quotes Rebecca Eisenberg, a law professor at the University of Michigan: "There isn't a whole lot of doctrinal support" for considering DNA as information rather than as a chemical.  That, for me, is a truly eye opening perspective.  Not because I didn't know about it before -- unfortunately, that view is all too prevalent among IP lawyers -- but rather because it is being defended and suggested as a possible grounds for appeal.  True, it may be precedent, but that does not mean it is good precedent.

Here's the thing: There may not be much "doctrinal support" for considering DNA as information, but there is a rather overwhelming amount of scientific and technical support for considering DNA as information rather than as a chemical, say starting with the vast majority of molecular biology and biochemistry papers published in Science, Nature, Cell, PNAS, and any other relevant journal you can think of.  For all of the last six decades, no less.  Oh, and then all those silly textbooks.  The genetics and molecular biology ones, obviously; not the law textbooks.

Judge Sweet, in my humble opinion, already smacked this one out of the park on p.4: "The facts relating to molecular biology are fundamental to the patents at issue and to the conclusions reached.  Consequently, in the findings which follow, the discussion of molecular biology precedes the facts concerning the development, application, and description of the patents."  (Whoa there!  Science and reason trump the law of man!  Or science and reason trump the law of lawyers?  Damn, now that is a novel legal theory.  And a welcome one.  Don't tell Sen. James Inhofe.) 

Unfortunately, Pollack misses this angle, and promulgates further the confusion that Judge Sweet's ruling spells doom for the biotech industry: "Some biotechnology investors and executives say that lack of patent protection for DNA could diminish investment in the field and remove incentives for companies to develop tests."  Never mind that, as described above, Judge Sweet's ruling applies only to patents on naturally occurring genes, which should ameliorate the concerns of most of the "some biotechnology investors and executives".  It is nonetheless true that diagnostics companies that rely on patents claiming naturally occurring sequences may have to reevaluate their business plans.  (For instance, they may want to be especially careful in issuing cease-and-desist letters, lest the ACLU and company get busy again.)  And it may be true that this small fraction of biotech businesses may have difficulty raising capital -- but time will tell.  If it turns out that development of new diagnostic assays lags as a result of more patents on human genes being invalidated, then we will have something real to talk about.  We might consider developing public policy around alternate incentives.  Until there is a demonstrated concern, however, it isn't clear to me that we should be so concerned about the fate of private investors who gambled on patents whose validity has long been questioned.

What Is The Real Impact Going To Be? 

To reiterate the numbers from my earlier post: of the roughtly 2% of US GDP that is derived from biotech, at a rough guess I would put only 1% of the total (so .01% of US GDP) in the molecular diagnostics category that depends explicitly on excluding other uses of patented human genes.  A few billion dollars a year, in other words, might be at risk.  But somebody is going to do the tests, and Judge Sweet's decision lists a variety of tests that cost about 1/3 of Myriad's; that is, before Myriad shut them down with cease-and-desist letters.  If you eliminate those patents, we might have to come up with some other way to incentivize the development and testing of assays.  Prizes come to mind as a fine thing to try.  They work.  Academics and garagistas will be happy to compete for those prizes, I am sure.

But the rest of the biotech industry shouldn't be concerned about this ruling, frankly.  They might even celebrate the fact that they now have access, potentially, to a whole bunch more genes that are naturally occurring.  Not just in humans, mind you, but any organism.  This opens up a rather substantial toolbox for anybody interested in using biological technologies derived from viruses, bacteria, plants, etc.  If it holds up over the long run, Judge Sweet's decision should accelerate innovation.  That is definitely a good thing.

DIY Cleanroom

Gizmodo and Make are both pointing to Bill Morris's DIY Cleanroom.  Compare it to the hoods shown in my post on Garage Biology in Silicon Valley a couple of days ago.

Morris reports that his goal is a Class 10,000 hood, a specification that is slightly more involved than I had remembered.

In any event, Morris' hood would be of great use to those doing cell culture at home.  I suspect you are going to want a better filter, for nabbing smaller contaminants, maybe higher airflow, and perhaps some way to hack up a laminar-flow set-up.

Cool.

Garage Biology in Silicon Valley

A couple of weeks ago I made a whirlwind trip to San Francisco that turned out to be all about garage biology.  I started off with a talk to the California Assembly Select Committee on Biotechnology.  Here are my slides (Carlson_CA_Assembly_February_2010.pdf), which focus on the role of small business and garage hackers in creating innovation in the Bioeconomy, and here is the agenda (PDF).  See my recent post on "Micro-Brewing the Bioeconomy" for the details of craft brewing as an example of distributed biological manufacturing.  I also did an event at the GBN for the book, and I'll post a link to the recording when it goes live.

I spent most of one Saturday hanging out at a garage biology lab in Silicon Valley.  When I walked in the door, I was impressed by the sophistication of the set-up.  The main project is screening for anti-cancer compounds (though it wasn't clear to me whether this meant small molecules or biologics), and the people involved have skillzzz and an accumulation of used/surplus equipment to accomplish whatever they want; two clean/cell-culture hoods, two biorobots (one of which is being reverse engineered), incubators, plate readers, and all the other doodads you might need.  They aren't messing around.  I didn't get into the details of the project, but the combination of equipment, pedigree, and short conversations with the participants told me all I needed to know.  That doesn't mean they will be successful, of course, just that I believe they are yet another example of what can be attempted in a garage.  This sort of effort is where new jobs, new economic growth, and, most importantly, desperately needed new technologies come from.  Garage innovation is at the heart of the way Silicon Valley works, and it is envied around the world.

IMG_0173.jpg
IMG_0174.jpgI continue to get push back from people who assert that "it is really too hard" to hack biology in a garage, or too expensive, or that garage labs just can't be up to snuff.  This sort of dissent usually comes out of National Labs, Ivy League professors, or denizens of the beltway.  All I can say to this is -- Doodz, you need to get out more.

So why am I not telling you the who and the where for the photos above?  Because, like many garage biology hackers, they are a little skittish given the way the Uncle Sam has been off his rocker for the last few years when it comes to mis-perceived biothreats (Shoot first, Google later).  The people who built the lab pictured above are pursuing a project that is technically well beyond anything discussed on the DIYBio list, and while they may be watching the DIYBio conversation they don't advertise what they are up to.  It would be better for all of us if we could rest assured that conversations about this sort of work could proceed in the open without guys showing up in biohazard suits with weapons drawn -- Youtube, at the 00:00:48 mark.  Words fail to describe this video.  Or, rather, I have plenty of choice words to describe the quality of the investigation and planning that went into an armed assault on the residence of an art professor whose many previous public shows and events included biological technologies including hacked bacteria -- and indeed I have shared those words with the appropriate individuals in DC, and will do so again -- but it won't do my blood pressure any good to go further down that road here.

While the innocuous art professor may be back at work, and while some may view this as water under the bridge, it is not my impression that Federal law enforcement officials truly understand the impact of their behavior.  (Here, I will try again: Dear Feds, You are making us less safe.)  The response to errant "enforcement"efforts (or "career enhancement", depending on your perspective) is exactly what you would expect -- people stop talking about what they are doing, making the job of sorting out potential threats all that much harder.  I recall giving a talk in DC in 2003 or so wherein I made this point to a room full of intelligence types (domestic and foreign), and only about half of them -- predominantly the younger ones -- understood that information was their only tool in this game.  The notion that you could effectively produce safety through prohibiting garage biology and related efforts is the height of folly.  See, for example, "And the Innovation Continues...Starting with Shake andBake Meth!" for the latest on the effectiveness of domestic prohibition of methamphetamine production.  The effect is -- surprise!!! -- more innovation.  Just like it always is.  However much garage biology we wind up with, we will be much safer if practitioners are willing to discuss what they are up to without worrying about misdirected badges, search warrants, and guns. 

To be sure, I don't have reason to suspect anything but good intentions and productive work originating from the garage lab shown above.  Nor is a drug screening project likely to result in something scary.  But I certainly can't know they won't make a mistake.  I would feel more comfortable if they, in turn, didn't feel like they had to keep a low profile so that there could be open discussion of potential missteps.  This applies to individuals and governments alike: "Above all else, let us insist that this work happens in the light, subject to the scrutiny of all who choose to examine it." (PDF)  And I am waaay more concerned about what the government might get up to behind closed doors than I am about activities of individuals.  

Next week I am headed to DC for another biosecurity/bioterrorism discussion, which will be interesting in light of the recent "F" grade given to US biopreparedness by the President's Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism.  See also my earlier analysis of the report.  I mention this here because the US Government still doesn't get the role of garage biology in much needed innovation (see the slides above from the talk to the CA Assembly Committee for a list of important technical advances from small businesses and individuals -- this discussion is also in the book).  Nor has the US Government clued into the PR job they have ahead of them with students who are gaining skills and who want to practice them in the garage.  Both the FBI and the Biological Weapons Commission Convention (sorry, Piers!) had a presence at iGEM in 2009 -- as liasons to students the FBI sent Agents whose cards read "Weapons of Mass Destruction Coordinator".  !!!Calling Chiat\Day!!!

There continues to be a prominent thread of conversation in Washington DC that "biohacking" is somehow aberrant and strange.  But apparently DIYBio, you'll be happy to hear, is a group composed of the Good Guys.  Everyone should feel happy and safe, I guess.  Or maybe not so much, but not for the reasons you might think.

The creation of a false dichotomy between "DIY Biotech" (good guys) and "Biohacking" (bad guys) lends unfortunate credence to the notion that there is an easily identifiable group of well-meaning souls who embrace openness and who are eager to work with the government.  On the contrary, in my experience there are a number of people who are actively hacking biology in their garages who intentionally keep a low profile (I am not certain how many and know of no existing measure, but see discussion above).  This tally included me until a little over a year ago, though now my garage houses a boat under restoration.  These people often consider themselves "hackers", in the same vein as people who hack computers, boats (!), cars, and their own houses.  Yes, it is all hacking, or Making, or whatever you want to call it, and not only is it generally innocuous but it is also the core of technological innovation that drives our economy.  And without direct interaction, I do not believe it is practical to ascribe motivation or intent to an individual - including and especially an incorporated individual - operating in a garage.  Thus, I strongly object to the establishment of a conversation related to biosecurity in which the term "biohacker" has any pejorative connotations precisely because it perpetuates the misconception that i) this group is quantifiable; ii) that the group has any unified motivations or identifiable ethical norms (or anti-norms); iii) that it can realistically be currently addressed (or assessed) as a "group".

Hmm...with that, I have run out of steam for the moment, and have real work to do.  More later.

Micro-Brewing the Bioeconomy: Beer as an Example of Distributed Biological Manufacturing (Updated, and again)

(Updated yet again, 19 June, 2011: Here is a technical report from Biodesic based on the post below (PDF).  "Microbrewing the Bioeconomy: Innovation and Changing Scale in Industrial Production")

(I used this data as part of my report on the bioeconomy and biosecurity for the Biodefense Net Assessment: Causes and Consequences of Bioeconomic Proliferation.)

Ah, beer.  The necessary lubricant of science.  Always the unacknowledged collaborator in the Nobel Prize.  Whether critical to the formulation of quantum mechanics in the pubs of Copenhagen, smoothing the way to the discovery of the double-helix in Cambridge, or helping celebrate an iGEM victory in that other Cambridge (congratulations again, almost-Dr. Brown and team), beer is always there.

And now it is helping me think about the future of biological manufacturing.  Not just by drinking it, though I can't say it hurts.  Yet.

Anyway, the rise of craft brewing in the US is an interesting test case, and a proof of principle, of distributed biological manufacturing successfully emerging in a market dominated by large scale industrial production.  To wit, Figure 1:

US_Brewery_Count_Biodesic.png
Figure 1.  The number of US large and small breweries over the last century.  The (official) count was forced to zero during Prohibition.  (Click on image for full-size.)

A Short, Oversimplified History of Craft Brewing

Before Prohibition, the vast majority of beer produced in the US was brewed by relatively small operations and distributed locally.  There was no refrigeration, nor were there highways and trucks, so beer had to drunk rather than produced and stored in large quantities (modulo some small amount of storage in basements, caves, etc.).  Moreover, the official count of breweries went to zero during the years 1920-1933.  After Prohibition, brewing was regulated and small scale producers were basically shut out of the market.

With the aid of refrigeration and transportation, large scale breweries took off.  Consolidation took its toll -- beer is pretty close to a commodity, after all -- and the number of breweries in the US shrank until about 1980.  In 1979, Jimmy Carter signed legislation reopening the market to small brewers.  This is an interesting and crucial point, because as far as I can tell nothing else substantive changed about the market.  (OK, so it was more complicated than this -- see updates below.)  Deregulation reopened the market to craft brewers and the industry blossomed through organic growth and the preferences of consumers (more on this in the Update below).  (Conclusion: Emerging small scale, distributed production can compete against an installed large scale infrastructure base.)

(Update 18 Aug 2010) There seems to be some upset out in blogland about the idea that Carter deregulated craft brewing.  See the first comment to this post.  I don't think it changes my story about biological manufacturing at all, but for the sake of clarity, here is this: On February 1, 1979, President Carter signed the Cranston Act, which allowed a single adult household to brew up to 100 gallons of beer per year.  A household with two adults could brew up to 200 gallons per year.  For more, see here, or this nice 2009 article from Reason Magazine by Greg Beato, "Draft Dodgers: For DIY brewers, Prohibition lasted until 1978. But onceunleashed, they revolutionized the industry."  From Beato's article: "After Prohibition ended, the Federal Alcohol Administration Act of 1935 laid out a new set of liquor laws. Home winemaking for family use was granted a tax exemption; home brewing was not. If you were making any amount of beer, you had to obtain a permit and comply with a long list of regulations."  Prior to the Cranston Act, brewing beer at home, or in small volumes anywhere, was hard to do because of federal regulations.  After the Cranston Act, people could concoct all kinds of interesting liquids at home.  So it sounds to me like Carter deregulated craft brewing.

(re-Update 19 August, 2010: Tom Hilton, at If I Ran the Zoo, makes some nice points here.  Namely, he observes that there were additional changes at the state level that legalized brewpubs.  Note that not all craft brewers are brewpubs, and this distinction appears to be glossed over in much of the criticism of this post.  Anyway, it is pretty clear that reality was more complicated than the summary I gave above.  No surprise there, though, as the heading of the section contains the word "oversimplified"...)

Better yet as a reference is a peer-reviewed article by Victor Tremblay and colleagues entitled "The Dynamics of Industry Concentration for U.S. Micro and Macro Brewers." (Link. Review of Industrial Organization (2005) 26:307-324)  Here is their description of what happened in 1979 (the original text contains an obvious typo that I have corrected in brackets):

Changes in government policy also benefited micro brewers. First, the legalization of home brewing in February of [1979] stimulated entry, since most early micro brewers began as home brewers. Second, states began lifting prohibitions against brewpubs in the early 1980s. Brewpubs were legal in only six states in 1984; Mississippi was the last state to legalize brewpubs in 1999. Third, the government granted a tax break to smaller brewers in February 1977. According to the new law, brewers with annual sales of less than 2 million barrels paid a federal excise tax rate of $7.00 per barrel on the first 60,000 barrels sold and $9.00 per barrel on additional sales. Brewers with more than 2 million barrels in sales paid an excise tax rate of $9.00 on every barrel sold. In 1991, the tax rate rose to $18 per barrel, but brewers with annual sales of less than 2 million barrels continued to pay only $7.00 per barrel on the first 60,000 barrels sold annually. This benefited the specialty sector, as all micro breweries and brewpubs have annual sales of less than 60,000 barrels and all of the larger specialty brewers have annual sales of less than 2 million barrels.

So a combination of changes to federal regulations and federal excise taxes enabled small players to enter a market they had previously been prohibited from.  That home brewing had been almost non-existent prior to 1979 points to another interesting feature of the market, namely that the skill base for brewing was quite limited.  Thus another effect of legalizing home brewing was that people could practice and build up their skills; they could try out new recipes and explore new business models.  And then, wham, in just a few years many thousands of people were participating in a market that had previously been dominated by large corporate players.

(end Update)

The definition of a "craft" brewer varies a bit across the various interested organizations.  According to the Brewers Association, "An American Craft Brewer is small, independent, and traditional."  Small means less than 2 million barrels a year (at 26 Imperial gal or 30.6 31 standard gal per barrel); independent means less than 25% owned by a non-craft brewer; traditional means either an all malt flagship beer or 50% of total volume in malt beer.  There is a profusion of other requirements to qualify as a craft brewer, some of which depend on jurisdiction, and which are important for such practical concerns as calculating excise tax.  Wikipedia puts the barrier for a craft brewer at less than 15,000 barrels a year.  According to the Brewers Association, as of the middle of 2009 there are about 1500 craft brewers in the US, and about 20 large brewers, and about 20 "others", with brewpubs accounting for about 2/3 of the craft brewers. 

Show Me the Hops.  Or Wheat.  Or Honey (if you must).

Brewpubs and microbreweries are so common that the majority of Americans live within 10 miles of a craft brewer, and it is a good bet that there is one quite close to where you live.  The Beer Mapping Project can help you verify this fact.  Please conduct your field research on foot.

Beer generates retail revenues of about $100 billion in the US (brewery revenues are probably less than half that), contributing combined direct and indirect jobs of about 1.9 million.  But craft brewers account for only a small fraction of the total volume of beer brewed in the US.  According to the Beer Institute's "Craft Brewers Conference Statistical Update - April 2007" (PPT), three brewers now supply 50% of the world's market and 80% of the US market.  See Figure 2, below. The Brewer's Association clarifies that only 5% of the volume of beer brewed in the US is from craft brewers, who manage to pull down a disproportionate 9% of revenues. (Conclusion: Small scale producers can command a premium in a commodity marketplace.)

US_market_share_Biodesic.png
Figure 2.  US beer market share.  (Click on image for full-size.)

Here is an interesting question to which I do not have an answer: how much beer brewed by large producers is actually bottled and distributed locally?  "Lot's of beer", where I don't have any real idea of what "lot's" means, is produced via contract brewing.  It may be that "large scale production" is therefore not as centralized as it looks, but is rather the result of branding.  This makes some sense if you think about the cost of transportation.  As beer (regardless of its source) is mostly water, you are paying to ship something around that is usually plentiful at the destination.  It makes a lot of sense to manufacture locally.  But, as I say, I have yet to sort out the numbers.

Brewing as an Example of Distributed Biological Manufacturing

All of the above makes brewing an interesting test case for thinking about distributed biological production.  Craft brewers buy feedstocks like everybody else, pay for bottles and probably for bottling services, and ship their product just like everybody else.  They may be much smaller on average than Anheuser Busch, but they survive and by definition make enough money to keep their owners and employees happy.  And they keep their customers happy.  And their thirsts quenched.

Above, I identified two important conclusions about the craft brewing market relevant to this story: 1) Craft brewing emerged in the US amidst an already established large scale, industrial infrastructure for producing and distributing beer.  2) Small scale, distributed production can command a premium at the cash register.

As we look forward to future growth in the bioeconomy, more industrial production will be replaced by biofactories, or perhaps "industrial biorefineries", whatever those are supposed to be.  Recall that the genetically modified domestic product (GMDP) now contributes about 2% of total US GDP, with the largest share for industrial products.

This story becomes particularly relevant for companies like Blue Marble, which is already producing high value, drop-in replacements for petrochemicals using biological systems.  (Full disclosure: Blue Mable and Biodesic are collaborating on several projects.)  As feedstocks, Blue Marble uses local waste agricultural products, macro- and micro-algae, sewage, and -- wait for it -- spent grains from the microbrewery next door.  (How's that for closing the loop?)  Products include various solvents, flavorings, and scents.

The craft brewing story tells us that consumers are quite willing to pay a premium for locally produced, high quality products, even before they learn -- in the case of Blue Marble -- that the product is organic and petroleum-free.  It also tells us that small scale production can emerge even amidst an existing large industry. 

Can Blue Mable and other companies compete against enormous, established chemical and petroleum companies?  In my experience, the guys (and they are nearly universally guys) at the top of the oil industry don't even get this question.  "It is all about steel in the ground", they say.  In other words, they are competing based on the massive scale of their capital investments and the massive scale of their operations and they don't think anybody can touch them.

But here is the thing -- Blue Marble and similar companies are going to be producing at whatever scale makes sense.  Buildings, neighborhoods, cities, whatever.  Any technology that is based on cow digestion doesn't have to be any bigger than a cow.  Need more production?  Add more cows.  This costs rather less than adding another supertanker or another refinery.  Blue Marble just doesn't require massive infrastructure, in large part because they don't require petroleum as a feedstock and are not dependent on high temperatures for processing.  Most of the time, Blue Marble can do their processing in plastic jugs sitting on the floor, and stainless steel only comes into the picture for food-grade production lines.  This means capital costs are much, much lower.  This is a point of departure for biomanufacturing when compared to brewing.

(Update: Perusing old posts, I discovered I did a decent job last year of putting this scale argument in the context of both computers and the oil industry, here.)

Beer is close to a commodity product, and it is the small scale producers who get a better price, even though their costs will be roughly the same as large scale producers.  Blue Marble generally has substantially higher margins than petrochemical producers -- and by focusing on the high margin portion of the petroleum barrel they are going to be stealing the cream away from much larger companies -- but Blue Marble's costs are much lower.  What is the financial situation of a large petrochemical company going to look like when they lose the market for esters, which can have margins of many hundreds of dollars per liter, and are left with margins on products closer to gas and diesel at dollars per liter?  This is a different sort of play than you would see in brewing.

Now, I am not guaranteeing that distributed biological production will win in all cases.  Large beer brewers clearly still dominate their market.   It may be that biological manufacturing will look like the current beer industry; a few large players producing large volumes, and a large number of small players producing much less but at higher margins.  But craft brewing is nonetheless an existence proof that small scale, distributed production can emerge and thrive even amidst established large scale competition.  And biological manufacturing is sufficiently different from anything else we have experience with that the present market size of craft brewing may not be that relevant to other products. 

GM Potatoes Approved in Europe for Industrial Starch Production

Not everyone is happy in Europe today.  Evil Genetically Modified (GM) crops are on the march.  After 12 years of deliberations, the EC approved the cultivation of BASF's Amflora potato for industrial uses or animal feed.  Amflora is only the second GM crop approved for cultivation in Europe.  Before getting into this too far, I want to make clear that such decisions should be based on science, and if the science says there are safety or health concerns then we should be cautious.  But the science, all the science I am aware of, says GM crops are safe, at least from a health perspective.  Non-peer reviewed yelping doesn't count.  (Leakage of transgenes is another matter, which I get to below, lest the reader think I am wholly uncritical of GM crops.)

According to the NYT, the EC's Health Commissioner John Dalli described the decision this way:

Responsible innovation will be my guiding principle when dealing with innovative technologies. After an extensive and thorough review ... it became clear to me that there were no new scientific issues that merited further assessment. ...All scientific issues, particularly those concerning safety, had been fully addressed. Any delay would have simply been unjustified.

Digging into this a bit, I found on the European Commission's site quite a long list of GM crops that are approved for various uses in Europe.  Not cultivation, mind you, but use.  Six member states presently "prohibit the use and/or sale of the GM product on its territory". 

The primary complaint by critics appears to be that Amflora contains antibiotic resistance genes, which is not the change that makes them useful in the field, but rather an old technology used to produce the plants in the first place.  That this very old technology is now being deployed in the field is the result of the slow approval process in Europe.  No new GM crop in the US would contain antibiotic resistance genes.  Why is this important?  Because those genes may leak out of the crop into other organisms.

According to the NYT, this risk was evaluated as being very low for the Amflora potato.  Fine.  But it is a real risk in general, one that has been observed in other GM crops.  Here is the relevant passage from of my book, in the context of using GM crops as industrial feedstocks (p165 -- refs are at bottom of this post):

Leakage of genes from GM crops into their unmodified cousins is potentially a threat if herbicide-resistance genes are transferred into weeds. Gene flow into close relatives has been observed in tests plot of Kentucky bluegrass and creeping bentgrass, which provided "the first evidence for escape of transgenes into wild plant populations within the USA."[47]  A similar result has now been demonstrated for a stable and persistent transfer of an herbicide-resistance gene from the widely cultivated Brassica napus, commonly known as rape or rapeseed, to its wild relative Brassica rapa.[48]  Within the confines of a laboratory, herbicide-resistance genes can be transferred with relative ease via pollen exchange between common weed species.[49]  These demonstrations may give pause to both policy makers and commercial interests. Any gene transfer in open cultivation that results in unintentional propagation of a new herbicide-resistant weed strain has the potential to cause substantial economic and physical damage.

The resulting potential threat to agricultural systems raises significant questions about the wisdom of relying on genetically modified crops for feedstock production.

If gene leakage can be minimized, then GM crops hold sufficient promise that they should be used.  The EC appears to believe that this is the case for Amflora potatoes.  Critics in Europe aren't satisfied.  But here is the truly nutty bit about criticism from Greenpeace and Friends of the Earth -- it is through their efforts that technological progress in Europe is so damn slow.  Why would any company want to go through the pain and expense of trying to get new technology (i.e., a GM crop that doesn't contain antibiotic resistance genes) into Europe when the only test case took 12 years to make it into the field?

At any rate, the Amflora decision may indicate the mood has changed at the EC level.  Not that the floodgates are likely to open, but perhaps GM crops will now be seen in a different light in Europe.

Refs from Biology is Technology excerpt:

47.  P. G. Johnson et al., Pollen-mediated gene flow from Kentucky bluegrass under cultivated field conditions,Crop Science 46, no. 5(2006): 1990; L. S. Watrud et al., From the cover: Evidence for landscape-level, pollen-mediated gene flow from genetically modified creeping bentgrass with CP4EPSPS as a marker, PNAS 101, no. 40(2004): 14533; J. R. Reichman et al., Establishment of transgenic herbicide-resistant creeping bentgrass (Agrostis stolonifera L.) in nonagronomic habitats, Molecular Ecology 15, no. 13(2006): 4243.

48.  S. I. Warwick et al., Do escaped transgenes persist in nature? The case of an herbicide resistance transgene in a weedy Brassica rapa population, Molecular Ecology 17, no. 5(2007): 1387-1395.

49.  I. A. Zelaya, M. D. K. Owen, and M. J. VanGessel, Transfer of glyphosate resistance: Evidence of hybridization in Conyza (Asteraceae), American Journal of Botany 94, no. 4(2007): 660.