November 2008 Archives

"Tracking the spread of biological technologies"

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I have an editorial in the Bulletin of the Atomic Scientists dated 21 November, 2008 (Open Access).

Regular readers will recall that I do not see that history provides useful examples of effective regulation of distributed technologies.  Here are the final 'graphs from the editorial:

The counterargument typically relies on inspiring fear and encouraging proactivity. We cannot wait for perfect policy to implement security measures, the thinking goes. Yet this argument obscures the investigation and debate that must come first: Is it at all possible to slow down the actions of potential aggressors? Will regulation increase knowledge of threats or further obscure them? Finally, will these efforts, whether successful or not, also retard crucial research required to produce countermeasures for both natural and artificial threats?

Most proponents of regulation have not addressed these questions. Greater knowledge of potential threats is clearly desirable. Reducing the threat from bioerror and bioterror is an even more important goal. Formulating effective policy requires acknowledging the pace and proliferation of biological technologies as well as carefully weighing any potential negative impacts of action.

Mostly Moved

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Thanks to the efforts of the team at LivingDot, I am mostly moved in to the new space online.  As I am still learning MovableType there will no doubt be a few stumbles over the next couple of weeks.

If you are looking for articles, I'll try to get those posted in the next couple of days.

Judith Miller on Bioterrorism Preparedness

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Judith Miller has a piece in the recent edition of City Journal carrying the title, "Bioterrorism's Deadly Math".  Her perspective is that after many years and billions of dollars, the U.S. remains quite vulnerable to attack.

Here is one interesting bit that stands out as good news about the Department of Homeland Security's National Biodefense Analysis and Countermeasures Center (NBACC): 

The agency's original plan was to operate the NBACC mostly in secret by classifying the entire center as a Sensitive Compartmented Information Facility (SCIF, pronounced "skiff")--a place where top-secret information and materials could be stored and discussed. But the NBACC's new director, J. Patrick Fitch, says that he intends to operate the lab with the greatest possible transparency. "Eighty percent of our projects and their results will be unclassified, and we will encourage our scientists to publish," he says. While his facility would be "SCIFable" in an emergency, he intends to encourage as much interaction as possible between NBACC scientists and their American and foreign counterparts. "In such a fast-moving area," he explains, "it's self-defeating to isolate yourself."

This is a welcome change.  There is also an independent advisory board looking over the NBACC's shoulder, but the idea of classified work on pathogens still makes me uneasy.

It is interesting to see Miller back on the biodefense beat.  Even if some of her prior work is now frowned on, she seems to have a knack for putting pieces together.

Update on Plans for GM Crop Research in Britain

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Last year I pointed out the complexities of arguments about GM food through the continuing debate in Europe and the U.K. about animal feed.  The diminishing availability of GM-free feed grain could lead to significant shortages, which in turn could drastically reduce the amount of meat in European markets.  (See "Re-Inventing The Food Chain (or "On Food Prices, In Vitro Meat, and GM Livestock Feed")."

Now the Independent reports that the U.K. is considering protecting GM crop research from domestic protest and attack.  The government may go so far as to bring that research onto defense installations in order to protect it better, as suggested by Andrew Grice in a story provocatively titled "Government to defy critics with secret GM crop trials".

Here is one 'graph from the article:

Professor Tim Benton, research dean at [the Leeds University] Faculty of Biological Science, said yesterday: "We need to find a way to do crop trials in a safe way and to minimise the environmental risk. We cannot carry on for the next 20 or 30 years saying it's too scary, the public is too frightened, it is politically too dangerous. There is absolutely no way we can move towards a world with food security without using GM technology. The amount of food we need could double because the population is growing, climate change will reduce yields and we will take land out of food production for biofuels."

A "Noxious Cocktail" in China's Air

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Yesterday's New York Times carries a story by Andrew Jacobs on a new UN study that describes the effects of industrial pollution on China's health, environment, and economy.  The article contains some slightly different estimates than my earlier posts on this issue, The Future of China's Economy, and More on China's Economy, Food Production, and Food Demand.

Here is the press release about the report from UNEP, and here is the report itself, "Atmospheric Brown Clouds: Regional assessment report with focus on Asia".

Here are a couple of tidbits about China from the Times story:

Although their overall impact is not entirely understood, Professor Veerabhadran Ramanathan, a professor of climate and ocean sciences at the University of California, San Diego, said ...some studies suggest that the plumes of soot that blot out the sun have led to a 5 percent decline in the growth rate of rice harvests across Asia since the 1960s.

...Henning Rodhe, a professor of chemical meteorology at Stockholm University, says... “The impacts on health alone is a reason to reduce these brown clouds,” adding that in China, about 3.6 percent of the nation’s annual gross domestic product, or $82 billion, is lost to the health effects of pollution.

In addition to the general effects of warming that reduce agricultural yields in Asia, farmers are evidently facing a reduction due to decreased insolation.  As long as our energy production is "carbon-positive", this is going to be a problem.

The health impact estimate above is on the high end of those I have found, but I don't see any reason to discount it relative to the others.  I wonder how long it will be before Asian pollution starts to have a measureable effect on health here on the West coast of the U.S.  Is anybody looking for this explicitly?  A positive correlation would have very interesting consequences in our international political economy.

Gene Synthesis Cost Update

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While at iGEM this past weekend, I learned that GeneArt is now charging $.55 per base for ~1 kB synthesis jobs, with delivery within 10 days.

Here is an interesting tidbit: They only charged iGEM teams $.20 per base.  Anybody have any idea whether this represents their internal cost, and how much margin this might include?

Here is an updated plot for synthesis and sequencing cost.  No new data, just a new rendering.

(Update: 12 November, 2008.  There is a news piece in last week's Nature that claims Illumina's Genome Analyzer (GA1) was just used to sequence a whole genome in 8 weeks for $250K.  However, the paper describing that sequencing efforts says:

We generated 135 Gb of sequence (4 billion paired 35-base reads) over a period of 8 weeks (December 2007 to January 2008) on six GA1 instruments averaging 3.3 Gb per production run. The approximate consumables cost (based on full list price of reagents) was $250,000.

Thus the price does not include labor, and is not a true commercial cost (labor is only truly free for professors).

I am therefore not sure if/how this price can be compared to the prices in the figure below.

Update 2: I fixed the significant figure issue with the cost axis.  Alas, Open Office does not give great control over the appearance of the digits.)

carlson_cost_per_base_nov_08.jpg

Amyris Opens Biodiesel Pilot Plant

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Amyris appears to be making good progress towards meeting their goal of getting biofuels to market by 2010.  They just opened their first pilot plant in California, with the aim of importing fuel into the US from Brazil within two years.  The output of the pilot plant will be used to gain EPA certification.  The announcement pretty well tracks with my previous posts about biofuels.

Here are a few graphs from the press release:

Amyris' diesel is characterized as a No Compromise™ fuel because it is designed to be a scalable, low‐cost renewable fuel with performance attributes that equal or exceed those of petroleum‐sourced fuels and currently available biofuels. Other attributes include:
  • Superior environmental performance: Preliminary analyses show that Amyris diesel fuel has virtually no sulfur and significantly reduced NOx, particulate, carbon monoxide and hydrocarbon exhaust emissions relative to petroleum‐sourced diesel fuel.
  • High blending rates: Because Amyris renewable diesel contains many of the properties of petroleum diesel, Amyris can blend the fuel at high levels ‐‐ up to 50  pecent ‐‐ compared with 10‐20 percent for conventional biodiesel and ethanol.
  • Compatibility with  existing infrastructure: Unlike many commercially available biofuels, Amyris expects to distribute its renewable diesel through the existing fuel distribution and storage infrastructure, thus speeding time to market while minimizing costs.
  • Adaptive: Amyris can produce its fuels from a broad range of feedstock including sugarcane and cellulosic biomass. It is starting with Brazilian sugar cane because it provides the most environmentally sound, economical, and scalable source of energy available today.
"This new diesel fuel has all the characteristics to make an important contribution toward solving our global transportation energy and climate crisis," said John Melo, chief executive officer of Amyris. "The opening of our pilot plant is a significant business marker for us, taking us one step closer to bringing our diesel fuel to market."

Craig Rubens at earth2tech provides interesting coverage, and his story notes:

Melo described the company's business model as "a capital-light model to scale up fast." The company plans to partner with existing ethanol plants and convert a portion of those partners' production capacity to make diesel and other chemicals using Amyris IP. The startup will then buy the products back from the refiner and take them to market, Melo said. The startup has already formed a joint venture with Santelisa Vale, Brazil's second largest sugar grower, called Crystalsev, which aims to produce 200 million gallons of fuel a year by 2011 at several of its existing ethanol plants at a price of less than $2 a gallon.

The Brazilian partnership, Melo explained, gives Amyris access to ports and ships to export the fuel. Amyris plans to import it to the U.S. and sell its to large customers, like Wal-Mart and the U.S. government. Foreign ethanol is hit with a 54-cent-per-gallon tariff as it comes into the U.S., but Amyris would be importing hydrocarbons, not ethanol, and therefore avoid the tariff. Amyris is already marketing other companies' biofuels in the Southeast to make sure its distribution channels will work.

To date, Amyris' strategy hasn't seamed particularly "capital light." The company has raised more than $120 million in capital (see previous coverage here and here) from heavy-hitting cleantech and biotech investors, including Kleiner Perkins, Khosla Ventures, TPG Biotech and DAG Ventures.

I understand the present need for scale, both physical and financial, and earth2tech's skepticism seems a bit naive.  Amyris is facing enormous competition, both from established petroleum companies and from other start-ups.  As I would not expect any of these companies to have a firm lock on IP surrounding biological production of fuels, Amyris must establish itself and its brand quickly and rely on first-mover advantage. (I wonder how thoroughly they are scrubbing the waste stream?  Dumpster diving for competitive intelligence takes on a new meaning here.)  Shell is dropping seven billion on upgrading a single refinery in Texas.  Amyris seems pretty light in comparison.

Writing at Cleantech, Emma Ritch provides an excellent tidbit: "The company has shelved its plans for a bio-gasoline".  "We're focused on the products with the highest value," Melo said. "We're not investing our resources in developing a bio-gasoline because we see the U.S. as the last gasoline-based economy."  That is particularly fascinating, as Melo is the former President of BP Fuels.  It is also a change since I heard Zach Serber speak at SB 4.0 last month in Hong Kong.  The fluctuating price of oil may be important here.

Unfortunately, Ritch mischaracterises the competitive landscape a bit: "Amyris plans to use the cheapest nonfood feedstock available, which for now means sugarcane... The company could also use algae for its biodiesel--much like Solazyme, LiveFuels, GreenFuel Technologies and many others."  In contrast to Amyris, the latter three companies are directly producting fuel in algae, with Solazyme feeding sugar to bugs in the dark and completely skipping photosynthesis. (Hmm...I wonder what sort of selection pressure that is putting on their algae strains?)  If Amyris does use algae -- sorry, when Amyris starts using algae -- the company will almost certainly be using it as a feedstock fed to microbes that then produce fuels.  This would require building a front-end process onto their yeast production system, but I don't see that as taking very long to happen.  See my earlier post on Blue Marble Energy.

Things are moving forward.  I would note that I see a lot of stainless steel in the photos of Aymris' pilot plant.  I am no fermentation jock, but it seems that they could probably use solvent resistent plastic as their culture vessels.  Here is one home-brew kit that basically just consists of plastic buckets.  Maybe that is a step for later.

Congratulations to everyone at Amyris.  Keep up the good work.

iGEM 2008: Surprise -- The Future is Here Already.

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I'm back from a weekend at MIT serving as a judge for the International Genetically Engineered Machines Competition.  Here are a few thoughts on the competition.

The "international" flavor continues to strengthen.  Of the six finalists, three were from the U.S., two from Europe, and one from Asia.  There were 85 teams registered, almost all of whom showed up.  I was hoping for more biofuels/energy projects, but perhaps that fad is already past.

The top three teams were (here are the full results): 1) Slovenia 2) Freiburg 3) Caltech.

First, a couple of slightly blurry iPhotos (when the hell is Apple going to upgrade that camera?):

IMG_0138  Tom Knight receives the BioBrick from the 2007 winner, Peking University.

IMG_0140 A collective dance party while the competitors wait for the judges.

IMG_0141 Tom Knight awards the BioBrick to the 2008 winners, Slovenia.

Several of the 2008 projects implement ideas that have appeared in science fiction stories and in my own speculations about the future of biological technologies:

UCSF characterized a fusion protein that enables epigenetic control of gene expression through chromatin silencing.  This, in effect, gives the user (which could be the cell itself) a new control knob for building memory circuits in eukaryotes.  I seem to recall that this is the basic innovation in Greg Bear's Blood Music that brings about the end of the world through Green Goo.  Go UCSF!

Caltech and NYMU-Taipei (check out the killer Wiki) both modified commensal E. coli strains to serve as therapeutics.  Caltech built a bunch of new functionality into the probiotic strain Nissle 1917, including microbicidal circuits, Vitamin B supplements, and lactase production (big kudos to Christina Smolke, here).  Taipei built a "Bactokidney" for people with kidney failure: cells that attach to the lining of the small intestine and absorb nasty substances that would otherwise need to be removed via dialysis.  These are both very cool ideas.

Seeing these projects brought back shades of a scenario published in Bio-era's "Genome Synthesis and Design Futures: Implications for the U.S. Economy".  (I wrote the original story, which was less complicated but slightly more nefarious than the Bio-era version, in 2005 as a short, provocative piece of a larger report for a TLA -- a three letter agency.)  Almost all the technology described below has been published in bits and pieces -- fortunately, it has not yet been put together in one microbe.

In 2008, the North Korean government launches a secret program to develop biological tools that can be used to pacify target populations for crowd control or military purposes. North Korea's research draws on Soviet work on modifying pathogens to express mood-altering peptides, and the demonstration by U.S. scientists at the National Institutes of Health that common commensal strains of E. coli could be modified to secrete specialized peptides in human intestines.  Modifying the same strain used by the NIH, available in an over-the-counter probiotic pill, the North Koreans secretly produce an organism that produces peptide hormones easily absorbed through the intestinal wall.

With further modifications to allow the peptides to enter the brain, the new strain produces a calming, almost sedative, effect on colonized individuals. Combined with a genetic circuit that confers both antibiotic resistance and upregulation of the peptides upon exposure to a chemical that can be dispersed like teargas, these modifications enable the government to pacify crowds in times of crisis. The E. coli can be distributed via food and water to target populations.

To maintain the presence of the genetic circuit within the population, the new strain is equipped with an antibiotic resistance mechanism from V. cholera that causes plasmids containing the entire genetic circuit, including the regulatory genes and the mood modification genes, to be horizontally transferred to other bacteria upon treatment with common antibiotics.

In 2009, Pyongyang uses military forces to suppress a widening political uprising against the regime. Reports of a "pacifying gas" quickly emerge, raising allegations about the use of chemical weapons. U.S. intelligence agencies claim that North Korea has used a novel combination of biological and chemical weapons against rioters, leading the U.S. to declare that Pyongyang has violated the international treaty on bioweapons. Pacifist biohackers undertake to recreate the microbe , or to invent new versions to use as "peace weapons" against armies.

When a U.S.-led coalition attempts to impose an economic embargo against North Korea, the Chinese government uses its military to secure supply lines to North Korea. A military standoff between U.S. and Chinese forces ensues.

Here is the original inspiration: "Toward a live microbial microbicide for HIV: Commensal bacteria secreting an HIV fusion inhibitor peptide". (I'd completely forgotten that I blogged the original paper.)

Slovenia won (again) with "Immunobricks" by engineering new vaccines. The technology they used forms the basis of arguments about rapid, distributed vaccine production we made in Genome Synthesis and Design Futures (Section 4.3, in particular), which I've also written about extensively here on this blog, and which will show up in my book.  Yet all of a sudden it's real, all the more so because it was an iGEM project.

From Slovenia's Wiki abstract:

Using synthetic biology approaches we managed to assemble functional "immunobricks" into a designer vaccine with a goal to activate both innate and acquired immune response to H. pylori. We successfully developed two forms of such designer vaccines. One was based on modifying H. pylori component (flagellin) such that it can now be recognized by the immune system. The other relied upon linking H. pylori components to certain molecules of the innate immune response (so called Toll-like receptors) to activate and guide H. pylori proteins to relevant compartments within the immune cell causing optimal innate and acquired immune response. Both types of vaccines have been thoroughly characterized in vitro (in test tubes or cells) as well as in vivo (laboratory mice) exhibiting substantial antibody response. Our strategy of both vaccines' design is not limited to H. pylori and can be applied to other pathogens. Additionally, our vaccines can be delivered using simple and inexpensive vaccination routes, which could be suitable also in third world countries.

If you've read this far into the post, you should definitely spend some time on Slovenia's Wiki.

Here's the short, pithy version: There is presently no vaccine for H. pylori.  Between June and October this year, seven undergraduates built and tested three kinds of brand new vaccines against H. pylori.  (They also put a whole mess of Biobrick parts into the Registry, which means those parts are all in the public domain.)

Yes, yes -- it's true, getting something to work in a mouse and in mammalian cell culture is a long way from getting it to work in humans, or even in ferrets.  But the skill level and speed of this work should make everyone sit up and take notice.

So it is worth pondering the broader implications of these projects.

The Slovenian team clearly has access to very high quality labs and protocols.  Mammalian cell culture can be very fiddly unless you know what you are doing and have the right equipment (I speak from painful experience, lo those many years ago in grad school).  The Caltech and Taipei teams also clearly have a great deal of support and mentoring.  Yet while bashing DNA and growing E. coli are not particularly hard, the design and testing of the coli projects is very impressive.

Despite all the support and money evident in the projects, there is absolutely no reason this work could not be done in a garage.  And all of the parts for these projects are now available from the Registry.

Over the past couple of years, in various venues, I have tried to point out both the utility and inevitability of proliferating biological technologies.  iGEM 2008 drives home the point yet again.  In particular, the ability to rapidly create vaccines and biological therapeutics points the way to increased participation by "amateurs", whether the professionals (and policy makers...and security types) are ready or not.  I'm also thinking back to "peer reviews" in which I was excoriated for suggesting this kind of work was within the reach of people with minimal formal training.  Because, really, you need a PhD, and an NIH grant, and tenure, to even think of taking on anything like a synthetic vaccine.  Oh, wait...

Although I've predicted in writing that this sort of thing would happen, I frankly expected practical implementation of both the rapid, synthetic vaccines and the modified commensal bacteria to take a few more years. Yet undergraduates are already building these things as summer projects.

It didn't really hit me until I started writing this post earlier this afternoon, but as I ponder the results from this year's iGEM only one thought comes to mind: "Holy crap -- hold on to your knickers."

The world is changing very, very quickly.

Heading to MIT and iGEM

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I'm off to give a talk at MIT on Friday and be a judge for iGEM again this weekend.

Here are talk coordinates (I've no idea how big the room is):

"Engineering (and) the Bio-economy"
Rob Carlson

7 November, 2008
12 to 2 PM
MIT
E38, 6th floor conference room.
292 main street, directly above the MIT press book store.

Can't wait to see what the students have come up with this year.

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