The Need for Fuels Produced Using Synthetic Biology

Among the most promising short term applications of Synthetic Biology is biological production of liquid fuels.  But beyond the technical and economic attraction of the project, the reasons we require progress in this area are manifest; diversification of fuel sources thereby reducing dependency on imports, improving air quality, reducing greenhouse gas and particulate emissions that contribute to climate change, eliminating the present coupling between biofuels and food crops, and carbon sequestration.

Bio-era is in the middle of scheduled briefings in Asia, the U.S., and Europe describing the present state of biofuels markets and associated technologies, and these trips, along with recent headlines concerning commodities prices and future fuel demands, have helped clarify the story in my mind.  Below I outline some of the factors in play:

Carbon and other Greenhouse Gas Emissions: The amount of water coming off Antarctica and Greenland scares the crap out of me.  It's true that this isn't my professional specialty, but I have been following the literature on polar ice mass and movement for a decade.  The news is just getting worse.

The present coupling between biofuels and food crops creates upward pressure on food price inflation and reduces (or eliminates) the economic incentive to produce biofuels: Ethanol demand has pushed up the price of corn, and in the U.S. politically motivated trade barriers to Brazilian ethanol derived from sugar cane threaten to keep corn prices high.  Palm oil is presently trading at historic highs, and at a ~30-40% premium to finished diesel, but this is actually driven by food demand, primarily from India and China.  I am a simple physicist by training, rather than a sophisticated economist, but given the increase in food demand I don't see the price coming down even with increased supply.  This puts anybody planning to refine palm oil into biodiesel completely underwater for the foreseeable future. 

China (and India) will require increasing resources over the coming decades: More on this in posts to come.  The numbers are mind boggling.

Ethanol is by no means an advanced biofuel; from both a technical and an economic perspective ethanol is a backwards biofuel: The future is all about producing biofuels that are high energy content (not ethanol), are not water soluble (not ethanol), can be easily integrated into the existing gasoline and diesel distribution infrastructure (not ethanol), and require minimal, if any, initial changes in engine technology (not ethanol).  The average age of an automobile in the U.S. is now at least 10 years (depending on who is counting, and how), which means engine technology turns over very slowly here.  It is faster in other countries (2-3 years in Japan, if memory serves), but this dramatically influences the speed with which new fuels can enter the market.

You don't want to be long on petroleum in ten years:

First, despite a greater than 10% annual growth in auto sales in China, petroleum demand has evidently plateaued due to increased biofuel blending.  I'm not sure I completely believe this yet, but it is an interesting assertion.

Second, three companies are already out in front with funding to use both traditional metabolic engineering and synthetic biology to produce microbes that churn out biofuels:

LS9 is "Developing Renewable Petroleum biofuels: new, clean, and sustainable fuels that fulfill our long and short term energy needs. Derived from diverse agricultural feedstocks, these high energy liquid fuels are renewable and compatible with current distribution and consumer infrastructure."

Synthetic Genomics, Craig Venter's shop, just announced a partnership with BP aimed at using organisms and genes found in subsurface hydrocarbon deposits to develop "cleaner energy production and improved recovery rates".

Amyris Biotechnologies recently received $20 million to develop direct microbial production of liquid biofuels.  Amyris, in particular, is well positioned to make some serious headway.  The company website suggests they are well on their way to making both butanol and biodiesel  (or more likely a precursor to diesel?) in microbes.  In an article in Technology Review, the new CEO, John Melo, says the company has already developed a metabolic pathway to produce a fuel equivalent to Jet-A.  This is particularly interesting given the recent announcement by the U.S. Air Force that it will replace at least 50% of its petroleum use with synthetic fuels by 2010.  In an article by Don Phillips, The New York Times is reporting that, "The United States Air Force has decided to push development of a new type of fuel to power its bombers and fighters, mixing conventional jet fuel with fuels from nonpetroleum sources that could eventually limit military dependence on imported oil."  At the moment, the immediate plan appears to utilize a synthetic fuel produced using natural gas, but anybody who can crack the aviation biofuel nut has immediate access to a 3.2 billion gallon per year market in the Air Force alone.

So how long is this all going to take?  Amyris CEO Melo mentions they hope, "To make a Jet-A equivalent with better properties on energy and freezing point with a $40 barrel cost equivalent by 2010 or 2011".  That's faster than I was expecting, but I find the time scale highly credible.  Below is a figure with data drawn from Jay Keasling's recent presentation to the UC Berkeley faculty senate on BP's investment in the Energy  Biosciences Institute.

The data represents a roughly billion-fold improvement in yield over 6 years.  (I've called this "pre-synthetic biology improvements" because the data is the result of applying fairly traditional metabolic engineering techniques, rather than the combination of Biobricks.  This is by no means a critique of Jay Keasling or his teams at UC Berkeley or Amyris, but rather a simple contrast of methodology.)

You would be hard pressed to find examples of that magnitude of improvement in any human industrial process over any 6 year period, but that is exactly what is possible when you turn to biology.  Moreover, the complexity of the isoprenoid pathway is probably about the same as you would expect for producing biobutanol or a Jet-A equivalent.  This is why John Melo is bullish about making progress on biofuels.  Given that Amyris is evidently already on the path towards butanol, diesel, and aviation fuel, five years is by no means an overly optimistic estimate of reaching commercial viability.  Note that this doesn't mean Amyris takes over the liquid fuels market overnight.  It can take decades for new technologies to make progress against existing infrastructure and investment.

But assuming Amyris, or any other company, is successful in these projects, it is worth considering first the resulting impact on the liquid fuels market, then more generally the effects on structure of the economy as a whole.

The economic considerations of scaling up direct microbial producing of biofuels are fundamentally and radically different than those of traditional petroleum production and refining.  The costs associated with finding a new oil field and bringing it into full production are considerable, but are also so variable, depending on location, quality, and local government stability, that they are a poor metric.  But a very clean measure of increasing gasoline and diesel supplies is the fractional cost of adding refining capacity, presently somewhere between US$ 1 and 10 billion dollars for a new petro-cracking plant, plus the five or so years it takes for construction and tuning the facility for maximum throughput.

In contrast, the incremental cost of doubling direct microbial production of a biofuel is more akin to setting up a brewery, or at worst case a pharmaceutical grade cell culture facility, which puts the cost between about US$ 10,000 and 100,000,000.  Pinning down the cost of a biofuel production facility is presently an exercise in educated speculation, but it is more likely to be on the low end of the scale suggested above, particularly for a fuel like butanol, which, unlike, ethanol, is not soluble in water and therefore does not require distillation; it can simply be pumped or skimmed off the top of the tank in a continuous process.  Beer brewing presently occurs at scales from garage operations bottling a few liters at a time to commercial operations running fermenters processing thousands to many millions of liters per year.  Thus, once in possession of the relevant strain of microbe, increasing production of a biofuel may well be feasible at the local level, thereby matched to fluctuations in demand.  Microbial biofuels could therefore be an excellent initial demonstration of distributed biological production (PDF warning).

In the end, the scalability of microbial production of biofuels depends in part on what materials are used as feedstocks, where those feedstocks come from, and how they are delivered to the site of production.  Whereas petroleum products are a primary feedstock of today’s economy, both as a raw material for fabrication and for the energy they deliver, it may eventually be possible to treat biomass or waste material as feedstocks for microbes producing more than just fuels.  But as I observed above, any biological production process  for biofuels that relies on a sugar or starch crop also used in food production will be subject to the same skewed market dynamics now playing out between food and conventional biofuels.

There are clear challenges to overcome in the years ahead, but given the progress already demonstrated I am comfortable we will find solutions with continued effort.

A Synthetic Enzymatic Pathway for Hydrogen Production from Starch

Zhang, et al., demonstrate a synthetic pathway consisting of 13 enzymes that turns starch into hydrogen.  The paper, at PLoSone, makes clear how important it is to ensure that the definition of Synthetic Biology, if there is a definition yet, includes not just new circuits in cells and new organisms but also cell free systems.  The article (High-Yield Hydrogen Production from Starch and Water by a Synthetic Enzymatic Pathway) is open access, so I won't bother to quote from it extensively.

But the details are pretty cool.  The authors used 11 off-the-shelf enzymes (from spinach, rabbit, E. coli, and yeast) ordered from Sigma, and two they purified themselves (from coli, and P. furiosus).  I imagine it won't be too long before those last two are also available commercially. Here is a paragraph that sums up the context of what the authors accomplished and where they will look for performance improvements:

This robust synthetic enzymatic pathway that does not function in nature was assembled by 12 mesophilic enzymes from animal, plant, bacterial, and yeast sources, plus an archaeal hyperthermophilic hydrogenase. The performance (e.g., reaction rate and enzyme stability) is anticipated to be improved by several orders of magnitude by using the combination of (a) enzyme component optimization via metabolic engineering modeling, (b) interchangeable substitution of mesophilic enzymes by recombinant thermophilic or even hyperthermophilic enzymes, (c) protein engineering technologies, and (d) higher concentrations of enzymes and substrates. ... This research approach will naturally benefit from on-going improvements by others in synthetic biology systems that are addressing cofactor stability, enzyme stability by additives, and co-immobilization, and development of minimal microorganisms that can be built upon to create an in vivo enzyme system that produces H2 in high yields.

What I think is most interesting about all this is that Zhang and colleagues have effectively just put a whole bunch of new Biobricks on the table.  Moreover, those new parts for producing biofuels are reasonably well characterized, at least in vitro.  A cursory search of the Registry of Standard Biological Parts doesn't turn up any of these enzymes, but since the gene sequences are either already in Genbank or are relatively easy to generate, this gap points to an area of expansion for Biobricks in general and the International Genetically Engineered Machines Competition (iGEM) in particular.

I suggest it is time to expand the horizons of iGEM beyond demonstration projects to start tackling real world problems.  The student teams have made fantastic progress over the past few years, with some projects winding up on the cover of high-profile journals.  I would like to see this year's iGEM participants take on biological production of fuels and materials, bioremediation, and biological carbon sequestration.  Even if popular attention has yet to come round, the problems we presently face are enormous (see my post "It's Time to Invest in Water Wings"), and through the combination of enthusiasm and creativity iGEM participants could start developing solutions today.

It's Time to Invest in Water Wings

Waterfront property in Puget Sound and the San Juan Islands is advertised in units of "no-", "low-", "medium-", and "high-bank".  Whenever I dream about a place to watch the sunset from, and to launch my kayak, some sort of beach usually plays a staring role.  But James Hansen and his colleagues say anybody with no- to medium-bank waterfront property could be in trouble fairly soon.

In a paper just published in Philosophical Transactions of the Royal Society, Hansen, the director of NASA's Goddard Institute for Space Sciences, and five eminent colleagues bluntly suggest: "...Civilization developed, and constructed extensive infrastructure, during a period of unusual climate stability, the Holocene, now almost 12,000 years in duration. That period is about to end."

Although the paper carries the rather prosaic title, “Climate change and trace gases”, The Independent leads off its coverage with, "The Earth today stands in imminent peril".  It isn't so surprising that The Independent would start slinging end-of-the-world rhetoric around at the drop of a hat an iceberg,  but in this case (in this case!) I think they are actually getting the story right.

Relying primarily on data, rather than upon climate models as does the IPCC, Hansen, et al., draw very different conclusions about what is happening at the poles of the planet than the recent international consensus report.  As other coverage has noted, the Hansen paper looks closely at what is happening as ice coverage is replaced by water, thereby dramatically lowering the albedo of the earth's surface, concomitantly increasing the amount of solar radiation absorbed at the surface of the planet.

GreenCarCongress notes that:

The authors explicitly disagree with the conclusions of the IPCC, which forsees little or no contribution to 21st century sea-level rise from Greenland and Antarctica. The paper’s authors argue that the IPCC analysis does not account well for the nonlinear physics of wet ice sheet disintegration, ice streams and eroding ice shelves, and point out that the IPCC conclusions are not consistent with the palaeoclimate evidence.

There is significant melting at the poles an on Greenland, and ignoring these phenomena just doesn't seem very smart.  The paper, in short, argues that we must rapidly move beyond even just limiting carbon emissions to agressively sequestering CO2 from the atmosphere.  The best way I can see to do that is with biology.

Consolidation in Biological Tech Sector

Continuing the fine tradition of innovation by acquisition characteristic of many large tech companies, Roche just bought NimbleGen for $272.5 million.

Here are some tidbits from the article:

"This acquisition represents a further milestone in our strategy to strengthen our position as a major player and complete solution provider in the genomics research market," Severin Schwan, the head of Roche Diagnostics, said in a statement.

Roche said the global market for microarray systems was worth about $600 million and grew by 10 percent in 2006.

...NimbleGen's revenues have been growing strongly, from $4.5 million in 2004, to $9.5 million in 2005 and $13.5 million in 2006, but it has accumulated a total loss of $44.5 million as of the end of 2006, including losses of $8.3 million in 2004, $5.2 million in 2005 and $6.8 million in 2006, according to its IPO filing.

Asia Biofuels Travelblog, Pt. 2

If this is Wednesday, it must be Singapore.  No, wait -- the signs all say Hong Kong.  I barely remember Monday.  The schedule says we were in Kuala Lumpur, and so do my photos of the Petronas Towers, but it took 10 minutes of brainstorming with Jim to remember where we had lunch on that day.

In the end, it was the push back on European criticisms of Malaysian palm oil that brought it back for us.  Let me explain: As I wrote about a few weeks ago, there is recent concern that clearing jungle and peat bogs to plant oil palms has been contributing 8-10% of global emissions of carbon dioxide in recent years.  When cleared, the soil and peat release somewhere between ten and fifty thousand years worth of fossil carbon dioxide into the atmosphere.  Such an immense pulse of greenhouse gas into the atmosphere completely overwhelms the benefits of planting this land with any crop destined for refining into biodiesel.  If it is true, we are talking about thousands of years worth of deficit – we are better off, by far, burning petrodiesel.

As a result of this sort of criticism, palm-to-biodiesel investment in Europe has crashed, and The Netherlands has recently banned the import of oil from land that has recently been peat bog.  Granted, the Holland is not the biggest market in Europe by any means, but they have a clear interest in keeping all their reclaimed land dry, which increased carbon emissions threaten via sea level rise.  (I wonder if in Holland you can hear the thunder sounds made by the icecap on Greenland as it melts?)  It is worth considering whether the rest of the EU will follow suit, given the stated policy of reducing carbon emissions by 20% compared with 1990 levels.  Some of the people listening to our presentations about biofuels here are in fact investors in palm plantations, and they were decidedly of the opinion that, at least in Malaysia, no virgin jungle or wetlands are being cleared form growing oil palm.  We were even invited out into the bush to check it out for ourselves.

Perhaps on the next trip.

As a result of the hubbub caused by accusations about carbon release from land cleaning in SE Asia, Malaysia and Indonesia this week sent a delegation to Europe to explain that all is in fact well.  Indonesia is claiming that it has 18 million hectares of degraded land it can use for planting oil palm -- land cleared illegally for timber harvest and now left to rot, as it were.  The word down here is that Indonesia has really cracked down on illegal logging, and the people on the ground seem to think this is credible.  But having just flown over large sections of Borneo, with all the rows of neatly planted oil palm, literally as far as the eye can see from 30,000 feet, I am led to wonder where the truth is.

More news on the topic this week.  From Bloomberg, via The Business Times (6 June, 1007):  According to the story, Indonesia “ups efforts to protect primary forests,” and “won’t allow oil palm growers to cut primary forests for establishing plantations”.  Rachmat Witoelar, Minister for Environment, claims that, “They will be planted in lots already empty.  There are plenty of these, 18 million hectares of them.”  The article goes on to say that Indonesia plans to add seven million ha of plantations by 2011, thereby roughly doubling the global supply of palm oil.

Palm oil has nearly doubled in price in recently, despite the almost quadrupling of supply in recent years.  The price appears to be supported almost entirely by food use of the oil in Asia (primarily India and China), and is presently at a 20-30% premium over the price of petrodiesel.  That means, for the time being, converting palm oil to biodiesel is way underwater.  The only palm oil flowing into gas tanks is due to mandates by national governments for blending, which happens regardless of price.  But that volume is small compared to food use.

Naturally, this leads to a discussion about whether palm oil will stay this high, or whether economic forces will somehow come into play and restore prices to the historical range.  I’m just a simple physicist, but I can’t see prices falling, and my guess is you don’t want to be short on palm oil.

If Indonesia indeed plants all that additional palm, because palm takes a few years to start producing oil, the land will gradually come into production over something like eight years.  This will be completely absorbed by a mere annual ~9% increase in demand, which is less than we have seen in recent years.  The economies of China and India are growing at 8-12% per year, depending on who is doing the accounting.  This suggests anyone who was planning on cheap palm oil for biodiesel is out of luck and needs to find a new feedstock.

But the connection to food markets is a general problem for biofuels these days.  There is already plenty of talk about price pressures on corn due to ethanol demands, and in general biofuels are putting significant pressure on food prices around the world.  And it doesn't look to be the case that we actually have enough arable land or water to simply start cultivating dedicated energy crops at large scale.  There is some hope for jatropha, but it takes a long time to mature and the number of trees presently in production is so small that assertions of it's commercial role are simply guesses.  China is evidently planning on planting 13 million hectares in jatropha -- an area the size of England -- but it just isn't clear what sort of oil production those trees will provide.

All this comes back to Synthetic Biology because in the medium to long term, breaking the connection between biofuels and food crops will only come from building new fuel production pathways in plants and microbes.

More on this in the coming days.

Rob and Jim's Ridiculous Adventure, Or Asia Biofuels Travelblog Pt. 1

(Saturday, 2 June)  Just moments ago, I was annoyed that my e-ticket had been rebooked as a paper ticket, requiring me to carry (and keep safe) 12 boarding passes for my flights over the next 10 days.  But I’ve just discovered a bonus.

Here I sit, not in business class, not in even in first class, but in a “super first class” seat on the top deck of a 747, shortly headed to Taipei and then to Kuala Lumpur along with Jim Newcomb, my colleague from bio-era.  The seat is courtesy of a client, who probably only paid for business class.  I have more legroom here than I do in my living room.  I have to stand up and take a few steps just to see what goodies are stocked in the seat-back pocket in front of me.  When I finally reach the row ahead of me, and retrieve the overnight kit, I find Cellular Day Cream, Cellular Hand Cream, Creamy Moisturizing Lip Balm, and finally, Cellular Lipo-Sculpting Eye Gel.

Jim is stuck back in cattle, err, business class, and I wonder how he is enjoying his Cellular Lipo-Sculpting Eye Gel.  He is that kind of guy.  Formerly of the CIA and various CEO and strategy jobs.  The perfect market for Lipo-Sculpting Eye Gel.  Ah, I know, I’ll regift him my tube of the stuff in order to make up for his lack of legroom.

Let me be clear: I don’t mind the luxury treatment one bit, and I plan to enjoy it.  Because the flight is leaving at 2 AM local and in the next 10 days we will visit 6 Asian financial capitals while giving 5-6 presentations a day, all day, every day.

It’s a tad ironic, then, that these presentations -- and all the associated frequent flier miles -- are in the service of describing the future of the biofuels market in Asia and Europe, which is closely coupled to the desire to reduce carbon emissions.  I’ve been cramming my head full of information about the carbon costs of various biofuels and the effects of carbon regulation on fuels markets.  I’m flying ~20,000 miles in the next 10 days, which, as Jamais Cascio might say, is a hell of a lot of cheeseburgers.

Hmmm…I wonder what the carbon cost is of toting all this Cellular Lipo-Sculpting Eye Gel back and forth across the Pacific at 35,000 feet?  Any thoughts, Jamais?

Changes Afoot

I've now moved on from the University of Washington to spend more time with bio-era and to get my start-up out of my garage.  The transition has left me little time to blog, but I hope to get back to writing more as things calm down a bit.

I'm writing this from the Shangri-La Hotel in Kuala Lumpur, where I am on a trip for bio-era.  More on this in posts yet to come.

The raindrops outside are enormous and copious.

New Microfabrication Methods

As my time at the University of Washington draws to a close, the students and post-docs I have been fortunate to work with are beginning to publish our work together.  I'll soon revise my main web-site, www.synthesis.cc, with links to all the publications related to Microscale Plasma Activated Templating (µPLAT), a new way to fabricate integrated electromechanical circuits in PDMS at room temperature, mostly outside the clean room.  I have spent way too much of my life in the clean room.

The point of all this work is to fabricate capable, yet inexpensive, MEMS and microfluidic devices for handling cells and reagents.  The job is by no means finished, but I'm pretty satisfied with the results so far.  We have managed to create in PDMS; single cell traps using Nickel magnetic relay elements; wires made of graphite, gold, nickel, palladium, silver, and, almost, constantan; electrostatic actuators and valves; thermopneumatic valves and peristaltic pumps; thermocouples made from combinations of patterned metals; plus ways of fabricating easy electrical connections between all these components, and between the circuits and the outside world.

Joseph Chao, now at the Biodesign Institute at ASU,  just sent a link to one of the papers, and I post it here so people can get an idea of what we've been up to for the last several years: "Rapid fabrication of microchannels using microscale plasma activated templating (µPLAT) generated water molds", is now online at Lab on a Chip.

Is Biology a science, or a Science?

There is an interesting debate surfacing in the pages of Nature about the future of biology.  In February, Evelyn Fox Keller published an essay entitled "A clash of two cultures" that started off asking the following questions:

Physicists come from a tradition oflooking for all-encompassing laws, but is this the best approach to use when probing complex biological systems?

Biologists often pay little attention to debates in the philosophy of science. But one question that has concerned philosophers is rapidly coming to have direct relevance to researchers in the life sciences: are there laws of biology? That is, does biology have laws of its own that are universally applicable? Or are the physical sciences the exclusive domain of such laws?

Keller concludes her essay by asserting, "Even though we cannot expect to find any laws governing the search for generalities in biology, some rough, pragmatic guidelines could be very useful indeed."

By "law", Keller means something akin to Conservation of Momentum, or Conservation of Energy.  Rather than simply a quantitatively predictive model, these are deep principles that govern the way the world works.  As a brief example, Keller focusses on the debate over the existence of scale free networks in biology.  Oddly, despite the fact that there are loads of papers on such scaling laws, Keller asserts those laws are rare: "First, power laws, although common, are not as ubiquitous as was thought; second, and far more importantly, the presence of such distributions tells us nothing about the mechanisms that give rise to them."

Professor Keller makes no mention of other kinds of apparent laws in biology, such as MacArthur and Wilson's species-area relationship presented first in The Theory of Island Biogeography, which deserves being called a law due to its appearance in a great deal of experimental data.  But I am most confused by the notion that physical laws might tell us about the mechanisms that give rise to them.  There is no "why" in conservation of momentum, nor in conservation of energy.  The deepest "explanation" of those laws is in the spatial and temporal symmetry of the universe -- translational symmetry gives you conservation of momentum and temporal symmetry gives you conservation of energy.  These are examples of Noether's Theorem, which says for every continuous symmetry there exists a conservation law.  This is one of the deepest results in all of physics, but there is no mechanism, no why, to be found anywhere in the mathematical statement of the theorem or in its physical consequences.

But even before Emily Noether, before James Clerk-Maxwell, before Newton and Leibniz -- before there was any modern mathematical systematization of physics -- there were a great many experimentalists accumulating data that looked a great deal like distributions.  Such as "air resistance tends to scale with volume"; or "the acceleration due to gravity is independent of mass"; or "planets sweep out equal areas in equal times during orbits around the sun".  But with considerable effort, and after several hundred years, we have well proven physical laws that describe all these observations.

Rather than there being no fundamental laws of biology, as Keller suggests, it seems far more likely to me that we are still collecting sufficient data to spot those laws and write them down.  And the biggest barrier to deriving any such laws is the quality of the data.  I've been hearing for 15 years how quantitative proteomics via mass spectroscopy is at hand, but the first clear demonstrations of truly quantitative, label-free mass spec were published only just last month in Nature Biotechnology (here is the News and Views piece by Bergeron and Hallett).  Similarly, only recently were guidelines for producing (and reproducing) quality mRNA data via gene chips decided upon.

Last week in Nature, Brian Enquist and Scott directly confront Keller's pessimism and come to quite the opposite conclusion:

In the opening of his seminal 1917 book On Growth and Form, D'Arcy Thompson quoted the eighteenth-century philosopher Immanuel Kant, who lamented that the field of chemistry had not yet embraced a mechanistic and mathematical expression of chemical phenomena. As a result, according to Kant, chemistry at that time was just a science, rather than a Science with a capital S. Despite Kant's view, however, as Thompson emphasizes, a great quantitative revolution proceeded to transform chemistry into a capital-S Science every bit as rigorous as physics. Thompson goes on to argue that biology is poised for just such a quantitative revolution.

Today, Thompson's thesis is being borne out; biology is becoming an increasingly rigorous quantitative Science that is finding more generality with each publication cycle. Most would agree that mathematical theories of quantitative genetics (including the modern synthesis), populations dynamics, organism interactions, epidemiology, ecosystem processes and growth and metabolism have together revolutionized biology, transforming it into a capital-S Science. This quantitative revolution would have been greatly muted, though, had investigators not been compelled, by Thompson's explicit advice, to identify general patterns and laws, to describe these quantitatively and to search for underlying mechanisms.

In this light, Keller's thesis that biology is a series of exceptional cases is a great leap backwards.

I find Keller's thesis all the more confusing given her biography of Biology, "Making Sense of Life".  In that excellent book, Keller recounts the history of modern biology with the theme, "Explaining Biological Development with Models, Metaphors, and Machines".  There is a clear trajectory in her history from natural language models of biological function towards more quantitative descriptions, all the while with participants flirting with writing down mathematical laws of biology.

In her Nature essay, Keller seems to suggest that the present profusion of data in biology suggests a complexity beyond description by general laws, and that this putative state of affairs is both acceptable to biologists and something to be more broadly expected and accepted:

In the past, biologists have been little concerned about whether their findings might achieve the status of a law. And even when findings seem to be so general as to warrant thinking of them as a law, the discovery of limits to their generality has not been seen as a problem. Think, for example, of Mendel's laws, the central dogma or even the 'law' of natural selection. Exceptions to these presumed laws are no cause for alarm; nor do they send biologists back to the drawing board in search of better, exception-free laws. They are simply reminders of how complex biology is in reality.

Again, I would differ and observe that experiments in physics didn't start to reveal any laws until people started working with simple systems.  Indeed, every physics experiment is highly engineered to be as simple as possible, so that only one thing is being measured, and only that one thing can vary.  The practice of engineering simple biological systems for the purpose of understanding how biology works is one of the driving forces behind Synthetic Biology.  As I recount in my forthcoming book, this effort is really only just getting under way, as the necessary tools have previously been either too expensive for broad use or have only just become available in any form.

Biology is definitely a Science, capitol "S" and all.  It will just take some time to write down the laws.

"DNA Factories"

Here is a short article by Emily Singer at Technology Review on commercial gene synthesis, "DNA Factories".  The article contains a couple of tidbits I haven't seen before:

[Codon Devices] plans to use itsenhanced synthesis capacity to find better enzymes for industrial processes. Since nature hasn't always come up with the most effective proteins, scientists often design a more effective enzyme by tweaking the DNA code used to make it. But it's difficult to predict in advance which tweaks will produce the best enzymes. Codon is now using its synthesis technology to carry out that process en masse--it makes millions of copies of the same genetic construct with slight variations--and then tests them to figure out which does its job best.

For example, scientists are now hot on the trail of the ideal cellulase--an enzyme that can break down cellulose in plants. More-efficient cellulases are important for producing cellulosic ethanol, which is ethanol derived from waste biomass rather than from corn starch or sugarcane, and therefore more cost-effective. "We can take the sequence for the cellulose enzyme in, say, a termite's gut, use a computer program to figure out different ways to optimize the sequence, churn out a million different versions, and then test them to find the top ten forms," says Brian Baynes, chief scientific officer and cofounder of Codon.

...The company is planning to open an expanded production facility, which will operate much like any other mass-production facility, except its product will be DNA. Codon intends to build a facility, slated to open this summer, that's much larger than current needs warrant to prepare for the DNA-synthesis boom.

That isn't quite direct confirmation that Codon has an internal effort underway to compete in the biofuels sector, but it is close enough.  There is a heading for "bio-energy" on the company web site, but little more info, and no word anywhere I can find on whether or not they have partners in this effort.  The site doesn't give any hints about the way they make libraries of variant genes, save that it is "proprietary technology".

Anybody from Codon care to comment?

Finally, as we explained in Genome Synthesis and Design Futures, at the present pace of price reductions constructing a genome the size of E. coli should cost less than US$10,000 within 10 years.  It isn't at all clear to me how many orders that size are going to come in, and Codon and its competitors may have to subsist on a large number of orders in the $10-1000 range.  So Codon's new gene foundry better guarantee a path towards a couple of orders of magnitude improvement in cost, or their margins are going to be seriously squeezed.