It is the End of the World as We Know it, and I feel Strangely Ambivalent: Synthetic Biology 5.0

Synthetic Biology 5.0 has come and gone.  I expected, as in previous years, to be busy liveblogging amid the excitement.  I tweeted some during the proceedings (here is Eric Ma's summary of #synbio5 tweets), but this is my first post about the meeting, and probably the last one.  I mostly just listened, took a few notes, and was delighted to see the progress being made.  I was not nearly as amped up about the proceedings as in previous years, and I am still trying to figure out why. 

Here are a couple of reasons I have sorted out so far.  It was the end of the beginning of synthetic biology.  The meeting was full of science and engineering.  And that's about all.  There were a few VC's and other investors sniffing around, but not nearly so many as in previous years; those who did show up kept a lower profile.  There were also fewer obvious government officials, no obvious spooks, no obvious law enforcement officers, nor any self-identified Weapons of Mass Destruction Coordinators.  And I only encountered a couple of reporters, though there must have been more.  I skipped 3.0 in Zurich, but at 1.0 at MIT, 2.0 at Berkeley (parts 1, 2, 3, 4, 5), and 4.0 in Hong Kong (part 1), there was much more buzz.  Synthetic Biology 5.0 was much shorter on hype than prior gatherings. 

There was substantially more data this year than previously.  And there was substantially less modeling.  All in all, Synthetic Biology is substantially more ... substantial.  It was like a normal scientific meeting.  About science.  No stunts from "civil society" groups looking for their next fear bullet point for fundraising.  No government officials proclaiming SB as the economic future of their city/state/country.  Just science.

What a relief.

And that science was nothing to sneeze at.  There were great talks for 3 days.  Here are a couple of things that caught my eye.

Jef Boeke from Johns Hopkins presented his plans to build synthetic yeast chromosomes.  I first heard this idea more than ten years ago from Ron Davis at Stanford, so it isn't brand new.  I did notice, however, that Boeke having all his synthetic chromosomes made in China.  Over the longer term this means China is getting a boost in building out future biomanufacturing platforms.  If the project works, that is.

As tweeted, Jack Newman from Amyris gave an update on commercialization of artemisinin; it should be on the market by the end of the year, which should be in time to help avert an expected shortfall in production from wormwood.  Fantastic.

Pam Silver and her various students and post-docs showed off a variety of interesting results.  First, Faisal Aldaye showed in vivo DNA scaffolds used to channel metabolic reactions, resulting in substantial increases in yield.  Second, Pam Silver showed the use of those scaffolds to generate twice as much sucrose from hacked cyanobacteria per unit of biomass as from sugar cane.  If that result holds up, and if the various issues related to the cost of bioreactors used to culture photosynthetic organisms are worked out, then Pam's lab has just made an enormous step forward in bringing about distributed biological manufacturing.

This is the sort of advance that makes me feel more sanguine about the future of MIcrobrewing the Bioeconomy.  It will take some years before the volume of Amyris' Biofene, or Gevo's bio-PET, or Blue Marble's bio-butyric acid begins to impact the oil industry.  But it is clear to me now as never before that the petroleum industry is vulnerable from the top of the barrel -- the high value, low volume compounds that are used to build the world around us in the form of petrochemicals.  Biology can now be used to make all those compounds, too, directly from sugar, cellulose, and sunlight, without the tens of billions of dollars in capital required to run an oil company (see The New Biofactories). 

So SB 5.0 was the end of the world as we know it.  Synthetic biology is now just another field of human endeavor, thankfully producing results and also thankfully suffering reduced hype.  I can see how the pieces are starting to fit together to provide for sustainable manufacturing and energy production, though it will be some years before biological technologies are used this way at scale.  Perhaps this is less in-your-face exciting for the attendees, the press, and the public, and that may be part of the reason for my ambivalence.  I fell asleep several times during the proceedings, which has never happened to me at SB X.0, even when overseas and jetlagged.  I have never before thought of achieving boredom as constituting progress.

Piracy, Food Security, and Global Supply Lines

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

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

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

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

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

Osama bin Laden and PCR

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

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

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

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

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

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

Myriad's Lawyers Want to Patent the Periodic Table

Interesting arguments today before a Federal Appeals Court concerning the "BRCA 1/2" patents.  Recall first that the U.S. Government has filed an amicus brief supporting the trial judge's ruling that naturally-occurring genes cannot be patented (see "Big Gene Patent (Busting) News???" and "Surprise Outbreak of Common Sense in Washington DC").

The Appellate Court is going to decide whether two genes (BRCA 1 and 2), in which mutations are correlated with breast cancer, can be patented.  Myriad Genetics and its lawyers say yes, the ACLU and several groups representing patients, scientists, and clinicians say no.  So did the trial judge.  The basic argument is about whether a naturally-occurring gene sequence that is used in a diagnostic test can be considered an invention.

Nature's The Great Beyond blog has a bit of reporting from yesterday's proceedings.  There is a passage from the blog post I think is worth exploring a bit further for the way the litigants and the judges are talking about the nature of DNA and the nature of elements such as lithium:

Both the lawyers and the judges repeatedly compared the case to efforts to extract a valuable mineral from the ground.

"Why isn't the ingenuity [that justifies patentability] the process of extracting [the mineral]" rather than in the mineral itself, [Judge Kimberly Moore] asked [defendent's attorney Greg] Castanias. "God made it. Man didn't make it."

Castanias retorted: "What we have here are new tools [that are] the products of molecular biologists. They are not the products of nature. They are not the products of God."

If that's the case, [Judge William Bryson] pushed Castanias, are you saying that isolation of pure lithium is properly an invention?

"Yes," the lawyer replied.

That is extraordinary.  Castanias' assertion is contrary to more than a century of U.S. case law and administrative rulings by the USPTO.  Products of nature are explicitly excluded in laws, rulings, and administrative decisions from coverage by patents.  Castanias wants the Appellate Court to rule that the elements in the periodic table, along with any other naturally-occurring substance, are in fact patentable.

The mind boggles.  Following Castanias' reasoning pure oxygen, pure water, and pure gold could all be patented because some process was employed for purification.  If this sort of argument held sway, you could even patent the moon because you require a human invention to go visit and nab a piece of it.  Yes, yes, I know that other inconvenient case law would get in the way of patenting a celestial body, which really doesn't make any sense anyway.  But that is the point.  The trial judge in this case was actually the first to issue a ruling that patents on naturally-occurring genetic sequences are prohibited by law (see "Big Gene Patent (Busting) News???").

This argument revolves in part around the nature of DNA.  Here is another excerpt from the Nature blog post:

Chris Hansen, a staff attorney with the ACLU, told the judges: "Myriad's entire business is built on the proposal that isolated DNA and [naturally occurring] DNA are identical." They don't write to patients with their test results, saying: "You've got a mutation in your isolated DNA but I have no idea what's going on in your body," he said.

Judge William Bryson countered that the act of isolating DNA involves breaking covalent bonds, thus creating a product that does not exist in nature.

"With respect, your honor, I think not," Hansen replied. "DNA is DNA."

But Greg Castanias, a lawyer with the Jones Day firm in Washington DC who represented the defendants, begged to differ. "Isolated DNA does not exist in nature," and wouldn't exist at all without human ingenuity, he said. The entire biotechnology industry, he added, is built on interpreting existing law to say that DNA isolation is sufficient to show the human invention that is required for a patent.

I found the language quoted to be quite interesting.  The notion that "isolated DNA does not exist in nature" is based on the defendants' definition of "isolated DNA".  Judge Sweet spent three pages of his original decision dealing with Myriad's assertions about "isolated DNA", but it is hard to know from the Nature blog post whether this was part of yesterday's conversation.  Here is Judge Sweet's definition (p. 92 of his decision): "Isolated DNA is therefore construed to refer to a segment of DNA nucleotides existing separate from other cellular components normally associated with native DNA, including proteins and other DNA sequences comprising the remainder of the genome, and includes both DNA originating from a cell as well as DNA synthesized through chemical or heterologous biological means".

This is quite close to Myriad's definition of "isolated DNA", but Judge Sweet still found that because the isolated DNA is the same sequence, and therefore conveys the same information, as the sequence in vivo, it cannot be patented because it is a product of nature.

Incidentally, the definition of isolated DNA given above appears to include DNA that is free in the environment.  Free DNA is found in marine and terrestrial environments.  That DNA can be taken up by other organisms via horizontal gene transfer, which means that free DNA is perfectly funtional.  Here, for example, is an interesting little study looking at the uptake of free DNA by aquatic bacteria.

The point being that humans did not invent DNA that is "separate from other cellular components".  Humans may have invented processes to concentrate and purify DNA, or to extract DNA from complex structures, but that does not mean that isolated DNA is itself a human invention.

Video from "Preserving National Security: The Growing Role of the Life Sciences"

A couple of weeks ago I spoke at an event run by the UPMC Center for Biosecurity, Preserving National Security: The Growing Role of the Life Sciences.  Here is the video of my presentation, followed by Roger Breeze, with an introduction by Gigi Gronvall.  There is a short panel discussion at the end of the clip.  Video of the rest of the meeting is also online, along with a conference report (PDF).

Ice Loss Acceleration in Antarctica and Greenland

This month's Geophysical Research Letters brings more ice sheet melting data to be concerned about.  A paper by Eric Rignot and colleagues at JPL, Caltech, UC Irvine, and Utrecht University demonstrates the "Acceleration of the contribution of the Greenland and Antarctic ice sheets to sea level rise".  Here is a nice summary at ScienceDaily that goes into some broader implications for sea level rise.  In addition to putting a bunch of nice data and analysis on the table, Rignot et al will contribute substantially to a broader understanding of the overall ice/water system near the poles.

The paper describes work integrating a variety of methods to build up a two decade-long picture of ice mass loss in Antarctica and Greenland.  The numbers by themselves are pretty impressive: the ice sheet loss rate was ~478 Gigatons/year in 2006, with an acceleration of ~36 Gigatons/year^2.  Note that this means the acceleration is 7.5% of the rate -- in other words, ice sheet mass loss is speeding up at a remarkable clip for a process that is ongoing at continental length-scales.  Notably, the authors report a very small uncertainty in the acceleration (about 5%), which means that we can be quite certain there is a large non-linear contribution that is reducing ice sheet mass (one that is proportional to time^2).

Here are a few tidbits that are not in the paper or associated press stories.  I wrote to Dr. Rignot to satisfy my curiosity about a couple of points, and he graciously responded and gave me permission to quote the emails here.

First, after staring at the ice loss rate and acceleration data for a little while, I got to wondering why the authors extracted a linear change in the rate of ice loss, which results in a constant acceleration.  Given the data, you might wonder whether the acceleration was actually increasing rather than being a constant.  In our brief email exchange, Dr. Rignot said that while the linear fit was the simplest fit, it appears that, in fact, the acceleration is increasing in Antarctica (no word from Dr. Rignot about Greenland).  The team is going to wait for a few more years worth of data -- to increase their certainty and better constrain the statistical significance -- before they talk more about it.

This is pretty important.  We are talking about adding a highly non-linear term to models of the total ice sheet mass, one that is proportional to (time^3).  Depending on the size of the change in acceleration, this could radically change estimates of sea level rise from melting.

The present paper already demonstrates that ice sheet loss will account for substantially more sea level rise than is included in the IPCC models.  In addition, the authors observe that increased mass loss is likely to lead to a substantial increase in the speed at which glaciers deliver ice to nearby water, something that is not adequately addressed (or is simply not included, if you are following that story) in IPCC forecasts.

Perhaps it is time to revisit investing in water wings.

An Engineered Bug that Produces Isobutanol from Cellulose

This morning, Tom Murray at The Hastings Center pointed me to a new paper from James Liao's lab at UCLA demonstrating the first engineered bug that produces isobutanol from cellulose.  Wendy Higashide, et al, ported the artificial butanol synthesis pathway from the group's earlier work in E. coli (see this previous post) into Clostridium cellulolyticum.  Here is the article.

Recall that butanol is a much better biofuel than is ethanol.  Butanol is also not hygoscopic (doesn't suck up water), which means it can be blended at any point in the distribution chain, whereas ethanol must be trucked/barged/piped in dedicated infrastructure until just upstream of a gas station in order to avoid pulling contaminating water into the fuel stream.  Butanol has a long history of use as a transportation fuel, and has been demonstrated to be a drop in replacement for gasoline in existing engines.  See, for example, the work of the 2007 iGEM team from Alberta, and my earlier post "A Step Toward Distributed Biofuel Production?"  One advantage of making butanol instead of ethanol is that butanol spontaneously phase separates from water (i.e., it floats to the top of the tank) at concentrations above about 7.5% by volume, which substantially reduces the energy required to separate the molecule for use as a fuel.

The press release accompanying the Higashide paper describes the work as a "proof of concept".  The team attempted to insert the butanol synthesis pathway into a Clostridum strain isolated from decaying grass -- a strain that naturally consumes cellulose.  Unfortunately, this Clostridium strain is not as well characterized as your average lab strain of coli, nor does it have anywhere near the same number of bells, knobs, and whistles for controlling the inserted metabolic genes.  The short summary of the paper is that the team managed to produce 660 mg of butanol per liter of culture.  This is only about 0.07% by volume, or ~100 times below the concentration at which butanol phase separates from water.  The team lays out a number of potential routes to improving this yield, including better characterization of the host organism, or simply moving to a better characterized organism.

So, a nice proof of principle.  This is exactly the sort of technological transformation I discuss in my book.  But this proof of concept is not anywhere near being economically useful or viable.  Nonetheless, this progress demonstrates the opportunities ahead in relying on biology for more of our industrial production.