On the Demise of Codon Devices

Nature is carrying a short news piece by Erica Check and Heidi Ledford on the end of Codon Devices, "The Constructive Biology Company".  I am briefly quoted in the discussion of what might have gone wrong.  I would add here that I don't think it means much of anything for the field as a whole.  It was just one company.  Here is last week's initial reporting by Todd Wallack at the Boston Globe.

I've been pondering this a bit more, and the following analogy occurred to me after I was interviewed for the Nature piece.  Codon, as described to me by various people directly involved, was imagined as a full-service engineering firm -- synthetic genes and genomes, design services, the elusive "bio-fab" that would enable one-stop conversion of design information into functional molecules and living systems.  Essentially, it seems to me that the founders wanted to spin up an HP of biology, except that they tried to jump into the fully developed HP of 1980 or 1990 rather than the garage HP of 1939.  Codon was founded with of order $50 million, with no actual products ready to go.  HP was founded with ~$500 (albeit 1939 dollars) and immediately started selling a single product, a frequency standard, for which there was a large and growing market.  HP then grew, along with it customers, organically over decades. Moreover, the company was started within the context of an already large market for electronics.

The synthetic biology market -- the ecology of companies that produce and consume products and services related to building genes and genomes -- still isn't very big.  A very generous estimate would put that market at $100 million.  This means the revenues for any given firm are (very optimistically) probably no more than a few tens of millions.  (The market around "old style" recombinant DNA is, of course, orders of magnitude larger.)  Labor, rather than reagents and materials, is still likely to be the biggest cost for most companies in the field.  And even when they do produce an organism, or a genetic circuit, with value, companies are likely to try to capture all the value of the learning that went into the design and engineering process. 

This leads to an important question that I am not sure is asked often enough by those who hope to make a living off of emerging biological technologies: Where is the value?  Is it in the design (bits), or in the objects (atoms)?  The answer is a bit complicated.

Given that the maximum possible profit margin on synthetic genes is falling exponentially, it would seem that finding value in those particular atoms is going to get harder and harder.  DNA is cheap, and getting cheaper; the design of genetic circuits (resulting in bits) definitely costs more (in labor, etc.) than obtaining the physical sequence by FedEx. That is the market that Codon leapt into.  If all of the value is in the design process, and in the learning associated with producing a new design, not many companies are going to outsource that value creation to a contractor.  If Codon had a particular design expertise, they could have made a go with that as a business model, as do electronics firms that have niche businesses in power electronics or ASICs.  There are certainly very large firms that design, but do not build, electronics (the new AMD, for example), but they didn't get that way overnight.  They have emerged after a very long (and brutal) process of competition that has resulted in the separation of design and manufacturing.  Intel is the only integrated firm left standing, in part because they set their sights on maintaining scale from day one (see the recent Economist article on the semiconductor industry for a nice summary of where the market is, and where it may be headed). 

In another area of synthetic biology, I can testify with an uncomfortably high degree of expertise that costs in the market for proteins (a very different beast than DNA) are much higher for atoms than for bits.  It is relatively easy for me to design (update: perhaps better phraseology would be "specify the sequence of") a new protein for Biodesic and have Blue Heron synthesize the corresponding gene.  It is rather less easy for me to get the actual protein made at scale by a third party (and it would be even harder to do it myself).  Whereas gene synthesis appears to be a commodity business, contract protein manufacturing is definitely not.  Expression and purification require knowledge (art).  Even if a company has loads of expertise in protein expression, in my experience they will only offer an estimate of the likelihood of success for any given job.  And even if they can make a particular protein, without a fairly large investment of time and money they may not be able to make very much of the protein or ship it at a sufficiently high purity.  Unlike silicon processing and chip manufacturing, it isn't clear that anyone can (yet) be a generalist in protein expression.  Once you get a protein manufacturing process sorted out, the costs quickly fall and the margins are excellent.  Until then: ouch.

So, for DNA bits are expensive and atoms are cheap.  For proteins, bits are cheap and atoms are initially very expensive.  Who knows how much of this was clear to the founders of Codon several years ago; I have only been able to articulate these ideas myself relatively recently.  It is still very early in the development of synthetic biology as a market, and as a sector of the economy. 

Mood Hacking at The World Economic Forum

(Update: see "Revisiting Mood Hacking with Scents", 3 December 2009.)

We are all familiar with the aromas used by stores in the hopes of motivating consumer frenzy.  Walk into some establishments and you may feel as if you have been smacked with a fragrant bunch of flowers.  Or possibly a fragrant leather shoe.  Maybe this actually encourages people to spend money.  It usually just makes me sneeze.

But what if the general strategy of behavior modification via perfumes of one kind or another really does work?  At the 2008 World Economic Forum in Davos, there was an explicit attempt to influence discussions through the use of custom scents designed for the occassion.

Here is a short excerpt from "Davos Aromas Deodorize Subprime Stench, Charm Dimon, Kissinger", by A. Craig Copetas (Bloomberg News):

"I know a lot of people think this is foolish,'' says Toshiko Mori, chairwoman of Harvard University's architecture department and one of the WEF delegates who initiated the perfume project. ``But the global economy is in dire straits and we must improve the quality of human spirits. Perfuming is a powerful tool in a much broader discourse. The fragrances will help us reach economic and political solutions at Davos.''

Here is CNN's take: "Smelly Davos unveils new world odor."  Ha.

The reader might imagine a room full of national security professionals debating the merits and ethics of this "technology".  We see two camps emerge.  The first group is shocked -- shocked! -- that biochemical warfare is being brought indoors to induce in captains of industry and policy makers a mood of compromise.  The second group notes that all it took to hack the mood of Boris Yeltsin was an open bottle of vodka.  The latter strategy has, of course, been used for millennia.

Hacking a the mood of an entire room full of people at once is an interesting twist, though.  What happens when someone modifies airborne rhinoviruses to express neuroactive peptides?  (See my post on iGEM 2008: "Surprise -- the Future is Here Already".)  Science fiction gave us the answer long ago.  Isaac Asimov had his characters wearing anti-viral filters in their nostrils even in his early stories.  Seems like filters with sufficiently small pores might make it hard to breathe.  And what happens if you sneeze?  "Ouch!" or "Ewww", I imagine.

Anyway, how would we even know that mood hacking was occurring?  Aside from simply noting changes in behavior, or getting, um, wind of the threat via human intelligence, we would have to measure any chemical or biological weapon directly.  But before pulling out the Tricorder and identifying a threat, we would first have to be constantly monitoring our environment in order to get a baseline of environmental signals.  So, we have already struck out.  No such monitoring is really happening.  We are just cherry picking a few things that are easy to see.  Oh, and still no Tricorder.

If the mood altering mechanism was delivered via a virus, we would have to not just monitor the number of viruses of any given species in the air, but also be sequencing all of them, all the time.  Again, we are striking out.

I have a hard time imagining that viral mood hacking threats are going to show up any time soon, but then we have no means of knowing either way.  Perhaps such things are already about.  How can you be sure you aren't part of "The Giving Plague"?

"The New Biofactories"

(Update: McKinsey seems to have pulled the whole issue from the web, which is too bad because there was a lot of good stuff in it.  The text of my contribution can be found below.)

I have a short essay in a special edition of the McKinsey Quarterly, What Matters.  My piece is waaaay back at the end of the printed volume, and all the preceding articles are well worth a look.  Other essayists include Steven Chu, Hal Varian, Nicholas Stern, Kim Stanley Robinson, Yochai Benkler, Vinod Khosla, Arianna Huffington, Joseph Nye, and many more.  Good company.

Here is the essay: "The New Biofactories" (PDF), Robert Carlson, What Matters, McKinsey & Company, 2009.

Well, that's it, then.

Finally, the book is done.  Aside from reviewing the proofs in a couple of months, and writing an afterword, it is at last out of my hands.

The title, finally, will be "Biology is Technology: The Promise, Peril, and Business of Engineering Life".  It will be in the Fall 2009 Catalog from Harvard University Press, with atoms showing up at approximately New Years.  I'll get around to updating the web site text eventually.

My brain is presently mush.  I haven't blogged in so long I'd forgotten the user name and password for my account.  I have a couple of posts in mind that I hope to get up over the weekend.

Otherwise, I can't wait to get back to actually doing science.  What a concept.

First: sleep.  No -- second sleep.  First: beer.

Advice for Future iGEM Teams

I'm giving a short talk to the University of Washington iGEM interest group tonight based on my experience watching the competition from the beginning and as a judge for the last couple of years.

The judges are given a long list of criteria for the various medals and awards.  The list has grown longer and more involved -- if the trend holds next year I expect it to be even more complicated.  There are many more teams than judges, so each of us sees only a small fraction of the teams in person on the first day of the Jamboree.  The only way we can keep things fair (and keep the teams straight in our heads) is to follow the judging criteria very closely.  We have a checklist.

It is important to remember in what follows that my academic training is in experimental physics, and I spend most of my time today trying to build stuff out of DNA.  I don't have anything against elegant and cool models; I simply groove more on elegant and cool atoms.  I speak only for myself and not for any other of the judges or organizers.

Here is what I plan to say this evening:

  1. You need to make easy for the judges to understand your objective and your design.
  2. Web pages can be too cool.  A rough rule of thumb: the cooler the web page is, the harder it is to understand.  A cool web page may be full of information, but as a judge it is the baud rate I care about.
  3. Fun is good.  Demonstrating actual learning is better.  Data trumps everything.
  4. In my experience, the more equations in your model, the less likely you will produce experimental data.  I find complexity as distracting in my own work as I do when I have something like 15 minutes to figure out the theoretical details of an iGEM project.  Keep it simple!
  5. Find a mentor to help tailor your story to your customers, namely the judges.  This past year the judges were a mixture of academics and industry types -- biologists, engineers, computer scientists, physicists; theorists, experimentalists, hackers.  All probably have PhDs in something or other, which means we are used to rapidly parsing stories that are packaged more like papers in Science and Nature than like facespace/mybook/twitterwikirama/whatever.  Those things may be the future of science for all I know, but your customers (the judges) don't play that game -- we are fogeys as far as you are concerned.  You have to market to us.
  6. Follow the directions!  Follow the checklist.  Make sure your DNA is to spec (e.g. meets the Biobrick(TM) standards).  Make sure it is in the Registry.  Get everything in on time.  Sometimes the organizers and judges screw up this part -- the way to resolve complaints is with reason and your own checklist.  No whinging.
  7. Here is a suggestion I made to the organizers after the last competition.  Even if they don't implement it, you should.  Everyone in the competition has completed some sort of laboratory course requiring basic experimental write-ups.  Make sure your web page has a basic lab write-up, no clicking or hunting required. You will do better if the judges don't have to spend even thirty seconds trying to figure out if you have actual data and where it might be hiding on your wiki, especially if other pages are better designed and easier to read.  If I recall from my student days, those write-ups go something like this, mostly in this order: "1. Here is what we wanted to do and why.  2. Here is what we did.  3. Model.  4. Data.  5. Conclusion."  Bonus: if it didn't work, why not?  iGEM and the Biobricks Foudation both need a failure archive.

Good luck next year!

Tamiflu-resistant Influenza Strains

(Update, 30 April 2009: I see from the server logs that this post is getting a lot of traffic today.  Please note that the contents of the post discuss the annual influenza strains in the US, not the "H1N1 Influenza A" strain, which at this time is susceptible to Tamiflu.)

The IHT is carrying a great article by Donald Mcneil on the sudden emergence of antiviral resistance in this year's circulating influenza viruses.  The title says it all: "Flu in U.S. found resistant to main antiviral drug".

Virtually all the flu in the United States this season is resistant to the leading antiviral drug Tamiflu...  The problem is not yet a public health crisis because this has been a below-average flu season so far and the chief strain circulating is still susceptible to other drugs.

There are two important points in this story.  First, the resistance seems to derive from a spontaneous mutation rather than having emerged from overuse of the drug:

"It's quite shocking," said Dr. Kent Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York. "We've never lost an antimicrobial this fast. It blew me away."

The mutation appears to have arisen in Norway, a country that the article suggests does not even use Tamiflu. Second, while the CDC is recommending that hospitals test all flu cases to find out whether patients are carrying a the resistant subtype, this capability is still not widespread:

"We're a fancy hospital, and we can't even do the ... test in a timely fashion," Sepkowitz said. "I have no idea what a doctor in an unfancy office without that lab backup can do."

I haven't written very much about the flu for a couple of years, but it is clear that the threat is still quite present.

The article ends with this bit of speculation:

And while seasonal flu is relatively mild, the Tamiflu resistance could transfer onto the H5N1 bird flu circulating in Asia and Egypt, which has killed millions of birds and about 250 people since 2003. Although H5N1 has not turned into a pandemic strain, as many experts recently feared it would, it still could -- and Tamiflu resistance in that case would be a disaster.

I'm not so sure that the resistance gene "could easily transfer onto the H5N1 bird flu".  It sounds like Mr. Mcneil may be giving more weight here to Henry Niman (who is quoted extensively in the article on other specific topics) than the rest of the community might.  This is not to say that such a transfer is unlikely -- this is the sort of thing that I fear we know so little about that we could make poor assumptions leading to even worse policy.  The mechanisms for recombination and reassortment of genes in the flu are still disputed in the literature.  But it's damn scary, either way, even if the probability of such a transfer is small.

In the end, if nothing else, what this demonstrates is that our technological base for both detecting and responding to infectious disease is still poorly developed.

Carl Zimmer on Synthetic Biology for Biofuels

Carl Zimmer has a nice piece in Yale Enivronment360 on continued efforts to build bugs that produce fuel, "The High-Tech Search For A Cleaner Biofuel Alternative".  The article extensively quotes Steve Aldrich, President of Bio-era, on the trade-offs of using sugar cane as a source material.

Craig Venter makes an appearance arguing that the best long-term bet is to build photosynthetic bugs that use atomspheric CO2 to directly produce fuel.  Maybe.  This would require containment facilities for culturing engineered bugs, where those facilities also must capture sunlight and CO2 to feed the bugs.  The costs for this infrastructure are not insignificant, and this is exactly what is presently standing in the way of large scale algal biodiesel production.

Here is the question I keep asking in these circles: why not just grow naturally occurring algae, which can be grown at extremely high yield in a wide variety of conditions, as food for bugs hacked to eat cellulose?  If there is no algae to be had, just throw in another source of cellulose or other biomass.  There would be minimal concern over growing modified organisms that might escape into the wild.  The processing of biomass into fuel under would also be under conditions that are easier to optimize and control.

I'm not suggesting this is the only answer, but rather that it appears to balance 1) the costs of infrastructure, 2) concerns over enviromental release of genetically modified organisms, and 3) provide an efficient processing infrastructure that could use a wide variety of feedstocks.

Garage Biology Project: Melamine-detection Bugs

Worried about whether your yogurt is safe?  Drop in some of  Meredith Patterson's home-brew bugs and see if they turn green.  The AP has a short story about Patterson and DIYBio: "Amateurs are trying genetic engineering at home".  No surprise that it is a bit short on details.

This story made it as far (temporarily) as the front page of The Huffington Post, which I find interesting.  I wonder whether the editors put it there out of genuine interest or to scare the crap out of their readers.

It's only been eight years since I first speculated about garage biology (PDF), and only three since the topic appeared in Wired (Splice it yourself).  iGEM has only been around since 2004.  Biology, for the most part, remains Open (See, "Thoughts on Open Biology"):

As in 2000, I remain today most interested in maintaining, andenhancing, the ability to innovate.  In particular, I feel that safe and secure innovation is likely to be best achieved through distributed research and through distributed biological manufacturing.  By "Open Biology" I mean access to the tools and skills necessary to participate in that innovation and distributed economy.

I find myself a bit surprised to feel a bit surprised that this is this is all going just as I expected (PDF).  (Aside: if there isn't a name for that, there should be; I predicted X, and not only am I surprised that it is coming true, I am surprised to feel surprised that it is coming true...because I really believed it was going to come true.  I think.)  From the AP story:

[Patterson]  learned about genetic engineering by reading scientific papers and getting tips from online forums. She ordered jellyfish DNA for a green fluorescent protein from a biological supply company for less than $100. And she built her own lab equipment, including a gel electrophoresis chamber, or DNA analyzer, which she constructed for less than $25, versus more than $200 for a low-end off-the-shelf model.

Frankly, I don't know whether to feel relieved or uneasy.  That ambivalence will probably characterize my response to this technology from here on out.  Whether we like it or not, we are about to find out what role garage biology will play in our physical and economic security (Journal article, PDF).

Data: Definitive(?) Evidence of Amplification and Accelerated Warming at the Poles

The ongoing American Geophysical Union meeting is full of cheery news.  According to a report in the IHT, more than 2 trillion tons of landlocked ice have melted since 2003 in Greenland, Antarctica, and Alaska.  Of that, more than half occurred in Greenland, and satellite measurements confirm that the melting is accelerating.

The new results follow on James Hansen's earlier work based on data, rather than models, suggesting that both warming and sea level rise are likely happen faster than the IPCC consensus estimates (see "It's time to Invest in Water Wings"), because the IPCC models explicitly exclude the effect of ice sheet movement and landlocked ice melting.

It gets even better.  Reduced sea ice coverage is also now strongly affecting the thermal balance of the poles:

As sea ice melts, the Arctic waters absorb more heat in the summer, having lost the reflective powers of vast packs of ice. That absorbed heat is released into the air in the autumn. That has led to autumn temperatures in the last several years that are 6 degrees Fahrenheit to 10 degrees (3.5 degrees to 6 degrees) warmer than they were in the 1980s.

Warming of the land and sea are coupled: "The loss of sea ice warms the water, which warms the permafrost on nearby land in Alaska, thus producing methane," itself a potent greenhouse gas, according to Julienne Stroeve, a research scientist at the National Snow and Ice Data Center in Boulder, Colorado.  (See my previous posts: "Methane Time Bomb" and "Update".)

With respect to the anomolously high Arctic temperatures, The Independent's Steve Connor wonders "Has the Arctic melt passed the point of no return?":

The phenomenon, known as Arctic amplification, was not expected to be seen for at least another 10 or 15 years and the findings will further raise concerns that the Arctic has already passed the climatic tipping-point towards ice-free summers, beyond which it may not recover.

The coupling of land and sea warming constitute a feedback mechanism that threatens to create runaway warming and increased methane emissions, which will only make things worse.  Only more data will help resolve any remaining uncertainty.  While we gather that data, our time to fiddle is running out.