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

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.