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.

"Saltwater Crops May Be Key To Solving Earth's Land Crunch"

Wired News is carrying a story by Alexis Madrigal on saltwater agriculture, focusing on a new Perspectives piece in Science by Jelte Rozema and Timothy Flowers.  Here is the opening paragraph from the Science piece, which contains some good numbers:

Currently, humans use about half of the fresh water readily available to them to support a growing world population [expected to be 9.3 billion by 2050]. Agriculture has to compete with domestic and industrial uses for this fresh water. Good-quality water is rapidly becoming a limited and expensive resource. However, although only about 1% of the water on Earth is fresh, there is an equivalent supply of brackish water (1%) and a vast quantity of seawater (98%). It is time to explore the agronomic use of these resources.

The authors go on to explore the many advantages, including 1) local agriculture (near coastal populations), 2) irrigation using seawater (yummy micronutrients as fertilizer), and 3) the utility of combined aquaculture practices.  The usual caveats about land use, local property rights, and environmental effects all apply.  But the numbers, at the depth presented, are impressive.

Here is a nice bit from Madrigal's story:

After taking into account environmental protections and other factors, [Robert] Glenn's report estimates that 480,000 square miles of unused land around the world could be used to grow a special set of salt-tolerant plants -- halophytes. Glenn's team calculated that this could produce 1.5 billion barrels of oil equivalent per year. That's 35 percent of the United States' liquid fuel needs.

Why aren't we already employing salt-tolerant plants to produce food and fuel?  Back to Rozema and Flowers:

...Although between 1996 and 2006 there were more than 30 reports of transformation of rice with different genes aimed at increasing salt tolerance, transgenic salt-tolerant rice is not close to release. The likely explanation is that salt tolerance is a complex trait determined by many different genes, so that transformation of multiple genes into a plant is required.

Wandering down this road a bit led me to Pamela Ronald's blog "Tomorrow's Table", one entry of which is up at the Nature Network and mentions local research in Bangladesh to create GM, salt-tolerant rice.  On a visit to Dhaka university, she explains the local imperative:

...Salinity is a problem for rice farmers here. Not only is the sea water rising, but fresh water supplies are under pressure partly because farmers are pumping more every year and also because Bangladesh is downstream from India, who gets first dibs on the fresh water through a network of dams. The result is that every year the saline lands encroach north, hurting rice yields, a serious problem here where the average Bengali receives 2/3 of their diet from rice.

The local research effort is proceeding both via breeding and genetic engineering.  Ronald writes of seeing "...Newly developed transgenic lines thriving under high salt concentrations that kill the conventional variety".  This is interesting both because the Bangladeshi team may be making progress and because a local team has taken on the task -- the country isn't going to be on any conventional list of biotech leaders.  So kudos to the local team.

What could we do to make this all go faster?  The story on salt-tolerance appears to be that it isn't yet a very well understood trait.  This means anyone interested in hacking plants to that end needs to have all the relevant genes and also a good way to get them into any given plant.

My guess is that this is going to start going a lot faster in systems where minichromosomes are up and running in plants of interest.  This will dramatically facilitate the insertion of genes into plants, without worrying about disrupting the endogenous genetic structure. I mentioned this in my post on SB 4.0, and just as a pointer here is the PLoS Genetics describing the creation of stably inheritable minichromosomes in Maize: "Meiotic Transmission of an In Vitro-Assembled Autonomous Maize Minichromosome".  Chromatin appears to have this technology working pretty well.  Recapitulating the work in rice and other crops will take time, of course, but my scrawled notes from Daphne Preuss' talk in Hong Kong suggest it went pretty fast in Maize once they figured out what they were doing.  I'll have more on this when I understand it better.

Cheery Reading: "WORLD AT RISK The Report of the Commission on the Prevention of WMD Proliferation and Terrorism"

In case you haven't seen the headlines the lase couple of days, Bob Graham and Jim Talent say we are doomed.  Mostly.  Sort of.  Maybe?

Here is the page to download the report.  In summary, the commission predicts an attack using a weapon of mass destruction with in the next five years.  They are more worried about biological weapons than nuclear ones.

Despite the grim tone of most of the text, here is something useful to squawk back at Chicken Little:

...One should not oversimplify or exaggerate the threat of bioterrorism. Developing a biological weapon that can inflict mass casualties is an intricate undertaking, both technically and operationally complex. 

That is among the more optimistic statements in the entire document.

I caught Bob Graham on the Colbert Report last night, and the interview helped me figure out what has been bugging me about the language used by the report and its authors as they talk to the press.  No, not the part where Graham and Colbert -- two grown men in suit and tie -- used copies of the report like GI Joe figures in desktop combat (see 2:30 -- that brief interlude was enlightening in a different way):

The lightbulb went off when Graham said "The most important thing we can do is make sure that we, and the rest of the world, are locking down all the nuclear and biological material so that it is not capable of leaking into the hands of terrorists."

That sounds great, and the report goes on at length about securing BSL-3 and -4 facilities here in the US so that nasty bugs are kept behind locked doors, doors that are guarded by guys with visible guns.  That constitutes a particular kind of deterrence, which is fine.  As I have spent far too much of my life working in clean rooms trussed up in bunny suits, I can only feel sympathy for the folks who will have to deal with that security and suit up to work in the lab every day.  But those bugs are dangerous, and biosafety in those facilities is no joke.  The near-term threat is undoubtedly from bugs that already exist in labs.

But this is where things start to go off the rails for me.  Graham didn't have a lot of time with Colbert, but his language was disturbingly absolute.  I am concerned the Commission's views on biological technologies aredysfunctionally bipolar.  Here is what I mean: Even though the text of report reassures me that the people who actually put words on the page have a sense of how far and how fast biological technologies are proliferating (which I get to below), the language used by the official spokesman involves "locking down all the biological materials".  I worry that "locking down" anything might be construed in Washington DC, or by the populace, as constituting sufficient security measures.  See my article from last year "Laying the foundations for a bio-economy" for an update on what has happened as a result trying to "lock down" methamphetamine production in the US.  Short summary: There is more meth available on the streets, and the DEA acknowledges that its efforts have created an environment in which it actually has worse intelligence about who is making the drug and how it gets distributed.

Frankly, I haven't quite sorted out all of the things that bother me about the report, the way we talk about security in this country, and the inevitable spread of powerful biological technologies.  What follows are some additional notes and ruminations on the matter.   

Here is what the text of the report has to say about the threat from DNA synthesis technologies:

The only way to rule out the harmful use of advances in biotechnology would be to stifle their beneficial applications as well--and that is not a realistic option. Instead, the dual-use dilemma associated with the revolution in biology must be managed on an ongoing basis. As long as rapid innovations in biological science and the malevolent intentions of terrorists and proliferators continue on trajectories that are likely to intersect sooner or later, the risk that biological weapons pose to humanity must not be minimized or ignored.

Hmm...well, yes.  I'm glad they acknowledge the fact that in order to benefit from the technology it must be developed further, and that security through proscription will retard that innovation.  I am relieved that this part of the report's recommendations do not include measures I believe would be immediately counterproductive.  The authors later write:

The more that sophisticated capabilities, including genetic engineering and gene synthesis, spread around the globe, the greater the potential that terrorists will use them to develop biological weapons. The challenge for U.S. policymakers is to prevent that potential from becoming a reality by keeping dangerous pathogens--and the equipment, technology, and know-how needed to weaponize them--out of the hands of criminals, terrorists, and proliferant states. 

The charge in the last sentence sounds rather infeasible to me.  Anyway, the Commission then puts responsibility for security on the heads of scientists and engineers working in the life sciences: 

The choice is stark. The life sciences community can wait until a catastrophic biological attack occurs before it steps up to its security responsibilities. Or it can act proactively in its own enlightened self-interest, aware that the reaction of the political system to a major bioterrorist event would likely be extreme and even draconian, resulting in significant harm to the scientific enterprise.

...ACTION: The Department of Health and Human Services and Congress should promote a culture of security awareness in the life sciences community.

Members of the life sciences community--universities, medical and veterinary schools, nongovernmental biomedical research institutes, trade associations, and biotechnology and pharmaceutical companies--must foster a bottom-up effort to sensitize researchers to biosecurity issues and concerns. Scientists should understand the ethical imperative to "do no harm," strive to anticipate the potential consequences of their research, and design and conduct experiments in a way that minimizes safety and security risks.

(This bit sounds like the Commission heard from Drew Endy.)

...The currently separate concepts of biosafety and biosecurity should be combined into a unified conceptual framework of laboratory risk management. This framework should be integrated into a program of mandatory education and training for scientists and technicians in the life sciences field, whether they are working in the academy or in industry. Such training should begin with advanced college and graduate students andextend to career scientists. The U.S. government should also fund the development of educational materials and reference manuals on biosafety and biosecurity issues. At the same time, the responsibilities of laboratory biosafety officers should be expanded to include laboratory security and oversight of select agents, and all biosafety officers should be tested and certified by a competent government authority.

The phrase "culture of security awareness" appears frequently.  This creeps me out more than a bit, particularly given our government's recent exhortations to keep an eye on our neighbors.  You never know who might be a sleeper.  Or a sleep-walking bioterrorist.  I make this point not entirely in jest.  Who wants to live in such a paranoid culture?  Particularly when it is not at all clear that such paranoia makes us safer.

To be fair, I called for something not too dissimilar in 2003 in The Pace and Proliferation of Biological Technologies.  It only makes sense to keep an eye out for potential bioterror and bioerror, and we should have some sort of educational framework to make sure that people are aware of the potential hazards as they hack DNA.  But seeing that language in a report from a legislatively-established body makes me start imagining Orwellian propaganda posters on the walls of labs around the country.  Ick.  That is no way to foster communication and innovation.

On a different topic, here is something that opened my eyes. The report contains a story about a Russian -- someone in charge of weighing out uranium for his coworkers -- who was able to continuously steal small amounts of fissile materiel because the scales were officially recognized to be calibrated only to within 3%.  By withholding a little each time, he amassed a stash of 1.6 kg of "90 percent enriched uranium", while the official books showed no missing materiel.  Fortunately the fellow was caught, because while he was a clever thief he was a not-so-clever salesman.  As part of subsequent non-proliferation efforts, the US government paid for more accurate scales in order to prevent another incident of stealing "a bomb's worth of uranium, bit by bit".  Holy shit.

It is nice to hear that this sort of leak has been plugged for the nuclear threat.  I hope our government clearly understands that such plugs are few and far between for biological threats.

"Tracking the spread of biological technologies"

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

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

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.