Harry Potter and The Future of Nature

How will Synthetic Biology and Conservation Shape the Future of Nature?  Last month I was privileged to take part in a meeting organized by The Wildlife Conservation Society to consider that question.  Here is the framing paper (PDF), of which I am a co-author.  There will be a follow-up paper in the coming months.  I am still mulling over what I think happened during the meeting, and below are a few observations that I have managed to settle on so far.  Others have written their own accounts.  Here is a summary from Julie Gould, riffing on an offer that Paul Freemont made to conservation biologists at the close of the meeting, "The Open Door".  Ed Gillespie has a lovely, must-read take on Pandora's Box, cane toads, and Emily Dickenson, "Hope is the thing with feathers".  Cristian Samper, the new head of the Wildlife Conservation Society was ultimately quite enthusiastic: Jim Thomas of ETC, unsurprisingly, not so much.

The meeting venue was movie set-like Cambridge.  My journey took me through King's Cross, with its requisite mock-up of a luggage trolley passing through the wall at platform nine and three-quarters.  So I am tempted to style parts of the meeting as a confrontation between a boyish protagonist trying to save the world and He Who Must Not Be Named.  But my experience at the meeting was that not everyone was able to laugh at a little tension-relieving humor, or even to recognize that humor.  Thus the title of this post is as much as I will give in temptation.

How Can SB and CB Collaborate?

I'll start with an opportunity that emerged during the week, exactly the sort of thing you hope would come from introducing two disciplines to each other.  What if synthetic biology could be used as a tool to aid in conservation efforts, say to buttress biodiversity against threats?  If the ongoing, astonishing loss of species were an insufficient motivation to think about this possibility, now some species that humans explicitly rely upon economically are under threat.    Synthetic biology might - might! - be able to offer help in the form of engineering species to be more robust in the face of a changing environment, such as enabling corals to cope with increases in water temperature and acidity, or it perhaps via intervening in a host-prey relationship, such as that between bats and white-nose disease or between bees and their mites and viruses.

The first thing to say here is that if the plight of various species can be improved through changes in human behavior then we should by all means work toward that end.  The simpler solution is usually the better solution.  For example, it might be a good idea to stop using those pesticides and antibiotics that appear to create more problems than they solve when introduced into the environment.  Moreover, at the level of the environment and the economy, technological fixes are probably best reserved until we try changes in human behavior.  After all, we've mucked up such fixes quite a few times already.  (All together now: "Cane Toad Blues".)  But what if the damage is too far along and cannot be addressed by changes in behavior?  We should at least consider the possibility that a technological fix might be worth a go, if for no other reason that to figure out how to create a back up plan.  Given the time scales involved in manipulating complex organisms, exploring the option of a back-up plan means getting started early.  It also means thoughtfully considering which interventions would be most appropriate and urgent, where part of the evaluation should probably involve asking whether changes in human behavior are likely to have any effect.  In some cases, a technical solution is likely to be our only chance.

First up: corals. We heard from Stanford's Steve Palumbi on work to understand the effects of climate change on corals in the South Pacific.  Temperature and acidity - two parameters already set on long term changes - are already affecting coral health around the globe.  But it turns out that in the lab some corals can handle remarkably difficult environmental conditions.  What if we could isolate the relevant genetic circuits and, if necessary, transplant them into other species, or turn them on if they are already widespread?  My understanding of Professor Palumbi's talk is that it is not yet clear why some corals have the pathway turned on and some do not.  So, first up, a bunch of genetics, molecular biology, and field biology to figure out why the corals do what they do.  After that, if necessary, it seems that it would be worth exploring whether other coral species can be modified to use the relevant pathways.  Corals are immensely important for the health of both natural ecosystems and human economies; we should have a back-up plan, and synthetic biology could certainly contribute.

Next up: bats. Bats are unsung partners of human agriculture, and they contribute an estimated $23 billion annually to U.S. farmers by eating insects and pollinating various plants.  Here is nice summary article from The Atlantic by Stephanie Gruner Buckely on the impact upon North American bats of white nose syndrome.  The syndrome, caused by a fungus evidently imported from Europe, has already killed so many bats that we may see an impact on agriculture as soon as this year.  European bats are resistant to the fungus, so one option would be to try to introduce the appropriate genes into North American bats via standard breeding.  However, bats breed very slowly, usually only having one pup a year, and only 5 or so pups in a lifetime.  Given the mortality rate due to white nose syndrome, this suggests breeding is probably too slow to be useful in conservation efforts.  What if synthetic biology could be used to intervene in some way, either to directly attack the non-native fungus or to interfere with its attack on bats.  Obviously this would be a hard problem to take on, but both biodiversity and human welfare would be improved by making progress here.

And now: bees. If you eat, you rely on honeybees.  Due to a variety of causes, bee populations have fallen to the point where food crops are in jeopardy.  Entomologist Dennis vanEngelstorp, quoted in Wired, warns "We're getting closer and closer to the point where we don't have enough bees in this country to meet pollination demands.  If we want to grow fruits and nuts and berries, this is important.  One in every three bites [of food consumed in the U.S.] is directly or indirectly pollinated by bees."  Have a look at the Wired article for a summary of the constellation of causes of Colony Collapse Disorder, or CCD -- they are multifold and interlocking.  Obviously, the first thing to do is to stop making the problem worse; Europe has banned a class of pesticide that is exceptionally hard on honeybees, though the various sides in this debate continue to argue about whether that will make any difference.  This change in human behavior may have some impact, but most experts agree we need to do more.  Efforts are underway to breed bees that are resistant to both pesticides and to particular mites that prey on bees and that transmit viruses between bees.  Applying synthetic biology here might be the hardest task of all, given the complexity of the problem.  Should synthetic biologists focus on boosting apian immune systems?  Should they focus on the mite?  Apian viruses?  It sounds very difficult.  But with such a large fraction of our food supply dependent upon healthy bees, it also seems pretty clear that we should be working on all fronts to sort out potential solutions.

A Bit of Good News

Finally, a problem synthetic biologists are already working to solve: malaria.  The meeting was fortunate to hear directly from Jay Keasling.  Keasling presented progress on a variety of fronts, but the most striking was his announcement that Sanofi-Aventis has produced substantially more artemisinin this year than planned, marking real progress in producing the best malaria drug extant using synthetic biology rather than by purifying it from plants.  Moreover, he announced that Sanofi and OneWorldHealth are likely to take over the entire world production of artemisinin.  The original funding deal between The Gates Foundation, OneWorldHealth, Amyris, and Sanofi required selling at cost.  The collaboration has worked very hard at bringing the price down, and now it appears that they can simply outcompete the for-profit pricing monopoly.

The stated goal of this effort is to reduce the cost of malaria drugs and provide inexpensive cures to the many millions of people who suffer from malaria annually.  Currently, the global supply fluctuates, as, consequently, do prices, which are often well above what those afflicted can pay.  A stable, high volume source of the drug would reduce prices and also reduce the ability of middle-men to sell doctored, diluted, or mis-formulated artemisinin, all of which are contributing to a rise of resistant pathogens.

There is a potential downside to this project.  If Sanofi and OneWorldHealth do corner the market on artemisinin, then farmers who currently grow artemisia will no longer have that option, at least for supplying the artemisinin market.  That might be a bad thing, so we should at least ask the question of whether the world is a better place with artemisinin production done in vats or derived from plants.  This question can be broken into two pieces: 1) what is best for the farmers? and 2) what is best for malaria sufferers?  It turns out these questions have the same answer.

There is no question that people who suffer from malaria will be better off with artemisinin produced in yeast by Sanofi.  Malaria is a debilitating disease that causes pain, potentially death, and economic hardship.  The best estimates are that countries in which malaria is endemic suffer a hit to GDP growth of 1.3% annually compared to non-malarious countries.  Over just a few years this yearly penalty swamps all the foreign aid those countries receive; I've previously argued that eliminating malaria would be the biggest humanitarian achievement in history and would make the world a much safer place.  Farmers in malarious countries are the worst hit, because the disease prevents them from getting into the fields to work.  I clashed in public over this with Jim Thomas around our respective testimonies in front of the Presidential Bioethics Commission a couple of years ago.  Quoting myself briefly from the relevant blog post,

The human cost of not producing inexpensive artemisinin in vats is astronomical.  If reducing the burden of malaria around the world on almost 2 billion people might harm "a few thousand" farmers, then we should make sure those farmers can make a living growing some other crop.  We can solve both problems.  ...Just one year of 1.3% GDP growth recovered by reducing (eliminating?) the impact of malaria would more than offset paying wormwood farmers to grow something else.  There is really no argument to do anything else.

For a bit more background on artemisinin supply and pricing, and upon the apparent cartel in control of pricing both the drug and the crop, see this piece in Nature last month by Mark Peplow.  I was surprised to learn that that the price of artemisia is set by a small group that controls production of the drug.  This group, unsurprisingly, is unhappy that they may lose control of the market for artemisinin to a non-profit coalition whose goal is to eliminate the disease.  Have a look at the chart titled "The Cost of Progress", which reveals substantial price fluctuations, to which I will return below.

Mr. Thomas responded to Keasling's announcement in Cambridge with a broadside in the Guardian UK against Keasling and synthetic biology more generally.  Mr. Thomas is always quick to shout "What about the farmers?"  Yet he is rather less apt to offer actual analysis of what farmers actually gain, or lose, by planting artemisia.

The core of the problem for farmers is in that chart from Nature, which shows that artemisinin has fluctuated in price by a factor of 3 over the last decade.  Those fluctuations are bad for both farmers and malaria sufferers; farmers have a hard time knowing whether it makes economic sense to plant artemisia, which subsequently means shortages if farmers don't plant enough.  Shortages mean price spikes, which causes more farmers to plant, which results in oversupply, which causes the price to plunge, etc.  You'll notice that Mr. Thomas asserts that farmers know best, but he never himself descends to the level of looking at actual numbers, and whether farmers benefit by growing artemisia.  The numbers are quite revealing.

Eyeballing "The Cost of Progress" chart, it looks like artemisia has been below the $400/kg level for about half the last 10 years.  To be honest, there isn't enough data on the chart to make firm conclusions, but it does look like the most stable price level is around $350/kg, with rapid and large price spikes up to about $1000/kg.  Farmers who time their planting right will probably do well; those who are less lucky will make much less on the crop.  So it goes with all farming, unfortunately, as I am sure Mr. Thomas would agree.

During his talk, Keasling put up a chart I hadn't seen before, which showed predicted farmer revenues for a variety of crops.  The chart is below; it makes clear that farmers will have substantially higher revenues planting crops other than artemisia at prices at or below $400/kg. 

The Strange Arguments Against Microbial Production of Malaria Drugs

Mr. Thomas' response in the Guardian to rational arguments and actual data was a glib accusation that Keasling is dismissing the welfare of farmers with "Let them plant potatoes".  This is actually quite clever and witty, but not funny in the slightest when you look at the numbers.  Thomas worries that farmers in African and Asia will suffer unduly from a shift away from artemisia to yeast.  But here is the problem: those farmers are already suffering -- from malaria.  Digging deeper, it becomes clear that Mr. Thomas is bafflingly joining the pricing cartel in arguing against the farmers' best interests.

A brief examination of the latest world malaria map shows that the most intense malaria hot spots are in Africa and Asia, with South America not far behind (here is the interactive CDC version).  Artemisia is primarily grown in Africa and Asia.  That is, farmers most at risk of contracting malaria only benefit economically when there is a shortage of artemisinin, the risk of which is maintained by leaving artemisia production in the hands of farmers. Planting sufficient quantities of artemisia to meet demand means prices that are not economically viable for the farmer.  There are some time lags here due to growing and processing the crop into the drug, but the upshot is that the only way farmers make more money planting artemisia than other crops is when there is a shortage.  This is a deadly paradox, and its existence has only one beneficiary: the artemisinin pricing cartel.  But we can now eliminate the paradox.  It is imperative for us to do so.

Once you look at the numbers there is no argument Mr. Thomas, or anyone else, can make that we should do anything but brew artemisinin in vats and bring the price as low as possible.

I had previously made the macro-scale economic arguments about humanitarian impacts economic growth.  Malarious countries, and all the farmers in them, would benefit tremendously by a 1.3% annual increase in GDP.  But I only realized while writing this post that the micro-scale argument gives the same answer: the farmers most at risk from malaria only make money growing artemisia when there is a shortage of the drug, which is when they are most likely to be affected by the disease.

I get along quite well in person with Mr. Thomas, but I have long been baffled by his arguments about artemisinin.  I heartily support his aims of protecting the rights of farmers and taking care of the land.  We should strive to do the right thing, except when analysis reveals it to be the wrong thing.  Since I only just understood the inverse relationship between artemisinin pricing and the availability of the drug to the very farmers growing artemisia, I am certain Mr. Thomas has not had the opportunity to consider the facts and think through the problem so that he might come to the same conclusion.  I invite him to do so.

Biodefense Net Assessment: Causes and Consequences of Bioeconomic Proliferation

Revenues from biotechnology continue to grow rapidly around the world.  For several years I have been trying to assess these revenues, in part as a proxy metric for technological capabilities.  A couple of years ago, I received a commission from the U.S. government to explore this topic for the 2012 Biodefense Net Assessment (BNA).  I recently received approval to release the resulting report, which carries the title "Causes and Consequences of Bioeconomic Proliferation: Implications for U.S. Physical and Economic Security" (PDF).  As far as I am aware, this is the first publicly-released document from the BNA. 

Carlson_BNA_cover.pngThere is a relatively small amount of information available about the BNA available on the web. The BNA is a quadrennial review required under Homeland Security Presidential Directive 10 (HSPD-10): "These assessments are meant to provide senior level decision makers with fresh, non-consensus, perspectives on key issues underlying the Nation's biodefense."  The first few pages of the report provide more information about the origin and use of the BNA.

My own motivation for doing this work is to better understand what is going on in the world.  When it comes to developing policy to improve security and safety, I unapologetically insist that data drive policy.  There are far too many people who develop policy in spite of data rather than in light of data.  That leads to messy thinking and demonstrably makes us less safe and less secure.  All that said, one conclusion from my work on this report is that nobody is doing a very good job of gathering and publishing the data necessary to understand the rapid technical and economic development of biotechnology around the world.

One final thought about the report: this particular document was funded by the U.S. government, and I was given a particular set of charges in the task (see pg iii-iv); the report is therefore tilted toward U.S. security concerns.  However, the basic analyses and conclusions are relevant to developing policy in any country, and for that matter to developing strategy for many private companies and other organizations.  I will continue work on this story, and look forward to engaging people around the globe in better understanding how our world is changing.

Here is the "Background" section of the report.  Please note that the report is now a few years old, and the bioeconomy has continued to grow rapidly around the world.

Biotechnology is becoming increasingly de-skilled and less expensive, leading to a proliferation of localized innovation around the world. In addition to major investments by growing economic powerhouses India and China, other developing countries such as Indonesia, Pakistan, and Brazil are equally intent on developing domestic biotech research and development capabilities. All of these countries are interested initially in producing drugs for diseases that predominantly affect their citizens, a project that requires a particular infrastructure and set of skills. Yet those same skills can be used to develop other applications, from fuels and materials to weapons, all of which can serve as a lever to increase power and presence on the world stage, thereby enabling developing countries to become rivals to the US both regionally and globally.

Economic demand will serve as a driver for ever greater proliferation of biotechnology. Today, in the US, revenues from genetically modified systems contribute the equivalent of almost 2% of GDP, and are growing in the range of 15 to 20% per year. China, among other countries, is not far behind and is following explicit government policy to substantially increase its independent, domestic development of new biological technologies to address such diverse concerns as healthcare, biomass production, and biomanufacturing. As is already the case in many other industries, trade between developing nations in biotech may soon exceed trade with the US. Therefore, among the challenges the US is likely to face in this environment is that the flow of technology, ideas, and skills may bypass US soil. Moreover, because skills and instrumentation are widely available, biotechnological development is possible in unconventional settings outside of universities and corporate laboratories. The resulting profusion of localized and distributed innovation is likely to provide a wide variety of challenges to US security, from economic competition, to intelligence gathering, to the production of new bio-threats.

Synthetic biology and "green" explosives

Here is my article with Dan Grushkin for Slate and Future Tense on "The Military's Push to Green Our Explosives", about using synthetic biology to make things go boom.  We had way more material than space, and we should probably write something else on the topic.

Here are the first three 'graphs:

Last year, when the United States military debuted footage of an iridescent drone the size and shape of a hummingbird buzzing around a parking lot, the media throated a collective hooah! Time magazine even devoted a cover to it. Meanwhile, with no fanfare at all--despite the enormous potential to reshape modern warfare--the military issued a request for scientists to find ways to design microbes that could produce explosives for weapons. Imagine a vat of genetically engineered yeast that produces chemicals for bombs and missiles instead of beer.

The request takes advantage of new research in synthetic biology, a science that applies engineering principles to genetics. To its humanitarian credit, in the field's short existence, scientists have genetically programmed bacteria and yeast to cheaply produce green jet fuels (now being tested by major airplane makers) and malaria medicines (scheduled for market in 2013). It's an auspicious beginning for a science that portends to revolutionize how we make things. In the future, we may harness cells to self-assemble into far more complex objects like cell phone batteries or behave like tiny programmable computers. The promise, however, comes yoked with risks.

The techniques that make synthetic biology such a powerful tool for positive innovation may be also used for destruction. The military's new search for biologically brewed explosives threatens to reopen an avenue of research that has been closed for 37 years: biotechnology developed for use in war.

Censoring Science is Detrimental to Security

Restricting access toscience and technology in the name of security is historically a losing proposition.  Censorship of information that is known to exist incentivizes innovation and rediscovery. 

As most readers of this blog know, there has been quite a furor over new results demonstrating mutations in H5N1 influenza strains that are both deadly and highly contagious in mammals.  Two groups, led by Ron Fouchier in the The Netherlands and Yoshihiro Kawaoka at The University of Wisconsin, have submitted papers to Nature and Science describing the results.  The National Science Advisory Board for Biosecurity (NSABB) has requested that some details, such as sequence information, be omitted from publication.  According to Nature, both journals are "reserving judgement about whether to censor the papers until the US government provides details of how it will allow genuine researchers to obtain redacted information".

For those looking to find more details about what happened, I suggest starting with Dorveen Caraval's interview with Fouchier in the New York Times, "Security in Flu Study Was Paramount, Scientist Says"; Kathleen Harmon's firsthand account of what actually happened when the study was announced; and Heidi Ledford's post at Nature News about the NSABB's concerns.

If you want to go further, there is more good commentary, especially the conversation in the comments (including from a member of the NSABB), in "A bad day for science" by Vincent Racaniello.  See also Michael Eisen's post "Stop the presses! H5N1 Frankenflu is going to kill us all!", keeping in mind that Eisen used to work on the flu.

Writing at Foreign Policy, Laurie Garrett has done some nice reporting on these events in two posts, "The Bioterrorist Next Door" and "Flu Season".  She suggests that attempts to censor the results would be futile: "The genie is out of the bottle: Eager graduate students in virology departments from Boston to Bangkok have convened journal-review debates reckoning exactly how these viral Frankenstein efforts were carried out."

There is much I agree with in Ms. Garrett's posts.  However, I must object to her assertion that the work done by Fouchier and Kawaoka can be repeated easily using the tools of synthetic biology.  She writes "The Fouchier episode laid bare the emptiness of biological-weapons prevention programs on the global, national, and local levels.  Along with several older studies that are now garnering fresh attention, it has revealed that the political world is completely unprepared for the synthetic-biology revolution."   As I have already written a book that discusses this confusion (here is an excerpt about synthetic biology and the influenza virus), it is not actually what I want to write about today.  But I have to get this issue out of the way first.

As far as I understand from reading the press accounts, both groups used various means to create mutations in the flu genome and then selected viruses with properties they wanted to study.  To clarify, from what I have been able to glean from the sparse accounts thus far, DNA synthesis was not used in the work.  And as far as I understand from reading the literature and talking to people who build viruses for a living, it is still very hard to assemble a functioning, infectious influenza virus from scratch.   

If it were easy to write pathogen genomes -- particularly flu genomes -- from scratch, we would quite frankly be in deep shit. But, for the time being, it is hard.  And that is important.  Labs who do use synthetic biology to build influenza viruses, as with those who reconstructed the 1918 H1N1 influenza virus, fail most of the time despite great skill and funding.  Synthesizing flu viruses is simply not a garage activity.  And with that, I'll move on.

Regardless of how the results might be reproduced, many have suggested that the particular experiments described by Fouchier and Kawaoka should not have been allowed.  Fouchier himself acknowledges that selecting for airborne viruses was not the wisest experiment he could have done; it was, he says, "really, really stupid".  But the work is done, and people do know about it.  So the question of whether this work should have been done in the first place is beside the point.  If, as suggested by Michael Eisen, that "any decent molecular biologist" could repeat the work, then it was too late to censor the details as soon as the initial report came out. 

I am more interested in the consequences of trying to contain the results while somehow allowing access to vetted individuals.  Containing the results is as much about information security as it is biological security.  Once such information is created, the challenge is to protect it, to secure it.  Unfortunately, the proposal to allow secure access only by particular individuals is at least a decade (if not three decades) out of date.

Any attempt to secure the data would have to start with an assessment of how widely it is already distributed.  I have yet to meet an academic who regularly encrypts email, and my suspicion is that few avail themselves of the built-in encryption on their laptops.  So, in addition to the university computers and email servers where the science originated, the information is sitting in the computers of reviewers, on servers at Nature and Science, at the NSABB, and, depending on how the papers were distributed and discussed by members of the NSABB, possibly on their various email servers and individual computers as well.  And let's not forget the various unencrypted phones and tablets all of those reviewers now carry around.

But never mind that for a moment.  Let's assume that all these repositories of the relevant data are actually secure.  The next step is to arrange access for selected researchers.  That access would inevitably be electronic, requiring secure networks, passwords, etc.  In the last few days the news has brought word that computer security firms Stratfor and Symantec have evidently been hacked recently.  Such attacks are not uncommon.  Think back over the last couple of years: hacks at Google, various government agencies, universities.  Credit card numbers, identities, and supposedly secret DoD documents are all for sale on the web.  To that valuable information we can now add a certain list of influenza mutations.  If those mutations are truly a critical biosecurity risk -- as asserted publicly by various members of the NSABB -- then that data has value far beyond its utility in virology and vaccinology.

The behavior of various hackers (governments, individuals, other) over the last few years make clear that what the discussion thus far has done is to stick a giant "HACK HERE" sign on the data.  Moreover, if Ms. Garrett is correct that students across the planet are busy reverse engineering the experiments because they don't have access to the original methods and data, then censorship is creating a perverse incentive for innovation.  Given today's widespread communication, restriction of access to data is an invitation, not a proscription.

This same fate awaits any concentration of valuable data.  It obviously isn't a problem limited to collections of sensitive genetic sequences or laboratory methods.  And there is certainly a case to be made for attempting to maintain confidential or secret caches of data, whether in the public or private interest.  In such instances, compartmentalization and encryption must be implemented at the earliest stages of communication in order to have any hope of maintaining security. 

However, in this case, if it true that reverse engineering the results is straightforward, then restriction of access serves only to slow down the general process of science.  Moreover, censorship will slow the development of countermeasures.  It is unlikely that any collection of scientists identified by the NSABB or the government will be sufficient to develop all the technology we need to respond to natural pathogens, let alone any artificial ones.

As with most other examples of prohibition, these restrictions are doomed before they are even implemented.  Censorship of information that is known to exist incentivizes innovation and rediscovery.  As I explored in my book, prohibition in the name of security is historically a losing proposition.  Moreover, science is inherently a networked human activity that is fundamentally incompatible with constraints on communication, particularly of results that are already disclosed.  Any endeavor that relies upon science is, therefore, also fundamentally incompatible with constraints on communication.  Namely developing technologies to defend against natural and artificial pathogens.  Censorship threatens not just science but also our security.