Harry Potter and The Future of Nature

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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. 
Keasling_Alternate_crops.png
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.

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Hi Rob

So you specifically invited me "to consider the facts and think through the problem" regarding artemisinin. I have done so and consider that your continued excitement about synthetic artemisinin is still misplaced. I'll address that below but first 2 quick observations about the first half of your post:

1) A historical note: Have you thought about how some of the problems you think might be addressed, theoretically, through synthetic biology emerged from the large scale and rushed application of a technology that wasn't properly understood at the time? Large scale burning of coal – and then other fossil fuels – for motive power seemed an industrial good for much of the past two centuries until scientific consensus belatedly supported what Svante Arrhenius first suggested in 1896: that the resulting CO2 would warm the atmosphere. Only more recently has the additional problem of ocean acidification become apparent. The cause of honeybee decline might still not be fully understood, but as you say, the recent EU moves against neonicotinoids are sensible and a part of a belated recognition that the “new” synthetic chemistry, now 150 years old, has massively harmed biodiversity (a story long resisted by the synthetic chemistry industry -- even today). What this speaks to is the need for real precaution and humility in the roll out of new technologies and not jumping to speculative claims about what a technology might do without equal enthusiasm for finding out the less desirable effects new technologies may have. Using synthetic biology to correct the mistakes of previous technology introductions might be a 'swallow the spider to catch the fly' kind of response (and you know what happened to that old woman…)

2) Your argument that we need to develop conservation-relevant applications of synthetic biology in order to understand if synthetic biology techniques might prove to be a plan B for dealing with biodiversity loss is strikingly similar to what the geoengineers argue. They want to develop the technological hardware to alter the Earth’s climate to understand if we might need it. It’s also not a million miles from what the biodefense guys argue when they say that we ('the good guys') need to develop bioweapons to understand them in case they ever get used against us by the 'bad guys'…in the meantime the technologies get developed, owned, and acquire their own momentum and lock in, regardless of the consequences.

As for artemisinin:

So as I understand it, you lay out two arguments for the value of synthetic biology-derived artemisinin: 1) it will make malaria drugs cheaper and therefore that’s best for combatting malaria overall 2) Artemisinin farmers are caught in a cartel that works against their interests – as people living in at-risk malarial areas – by keeping Artemisia-based drug prices high. Both arguments basically accept that the synbio-derived version will be cheaper.

In your post the revealing comment is that you say this second argument “you only realized while writing [your] post,” which leads me to suspect it’s not based on much actual investigation into the politics or economics of the market for Artemesia, but is a bit of intellectual theorizing on your part, Ie, it sounds like a good argument in the abstract, but how does it match the reality?

For background, it’s worth looking at the various arguments that have been put forward over the years for why Syn Bio-derived artemisinin might possibly be a good thing to develop.

First there is the fundamental purpose for the project, namely, a way to develop an industrial platform for producing isoprenoid chemicals. That’s the honest reason we now have semi-synthetic artemisinin in the market. – Vince Martin, who did the original work, is fairly candid in saying that he and his colleagues were simply looking for a candidate molecule that could attract funding to their isoprenoid platform work and that artemisinin fit the bill perfectly – synthetic artemisinin had a compelling story, a funder with deep pockets and a great PR angle. They went to the Gates Foundation and leveraged philanthropic money to found a startup company (Amyris) and, once the microbial platform was built for artemisinic acid, Amyris turned its attention back to what it was really interested in: other isoprenoids such as biofuels, high value compounds such as rubber, patchouli, squalane etc...

The ‘story’ of SSA (semi-synthetic artemisinin) has changed over the years: Jay Keasling first claimed that it would overcome environmentally damaging means of producing artemisinin, but dropped that argument quite quickly. He then claimed it would fill in the shortfall in artemisinin production, but dropped that argument when it became apparent there was overproduction of botanically-derived artemisinin. He and Amyris then claimed synthetic artemisinin could be used to smooth out the boom and bust cycle – which was a bit more nuanced an argument, but not ultimately convincing since it imagined a pharmaceutical company refraining from 'firing up its bioreactors' in years when botanical production was assured, even though the single source would be advantageous (ie, not having to source from different botanical producers). It also ignored the fact that there was already a concerted effort to overcome the swings in production through the A2S2 (Assured Artemisinin Supply System initiative) and that those swings have been largely overcome. Finally, just recently Jay Keasling has admitted that, yes, the aim (his aim anyway) is to replace all of the botanical production but now the rationale is that this is a means of undercutting the economics of production of monotherapies that may be responsible for emerging artemisinin resistance. (That’s unproven, by the way). That’s the way a drug company argues, ie, if you hand us control of the entire market we can stamp out less savory practices and the price you pay for that is that we, the drug company, end up with a monopoly.

A few observations on where I disagree with your analysis:

1. There is no 'pricing cartel.' I wonder if you relied on Keasling’s language [from Cambridge?], which, as far as I can tell, refers to the A2S2 (Assured Artemisinin Supply System) initiative. A2S2 is a very sensible process in which all the players in the production of ACTs (funders, growers, processors, drug companies) have been working together to ensure a stable supply of botanical artemisinin to deal with the swings in prices that existed before there was a real structured market. It’s a sensible way to ensure steady supply of a life-saving drug, which is as good a reason as any for all the players in the market to collaborate. It has been a very successful endeavor and botanical production is now meeting demand (and indeed demand is expected to drop in the next little while for technical reasons to do with monitoring). From my conversations with players in the supply chain, Jay’s 'cartel' and 'price fixing' characterization has raised a lot of hackles and is inaccurate, though those involved suggest he may not understand the A2S2 process. Or do you have other sources for your ‘cartel’ claim? As cartels go, they are not very successful so far at pushing up prices (see below)… they could use some coaching from OPEC, or Monsanto.

2. There is no evidence that synthetic artemisinin is or will be any cheaper than botanical artemisinin. Its real advantage to drugmakers is not so much price as the fact that it can be more easily controlled when it is brewed from a single source, so the drug companies don't have to maintain complicated sourcing arrangements. Initially the SSA consortium promised $100 per kilo artemisinin, which would indeed have been a killing blow to natural artemisinin but they didn't actually realize that promise. What they realized instead was around $380-$420 per kilo and that is after their production and development costs being heavily subsidized by Gates, etc. We don't yet know the actual cost of SSA. It will be determined over time by the cost of sugar, the cost of energy and the internal costs of Sanofi Aventis and others.

The great misconception about natural artemisinin pricing is that it has been very high and that is higher than what SSA is offering to the market. The average price is actually quite low. If you take the 745 metric tons of artemisinin that has been imported into India over the last 10 years for processing by the large Indian generic pharmaceutical companies, the average price of the last 10 years is $370 per kg…a price point which is, in fact, lower than what the SSA promoters are targeting. Nor is the fair price of botanically-derived artemisinin necessarily going to always be above SSA in the future. New breeding work on artemisia is developing varieties in which the leaves have higher yield of artemisinin per leaf. (Indeed Gates are also funding some of that work.) That combined with improvements in extraction efficiency and denser plantings could mean increased yields so that producers may yet be able to compete on price while still realizing a livelihood -- maybe even do better in keeping price down -- who knows? That said, even if botanical artemisinin ends up cheaper Sanofi may yet choose to keep their own in-house SSA source because it is simpler. Note that artemisinin price is only 40% of a final ACT drug price. So final drug prices are at best only partly determined by ingredient costs.

3. The idea that taking 100% control over global artemisinin production and driving down price through synthetic production will drive out the monotherapies market is a convenient argument for a pharmaceutical company looking to justify monopoly behavior but is unrealistic as an anti-monotherapy strategy. In part, this is because there is no proof that SSA will be cheaper (see above). A2S2, for example, already has mechanisms to delist anyone who is discovered to be selling into that other market. Realistically the 'other' market outside ACTs production (including monotherapies) will always be there and will always find ways to get hold of cheap artemisia leaf, which, from some quarters, is quite elastic in price. Consider what happens to the growers, extractors etc who formerly sold to Sanofi but have just discovered Sanofi no longer wants their product – where do you think they are likely to sell to now that Sanofi is no longer buying their product? Far from starving the monotherapy producers, this move may be a boon for that 'other market'.

4. You talk about 'a few thousand farmers'. The most knowledgeable people in the artemisinin supply chain peg the number of farmers at about 100,000 and point out that the social impact of lost livelihoods is about 3-5 times that (account for families).

5. The graph showing that farmers in China and Vietnam could switch to potatoes was used by Jay in his talk in Cambridge in the absence of context. It was originally used as a part of a report by the Boston Consulting Group showing how artemisia farmers need ways to improve their incomes, not to look at feasible alternatives to artemesia. Many artemesia farmers in China do grow potatoes already (it turns out it’s an excellent break crop for artemisia) but then again many regions where artemisia grows cannot grow potatoes – that’s true in parts of China and very true in East Africa. Also artemisia farmers already do grow food eg, Madagascan artemisia farmers rotate their production with rice since they have two growing seasons per year. It’s not that artemisia farmers aren't growing food – they are. Artemesia is a cash crop ON TOP of food production – it’s the crop that keeps them out of poverty. Take away artemisia and they will still have some food but little to no cash.

What is perhaps most worrying is that Jay's pronouncements about intending to take over the entire supply of artemisinin and claiming to undercut botanical production may already be driving farmer planting decisions right now as well as investment decisions. As Malcolm Cutler of A2S2 warns in the Nature article that you link to: “If it’s brought in too fast it could create huge shortages, because people will stop producing the natural stuff.” If farmers decide not to plant because they fear they can't compete with SSA, we may be in for shortages in 2015 – that really would be a tragedy. If there isn't enough artemisinin for ACTs people may die. Introducing synthetic artemisinin the wrong way will not only hurt the farmers who lose their livelihood, but could also hurt malaria sufferers.. Indeed I’m told there seem to be some lessons from previous misguided communication led by CHAI (Clinton Health Access initiative) a few years ago when their unrealistic attempt to lower ACT prices led to a complete stoppage of Artemisia plantations in China, and in fact, contributed to the more recent shortage and price surge.

From my conversations with those in the supply chain it seems there is now an urgent need to clarify (and most probably rectify) the public communication around SSA introduction. Are Jay Keasling’s public statements his own or does this reflect the position of the SSA consortium? Has the consortium really decided on an all-out take-over of the market for reasons that are removed from the real needs of malaria sufferers and farmers?

Jim

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