A Few Thoughts and References Re Conservation and Synthetic Biology

Yesterday at Synthetic Biology 7.0 in Singapore, we had a good discussion about the intersection of conservation, biodiversity, and synthetic biology. I said I would post a few papers relevant to the discussion, which are below.

These papers are variously: the framing document for the original meeting at the University of Cambridge in 2013 (see also "Harry Potter and the Future of Nature"), sponsored by the Wildlife Conservation Society; follow on discussions from meetings in San Francisco and Bellagio; and my own efforts to try to figure out how quantify the economic impact of biotechnology (which is not small, especially when compared to much older industries) and the economic damage from invasive species and biodiversity loss (which is also not small, measured as either dollars or jobs lost). The final paper in this list is my first effort to link conservation and biodiversity with economic and physical security, which requires shifting our thinking from the national security of nation states and their political boundaries to the natural security of the systems and resources that those nation states rely on for continued existence.

"Is It Time for Synthetic Biodiversity Conservation?", Antoinette J. Piaggio1, Gernot Segelbacher, Philip J. Seddon, Luke Alphey, Elizabeth L. Bennett, Robert H. Carlson, Robert M. Friedman, Dona Kanavy, Ryan Phelan, Kent H. Redford, Marina Rosales, Lydia Slobodian, Keith WheelerTrends in Ecology & Evolution, Volume 32, Issue 2, February 2017, Pages 97–107

Robert Carlson, "Estimating the biotech sector's contribution to the US economy", Nature Biotechnology, 34, 247–255 (2016), 10 March 2016

Kent H. Redford, William Adams, Rob Carlson, Bertina Ceccarelli, “Synthetic biology and the conservation of biodiversity”, Oryx, 48(3), 330–336, 2014.

"How will synthetic biology and conservation shape the future of nature?", Kent H. Redford, William Adams, Georgina Mace, Rob Carlson, Steve Sanderson, Framing Paper for International Meeting, Wildlife Conservation Society, April 2013.

"From national security to natural security", Robert Carlson, Bulletin of the Atomic Scientists, 11 Dec 2013.

Late Night, Unedited Musings on Synthesizing Secret Genomes

By now you have probably heard that a meeting took place this past week at Harvard to discuss large scale genome synthesis. The headline large genome to synthesize is, of course, that of humans. All 6 billion (duplex) bases, wrapped up in 23 pairs of chromosomes that display incredible architectural and functional complexity that we really don't understand very well just yet. So no one is going to be running off to the lab to crank out synthetic humans. That 6 billion bases, by the way, just for one genome, exceeds the total present global demand for synthetic DNA. This isn't happening tomorrow. In fact, synthesizing a human genome isn't going to happen for a long time.

But, if you believe the press coverage, nefarious scientists are planning pull a Frankenstein and "fabricate" a human genome in secret. Oh, shit! Burn some late night oil! Burn some books! Wait, better — burn some scientists! Not so much, actually. There are a several important points here. I'll take them in no particular order.

First, it's true, the meeting was held behind closed doors. It wasn't intended to be so, originally. The rationale given by the organizers for the change is that a manuscript on the topic is presently under review, and the editor of the journal considering the manuscript made it clear that it considers the entire topic under embargo until the paper is published. This put the organizers in a bit of a pickle. They decided the easiest way to comply with the editor's wishes (which were communicated to the authors well after the attendees had made travel plans) was to hold the meeting under rules even more strict than Chatham House until the paper is published. At that point, they plan to make a full record of the meeting available. It just isn't a big deal. If it sounds boring and stupid so far, it is. The word "secret" was only introduced into the conversation by a notable critic who, as best I can tell, perhaps misconstrued the language around the editor's requirement to respect the embargo. A requirement that is also boring and stupid. But, still, we are now stuck with "secret", and all the press and bloggers who weren't there are seeing Watergate headlines and fame. Still boring and stupid.

Next, It has been reported that there were no press at the meeting. However, I understand that there were several reporters present. It has also been suggested that the press present were muzzled. This is a ridiculous claim if you know anything about reporters. They've simply been asked to respect the embargo, which so far they are doing, just like they do with every other embargo. (Note to self, and to readers: do not piss off reporters. Do not accuse them of being simpletons or shills. Avoid this at all costs. All reporters are brilliant and write like Hemingway and/or Shakespeare and/or Oliver Morton / Helen Branswell / Philip Ball / Carl Zimmer / Erica Check-Hayden. Especially that one over there. You know who I mean. Just sayin'.)

How do I know all this? You can take a guess, but my response is also covered by the embargo.

Moving on: I was invited to the meeting in question, but could not attend. I've checked the various associated correspondence, and there's nothing about keeping it "secret". In fact, the whole frickin' point of coupling the meeting to a serious, peer-reviewed paper on the topic was to open up the conversation with the public as broadly as possible. (How do you miss that unsubtle point, except by trying?) The paper was supposed to come out before, or, at the latest, at the same time as the meeting. Or, um, maybe just a little bit after? But, whoops. Surprise! Academic publishing can be slow and/or manipulated/politicized. Not that this happened here. Anyway, get over it. (Also: Editors! And, reviewers! And, how many times will I say "this is the last time!")

(Psst: an aside. Science should be open. Biology, in particular, should be done in the public view and should be discussed in the open. I've said and written this in public on many occasions. I won't bore you with the references. [Hint: right here.] But that doesn't mean that every conversation you have should be subject to review by the peanut gallery right now. Think of it like a marriage/domestic partnership. You are part of society; you have a role and a responsibility, especially if you have children. But that doesn't mean you publicize your pillow talk. That would be deeply foolish and would inevitably prevent you from having honest conversations with your spouse. You need privacy to work on your thinking and relationships. Science: same thing. Critics: fuck off back to that sewery rag in — wait, what was I saying about not pissing off reporters?)

Is this really a controversy? Or is it merely a controversy because somebody said it is? Plenty of people are weighing in who weren't there or, undoubtedly worse from their perspective, weren't invited and didn't know it was happening. So I wonder if this is more about drawing attention to those doing the shouting. That is probably unfair, this being an academic discussion, full of academics.

Secondly (am I just on secondly?), the supposed ethical issues. Despite what you may read, there is no rush. No human genome, nor any human chromosome, will be synthesized for some time to come. Make no mistake about how hard a technical challenge this is. While we have some success in hand at synthesizing yeast chromosomes, and while that project certainly serves as some sort of model for other genomes, the chromatin in multicellular organisms has proven more challenging to understand or build. Consequently, any near-term progress made in synthesizing human chromosomes is going to teach us a great deal about biology, about disease, and about what makes humans different from other animals. It is still going to take a long time. There isn't any real pressing ethical issue to be had here, yet. Building the ubermench comes later. You can be sure, however, that any federally funded project to build the ubermench will come with a ~2% set aside to pay for plenty of bioethics studies. And that's a good thing. It will happen.

There is, however, an ethical concern here that needs discussing. I care very deeply about getting this right, and about not screwing up the future of biology. As someone who has done multiple tours on bioethics projects in the U.S. and Europe, served as a scientific advisor to various other bioethics projects, and testified before the Presidential Commission on Bioethical Concerns (whew!), I find that many of these conversations are more about the ethicists than the bio. Sure, we need to have public conversations about how we use biology as a technology. It is a very powerful technology. I wrote a book about that. If only we had such involved and thorough ethical conversations about other powerful technologies. Then we would have more conversations about stuff. We would converse and say things, all democratic-like, and it would feel good. And there would be stuff, always more stuff to discuss. We would say the same things about that new stuff. That would be awesome, that stuff, those words. <dreamy sigh> You can quote me on that. <another dreamy sigh>

But on to the technical issues. As I wrote last month, I estimate that the global demand for synthetic DNA (sDNA) to be 4.8 billion bases worth of short oligos and ~1 billion worth of longer double-stranded (dsDNA), for not quite 6 Gigabases total. That, obviously, is the equivalent of a single human duplex genome. Most of that demand is from commercial projects that must return value within a few quarters, which biotech is now doing at eye-popping rates. Any synthetic human genome project is going to take many years, if not decades, and any commercial return is way, way off in the future. Even if the annual growth in commercial use of sDNA were 20% — which is isn't — this tells you, dear reader, that the commercial biotech use of synthetic DNA is never, ever, going to provide sufficient demand to scale up production to build many synthetic human genomes. Or possibly even a single human genome. The government might step in to provide a market to drive technology, just as it did for the human genome sequencing project, but my judgement is that the scale mismatch is so large as to be insurmountable. Even while sDNA is already a commodity, it has far more value in reprogramming crops and microbes with relatively small tweaks than it has in building synthetic human genomes. So if this story were only about existing use of biology as technology, you could go back to sleep.

But there is a use of DNA that might change this story, which is why we should be paying attention, even at this late hour on a Friday night.

DNA is, by far, the most sophisticated and densest information storage medium humans have ever come across. DNA can be used to store orders of magnitude more bits per gram than anything else humans have come up with. Moreover, the internet is expanding so rapidly that our need to archive data will soon outstrip existing technologies. If we continue down our current path, in coming decades we would need not only exponentially more magnetic tape, disk drives, or flash memory, but exponentially more factories to produce these storage media, and exponentially more warehouses to store them. Even if this is technically feasible it is economically implausible. But biology can provide a solution. DNA exceeds by many times even the theoretical capacity of magnetic tape or solid state storage.

A massive warehouse full of magnetic tapes might be replaced by an amount of DNA the size of a sugar cube. Moreover, while tape might last decades, and paper might last millennia, we have found intact DNA in animal carcasses that have spent three-quarters of a million years frozen in the Canadian tundra. Consequently, there is a push to combine our ability to read and write DNA with our accelerating need for more long-term information storage. Encoding and retrieval of text, photos, and video in DNA has already been demonstrated. (Yes, I am working on one of these projects, but I can't talk about it just yet. We're not even to the embargo stage.) 

Governments and corporations alike have recognized the opportunity. Both are funding research to support the scaling up of infrastructure to synthesize and sequence DNA at sufficient rates.

For a “DNA drive” to compete with an archival tape drive today, it needs to be able to write ~2Gbits/sec, which is about 2 Gbases/sec. That is the equivalent of ~20 synthetic human genomes/min, or ~10K sHumans/day, if I must coin a unit of DNA synthesis to capture the magnitude of the change. Obviously this is likely to be in the form of either short ssDNA, or possibly medium-length ss- or dsDNA if enzymatic synthesis becomes a factor. If this sDNA were to be used to assemble genomes, it would first have to be assembled into genes, and then into synthetic chromosomes, a non trivial task. While this would be hard, and would to take a great deal of effort and PhD theses, it certainly isn't science fiction.

But here, finally, is the interesting bit: the volume of sDNA necessary to make DNA information storage work, and the necessary price point, would make possible any number of synthetic genome projects. That, dear reader, is definitely something that needs careful consideration by publics. And here I do not mean "the public", the 'them' opposed to scientists and engineers in the know and in the do (and in the doo-doo, just now), but rather the Latiny, rootier sense of "the people". There is no them, here, just us, all together. This is important.

The scale of the demand for DNA storage, and the price at which it must operate, will completely alter the economics of reading and writing genetic information, in the process marginalizing the use by existing multibillion-dollar biotech markets while at the same time massively expanding capabilities to reprogram life. This sort of pull on biotechnology from non-traditional applications will only increase with time. That means whatever conversation we think we are having about the calm and ethical development biological technologies is about to be completely inundated and overwhelmed by the relentless pull of global capitalism, beyond borders, probably beyond any control. Note that all the hullabaloo so far about synthetic human genomes, and even about CRISPR editing of embryos, etc., has been written by Western commentators, in Western press. But not everybody lives in the West, and vast resources are pushing development of biotechnology outside of the of West. And that is worth an extended public conversation.

So, to sum up, have fun with all the talk of secret genome synthesis. That's boring. I am going off the grid for the rest of the weekend to pester litoral invertebrates with my daughter. You are on your own for a couple of days. Reporters, you are all awesome, make of the above what you will. Also: you are all awesome. When I get back to the lab on Monday I will get right on with fabricating the ubermench for fun and profit. But — shhh — that's a secret.

On DNA and Transistors

Here is a short post to clarify some important differences between the economics of markets for DNA and for transistors. I keep getting asked related questions, so I decided to elaborate here.

But first, new cost curves for reading and writing DNA. The occasion is some new data gleaned from a somewhat out of the way source, the Genscript IPO Prospectus. It turns out that, while preparing their IPO docs, Genscript hired Frost & Sullivan to do market survey across much of life sciences. The Prospectus then puts Genscript's revenues in the context of the global market for synthetic DNA, which together provide some nice anchors for discussing how things are changing (or not).

So, with no further ado, Frost & Sullivan found that the 2014 global market for oligos was $241 million, and the global market for genes was $137 million. (Note that I tweeted out larger estimates a few weeks ago when I had not yet read the whole document.) Genscript reports that they received $35 million in 2014 for gene synthesis, for 25.6% of the market, which they claim puts them in the pole position globally. Genscript further reports that the price for genes in 2014 was $.34 per base pair. This sounds much too high to me, so it must be based on duplex synthesis, which would bring the linear per base cost down to $.17 per base, which sounds much more reasonable to me because it is more consistent with what I hear on the street. (It may be that Gen9 is shipping genes at $.07 per base, but I don't know anyone outside of academia who is paying that low a rate.) If you combine the price per base and the size of the market, you get about 1 billion bases worth of genes shipped in 2014 (so a million genes, give or take). This is consistent with Ginkgo's assertions saying that their 100 million base deal with Twist was the equivalent of 10% of the global gene market in 2015. For oligos, if you combine Genscript's reported average price per base, $.05, with the market size you get about 4.8 billion bases worth of oligos shipped in 2014. Frost & Sullivan thinks that from 2015 to 2019 the oligo market CAGR will be 6.6% and the gene synthesis market will come in at 14.7%.

For the sequencing, I have capitulated and put the NextSeq $1000 human genome price point on the plot. This instrument is optimized to sequence human DNA, and I can testify personally that sequencing arbitrary DNA is more expensive because you have to work up your own processes and software. But I am tired of arguing with people. So use the plot with those caveats in mind.

NOTE: Replaces prior plot with an error in sequencing price.

NOTE: Replaces prior plot with an error in sequencing price.

What is most remarkable about these numbers is how small they are. The way I usually gather data for these curves is to chat with people in the industry, mine publications, and spot check price lists. All that led me to estimate that the gene synthesis market was about $350 million (and has been for years) and the oligo market was in the neighborhood of $700 million (and has been for years).

If the gene synthesis market is really only $137 million, with four or 5 companies vying for market share, then that is quite an eye opener. Even if that is off by a factor of two or three, getting closer to my estimate of $350 million, that just isn't a very big market to play in. A ~15% CAGR is nothing to sneeze at, usually, and that is a doubling rate of about 5 years. But the price of genes is now falling by 15% every 3-4 years (or only about 5% annually). So, for the overall dollar size of the market to grow at 15%, the number of genes shipped every year has to grow at close to 20% annually. That's about 200 million additional bases (or ~200,000 more genes) ordered in 2016 compared to 2015. That seems quite large to me. How many users can you think of who are ramping up their ability to design or use synthetic genes by 20% a year? Obviously Ginkgo, for one. As it happens, I do know of a small number of other such users, but added together they do not come close to constituting that 20% overall increase. All this suggests to me that the dollar value of the gene synthesis market will be hard pressed to keep up with Frost & Sullivan estimate of 14.7% CAGR, at least in the near term. As usual, I will be happy to be wrong about this, and happy to celebrate faster growth in the industry. But bring me data.

People in the industry keep insisting that once the price of genes falls far enough, the ~$3 billion market for cloning will open up to synthetic DNA. I have been hearing that story for a decade. And then price isn't the only factor. To play in the cloning market, synthesis companies would actually have to be able to deliver genes and plasmids faster than cloning. Given that I'm hearing delivery times for synthetic genes are running at weeks, to months, to "we're working on it", I don't see people switching en mass to synthetic genes until the performance improves. If it costs more to have your staff waiting for genes to show up by FedEx than to have them bash the DNA by hand, they aren't going to order synthetic DNA.

And then what happens if the price of genes starts falling rapidly again? Or, forget rapidly, what about modestly? What if a new technology comes in and outcompetes standard phosphoramidite chemistry? The demand for synthetic DNA could accelerate and the total market size still might be stagnant, or even fall. It doesn't take much to turn this into a race to the bottom. For these and other reasons, I just don't see the gene synthesis market growing very quickly over the next 5 or so years.

Which brings me to transistors. The market for DNA is very unlike the market for transistors, because the role of DNA in product development and manufacturing is very unlike the role of transistors. Analogies are tremendously useful in thinking about the future of technologies, but only to a point; the unwary may miss differences that are just as important as the similarities.

For example, the computer in your pocket fits there because it contains orders of magnitude more transistors than a desktop machine did fifteen years ago. Next year, you will want even more transistors in your pocket, or on your wrist, which will give you access to even greater computational power in the cloud. Those transistors are manufactured in facilities now costing billions of dollars apiece, a trend driven by our evidently insatiable demand for more and more computational power and bandwidth access embedded in every product that we buy. Here is the important bit: the total market value for transistors has grown for decades precisely because the total number of transistors shipped has climbed even faster than the cost per transistor has fallen.

In contrast, biological manufacturing requires only one copy of the correct DNA sequence to produce billions in value. That DNA may code for just one protein used as a pharmaceutical, or it may code for an entire enzymatic pathway that can produce any molecule now derived from a barrel of petroleum. Prototyping that pathway will require many experiments, and therefore many different versions of genes and genetic pathways. Yet once the final sequence is identified and embedded within a production organism, that sequence will be copied as the organism grows and reproduces, terminating the need for synthetic DNA in manufacturing any given product. The industrial scaling of gene synthesis is completely different than that of semiconductors.

70 Years After Hiroshima: "No government is well aware of the economic importance of biotechnology"

I was recently interviewed by Le Monde for a series on the impact of Hiroshima on science and science policy, with a particular focus on biotechnology, synthetic biology, and biosecurity. Here is the story in French. Since the translation via Google is a bit cumbersome to read, below is the English original.

Question 1

On the 16 of July 1945, after the first nuclear test at large scale in New Mexico (called trinity) the American physicist Kenneth Bainbridge, head of the shooting, told Robert Oppenheimer, head of the Manhattan Project, "Now we are all sons of bitches ".

In your discipline, do you feel that the time the searchers might have the same revelation has been reached ? Will it be soon?

I think this analogy does not apply to biotechnology. It is crucially important to distinguish between weapons developed in a time of war and the pursuit of science and technology in a time of peace. Over the last thirty years, biotechnology has emerged as a globally important technology because it is useful and beneficial. 

The development and maintenance of biological weapons is internationally outlawed, and has been for decades. The Trinity test, and more broadly the Manhattan Project, was a response to what the military and political leaders of the time considered an existential threat. These were actions taken in a time of world war. The scientists and engineers who developed the U.S. bombs were almost to a person ambivalent about their roles – most saw the downsides, yet were also convinced of their responsibility to fight against the Axis Powers. Developing nuclear weapons was seen as imperative for survival.

The scale of the Manhattan Project (both in personnel and as a fraction of GDP) was unprecedented, and remains so. In contrast to the exclusive governmental domain of nuclear weapons, biotechnology has been commercially developed largely with private funds. The resulting products – whether new drugs, new crop traits, or new materials – have clear beneficial value to our society.

Question 2

Do you have this feeling in other disciplines? Which ones ? Why?

No. There is nothing in our experience like the Manhattan Project and nuclear weapons. It is easy to point to the participants’ regrets, and to the long aftereffects of dropping the bomb, as a way to generate debate about, and fear of, new technologies. The latest bugaboos are artificial intelligence and genetic engineering. But neither of these technologies – even if they can be said to qualify as mature technologies – is even remotely as impactful as nuclear weapons.

Question 3

What could be the impact of a "Hiroshima" in your discipline?

In biosecurity circles, you often hear discussion of what would happen if there were “an event”. It is often not clear what that event might be, but it is presumed to be bad. The putative event could be natural or it could be artificial. Perhaps the event might kill many people as Hiroshima. (Though that would be hard, as even the most deadly organisms around today cannot wipe out populated cities in an instant.) Perhaps the event would be the intentional use of a biological weapon, and perhaps that weapon would be genetically modified in some way to enhance its capabilities. This would obviously be horrible. The impact would depend on where the weapon came from, and who used it. Was it the result of an ongoing state program? Was it a sample deployed, or stolen, from discontinued program? Or was it built and used by a terrorist group? A state can be held accountable by many means, but we are finding it challenging to hold non-state groups to account. If the organism is genetically modified, it is possible that there will be pushback against the technology. But biotechnology is producing huge benefits today, and restrictions motivated by the response to an event would reduce those benefits. It is also very possible that biotechnology will be the primary means to provide remedies to bioweapons (probably vaccines or drugs), in which case an event might wind up pushing the technology even faster.

Question 4

After 1945, physicists, including Einstein, have committed an ethical reflection on their own work. has your discipline done the same ? is it doing the same today ?

Ethical reflection has been built into biotechnology from its origins. The early participants met at Asilomar to discuss the implications of their work. Today, students involved in the International Genetically Engineered Machines (iGEM) competition are required to complete a “policy and practices” (also referred to as “ethical, legal, and social implications” (ELSI)) examination of their project. This isn’t window dressing, by any means. Everyone takes it seriously. 

Question 5

Do you think it would be necessary to rase the public awarereness about the issues related to your work?

Well, I’ve been writing and speaking about this issue for 15 years, trying to raise awareness of biotechnology and where it is headed. My book, “Biology is Technology”, was specifically aimed at encouraging public discussion. But we definitely need to work harder to understand the scope and impact of biotechnology on our lives. No government measures very well the size of the biotechnology industry – either in terms of revenues or in terms of benefits – so very few people understand how economically pervasive it is already. 

Question 6

What is, according to you, the degree of liberty of scientists face to political and industrial powers that will exploit the results of the scientific works?

Scientists face the same expectation of personal responsibility as every other member of the societies to which they belong. That’s pretty simple. And most scientists are motivated by ideals of truth, the pursuit of knowledge, and improving the human condition. That is one reason why most scientists publish their results for others to learn from. But it is less clear how to control scientific results after they are published. I would turn your question in another direction, and say politicians and industrialists should be responsible for how they use science, rather than putting this all on scientists. If you want to take this back to the bomb, the Manhattan Project was a massive military operation in a time of war, implemented by both government and the private sector. It relied on science, to be sure, but it was very much a political and industrial activity – you cannot divorce these two sides of the Project.

Question 7

Do you think about accurate measures [?] to prevent further Hiroshima?

I constantly think about how to prevent bad things from happening. We have to pay attention to how new technologies are developed and used. That is true of all technologies. For my part, I work domestically and internationally to make sure policy makers understand where biotechnology is headed and what it can do, and also to make sure it is not misused. 

But I think the question is rather off target. Bombing Hiroshima was a conscious decision made by an elected leader in a time of war. It was a very specific sort of event in a very specific context. We are not facing any sort of similar situation. If the intent of the question is to make an analogy to intentional use of biological weapons, these are already illegal, and nobody should be developing or storing them under any circumstances. The current international arms control regime is the way to deal with it. If the intent is to allude to the prevention of “bad stuff”, then this is something that every responsible citizen should be doing anyway. All we can do is pay attention and keep working to ensure that technologies are not used maliciously.

Brewing Bad Biosecurity Policy

Last week brought news of a truly interesting advance in porting opioid production to yeast. This is pretty cool science, because it involves combining enzymes from several different organisms to produce a complex and valuable chemical, although no one has yet managed to integrate the whole synthetic pathway in microbes. It is also potentially pretty cool economics, because implementing opiate production in yeast should dramatically lower the price of a class of important pain medications to a point that developing countries might finally be able to afford.

Alongside the scientific article was a Commentary – with images of drug dens and home beer brewing – explicitly suggesting that high doses of morphine and other addictive narcotics would soon be brewed at home in the garage. The text advertised “Home-brew opiates” – wow, just like beer! The authors of the Commentary used this imagery to argue for immediate regulation of 1) yeast strains that can make opioids (even though no such strains exist yet), and 2) the DNA sequences that code for the opioid synthesis pathways. This is a step backward for biosecurity policy, by more than a decade, because the proposal embraces measures known to be counterproductive for security.

The wrong recipe.

I'll be very frank here – proposals like this are deep failures of the science policy enterprise. The logic that leads to “must regulate now!” is 1) methodologically flawed and 2) ignores data we have in hand about the impacts of restricting access to technology and markets. In what follows, I will deal in due course with both kinds of failures, as well as looking at the predilection to assume regulation and restriction should be the primary policy response to any perceived threat.

There are some reading this who will now jump to “Carlson is yet again saying that we should have no regulation; he wants wants everything to be available to anyone.” This is not my position, and never has been. Rather, I insist that our policies be grounded in data from the real world. And the real world data we have demonstrates that regulation and restriction often cause more harm than good. Moreover, harm is precisely the impact we should expect by restricting access to democratized biological technologies. What if even simple analyses suggests that proposed actions are likely to make things worse? What if the specific policy actions recommended in response to a threat have already been shown to exacerbate damage from the threat? That is precisely the case here. I am constantly confronted with people saying, "That's all very well and good, but what do you propose we do instead?" The answer is simple: I don't know. Maybe nothing. Maybe there isn't anything we can do. But for now, I just want us to not make things worse. In particular I want to make sure we don't screw up the emerging bioeconomy by building in perverse incentives for black markets, which would be the worst possible development for biosecurity.

Policy conversations at all levels regularly make these same mistakes, and the arguments are nearly uniform in structure. “Here is something we don't know about, or are uncertain about, and it might be bad – really, really bad – so we should most certainly prepare policy options to prevent the hypothetical worst!” Exclamation points are usually just implied throughout, but they are there nonetheless. The policy options almost always involve regulation and restriction of a technology or process that can be construed as threatening, usually with little or no consideration of what that threatening thing might plausibly grow into, nor of how similar regulatory efforts have fared historically.

This brings me to the set up. Several news pieces (e.g., the NYT, Buzzfeed) succinctly pointed out that the “home-brew” language was completely overblown and inflammatory, and that the Commentary largely ignored both the complicated rationale for producing opioids in yeast and the complicated benefits of doing so. The Economist managed to avoid getting caught up in discussing the Commentary, remaining mostly focussed on the science, while in the last paragraph touching on the larger market issues and potential future impacts of “home brew opium” to pull the economic rug out from under heroin cartels. (Maybe so. It's an interesting hypothesis, but I won't have much to say about it here.) Over at Biosecu.re, Piers Millet – formerly of the Biological Weapons Convention Implementation Support Unit – calmly responded to the Commentary by observing that, for policy inspiration, the authors look backward rather than forward, and that the science itself demonstrates the world we are entering requires developing completely new policy tools to deal with new technical and economic realities.

Stanford's Christina Smolke, who knows a thing or two about opioid production in yeast, observed in multiple news outlets that getting yeast to produce anything industrially at high yields is finicky to get going and then hard to maintain as a production process. It's relatively easy to produce trace amounts of lots of interesting things in microbes (ask any iGEM team); it is very hard and very expensive to scale up to produce interesting amounts of interesting things in microbes (ask any iGEM team). Note that we are swimming in data about how hard this is to do, which is an important part of this story. In addition to the many academic examples of challenges in scaling up production, the last ten years are littered with startups that failed at scale up. The next ten years, alas, will see many more.

Even with an engineered microbial strain in hand, it can be extraordinarily hard to make a microbe jump through the metabolic and fermentation hoops to produce interesting/useful quantities of a compound. And then transferring that process elsewhere is very frequently its own expensive and difficult effort. It is not true that you can just mail a strain and a recipe from one place to another and automatically get the same result. However, it is true that all this will get easier over time, and many people are working on reproducible process control for biological production.

That future looks amazing. I've written many times about how the future of the economy looks like beer and cows – in other words, that our economy will inevitably be based on distributed biological manufacturing. But that is the future: i.e., not the present. Nor is it imminent. I truly wish it were imminent, but it is not. Whole industries exist to solve these problems, and much more money and effort will be spent before we get there. The economic drivers are huge. Some of the investments made by Bioeconomy Capital are, in fact, aimed at eventually facilitating distributed biological manufacturing. But, if nothing else, these investments have taught me just how much effort is required to reach that goal. If anybody out there has a credible plan to build the Cowborg or to microbrew chemicals and pharmaceuticals as suggested by the Commentary, I will be your first investor. (I said “credible”! Don't bother me otherwise.) But I think any sort of credible plan is years away. For the time being, the only thing we can expect to brew like beer is beer.

FBI Supervisory Special Agent Ed You makes great use of the “brewing bad” and “baking bad” memes, mentioned in the Commentary, in talking to students and professionals alike about the future of drug production. But this is in the context of taking personal responsibility for your own science and for speaking up when you see something dangerous. I've never heard Ed say anything about increasing surveillance and enforcement efforts as the way forward. In fact, in the Times piece, Ed specifically says, “We’ve learned that the top-down approach doesn’t work.” I can't say exactly why Ed chose that turn of phrase, but I can speculate that it is based 1) on his own experience as a professional bench molecular biologist, 2) the catastrophically bad impacts of the FBI's earlier arrests and prosecutions of scientists and artists for doing things that were legal, and 3) the official change in policy from the White House and National Security Council away from suppression and toward embracing and encouraging garage biology. The standing order at the FBI is now engagement. In fact, Ed You's arrival on the scene was coincident with any number of positive policy changes in DC, and I am happy to give him all the credit I can. Moreover, I completely agree with Ed and the Commentary authors that we should be discussing early on the implications of new technologies, an approach I have been advocating for 15 years. But I completely disagree with the authors that the current or future state of the technology serves as an indicator of the need to prepare some sort of regulatory response. We tried regulating fermentation once before; that didn't work out so well [1]. 

Badly baked regulatory policy.

So now we're caught up to about the middle of the Commentary. At this point, the story is like other such policy stories. “Assume hypothetical thing is inevitable: discuss and prepare regulation.” And like other such stories, here is where it runs off the rails with a non sequitur common in policy work. Even if the assumption of the thing's inevitability is correct (which is almost always debatable), the next step should be to assess the impact of the thing. Is it good, or is it bad? (By a particular definition of good and bad, of course, but never mind that for now.) Usually, this question is actually skipped and the thing is just assumed to be bad and in need of a policy remedy, but the assumption of badness, breaking or otherwise, isn't fatal for the analysis.

Let's say it looks bad – bad, bad, bad – and the goal of your policy is to try to either head it off or fix it. First you have to have some metric to judge how bad it is. How many people are addicted, or how many people die, or how is the crime rate affected? Just how bad is it breaking? Next – and this is the part the vast majority of policy exercises miss – you have to try to understand what happens in the absence of a policy change. What is the cost of doing nothing, of taking no remediating action? Call this the null hypothesis. Maybe there is even a benefit to doing nothing. But only now, after evaluating the null hypothesis, are you in a position to propose remedies, because only now you have a metric to compare costs and benefits. If you leap directly to “the impacts of doing nothing are terrible, so we must do something, anything, because otherwise we are doing nothing”, then you have already lost. To be sure, policy makers and politicians feel that their job is to do something, to take action, and that if they are doing nothing then they aren't doing their jobs. That is just a recipe for bad policy. Without the null hypothesis, your policy development is a waste of time and, potentially, could make matters worse. This happens time and time again. Prohibition, for example, was exactly this sort of failure, and cost much more than it benefited, which is why it was considered a failure [2].

We keep making the same mistake. We have plenty of data and reporting, courtesy of the DEA, that the ongoing crackdown on methamphetamine production has created bigger and blacker markets, as well as mayhem and violence in Mexico, all without much impact on domestic drug use. Here is the DEA Statistics & Facts page – have a look and then make up your own mind.

I started writing about the potential negative impacts of restricting access to biological technologies in 2003 (PDF), including the likely emergence of black markets in the event of overregulation. I looked around for any data I could find on the impacts of regulating democratized technologies. In particular, I happened upon the DEA's first reporting of the impacts of the then newly instituted crackdown on domestic methamphetamine production and distribution. Even in 2003, the DEA was already observing that it had created bigger, blacker markets – that are by definition harder to surveil and disrupt – without impacting meth use. The same story has played out similarly in cocaine production and distribution, and more recently in the markets for “bath salts”, aka “legal highs”. 

That is, we have multiple, clear demonstrations that, rather than improving the world, restricting access to distributed production can instead cause harm. But, really, when has this ever worked? And why do people think going down the same path in the future will lead anywhere else? I am still looking for data – any data at all – that supports the assertion that regulating biological technologies will have any different result. If you have such data, bring it. Let's see it. In that absence of that data, policy proposals that lead with regulation and restriction are doomed to repeat the failures of the past. It has always seemed to me like a terrible idea to transfer such policies over to biosecurity. Yet that is exactly what the Commentary proposes.

Brewing black markets.

The fundamental problem with the approach advocated in the Commentary is that security policies, unlike beer brewing, do not work equally well across all technical and economic scales. What works in one context will not work in another. Nuclear weapons can be secured by guns, gates, and guards because they are expensive to build and the raw materials are hard to come by, so heavy touch regulation works just fine. There are some industries – as it happens, beer brewing – where only light touch regulation works. In the U.S., we tried heavy touch regulation in the form of Prohibition, and it failed miserably, creating many more problems than it solved. There are other industries, for example DNA and gene synthesis, in which even light touch regulations are a bad idea. Indeed, light touch regulation of has already created the problem it was supposed to prevent, namely the existence of DNA synthesis providers that 1) intentionally do not screen their orders and 2) ship to countries and customers that are on unofficial black lists.

For those who don't know this story: In early 2013, the International Council for the Life Sciences (ICLS) convened a meeting in Hong Kong to discuss "Codes of Conduct" for the DNA synthesis industry, namely screening orders and paying attention to who is doing the ordering. According to various codes and guidelines promulgated by industry associations and the NIH, DNA synthesis providers are supposed to reject orders that are similar to sequences that code for pathogens, or genes from pathogens, and it is suggested that they do not ship DNA to certain countries or customers (the unofficial black list). Here is a PDF of the meeting report; be sure to read through Appendix A.

The report is fairly anodyne in describing what emerged in discussions. But people who attended have since described in public the Chinese DNA synthesis market as follows. There are 3 tiers of DNA providers. The first tier is populated with companies that comply with the various guidelines and codes promulgated internationally because this tier serves international markets. There is a second tier that appears to similarly comply, because while they serve primarily the large internal market these companies have aspirations of also serving the international market. There is a third tier that exists specifically to serve orders from customers seeking ways around the guidelines and codes. (One company in this tier was described to me as a "DNA shanty", with the employees living over the lab.) Thus the relatively light touch guidelines (which are not laws) have directly incentivized exactly the behavior they were supposed to prevent. This is not a black market, per se, and cannot be accurate described as illegal, so let's call it a "grey market".

I should say here that this is entirely consistent with my understanding of biotech in China. In 2010, I attended a warm up meeting for the last round of BWC negotiations. After that meeting, I chatted with one of the Chinese representatives present, hoping to gain a little bit of insight into the size of the Chinese bioeconomy and the state of the industry. My query was met with frank acknowledgment that the Chinese government isn't able to keep track of the industry, does't know how many companies are active, or how many employees they have, or what they are up to, and so doesn't hold out much hope of controlling the industry. I covered this a bit in my 2012 Biodefense Net Assessment report for DHS. (If anyone has any new insight into the Chinese biotech industry, I am all ears.) Not that the U.S. or Europe is any better in this regard, as our mechanisms for tracking the biotech industry are completely dysfunctional, too. There could very well be DNA synthesis providers operating elsewhere that don't comply with the recommended codes of conduct: we have no real means of broadly surveying for this behavior. There are no physical means either to track it remotely or to control it.

I am a little bit sensitive about the apparent emergence of the DNA synthesis grey market, because I warned for years in print and in person that DNA screening would create exactly this outcome. I was condescendingly told on many occasions that it was foolish to imagine a black market for DNA. And then we have to do something, right? But it was never very complicated to think this through. DNA is cheap, and getting cheaper. You need this cheap DNA as code to build more complicated, more valuable things. Ergo, restrictions on DNA synthesis will incentivize people to seek, and to provide, DNA outside any control mechanism. The logic is pretty straightforward, and denying it is simply willful self-deception. Regulation of DNA synthesis will never work. In the vernacular of the day: because economics. To make it even simpler: because humans.

So the idea that people are still suggesting proscription of certain DNA sequences is a viable route to security just rankles. And it is demonstrably counterproductive. The restrictions incentivize the bad behavior they are supposed to prevent, probably much earlier than might have happened otherwise. The take home message here is that not all industries are the same, because not all technologies are the same, and that our policy approaches should take into account these differences rather than papering over them. In particular, restricting access to information in our modern economy is a losing game. 

Where do we go from here?

We are still at the beginning of biotech. This is the most important time to get it right. This is the most important time not to screw up and make things worse. And it is important that we are at the beginning, because things are not yet screwed up.

Conversely, we are well down the road in developing and deploying drug policies, with much damage done. To be sure, despite the accumulated and ongoing costs, you have to acknowledge that it is not at all clear that suddenly legalizing drugs such as meth or cocaine would be a positive step. I am not in any way making that argument. But it is abundantly clear that drug enforcement activities have created the world we live in today. Was there an alternative? If the DEA had been able to do cost/benefit analysis of the impacts of its actions – that is, predict the emergence of DTOs and their role in production, trafficking, and violence – would the policy response 15 years ago have been any different? If Nixon had more thoughtfully considered even what was known 50 years about about the impacts of proscription, would he have launched the war on drugs? That is a hard question, because drug policy is clearly driven more by stories and personal politics than by facts. I am inclined to think the present drug policy mess was inevitable. Even with the DEA's self-diagnosed role in creating and sustaining DTOs, the national conversation is still largely dominated by “the war on drugs”. And thus the first reaction to the prospect of microbial narcotics production is to employ strategies and tactics that have already failed elsewhere. I would hate to think we are in for a war on microbes, because that is doomed to failure.

But we haven't yet made all those mistakes with biological technologies. I continue to hope that, if nothing else, we will avoid making things worse by rejecting policies we already know won't work. 

Notes:

[1] Pause here to note that even this early in the set up, the Commentary conflates via words and images the use of yeast in home brew narcotics with centralized brewing of narcotics by cartels. These are two quite different, and are perhaps mutually exclusive, technoeconomic futures. Drug cartels very clearly have the resources to develop technology. Depending on whether you listen to the U.S. Navy or the U.S. Coast Guard, either 30% or 80% of the cocaine delivered to the U.S. is transported at some point in semisubmersible cargo vessels or in fully submersible cargo submarines. These 'smugglerines', if you will, are the result of specific technology development efforts directly incentivized by governmental interdiction efforts. Similarly, if cartels decide that developing biological technologies suits their business needs, they are likely to do so. And cartels certainly have incentives to develop opioid-producing yeast, because fermentation usually lowers the cost of goods between 50% and 90% compared to production in plants. Again, cartels have the resources, and they aren't stupid. If cartels do develop these yeast strains, for competitive reasons they certainly won't want anyone else to have them. Home brew narcotics would further undermine their monopoly.

[2] Prohibition was obviously the result of a complex socio-political situation, just as was its repeal. If you want a light touch look at the interaction of the teetotaler movement, the suffragette movement, and the utility of Prohibition in continued repression of freed slaves after the Civil War, check out Ken Burns's “Prohibition” on Netflix. But after all that, it was still a dismal failure that created more problems than it solved. Oh, and Prohibition didn't accomplish its intended aims. Anheuser-Busch thrived during those years. Its best selling products at the time were yeast and kettles (see William Knoedleseder's Bitter Brew)...

Announcing Bioeconomy Capital

I am pleased to announce the launch of Bioeconomy Capital. Our investments so far are:

  • Riffyn, which is building software that provides experimental process design and analytics software to improve reproducibility and tech transfer in life science and materials R&D;
  • Synthace, which is increasing the reliability, quality, and scale of biological science;
  • RoosterBio, which is is creating exponential advances in stem cell manufacturing to provide raw materials for cell-based therapies, biofabrication, and cellular ink for 3D BioPrinting.

Biosecurity is Everyone's Business (Part 2)

(Here is Part 1.)

Part 2. From natural security to neural security

Humans are fragile. For most of history we have lived with the expectation that we will lose the use of organs, and some of us limbs, as we age or suffer injury. But that is now changing. Prostheses are becoming more lifelike and more useful, and replacement organs have been used to save lives and restore function. But how robust are the replacement parts? The imminent prospect of technological restoration of human organs and limbs lost to injury or disease is cause to think carefully about increasing both our biological capabilities and our technological fragilities.

Technology fails us for many reasons. A particular object or application may be poorly designed or poorly constructed. Constituent materials may be faulty, or maintenance may be shoddy. Failure can result from inherent security flaws, which can be exploited directly by those with sufficient technical knowledge and skill. Failure can also be driven by clever and conniving exploits of the overall system that focus on its weakest link, almost always the human user, by inducing them to make a mistake or divulge critical information. Our centuries of experience and documentation of such failures should inform our thinking about the security of emerging technologies, particularly as we begin to fuse biology with electronic systems. The growing scope of biotechnology will therefore require constant reassessment of what vulnerabilities we are introducing through that expansion. Examining the course of other technologies provides some insight into the future of biology.

We carry powerful computers in our pockets, use the internet to gather information and access our finances, and travel the world in aircraft that are often piloted and landed by computers. We are told we can trust this technology with our financial information, our identities and social networks, and, ultimately, our lives. At the same time, technology is constantly shown to be vulnerable and fragile at a non-trivial rate -- resulting in identity theft, financial loss, and sometimes personal injury and death. We embrace technology despite well-understood risks; automobiles, electricity, fossil fuels, automation, and bicycles all kill people every day in predictable numbers. Yet we continue to use technology, integrating it further into multiple arenas in our lives, because we decide that the benefits outweigh risks.

Healthcare is one arena in which risks are multiplying. The IT security community has for some years been aware of network vulnerabilities in medical devices such as pacemakers and implantable defibrillators. The ongoing integration of networked medical devices in health care settings, an integration that is constantly introducing both new capabilities and new vulnerabilities, is now the focus of extensive efforts to improve security. The impending introduction of networked, semi-autonomous prostheses raises obvious similar concerns. Wi-fi enabled pacemakers and implantable defibrillators are just the start, as soon we will see bionic arms, legs, and eyes with network connections that allow performance monitoring and tuning.

Eventually, prostheses will not simply restore "human normal" capabilities, they will also augment human performance. I learned recently that DARPA explicitly chose to limit the strength of its robotic arm, but that can't last: science fiction, super robotic strength is coming. What happens when hackers get ahold of this technology? How will people begin to modify themselves and their robotic appendages? And, of course, the flip side of having enhanced physical capabilities is having enhanced vulnerabilities. By definition, tuning can improve or degrade performance, and this raises an important security question: who holds the password for your shiny new arm? Did someone remember to overwrite the factory default password? Is the new password susceptible to a dictionary attack? The future brings even more concerns.  Control connections to a prosthesis are bi-directional and, as the technology improves, ever better neural interfaces will eventually jack these prostheses directly into the brain. "Tickling" a robotic limb could take on a whole new meaning, providing a means to connect various kinds of external signals to the brain in new ways.

Beyond limbs, we must also consider neural connections that serve to open entirely novel senses. It is not a great leap to envision a wide range of ensuing digital-to-neural input/output devices. These technologies are evolving at a rapid rate, and through them we are on the cusp of opening up human brains to connections with a wide range of electromechanical hardware capabilities and, indeed, all the information on the internet.

Just this week saw publication of a cochlear implant that delivers a gene therapy to auditory neurons, promoting the formation of electrical connections with the implant and thereby dramatically improving the hearing response of test animals. We are used to the idea of digital music files being converted by speakers into sound waves, which enter the brain through the ear. But the cochlear implant is basically an ethernet connection wired to your auditory nerve, which in principal means any signal can be piped into your brain. How long can it be before we see experiments with a cochlear (or other) implant that enables direct conversion of arbitrary digital information into neural signals? At that point, "hearing" might extend into every information format. So, again we must ask, who holds the password to your brain implant

Hacking the Bionic Man

As this technology is deployed in the population it is clear that there can be no final and fixed security solution. Most phone and computer users are now all too aware that new hardware, firmware, and operating systems always introduce new kinds of risks and threats. The same will be true of prostheses. The constant rat race to chase down security holes in new products upgrades will soon extend directly into human brains. As more people are exposed to medical device vulnerabilities, security awareness and improvement must become an integrated part of medical practice. This discussion can be easily extended to potential vulnerabilities that will arise from the inevitable integration into human bodies of not just electromechanical devices, but of ever more sophisticated biological technologies. The exploration of prosthesis security, loosely defined, gives some indication of the scope of the challenge ahead.

The class of things we call prostheses will soon expand beyond electromechanical devices to encompass biological objects such as 3D printed tissues and lab-grown organs. As these cell-based therapies begin to enter human clinical trials, we must assess the security of both the therapies themselves and the means used to create and administer them. If replacement organs and tissues are generated from cells derived from donors, what vulnerabilities do the donors have? How are those donor vulnerabilities passed along to the recipients? Yes, you have an immune system that does wonders most of the time. But are your natural systems up to the task of handling the biosecurity of augmented organs?

What does security even mean in this context? In addition to standard patient work-ups, should we begin to fully sequence the genomes of donor tissues, first to identify potential known health issues, and then to build a database that can be re-queried as new genetic links to disease are discovered? Are there security holes in the 3D printers and other devices used to manipulate cells and tissues? What are the long term security implications of deploying novel therapeutic tissues in large numbers of military and civilian personnel? What are the long-term security implications of using both donor and patient tissue as seeds of induced pluripotent stem cells, or of differentiating any stem cell line for use in therapies? Do we fully understand the complement of microbes and genomes that may be present in donor samples, or lying dormant in donor genomes, or that may be introduced via laboratory procedures and instruments used to process cells for use as therapies? What is the genetic security of a modified cell line or induced pluripotent stem cell? If there is a genetic modification embedded in your replacement heart tissue, where did the new DNA come from, and are you sure you know everything that it encodes? As with information technologies, we should expect that these new biological technologies will sometimes arrive with accidental vulnerabilities; they may also come with intentionally introduced back doors. The economic motivation to create new protheses, as well as to exploit vulnerabilities, will soon introduce market competition as a factor in biosecurity. 

Competition often drives perverse strategic decisions when it comes to security. Firms rush to sell hardware and software that are said to be secure, only to discover that constant updates are required to patch security holes. We are surrounded by products in endless beta. Worse yet, manufacturers have been known to sit on security holes in the naive hope that no one else will notice. Vendors sometimes appear no more literate about the security of hardware and software than are their customers. What will the world look like when eletromechanical and biological prostheses are similarly in constant states of upgrade? Who will you trust to build/print/grow a prosthesis? Are you going to place your faith in the FDA to police all these risks? (Really?) If you decide to instead place your faith in the market, how will you judge the trustworthiness of firms that sell aftermarket security solutions for your bionic leg or replacement liver?

The complexity of the task at hand is nearly overwhelming. Understanding the coming fusion of technologies will require competency in software, hardware, wetware, and security -- where are those skill sets being developed in a compatible, integrated manner? This just leads to more questions: Are there particular countries that will have a competitive advantage in this area? Are there particular countries that will be hotbeds of prosthesis malware creation and distribution?

The conception of security, whether of individuals or nation states, is going to change dramatically as we become ever more economically dependent upon the market for biological technologies. Given the spreading capability to participate and innovate in technology development, which inevitably amplifies the number and effect of vulnerabilities of all kinds, I suspect we need to re-envision at a very high level how security works.

[Coming soon: Part 3.]