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If you have a specific link you are trying to follow, and it has dashes between words, try replacing them with underscores. E.g., instead of "www.synthesis.cc/x-y-z", try "www.synthesis.cc/x_y_z". If the URL ends in "/x.html", try replacing that with "/x/".

I will be repairing links, etc., as I find them.

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.

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 aretremendously 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.

Tim Cook is Defending Your Brain

Should the government have the right to troll through your thoughts and memories? That seems like a question for a "Minority Report" or "Matrix" future, but legal precedent is being set today. This is what is really at stake in an emerging tussle between Washington DC and Silicon Valley.

The Internets areall abuzz with Apple's refusal to hack an iPhone belonging to an accused terrorist. The FBI has served a court order on Apple, based on the All Writs Act of 1789, requiring Apple to break the lock that limits the number of times a passcode can be tried. Since law enforcement has been unable to crack the security of iOS on its own, it wants Apple to write special software to do the job. Here is Wired's summary. This NYT story has additional good background. The short version: should law enforcement and intelligence agencies be able to compel corporations to hack devices owned by citizens and entrusted with their sensitive information? 

Apple CEO Tim Cook published a letter saying no, thank you, because weakening the security of iPhones would be bad for his customers and "has implications far beyond the legal case at hand". Read Cook's letter; it is thoughtful. The FBI says it is just about this one phone and "isn't about trying to set a precedent," in the words of FBI Director James Comey. But this language is neither accurate nor wise — and it is important to say so.

Once the software is written, the U.S. government can hardly argue it will never be used again, nor that it will never be stolen off government servers. And since the point of the hack is to be able to push it onto a phone without consent (which is itself a backdoor that needs closing), this software would allow breaking the locks on any susceptible iPhone, anywhere. Many commentators have observed that any effort to hack iOS this once would facilitate repetitions, and any general weakening of smartphone security could easily be exploited by governments or groups less concerned about due process, privacy, or human rights. (And you do have to wonder whether Tim Cook's position here is influenced by his experience as a gay man, a demographic that has been persecuted, if not actually prosecuted, merely for thought and intent by the same organization now sitting on the other side of the table. He knows a thing or two about privacy.)  U.S. Senator Ron Wyden has a nice take on these issues. Yet while these are critically important concerns for modern life, they are shortsighted. There is much more at stake here than just one phone, or even the fate of a one particular company. The bigger, longer term issue is whether governments should have access to electronic devices that we rely on in daily life, particularly when those devices are becoming extensions of our bodies and brains. Indeed, these devices will soon be integrated into our bodies — and into our brains.

Hacking electronically-networked brains sounds like science fiction. That is largely because there has been so much science fiction produced about neural interfaces, Matrices, and the like. We are used to thinking of such technology as years, or maybe decades, off. But these devices are already a reality, and will only become more sophisticated and prevalent over the coming decades. Policy, as usual, is way behind.

My concern, as usual, is less about the hubbub in the press today and instead about where this all leads in ten years. The security strategy and policy we implement today should be designed for a future in which neural interfaces are commonplace. Unfortunately, today's politicians and law enforcement are happy to set legal precent that will create massive insecurity in just a few years. We can be sure that any precedent of access to personal electronic devices adopted today, particularly any precedent in which a major corporation is forced to write new software to hack a device, will be cited at least decades hence, when technology that connects hardware to our wetware is certain to be common. After all, the FBI is now proposing that a law from 1789 applies perfectly well in 2016, allowing a judge to "conscript Apple into government service", and many of our political representatives appear delighted to concur. A brief tour of current technology and security flaws sets the stage for how bad it is likely to get.

As I suggested a couple of years ago, hospital networks and medical devices are examples of existing critical vulnerabilities. Just in the last week hackers took control of computers and devices in a Los Angeles hospital, and only a few days later received a ransom to restore access and functionality. We will be seeing more of this. The targets are soft, and when attacked they have little choice but to pay when patients' health and lives are on the line. What are hospitals going to do when they are suddenly locked out of all the ventilators or morphine pumps in the ICU? Yes, yes, they should harden their security. But they won't be fully successful, and additional ransom events will inevitably happen. More patients will be exposed to more such flaws as they begin to rely more on medical devices to maintain their health. Now consider where this trend is headed: what sorts of security problems will we create by implanting those medical devices into our bodies?

Already on the market are cochlear implants that are essentially ethernet connections to the brain, although they are not physically configured that way today. An external circuit converts sound into signals that directly stimulate the auditory nerves. But who holds the password for the hardware? What other sorts of signals can be piped into the auditory nerve? This sort of security concern, in which networked electronics implanted in our bodies create security holes, has actually been with us for more than a decade. When serving as Vice President, Dick Cheney had the wireless networking on his fully-implanted heart defibrillator disabled because it was perceived as a threat. The device contained a test mode that could exploited to fully discharge the battery into the surrounding tissue. This might be called a fatal flaw. And it will only get worse.

DARPA has already limited the strength of a recently developed, fully articulated bionic arm to "human normal" precisely because the organization is worried about hacking. These prosthetics are networked in order to tune their function and provide diagnostic information. Hacking is inevitable, by users interested in modifications and by miscreants interested in mischief.

Not content to replace damaged limbs, within the last few months DARPA has announced a program to develop what the staff sometimes calls a "cortical modem". DARPA is quite serious about developing a device that will provide direct connections between the internet and the brain. The pieces are coming together quickly. Several years ago a patient in Sweden received a prosthesis grafted to the bone in his arm and controlled by local neural signals. Last summer I saw Gregoire Courtine show video of a monkey implanted with microfabricated neural bridge that spanned a severed spinal cord; flip a switch on and the monkey could walk, flip it off and the monkey was lame. Just this month came news of an implanted cortical electrode array used to directly control a robot arm. Now, imagine you have something like this implanted in your spine or head, so that you can walk or use an arm, and you find that the manufacturer was careless about security. Oops. You'll have just woken up — unpleasantly — in a William Gibson novel. And you won't be alone. Given the massive medical need, followed closely by the demand for augmentation, we can expect rapid proliferation of these devices and accompanying rapid proliferation of security flaws, even if today they are one-offs. But that is the point; as Gibson has famously observed, "The future is already here — it's just not evenly distributed yet."

When — when — cortical modems become an evenly distributed human augmentation, they will inevitably come with memory and computational power that exceeds the wetware they are attached to. (Otherwise, what would be the point?) They will expand the capacity of all who receive them. They will be used as any technology is, for good and ill. Which means they will be targets of interest by law enforcement and intelligence agencies. Judges will be grappling with this for decades: where does the device stop and the human begin? ("Not guilt by reason of hacking, your honor." "I heard voices in my head.") And these devices will also come with security flaws that will expose the human brain to direct influence from attackers. Some of those flaws will be accidents, bugs, zero-days. But how will we feel about back doors built in to allow governments to pursue criminal or intelligence investigations, back doors that lead directly into our brains? I am profoundly unimpressed by suggestions that any government could responsibly use or look after keys to any such back door.

There are other incredibly interesting questions here, though they all lead to the same place. For example, would neural augmentation count as a medical device? If so, what does the testing look like? If not, who will be responsible for guaranteeing safety and security? And I have to wonder, given the historical leakiness of backdoors, if governments insist on access to these devices who is going to want to accept liability inherent in protecting access to customers' brains? What insurance or reinsurance company would issue a policy indemnifying a cortical modem with a known, built-in security flaw? Undoubtably an insurance policy can be written that exempts governments from responsibility for the consequences of using a backdoor, but how can a government or company guarantee that no one else will exploit the backdoor? Obviously, they can do no such thing. Neural interfaces will have to be protected by maximum security, otherwise manufacturers will never subject themselves to the consequent product liability.

Which brings us back to today, and the precedent set by Apple in refusing to make it easy for the FBI to hack an iPhone. If all this talk of backdoors and golden keys by law enforcement and politicians moves forward to become precedent by default, or is written into law, we risk building security holes into even more devices. Eventually, we will become subject to those security holes in increasingly uncomfortable, personal ways. That is why it is important to support Tim Cook as he defends your brain.