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.

Staying Sober about Science

The latest issue of The Hastings Center Report carries an essay of mine, "Staying Sober about Science" (free access after registration), about my thoughts on New Directions: The Ethics of Synthetic Biology and Emerging Technologies (PDF) from The Presidential Commission for the Study of Bioethical Issues.

Here is the first paragraph:

Biology, we are frequently told, is the science of the twenty-first century. Authority informs us that moving genes from one organism to another will provide new drugs, extend both the quantity and quality of life, and feed and fuel the world while reducing water consumption and greenhouse gas emissions. Authority also informs that novel genes will escape from genetically modified crops, thereby leading to herbicide-resistant weeds; that genetically modified crops are an evil privatization of the gene pool that will with certainty lead to the economic ruin of small farmers around the world; and that economic growth derived from biological technologies will cause more harm than good. In other words, we are told that biological technologies will provide benefits and will come with costs--with tales of both costs and benefits occasionally inflated--like every other technology humans have developed and deployed over all of recorded history.

And here are a couple of other selected bits:

Overall, in my opinion, the report is well considered. One must commend President Obama for showing leadership in so rapidly addressing what is seen in some quarters as a highly contentious issue. However, as noted by the commission itself, much of the hubbub is due to hype by both the press and certain parties interested in amplifying the importance of the Venter Institute's accomplishments. Certain scientists want to drive a stake into the heart of vitalism, and perhaps to undermine religious positions concerning the origin of life, while "civil society" groups stoke fears about Frankenstein and want a moratorium on research in synthetic biology. Notably, even when invited to comment by the commission, religious groups had little to say on the matter.

The commission avoided the trap of proscribing from on high the future course of a technology still emerging from the muck. Yet I cannot help the feeling that the report implicitly assumes that the technology can be guided or somehow controlled, as does most of the public discourse on synthetic biology. The broader history of technology, and of its regulation or restriction, suggests that directing its development would be no easy task.8 Often technologies that are encouraged and supported are also stunted, while technologies that face restriction or prohibition become widespread and indispensable.

...The commission's stance favors continued research in synthetic biology precisely because the threats of enormous societal and economic costs are vague and unsubstantiated. Moreover, there are practical implications of continued research that are critical to preparing for future challenges. The commission notes that "undue restriction may not only inhibit the distribution of new benefits, but it may also be counterproductive to security and safety by preventing researchers from developing effective safeguards."12 Continued pursuit of knowledge and capability is critical to our physical and economic security, an argument I have been attempting to inject into the conversation in Washington, D.C., for a decade. The commission firmly embraced a concept woven into the founding fabric of the United States. In the inaugural State of the Union Address in 1790, George Washington told Congress "there is nothing which can better deserve your patronage than the promotion of science and literature. Knowledge is in every country the surest basis of publick happiness."13

The pursuit of knowledge is every bit as important a foundation of the republic as explicit acknowledgment of the unalienable rights of life, liberty, and the pursuit of happiness. Science, literature, art, and technology have played obvious roles in the cultural, economic, and political development of the United States. More broadly, science and engineering are inextricably linked with human progress from a history of living in dirt, disease, and hunger to . . . today. One must of course acknowledge that today's world is imperfect; dirt, disease, and hunger remain part of the human experience. But these ills will always be part of the human experience. Overall, the pursuit of knowledge has vastly improved the human condition. Without scientific inquiry, technological development, and the economic incentive to refine innovations into useful and desirable products, we would still be scrabbling in the dirt, beset by countless diseases, often hungry, slowly losing our teeth.

There's more here.

References:

8. R. Carlson, Biology Is Technology: The Promise, Peril, and New Business of Engineering Life (Cambridge, Mass.: Harvard University Press, 2010).

12. Presidential Commission for the Study of Bioethical Issues, New Directions, 5.

13. G. Washington, "The First State of the Union Address," January 8, 1790, http://ahp.gatech.edu/first_state_union_1790.html.

Shame On You, Portland!

What Happened to March?  I got on a plane this morning headed for New York, but somehow arrived on April 1st.  It's the only explanation for this:

Portland hurts Tibetans
(China Daily)
Updated: 2010-03-11 07:51

While many in the international community are watching with anxiety to see if Washington moves to repair its ties with Beijing, a reckless decision by an American city is rubbing salt into the unhealed wound of the world's most important bilateral relations.

The city of Portland, Oregon, proclaimed Wednesday, March 10, their "Tibet Awareness Day" despite strong opposition from the Chinese government.

While most people and most countries in the world recognize Tibet as part of China, the decision by the American city interferes in China's internal affairs and is an open defiance of China's state sovereignty.

It could have an adverse effect on Sino-US relations, which has yet to recover from major deterioration following Washington's $6.4-billion arms sale to Taiwan and US President Barack Obama's meeting with the Dalai Lama.

The designation of the "Tibet Awareness Day" was apparently orchestrated by the Dalai Lama clique, which has been engaged in activities aimed to separate China and undermine Tibet's stability in the guise of religion.

It is still beyond our belief that politicians in Portland have chosen to celebrate a handful of fanatics trumpeting Tibet independence while turning a blind eye to either history or the status quo of present-day Tibet. History has told us that Tibet has always been a part of China, and there is ample evidence proving the fact that Tibetan people now enjoy a much better life and enjoy the full freedom of religion.

Americans are well-known for putting individual freedom above everything. While the city of Portland entertains a few Tibet separatists, has it ever occurred to its decision-makers that their move are infringing on the interest of 2.8-million Tibetans here in China?

Whither Gene Patents?

Wired and GenomeWeb (subscription only) have a bit of reporting on arguments in a case that will probably substantially affect patents on genes.  The case is Association of Molecular Pathology , et al. v. US Patent and Trademark Office, otherwise known as "the BRCA1 case", which seeks to overturn a patent held by Myriad Genetics on a genetic sequence correlated with breast cancer.

Here is a brief summary of what follows: I have never understood how naturally occurring genes can be patentable, but at present patents are the only way to stake out a property right on genes that are hacked or, dare I say it, "engineered".  So until IP law is changed to allow some other form of protection on genes, patents are it.

The ACLU is requesting a summary judgment that the patent in question be overturned without a trial.  Success in that endeavor would have immediate and enormous effect on the biotech industry as a whole, and I doubt the ACLU is going to get that in one go.  (Here is the relevant recent ACLU press release.)

However, the lawsuit explicitly addresses the broader question of whether any patents should have been granted in the first place on human genes.  This gets at the important question of whether isolating and purifying a bit of natural DNA counts as an invention.  Myriad is arguing that moving DNA out of the human genome and into a plasmid vector counts as sufficient innovation.  This has been at the core of arguments supporting patents on naturally occurring genes for decades, and it has never made sense to me for several reasons.  First, changing the context of a naturally occurring substance does not constitute an invention -- purifying oxygen and putting it in a bottle would never be patentable.  US case law is very clear on this matter.  Second, moving the gene to a new context in a plasmid or putting into a cell line for expression and culturing doesn't change its function.  In fact, the whole point of the exercise would be to maintain the function of the gene for study, which is sort of the opposite of invention.  Nonetheless, Myriad wants to maintain its monopoly.  But their arguments just aren't that strong.

GenomeWeb reports that defense attorney Brian Poissant, argued that "'women would not even know they had BRCA gene if it weren't discovered'under a system that incentivizes patents."  This is, frankly, and with all due respect, a manifestly stupid argument.  Mr. Poissant is suggesting that all of science and technology would stop without the incentive of patents.  Given that most research doesn't result in a patent, and given that most patent application are rejected, Mr. Poissant's argument is on its face inconsistent with reality.  He might have tried to argue more narrowly that developing a working diagnostic assays requires a guarantee on investment through the possession of the monopoly granted by a patent.  But he didn't do that.  To be sure, the assertion that the particular gene under debate in this case would have gone undiscovered without patents is an untestable hypothesis.  But does Mr. Poissant really want the judge to believe that scientists around the world would have let investigation into that gene and disease lie fallow without the possibility of a patent?  As I suggested above, it just isn't a strong argument.  But we can grind it further into the dust.

Mr. Poissant also argued "that if a ruling were as broadly applied here as the ACLU would like then it could 'undermine the entire biotechnology sector.'"  This is, at best, an aggressive over generalization.  As I have described several times over the past couple of years (here and here, for starters), even drugs are only a small part of the revenues from genetically modified systems.  Without digging into the undoubtedly messy details, a quick troll of Google suggests that molecular diagnostics as a whole generate only $3-4 billion a year, and at a guess DNA tests are probably a good deal less than half of this.  But more importantly, of the nearly ~2% of US GDP (~$220-250 billion) presently derived from biological technologies, the vast majority are from drugs, plants, or bacteria that have been hacked with genes that themselves are hacked.  That is, both the genes and the host organisms have been altered in a way that is demonstrably dependent on human ingenuity.  What all this means is that only a relatively small fraction of "the entire biotechnology sector" is related to naturally occurring genes in the first place.   

I perused some of the court filings (via the Wired article), and the defense needs to up its game.  Perhaps they think the weight of precedent is on their side.  I would not be as confident as they are. 

But neither is the plaintiff putting its best foot forward.  Even though I like the analysis made comparing DNA patents to attempts to patent fresh fruit, it is unclear to me that the ACLU is being sufficiently careful with both its logic and its verbiage.  In the press release, ACLU attorey Chris Hansen is quoted as saying "Allowing patents on genetic material imposes real and severe limits on scientific research, learning and the free flow of information."  GenomeWeb further quotes the ACLU's Hansen as saying "Patenting human genes is like patenting e=mc2, blood, or air."

As described above, I agree that patenting naturally occurring genes doesn't make a lot of sense.  But we need some sort of property right as an incentive for innovators.  Why should I invest in developing a new biological technology, relying on DNA sequences that have never occurred in nature, if anybody can make off with the sequence (and revenues)?  As it happens, I am not a big fan of patents -- they cost too damn much.  At present, the patent we are pursuing at Biodesic is costing about ten times as much as the capital cost of developing the actual product.  Fees paid to lawyers account for 90% of that.  If it were realistically possible to engage the patent office without a lawyer, then the filing fees would be about the same as the capital cost of development, which seems much more reasonable to me.

I go into these issues at length in the book.  Unfortunately, without Congressional action, there doesn't seem to be much hope for improvement.  And, of course, the direction of any Congressional action will be dominated by large corporations and lawyers.  So much for the little guy.