Myriad's Lawyers Want to Patent the Periodic Table

Interesting arguments today before a Federal Appeals Court concerning the "BRCA 1/2" patents.  Recall first that the U.S. Government has filed an amicus brief supporting the trial judge's ruling that naturally-occurring genes cannot be patented (see "Big Gene Patent (Busting) News???" and "Surprise Outbreak of Common Sense in Washington DC").

The Appellate Court is going to decide whether two genes (BRCA 1 and 2), in which mutations are correlated with breast cancer, can be patented.  Myriad Genetics and its lawyers say yes, the ACLU and several groups representing patients, scientists, and clinicians say no.  So did the trial judge.  The basic argument is about whether a naturally-occurring gene sequence that is used in a diagnostic test can be considered an invention.

Nature's The Great Beyond blog has a bit of reporting from yesterday's proceedings.  There is a passage from the blog post I think is worth exploring a bit further for the way the litigants and the judges are talking about the nature of DNA and the nature of elements such as lithium:

Both the lawyers and the judges repeatedly compared the case to efforts to extract a valuable mineral from the ground.

"Why isn't the ingenuity [that justifies patentability] the process of extracting [the mineral]" rather than in the mineral itself, [Judge Kimberly Moore] asked [defendent's attorney Greg] Castanias. "God made it. Man didn't make it."

Castanias retorted: "What we have here are new tools [that are] the products of molecular biologists. They are not the products of nature. They are not the products of God."

If that's the case, [Judge William Bryson] pushed Castanias, are you saying that isolation of pure lithium is properly an invention?

"Yes," the lawyer replied.

That is extraordinary.  Castanias' assertion is contrary to more than a century of U.S. case law and administrative rulings by the USPTO.  Products of nature are explicitly excluded in laws, rulings, and administrative decisions from coverage by patents.  Castanias wants the Appellate Court to rule that the elements in the periodic table, along with any other naturally-occurring substance, are in fact patentable.

The mind boggles.  Following Castanias' reasoning pure oxygen, pure water, and pure gold could all be patented because some process was employed for purification.  If this sort of argument held sway, you could even patent the moon because you require a human invention to go visit and nab a piece of it.  Yes, yes, I know that other inconvenient case law would get in the way of patenting a celestial body, which really doesn't make any sense anyway.  But that is the point.  The trial judge in this case was actually the first to issue a ruling that patents on naturally-occurring genetic sequences are prohibited by law (see "Big Gene Patent (Busting) News???").

This argument revolves in part around the nature of DNA.  Here is another excerpt from the Nature blog post:

Chris Hansen, a staff attorney with the ACLU, told the judges: "Myriad's entire business is built on the proposal that isolated DNA and [naturally occurring] DNA are identical." They don't write to patients with their test results, saying: "You've got a mutation in your isolated DNA but I have no idea what's going on in your body," he said.

Judge William Bryson countered that the act of isolating DNA involves breaking covalent bonds, thus creating a product that does not exist in nature.

"With respect, your honor, I think not," Hansen replied. "DNA is DNA."

But Greg Castanias, a lawyer with the Jones Day firm in Washington DC who represented the defendants, begged to differ. "Isolated DNA does not exist in nature," and wouldn't exist at all without human ingenuity, he said. The entire biotechnology industry, he added, is built on interpreting existing law to say that DNA isolation is sufficient to show the human invention that is required for a patent.

I found the language quoted to be quite interesting.  The notion that "isolated DNA does not exist in nature" is based on the defendants' definition of "isolated DNA".  Judge Sweet spent three pages of his original decision dealing with Myriad's assertions about "isolated DNA", but it is hard to know from the Nature blog post whether this was part of yesterday's conversation.  Here is Judge Sweet's definition (p. 92 of his decision): "Isolated DNA is therefore construed to refer to a segment of DNA nucleotides existing separate from other cellular components normally associated with native DNA, including proteins and other DNA sequences comprising the remainder of the genome, and includes both DNA originating from a cell as well as DNA synthesized through chemical or heterologous biological means".

This is quite close to Myriad's definition of "isolated DNA", but Judge Sweet still found that because the isolated DNA is the same sequence, and therefore conveys the same information, as the sequence in vivo, it cannot be patented because it is a product of nature.

Incidentally, the definition of isolated DNA given above appears to include DNA that is free in the environment.  Free DNA is found in marine and terrestrial environments.  That DNA can be taken up by other organisms via horizontal gene transfer, which means that free DNA is perfectly funtional.  Here, for example, is an interesting little study looking at the uptake of free DNA by aquatic bacteria.

The point being that humans did not invent DNA that is "separate from other cellular components".  Humans may have invented processes to concentrate and purify DNA, or to extract DNA from complex structures, but that does not mean that isolated DNA is itself a human invention.

Video from "Preserving National Security: The Growing Role of the Life Sciences"

A couple of weeks ago I spoke at an event run by the UPMC Center for Biosecurity, Preserving National Security: The Growing Role of the Life Sciences.  Here is the video of my presentation, followed by Roger Breeze, with an introduction by Gigi Gronvall.  There is a short panel discussion at the end of the clip.  Video of the rest of the meeting is also online, along with a conference report (PDF).

Ice Loss Acceleration in Antarctica and Greenland

This month's Geophysical Research Letters brings more ice sheet melting data to be concerned about.  A paper by Eric Rignot and colleagues at JPL, Caltech, UC Irvine, and Utrecht University demonstrates the "Acceleration of the contribution of the Greenland and Antarctic ice sheets to sea level rise".  Here is a nice summary at ScienceDaily that goes into some broader implications for sea level rise.  In addition to putting a bunch of nice data and analysis on the table, Rignot et al will contribute substantially to a broader understanding of the overall ice/water system near the poles.

The paper describes work integrating a variety of methods to build up a two decade-long picture of ice mass loss in Antarctica and Greenland.  The numbers by themselves are pretty impressive: the ice sheet loss rate was ~478 Gigatons/year in 2006, with an acceleration of ~36 Gigatons/year^2.  Note that this means the acceleration is 7.5% of the rate -- in other words, ice sheet mass loss is speeding up at a remarkable clip for a process that is ongoing at continental length-scales.  Notably, the authors report a very small uncertainty in the acceleration (about 5%), which means that we can be quite certain there is a large non-linear contribution that is reducing ice sheet mass (one that is proportional to time^2).

Here are a few tidbits that are not in the paper or associated press stories.  I wrote to Dr. Rignot to satisfy my curiosity about a couple of points, and he graciously responded and gave me permission to quote the emails here.

First, after staring at the ice loss rate and acceleration data for a little while, I got to wondering why the authors extracted a linear change in the rate of ice loss, which results in a constant acceleration.  Given the data, you might wonder whether the acceleration was actually increasing rather than being a constant.  In our brief email exchange, Dr. Rignot said that while the linear fit was the simplest fit, it appears that, in fact, the acceleration is increasing in Antarctica (no word from Dr. Rignot about Greenland).  The team is going to wait for a few more years worth of data -- to increase their certainty and better constrain the statistical significance -- before they talk more about it.

This is pretty important.  We are talking about adding a highly non-linear term to models of the total ice sheet mass, one that is proportional to (time^3).  Depending on the size of the change in acceleration, this could radically change estimates of sea level rise from melting.

The present paper already demonstrates that ice sheet loss will account for substantially more sea level rise than is included in the IPCC models.  In addition, the authors observe that increased mass loss is likely to lead to a substantial increase in the speed at which glaciers deliver ice to nearby water, something that is not adequately addressed (or is simply not included, if you are following that story) in IPCC forecasts.

Perhaps it is time to revisit investing in water wings.

An Engineered Bug that Produces Isobutanol from Cellulose

This morning, Tom Murray at The Hastings Center pointed me to a new paper from James Liao's lab at UCLA demonstrating the first engineered bug that produces isobutanol from cellulose.  Wendy Higashide, et al, ported the artificial butanol synthesis pathway from the group's earlier work in E. coli (see this previous post) into Clostridium cellulolyticum.  Here is the article.

Recall that butanol is a much better biofuel than is ethanol.  Butanol is also not hygoscopic (doesn't suck up water), which means it can be blended at any point in the distribution chain, whereas ethanol must be trucked/barged/piped in dedicated infrastructure until just upstream of a gas station in order to avoid pulling contaminating water into the fuel stream.  Butanol has a long history of use as a transportation fuel, and has been demonstrated to be a drop in replacement for gasoline in existing engines.  See, for example, the work of the 2007 iGEM team from Alberta, and my earlier post "A Step Toward Distributed Biofuel Production?"  One advantage of making butanol instead of ethanol is that butanol spontaneously phase separates from water (i.e., it floats to the top of the tank) at concentrations above about 7.5% by volume, which substantially reduces the energy required to separate the molecule for use as a fuel.

The press release accompanying the Higashide paper describes the work as a "proof of concept".  The team attempted to insert the butanol synthesis pathway into a Clostridum strain isolated from decaying grass -- a strain that naturally consumes cellulose.  Unfortunately, this Clostridium strain is not as well characterized as your average lab strain of coli, nor does it have anywhere near the same number of bells, knobs, and whistles for controlling the inserted metabolic genes.  The short summary of the paper is that the team managed to produce 660 mg of butanol per liter of culture.  This is only about 0.07% by volume, or ~100 times below the concentration at which butanol phase separates from water.  The team lays out a number of potential routes to improving this yield, including better characterization of the host organism, or simply moving to a better characterized organism.

So, a nice proof of principle.  This is exactly the sort of technological transformation I discuss in my book.  But this proof of concept is not anywhere near being economically useful or viable.  Nonetheless, this progress demonstrates the opportunities ahead in relying on biology for more of our industrial production.

Ah, technology...

I just finished addressing a meeting in Islamabad, Pakistan -- Synthetic Biology and its Dual Use.  I was scheduled to give my talk via two-way video teleconference that turned out to be ... one-way.  So rather than being able to interact with my audience, I had to simply page through my presentation on my end and hope they were still listening.  I was basically practicing my talk, except there was a live video connection to the other side of the world.  Very strange.

Garage Innovation and Recreational Drugs

(12 July, 2012: Updated with a few comments on recent US efforts to ban synthetic drugs.)

When a carpenter turns to chemistry to pay the rent, you can be certain innovation has been democratized.  As told by Jeanne Whalen in The Wall Street Journal, chemo-entrepreneur David Llewellyn found it an easy transition to begin making recreational drugs when his construction business tanked.  Llewellyn specializes in making "legal high" drugs for sale in Europe, always ready to move onto the next compound when authorities ban whatever he has been selling.  And he intends to keep operating that way: "Everything we sell is legal. I don't want to go to jail for 14 years."  This story has interesting implications for anyone interested in the future of synthetic biology, and in particular those who feel that regulating access to tools, skills, and materials will lead to a safer world.  But I will get to that later.

Welcome to the real world, Neo.  And to the spotlight.

Mr. Llewellyn looks to academic literature for inspiration for the next drug, and the WSJ named Purdue chemist David Nichols' papers as the source of several such drugs.  The WSJ article led Nichols to pen an essay for the 6 January issue of Nature entitled "Legal highs: the dark side of medicinal chemistry".  He writes: "Although some of my results have been, shall we say, abused, one cannot know where research ultimately will lead. I strive to find positive things, and when my research is used for negative ends it upsets me."  The essay constitutes a bit of soul searching, with an unspoken conclusion that he is doing the best he can to try to make the world a better place.  Here is NPR's version of a subsequent AP story on Professor Nichols.

Underlying the Professor's discomfort is that simple fact that science, as a method and as information, is value neutral.  By this I mean that regardless of what prompted a particular line of research (which might, in fact, be motivated by particular values), the resulting information is neither good nor bad.  It is just information.  That said, obviously that information will be used by humans for both good and bad ends.  This is about as close as I can get to a statement of fundamental human nature.  Humans will do good things and they will do bad things -- just as we always have -- with "good" and "bad" of course being highly contingent definitions.

The world we live in is dirty, full of disease and despair, and some people have no problem contributing to the mess.  It is very easy to sometimes forget this when working within a university.  But Science (with a capital "S", please) is just another human institution, inhabiting that same dirty world.  Anyone who does anything that hurts another person in today's world is likely using some bit of science or technology invented by somebody who was attempting to improve the world.  Pointing a finger at Professor Nichols as the source of information used to manufacture drugs that cause harm is like pointing a finger at whomever invented the screwdriver as the source of suicide bombers, or like pointing a finger at Isaac Newton as the source of ballistic missiles.  Academic publishing makes it easy to trace Professor Nichols by his research, and thus to point a finger at him, but that completely misses the point and is a distraction.

Laboratory-Adept Entrepreneurs: Just Trying to Pay the Rent

For his own part in this story, David Llewellyn is self-cast as a bit of a underdog trying to make an interesting living while keeping just this side of today's definition of "good".  From Ms. Whalen's WSJ article:

Mr. Llewellyn is part of a wave of laboratory-adept European entrepreneurs who see gold in the gray zone between legal and illegal drugs. They pose a stiff challenge for European law-enforcement, which is struggling to keep up with all the new concoctions. Last year, 24 new "psychoactive substances" were identified in Europe, almost double the number reported in 2008, according to the Lisbon-based European Monitoring Centre for Drugs and Drug Addiction, or EMCDDA.

As he scurries to stay ahead of the law, authorities have put speed bumps, not roadblocks, in his path. Mr. Llewellyn says Belgian customs officials recently raided one of his storehouses and seized his chemicals, threatening to use environmental laws to shut him down. And he says he may have to move one of his production labs from the Netherlands because authorities there are planning to outlaw the use of certain lab equipment without a professional license.

...Other than that, however, Mr. Llewellyn's business is cruising along largely unimpeded. He and eight employees make drugs in a pair of "underground" labs--one in Holland and a new, $190,000 lab in Scotland.

If you are inclined to believe that it should be easy to solve problems through regulation or licensing, the very existence of Mr. Llewellyn's operation might give you pause.  If the Belgian authorities threaten to shut him down with environmental laws, it isn't going to be that hard to get them to go away because so many other "legitimate" businesses somehow manage to comply with those same environmental laws even while using the same raw materials -- and the "legitimate" companies are probably managing this with much lower profit margins.  Or perhaps governments could attempt to impose license restrictions on anyone using a particular material or laboratory instrument, but then of course they would be imposing those costs on all such users, "legitimate" or otherwise.  Finally, you might hope to directly stop Mr. Llewellyn from making or selling his wares.  And then you would fail outright, because there are so many potential compounds of interest that the regulations would have to restrict making anything that might someday be found to possibly cause harm to humans.  And that would shut down the entire chemical industry, and thus the entire economy.

(Update: Wired is reporting that a ban on certain synthetic drugs signed into law by President Obama in June of 2012 has already been made obsolete -- within a few weeks -- by new compounds not covered by the law.  Senator Charles Schummer called the law "the final nail in the coffin for the legal sale of bath salts."  Not so much, I guess.)

Trouble for a Nose

Mr. Llewellyn describes Nopaine, a chemical derivative of Ritalin, as "every bit as good as cocaine. You can freebase it. You can snort it like crack."

Whatever one thinks of Mr. Llewellyn's product guarantees, or of his marketing copy, he might be right.  Nopaine might be as "good" as cocaine.  Or it might, as is the concern of Professor Nichols, cause death, liver cancer, or other long-term damage.  But Mr. Llewellyn can make it to market with a synthetic compound created in his "underground lab" without having to find out whether it is good or bad.

Whether you like it or not, innovation of this sort is here to stay.  It may be hard these days to buy a chemistry set for your kid that is in any way interesting, but it is demonstrably easy to incorporate and get one's mitts on enough information and raw materials to synthesize compounds new to science.  And even if this becomes hard in any particular country, the general problem of widely accessible information and infrastructure is here to stay.       

Many of the "legal highs" evidently come from China, as must some of the raw materials used by Mr. Llewellyn and his ilk.  Ms. Whalen's earlier article "Designer Drugs Baffle Europe", from July of 2010, notes that in China "lax control of chemicals makes it easier for manufacturers to obtain the raw ingredients."  Her later article suggests that China is attempting to control the manufacture and sale of some new compounds, but I am not sure I have much confidence in that effort.  If it becomes too annoying (and it will never be more than annoying for those interested in making and selling drugs) to operate in China, or somewhere in Eastern Europe, they will pick up and move elsewhere.  And they will still have access to international markets wherever they go.  Our policy may be to fight them, to chase them away, but we will never fully prevail.

Which brings us back to definitions of "good" and "bad".  "Bad" Mr. Llewellyn isn't acting alone; he has "bad" customers.  Their aggregate demand supports the market.  (Oh, and wait a moment -- what Mr. Llewellyn is doing is actually legal, so therefore it is "good"?)  Unless governments somehow come up with a way to keep people from imbibing "bad" substances, defined as "bad" on any given day, the demand for those substances isn't going away.

Chemistry Today, Biology Tomorrow

There was a time when synthetic chemistry was not so easy.  And then some time passed, and now today we can order novel psychoactive drugs over the Internet.  Or make them ourselves.

Today it is hard to build a genetic circuit that does exactly what you want.  Synthetic biology is in its infancy.  Yet it is already possible to outfit a lab in your garage (at least in the US) that is sufficient to do all kinds of interesting things.  And if you don't have room in your garage, then you can stroll down to the corner DNA hackspace.  (Update: Genspace's Dan Grushkin wrote in to observe that I have unintentionally juxtaposed drug production and Genspace in an unfortunate way, which was of course not my intent at all.  Note that I did this to myself, too, as one of the former examples was my own garage lab.)  Access to tools doesn't make molecular biology easy, but it does give you the opportunity to learn, and perhaps to innovate.

And thus people will innovate with biological tools and information just as they have with everything else.  That innovation will be "good", and it will be "bad".  Regulation will not be a panacea for biological technologies, and will not necessarily make the world a safer place, just as regulation fails in the case of chemistry.  As I argued last month in Garage Innovation in The Scientist, restriction of access will always produce perverse incentives when there is an "attempt to control tools and skills in the context of a market in which consumers are willing to pay prices that support use of those tools and skills".

I am reminded of my experience last year at a warm-up meeting for the 2011 Review Conference for the Biological Weapons Convention.  At one point in the discussion, one delegate asserted that "garage or DIYBio is only a problem in the US.  In our country it is illegal to do such things."

I wonder if this delegate knows whether or not a chemo-entrepreneur has an "underground lab" next door?

"Garage Innovation" in The Scientist

My column in this month's The Scientist is now available online.  "Garage Innovation" was written based on my presentation to the Presidential Commission on for the Study of Bioethical Issues and my experience over the last few years navigating discussions on regulating biological technologies.

I had to write the piece without having access to the Commission's recommendations, and relying instead on press reports of what Commission members said about the draft.  Now that I have perused the report (BIG PDF), I mostly like what I see.  Here is the relevant press release.  I'll have something more on the report after I have a chance to sit down and fully digest it.

Favorite Books of 2010

Biology is Technology is on the favorite books of 2010 list at Foreign Policy:

Mankind is at the threshold of a new leap forward in our understanding of how life works, and this book shines a light on the path ahead by approaching the subject as a series of engineering and technology problems. The book is sophisticated, clear, and eye-opening in explaining the promise, and peril, of a profound revolution in genetics and molecular biology.