(Cross-posted from synthesis.)

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.

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?
(Cross-posted from synthesis.)

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.  But not anywhere near being economically useful or viable.  Nonetheless, this sort of progress demonstrates the opportunities ahead in relying on biology for more of our industrial production.

Book Availability

| No Comments | No TrackBacks
Hardback copies are again showing up at Amazon, though in small numbers.  I just received the first paperback copy from Harvard Press.  Should be available soon at bookstores and Amazon etc for $14-16.

"Essential Reading"

| No Comments | No TrackBacks
Chemistry World says Biology is Technology is "essential reading for anyone wishing to understand the current state of biotechnology/synthetic biology and the opportunities/dangers therein."

Fine PROSE

| No Comments | No TrackBacks
Biology is Technology won the American Publishers PROSE award for best Engineering and Technology book of 2010.

Hardback Sold Out: Kindle Edition Finally Here

| No Comments | No TrackBacks
The hardback edition of Biology is Technology evidently sold out at Amazon over the holidays.  My thanks to everyone who bought a copy -- I trust you will enjoy it.  The paperback edition is due out in a couple of months, and to my pleasant surprise the Kindle edition just became available.

"Favorite books of 2010" list at Foreign Policy

| No Comments | No TrackBacks
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.

Page Turner

| No Comments | No TrackBacks

Chapter 1

| No Comments | No TrackBacks
What Is Biology?

Biology is technology. Biology is the oldest technology. Throughout the history of life on Earth, organisms have made use of each other in sophisticated ways. Early on in this history, the ancestors of both plants and animals co-opted free-living organisms that became the subcellular components now called chloroplasts and mitochondria. These bits of technology provide energy to their host cells and thereby underpin the majority of life on this planet.

It's a familiar story: plants, algae, and cyanobacteria use sunlight to convert carbon dioxide into oxygen. Those organisms also serve as food for a vast pyramid of herbivores and carnivores, all of whom produce carbon dioxide and other wastes that plants then use as resources.

Interactions between organisms constitute a global natural economy that moves resources at scales from the molecular to the macroscopic, from a few nanometers (10-9) to many megameters (106). Humans have always explicitly relied on this biological economy to provide food, oxygen, and other services. Until recently, our industrial economy relied primarily on nonbiological technologies; the industrial revolution was built primarily on fire, minerals, and chemistry. Now, however, our economy appears to be changing rapidly, incorporating and relying upon new organisms whose genomes have been modified through the application of human effort and ingenuity.

In 2007, revenues in the United States resulting from genetic modification of biological systems were the equivalent of almost 2 percent of gross domestic product (GDP). The total includes all the products we include under the moniker "biotechnology"--drugs, crops, materials, industrial enzymes, and fuels (see Chapter 11). Compare that 2 percent to the percent added in 2007to GDP from the following sectors: mining, 2 percent; construction, 4.1 percent; information and broadcasting, 4.7 percent; all of manufacturing, 11.7 percent; transportation and warehousing, 2.9 percent; finance, 20.7 percent; and all of government, 12.6 percent. [1] (One might expect the contribution from finance to be somewhat smaller in the future.)
 
While still modest in size compared with other sectors, biotech revenues are growing as fast as 20 percent annually. Moreover, the sector is extremely productive. During the years 2000-2007, the U.S. economy expanded by about $4 trillion, and biotech revenues grew by almost $200 billion.

Biotechnology companies currently employ about 250,000 people in the United States, out of a total labor force of 150 million. [2] Therefore, less than one-sixth of 1 percent of the national workforce generated approximately 5 percent of U.S. GDP growth during those seven years.  Despite the fact that the underlying technology is presently immature compared with other sectors of the economy, current biotechnology demonstrates impressive and disproportionate economic performance.

Rapid revenue growth in the sector is the result of new products that create new markets, such as drugs and enzymes that help produce fuels. It also comes from displacing products made using older industrial methods. Bioplastics that started entering the market in 2007 and 2008 appear to require substantially less energy to produce than their petroleum-based equivalents.

Yet, as with any other technology, biological technologies are subject to the hard realities of the market. New products may fail for many reasons, including both overoptimistic assessment of technical capabilities and customer inertia. In addition, biotechnology must compete with alternate methods of producing materials or fuels, methods that may have a century's head start. Biological production must also compete for feedstocks with other human uses of those feedstocks, as is now occurring in the commercialization of first-generation biofuels produced from sugar, corn, and vegetable oil. It is no surprise that many biofuel producers are presently caught up in the collision between food and fuel; crops, and the resources used to grow them, are likely to have higher value as food than as fuel.

The economic system that governs these products is today primarily composed of interconnected marketplaces, full of businesses large and small. Those markets are increasingly global, and the flow of information is at least as important as the flow of physical goods. Technology supports the spread of those markets, and technology is the subject of many of those markets. New technologies provide opportunities to expand markets or launch entirely new ones. Here I use the word "market" in the broadest sense, which Wikipedia (presently) defines as "any of a variety of different systems, institutions, procedures, social relations and infrastructures whereby persons are coordinated, goods and services are exchanged and which form part of the economy."[3] I do not mean any particular market, nor necessarily the "free market," nor any particular set of transactions governed by any particular set of rules and denominated in any particular currency.

In general, as we shall see, there is no reason to think that any country's lead in developing or using biological technologies will be maintained for long. Nor will the culture and experience of any given country dominate the discussion. Access to biological technologies is already ubiquitous around the globe. Many countries are investing heavily to build domestic capabilities with the specific aim of improving health care, providing fuels and materials, and increasing crop yields.

Research efforts are now accelerating, aided by rapid advances in the technology we use to manipulate biological systems. It is already possible to convert genetic information into electronic form and back again with unprecedented ease. This capability provides for an element of digital design in biological engineering that has not heretofore been available. More important, as measured by changes in commercial cost and productivity, the technology we use to manipulate biological systems is now experiencing the same rapid improvement that has produced today's computers, cars, and airplanes. This is evidence that real change is occurring in the technologies underlying the coming bioeconomy.

The influence of exponentially improving biological technologies is only just now starting to be felt. Today writing a gene from scratch within a few weeks costs a few thousand dollars. In five to ten years that amount should pay for much larger constructs, perhaps a brand-new viral or microbial genome. Gene and genome-synthesis projects of this larger scale have already been demonstrated as academic projects. When such activity becomes commercially viable, a synthetic genome could be used to build an organism that produces fuel, or a new plastic, or a vaccine to combat the outbreak of a new infectious disease.

This book is an attempt to describe a change in technology that has demonstrably profound social and economic implications. Some parts of the story that follows I know very well, either because I was fortunate to witness events or because I was in a position to participate. Other parts of the story come in because I had to learn something new while attempting to paint a picture of the future. Delving into details is necessary in places in order to appreciate the complexity of biological systems, the challenge of engineering those systems, and the implications of that technology for public policy, safety, and security. Whatever else the reader takes from this book, the most important lesson is that the story is incomplete. Biology is technology, and as with any other technology, it is not possible to predict exactly where the project will go. But we can at least start with where that technology has been.
 
Engineering Organisms Is Difficult, for Now

Explicit "hands-on" molecular manipulation of genomes began only in the mid-1970s, and we are still learning the ropes. Most genetically modified systems do not yet work entirely as planned. Biological engineering as practiced today proceeds by fits and starts, and most products on the market now result from a process that remains dominated by trial and error. The primary reason that the engineering of new organisms has been slow in coming is that simply understanding naturally occurring organisms remains hard.

The initial phase of biological engineering, covering the last thirty years or so, coincided with efforts to describe the fundamentals of molecular biology. In that time we moved from discovering the number of genes in the human genome to building automated machines that read entire microbial genomes during a lunch break. Science has accumulated enough knowledge to support basic genetic changes to microbes and plants; those changes enable a wide range of first-generation products.

What was cutting-edge technology three decades ago is today routine in university lab courses and has already been included in the curricula of many high schools. While simple modifications of single-celled organisms are now commonplace, the scientific frontier has, of course, moved. Today, academic and industrial researchers alike are working with multicellular organisms and contending with the attendant increase in biochemical and developmental complexity.

And yet progress can appear slow, particularly to those who have followed the information technology revolution. Governments and big business once dominated computing. Today, entrepreneurs and garage hackers play leading roles in developing computing technologies and products, both hardware and software.
 
Thus, Stewart Brand, founder of the Whole Earth Catalog, organizer of the first Hackers' Conference in 1984, and cofounder of the Whole Earth 'Lectronic Link (WELL) and the Global Business Network, wonders: "Where are all the green biotech hackers?"[4] To which I answer: "They are coming." The tools necessary to understand existing systems and build new ones are improving rapidly. As I will discuss in Chapter 6, the costs of reading and writing new genes and genomes are falling by a factor of two every eighteen to twenty-four months, and productivity in reading and writing is independently doubling at a similar rate. We are just now emerging from the "slow" part of the curves, by which I mean that the cost and productivity of these technologies are now enabling enormous discovery and innovation. Consequently, access to technology is also accelerating. "Garage biology" is here already; in Chapter 12 I share a bit of my own experience sorting out how much innovation is possible in this context.

Public Expectations for Advances in Biological Technologies

The new knowledge and inventions that science provides can take many decades to become tools and products--things people can buy and use--that generate value or influence the human condition. That influence is, of course, not uniformly beneficial. But we generally cannot know whether a technology is, on balance, either valuable or beneficial until it is tested by actual use. It is in this context that we must examine new biological technologies.

Biological technologies are subject to both unreasonable expectations and irrational fear. Practitioners and policy makers alike must contend with demands by the citizenry to maximize benefit speedily while minimizing risk absolutely. These demands cannot be met simultaneously and, in many cases, may be mutually exclusive. This tension then produces an environment that threatens much-needed innovation, as I argue in detail in the latter half of this book.

Often sheer surprise can play as great a role in public responses as the science itself. By the nature of the scientific process, most results reported in the press are already behind the state of the art. That is, while ideally science is news of the future, the press actually reports the past. Scientific papers are submitted for publication months after work is finished, go through a review and editing process consuming additional months, and finally appear in print many months after that, all the while being surpassed by ongoing research. Given the pace of technological improvement and consequent increased capabilities in the laboratory, more and more new science is being squeezed into the time between discovery and publication of old results.

Only if we recognize that organisms and their constituent parts are engineerable components of larger systems will we grasp the promise and the peril of biological technologies. Conversely, failing in this recognition will cloud our ability to properly assess the opportunity, and the threat, posed by rapid changes in our ability to modify biological systems.

We are in the midst of realizing capabilities first forecast more than fifty years ago. The development of X-ray crystallography and nuclear magnetic resonance in the decades before 1950 opened a window to the molecular world, providing a direct look at the structure of natural and synthetic materials. During that same time period the elucidation of information theory, cybernetics, and basic computational principles set the stage for today's manipulation of information. Biology is the fusion of these two worlds, in which the composition and structure of matter determines its information content and computational capabilities. This description may also be applied to computers, but biology is in addition a state of matter, if you will, that is capable of self-editing and self-propagation. It is no surprise, then, that given our improving abilities to measure and manipulate molecules, on the one hand, and to apply powerful computational techniques to understand their behavior, on the other, biology is today consuming considerable attention. Today's science and technology provide a mere glimpse of what is in store, and we should think carefully about what may happen just down the road.

What Is Biological Engineering?

As we shall see in the following chapters, the development of new mathematical, computational, and laboratory tools will facilitate the building of things with biological pieces--indeed, the engineering of new biological artifacts--up to and including new organisms and ecosystems. The rest of this book explores how this may transpire. But first we have to understand what engineering is. Aeronautical engineering, in particular, serves as an excellent metaphor when considering the project of building novel biological systems. Successful aeronautical engineers do not attempt to build aircraft with the complexity of a hawk, a hummingbird, or even a moth; they succeed by first reducing complexity to eliminate all the mechanisms they are unable to understand and reproduce. In comparison, even the simplest cell contains far more knobs, bells, and whistles than we can presently understand. No biological engineer will succeed in building a system de novo until most of that complexity is stripped away, leaving only the barest essentials.
 
A fundamental transformation occurred in heavier-than-air-flight, start-ing about 1880. The history of early aviation was full of fantastical machines that might as well live in myth, because they never flew. The vast majority of those failed aircraft could, in fact, never leave the ground. They were more the product of imagination and optimism than of concrete knowledge of the physics of flight or, more important, practical experience with flight.

In about 1880, Louis-Pierre Mouillard, a Frenchman living in Cairo, suggested that rather than merely slapping an engine on a pair of wings and hoping to be pulled into the air, humans would achieve powered flight only through study of the practical principles of flight. And that is just the way it worked. Aviation pioneers made it into the air through careful observation and through practice. These achievements were followed by decades of refinement of empirical design rules, which were only slowly displaced in the design process by quantitative and predictive models of wings and engines and control systems. Modern aircraft are the result of this process of learning to fly.

And so it goes with virtually every other human technology, from cars to computers to buildings to ships, dams, and bridges. Before inanimate objects are constructed in the world today, they are almost uniformly first constructed virtually--built and tested using sophisticated mathematical models. Analogous models are now being developed for simple biological systems, and this effort requires molecules that behave in understandable and predictable ways. The best way to understand how biological technology is changing is by starting with another metaphor, one that relies on the best toy ever devised: LEGOS.

Notes

1. Bureau of Economic Analysis, Industry Economic Accounts, "Value added by industry as a percentage of gross domestic product," www.bea.gov/industry/gpotables/gpo_action.cfm?anon=78432&table_id=22073&format_type=0.

2. See the CIA World Factbook, www.cia.gov/library/publications/the-world-factbook/index.html.

3. Wikipedia, http://en.wikipedia.org/wiki/Market (accessed 20September 2008).

4. J. Tierney, "An early environmentalist, embracing new 'heresies,'" New York Times,27 February 2007.