Life After JCVI-syn1.0: ‘New’ Adventures in Media Coverage, Politics, National Security, and—Oh, Yes—The Promise of Synthetic Biology.

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes regularly to Skeptic as well.  He may be contacted at krausekc@msn.com.

Craig Venter is no stranger to success—or to glitzy headlines in the popular press. By 1995, the “bad-boy” of molecular biology had overwhelmed his critics by becoming the first person to decode an entire genome, that of Haemophilus influenzae.  Then, as part of a larger goal to distinguish life’s minimal genome, he did it again, sequencing the bacterium Mycoplasma genitalium.

Perhaps most memorably, in 2000, Venter effectively humiliated the U.S. government by winning the race to unravel and sequence a rough draft of the human genome, sixty percent of which turned out to be his own.  He and his privately-funded team at Celera Genomics accomplished this feat using their new and, to that point, much maligned “shotgun” sequencing method that, in the end, allowed them to expose the chain more accurately and less expensively than the simultaneous $3 billion NIH project led by Francis Collins.

Then, in 2007, Venter stunned the world yet again when he transformed one life form, Mycoplasma capricolum, into another, M. mycoides, by transferring the latter’s native genome into the former’s evacuated cell.  But Venter wasn’t one to rest on his laurels.  A year later, he and his twenty-member “dream team” at the J. Craig Venter Institute, came astoundingly close to actually creating life by constructing M. genitalium’s entire genome from scratch.  In his enlightening, if somewhat self-gratifying autobiography, A Life Decoded, Venter revealed his grand designs:

I now want to go further.  My company, Synthetic Genomics, Inc. [SGI], is already trying to develop cassettes—modules of genes—to turn an organism into a biofactory that could make clean hydrogen fuel from sunlight and water or soak up more carbon dioxide.  From there I want to take us far from shore into unknown waters, to a new phase of evolution, to the day when one DNA-based species can sit down at a computer to design another.  I plan to show that we understand the software of life by creating true artificial life.

And, given the record, one has to believe he’ll eventually accomplish every bit of it.  Indeed, in connection with his latest conquest of the popular headlines, Venter, along with project co-leader Daniel Gibson and their colleagues at the Venter Institute came at least one colossal step closer to doing so.  On May 20, 2010, they announced the “Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome” in the prestigious journal Science.  Their ambitious project was funded primarily by SGI to the tune of $40 million.

Venter’s “new” cell consisted of two components.  The donor was a 1.08 million base pair chromosome digitally synthesized from the natural M. mycoides blueprint—but with a few crucial changes.  The recipient was a M. capricolum shell and cytoplasm.  The cell’s progeny, capable of continuous self-replication, demonstrate the expected phenotypic properties and thus appear to be controlled solely by the donor’s synthetic genome.  More than a billion daughter cells later, a strain of M. mycoides austerely christened JCVI-syn1.0 now awaits regeneration in a Maryland freezer.

So, exactly what has Venter achieved this time?  Certain popular headlines have misstated the feat rather wildly.  Popular Mechanics called it the “First Synthetic Cell.”  New Scientist termed it an “Immaculate Creation.”  Refusing to be outdone, the Wall Street Journal and the Guardian celebrated the creation of a “Synthetic Organism,” and a “Synthetic Life Form,” respectively.

In a thoughtful opinion piece in the May 27 Nature, however, eight diversely situated yet highly respected experts on synthetic biology attempted to clarify the situation.  Some focused on the essential facts.  Harvard geneticist George Church, for example, differentiated the creation of life from the synthesis of DNA by way of a vivid analogy: “Printing out a copy of an ancient text,” he said, “isn’t the same as understanding the language.”  More skeptical yet was Reed College professor of humanities, Mark Bedau, who rejected even the less ambitious claim to have created a synthetic cell.  Venter’s new bacterium, he argued, is just a cell with a prosthetic genome accounting for only 1 percent of the organism’s dry weight.

Others were more philosophical and reflective.  Arthur Kaplan, bioethicist at the University of Pennsylvania, announced quite optimistically that Venter has begat “an end to a debate about the nature of life that has lasted thousands of years.”  JCVI-syn1.0, he contended, seems to “extinguish” all vitalist views, including religious claims, that life requires some “special force or power”—other than human ingenuity, that is—to exist.  And finally, David Deamer, biomolecular engineer at the University of California, Santa Cruz, wrote that, thanks to Venter’s successful reassembly of a synthetic genome, we might soon be able to “answer one of the great remaining questions of biology: how did life begin?”

However ambitious, neither Venter nor his colleagues are especially given to hyperbole or delusions of grandeur.  In their May 20 press release, the Venter Institute claims no more than the “successful construction of the first, self-replicating, synthetic bacterial cell.”  In their original research article, they acknowledge the natural origin of the recipient cell’s cytoplasm, but point out that JCVI-syn1.0’s progeny act “as if the whole cell had been produced synthetically.”  Moreover, Venter admits in the paper’s introduction that “our genomic knowledge remains very limited” and that “[n]o single cellular system has all of its genes understood in terms of their biological roles.”

No matter how one characterizes it, Venter’s latest accomplishment developed out of a larger project that began in 1995.  When he sequenced M. genitalium, the bacterium with the smallest genetic complement of any known organism capable of growth in the laboratory, his ultimate goal was to build a cell with the minimum genome needed to survive.  At that time, Venter discovered that 100 of that species’ 485 protein-coding genes were expendable when disrupted one-at-a-time.

JCVI-syn1.0’s genome is almost twice as voluminous as that of M. genitalium.  But Venter plans to whittle away at its genetic complement as well, until he can exploit a minimal cell as a platform for distinguishing the function of every gene essential to its existence.  The ultimate triumph, of course, would be to combine the technical successes of synthesis and transplantation with a profound knowledge of genetic utility into something genuinely magnificent.  If, through these researchers’ hard work and creative genius, we learn to control entire genomes from their very inception—to make them do our bidding—indeed, what can’t we accomplish?

Which is precisely the heady question that has many lay people, politicians, and some experts on edge.  Also on May 20, Barack Obama penned a letter on the subject to Dr. Amy Gutmann, University of Pennsylvania President and now co-chair (along with Emory University President James Wagner) of the president’s bioethics commission.  Palpably concerned, Obama asked Gutmann to prepare a broad study of this “scientific milestone” within six months, focusing on “potential health, security or other risks” and “identifying appropriate ethical boundaries.”  Strangely, the president requested that the commission “consult with a range of constituencies,” including “faith communities.”

On May 27, the editors of Nature cautiously praised Obama’s inquiry, calling it a “belated step in the right direction.”  Urging the swift establishment of an international framework of governance on synthetic biology, the editors warned that the construction and transplantation of whole genomes “may be routine within five years,” and that universities, individual investigators, and governments are “almost certainly not attentive enough to security risks” posed by “do-it-yourself” biologists.

Others appear somewhat less distressed.  Although troubled by the participation of nonprofessionals in this nascent “life sciences revolution,” health experts Mildred Cho and David Relman de-emphasized the potential risks associated with JCVI-syn1.0.  In the July 2 Science, they argued that Venter’s latest accomplishments “do not cause particular concern” in terms of biosecurity, and that “few, if any, new ethical issues are raised.”  More vital for Cho and Relman is the scientific community’s relationship with an already distrustful public.  Now more than ever, they advised, synthetic biologists need to communicate their intentions, minimize conflicts of interest, and abstain from incendiary language referring to “programmed” or “artificial life.”

Then, on July 8-9, 13 prominent scientists gathered to testify before the president’s bioethics committee in Washington D.C.  Some contended that, despite Venter’s research, very little in biology has changed during the last 50 years in terms of security threats, and that existing regulations and oversights were sufficiently broad and brawny to handle the difference.  Harvard geneticist Raju Kucherlapati, for instance, remarked that the same concerns were raised and addressed beginning 35 years ago in response to recombinant DNA technology.

Others, including Venter himself, argued that the rules of game have indeed changed considerably because of the relative ease with which large chunks of DNA can now be constructed with a synthesizer from digital code.  Now, they warned, the process is available even to students and amateurs.  These witnesses called for further regulations requiring DNA synthesis businesses—including Blue Heron Biotechnology, for example, the company that filled the Venter Institute’s order—to screen requests for the sequences of known pathogens that could be used as bioweapons.  The commission is scheduled to convene again in September and November of this year.

But Venter and his colleagues were keenly aware of these concerns when they created JCVI-syn1.0.  To make the cell’s progeny retraceable to their owners and to distinguish them from their natural counterparts, the team inserted into JCVI-syn1.0’s genome four “watermarks”: the key to an alphanumeric code, a website address for those who have solved it, the names of the 46 scientists who contributed to the project, and pithy quotes from James Joyce, Robert Oppenheimer, and Richard Feynman (“What I cannot build I cannot understand”).  Venter also disabled the native genes rendering M. mycoides a bothersome bug that causes mastitis in goats.

But the project’s breakthrough has triggered a dynamic discussion regarding future safeguards.  Although cells with synthetic genomes are unlikely to survive outside the laboratory, they could be programmed with limited lifespans or on/off switches, as Bedau has suggested.  Or perhaps they could be engineered with sequences that simply cannot exist in nature.  Though an environmental group, Friends of the Earth, has asked the FDA and the EPA to “fully regulate all synthetic biology experiments and products,” it may turn out that private entities—with government assistance, of course—are better equipped and motivated to oversee their experiments and control their outcomes.

So what about the potential benefits of JCVI-syn1.0?  Venter admits that his cell is of no immediate practical use.  Such latency is typical of great science, after all.  But Venter remains tightly focused on the future, including possible applications he envisioned long ago.  Already, he and SGI are collaborating with Exxon Mobil—which is prepared to spend $600 million on the venture—to create a novel strain of algae capable of capturing carbon dioxide and using it to manufacture diesel fuel.  Venter has also received funding from the NIH and is working with Novartis, in hopes of quickly developing synthetically derived proteins for use in flu vaccines.

Such are only isolated examples, of course, in a brave new world of limitless potential.  Combining chemistry, cell biology, genetics, and computer science, synthetic biology is no doubt as much a Pandora’s box as it is a magician’s hat.  But let’s hope that scientific curiosity and entrepreneurial passion drive the impending debate at least as forcefully as fear and, most certainly, envy.  With inspired innovators like J. Craig Venter and his colleagues in the game—peering over the box’s edge or past the hat’s brim—we might finally learn to expect and, in appropriate cases, appreciate the unexpected.

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