As an employee of the National Institutes of Health in the '80s, J. Craig Venter once found himself trailed by two men in suits. After shadowing him for a day in their brown Ford Fairlane, they appeared unannounced at his lab, where they showed him ID cards from the Department of Defense. The men asked him about his work on receptor proteins, which make cells sensitive to chemicals such as adrenaline. Might those proteins also be used to detect nerve poisons? While Venter had previously organized war protests, he'd also served as a medic in Vietnam, and his current research interests coincided with the military's. The questions they were asking were scientifically pertinent. So he accepted a Defense research grant of $250,000.
The NIH was not pleased. Administrators looked upon the money with institutional jealousy. Begrudgingly they set up a special account for his nerve poison research -- and bluntly informed Venter that he was "perhaps too entrepreneurial."
That, of course, was an understatement. Within a decade, Venter was in direct competition with the NIH, backed by $300 million in corporate funding against the agency's multibillion-dollar budget, engaged in arguably the most high-stakes clash in the history of science. The Human Genome Project, which made Venter one of the most admired and reviled figures in the world, has provided a genetic template for studying our species. At the same time, Venter's success dramatizes a paradigm shift in the culture of science, demonstrating the power of noninstitutional research. In the 20th century, the tenured professional supplanted the independent gentleman scientist: James Watson succeeded Charles Darwin. In the 21st century, the tenured professional is becoming outmoded, replaced by the intellectual entrepreneur: The mantle is passing from Watson to Venter.
Like Darwin, Venter was not quick to show his potential. In high school, the only A's he received were in P.E., wood shop and swimming, and, while he was a good enough athlete to get offered a scholarship by Arizona State, he opted instead for bodysurfing on the Southern California beaches and a night job pricing toys at Sears. That came to an end with the Vietnam War. He joined the Navy, which offered him his choice of positions after he scored an unexpected 143 on an IQ test. The medical corps looked best, because it required the briefest tour. Thus began Venter's unlikely career in medicine and science, propelled by the intoxication of accomplishment, leading from the tents of Da Nang to the lecture halls of U.C. San Diego to the laboratories of SUNY Buffalo, where he taught and conducted research for several years before taking a position at the NIH.
The rapidity of Venter's ascent, however, could never keep pace with his ambition, or his ego, and his tenure at the NIH was tempestuous from beginning to end. In his new memoir, "A Life Decoded," he constantly casts himself as a prophet amongst philistines: "I knew that I had made a breakthrough that could change genomic science," he writes of his most storied struggle, "and I was wasting my time, energy, and emotion on battling with a group that had no serious interest in letting an outsider analyze the human genome."
So he left. Simply put, Venter believed that he had a faster and cheaper way to sequence the genome than was feasible using the approved methodology, and that other laboratories were thwarting him because of territorialism and fear of losing funding. His assessment was essentially accurate, and their caution was largely justified. Venter's approach, called shotgun sequencing, was daring scientifically and risky politically, unproven at a scale even approaching the human genome, yet likely to make Congress question why the government was allocating so much for the NIH's safer methods. In other words, funding for him might mean less funding all around, and if he failed to deliver, no second chance for the genome.
Private money, on the contrary, was a different matter. By leaving the NIH, Venter escaped the entrenched interests of a stratified bureaucracy, entering into a realm that embraced risk as an investment strategy. Of course, for a scientist interested in answering fundamental questions rather than improving shareholder returns, that can present a different set of problems.
Venter's turbulent relationship with HealthCare Ventures, which funded his Institute for Genomic Research when he left the NIH, and with PerkinElmer, with which he formed Celera Genomics after his HealthCare Ventures partnership collapsed, amply illustrate the challenges of intellectual entrepreneurship in a venture capitalist economy. Businesses want to protect their investments, which translates into monopoly control or secrecy, policies anathema to open scientific exchange.
Moreover, expectations are often unrealistic. Venter scornfully writes of the "one gene, one protein, one billion dollars" mantra -- referring to the manufacture of drugs in a petri dish -- and points out that fewer than a dozen of the approximately 23,000 human genes have ultimately been lucrative for investors. Good research takes time, and success often rests on failure, notions that every Ph.D. understands but that confound the average MBA.
Venter got the human genome first -- and considerably accelerated the NIH effort in the process -- because he held nothing sacred other than the quest for knowledge. At times, sheer stubbornness drove him forward. He made his $300 million deal with PerkinElmer despite his failed HealthCare Ventures partnership, and ignoring advice from his lawyer to "get the hell away from them while you still can," for the simple reason that the human genome was "the biggest prize in biology," and was attainable only with big pharmaceutical money.
In other instances, he engineered shrewd compromises, such as publicly releasing the raw genome while constructing restricted-access databases designed to make the sequences more useful for industry. He was fired by Celera anyway -- officially because Celera was moving into drug discovery, unofficially because the company could no longer contain his ego -- but not before he had a chance to announce, at a televised ceremony in the Clinton White House on June 26, 2000, that "for the first time, our species can read the chemical letters of its genetic code." And afterward? That was the real start of Venter's career as an intellectual entrepreneur.
The key to intellectual entrepreneurship is self-autonomy. The intellectual entrepreneur is not beholden to institutional politics or public opinion. One obvious example is Ray Kurzweil, whose '70s invention of the flatbed scanner and development of character-recognition software provided him with the security to extend his investigation of artificial intelligence into fields ranging from economics to history. More interesting, and significant, is the case of Stephen Wolfram, who has devoted a quarter-century to developing a radical new approach to the sciences as a whole, funded by commercial sales of Mathematica, his highly popular mathematics software. His project is not exactly modest.
"Three centuries ago science was transformed by the dramatic new idea that rules based on mathematical equations could be used to describe the natural world," he claims at the outset of his self-published 1,280-page treatise. "My purpose ... is to initiate another such transformation, and to introduce a new kind of science that is based on the much more general types of rules that can be embodied in simple computer programs."
The idea that the universe is an overgrown mainframe, and that meaningful physics experiments can be done by running software on a Sun workstation, was heretical enough to make life uncomfortable for Wolfram at the famously open Institute for Advanced Studies in the '80s. With sales of Mathematica supporting development of Mathematica for his own purposes, Wolfram has since been able to establish the independence to pursue his maverick work -- reducing all phenomena in nature to a few lines of code -- and to present this new kind of science on his own terms.
Yet it would be a mistake to assume that intellectual entrepreneurship is synonymous with personal wealth. In November, a 39-year-old surfer named Garrett Lisi posted a paper, "An Exceptionally Simple Theory of Everything," on the physics pre-print archive arXiv.org, which claimed to unify all the known particles and forces of nature by showing how they related on the 248 points of an eight-dimensional mathematical pattern. While still unproven, his model directly addresses the most fundamental problem in physics, which eluded even Einstein -- the integration of quantum mechanics and general relativity -- and provides a testable alternative to string theory. Lisi has supported himself by building bridges and guiding hikes, often residing in a yurt. Shunning university affiliation, he has negotiated an independent living, an intellectual entrepreneur whom nobody would mistake for a mogul.
Still, money doesn't hurt, especially in a costly field such as Venter's, and the extraordinary range of his intellectual entrepreneurship has depended largely on the $150 million in Celera stock transferred to his own nonprofit foundation upon his departure. That foundation funds his diverse research interests, keeping pace with his curiosity, and exploiting new scientific opportunities, as no peer-reviewed grant ever could.
As always, his ambition is epic. "I decided to move forward, to at least strive to do something new that could have an even bigger impact than sequencing the human genome," he says of his work following his Celera ouster. That quest has resulted in two related projects, one of which entails trawling the world's oceans for microbial life, and the other of which involves creation in the laboratory of the world's first synthetic organism. Both are controversial, on account of their vast potential to make money, especially if combined and patented. Critics often refer to the J. Craig Venter Institute as Microbesoft.
Nevertheless, the scientific justification for his work is unimpeachable. Before Venter began sailing the seas on his personal research vessel -- essentially a yacht with a lab bench -- some 6,000 species of microorganism were known. Since setting out on his quest to sequence "a genome of the ocean," he's added tens of thousands to the roster, and discovered 1.3 million new genes, more than doubling the number cataloged for all species before he set sail. The data is overwhelming if considered en masse, yet already can be searched to map worldwide biodiversity, and to monitor environmental changes as global warming advances, a living litmus test.
Complementary to this blossoming of the phylogenetic tree is Venter's effort to prune the genome of an individual species to the operational minimum. That species is Mycoplasma genitalium, a bacterium that already has one of the smallest genomes of any organism, 482 genes arranged in a circular chromosome. Knocking out as many of these as possible, reducing the total to 381, Venter has created a synthetic genome for a new species he calls Mycoplasma laboratorium. The science is exhilarating. Venter's synthetic organism has the potential to reveal the minimum conditions for life -- to suggest how we arose from insensible chemicals -- and to provide researchers with a lab-in-a-membrane as additional genes are introduced to the artificial organism's chromosome.
Some of those genes might be taken from Venter's oceanic catch of 1.3 million, approximately 800 of which allow aquatic species to harvest light in myriad ways, and thousands of which are involved in the processing of hydrogen. With Mycoplasma laboratorium as a chassis, bacterial power plants might provide an environmentally responsible alternative to oil, a concept that Venter has not overlooked, and that his Institute for Biological Energy Alternatives seems poised to exploit.
Yet even if Venter does cash in, his past behavior suggests that the money will only fund future research that otherwise might not be undertaken by anyone, least of all those bound by institutional protocols. The terms of intellectual entrepreneurship are necessarily economic, but money is merely a conduit: The investment pays a dividend of future discoveries. Some will abuse that trust, just as Korean stem cell researcher Hwang Woo-Suk abused the old institutional framework. Most scientists are not like Hwang Woo-Suk, who claimed he had created human embryonic stem cells through cloning, and was later charged with fraud and embezzlement. While seldom as ambitious as Venter, or as curious, most share his interest in understanding how the world works.
In fact, Venter and his fellow intellectual entrepreneurs differ from 20th century tenured professionals most of all in their resemblance to the researchers who the tenured professionals ostensibly eradicated: 19th century gentleman scientists, such as Darwin, who answered only to themselves. The resurrection of the independent scientist makes sense, following a century of institutionalization. Professionalized specialization was a necessary mechanism for processing the bounty of 19th century discovery, but focus can take knowledge only so far before perspective is wanted again. Intellectual entrepreneurship accomplishes this within the context of the 21st century economy, leveraging new millennium technologies.
Perhaps no project of Venter's embodies the return of speculative independence more than his decision to read his own DNA. Self-sequencing has naturally inspired accusations of megalomania, but has also provided a basis for worthy science. Comparison of his genome to the Celera/NIH standard can address questions about genetic variation within our species, and about how and when genes are physically expressed. At present, none of this is well understood, contrary to what for-profit DNA testing services such as 23andMe would like people to believe.
For instance, variants of the genes ENPP1 and CAPN10 are both linked to susceptibility to diabetes, and Venter has the high-risk variant of the former but not the latter. He notes that "our understanding of genetic influences is far from clear, and yet to be determined is how the apparently contradictory results from these two genes influence my overall type 2 diabetes risk. Nor are genes the whole story, for activity and obesity play a huge role in the development of adult diabetes."
At the forefront of science, Venter's million-dollar decision to examine his own genome echoes the 19th century tradition of scientists experimenting on themselves. Perhaps most famously, Royal Society president Humphry Davy discovered the effects of nitrous oxide by inhaling various gases, a significant physiological finding (and also, for him, an addictive one). Reading his own DNA with unprecedented precision, Venter has detected sequences that correlate not only with diabetes, but also with Alzheimer's and heart disease, and accordingly has taken provisional measures to preserve his health.
Over the next few decades, the relationship between genes and environment -- the mysterium tremendum of genomics -- will play out, tangibly, in his own body. It won't be the sort of statistically significant clinical study, or controlled laboratory experiment, that the NIH would fund, but scientific insights also come from introspection. The 19th century gentleman scientist implicitly understood this. The 21st century intellectual entrepreneur explicitly embraces it, for the benefit of everyone.
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