On June 26 of this year, the White House announced the sequencing of human genetic code, an achievement that ushers in a new era in the understanding of the human species. "Without a doubt, this is the most wondrous map ever produced by mankind," proclaimed President Clinton. "It will revolutionize the diagnosis, prevention, and treatment of most, if not all, human disease."
Flanking Clinton on the podium were the two men most responsible for leading the scientific efforts that produced this "book of life," Francis Collins, M.D. and Ph.D., director of the publicly funded National Human Genome Research Institute, and J. Craig Venter, Ph.D., president and chief scientific officer of Celera Genomics Corp., a unit of PE Corp. For their efforts and the ultimate impact their work will have on our lives, IndustryWeek is recognizing the dynamic pair as Technology Leaders of the Year.
The achievement of these scientists and their teams is difficult to overstate. Just as the alphabet is to literature, their work is the foundation of the story of human life. Unlocking the genetic code ultimately will give scientists a view of both health and disease at the molecular level. Some 3.1 billion chemical units (or "base pairs") distributed in our chromosomes make up the code of our DNA. We now know essentially what order or sequence they are in. Over the next century we will learn how the sequence of specific segments of code -- the genes, of which there are about 80,000 -- make us what we are.
Interpretation of this data will, for instance, allow identification of individuals at high risk for disease so that monitoring and early treatment efforts can focus on them. Knowledge of individual genetic variation will allow personalized medicine --highly efficacious, controlled-dosage drugs tailored for individual genetic defects with side effects minimized. Gene therapy itself will correct illness-producing genetic defects. Bits and pieces of the human body will be engineered for tissue regeneration or automated drug testing. Computer models based on genetic code will simulate cellular activities, reducing human and animal testing.
Controversial issues abound, as well; possibly the biggest is the specter of discrimination based on genetic makeup. But controversy has been a part of most great scientific achievements, and certainly Venter and Collins have faced their share as they met the challenges of their respective efforts.
Perhaps the most publicized issue occurred in 1998 when Venter and his newly formed company, Celera Genomics, announced they would apply a radical technique to sequencing and complete the genome in three years. Those in the national Human Genome Project (HGP), sponsored in large part by the National Institutes of Health (NIH), were stunned, even angered by the declaration. Yet the competition sparked the publicly funded project to accelerate its efforts.
What began in 1986 as a U.S. Dept. of Energy project to study the effect of nuclear radiation on human biology, gathered momentum with the help of important advances in sequencing technology and data analysis. The effort exploded in a flurry of activity by the public and private factions, leading to the joint announcement in June that both had completed drafts of the human genome sequence.
Just as the two groups took different paths to their respective goals, so, too, did the men who led those efforts. Both came to their respective projects as world-class scientists. Venter is credited with inventing a now universally implemented gene-sleuthing technique based on ESTs (expressed sequence tags). He and his group have sequenced the most and largest genomes of organisms other than humans with a technique he helped perfect called shotgun sequencing; Venter also has pioneered the use of automated gene-sequencing machines. Collins and his teams identified the genes responsible for cystic fibrosis, neurofibromatosis, and Huntington's disease. His research laboratory continues to explore the molecular genetics of adult-onset diabetes, breast cancer, and prostate cancer.
While both researchers demonstrated exceptional talent and savvy in building their organizations and motivating them to high productivity in the quest for the human genome sequence, their approaches diverge when it comes to science. Venter always has challenged not only authority, but basic science itself. "This is an individual who is a true inventor, a true trailblazer, a man who has shaken up the scientific establishment," says Ari Patrinos, associate director of the U.S. Dept. of Energy's Office of Science, Washington, and the man credited with brokering the agreement to jointly announce the researchers' success. "This is opposed to Dr. Collins, who has always operated within the existing system and works to build consensus."
Regarding Venter, Patrinos adds, "When you challenge the scientific establishment and go against conventional wisdom, you tend to rub a lot of people the wrong way. He has been impatient about what he perceives as the scientific community 'not getting it' with respect to opportunities and challenges in the area of genetics and molecular biology, and quite frankly, he has been more often right than wrong. His irreverence at the time was translated eventually into wisdom, as the world witnessed this year."
Craig Venter, a champion backstroker in high school, chose life as a beach bum after graduation, working at Sears Roebuck & Co. in the evening to support his Newport Beach, Calif., surfing habit. He eventually enlisted in the U.S. Navy, saw duty in Vietnam as a hospital corpsman, then whizzed through university studies in six years to obtain doctorates in physiology and pharmacology.
In 1984 he landed a position in the lab of neurological disorders and stroke at the National Institutes of Health. There he invented the EST method of gene discovery, and, along with the help of the first generation of automated gene-sequencing devices, published a paper on 347 newly discovered human genes. That was after just one year's work at a time when only about 3,000 genes were known (about 8,000 are known today). Venter's gene discovery continued at a rate of about 25 per day. NIH management was so excited by Venter's work that patents were filed on the gene ESTs. However, the director of the HGP at the time, James Watson (who with Francis Crick identified the double-helix structure of DNA and who became the first leader of the HGP in 1990), criticized the work, saying it lacked scientific creativity. When the dust settled the patent applications were withdrawn, and Watson left the HGP, making way for Collins to assume its leadership at the beginning of 1993. The NIH also lost Venter, who obtained venture capital to start The Institute for Genetic Research (TIGR) in 1992 in Rockville, Md., the model for all massively parallel DNA-sequencing facilities in operation today, according to Venter. Under his leadership, TIGR (pronounced "tiger") grew from a rented building to an ESTs and genome-sequencing powerhouse. TIGR laid the foundation for the technology, scientific approach, and computer programs exploited by Celera Genomics. At TIGR Venter published the first complete genome of a living organism, the H. influenzae bacteria, a DNA sequence of 1.8 million base pairs, in 1995. The yearlong effort employed shotgun sequencing, in which the DNA of the entire genome is fractured into small pieces, the pieces sequenced, and the genome reconstructed by computer algorithms.
The results astonished the scientific community. In fact, Venter had applied to NIH for funding of the project, but was turned down by the agency, which claimed the technology would not work on such a large genome. In 1979 shotgun sequencing was used by another investigator to sequence a bacterium of some 50,000 base pairs. Until TIGR's H. influenzae sequencing, no one had extended the approach to sequence anything larger. TIGR also completed sequences of tuberculosis, malaria, and meningitis pathogens.
"While shotgun sequencing and gene-finding concepts similar to ESTs had been practiced by others, Craig took them to absurd extremes," says Mark Adams, Celera's vice president, genome programs, and a colleague of Venter's since his NIH days. "His real contribution is showing that these techniques are useful at ridiculous scale, by taking the raw ideas and converting them into an industrial process."
Collins describes Venter's style in terms of risk: "I would say his strength is that he is willing to take risks, and they are grand risks, too, on a large scale that many others would shy away from."
Enter the unsung hero. In 1998 Michael W. Hunkapiller, president of a company now known as Applied Bio-systems, Foster City, Calif., and developer of a next-generation, higher-throughput DNA sequencing machine called the ABI Prism 3700, contacted Venter and suggested he lead a new company. The idea was to outfit the organization with his new sequencers (there are now 300, costing about $300,000 each), and beat the HGP to the punch on the human genome sequence. Venter accepted the challenge (his wife, Claire Fraser, a molecular biologist, took the reins at TIGR), and in May 1998 helped create Celera Genomics, predicting the company would sequence the human genome by 2001. In the process of helping to found Celera he assembled the largest sequencing facility, as well as the largest civilian computer capability in terms of data storage, in the world. Once the operation was running, its mission -- shotgunning the sequence of the human genome-was accomplished in about a year.
"If I am to take credit for anything, I'm the overall strategist," says Venter. "But the thing that I have done the best is to hire world-class people who created a team at a time when all of their colleagues were saying this was absolutely impossible." According to Venter, a multidisciplinary team of Celera's capability has never been assembled before. That team includes molecular biologists, biochemists, computer and software engineers, even designers of semiconductor chips. "I look for people who are risk tolerant, who truly know their stuff, and who are self motivated. I don't micromanage. I paint the overall vision, then turn them loose and rely on their expertise. Nothing happens here because I order it to happen."
Those at Celera who work with Venter describe him as a leader of exceptionally high standards, but also a warm, personable, even humorous man, quite unlike his image in the press. "The built-in prejudice before some people interact with me is that I'm a tyrant and an ogre, but they find out differently by working with me," says Venter. "When I'm attacked, I probably bite back pretty good, but I don't rule by command or by beating people up."
Venter has a quality often associated with genius: the ability to connect bits of information and come to unique conclusions. He doesn't come to meetings with a vision, but rather likes to talk things through and build a vision with his team, according to Adams. "He likes to understand things at a great level of detail, what the rate-limiting steps are, because he's always thinking ahead to the next one," he says. "He'll make connections faster than a lot of us will. I'd characterize him as a nonlinear thinker." He's also a great cheerleader. "Craig does a really good job of making things straightforward," adds Adams. "He brings you along so you don't doubt for a moment that what he is talking about is doable. And the enthusiasm and commitment he feels about a project is really infectious."
Just as knowledge of the sequence of the human genome is really a starting point, Celera is at a starting point in converting its information into a business. The company, which has grown to employ 700, earned $42.7 million in fiscal 2000 on database subscriptions and other genome services, up 240% over 1999. Celera will continue sequencing activities (genomes of the fruit fly and the mouse also have been shotgunned for comparison purposes), while applying its computing power to make the data more reachable and valuable. "Would I be satisfied sequencing the human genome and then walking away?" asks Venter. "The answer is clearly 'no.'"
In 1993 Francis Collins agreed to lead the national HGP as director of the National Human Genome Research Institute, Bethesda, Md. He found his challenge was to meld the efforts and unify the interests of an assortment of laboratories, many of which were not under his direct control. This group evolved into 16 centers in six countries, including national centers in France, Japan, Germany, and China; three sequencing centers funded by NIH at Washington University, Massachusetts Institute of Technology, and Baylor College of Medicine; the Joint Genome Institute sponsored by the Dept. of Energy; and the Sanger Center in England supported by the Wellcome Trust.
"Collins is talented scientifically, but also has an incredible ability to lead large groups of people," says the Dept. of Energy's Patrinos. "Scientists can have powerful egos and are generally not easy to organize and lead. You have to inspire, cajole, and gently nudge to keep them in lock step. The only way you can do that successfully is to be just as smart, just as committed, and just as hard working as they are, and that is absolutely the case with Dr. Collins."
Regarding Collins, Venter notes, "I would describe his job as herding cats. There were all these scientific labs vying for the funding and the credit independently. Trying to get all these labs to work together as a team and have that be a successful organization, instead of trying to kill each other off, takes a real skill set. It's an administrative job, but at the same time not one where he has direct control over the outcome. So I think he deserves a lot of credit for getting all those cats in a herd."
Along the way Collins overcame problems of coordination and communication to set a new standard for government projects of such magnitude. "In the past this has been a cottage industry, small labs of 10 people with a few grants working on focused goals with a short time span," says George Weinstock, codirector, Human Genome Sequencing Center, Baylor College of Medicine, Houston. "Francis has set the precedent for how you get people to communicate and to stay on budget and on time, how you get scientists to interact with each other, how you get government to interact with scientists, and how you deal with the media and the visibility. We now have a new model, a new paradigm of how to do 'big science' in the biological community."
Home schooled until sixth grade, Collins fell in love with molecular biology and medical genetics while studying for a Ph.D. in physical chemistry and his M.D. He accepted a faculty post at the University of Michigan in 1984 where he collaborated to uncover the cystic fibrosis and other disease-producing genes. It was his success in this environment, highly competitive for funding and recognition, that demonstrated Collins' leadership capabilities, grasp of the science, and knowledge of applications-and which caught the attention of the NIH. At first Collins refused the directorship of the national HGP. "When Jim Watson resigned and I was approached about stepping into that role," says Collins, "I actually turned it down the first time. "Then I thought to myself, 'Are you nuts? This is only going to happen once in history and you have a chance to lead this and you are saying no? Wake up.'"
The early efforts of the HGP were those of building infrastructure and testing technology on simple organisms. Unlike Celera's shotgun approach, the national program opted initially for a strategy called "mapping" that identifies landmarks (short stretches of unique sequence) along the genome. It's not unlike mapping the U.S. for major cities, mountain peaks, and rivers, but leaving out the city streets and houses. Map in hand, the plan was to divide the genome into units of 150,000 base pairs (called BACs), assign them to the various labs, and sequence them in complete detail individually. The units then would be assembled, with location of individual BACs guided by the landmarks, to create the whole genome. Completion of the project was targeted for 2005.
In 1996 Collins established pilot projects at individual labs to see who could scale up for high-volume sequencing. The exercise was designed to see which labs could grow their physical facilities, but also to test the management and organizational skills of lab leaders. The result was a focus on five labs, a group called the G5: Washington University, MIT, Baylor, the Dept. of Energy center, and the Sanger Center. This decision caused rearrangements of responsibilities, with the potential to threaten some of the egos and individual agendas of those participating in the project. Yet it became a showcase for Collins' management skills.
"Francis has a manner of presenting things in a way that makes everybody feel good," says Baylor's Weinstock. "There is always some tension, some fear that your turf might be allocated to someone with more capacity. Francis has a very soft touch. He can be very understanding, and he can look at both sides of the situation and make people feel that even if the decision that is being made is not necessarily the best one for them, it's certainly the best one for the project."
To maintain effective communication within the G5, Collins disciplined the group to participate in weekly conference calls to share methodology and see who needed help. "Francis is often the person who sets the agenda for these discussions, and then is the person who says the least," says Weinstock. "While he may have his own needs in terms of how to move the project along, he handles all that behind the scenes and allows the groups to interact with each other in a way that builds relationships that can keep the project moving forward."
The introduction of Hunkapiller's sequencing machines in 1998 was not lost on the HGP, and coincided with the successful scale-up of the G5 to carry the majority of the sequencing load. Nor could HGP ignore the footsteps of a Rockville, Md. start-up that was suggesting it could sequence the genome by 2001.
At this point Collins decided that instead of doing a deep sequencing of each of the BACs, the HGP would target a "working draft" of each, allowing sequencing to be run quickly enough to cover the genome by late spring of 2001. To build accuracy, sequencing is done in as many different samples as it takes to see any base pair up to eight times. To create its draft, the HGP would stop at three to four, giving the findings enough accuracy to be valuable for gene hunting. Its hurry-up offense now outfitted with the latest sequencing technology, the HGP delivered its working draft in about 18 months. The race to the starting line was virtually a tie.
The HGP will finish its deep sequencing of the complete genome over the next two years. For now, Collins spends about half his time on the ethical, legal, and social issues raised by the knowledge of genetic information. "The most pressing one is to put into place effective legislative protections against genetic discrimination," he says. "No one should have to fear finding out something about their DNA that might be quite useful in terms of preventive medicine, [but] that then may be used to take away a person's health insurance or job. Right now those protections are insufficient. I have an opportunity now not only to advocate for the promise of this science for solving many problems in medicine, but also to advocate for solutions to some of these potential misuses that otherwise could really ruin the whole thing."