By Mark D. Uehling
April 15, 2003 | “This whole meeting has been a mixture of exhilaration and terror,” said Francis Collins, director of the National Human Genome Research Institute. If Collins was scared, having run the public effort to sequence the human genome, imagine the reeling minds of preachers, financiers, teachers, and other civilians attending “The Future of Life,” a conference sponsored by Time magazine in Monterey, Calif.
The February meeting looked both backward at the discovery of the double helix and forward to the benefits and havoc DNA may wreak. Genomics, clearly, isn’t for only scientists anymore. Ordinary citizens gawked at the speakers, begging autographs and snapshots of uber-nerds and scientists such as Leroy Hood, Ray Kurzweil, Richard Dawkins, Stewart Brand, and E.O. Wilson. The conference featured a baroness, an ambassador, and two Nobelists.
HTS Tools for Academia?
As Collins sketched a number of April events to celebrate the finished human genetic sequence, including a plan to dispatch 1,000 geneticists to speak at public schools, he also gave the audience a glimpse at his agenda for future federal research. His goals: finding the functional elements of the genome, not to mention all the proteins and their interactions.
Collins added that high-throughput screening (HTS) techniques now found in only industry should be developed for academic labs. Likewise, he will request more dollars to develop academic uses of microarrays and a computational model of the cell. Another bullet point was vague but tantalizing: “develop large human cohorts for genotype-phenotype correlations.” Is a “cohort” a database? If so, that could be both scientifically powerful and politically controversial.
Although it was rushed, Collins’ presentation was astoundingly ambitious (see What’s Next? Not the Post-Genomic Era” page 27). “In 2010,” he said, “if all goes the way we expect, it will be possible for all of us to find out what we are at risk for. We will all have risks for something. There are no perfect specimens.”
Well, maybe one: James Watson, president of Cold Spring Harbor Laboratory and co-discoverer of the double helix. A Nobel laureate, Watson (see Genes, Girls, and Honest Jim, page 28) has little regard for political correctness. That was endearing in a conference about drugged crops, cloned babies, and bioterrorism plagues.
So it was cheery to hear again about The Eagle, the Cambridge pub where James Watson and Francis Crick relaxed after toiling in the lab for as long as a whole five hours a day. Their best clue to the structure of DNA had come from Rosalind Franklin, a loner who wanted nothing to do with them. “She did not go out of her way to make herself attractive,” Watson said. In a room filled with admiring science groupies, the hunched, rumpled, red-eyed Watson was treated like George Clooney.
Like Watson, J. Craig Venter, president of the Institute for Genomic Research, also was interviewed onstage. Venter had plenty to say about competitors’ efforts to delve into the genome. “The problem is the scientific literature is full of associations between changes in genetic code and disease,” he said. “Most of those will not stand up to the test of regular science.”
Finding useful connections between genes and diseases, he hinted, will take far larger databases than now exist. “Imagine a database with 10,000 or 100,000 genomes and the corresponding clinical data to go with it,” Venter said. “We’d be able to look at changes across the genetic code, getting away from this notion of one gene, one disease. That’s a fallacy.”
Another shaky idea, Venter said, is that anyone in industry has a clue. “Once both Francis [Collins] and I published the analysis of the genome, the pharmaceutical and biotech industry almost stopped dead using genomics,” he said. “It clearly went from this notion of one drug, one gene, one billion dollars -- to the complexity of our biology. And [biotech and pharmaceutical companies] don’t know how to use [the data] intelligently now. Those patent portfolios are absolutely worthless -- they don’t even get pennies on the dollar for them.”
One of Venter’s closest ex-Celera aides was also present. Hamilton Smith, now scientific director of the Institute for Biological Energy Alternatives, won a 1978 Nobel prize for the chemicals that cut DNA precisely. Smith sounded most excited about nanotechnology. “You will pour DNA into a nanotube at the top, and at the bottom will be the sequence,” Smith said. “We will move into the era of individualized medicine much more rapidly than we would expect.”
The genomic and medical paths are also converging for Ralph Merkle, vice president of technology assessment at the Foresight Institute, established by the leading visionary of nanotechnology, Eric Drexler. As Merkle explained, the body’s own enzymes already can repair one strand of DNA’s double helix. Nanorobots in cells could theoretically work on errors found on both strands. “The idea of using externally provided information to guide the DNA repair process seems feasible,” he said. “This is going to lead to a revolution in medicine.”
Nanotech and Biomedicine
Merkle is well aware of proposals to ban nanotech research, concerns spawned by novels such as Michael Crichton’s “Prey.” Merkle opposes any constraints. He noted Charles Babbage could have built a rudimentary computer in the 1840s using the same relays found in the telegraph industry. “He had it all nailed,” Merkle said of Babbage. “We could have had [the computer] a century before. It’s worth pondering. How did we miss that? The most important invention of the 20th century! Delays in research are major. When we have a research crash, no one notices.”
The marvel of the Time meeting was that for every speaker like Merkle, proposing to double the human lifespan, there was someone like Paul Gelsinger, vice president of Circare, an organization dedicated to protecting the rights of patients in research. In 1999, Gelsinger’s son Jesse died in a clinical trial of gene therapy at the University of Pennsylvania.
‘The System Failed My Son’
When his son’s doctors explained the experiment they were about to conduct, Gelsinger said, “It was a beautiful picture. It was impossible to say no. And yet it killed him. I’ve seen a lot of enthusiasm out of a lot of people without stressing the danger of what they’re doing. The system failed my son at every level.”
Gelsinger’s remarks were calm and unemotional. But they occasioned several sympathetic outbursts from the audience. (Participants often both complained about the pharmaceutical industry and implored it to discover new drugs faster.) Gelsinger singled out a well-known bioethicist and the doctors on Penn’s institutional review board (IRB), which he said was shot through with financial and personal conflicts of interest.
Gelsinger’s comments about the limits of IRBs were echoed, improbably enough, by Dean Hamer, chief of the gene structure and regulation section of the National Cancer Institute, who is best known for his discovery of genetic links to sexual orientation. Hamer said part of the problem with clinical trials is the secret blueprint guiding each one – a proprietary, regulatory document known as the study protocol. “The way they conduct the trial is completely hidden,” Hamer said. “That’s plain wrong. All drug trials need to be open.”
Even Hamer, however, was bullish to the core. Walking the audience through the role of the neurotransmitter dopamine in the brain, Hamer said the next big crop of drugs might be to help with addictions of all kinds. “Almost all addictions have a common basic brain mechanism,” he said. “The next breakthrough that I’m thinking about is, we will have drugs to get over addictions,” which, he said, account for half of all hospital admissions.
Twenty Years On, Zip
On the clinical front, the meeting presented at least one speaker on intimate terms with the pace of scientific progress. “We will find cures for diseases,” said Nancy Wexler, a Columbia University neuropsychologist, relating her own hopes for genomics. She reviewed a bit of her own quest for the gene for Huntington’s disease. That gene, identified 10 years ago, has been studied in worms, fruit flies, and other creatures, she noted, but “the treatment is no better than when my mother died in 1978.”
For Wexler, one of the primary obstacles to finding a return on the nation’s investment in genomic research is more mundane. Despite a diagnostic test, only three percent of at-risk patients have been checked for Huntington’s disease, she said. The underlying reason is fear of losing insurance. Without effective treatments, and insurance to pay for them, many patients will prefer a “don’t ask, don’t tell” policy for their inherited diseases. That, in turn, could delay efforts to recruit patients for clinical trials to make the work of Watson, Venter, Smith, Collins et al. bear fruit.
SIDEBAR: The Business of Life
In addition to its scientific luminaries, the “Future of Life” podium was salted with observers such as venture capitalist Steven Burrill. “We have digitized biology,” he said. “That has brought a new set of players.” Burrill said he was increasingly interested in companies developing diagnostic tests.
Juan Enriquez, director of the Life Science Project at Harvard Business School, took a more historical approach. To him, every revolution in industry (railroads, cars, computers) has begun with hundreds of companies that gradually perish or merge into five major survivors. So, too, with genomics, he said.
The catch now is that human resources are scarce. In an era when Novartis scientists voluntarily emigrated from Switzerland to Boston, Enriquez said, only 15 percent of scientists from China choose to return to their native land. “You have to treat people carefully,” he said. “You can make your nation very rich, or lose it very quickly.”
Commenting about potential political restrictions on research, Enriquez said the toll might be bigger than lawmakers appreciate: “If we can’t make this work, someone else might.” He noted that countries such as Canada, for all their well-intentioned regulations, have no well-known companies making drugs.
SIDEBAR: Tech Prophets
The air in Monterey was full of predictions, some practical and some not. Caroline Kovac, general manager of IBM Life Sciences, said a tectonic shift is under way, endangering the pharmaceutical companies and the mega-drugs they can’t seem to find: “The blockbuster won’t go away. But the model will change, and those companies that don’t get it may not be around.”
Artificial reality pioneer Jaron Lanier, chief scientist of Advanced Network and Services, took a more fanciful approach. He hopes technology serves up a system for nonverbal communication and virtual copulation that would allow people to transcend the limits of their bodies and cable modems.
Addressing the possibilities of genetics and bioinformatics, Lanier was dismissive. “The biologists have been sold a bill of goods by the software engineers,” he said. “It wasn’t as good as what they promised. To put it bluntly,” he added, “the software still sucks. It won’t be able to handle the complexity we’ll see.”
Sun Microsystems' Bill Joy was sober, reserved, and optimistic. The company’s chief scientist and CEO warned that his fellow speakers might not be dreaming big enough.
“People have to be wary if people say something is impossible,” Joy said. “By 2010, the hardware is likely to get about 30 times faster than it is today. Our ability to create software is likely to increase at the same amount.” Joy suggested digital analyses of entire cells could become 1,000 times faster. “A calculation that would take a year today would take about eight hours,” he forecast.