 MSNBC.com |
Summer 2005 - The human genome project may be near completion, but the "real" human-genome project is just getting underway. Scientists now know the sequences of most of our genes. But they don't necessarily know how those genes work or, considering that most of the genome is "junk" DNA that doesn't contribute to the body's normal functioning, whether they work at all. In other words, we've got all the pieces, but we still need to put the puzzle together. Many of the geneticists who worked on the original HGP are now pursuing follow-up projects on their "genes of interest." Here are four who will help give us the complete picture.
The Matchmaker
Leroy Hood is given to car metaphors. "If you want to understand a car, you can't just study the carburetor," he says. "You need to study all the parts and how they function together as the car travels." If that's true, Hood must be the world's best mechanic (metaphorically speaking, of course). When he first went to Caltech in 1970 on a three-year fellowship, he told his department chair that he wanted to spend half his time doing biology and half doing technology development—with the ultimate idea of using that technology to study all the parts of the body simultaneously, as a system, via multiple perspectives. Hood had a vision of devices that could read human DNA and proteins, and computer systems that could analyze the results. "At the end of the three years [the chair] urged me in the strongest possible terms to give up the technology," Hood says. But Hood was stubborn, and he was also right. Now, as president and director of the Institute for Systems Biology—a one-of-a-kind organization based in Seattle and independent of academia—he is a scientific matchmaker, bringing biologists together with chemists, engineers, computer scientists and applied physicists.
Hood's fingerprints are all over modern genetics. He was one of the earliest advocates of the Human Genome Project, at a time when many people thought sequencing the genome was a largely useless, and maybe impossible, goal. He is also one of the people who made the project possible by inventing DNA and protein sequencers, which "read" the molecular contents of those chemicals, and synthesizers, which allow scientists to produce large quantities of them for experimentation. He has played a role in founding several of the country's best-known biotech firms, including Amgen and Applied Biosystems.
Lately he's been working on a project that analyzes how protein molecules fold (page 52)—and, as a result, how they interact with other chemicals in the body to either keep systems running, build new bodily components or, alternately, cause disease. If he ever needed proof that technology and biology were made for each other, the protein-folding project is it. The task would take "a hundred thousand years with our computers," Hood says. But he has a corporate partner in IBM and access to the company's Grid system, which uses "brain" power from computers around the world to do immensely complicated math.
The Quick Study
When colleagues say there ain't no mountain high enough for Rick Young, they mean it: an avid skier and climber, he's hiked the Himalayas three times. But years from now, they may regard as his true triumph a task that once seemed even more daunting. Young studies transcription factors, which he describes as switches that turn genes on or off. (There are about 2,000 transcription factors in the human body.) A century ago, he says, it would have taken one scientist one century to understand one switch working on one gene. Now, he says, it takes "one person about two weeks to understand what one transcription factor is doing across the entire genome." That's largely because Young has figured out the fastest way to do it.
Young's lab can take a living cell "going about its business," he says, and freeze it in action by adding formaldehyde. The chemical cross-links the transcription factors to DNA in the nucleus, capturing them where they're acting (the factors do their work by binding to the DNA strands as the genetic material is copied). Then all Young has to do is break the cells open and identify which DNA sequences the transcription factors are stuck to.
Armed with Young's techniques, scientists of the future should someday be able to study diseases that stem from problems with transcription factors—including diabetes, cancer and immune dysfunction. With luck, pharmaceutical companies will then be able to create drugs that simply turn the relevant switches on or off. And "someday" may be just a few years away, says Young, particularly for diseases like diabetes that are controlled by a particular type of transcription factor called a nuclear hormone receptor. Transcription factors in this group can often be induced to drastically change their activity if they bind to other molecules. One nuclear hormone receptor called HNF4alpha even binds to fatty acids, which are part of a regular diet. Francis Collins, the leader of the Human Genome Project, recently published papers suggesting that HNF4alpha plays a major role in diabetes. "So here is a factor that's controlling the genes in your pancreas and liver, and it senses what you eat," says Young. "What we don't know yet is, how would you modify your diet to have a beneficial effect?" Given how fast Young usually works, it probably won't be long until we do.
The Math Magician
It's a truism that some scientists are stymied by an inability to communicate their ideas to people outside their fields. Eric Lander isn't one of them. Here he is on modern medicine: "It's like taking your car to a mechanic who has no idea what's under the hood and is trying to fix the car based on listening to the noises it makes." (What is it with geneticists and cars, anyway?) And here's Lander on trying to study big problems with tools made for a small scale, which is largely what science has been doing all along: "It's like trying to see continental drift by walking around Cape Cod." And on the genome: "Evolution has been carrying out experiments for the last 3.5 billion years. It gets up every morning and says, 'Let's change a few letters.' And then it leaves us notes."
Lucky for us, Lander knows how to read those notes. A Rhodes scholar originally trained as a mathematician, he is now quite possibly the country's leading molecular geneticist, the founder of one of the world's first and best genome-sequencing centers (the Whitehead Institute/MIT Center for Genome Research) and one of a small coterie of visionaries behind the Human Genome Project. Unlike many scientists, he puts his snappy metaphors to frequent use—he's a beloved teacher on the MIT campus, and he's got awards to show for that, too. He won the Westinghouse Prize when he was just 17 for a paper proving that quasi-perfect numbers exist only in theory. Oh, and he's a really nice guy. In short, he's the sort of scientist you'd think would exist, well, only in theory.
Not bad for someone who started his scientific career as a dabbler, auditing a biology course at Harvard along with younger students and "moonlighting, cloning fruit-fly genes in labs at night." (During that time he was also teaching economics at Harvard Business School, even though, he admits, he knew very little about the topic and his degree was actually in math.) In the early 1980s, he happened to meet an MIT geneticist who was working on ways to scan human DNA for genes that were the sole causes of specific diseases. The real trick, though, was figuring out which genes were involved in more-complex diseases with multiple causes like cancer. Lander wasn't really a scientist, but he had an idea for a statistical technique that might help. Within two years he had launched his genome-research institute. And that was pretty much the end of teaching econ.
The Whitehead Institute would go on to lead the effort to map the human and mouse genomes. Lander essentially provided the mathematical scaffolding for the full human-genome sequence, giving scientists a template by which to organize their data. His techniques have also helped other scientists identify genes involved in cancer, diabetes and inflammation, among others. These days Lander has returned to his mathematical roots. With the genome sequenced, he says, his job now is "purifying the information away from the molecules," trying to understand DNA at a submolecular level with sophisticated mathematical techniques. He still focuses on multigene diseases—for example, tracking down all the mutations that can cause cancer. "That's a finite problem—a big one, but big shouldn't scare us anymore," he says.
The Optimist
Inder Verma is one of very few people with anything good to say about HIV. "It becomes part and parcel of the chromosome and stays there for years," he says. "And it has learned the trick of allowing itself to grow in cells that aren't dividing." Neither of which is a good thing if you're an HIV patient, of course. But if you're Verma, and your goal is to "take a virus and convert it into a friend," then HIV is your best buddy. Several years ago Verma was pondering one of the biggest problems with gene therapy—how to introduce genes into existing cells. "You can't inject billions of new cells with a needle," he thought. "You can give [drugs], but that's a very inefficient process." Viruses, over millions of years of evolution, have solved the problem by insinuating themselves into cells and co-opting the cellular-reproduction machinery—without killing their new hosts. So why not use them to our advantage? Verma's lab decided to strip down a virus, removing the disease-causing components while making use of the cellular-hijacking machinery. But which virus? The obvious choice was HIV, since scientists already knew a great deal about it. The result was a "friendly" HIV strain that could (theoretically, at least) introduce new genes into patients who lacked properly working versions of them.
Since then, scientists have commandeered a number of other viruses for therapeutic purposes. Verma admits that the field still faces some major challenges. Ironically, one of them is the question of how to overcome a patient's immune system—the very thing HIV's disease-causing parts, now removed, would normally target. (The short-term solution is suppressing the immune system with drugs.) Producing gene-therapy viruses on a large scale is another ongoing problem. Nonetheless, Verma says he expects to see gene therapy available for cancer patients with-in the next 10 years. "We don't want to get too cocky," he says. "Yes, man made it to the moon, but the physical principles, like gravity, were already known," whereas even the basic principles of gene therapy are still somewhat hazy. On the other hand, he adds, "we have to be optimistic. Usually timetables are beaten. I went to a meeting in India recently, and the title was 'Can Cancer Be a Chronic Disease?' Who would have even thought to ask?"