Fighting Disease On The Molecular Front : Leroy Hood Built A Better Gene Machine And The World Beat A Path To His Lab

When you walk out of the elevator and into Leroy Hood’s molecular biology lab on the Caltech campus in Pasadena, you don’t get any particular sense of electricity in the work spaces or tension in the halls. Despite the profusion of centrifuges, tissue cultures and microscopes, the atmosphere seems so drowsily low-key that the place could easily be a junior college biology lab instead of one of the most respected, successful and, in some circles, feared facilities in the country.

The reason it’s so regarded is the size and productivity of Leroy Hood’s lab. Unlike most labs, which at best have eight or 10 workers who at best might publish 5 to 10 papers a year, Hood has 65 people who put out 30 to 40 papers a year (Hood himself has published more than 250). Working in some instances with medical research centers, they’ve done award-winning work in the molecular biology of the immune system. They’ve discovered a new diagnostic tool and a potentially much more effective and safe vaccine for Hepatitis B, which affects about 200 million people worldwide and is a leading cause of liver cancer. They’ve discovered a new and hitherto unsuspected class of renegade proteins called prions, which may lead to an understanding of the causes of such degenerative disorders as Alzheimer’s disease. They’ve come up with a simple blood test for diagnosing T-cell leukemia and have defined the process by which cancer genes transform normal cells into cancerous tumors. Most important, perhaps, they’ve developed four new microchemical instruments that, by allowing the workers to analyze and synthesize genes and proteins, have opened up whole new worlds of research.

Because the Hood lab is so large and formidable (the facility runs 24 hours a day), a lab staffer merely has to mention at a conference that the lab is working on a project and tremors race through the field. “The level of fear that people go through is really quite amazing,” says Mitchell Kronenberg, a postdoctoral fellow who’s worked with Hood for the last nine years. Because of the lab’s size, “people from the outside see us as a big army, organized to scorch the earth. In fact, it’s more like an amoeba, disorganized and moving in a lot of different directions.”

But people don’t know that, he says. When he was out looking for a teaching job, “people would always say: ‘Well, how can you compete with Lee Hood’s lab?’ I’d say: ‘Well, you know, I’m from that lab, and I know that in most cases you’re really competing with one or two “postdocs” and a graduate student.’ ”

Some labs live in such terror that the Hood lab will beat them to publication, Kronenberg says, that their research papers are professionally embarrassing. Kronenberg says he saw one paper on which the authors couldn’t have spent more than three days, instead of the usual two weeks or more. There were a dozen major spelling errors and wrong names, and the authors wrote things like “we have found 14 cases” and then listed only 13. “It was clear that these guys must have been scared to death of us, and they just felt they had to get it out.”

In another instance, Kronenberg says, a young researcher at a recent major conference began a talk on the subject of T-cell receptors with the remark that he’d had a discussion with Leroy Hood “and we agreed that we would use his nomenclature for the variable genes of the T-cell receptor”--whereupon everyone in the room started to laugh. The feeling was, how could anyone just starting out possibly have had an equal discussion with the eminent Lee Hood?

In contrast to his formidable reputation, Hood, in person, is a clean-cut, soft-spoken molecular biologist (he also has an MD) who wears khaki shorts and short-sleeve plaid shirts to work and whose idea of a big night on the town is dinner in a sushi bar. He grew up in Shelby, Mont., surrounded by 100,000-acre wheat farms. In high school, Hood blossomed, quarterbacking the football team (undefeated in Hood’s last 3 1/2 years), acting in school plays, performing in the band, competing on the debating team and editing the yearbook. When, at the end of his high school career, he became the first Westinghouse Science Talent winner from Montana, 500 people--a quarter of the town’s population--showed up at the train station to see him off to Washington.

Although Hood has come a long way since he got on that train, in many respects, friends say, he still acts like that small-town Montana boy, alternating the same four plaid shirts day after day at the lab, dining at the same three Pasadena restaurants and, most of all, acting like “a 47-year-old Boy Scout”--which is to say eager, energetic and unfailingly enthusiastic about science. “I can’t imagine a better life than what I’m doing,” Hood says. “We’re right at the frontier of a series of different fields. It’s an incredibly exciting life.”

Although most people start to slow down when they reach their mid-40s, Kronenberg says, “Lee is driven like a 30-year-old postdoc.” He sleeps only four or five hours a night, runs 10 miles a day and sometimes shows up for work at 5 in the morning.

Furthermore, as opposed to many other professionals in this highly competitive field, Hood is not riddled with self-doubt. “You can criticize him to his face,” Kronenberg says, “and, unlike many people I know, he won’t get offended.”

“Lee thinks that anarchy brings out creativity,” Kronenberg adds, which is one reason students like working for him: there isn’t any chain of command, and graduate students are treated as peers.

In addition, Kronenberg says, Hood “pretty much lets you do what you want. . . . If it’s blatantly silly, he might try to discourage you right at the beginning. But if you really want to do it, you still can.”

The two most common complaints about Hood are that his lab is more of a factory than a research facility and that he spreads himself too thin. Although Hood disputes the factory charge, it’s more difficult to argue that he doesn’t try to do the work of three people. Not only does he run a lab that is five times the size of most other facilities, but he is also director of the Caltech Cancer Center and chairman of Caltech’s Biology Division. He directs about 30 postdoctoral fellows and 10 graduate students. He’s the editor of five professional journals, a science adviser to Congress, a member of the National Academy of Sciences, author of four textbooks and a frequent visitor to most of Europe and North America to give talks and seminars.

It’s hard to believe the amount of traveling Hood does, Kronenberg says. “He’ll go to England for a day, come back the next day, be here a day and then go off to New York.” Once, Kronenberg says, for Hood’s birthday, everybody at lab wore T-shirts that read “The Lee Hood World Tour” and that had a drawing of the globe and dots for all the cities Hood had visited that year. “I still wear (the shirt) occasionally. And people (at the lab) joke: ‘Oh, who’s Lee Hood?’--like they’ve never heard of him before.”

As a research scientist, Hood initially made his reputation working in two different areas of molecular biology: antibodies, the molecules that defend against infections, and transplantation antigens, the molecules that help decide whether to accept or reject transplanted organs. But Hood’s most significant contribution to science, says his principal associate at the lab, New Zealand-born biochemist Steven Kent (the researcher who discovered the new Hepatitis B vaccine), has been in an area that some biologists don’t even consider real science--methodology and instrumentation.

Because some of the most interesting and significant proteins in molecular biology exist only in millionths-of-a-gram quantities on the surface of cells, getting enough of a particular protein to conduct any research used to take as long as 10 years and cost enormous amounts of money. What was needed were machines that could not only perform the extremely complex chemistries automatically but that also could do so with a tiny fraction of the protein previously required.

As a graduate student in the mid-’60s, Hood had worked under Caltech biologist William J. Dreyer, who for years had expounded the heretical thesis that what drives the pace of scientific progress isn’t so much the quality of scientific talent, which is pretty much constant from year to year, as the available technology. Inspired by Dreyer, Hood in 1975 assembled a team, led by Caltech chemist Mike Hunkapiller, to build a protein sequencer--a machine that would use automated chemical analysis to determine the structure of a given protein.

At first, Hood encountered a lot of resistance to the idea. The major funding organizations were set up to fund research on organs such as the heart or lungs, or diseases such as cancer or diabetes, and funding for instrumentation didn’t readily fit any existing slot. As for other molecular biologists, Hood says, they regarded the development of such an instrument as “a second-rate endeavor” unworthy of a research scientist.

“After about the first year and a half of my being an assistant professor here at Caltech,” Hood says, “one of the professors came to me and said: ‘Are you sure it’s a good idea to spend so much of your time doing instrumentation? Wouldn’t you be better off in terms of your tenure and promotion if you concentrated on the immunology, the biology and the other things?’ ”

Although the protein sequencer would undoubtedly have been disastrous for his career if it had failed, Hood says, all doubts vanished by the end of 1980, when he had a working prototype. The ability to work with as little as 1/10,000th of the protein previously required to do research opened up new worlds of possibilities.

The sudden realization that the Hood lab was the only one in the world with such a sensitive sequencer caused resentment and uneasiness among other researchers. Those who had once ridiculed the concept now lined up to get some time on Hood’s machine. “People were very insistent that their project was very important,” Hood says. “ ‘Gee, it’s unfair. You developed these things and you’re keeping them to yourselves.’ And ‘who were we,’ they’d ask, to decide whether their project was appropriate for this machine or not?”

To take the pressure off his lab, Hood searched for a company to develop a commercial version of the protein sequencer. He was turned down 19 times in a row before a start-up company in the San Francisco Bay area decided to take on the task. In molecular biology labs around the world, the protein sequencer is now as standard a piece of equipment as the microscope.

In one of the machine’s early applications, Hood determined the molecular structure of interferon, which some scientists thought might be a “magic bullet” that would attack cancer cells without harming healthy tissue. The problem with interferon was that it was so difficult to isolate from living cells that one estimate put its cost at $22 billion a pound.

“At the time,” Hood says, “no one else in the world could do the kinds of things that we could do, and that’s what made the situation so strikingly unique. From the time people were aware that we were even beginning to try to do the structure of these interferons, there was a constant parade and charade of phone calls and people coming by to chat--’Would you be interested in a $200,000 grant to carry on a collaboration with us?’ ” At other times, strangers showed up at the lab, trying to pry the interferon sequence out of the lab technicians. It became such a standing joke that Hood’s people began to make up arbitrary interferon sequences, posting them on a bulletin board every week.

When the lab finally came up with the sequence for interferon, Hood announced it at a large international meeting, at which people jumped up, took pictures and ran for the telephones. Afterward, he says, people came up to him and said he was either very noble or “naive” to give away such a valuable secret for other labs to clone. “Well, we weren’t naive,” Hood says. “Cloning interferon was not something I wanted to get into.”

Hood’s intuition proved prescient. Not only was interferon not a magic bullet, but it also has debilitating side effects, though it still may prove useful in the treatment of hepatitis, herpes, colds and certain cancers.

After coming up with the protein sequencer, Hood’s instrumentation group went on to develop a DNA synthesizer to create strands of DNA; a protein synthesizer for making protein in the lab, and, finally, their latest invention (still under development): a laser-equipped sequencer for determining the structure of DNA.

For people outside molecular biology, it’s hard to appreciate what a difference these sequencers and synthesizers have meant to basic research. “With the new chemistry that Steve Kent has devised,” Hood says, “we can synthesize whole proteins and study their function in ways that just weren’t possible a couple of years ago.” In the past, researchers would have been deliriously happy to have so much as a milligram of a certain protein; now, Hood says, any researcher can turn out a gram, 10 grams--whatever is wanted.

In other instances, Hood adds, it might have been necessary to kill 1,000 mice to get enough of a particular protein to do a given experiment; these machines allow a researcher to get by with the destruction of only one or two. Perhaps even more telling, the first gene synthesis took 20 assistants five or six years to accomplish. With the machine, Hood says, “We synthesized that same gene in less than a day, using part of the technician’s time.”

Hood compares the effect on biology of the two sequencers and two synthesizers to the effect cyclotrons and particle accelerators had on high-energy physics: “They let physicists penetrate down to the basic structure of matter.” And in conjunction with recombinant DNA and monoclonal antibody techniques--the other two major technological advances of the last decade--these new machines allow medical researchers “to manipulate and analyze genes and proteins in a way that was utterly impossible before.”

In the immediate future, the Hood lab plans to do further research on antibodies, T-cell receptors, which allow T cells to recognize the modified molecules that cause cancer, and cell-surface genes called HLA genes, which determine whether transplanted organs will be rejected or not. Such research could lead to a solution to the graft-rejection problem as well as allow doctors to prepare gene catalogues that would help them predict the likelihood that any given individual would come down with such diseases as juvenile diabetes or rheumatoid arthritis.

In the area of neurobiology, Hood’s lab has been able to trace a neurological disorder in a strain of mutant mice--uncontrollable and fatal shivering--to a specific gene defect, the first time that has ever been done in a mammal. Hood’s people then used the rodent gene to clone a human gene, thereby opening a new avenue of study for such diseases as multiple sclerosis and Guillain-Barre syndrome.

Hood’s remaining areas of interest are hormones and growth factors. Studies of hormones, Hood says, are fundamental to understanding the growth and development of human beings. And an understanding of growth factors, which the body mobilizes to create connective tissue for repairing wounds or fighting pathogens, could show why, under some conditions, normal hormonal-growth mechanisms can go astray and cause cancer.

The eventual result of all this research--still many years down the road--will be an understanding of how genes are regulated, how the nervous system functions and how a fertilized egg becomes a complete individual. Furthermore, Hood adds, it won’t be pie-in-the sky research that needs an elaborate rationale. It will have direct implications for the health and well-being of human beings. The T-cell research alone, Hood says, will “revolutionize” modern medicine in the next 5 to 10 years by giving scientists the tools to diagnose and treat degenerative and auto-immune diseases.

Although Hood doesn’t say what his even longer-range plans are, the people who work for him wouldn’t be surprised to one day see him go into business, politics or even, laughs one of the lab’s postdoctoral fellows, “start a new religion.” It is also not inconceivable that he might win a Nobel Prize, the only major professional achievement he has yet to attain.

Getting a Nobel, Mitchell Kronenberg points out, is not just a matter of sitting around and waiting to be awarded one. Like most important honors, it’s a political award--that is to say, in order to win it you have to “call attention to your accomplishments.” For scientists, one way to do that is to publish papers and hold seminars, which Hood does in profusion. The other way is to find excuses to go to Stockholm. Kronenberg says Hood doesn’t do it consciously, since he’s not a calculating guy, but given that country’s modest scientific importance, “I think he’s made more than the expected number of trips to Sweden.”

Hood himself says that he really doesn’t think about the Nobel Prize, pointing out that the awarding of the prize can be somewhat arbitrary and that lots of people who deserve it never win. Also, he’s won prizes before, and once you win them they’re over--and then you go on to something else. As far as prizes opening up any doors for him: “I already get 10 job offers a year, which is more than I can handle anyway.”