Rebecca L. Rawls
C&EN Washington

	[Photo by Paul Fetters]

A few minutes after the scheduled  hour, Thomas R. Cech comes  quickly out of his well-appointed office in the handsome complex of buildings in Chevy Chase, Md., that is the headquarters of the Howard Hughes Medical Institute (HHMI) . Gracious and informal, Cech nevertheless gives the impression of a busy man.

No doubt he is. Since last January, when he became president of HHMI, the 52-year-old chemist has been jetting back and forth roughly every other week between this post and the University of Colorado , Boulder, where he continues to head his world-renowned biochemistry laboratory.

That adds up to "a full-time job in Maryland on top of a fairly major one in Colorado," as Cech describes it, and a schedule that he admits is brutal.

"It's a huge number of hours per week," Cech says. "But, on the positive side, it keeps me from losing touch with what it's really like to do science. And I think it may be important for a major science administrator to maintain some contact with what it takes to really be involved in the process of what we are funding. As long as I keep an active lab, it will be impossible for me to become insulated."

[Photo by William Geiger]

Cech recently talked with C&EN about his decision to take on the leadership of the country's largest private supporter of both biomedical research and science education. He spoke, as well, of some of the directions in which he hopes to steer the institute in the years ahead.

"There's a sort of electric excitement when someone comes into a new field, perhaps a little naively at first," Cech notes. "They are a newcomer; they don't know all the ropes. But they bring a whole new way of looking at things that can often solve problems that people who have been looking at those problems for a long time might not be seeing. A fresh look."

Although Cech isn't referring to his own experience of taking over the presidency of HHMI, a fresh look may be exactly what he brings to the institute. He comes to the position with impeccable credentials as a chemist and biomedical researcher--including a Nobel Prize in Chemistry. But he's definitely a newcomer to science administration. And tapping a chemist, rather than a physician, to head an institution that has come to play an influential role in shaping the direction of biomedical research raised a few eyebrows when HHMI announced its choice last year.

In fact, Cech's association with the institute is a long-standing one: He's been supported by HHMI as an investigator since 1988. And the research areas that he's been exploring--like much of chemistry today--have clear implications for eventual understanding of health and disease.

His background as a chemist "certainly gives me a tremendous appreciation for work that tries to get to the atomic and chemical basis of problems," Cech says. "I always get the most excited, personally, when the chemical and mechanistic basis for biological phenomena can be identified.

"But in my own work, I've always thought it was a bit sterile to think of biomolecules as just chemical entities," Cech adds. "They are wonderful chemical entities. But at the same time, the thing that is very exciting is the way that they are choreographed into interactions with each other in the living cell. In my own group, we've always tried to relate the chemistry that we do back to what's happening in a living system."

Many of the most important biomedical problems are currently understood at what Cech calls "the phenomenological level, not the molecular level. I don't see that as a discouraging thing," he adds. "I see it as an opportunity."

Cech has been a superstar among biologically oriented chemists since 1982, when he and Sidney Altman of Yale University independently found that RNA can have catalytic functions. The two shared the 1989 Nobel Prize in Chemistry for this work.

More recently, the Cech lab has probed the mechanisms of RNA catalysis, particularly in the microorganism Tetrahymena thermophila. In addition, his group has been studying the structure and replication of the tips of chromosomes, called telomeres. Cancer cells and some healthy cells keep replenishing their telomeres through the action of an enzyme called telomerase, which is also under study in Cech's lab.

That research has been very satisfying. "I think we've had a pretty successful run," he says. The research "has branched out in some new directions with the telomerase work, and that's been great. But I've always been interested in, and felt a responsibility, really, to do more than just the research."

Science education rates high among his other interests. A gifted and engaging lecturer, Cech has taught undergraduate general chemistry at Colorado for six of the past eight years, in addition to directing the research of graduate students. Since winning the Nobel Prize, he's also served on a number of outside review panels for organizations such as the Packard Foundation , the Burroughs Wellcome Fund , the Salk Institute , and the Whitehead Institute at Massachusetts Institute of Technology.

Serving on such outside panels has been useful, Cech says, but not quite hands-on enough to satisfy him. "These visiting committees come and listen, make some pronouncements, and then go, leaving it to the people there to do the real work of trying to implement the fragmentary vision that you leave them with. That's not the way to get things done. In a research lab, the vision may sound great, but by the next day, there are already problems with it. You have to adjust it, and you have to recover from times when things aren't going well. It requires continuous effort. I think the same is true with science policy, with running scientific institutions at the national level, and with science education.

"I came to realize," Cech says, "that I wouldn't really fulfill my desire to make a large-scale impact unless I jumped in with both feet."

The offer to become president of HHMI came a little sooner than he had hoped, however. He had promised his wife that he would wait until their children were through high school before moving anywhere, and "that was still five years away last year when I was approached about this job," Cech says. The opportunity, he felt, was too good to pass up.

Indeed, it's easy to see why heading up HHMI would be attractive to someone who wants to make a national impact on biomedical research and education. Although established in 1953 as a medical research institute, HHMI really took on its present character in 1985. That's when the trustees sold HHMI's principal asset, Hughes Aircraft, to General Motors for approximately $5 billion. They converted the income into an endowment to support a greatly expanded program of biomedical research.

In 1984, the institute supported 54 investigators and had a budget of $36 million. As Cech takes the helm, the institute's resources have grown to about $13.1 billion, thanks largely to the surging stock market of the intervening years. Its annual budget for biomedical research is now about $460 million, with new investigators announced in May bringing the total number receiving support to 353 ( C&EN, May 15, page 36 ). In addition, HHMI spends about $100 million a year on grants to improve science education, a program that began in 1987.

The institute actually employs the researchers it supports. That means HHMI pays their salaries and rents laboratory space for them at the universities or other research facilities where they work, in addition to purchasing research equipment, providing stipends for postdocs, and picking up the other costs of running a biomedical research program. In return, investigators commit three-quarters of their time to research and the rest to other professional activities, with priority given to activities at their own institution, such as teaching or administration.

The strategy at HHMI has been to try to identify areas of biomedical research likely to have a major impact in the coming decades and then to hire the most promising researchers in those areas. The institute has been very successful in hiring the people it wants because it supports them generously and gives them largely free rein to follow their instincts in their research. Support is generally for five years at a time, and it can be renewed as long as the researcher continues to do outstanding work.

"We support people, not projects," Cech says, noting that HHMI has built a reputation for banking on its ability to choose researchers who will take on important problems and be productive in addressing them. The approach frees researchers from what Cech calls "detailed grants management responsibilities." And researchers love it.

Cech is quick to point out his admiration for the vision and accomplishments of HHMI in recent years under the direction of his predecessor as president, Purnell W. Choppin, and the vice president and chief scientific officer, W. Maxwell Cowan, who retired in March. "We're not going to disband the very successful biomedical research program or the science education program," Cech says. But he is already moving to begin what he's calling "an evolution in what HHMI means to the scientific community."

He's spending his first year "getting our leadership team on line." In addition to Cech, the institute has three new vice presidents: David A. Clayton, who had been HHMI's senior scientific officer, is the vice president for science development. Gerald M. Rubin, a professor of genetics at the University of California, Berkeley , is the vice president for biomedical research. And Nestor V. Santiago, an investment officer from the International Monetary Fund, has become chief investment officer and a vice president.

The new team is spending much of this year shaping its plans for the future. "We need to know in five and 10 years' time where we want to be, depending on different stock market scenarios," Cech explains. With all of its income coming from the Hughes endowment, the institute's future is largely shaped by the success of its investments.

"As the endowment grows--which it has, historically, faster than inflation--instead of putting the additional funds into existing programs, we want to develop new programs that cut across in a different direction," Cech says. "We will use the additional funds for these new initiatives.

"It's really more than a vision at this point," Cech says. "It's a plan."

The team has two initiatives in mind. One is to change the way the institute's biomedical research and science education programs interact with each other. HHMI "has had a marvelously successful program in each area, but there has been quite a significant wall between the two," Cech says.

[Photo by Rebecca Rawls]

"The investigators have generally not been told much and certainly have not been asked to participate in the education program activities," Cech explains.

Based in part on his own experience, Cech believes that many HHMI investigators want to be involved in improving science education in its broadest sense. "Our investigators are going to do this, whether we encourage it or not," he says. "We have such innovative people with such terrific minds in the biomedical area, it's really a natural thing for us to give them the opportunity to become involved in some of the activities on the education side."

Exactly what form this involvement might take is still being worked out. One thing, however, is clear: The impetus for specific projects will come from the investigators themselves. "There's not going to be a single program because it's important that people do things only if they love them," Cech says. "They will only do this well if they want to do it."

It's likely the involvement will take many forms. "Some of our investigators who are teaching medical students say that the medical curriculum on their campuses is antiquated and that they have some ideas about how to make it more dynamic, more relevant, more forward-looking. We have some investigators who would love the opportunity to be involved in medical school curriculum development.

"But there's another investigator somewhere else who doesn't care at all about that," Cech goes on. "He's concerned about the evolution versus creation debate" and the fact that so many people in the general public have little idea of how much scientists know about evolution. "Many of our investigators see evolution happening in their laboratories on a weekly basis. It's not just a theory, it's something that's predictable, that they use, and that obeys all the laws of science. This person would like to develop materials that would get the general public informed and perhaps even excited about what wonderful things natural selection and the evolutionary process are.

"Yet another investigator isn't interested in that at all," Cech notes. "She's interested in enriching science education on campus by having more laboratory experiences of a more open-ended, inquiry-based sort incorporated into the curriculum. She'd like to work with teachers and with science educators to develop those sorts of materials."

What Cech hopes for is to connect researchers who have these interests with HHMI's resources in science education. "Often visionaries don't know the process by which they would put their vision into a productive working situation," he says. "We can provide funds and structure for these activities."

Cech's second initiative is to substantially increase HHMI's efforts in the field of computational biology. Computers came rather late to biology, he points out. As recently as a decade ago, he says, they were used mostly for word processing to write manuscripts. "Now graduate students and postdocs in biomedical research laboratories are often spending half of their productive working hours sitting in front of a computer terminal."

And that trend, he's convinced, will continue. "If we jump forward 20 years and think about what things will be like then, we can imagine that bioinformatics and genomics are going to be the basis by which your physician decides how to treat you," Cech says. "Instead of a blood test that looks at liver enzymes, you may be getting a complete expression pattern of a particular set of genes, which will tell the physician which therapeutic regime is most appropriate for your case.

"We want to have a major role in supporting the sort of research activities that will lead to that end point 20 years from now," Cech says.

One example of the kind of research Cech has in mind is that of Patrick O. Brown , an HHMI investigator who is also an associate professor of biochemistry at Stanford University School of Medicine . Brown makes microarrays of different genes from patients who have a particular form of cancer known as large-cell lymphoma. He's working to develop computational methods to sort and display the data from numerous such arrays in ways that allow him to identify patterns of gene expression.

Such patterns can be the basis for sorting out subpopulations of patients who are likely to respond similarly to particular types of treatment. That information could radically change the nature of human clinical trials for candidate drugs, Cech suggests, and lead to the identification of drugs and other therapies that work very well when targeted to the right patients.

Potentially even more important, though, is the wealth of information contained in such arrays about the disease process itself. "Why is a particular set of genes all off in one population and on in another?" Cech asks. "Right now, we are just reading the information as a sort of fingerprint. The real advance will be to glean from this vast amount of information what it is telling us about the origin and development of disease. That's going to be where the clues for rational treatment come from. And that's where we are really still in the dark."

HHMI has been supporting Brown and a few other computationally oriented biologists for a number of years. The new initiative would substantially increase that effort. In May, HHMI announced 12 new investigators in computational biology.

As has been the case with other fields that the institute has focused on, HHMI aims to identify promising researchers, support them well, and give them the opportunity to tackle the major problems in the field. In this particular field, computers are likely to be a major expense. So, too, are computational experts to work as support staff for investigators.

"Salaries for computational experts are often difficult for universities and granting agencies to deal with," Cech says. They may be used to paying postdoctoral fellows $25,000 to $30,000 a year, when the starting salary for a young, promising person with a computing firm may be $80,000, he explains. "We can offer the capability for computational investigators to pay market-level salaries for their staff in order to be able to actually mount a sustained effort in this area."

Over the next decade, Cech expects HHMI to commit at least $200 million to research in this area. "There will be a lot more where that came from," he says. "We are just starting to ramp this up."

Busy as he is, it's clear that Cech is also enjoying himself immensely-- "even more than I thought I would," he says. "The people here are wonderful. The staff is energized; they are really good at what they do and very receptive to thinking about different ways of doing things.

"I guess I'm still in a bit of honeymoon period, and perhaps I'll be singing a different tune next year," he adds. "But so far, it's been very exciting, and I've had no regrets."

Top

Chemical & Engineering News
Copyright © 2000 American Chemical Society