"The emergence of these data completely changes the way biology can—and will—be done," says David Botstein, director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University. "From now on, biologists will design their experiments so as to look at the activity of an entire genetic system, rather than one gene at a time. But to do this, they will need to focus on quantitative biology—with, ultimately, an exact and predictable understanding of biological systems."

The planners of these centers all want to bring the "hard sciences," such as physics or computer science, into close contact with biology. One such advocate, HHMI Vice President Gerald M. Rubin, was appointed in May to be director of the Institute's interdisciplinary biomedical research campus, Janelia Farm. "People are generating information much faster than they can analyze it," Rubin explains, "and much of this information can't be analyzed without using physical, statistical and computational techniques."

The question now is how to arrange a productive marriage between these two cultures. Should the new centers be located in universities or in freestanding research institutes? Should they focus on provoking new discoveries in biomedical science, or on enlightening the rest of the scientific community? Moreover, each center has its own interpretation of "interdisciplinary." And some scientists are grumbling that money will be taken away from their own projects to finance what they see as a gamble. But the founders and directors of these centers are full of hope.

"We need to stir up the pot and create new flavors," says Matthew P. Scott, an HHMI investigator at the Stanford University School of Medicine who now heads an interdisciplinary program there called Bio-X. He notes that some Stanford biologists have been collaborating with researchers in the hard sciences for years. "For example, the cell sorter was invented here by immunologists working with engineers, and in recent years geneticists such as [HHMI investigator] Pat Brown teamed up with engineers to design microarrays—an amazing technology that allows us to systematically look at whole genomes." Yet, Scott says, "many biologists are not taking advantage of chemistry, physics or engineering in any way. As a result, they are running up against challenges that could be overcome by the techniques—or even ideas—of people in these other fields."

Of course it is not enough to simply throw people from different disciplines into the same building, Scott points out. "Proximity alone will not work," he says. "It will be necessary for people to talk, share ideas, explore possible collaborations. That's why we plan to have social events, scientific presentations and meetings—they are a key part of the picture. In fact, the social experiment is the most challenging part."

To spearhead the Bio-X program, Stanford built the Clark Center, an ultramodern structure scheduled to open this summer. The center was named after Jim Clark, a former Stanford professor and cofounder of Netscape, who pledged $150 million to set up Bio-X. (Clark later reduced his gift to $90 million in a protest over national policy on stem cell research.) Its 42 faculty members are being recruited from more than 25 departments in fields including biology, chemistry, medicine, surgery, electrical engineering, mechanical engineering, physics and computer science. Part of the building will be used for teaching—in labs, not classrooms.

In addition, Bio-X wants to connect with more distant disciplines. "It's important to remember that this is a university, not a research institute," says Scott. "One of our goals is to provide educational opportunities, some of which will, I hope, spur creativity in arts as well as science, and also consideration of the social impact of science. With all that we are learning about life and human origins, migrations of people traced with genetics, and the ways brains work, there's food for thought for philosophers, historians and sociologists. Law, too, has major connections to biology in bioethics, stem cell regulations, transgenic plants in agriculture, etcetera."

According to Scott, 260 Stanford professors have expressed interest in being affiliated with the Bio-X program. "We're identifying groups with overlapping interests," he says. "For example, robotics experts who want to work with surgeons, or microbiologists who want to collaborate with physicists and computer scientists to do simulations of cell circuits—it's surprising how many there are!"

A NEW "SYSTEMS BIOLOGY"
In California alone, half a dozen other universities are starting centers for interdisciplinary biomedical research. For instance, three campuses in the University of California system—the University of California at San Francisco (UCSF), UC Berkeley and UC Santa Cruz—have banded together to develop the California Institute for Quantitative Biomedical Research (QB3), and each of the three universities is building a center for it. UCSF's center is located at Mission Bay, in a new campus that is going up in what was previously an area of dilapidated warehouses and abandoned rail yards. The wide-ranging group of researchers being hired for it is expected to develop tools for a new "systems biology."

As Marvin Cassman, executive director of QB3, explains, "Biology is now ready to move on from its recent focus on individual genes and molecules to ‘networks of interaction' at every level—molecules, genes, cells, tissues, organs and even entire organisms—in other words, systems biology. Organisms are determined primarily by networks, not individual genes, and we want to understand all the architecture of the networks on a systems level, the way engineers think about it."

"You need many disciplines for systems biology," continues Cassman, who was formerly director of the National Institute of General Medical Sciences in Bethesda, Maryland. "You need genetics, genomics and proteomics so you can analyze the components (genes and proteins) that interact. You need physical chemistry and biochemistry to measure these interactions, and imaging tools to record where and when they occur. Then you need structural biology to understand why and how the molecules interact." In addition, he says, "you need computational expertise to integrate all these elements," as well as expertise in building models.

Not to be left behind, the University of Southern California has started construction of a Molecular & Computational Biology Building for "interdisciplinary research at the forefront of the biological sciences," according to a university announcement. Its "hybrid" labs will be designed for "a new kind of biologist who combines the approaches of computational biology with those of molecular biology."

Other parts of the country are showing similar activity. "Everywhere I go," says David A. Clayton, who travels a great deal as HHMI vice president and chief scientific officer, "it's déjà vu all over again: new centers for biotech and proteomics, combined with computational biology and chemical synthesis. But staying at the edge of rapidly evolving technology is a big challenge. Only the most research-intensive institutions will have a chance of success."

In the Midwest, the University of Michigan is about to open a Life Sciences Institute building, which will bring together researchers from three broad areas of biology—genomics and proteomics; molecular and cellular biology; and structural, chemical and computational biology. Its charter members include HHMI investigators David Ginsburg, a geneticist, and John B. Lowe, a pathologist. Its director, Alan R. Saltiel, is a cell biologist who believes that at the center of the institute's three fields lies "a deeper understanding of life at the cellular level."

"The Life Sciences Institute…is somewhat of an experiment," states a University of Michigan news release, because it will try to break down the traditional walls of academic departments and because its scientists will work in a new "lab without walls" that is designed to foster interaction. Saltiel hopes these scientists will develop and use new research tools to "advance the life sciences into the next level of sophistication." As in most centers that are based in universities, however, the scientists will be there only half the time. The other half will be spent teaching and carrying out normal duties in their own departments, where they will have dual appointments.

One university that seems particularly interested in bringing a message about genomics to its entire campus is Duke University in Durham, North Carolina. Its Institute for Genome Sciences and Policy, which was launched in 2000, includes a Center for Genome Ethics, Law, and Policy, as well as four centers dealing with genetics, human disease, genome technology, and bioinformatics. Huntington F. Willard, its new director, declares that "the genomic revolution will have as much impact on our lives as did the industrial revolution," but acknowledges that it may create "fear and confusion, as well as knowledge and progress, along the way." He believes that besides producing fundamental changes in medical science, genomics will affect law, ethics, religion, business and other fields, altering everything from the foods we eat to how we view ourselves. Therefore, he says, Duke wants to ensure that "every student, from freshmen up to graduate and professional students in all fields, will have contact with the genome and its implications."

Meanwhile, not surprisingly, Ivies such as Harvard and Yale have developed ambitious plans of their own for stimulating interdisciplinary research. And many other colleges, universities, medical schools and research centers are also building new structures in which biologists and other scientists with overlapping research interests can use adjacent labs, share equipment and, it is hoped, interact creatively.

With so many centers out there, often using the same buzzwords, will they be able to deliver on their promises?

EASIER TO SAY THAN DO
The success of the new centers will depend in part on who is chosen to direct them and where these leaders place their bets. (Right now the competition for qualified, imaginative directors is said to be fierce.) It is also contingent on whether funds will still be available for the centers after they are built. And it especially hinges on whether deliberate attempts at cross-fertilizing diverse disciplines really work—and, if so, which research structures are most effective.

Princeton's Botstein observes that when one is educated in a particular discipline, one acquires a certain set of skills. However, he adds, "You also acquire a set of prejudices and ways of looking at the world. Along with those perspectives comes a specialized language that's often ineffective in communicating with people in distant—and even not-so-distant—disciplines. It's a Tower of Babel out there! It's very difficult to get biologists to learn math and even more difficult to get mathematicians to take biology seriously—they don't want to be beginners all over again and have to assimilate a huge amount of information. It's like the difference between a 13-year-old and a 20-year-old who are placed in a new environment where they have to learn a new language. The 13-year-old will learn to speak it without any accent, but that's much more difficult for the 20-year-old, who will always sound foreign."

Botstein's solution to this problem is to start earlier—with college freshmen and sophomores. He just moved from Stanford to Princeton's Lewis-Sigler Institute for Integrative Genomics, which was founded by Shirley M. Tilghman before she became president of Princeton in 2001. "The institute has now acquired a major focus on teaching at the undergraduate level," he says. "We'll try to put in place an introductory course for freshmen and sophomores that will include biology, chemistry, physics and computation right from the start. It will be an alternate route for students who want to major in science. Premeds make up the overwhelming majority of science students, so most undergraduate education in biology is focused entirely on pleasing medical examining boards. Yet that is not what biologists of the future really need—which is more math. They will get it here."

Another problem is that most of the new centers are being erected within existing colleges and universities, where their founders must overcome traditional barriers between academic departments. Only a few of the new interdisciplinary centers—including the Institute for Systems Biology, founded by Leroy Hood in Seattle, Washington, and HHMI's Janelia Farm Research Campus in Ashburn, Virginia, which is scheduled to open in three years—are freestanding.

In academia, "the tenure system works against collaborations among research scientists," explains Gerald Rubin. He believes this is true even when the scientists are in the same department, because such collaborations may make it hard to distinguish one person's achievements from the other's—thus retarding the career advancement of both. But it is even more of a hurdle for researchers who collaborate across disciplines, because the joint product of such collaborations may seem unimportant to each discipline.

Rubin often points to the growth of bioinformatics for biological research. "A reason why it got developed in the commercial sector, and not in universities," he says, "is that people in academic biology departments didn't think bioinformatics was real biology, while people in computer science didn't think it was real cutting-edge computer science. To get tenure, you have to do what the guild says is the pure stuff of your discipline."

Leroy Hood, a long-time advocate of new techniques for advancing biological research—he led the team that developed the automated DNA sequencer, the tool that made the Human Genome Project possible—recently abandoned academia to start the Institute for Systems Biology. "The university culture and bureaucracy just could not have sufficient flexibility" for the cross-disciplinary work he was planning, Hood said.

Starting with a blank slate has both advantages and disadvantages, notes Matthew Scott of Stanford's Bio-X program. "Janelia Farm won't have to deal with any of the entrenched subdivisions you have in universities," he says. "On the other hand, we have certain strengths of our own. We already have a fantastic group of people with different skills, even though some of them don't know each other yet."

As to what will constitute success for the new centers, "Janelia Farm will be a success story depending on the degree to which we have been able to do something that other places can't do," says David Clayton. According to Scott, success will be measured by the ability "to graduate students who have a remarkable breadth and can bring to bear multiple approaches on problems in biology," as well as by new discoveries that emerge from the efforts of Bio-X participants.

For Marvin Cassman of QB3, success will be developing an infrastructure that stimulates collaborations so that large numbers of students and postdocs work across disciplines. "They will be the key," he says. "They always are."

For now, however, we'll just have to wait. "It's too early to tell how successful any of the centers will be," comments Clayton. "We'll know 10 years from now."

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Photos: From top: Karl Bates/University of Michigan; Matthew Scott; Duke University Medical Center

Reprinted from the HHMI Bulletin,
June 2003, pages 24-28.
©2003 Howard Hughes Medical Institute