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In this issue's John Harvard's Journal:
Restored - Thinning Ranks - Big Thinking About Science - Harvard Portrait: Everett Mendelsohn - Completing the Campaign - Berkowitz Appeals Tenure Denial - An Accident Waiting to Happen? - Sampler of Shrubs and Vines Planned by Arboretum - Russia 2000 - Radcliffe: Stasis and Movement - Brevia - A Nod to Ham Rice - Riches Richly Rewarded - The Undergraduate: Home Ground - Sports: Tornado on Ice - Sports: Wrapping Up Winter's Games

Professor Stuart Schreiber directs one of several new interdisciplinary science initiatives. STU ROSNER

Big Thinking About Science

By looking at some of the smallest objects in nature, Harvard has declared that it is thinking big about science. Following recent and pending efforts, respectively, to bring together the humanities faculty (in the Barker Center) and the social scientists (Knafel Center), on January 29 Jeremy R. Knowles, dean of the Faculty of Arts and Sciences (FAS), announced sweeping science initiatives. During the next five years, he said, Harvard will invest $150 million to $200 million "to help secure the future of scientific research and education at the University."

The effort begins with the establishment of at least two new FAS research centers this year. A Center for Genomics and Proteomics, in the Biological Laboratories, will explore the ways in which an organism's genes and proteins work together as a whole. The Center for Imaging and Mesoscale Structures, in the Mallinckrodt and McKay Laboratories, will probe the properties of materials in the boundary area between classical and quantum mechanics. The centers' creation reflects consensus among Knowles and a group of fellow faculty members about several of the most exciting frontiers for research, fields attractive to creative professors and talented students alike. Their structure also recognizes recent changes in scientific techniques and perspectives--a rethinking, in effect, of how the pursuit of scientific education and research must be organized and funded.

"There's been some movement away from the traditional way of locating research at universities and educational institutions," says Knowles, who as Houghton professor of chemistry speaks from firsthand knowledge. "The paradigm of the past 50 years, of inviting scientists to join one's faculty, setting them up as principal investigators, and encouraging them to raise funds and establish a freestanding research group, has become uncertain. More is needed in the way of a support system. The most exciting science now often requires facilities that no one investigator can afford or maintain; they must be acquired institutionally."

Such facilities are the only route of access to the otherwise invisible world of mesoscale structures, a term describing machines and materials from 1 to 100 nanometers (billionths of a meter)--only a few atoms or so--in size. Mallinckrodt professor and chair of the physics department David R. Nelson points out that "the laws of mechanics and electrical circuits, familiar from everyday experience, break down in the mesoscale regime. The operation of these devices depends crucially on the laws of quantum mechanics.

"The macroscopic description of nature, what we call classical physics," Nelson says, "is really a simplification of what goes on at a quantum scale. For example, energy no longer varies continuously, but comes in quantized amounts, which can make a huge difference in the behavior of electrical circuits."

Virtually no resistance impedes the progress of electricity through mesoscale structures, opening up the possibility of smaller, faster computers and other electronic devices. The potential for innovation is almost endless. Indeed, professor of chemistry Charles M. Lieber has developed a pair of microtweezers used for lifting and moving small groups of molecules, an implement so small that one needs the magnification of a scanning tunneling electron microscope to see it. It is the cost of the machines needed to see and create mesoscale structures (individual pieces of equipment may cost more than $250,000 each) that increasingly stymies traditional conceptions of research funding.

"The issue here," according to Knowles, "is how do you know whether you've done what you set out to do? These instruments are costly, but absolutely necessary in order to achieve the kind of stunning results we're starting to see, and that we're going to see, over the next few years."

In a paradoxical way, the fact that combined departmental resources are necessary to acquire them creates an unexpected boon for research: interdisciplinary cooperation and collaboration. Already, both Cambridge- and Longwood Medical Area-based researchers are linking up in new ways to explore the potential of these new technologies. Lieber and Timothy J. Mitchison, professor of cell biology at Harvard Medical School, have begun discussing how to use the properties of small molecular groups to image the organelles of a cell, just as we now use magnetic resonance to view individual organs in the human body. Knowles expects the intra-institutional currents ultimately to flow far deeper. Reflecting on his arrival at the University in 1974, he recalls, "One of the reasons I originally came here was the much lower level of departmental circumscription at Harvard. I remember, early on, saying to Robert Burns Woodward [the 1965 Nobel laureate in chemistry] that some people might not be comfortable calling what I did chemistry. He replied 'Jeremy, if it's interesting, it's chemistry!'

"I've always admired that spirit," Knowles says, "and what we're seeing now is an even greater porosity in the boundaries between departments. When you think of it, it's only been about 100 years since departments first began to define the subunits of the faculty. What one is seeing now is a more barrier-free landscape in which fences, instead of being tidy and useful, are actually hindrances to intellectual travel."

The unique availability of instrumentation to carry out new experiments will oblige both researchers and students to beat new paths across the campus, and engage in conversations where there have been only occasional dispatches. The imaging and mesoscale structures center was conceived by faculty members from physics, chemistry, engineering and applied sciences, and other disciplines. And work in the burgeoning fields of genomics and proteomics will require researchers to seek out new alliances among geneticists, biologists, chemists, computer scientists, and perhaps even linguists, to help determine exactly what the words mean.

Few of us probably even know we have a proteome--the full complement of an organism's proteins, just as the genome is the full complement of one's genes. Our knowledge of the genome is largely due to the establishment and emerging success of the human genome project, the nationwide undertaking that gave scientists the support to begin identifying the 100,000 or so individual genes of Homo sapiens. Along the way, scientists began to realize that these genes are less like individual artisans, hammering out proteins one by one, than an extensive society, with behavior, intramural stimuli and responses, and sophisticated organization.

"In the past, genetic techniques forced us to focus on perturbing single genes or proteins, after which we carefully investigated the effect on an entire cell," says Stuart L. Schreiber, Loeb professor of chemistry. As codirector of the Institute for Chemistry and Cell Biology, another FAS-Medical School joint venture, Schreiber is trying to optimize that approach by systematically manufacturing thousands of similar small molecules with which to provoke cellular responses. The objective is to learn more quickly about how multiple variations on a single protein "theme" affect a cell's health and behavior.

At the same time, Schreiber explains, "Although much has been learned, and that approach will continue to be used, it unfortunately misses a kind of 'ripple effect' that you see in the genome." So now, by using so-called "arrays" that clearly display which of a cell's genes are turned on or off at a given moment, genomics researchers can watch from beginning to end how an organism responds sequentially to given stimuli. "That is," Schreiber continues, "if you perturb one gene, you can see other genes turning on and off throughout the genome. So, if we throw a pebble in the genome pond, we not only feel the effect on our feet where we're standing; we can see how it impacts the shore all around the pond."

The penetrating understanding that genomics gives us has been available only to certain biotechnology companies and genome research centers. As these techniques become more widely used among basic researchers and clinical investigators seeking new ways to diagnose and treat disease, we may be startled by what we learn about the dynamics of genetic control over our lives. Already, the entire genomes of yeast, certain worms, and several other research organisms have been completely characterized and are beginning to yield their secrets.

"This is not at all a case where we know what's going to happen when we start looking around," says Douglas A. Melton, professor of biochemistry and molecular biology and chairman of the department of molecular and cellular biology. "This is going to be a period of simple discoveries, in which we'll have a few years of collection of hard data, and then a lot of hard thinking about it. We're exploring a new planet, and there will be much to analyze."

Although the new centers will both necessitate and facilitate the hiring of new faculty, the presence of skilled technicians to run the equipment and specialists to help interpret the incoming tide of data will be just as important. A major challenge will be developing systems to winnow, process, and store all this information. Equally crucial will be the development of new proteomics techniques, which have not yet been perfected to the same extent as genomics tools.

Knowles traces the decision to pursue these new science initiatives to a series of meetings he began to hold last year with Melton, Nelson, Schreiber, Daniel L. Hartl (professor of biology and chairman of the department of organismic and evolutionary biology), H.T. Kung (Gates professor of computer science and electrical engineering), and Michael B. McElroy (Butler professor of environmental studies and chairman of the department of earth and planetary sciences). They sought to identify new cross-cutting areas that would have significant impact in the years to come.

"The underlying motivation was that we are an educational institution responsible for educating undergraduates and graduate students," Knowles says, contrasting the FAS to research institutes where scientists are largely or entirely free from teaching duties. "It would be irresponsible, considering the quality of students we attract, not also to have the most exciting research here. The faculty that teach our students must be doing experiments that are defining or redefining their fields."

As a conversation with professor of chemistry and physics Eric J. Heller shows, students are already curious about the quantum world, and ready to begin experimenting with it. Heller's graduate student Jesse Hersch has constructed a microwave "resonator" that replicates the wave behavior of electrons in a mesoscale device constructed by Robert M. Westervelt, McKay professor of applied physics and professor of physics. Heller, whose dual appointment personifies the interdisciplinary spirit of the new centers, says that Hersch's resonator allows them to check Westervelt's calculations, and even displays some intriguing wave-diffraction phenomena they had not expected to see.

"The interesting thing about Westervelt's device is that it allows us to see quantum behavior in the electrons," Heller says. "Once you can do that, you can start thinking about electronic and computing applications at a smaller scale than ever before. We are about to enter a new world through this new initiative, and it's very exciting to be a part of it."

The two new centers just begin Harvard's science initiative, Knowles says. Future projects may include centers for the study of the connection between nerve cells and behavior, for understanding the impact of global climate change on evolution, and for the development of new Internet-based search engines to mine the richness of large databases.

"We're very fortunate to have the resources to commit to ensuring that the most exciting work will be done here in 2010 and 2020," he says. "It's an investment in the excitement of scientific research, and in the excellence of an educational institution."

~ John F. Lauerman

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