$1.5 million from Keck Foundation establishes biophysics program

By Roger Segelken

A $1.5 million grant from the W.M. Keck Foundation has established a research/training program in biophysics to be conducted jointly by Cornell in Ithaca and Weill Cornell Medical College in New York City.

Through the program, called Cellular and Molecular Biophysics of Signal Transduction, biomedical scientists and student researchers hope to discover the chemical and physical codes in signal transduction, the exceedingly complex and incompletely understood system of cell communication through molecule-to-molecule handshakes used throughout the body to get its most important business done.

In addition to the Keck "seed" funding to establish the program over the first three years, Cornell is contributing about $500,000 in support as well as tuition for Keck graduate students. Individual research projects will be funded by grants obtained by faculty members.

"Without communication between our cells, transduced through cell surfaces and among components within our cells, our bodies are just collections of chemicals," explained Barbara Baird, professor of chemistry and chemical biology at Cornell in Ithaca and co-director of the Keck biophysics program. Her laboratory uses biochemical and biophysical methods to investigate cell-surface immune receptors and their role in transmembrane signaling.

"We're beginning to identify many of the proteins and other pieces of pieces of the puzzle, thanks to a long history of biochemistry and molecular genetics, leading up to the Human Genome Project and the emerging science of proteomics," Baird said. "Now if we could just figure out the fundamental organization of signal transduction, we would have a chance of understanding how systems in our body work normally, what goes wrong when signals are crossed and how we can medically intervene to make corrections," she said.

The second co-director of the new Keck program, Frederick R. Maxfield, professor and chair of the Department of Biochemistry at Weill Cornell Medical College, said: "This program, so generously funded by the W.M. Keck Foundation, will not only advance our understanding of cell function but will serve as a model for effectively integrating interdisciplinary biomedical researchers." Maxfield's laboratory uses digital fluorescence microscopy and biophysical methods to study the trafficking and distribution of lipids and proteins in living cells.

Co-director Baird cites these examples of cell-signaling-related problems:

• Cholesterol is essential within cell membranes for maintaining specialized "targeting" structures that help recruit the right proteins into signaling complexes. But improper regulation of cholesterol transport is an early step toward atherosclerosis.

• Immune responses, including undesirable outcomes, such as organ rejection and allergies, depend on receptors clustered on the cell surface that selectively gather other signaling molecules. Without a better understanding of the differentiating details, medical treatments of immune disorders can simultaneously damage normal immune function.

• Loss of control of normal cell growth leads to cancer that spreads by metastasis. Structural understanding of the regulating proteins and how these activities are influenced within the context of the signaling pathways opens opportunities for designing new drugs.

• Early signs of cell-based disorders such as Alzheimer's disease can be detected by examining thick sections of living tissue using a technique called multiphoton laser-scanning fluorescence microscopy, which is under development at Cornell. Biomedical applications of another powerful technique, electron-spin resonance (ESR) spectroscopy, are just beginning to emerge.

One objective of the new Keck program is technology development and implementation. A multiphoton microscope will be installed for applied research at Weill Cornell Medical College and an advanced ESR instrument, which is uniquely suited for understanding the organization of lipids and membrane proteins, will be assembled on Cornell's Ithaca campus.

Noting that a comprehensive understanding of signal transduction will require decades of work by teams of scientists around the world, leaders of the Keck program at Cornell propose to begin immediately to train the next generation of scientists who can transcend traditional barriers between scientific disciplines. Initially, five graduate students and five postdoctoral fellows will be trained through intercampus courses, special seminars and research opportunities.

Antonio M. Gotto Jr., M.D., dean of Weill Cornell Medical College, said: "The Keck program will examine the structure, organization and regulation of signaling complexes at the cell surface. This central problem in cell biology provides a compelling opportunity to focus the efforts of this expert team of researchers. I am grateful to the foundation for its faith in our mission and abilities."

President Hunter Rawlings sees the Keck program as a important component of the new Tri-Institutional Collaboration among Cornell and Weill, Memorial Sloan-Kettering Cancer Center and The Rockefeller University. He said: "This project, which is both cutting edge and highly interdisciplinary, will benefit Cornell's students as well as stimulate new and exciting research with the potential to significantly advance medical science."

Sanford I. Weill, chair of Weill Cornell's Board of Overseers, said: "The Keck Foundation's support has been vital to path-breaking scientific and medical research. We are deeply grateful for this grant, which will further our knowledge of molecular biology and advance human health."

Established in 1954 for general charitable purposes, the W.M. Keck Foundation, which is based in Los Angeles, makes grants to provide far-reaching benefits for humanity in the fields of science, engineering and medical research.

Among the first to join the new biophysics program, along with co-directors Baird and Maxfield, are:

• Olaf S. Anderson, M.D., professor in Weill Cornell Medical College's departments of physiology and biophysics and biochemistry and structural biology. His laboratory studies the selective transfer of material and information across biological membranes.

• Marvin Gershengorn, M.D., chief of the medical college's Division of Molecular Medicine and co-chair of the physiology, biophysics and molecular medicine Ph.D. program. The Gershengorn laboratory uses molecular biology/biochemistry and computational simulations to study the biology of cell-surface receptors.

• Tim McGraw, associate professor of biochemistry at the medical college and director of the graduate program in biochemistry and structural biology. His laboratory uses chemical and cell biological methods to investigate constitutive and regulated endocytic trafficking in cultured cell lines.

• Tim Ryan, assistant professor in the biochemistry department at the medical college, where he studies the molecular basis of synaptic transmission in the mammalian brain.

• Xin-Yun Huang, associate professor of physiology at the medical college. His laboratory uses biochemical, molecular biological and biophysical approaches to study transmembrane signaling by receptors for neurotransmitters, hormones, odorants, pheromones and some addictive drugs.

• Hao Wu, assistant professor of biochemistry at the medical college. Her research uses X-ray crystallography to focus on mechanisms of receptor activation in autoimmune and inflammatory diseases.

• Richard Cerione, professor in Cornell's departments of chemistry and chemical biology and of molecular medicine. The Cerione laboratory focuses on understanding the molecular mechanisms by which signals are transmitted from cell surface receptors to biological effectors.

• Gerald Feigenson, Cornell professor of molecular biology and genetics. The Feigenson research group explores the relationship between lipid structure and the behavior of lipid mixtures.

• Jack Freed, professor in Cornell's chemistry and chemical biology department. The Freed laboratory has pioneered new methods of ESR spectroscopy for the study of membranes and membrane-bound proteins by developing the technique of two-dimensional ESR.

• Manfred Lindau, associate professor in Cornell's applied and engineering physics school. The main focus of his research is to provide a detailed mechanistic and molecular understanding of biological membrane fusion events and their function in the dynamics of secretion.

• Watt W. Webb, Cornell professor and former director of the applied and engineering physics school. The Webb laboratory develops modern optical instrumentation for imaging and measuring the dynamics of biochemical processes in living systems. One of his laboratory's inventions, the multiphoton laser-scanning fluorescence microscope, permits deep imaging of relevant biological tissues.