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lerner/Photo President's Introduction

Richard A. Lerner, M.D.

This year has been one of significant transition at The Scripps Research Institute. Nevertheless, through all the changes, we have maintained our impressive array of scientific accomplishments, expanded facilities to accommodate ongoing growth, and made important new faculty appointments. Sadly, this year marked the passing of TSRI's dean of graduate studies and chairman of the Department of Cell Biology, Norton B. Gilula, Ph.D., after a valiant struggle with cancer. Dr. Gilula made an indelible imprint on the quality and character of the Institute, and we all miss his keen insights, sound scientific judgment, generosity of spirit, leadership ability, and friendship. His death is a great loss to the scientific community.

Taking over many of Dr. Gilula's responsibilities, Jeffery Kelly, Ph.D., Lita Annenberg Professor, Department of Chemistry, and The Skaggs Institute for Chemical Biology, is now acting dean of the Graduate Studies Program and Acting Vice President, Academic Affairs. While conducting an ongoing program of laboratory studies, Jeff will assist me with policy issues related to the direction of scientific activities at the Institute. In addition, Sandra L. Schmid, Ph.D., is the new chairman of the Department of Cell Biology. She has been a member of TSRI's faculty for more than 10 years and has distinguished herself as an outstanding scientist whose work is widely respected in the international scientific community.

TSRI continues to enjoy a collegial and productive relationship with Novartis, which recently exercised a 5-year renewal on our research funding agreement. Clearly, this arrangement is of paramount importance to the continuation of TSRI's long-range initiatives, and we expect many more years of fruitful efforts.

With more than 1000 manuscripts submitted for publication by TSRI's scientists, singling out a small number of scientific accomplishments is difficult. However, a description of a few will connote the breath of achievements in a multiplicity of research areas.

Carlos Barbas, Ph.D., professor, Department of Molecular Biology and the Skaggs Institute, developed a method of producing and combining proteins as modular building blocks capable of functioning as genetic switches to turn genes on or off on demand. Dr. Barbas calls this method "an operating system for genomes." The goal is to develop a new class of therapeutic proteins that can inhibit or enhance the synthesis of proteins, providing a new strategy for fighting diseases of either somatic or viral origin. Members of the Barbas laboratory are developing proteins that may inhibit the growth of tumors, halt HIV disease, and even make healthier corn. They have shown that they can use their alphabet of proteins to specifically turn genes on or off at will.

A team of scientists studying a human DNA repair enzyme, led by John Tainer, Ph.D., professor, Department of Molecular Biology and the Skaggs Institute, discovered an evolutionary adaptation that highlights a fundamental advantage in the way human cells repair DNA damage. The scientists found that a key DNA repair enzyme is optimized to remain bound to its toxic, damaged DNA products until the next enzyme in the DNA repair pathway can take over. This adaptation allows DNA repair in human cells to be coordinated between subsequent enzymes in the pathway, rather than having harmful DNA damage intermediates exposed in the cell. This finding has implications, for example, in cancer chemotherapy regimens, because it may be possible to overwhelm DNA repair processes when the amount of damage is particularly extensive.

Work in my laboratory this year, done in collaboration with Peter Schultz, Ph.D., professor, Department of Chemistry and the Skaggs Institute, revealed that gradual genetic changes may be the source of many, if not all, illnesses of aging, including breast cancer, osteoporosis, Alzheimer's disease, and arthritis. The results indicate that aging and its associated diseases can be traced to a gradual increase in errors in cell division in tissues throughout the body. This functional change begins slowly in middle age and increases gradually with advancing age. Although scientists had previously thought that aging is a disease in which cells stop dividing, our work suggests that aging is a disease of quality control. With advancing age, altered gene expression results in cells with diminished function. Errors in cell division lead to the altered expression of a collection of key genes in the cells. Altered gene expression gradually causes the loss of tissue function, a condition that results in aging.

Researchers led by Chi-Huey Wong, Ph.D., professor, Department of Chemistry and the Skaggs Institute, have a new tool to address the growing problem of antibiotic resistance. They have focused on aminoglycosides, a family of antibiotics that includes such drugs as neomycin. Bacteria, which create the proteins they need to survive, are constantly evolving and mutating in ways that circumvent the activity of antibiotics. To circumvent the problem, Dr. Wong and his colleagues found a way to bind an antibiotic to the bacteria's RNA. This binding prevents the formation of proteins that allow the bacteria to become resistant to antibiotics. The approach could yield a drug 1000 times more effective than the original antibiotic.

The building of the facility to house the new Institute for Childhood and Neglected Diseases continued this year; the first scientists are expected to take occupancy of their laboratories in January 2001. When fully occupied, this facility will house some 150 scientists and support staff. The unique contribution of John and Rebecca Moores, a collection of rare automobiles and a collection of important U.S. coins, was auctioned on TSRI's behalf. The proceeds provided the lead gift toward the establishment of the new institute.

Scientists and clinicians selected to participate in The Skaggs Clinical Scholars Program, established with a contribution of $2 million from the Skaggs family, completed their first year of collaboration. The goal of the program, which is chaired by Ernest Beutler, M.D., chairman, Department of Molecular and Experimental Medicine, is to more closely integrate clinical and basic research within the Scripps organization by selecting research-oriented clinicians and funding meritorious collaborative research projects between each clinical scholar and a TSRI scientist. The broader goal is to expand the body of knowledge related to human disease and to develop effective therapeutic interventions.

A number of prominent researchers joined the scientific staff at TSRI this year, bringing the number of faculty members to more than 275. They include Joel N. Buxbaum, M.D., former professor of medicine, NYU School of Medicine; Bruce Beutler, M.D., former professor, University of Texas Southwestern Medical Center at Dallas; Dong-Er Zhang, Ph.D., former assistant professor, Department of Medicine, Harvard Medical School; Heidi Stuhlmann, Ph.D., former assistant professor, Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine; John R. Yates, Ph.D., former associate professor, Molecular Biotechnology, University of Washington; Mark R. Mayford, Ph.D., former assistant professor, Department of Neurosciences, University of California, San Diego; Aniko Bartfai, Ph.D., former associate professor, Department of Psychology, Stockholm University; Ulo Langel, Ph.D., former associate professor, Department of Neurochemistry and Neurotoxicology, Stockholm University; and Geoffrey Chang, Ph.D., who recently completed a postdoctoral fellowship at California Institute of Technology.

This year, as in years past, numerous TSRI faculty members were recognized by their peers with prestigious awards and honors. K. Barry Sharpless, Ph.D., professor, Department of Chemistry and the Skaggs Institute, was selected to receive the National Academy of Sciences Award in Chemical Sciences. The prize is awarded for innovative research that contributes to a better understanding of the natural sciences and to the benefit of humanity. Ian Wilson, D.Phil., professor, Department of Molecular Biology and the Skaggs Institute, was elected to fellowship in the Royal Society of London, the independent scientific academy of the United Kingdom founded in 1660. Chi-Huey Wong, Ph.D., professor, Department of Chemistry and the Skaggs Institute, was selected to receive a 2000 Presidential Green Chemistry Challenge Award, jointly presented by the director of the U.S. Environmental Protection Agency, the director of the White House Office of Science and Technology, and the president of the American Chemical Society. Geoffrey Chang, Ph.D., assistant professor, Department of Molecular Biology, received a Presidential Early Career Award for Scientists and Engineers.

As we enter a new millennium, I feel that TSRI is in a unique position to exploit the riches of the sequencing of the human genome, to expand on the prodigious body of knowledge elucidated by our own faculty, to play a role in training the next generation of scientists through the Graduate Studies Program, and to ultimately have a positive effect on alleviating human suffering.

Gilula In Remembrance
Norton B. Gilula, 1944-2000

Norton B. Gilula, Ph.D.

Dr. Norton B. Gilula died on September 27, 2000, at the age of 55, after a year-long struggle with non-Hodgkin lymphoma. To me, he was more than a much admired colleague, esteemed scientist, broad-ranging intellectual, and visionary educator; for many years he was my dear friend. Dedicated, complicated, compassionate, humorous, brilliant, and gracious--Bernie had many facets, and we will miss them all in a profound way for years to come.

W.H. Auden said the following on the death of T.S. Eliot, "To me the proof of a man's goodness is the effect he has upon others." That sentiment sums up the essence of Bernie in my mind. He was always more concerned about your well-being than about his own, making sure that your needs were attended to, your issues were aired, your problems were solved. Until his last days, he was fully engaged in the scientific enterprise, often coming into the laboratory or the office straight from a chemotherapy treatment at the hospital. One of the things I most admired about Bernie was his unwavering resolve to keep doing what he loved best: helping people, mentoring students, and solving scientific problems.

Bernie was a well-known and highly regarded cell biologist with a multifaceted professional career. In March 2000, he was appointed Vice President of Scientific Affairs at TSRI. He served at this post while still maintaining a vibrant laboratory and leadership of the Graduate Studies Program. I recruited Bernie to the staff of the Institute in 1986; in 1988, he was named dean of the Graduate Studies Program, a program that was in every sense his vision, his dream, and his accomplishment. In 1991, he was appointed chairman of the Department of Cell Biology. I felt strongly at the time that his unique combination of skills, breadth of scientific understanding, and ability to inspire and motivate students and colleagues made him the perfect candidate for the job. In addition to these demanding responsibilities, he maintained his editorship of the Journal of Cell Biology, which he attended to with great dedication and commitment, and found the time to vanquish me on the golf course on a frequent and continuing basis.

In addition to his superior intellect, Bernie had athletic talent; in 1962, he entered Southern Illinois University on a football scholarship. After receiving a bachelor's degree in physiology and chemistry, he went on to earn a master's degree in physiology at the university. In 1968, he entered the Ph.D. program in physiology at the University of California, Berkeley. While there, he was introduced to the field of cell biology, in which he spent his entire scientific career.

A postdoctoral fellowship followed at Harvard University, where he did seminal work on gap junctions with Daniel Goodenough. In 1972, he moved to New York City to pursue postdoctoral studies at The Rockefeller University. A year later, he was appointed an assistant professor and later became an associate professor, a position he held at Rockefeller until 1981. That year he moved to Houston to accept an appointment as a professor in the Department of Cell Biology at Baylor College of Medicine.

Five years later, Bernie and his family moved to La Jolla, where he continued his prolific scientific career at TSRI and assumed important leadership positions that would leave an indelible mark on the quality and character of the Institute. His voracious appetite for knowledge and discovery, his keen and discerning eye for good science, and his overarching desire to teach and mentor enabled him to develop a superb cadre of young scientists who formed the core of the new Department of Cell Biology.

As a doctoral student at the University of California, Berkeley, he studied invertebrate gap junctions with Peter Satir, Dan Branton, and Daniel Mazia and realized the importance of the junctions in providing a pathway for the transfer of information between cells. In one of his early fundamental contributions, using cell biological and genetic methods, he showed that the gap junction provides the pathway for cell-to-cell communication of molecular information in the form of inorganic ions and metabolites. Subsequently, using a coculture system, he and his colleagues extended these studies to show that gap junctional communication can be used to transmit biologically important molecules, such as cyclic nucleotides, between cells.

In parallel with these studies, using electron microscopic measurement of gap junctional communication, he and his coworkers found that the appearance of gap junctions was intimately related to the timing of important morphogenetic events. In the early 1980s, Bernie continued his efforts on defining the role of gap junctions during development and differentiation. In experiments on Xenopus embryos and hydra, antibody perturbation methods were applied to uniquely reveal that gap junctional communication makes an important contribution to patterning events during development. More recently, he and his colleagues used targeted gene disruption of a lens connexin to examine the importance of gap junctional communication in maintaining lens transparency.

Another area on which Bernie focused his research efforts was the structure-function relationship of the gap junction. Bernie and his colleagues were among the first to identify and characterize the multigene family of proteins that form the gap junction structures in vivo and to show that the purified proteins can be reconstituted to form conducting channels. These studies ultimately led to resolution of the structure of the gap junction channel at 7 Å and furthered our understanding of the oligomeric organization of the junction protein to form membrane channels.

Although his achievements were significant in so many areas of science, Bernie was perhaps most proud of the role he played in establishing, shaping, and nurturing the Graduate Studies Program at TSRI. It is certainly no small task to create a new graduate program of quality, scope, and depth, and Bernie worked every day to ensure that each detail was attended to and that each good idea was thoroughly developed, improved, and implemented. Each student was special to him, and I know he derived enormous personal and professional pleasure from the students' accomplishments and triumphs. In recognition of his pivotal role in establishing and guiding the program, two perpetual graduate student fellowships have been established in his name, and the offices housing the graduate student program have been named the Norton B. Gilula Center for Graduate Studies.

I marveled at Bernie's strength, decency, and integrity as a scientist, colleague, mentor, friend, and cancer patient. To the end he was hopeful, encouraged, and resilient. There were lessons in Bernie for all of us, but perhaps none was greater than his zest for life and learning and for showing the wonder of science to those around him. Bernie truly was a mensch, an enlightened gentleman.

-- Richard A. Lerner



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