Verna and Marrs McLeanLectures in BiocheMistry

The ForTy-Third AnnuAl

Beth Levine, Md randy schekman, Phd

March 12, 2015Cullen Building Main Auditorium

Dr. Randy Schekman fused genetic and biochemical approaches into a powerful experimental attack that revealed how proteins enter and move between the membrane-bound compartments of the cell. Born in Saint Paul, Minnesota, Dr. Schekman grew up in California, attending Western High school in Anaheim. He attributes his youthful enthusiasm for science and math to his father, who was an engineer. In the 9th grade, Dr. Schekman bought a microscope—from money he earned mowing lawns and babysitting—to watch bugs in pond scum, ultimately winning a Science Fair. (That microscope now resides in the Nobel Museum.) As an undergraduate at UCLA, he found his passion for research working with Dr. Dan Ray on bacteriophage replication, a passion enhanced by encountering The Double Helix by Dr. James Watson, which he read nonstop. “To me, that was it. I knew this was what I wanted.” A year abroad in a laboratory at the University of Edinburgh confirmed his conviction, which he then pursued with Dr. Arthur Kornberg at Stanford University, gaining his PhD in 1975. It was during his thesis work on replication of ΦX174, that he began to appreciate the power of biochemistry in elucidating what molecules can do and the essential role of genetics in defining their physiological context. Listening to a lecture by Dr. George Palade, one of the giants in the field of protein secretion, Dr. Schekman found he wanted to know exactly how secretion occurred. As a postdoc in Dr. John Singer’s lab at UCSD, he learned about membranes, but found that vesicles were difficult to study in mammalian cells. When he joined the faculty at UC Berkeley in 1976, he opted to pursue his interests in yeast, a more genetically tractable organism that was also amenable to biochemical approaches. Since 1990, Dr. Schekman has been a Howard Hughes Investigator at UC Berkeley, where he is currently Professor of Molecular and Cell Biology.

Initially, Dr. Schekman focused on the vesicle-mediated delivery of proteins and membrane material to the growing bud, a process analogous to secretion in mammalian cells. Because this process is essential, he screened for temperature-sensitive mutants by examining them for morphological changes. His first hit was a mutation in the Sec1 gene, which led to cells that were jam-packed with vesicles at high temperature. Similar approaches ultimately yielded hundreds of mutants, located in 23 genes. Using a clever selection

protocol, Dr. Schekman honed in on the initial step in secretion, the insertion of proteins through the membrane, finding multiple new secretory genes, including Sec61, which forms the protein translocation channel in the endoplasmic reticulum. With the genetic structure of the pathway defined, Dr. Schekman turned to the more difficult challenge of determining the roles of the gene products. By asking whether extracts from two different mutant cells could complement one another, he was able to reconstitute individual steps in the secretory pathway and then study them in detail using purified proteins. Comparisons of the proteins responsible for yeast secretion with those in bacteria and mammalian cells revealed that the secretory pathway is highly conserved throughout evolution.

Dr. Schekman has earned many awards and honors. He was elected to the National Academy of Sciences in 1992 and served as Editor-in-Chief for PNAS from 2006 to 2011. Since 2011, Dr. Shekman has been Editor-in-Chief of eLife, a successful new journal that promises “pain-free publishing for your best science.” In 2002, he was selected for the Albert Lasker Award in Basic Medical Research and in 2013 he shared the Nobel Prize in Physiology or Medicine with Drs. James Rothman and Thomas Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.

randy schekMan, Phd

2:00 p.m.Genes and proteins required for secretion

of large particles and mirnas

Dr. Beth Levine has made fundamental discoveries that have helped to open up a new field of biomedical research—the role of autophagy in human health and disease. As a child growing up in Springfield, New Jersey, Dr. Levine read biographies about Albert Schweitzer and dreamed of curing infectious diseases in third world countries. These dreams faded during her youth and she ended up majoring in French Studies as an undergraduate at Brown University. As Dr. Levine says, “I was fascinated by thinking about philosophy in a foreign language—an endeavor that I think is somewhat analogous to the scientific discovery process.” In college she had an epiphany that she wanted to go into medicine. She received her medical degree from Cornell University Medical College in 1986, completing her residency at Mount Sinai Hospital. It was during her medical training that she gradually gravitated toward becoming a research scientist, which she pursued as a postdoctoral fellow at The Johns Hopkins Hospital with Dr. Diane Griffin. Following her interests in infectious disease, she delved into the mechanisms of alphavirus-induced encephalitis, find ing, among other things, that expression of the Bcl-2 oncogene converted a lytic infection to a persistent one. In 1992, Dr. Levine became an Assistant Professor of Medicine at Columbia University College of Physicians & Surgeons. There, she made the seminal discovery that a novel Bcl-2-interacting protein, Beclin 1, induced autophagy and inhibited tumorigenesis. In 2004, Dr. Levine moved to UT Southwestern Medical Center, where she was named the Jay P. Sanford Professor in Infectious Disease and Chief of the Division of Infectious Disease. Since 2008, Dr. Levine has been a Howard Hughes Investigator. In 2011, Dr. Levine was appointed the Charles Cameron Sprague Distinguished Chair in Biomedical Sciences and Director of the Center for Autophagy Research.

The proper functioning of all eukaryotic cells depends on their ability to use a lysosomal pathway known as autophagy. Dr. Levine showed that posttranslational modification of Beclin 1, regulation of its subcellular localization, and regulation of its binding to other proteins all play crucial roles in determining the activity of the Beclin 1-containing class III phosphatidylinositol 3-kinase protein complex that is essential for formation of the autophagosomal membrane. Dr. Levine’s lab has uncovered important roles that Beclin 1 and the

autophagy pathway play in normal physiology and in protection against disease, including development, tumor suppression, innate immu-nity against intracellular pathogens, lifespan extension, apoptotic corpse clearance, cell death regulation, pro-tection against neurodegenerative diseases, and exercise-induced bene-ficial effects on glucose metabolism. Remarkably, the products of several oncogenes, including Bcl-2, the protein kinase Akt, the oncogenic epidermal growth factor receptor tyrosine kinase, and the oncogenic gammaherpesvirus-encoded Bcl-2-like proteins, inactivate Beclin 1 function and autophagy. Recently, Dr. Levine and her colleagues have identified an autophagy-inducing peptide called Tat-beclin 1. Treatment of mice with this peptide helps protect them from

several infectious diseases, including HIV and West Nile virus. Thus, this peptide may have therapeutic potential for the prevention and treatment of a range of human diseases.

For her outstanding work in the field of autophagy, Dr. Levine was elected to the American Society of Clinical Investigation in 2000, to the American Association of Physicians in 2005, and to the National Academy of Sciences in 2008. Her awards and honors include the Edith and Peter O’Donnell Award in Medicine in 2008 and the ASCI Stanley J. Korsmeyer Award in 2014.

Beth LeVine, Md

3:35 p.m.Molecular regulation and Functions of Beclin 1

and the autophagy Pathway

nobel Laureatesof the Verna and Marrs McLean

Lectures in Biochemistry

Paul BergHans Adolf Krebs

Bengt I. SamuelssonWalter Gilbert

Francis Harry Compton CrickArthur KornbergSalvador E. Luria

D. Carleton GajdusekGeorge E. PaladeSydney Brenner

J. Michael BishopJames Dewey Watson

Thomas R. CechAaron Klug

David BaltimoreMax Ferdinand PerutzJoseph L. Goldstein

Michael S. BrownSir Paul M. NursePhillip A. Sharp

Christiane Nüsslein-VolhardRichard Axel

Harold E. VarmusLeland H. Hartwell

Martin RodbellH. Robert HorvitzMario R. Capecchi

Robert J. LefkowitzPeter C. Agre

Eric F. WieschausJack W. SzostakRoger Y. Tsien

Brian K. KobilkaRandy Schekman

Verna and Marrs McLean loved youth and valued education. This department was named in tribute to their leadership and dedication. Their example continues to inspire.

the Verna and Marrs McLean department of Biochemistry and Molecular Biology at Baylor College of Medicine was established to promote an essential medical science focused on the knowledge of chemical reactions in the living cell, and to provide students with sound scientific principles on which to base their clinical experience. It has since expanded to provide graduate education and research training leading to a Ph.D. degree. The research programs in the department cover a broad spectrum of basic science aimed at advancing knowledge in many areas, from protein function at an atomic level to systems biology. The diversity of research topics and the collaborative spirit of a world-class faculty provide a vibrant training environment for students and postdoctoral trainees. The department supports the National Center for Macromolecular Imaging, which provides a resource for the structural determination of proteins and large protein complexes through cryoelectron microscopy. It has assumed a national leadership role in the scientific community through numerous collaborations and continuous innovation.

the Verna and Marrs McLean Lecture series was inaugurated in 1972 by Salih J. Wakil, Distinguished Service Professor and Chairman Emeritus, in honor of an outstanding Texas family for their generous support of the department. Verna and Marrs McLean shared a philosophy of civic and humanitarian responsibility and a keen commitment to education. Although they were personally generous and supported many philanthropic causes, the McLeans believed that their greatest contribution was to set an example that encouraged others to make equally strong commitments. This tradition has been maintained by their children and grandchildren, as exemplified by the recent endowment of the Ruth McLean Bowman Bowers Professorship, which supports a new faculty member in the department, as well as the establishment of the new Ruth McLean Bowman Bowers “Excellence in Research” award.