UCSF Professor Peter Walter Receives Lasker Award for Basic Research

Peter Walter, PhD, professor of biochemistry and biophysics at UC San Francisco, has received the 2014 Lasker Basic Medical Research Award.

Popularly known as the “American Nobels,” the Lasker Awards are among the most prestigious honors in science and medicine.

Walter, 59, was honored for his groundbreaking work on a cellular quality-control system known as the unfolded protein response, or UPR. Found in organisms ranging from yeast to humans, the UPR is crucial to life, and disruptions in its workings are believed to play a role in neurodegenerative diseases, cancer, diabetes and other illnesses. Walter, a Howard Hughes Medical Institute investigator since 1997, shares the award with Kazutoshi Mori, PhD, a leading UPR researcher at Kyoto University in Japan.

Walter is the 12th UCSF faculty member to receive either a Basic Medical Research Award or a Clinical Medical Research Award from the Lasker Foundation.

“This is an exciting day for UCSF and for the world of science,” said UCSF Chancellor Sam Hawgood, MBBS. “Peter Walter has received widespread acclaim for his discoveries on how the cell ensures that proteins are properly constructed, especially when the cell’s quality control systems are overwhelmed. We now know that when these basic systems malfunction, serious diseases can result. His work is a perfect example of the importance of basic biomedical research, its impact on health, and its importance for society.”

Proteins, the building blocks of all organisms, are constantly being synthesized inside cells. But when they are first made, proteins are simple, linear chains of amino acids, known as polypeptides. These chains must fold into proper three-dimensional shapes before they can be sent off to do their job.

To undergo folding, many newly synthesized polypeptide chains enter a maze-like structure in the cell called the endoplasmic reticulum (ER), the first station on their journey to the cell surface. The ER serves as a checkpoint: only well-folded proteins are allowed to exit the ER to be shuttled to their destinations. In this way, the cell ascertains that only properly working protein machines arrive at the cell surface, where they help the cell communicate with other cells in the organism.

For the ER to work optimally, it must have adequate capacity to keep up with the rate of protein synthesis. If too little ER is present to handle the number of proteins being synthesized – a state known as ER stress – a logjam of misfolded proteins ensues within the ER.

In studies of yeast beginning in the early 1990s, Walter and colleagues determined that a sensor molecule called Ire1, which is embedded in the ER membrane, detects ER stress. Ire1 then sends a signal to the cell nucleus that prompts the expression of genes to help the cell regain equilibrium. The discovery of Ire1 led to the unveiling of a suite of parallel pathways in animal and human cells that collectively make up the UPR, which simultaneously slows down protein synthesis and increases the abundance of ER.

Unfolded proteins can be a menace - they tend to stick together, for example, forming the pathological clumps seen in neurodegenerative diseases – so the UPR has a built-in time limit: if a cell’s balance between ER abundance and protein synthesis cannot be restored fairly quickly, the UPR shifts to a signaling mode that causes the cell to self-destruct.

This “do or die” control over the fate of cells in conditions of ER stress can cause disease by malfunctioning in either direction. In retinitis pigmentosa, for example, misfolded proteins push the UPR to the limit, inducing self-destruction in the eye’s retinal cells, gradually robbing patients of their sight. Similarly, in type II diabetes, a continual demand for insulin may overwhelm the ER in beta cells of the pancreas, which eventually succumb to UPR-induced cell death. And in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, the UPR may kill neurons that are undergoing ER stress as protein aggregates accumulate.

On the other hand, the UPR’s cell-protective role may be hijacked by some viruses to create additional ER, aiding their replication. Cancer cells may also take advantage of the UPR to promote their own proliferation, an idea that Walter is currently exploring with a Collaborative Innovation Award from the Howard Hughes Medical Institute (HHMI).

“We are particularly proud that our initial discoveries in brewer’s yeast cells have laid the foundation to uncover these fundamental mechanisms of protein quality control,” Walter said. “Yeast research led the way in unraveling the unique mechanisms by which the UPR allows the ER to communicate with the nucleus. To me it is very rewarding to see that the salient lessons learned from this tiny model organism proved directly applicable to our understanding of mammalian cell physiology and now hold promise to lead to new therapeutic strategies in numerous diseases.”

Walter, who joined the UCSF faculty in 1983, is the recipient of some of the other most esteemed prizes in biomedical science, including the Shaw Prize in Life Science and Medicine (2014); the Paul Ehrlich and Ludwig Darmstaedter Prize (2012); the Otto Warburg Medal (2011); the Gairdner International Award (2009); the E.B. Wilson Medal (2009); the Stein and Moore Award (2009); and the Wiley Prize in Biomedical Sciences (2005). He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the European Molecular Biology Organization, and is co-author of a celebrated textbook, Molecular Biology of the Cell, now in its sixth edition.

Launched in 1945 by the Albert and Mary Lasker Foundation, the Lasker Awards are given in four categories to “scientists, physicians, and public servants who have made major advances in the understanding, diagnosis, treatment, cure, and prevention of human disease,” according to the foundation’s website.

“For nearly 70 years the Lasker Awards have honored extraordinary individuals who have made fundamental biological discoveries, developed therapies to dramatically improve patient care, and provided mentorship and leadership to pave the way for the next generation of scientists,” said Claire Pomeroy, President of the Lasker Foundation. “This year’s laureates join that tradition and illustrate to the public why science is so worthy of our support.”

UCSF is the nation’s leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco.