Five UCSF scientists elected to National Academy of Sciences

Five UCSF faculty scientists are among the 72 new members and 18 foreign associates from 15 countries elected recently to the National Academy of Sciences, the Academy has announced.

Their election, announced on April 28, brings to 36 the current number of current Academy members at UCSF. Seventeen members were elected from all of the University of California campuses.

Election to the Academy is considered one of the highest honors an American scientist can receive. The scientists were elected in recognition of their distinguished and continuing achievements in original research.

The new UCSF members are:

• Douglas Hanahan, PhD, an American Cancer Society Research Professor in the Department of Biochemistry and Biophysics, and member, UCSF Helen Diller Family Comprehensive Cancer Center
• John Sedat, PhD, professor of biochemistry and biophysics
• Kevan Shokat, PhD, professor of cellular and molecular pharmacology and a Howard Hughes Medical Institute investigator
• Michael Stryker, PhD, William F. Ganong Endowed Chair in Physiology
• Jonathan S. Weissman, PhD, professor of cellular and molecular pharmacology and a Howard Hughes Medical Institute investigator

Hanahan, a leader in the development of genetically engineered mouse models of human cancers, is working to elucidate the mechanisms of cancers and to identify therapeutic strategies.

In the mid 1980s, Hanahan produced some of the first ‘oncomice’ – mice genetically engineered to develop organ-specific human cancers. He has used the models to investigate the multi-stage pathways that govern tumor formation and progression, and to explore the benefits of targeted therapies, in particular strategies aimed at blocking the growth of blood vessels to tumors, which rely on the blood supply for growth. This approach is known as angiogenesis inhibition.

He discovered, in collaboration with the late Judah Folkman at Harvard Medical School, the “angiogenic switch,” which is activated to produce new blood vessels in early stage lesions preceding overt tumors. A current focus of his work is elucidating the “organ of genesis” of tumors, in which multiple cell types assemble with overtly transformed cells to form aberrant, expansive microenvironments of cancer.

Most recently, he and UCSF colleague Gabriele Bergers, PhD reported evidence that angiogenesis inhibitors—drugs designed to starve tumors or their blood supply—succeed at first, but then promote more invasive cancer growth in animals. This provocative finding, he says, warrants further study in model systems and in humans to elucidate mechanisms that could in turn lead to strategies for harnessing the drugs more effectively.

He has also used genetically engineered mouse models to investigate mechanisms of self tolerance to the pancreatic beta cells, which are destroyed by the immune system in type I diabetes; he found, for example rare tolerance-inducing cells in the thymus that express the beta-cell specific insulin gene.

As a graduate student, Hanahan developed high efficiency plasmid transformation methods and E. coli strains that have facilitated DNA cloning procedures; his work on E. coli transformation (the production of “competent cells”) has facilitated molecular genetics research in the life sciences.

Sedat’s research is aimed at understanding chromosome structure at the highest levels of organization, and he has taken significant steps toward characterizing the relationship between chromosome structure and function.

A chromosome is a thread-like package of genes and other DNA located in the nucleus of a cell. In spite of considerable effort over the past few decades, only recently has it been possible to determine the nature of even the simplest level of chromosome organization. Understanding the complex architecture of chromosomes is extremely important because it modulates gene expression and, as a result, any structural changes can affect potential disease states.

One area of study at Sedat’s lab at UCSF focuses on the defined, three-dimensional folding patterns of chromosomes in Drosophila, or fruit flies, and the possible changes in that architecture over the course of development.

To conduct such studies, Sedat and his team have developed several innovative microscopic techniques specially tailored for three-dimensional structures. Along with computer image processing methods, these techniques provide a new way of seeing inside a cell.

Sedat and fellow UCSF professor of biochemistry and biophysics David Agard, PhD, led a team of scientists to develop a device known as the Optical Microscope eXperimental, or OMX, one of the world’s highest-resolution wide-field light microscopes.

The device utilizes a technology called “structured illumination,” in which a carefully designed pattern of light-similar to a bar code-is used to illuminate a previously unobservable object.

Sophisticated computer software is then able to digitally reconstruct a single three-dimensional, ultra-high-resolution image from the multiple images generated with the illumination pattern.

In addition, the OMX was designed with extremely fast cameras and shutters capable of acquiring 10 three-dimensional images at four simultaneous wavelengths per second.  By producing rapid multi-dimensional images of live samples in real time, the device reveals cellular processes in action.

Shokat is an internationally renowned leader in studying protein kinases, the vital signaling molecules that are present in all cells. Kinases are responsible for most of the molecule-to-molecule communication in cells—cascades of signals that direct movement and metabolism, cancer and cell death.

By better understanding the role of the body’s more than 500 different kinases, Shokat hopes to determine which of them should be targeted to treat diseases such as cancer and immune dysfunction. To achieve this goal, he and the members of his lab at UCSF combine the tools of synthetic organic chemistry, structural biology, genetics and mathematical modeling to gain insight into how signaling networks transmit information in both normal and disease settings.

In February, Shokat and his team announced a breakthrough: a new drug that successfully blocked cancer’s main source of growth when tested in mice.

Far more potent than similar compounds already in clinical trial, the drug short-circuits the normal ability of cells to sense the need to grow and divide—a signal that cancer cells exploit to spread in the body.

Normally, a kinase in cells called mTOR integrates information about a cell’s nutritional and energy needs and prompts the cell to manufacture key proteins for cell growth. Cancer then exploits this signal for its own growth.

The new drug, however, blocks each of the two mTOR signal pathways—a significant improvement over another drug currently being tested, rapamycin, which only blocks one pathway.

Dubbed a TORKinib because it inhibits the mTOR signal, the new compound is now being readied for clinical trials in patients. Shokat and his team plan to test the drug against a range of cancers—colorectal, lung, breast, multiple myeloma, and others—to determine which cancer is most sensitive to it.

Stryker is a pioneer of research into the mechanisms responsible for the development of neural connections and the capacity for these connections to adapt and change in the fully developed central nervous system.

The goal of his research, most of which is done on the visual cortex of mice, is to gain insight into the way in which nerve fibers grow and make the connections that lead to all aspects of brain functioning in humans.

By learning the way in which nerve cells communicate to form connections – and the critical periods during which these connections are refined, both prenatally and during infancy – researchers hope to be able to prevent nerve connections from forming incorrectly and to correct malformations when they do occur.

Understanding the way in which the brain assembles and wires itself could provide insights into the cause of developmental disorders that occur prenatally or near the time of birth.  Some of these disorders, characterized by loss of movement or loss of other nerve function, fall under the general category of cerebral palsy.

Discoveries could also provide researchers with insights into the molecular tools needed to stimulate the assembly of functional neural networks following spinal cord injuries or other central nervous system damage, such as stroke. While scientists are currently focused on trying to identify ways to prompt neurons to regenerate after injury to the central nervous system, they will eventually need to determine how to get neurons to make the right connections once they regenerate.

The research could even offer insights into the mechanisms by which the brain wires itself for cognitive processes, such as learning and memory, which could lead to treatments for learning disabled people.

In normal development, neural connections to and within the visual cortex are refined through the action of mechanisms of neural plasticity in combination with specific molecular signals. In lab studies, Stryker’s team induces brain plasticity through manipulations of genes or visual experience or by pharmacological or neurophysiological intervention in order to discover what cellular mechanisms and what changes in cortical circuitry are responsible for rapid, long lasting changes in neuronal responses. They analyze these changes using microelectrode recordings, novel techniques for measurement of optical and metabolic signals related to neural activity, including 2-photon microscopy and intrinsic signal imaging, and anatomical and neurochemical tracing of connections.

Weissman’s lab studies the cellular machinery that ensures proper protein folding, and the consequences of protein misfolding, particularly as relates to prions. The lab also focuses on systems biology—the development of approaches and tools to probe complex interactions in biological systems.

In a seminal series of studies, his lab developed an approach for creating in a test tube infectious “prion” forms of a protein. This work yielded the first direct demonstration of the “protein only” hypothesis proposed by UCSF Nobel laureate Stanley Prusiner, which proposed that prions represent a new class of infectious particles composed solely of a host protein.

Weissman’s ability to create synthetic prions also provided a powerful system for studying some of the most perplexing features of prion biology, including “species barriers,” which inhibit transmission between even closely related prion proteins, and prion strains wherein infectious particles composed of the same protein give rise to markedly different heritable prion states. His work established that strains are “encoded” within the conformation of the misfolded protein itself, thereby resolving one of the major mysteries of the prion field since, with no nucleic acid genome to mutate, it was unclear what could account for heritable strain differences.

This year, Weissman’s lab reported the development of a powerful tool for quickly identifying, and measuring levels of, proteins in cells. Unlike microarray technology, which identifies and measures levels of messenger RNA—a key step in the conversion of DNA code into protein—the new high-throughput technique, called ribosome profiling, tracks the conversion of messenger RNA into protein, itself.

Ribosomes are molecular machines that bind to messenger RNA and translate the RNA message into protein. The new technique, similar in speed, depth and accuracy to microarray technology, determines which proteins, and how many, are being produced, as well as how fast they are moving, in response to changing conditions.

The ability to monitor precisely which proteins a cell makes should inform many aspects of biology, including developmental biology, learning and aging.  The technology may help scientists pinpoint which proteins drive specific diseases, and which of those proteins might be the best target for new drugs.

The National Academy of Sciences is a private, nonprofit honorific society of distinguished scholars engaged in scientific and engineering research, dedicated to the furthering science and technology and to their use for the general welfare.  Established in 1863, the National Academy of Sciences has served to “investigate, examine, experiment, and report upon any subject of science or art” whenever called upon to do so by any department of the government.  For more information, or for the full list of newly elected members, visit www.nasonline.org/site/PageServer.

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