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JEFFREY SMITH, PH.D.
Director, Program for Excellence in Nanotechnology
Director, Center on Proteolytic Pathways
Tumor Microenvironment
858.646.3121 (phone)
858.646.3192 (fax)
jsmith@burnham.org
RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATIONS
Biography
Jeffrey Smith earned his Ph.D. in biological sciences at UC Irvine in 1987. Following postdoctoral training at The Scripps Research Institute, he was appointed to their staff in 1991. Dr. Smith was recruited to The Burnham Institute in 1995.
Selected Publications
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
THE CENTER ON PROTEOLYTIC PATHWAYS
In 2004 the National Institutes of Health (NIH) selected a team led by Jeffrey Smith, Ph.D., to establish the Center on Proteolytic Pathways (CPP). As part of the NIH Roadmap for Medical Research, the center develops technology to study the behavior of proteins and to disburse that knowledge to the scientific community at large.
Proteases are a class of enzymes that regulate much of what happens in the human body, both inside the cell and out, by cleaving peptide bonds in proteins. Through this activity, they govern the four essential cell functions—differentiation, motility, division and death—and activate important extracelluar episodes, such as the cascading effect in blood clotting. Simply stated, life could not exist without them.
Proteolytic pathways, or proteolysis, are the series of events controlled by proteases that occur in response to specific stimuli. In addition to the clotting of blood, the production of insulin can be viewed as a proteolytic pathway, as the activation, regulation and inhibition of that protein is the result of proteases reacting to changing glucose levels and triggering other proteases downstream.
The Need and Opportunity for the Center on Proteolytic Pathways
Proteolytic pathways are key to the pathology of virtually every type of human disease, including, but not limited to, viral infections, inflammation, thrombosis, cancer, Alzheimer’s and emphysema. Any advance in this field that increases understanding of proteolysis and presents opportunities to regulate it could potentially provide health benefits so far-reaching that we cannot fully imagine their impact.
Although the completion of the Human Genome Project identified the majority of human proteases, major and fundamental gaps exist that prevent meaningful scientific research. We do not know the focus of most of these proteases. We do not know how each protease recognizes its target substrate (the protein that it will cleave and activate), nor is it clear how these important enzymes link to other cellular pathways.
The Center on Proteolytic Pathways aims to fill these holes by developing technology to study these problems and distributing it to other scientists; we will be a national resource, disseminating much of the information through the Proteolytic Map (PMAP) at http://protease.burnham.org. It is our hope that by providing investigative tools to other researchers, the proteolytic knowledge base will grow rapidly, and can be translated into therapeutic benefit for disease.
The Research Team
The scientists participating in the CPP represent some of the world leaders in chemical biology, computational biology and biological imaging. Through their experience, guidance, insight, scientific curiosity and passion for this program, the CPP will move forward quickly and effectively, meeting its goal to make proteolysis a known by the year 2020.
Dr. Smith’s laboratory also has a longstanding interest in developing new methods for proteomics. In particular, they have been interested in activity-based proteomics, in which small molecules are used to tag active sites within enzymes. By constructing such probes so that they react broadly with many members of an enzyme class, one can quantify and identify active enzymes within any biological sample. With this strategy, one can use the power of chemistry as a “separation tool” to parse the proteome into easily understandable classes. Because the chemical probes that are used for activity-based proteomics bind at the active site of a class of enzymes, one can also use this method to screen for drugs that inhibit a particular enzyme. Since activity-based probes usually bind to the homologues in an enzyme family, such drug screening also reveals cross-reactivity of many compounds, information that can be used to eliminate unwanted side effects of drugs. Our group used this approach to identify fatty acid synthase as a drug target in oncology, and to reveal that Orlistat, a drug already approved for treating obesity, is a lead antagonist of this enzyme.
HEART DISEASE
Program of Excellence in Nanotechnology
An estimated 60 million Americans suffer from at least one form of cardiac disease today, and one million of these will die each year, many without the presentation of prior symptoms. Through a Program of Excellence in Nanotechnology (PEN) Grant from the National Heart, Lung and Blood Institute, an arm of the National Institutes of Health, Dr. Smith leads a group of researchers from The Burnham Institute for Medical Research, the University of California Santa Barbara and the Scripps Research Institute in investigating how to build tiny devices, both synthetic and biological, that will deliver drugs and other treatments specifically to the diseased areas of a heart.
Dr. Smith and his collaborators are focusing on vulnerable plaque, one of the heart’s worst enemies. Buildup of atherosclerotic plaques on arterial walls poses a health risk for several reasons, including occlusion or the blockage of the artery and subsequent restriction of blood flow. Just as serious is the rupture of these plaques, which many scientists believe account for nearly 70 percent of myocardial infarcts in this country. Recent research shows that the most promising therapeutic approach is plaque stabilization, rendering the atherosclerotic lesion more resistant to rupture.
An important element in the equation is that only a subset of these plaques are vulnerable, or prone to rupture. It is these differences in structure and composition that serve as the lynchpin for Dr. Smith’s PEN project, called Nanotherapy for Vulnerable Plaque. For nanomedicine to work, for nanodevices to effectively deliver their pharmaceutical payloads, they must first find the designated tissue, which is called targeting.
Other aspects of the research include delivery of medicine to the tissue, how to stabilize the plaque, and attaching devices with an on/off switch that will sense changes in the tissue or plaque and initiate therapy automatically.
CANCER RESEARCH
Fatty Acid Synthase
Fatty acids synthase (FAS) is the single eukaryotic enzyme responsible for converting dietary carbohydrate to fat. Given this pivotal role, the enzyme has long been considered as a potential drug target in controlling obesity. Surprisingly, FAS is also strongly linked to tumor progression. The enzyme is up-regulated in all types of solid tumors; and in breast and prostate cancer, increases in its expression are linked to the transition to hormone-independent growth.
Our interest in FAS centers on three objectives: 1) to better understand the role of FAS in tumor cell metabolism in order to identify which patients would best benefit from FAS-directed therapy; 2) to discover and develop small molecules that are able to kill tumor cells through exploiting this FAS-dependence while causing minimal damage to normal tissues; and 3) to identify the mechanisms by which the inhibition of FAS leads to tumor cell death so that targeted therapies may be developed.
Rather than view FAS as a stand-alone tumor marker or target, we are investigating the upregulation of fatty acid production as part of an overall shift in a tumor’s metabolism. The existence of unique tumor metabolism has been known for decades but the specifics have not yet been described due to limitations in technology. We are using state-of-the-art NMR spectroscopy and mass spectrometry to observe the metabolome of breast tumor cells and identifying changes that occur as a cells moves from from normalcy to premalignancy to metastasis. Additionally, we are able to observe the effects of FAS inhibition on the metabolism of these tumor cells to better understand why FAS is necessary for their survival.
The current chemical and molecular biology tools with which we inhibit FAS are very effective in a laboratory setting but are poor therapeutic agents. That is why we are working with medicinal and synthetic chemists to improve known FAS inhibitors and discovering novel pharmacophores. These compounds inhibit FAS through mechanisms different than the currently available agents and also display more “drug-like” properties, making them promising anticancer lead compounds.
Ileal Bile Acid Binding Protein
Ileal bile acid binding protein (IBABP) is a member of a family of cytoplasmic fatty acid binding proteins. IBABP is unique in that it binds selectively to bile acids, and not to fatty acids. It is generally believed that IBABP has a central role in regulating the cytoplasmic levels of bile acid, and is therefore important in regulating the cholesterol balance in the body.
Our group has discovered that three variants of IBABP can be expressed in cells. One of these variants, which has a fifty amino acid residue N-terminal extension, is the predominant form of IBABP in colon cancer cells. Interestingly, this variant of IBABP arises from an alternative transcriptional start site in the IBABP gene. The role of IBABP and its variants in the onset and progression of colon cancer has not been examined. However, there is considerable support for the idea that toxic secondary bile acids contribute to the onset and progression of colon cancer. The objectives of our studies with IBABP are three-fold; 1) to clarify the transcriptional regulation of IBABP and its variants, particular as it relates to colon cancer, 2) define the role of the long form of IBABP in tumor cell growth and survival, and 3) determine if IBABP is a receptor for a bile acid called ursodeoxycholic acid, which has chemopreventative properties.
INFECTIOUS DISEASE
Thioesterases in Siderophore Biosynthesis
Bacterial pathogens including Y. pestis, Vibrio, Salmonella, and Listeria, all require iron to survive. However, at physiologic pH, Fe3+ is insoluble at concentrations above 10-18 M, and in humans, the concentration of free Fe3+ is maintained at less than 10-24 M to prevent iron toxicity. This exceedingly low concentration of iron presents a major chal¬lenge to bacterial pathogens, one that they have met by developing an elaborate system to synthesize small molecule iron chelators called siderophores. Siderophores are secreted into the host, where they confiscate iron from host proteins like transferrin and then deliver the iron back to the pathogen through an intricate transport system.
Our group is focusing on Y. pestis, the causative agent of the plague, and a Category A biodefense target. Y. pestis synthesizes a siderophore called yersiniabactin. The six genes essential for yersiniabactin synthesis are encoded within a “high pathogenicity island.” Of these six genes, two are thioesterases that have homology to the thioesterase of human fatty acid synthase. My lab is currently testing the hypothesis that the Y. pestis thioesterases can be targeted for drug development. Importantly, the high pathogenicity island containing the genes for synthesis of yersiniabactin has been laterally transferred to other strains of bacteria, making them pathogenic. This includes a strain of E. Coli that is responsible for persistent urinary tract infections. Therefore, we believe that antagonists of yersiniabactin synthesis are likely to have applications beyond the biodefense arena.
Our current objectives are to: 1) determine the three dimensional structure of the Y. pestis thioesterases, 2) screen highly diverse compound libraries to identify lead antagonists of the thioesterases, and 3) use structure-guided design to synthesize highly potent antagonists of the thioesterases for subsequent drug development.
Metalloproteinases in Smallpox
Although vaccination eliminated natural outbreaks of variola from the human population, this pathogen remains a substantial risk given the current geopolitical climate and the potential for bioterrorism. The variola virus encodes two proteases: one a cysteine and one metallo, and both are essential for maturation of the viral coat proteins. Given our groups track record in the study of metalloproteinases, we are developing lead antagonists of the variola metalloproteinase. Along with collaborators here at the Burnham Institute, our objectives are three-fold: 1) to express substantial quantities of the active metalloproteinase, 2) to crystallize the protease and solve its three-dimensional structure, and 3) to use structural information to guide the design of small molecule antagonists of the variola metalloproteinase.
