Ph.D., Stanford University, Pharmacology, 1982.
B.S., Brown University, Engineering, 1975.
B.A., Brown University, Mathematics, 1975.
My lab is currently closed, but I continue to be involved in research in collaborative and advisory roles.
My lab's research was focused on the basic biology of retroviruses and adeno-associated viruses (AAV), with an emphasis on the application of our findings to the design and use of viral vectors in human gene therapy. Our retroviral vectors and vector packaging cell lines were used in the first human gene transfer and gene therapy trials in the U.S., and since then have been used in many gene therapy trials worldwide. Major goals were treatment of muscular dystrophy associated with defects in the dystrophin protein and lung disease associated with alpha-1 antitrypsin deficiency. We have found that vectors based on AAV type 6 promote efficient gene transfer and long-term gene expression in muscles and lungs of animals, and these methods should be useful to treat these diseases in humans.
Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) cause contagious lung and nasal cancers in sheep and goats. We have shown that the envelope proteins of JSRV and ENTV are the active oncogenes in these retroviruses. We also determined that hyaluronidase 2 (Hyal2) is the cellular receptor that binds envelope and is required for cell entry by both viruses. However, envelope interaction with Hyal2 plays no role in oncogenesis. Instead, both envelope proteins cause cancer by a virus entry receptor-independent mechanism that involves activation of the PI3-kinase/Akt pathway. Interestingly, the type of peripheral adenocarcinoma caused by JSRV is similar in phenotype to about 25% of human lung cancers, a major cause of human cancer mortality, and human Hyal2 functions as an efficient cell-entry receptor for JSRV. However, we have not found any association of JSRV with human lung cancer, but are continuing to explore this possibility.
One aspect of our research focused on the XMRV retrovirus (xenotropic murine leukemia virus-related virus) and its reported association with prostate cancer and chronic fatigue syndrome (CFS). We entered this field after we found that XMRV was produced at very high levels from the commonly-used 22Rv1 human prostate cancer cell line. 22Rv1 cells were derived from a prostate tumor removed from a patient in 1991, and our results suggested that XMRV had been in humans at least since 1991. However, XMRV had no direct transforming activity in our hands, leaving a puzzle regarding how XMRV might be causing cancer. In later studies we focused on how XMRV might be involved in CFS, and found that XMRV could kill neuroblastoma cells, indicating a neurotoxic activity of XMRV that might be involved in CFS. This toxic effect was mediated by interaction of the virus with its cell-entry receptor, Xpr1, which we recently found was an atypical G-protein-coupled receptor that regulated cAMP levels in the neuroblastoma cells. XMRV infection blocked Xpr1-mediated signaling resulting in reduced cAMP levels and cell death.
It is now known that XMRV was not present in the original tumor from which 22Rv1 cells were derived, but instead, arose during passage of these cells as a xenograft in mice. The original findings of XMRV association with prostate cancer and CFS have not been confirmed by others, including us, and it has become clear that detection of XMRV in early studies was due to contamination with XMRV virus from 22Rv1 cells, and later, with plasmid clones of XMRV. However, it will still be interesting to study the role of Xpr1 in cell biology, including a search for possible natural ligands that might regulate Xpr1 activity. Xpr1 orthologs are present in many organisms, including plants, animals and fungi, and XMRV has provided a window into what may be an important regulatory pathway in a wide range of living things.
1993-2013, Member, Fred Hutchinson Cancer Research Center, Human Biology and Basic Sciences Divisions
American Society for Microbiology
Honors and Awards
2002, Highly Cited Researcher, Thomson ISI
1999, Researcher of the Year Award, National Hemophilia Foundation
1998, R&D 100 Award for Retrovirus Packaging Cells and Vectors, R&D Magazine
1984-1986, Special Fellow, Leukemia Society of America
1982-1984, Fellow, Leukemia Society of America
Compositions and Methods for Efficient AAV Vector Production, Patent Number: 7208315, 2007, FHCRC, United States of America.
Polymerase I Promoter Plasmid and Vector Constructs, Patent Number: 6368862, 2002, FHCRC, United States of America.
Cap-Independent Multicistronic Retroviral Vectors, Patent Number: 6319707, 2001, FHCRC, United States of America.
Novel Mus Dunni Endogenous Virus (MDEV) Packaging Cell Lines, Patent Number: 6136598, 2000, FHCRC, United States of America.
10A1 Retroviral Packaging Cell Lines and Uses Thereof, Patent Number: 5766945, 1998, FHCRC, United States of America.
Method for Increasing Transduction of Cells by Adeno-Associated Virus Vectors, Patent Number: 5834182, 1998, FHCRC, United States of America.
Retrovirus Packaging and Producer Cell Lines Based on Gibbon Ape Leukemia Virus, Patent Number: 5470726, 1995, FHCRC, United States of America.
Retroviral Gene Transfer into Diploid Fibroblasts for Gene Therapy, Patent Number: 5219740, 1993, FHCRC, United States of America.
DNA Constructs for Retrovirus Packaging Cell Lines, Patent Number: 4861719, 1989, FHCRC, United States of America.