Expert Details

Molecular Pathology and Novel Solutions to Thrombosis, Cancer, Sepsis, Immunopathology.

ID: 726428 California, USA

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Expert has pioneered the identification of the proteins of the Coagulation cascade responsible for Thrombosis, Hemostasis, Disseminated Intravascular Coagulation, Sepsis, Inflammation and the roles in neoplastic cell invasion and metastasis. He was the first to successfully identify and isolate Factor VIII, Hemophiliac factor, vom Willibrand Factor, and Tissue Factor (TF, thromboplastin) the cell surface receptor that initiates and drives the coagulation cascade and its many resulting pathobiologies and clinical disease, accounting for as much as twenty percent of the mortality of the Western world. He produced the monoclonal antibodies (mAbs) to these proteins for research and therapy.

Expert first elucidated the structure:function of TF in thrombosis and sepsis and with selected monoclonal antibodies to completely rescue primates from 100% lethal sepsis. Similar mAbs have been shown to prevent survival of neoplastic cell metastases in vivo.

Expert pioneered analysis immunochemically of the coagulation cascade proteins. Further and current research is mapping the complex molecular pathways of sepsis which is highly influenced and controlled by the intracellular cytoplasmic domain of TF in conjunction with the cell surface Protease Activated Receptors (PARs). Detailed genetic and other interventional strategies are revealing previously unknown molecular pathways responsible for the severe morbidity and mortality of sepsis. Synthetic compounds to intervene as being successfully identified that function well in vivo in animal models of severe sepsis.

These and other aspects of the molecular pathobiology, pathophysiology and therapeutic intervention are in process.

Expert conceived and advanced novel approaches to tumor eradicative therapy independent of tumor type.
The first is Selective Tumor Vascular Thrombosis which specifically targets a modified Tissue Factor (the initating molecule of the coagulation and thrombosis cascades) to only tumor microvasculature which completely thromboses the tumor vasculature producing complete infarctive necrosis of the tumor. This has used two independent designs. The first using monoclonal antibody targeting. The second using peptides linked to modified Tissue Factor which localize only to tumor microvasculature, enabling function of modified Tissue Factor protein to completely thrombosis only the tumor associated vasculature and complete erradication of the tumor independent of tumor type. The clinical safety and specificity of localization has now been evaluated in the first cohort of humans.

The second independent class of cancer chemotherateutics are called PreProDrugs. These depend on the novel cell surface expression, only in tumors, of the only asparaginyl protease in the human genome. This protease is transported by certain integrins to the surface of tumor cells and tumor vascular endothelial cells, which is necessary for invasive property of neoplastic cells and growth of the tumor vasculature to nourish tumor cells. The drugs are cell impermeable and are only converted to cell permeable prodrugs by encounter with the protease:integrin complex. Upon entering cells of the tumor they are converted to fully cytotoxic derivatives that kill all cells in the tumor, and only in the tumor.

Expert was the first to successfully clone and express Tissue Factor, the initiating molecule of the coagulation protease cascade that is responsible for the coagulation, microthrombotic and lethality of acute severe sepsis. with the patents on Tissue Factor and on monoclonal antibodies to it, he demonstrated the rescue of primates from 100% lethality to 0% lethality. This was safe in chimpanzees.
Next more complex molecular pathogenesis of severe sepsis has been discovered where the cell surface domain as well as the cytoplasmic domain initiate and control cell signaling pathways the lead to the vascular permeability of sepsis, The key cell in this innate immune response is the lymph node dendritic cell that directly mediates the vascular injury and lethality.
The precise molecular signaling pathways, intervention, therapeutic drug design, and related issues have permitted profound reversal of disease characteristics and lethality in an array of genetically modified in vivo sepsis models.

Expert has more than fifty years of experience in advancing vascular medicine, vascular biology, and novel therapeutic intervention. He was the first to clone, express and elucidate the structure-function details of Tissue Factor (TF, thromboplastin) the initiating molecule of the coagulation, Hemostasis, Thrombosis cascade and diseases which drives sepsis and its mortality 30-60% of severe sepsis) and initiates or participates in nearly twenty percent of disease driven mortality in the U.S. and Europe. He has devised and advanced monoclonal antibody therapeutic intervention; and has also pioneered tumor specific thrombotic-infarctive necrosis and tumor eradication therapy research. Expert was the first to identify correctly Factor VIII (Hemophiliac Factor) and separately von Willibrand Factor, the most common cause of hemostatic defects.

Expert pioneered the immune response that drives through both innate and adaptive immune responses the coagulation clotting cascade. These responses are major causes of morbidity and mortality of man.

Shortly after the founding of Centocor, Inc., the pioneering venture into monoclonal antibodies and therapy, by Hubert Schoemaker, PhD in 1979, he began to consult Expert in regard to the therapeutic targets and technology. He continued until Centocor was acquired by J&J. Then, he consulted for J&J about generation of monoclonal antibodies, and re-engineered versions, for possible treatment of sepsis and other diseases. Expert consulted from 1982-85 for Eli Lilly on monoclonal antibodies and potential therapeutic interventions in clinical sepsis. Expert was a consultant to Becton-Dickinson 1977-80 on scientific directions, opportunities in new therapeutic discoveries, and related topics to the Chairman and to the CEO and senior management.Expert founded Corvas International, Inc. and was Chairman of the Board 1987-97. The goal was the discovery of new and novel small molecule inhibitors of the thrombogenic cascade, ones that could arrest and/or prevent the thrombotic process safely and effectively. These goals were in part achieved as well as others. Corvas merged into Dendreon later and continues there. Expert is a member of the Scientific Advisory Board of VGX Pharmaceuticals, Inc. This firm is the leader and IP owner of the key intellectual property for DNA vaccines and related immuno-therapeutics. The National Institutes of Health have now funded a large clinical trial for its HIV vaccines. The VGX flu vaccine is approaching clinical trials. VGX aquired Inovio, Inc. for its engineering of instruments for DNA vaccine delivery and is proceeding successfully.

Education

Year Degree Subject Institution
Year: 1957 Degree: MD Subject: Medicine Institution: Stanford University School of Medicine
Year: 1953 Degree: A.B. Subject: Biology Institution: Stanford University

Work History

Years Employer Title Department
Years: 1965 to Present Employer: Undisclosed Title: Professor Department: Immunology and Microbial Sciences
Responsibilities:
Head of Research Unit funded by National Institutes of Health; Heart, Lung, Blood Institute; other sources.
Years Employer Title Department
Years: 1968 to 1974 Employer: Scripps Clinic and Research Foundation Title: Founder and Head Department: Pathology
Responsibilities:
Create the Dept. Pathology. Lead formation and direct participation in Anatomic Pathology, laboratory medicine, and initiate and personally perform Nuclear Medicine. This was done with 50% effort, 50% research effort.
Dept. fully developed therefore I decided to resign to conduct research 100% effort.
Years Employer Title Department
Years: 1962 to 1965 Employer: Univ. Calif. Los Angeles (UCLA) Title: Assistant Professor Department: Pathology
Responsibilities:
Clinical Anatomic Pathology, Surgical Pathology, Dermatopathology. Medical student and MD resident training.
Years Employer Title Department
Years: 1960 to 1962 Employer: US National Academy of Sciences Title: Pathologist and Investigator, Chromosomal Damage Department: Atomic Bomb Casualty Commission, Hiroshima, Japan
Responsibilities:
Anatomic Pathology of Atomic Bomb Survivors and Controls. Community pathology services. Establish methods for analysis of chromosomal imaging of lymphocytes from Survivors and Control to search for chromosomal breaks.

Required Legal Immigration to Japan and ability in spoken Japanese.

Additional Experience

Expert Witness Experience
Testimony before Congress as well as California Legislature. Participation and presentation to governmental groups including "interest" groups in the pharmaceutical, biotechnology and related industries. Advisory Member appointed to the 1993 Presidential Health Care reform program by Clinton. Advisory Member to analysis and possible reorganization of the National Institutes of Health. Testimony and public television support of the reorganization of research support to Universities in Belgium with the President of Belgium. Invited advisory member to the meeting of the German Government on support and direction of Cancer Research, etc.

Career Accomplishments

Associations / Societies
American Society for Clinical Investigation.
American Society for Biochemistry and Molecular Biology.
American Association of Immunologists.
American Society of Hematology.
American Society for Investigative Pathology.
American Association for the Advancement of Science.
International Society on Thrombosis and Haemostasis.
Association of University Pathologists (Pluto Club).
American Heart Association.
The Protein Society.
Association of American Physicians.
North American Vascular Biology Organization.
Molecular Medicine Society.
American Liver Foundation.
American Association for Cancer Research.
Licenses / Certifications
Anatomic Pathology, Japan
American Board of Pathology, 1965.
Special Certification in Immunopathology, 1984.(The First)
Awards / Recognition
University of Helsinki Medal, 1973.
Lilly Award Lecture, American Association for the Study of Liver Diseases, 1976.
The College de France Medal, 1981.
Lecturer and Visiting Professor, College de France, Paris, 1981.
The Annual Invited Lecture, National Blood Club, Washington, D.C., 1982.
The J.W. McLaughlin Award, University of Texas, 1983.
Inaugural Address, Thrombosis Research Institute, London, 1990.
John A. Lynch Award in Molecular Biology, University of Notre Dame, 1992.
Rous-Whipple Prize, American Society for Investigative Pathology, 1995.
Distinguished Career Award, the International Society for Thrombosis and Haemostasis, Jerusalem, 1995.
Fellow, American Association for the Advancement of Science, 1996.
Member, Institute of Medicine, National Academy of Sciences, 1997.
Fellow, Council on Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 1997.
Publications and Patents Summary
He has 322 published articles, three more being submitted. He has 64 issued patents and additional applications.

Fields of Expertise

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