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GREAT CHANGES IN HEALTH CARE IN THE PAST 40 YEARS

GREAT CHANGES IN HEALTH CARE IN THE PAST 40 YEARS. Large increase in life expectancy Great improvements in prevention of disease ( cardiovascular: statins, hypertension management, lifestyle, etc.) Improvements in diagnosis and early detection (imaging: CT,

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GREAT CHANGES IN HEALTH CARE IN THE PAST 40 YEARS

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  1. GREAT CHANGES IN HEALTH CARE IN THE PAST 40 YEARS • Large increase in life expectancy • Great improvements in prevention of disease ( cardiovascular: • statins, hypertension management, lifestyle, etc.) • Improvements in diagnosis and early detection (imaging: CT, • MRI, US; other technology-related; molecular diagnosis) • Improvements in treatment of disease (technology-related: • intensive care, pacemakers, etc.; novel drugs: cancer • chemotherapy, AIDS, etc.)

  2. ROLES OF SCIENTIFIC DISCOVERY IN THE IMPROVEMENT OF HEALTH CARE. • Basic research and discovery provides the foundation for • great advances in medical practice (Fleming & penicillin; • Lauterbur & MRI, etc.). • 2. Applied research and development are always based on • discoveries in basic research. It benefits directly healthcare • (i. e., coronary stents, laparoscopic & robotic surgery, new • generations of antibiotics, etc.).

  3. PROTEINS ARE THE MACHINES OF OUR BODY • Chemical processes (enzymes) • Physical processes • Regulators • Immune response (antibodies) • There are many thousands of different proteins • in our cells, each of which has a specific function.

  4. PROTEIN SYNTHESIS AND DEGRADATION DNA RNA Protein synthesis Protein Amino acids Protein degradation …

  5. MAIN FUNCTIONS OF PROTEIN DEGRADATION amino acids amino acids NORMAL PROTEIN ABNORMAL PROTEIN • Removal of abnormal • or misfolded proteins • prevents toxicity to cells 2. Degradation of normal regulatory proteins stops their action (“switch off”)

  6. QUESTION: HOW ARE CELLULAR PROTEINS DEGRADED AT A HIGHLY SELECTIVE AND REGULATED MODE?

  7. STAGES AND MILESTONES IN THE RESEARCH 1969-71: The degradation of tyrosine aminotransferase in cells requires energy 1977-78: Isolation of a small protein (ubiquitin) required for energy- dependent protein degradation 1979-1980: Discovery of linkage of ubiquitin to proteins destined for degradation; proposal of the ubiquitin tagging hypothesis 1980- 1990: Identification of enzymes involved in ubiquitin-mediated protein degradation 1990-present: Roles of the ubiquitin system in the control of cell division

  8. Ubiquitin- a protein that marks other proteins for degradation

  9. PROTEINS ARE TAGGED FOR DEGRADATION BY LINKAGE TO UBIQUITIN CHAIN Proteins linked to ubiquitinchains are degraded by the proteasome Linkage of ubiquitin chain to protein by specific enzymes (E1, E2, E3) Goldberg, 2005

  10. STAGES AND MILESTONES IN THE RESEARCH 1969-71: The degradation of tyrosine aminotransferase requires energy 1977-78: Isolation of a small protein (ubiquitin) required for energy- dependent protein degradation 1979-1980: Discovery of ligation of ubiquitin to proteins; proposal of the ubiquitin tagging hypothesis 1980- 1990: Identification of enzymes involved in ubiquitin-mediated protein degradation 1990-present: Roles of the ubiquitin system in the control of cell division

  11. THE CELL DIVISION CYCLE

  12. Cyclin E Cyclin A p27 Level Skp2 Cks1 Time S G0/G1 NON-DIVIDING CELLS DIVIDING CELLS  Oscillation in levels of proteins that regulate cell division

  13. Some roles of ubiquitin-mediated protein degradation. • Control of cell division • Signal transduction • Regulation of gene expression • Responses to inflammation • Immune response • Embryonic development • Apoptosis • Protein quality control by removal of abnormal proteins

  14. INVOLVEMENT OF THE UBIQUITIN SYSTEM IN DISEASES • Cancer (many types) • Neurodegenerative diseases: Parkinson’s; Alzheimer’s; Huntington’s • Mental retardation (Angelman’s syndrome) • Viral diseases (AIDS virus multiplication) • Muscle wasting (cachexia)

  15. INVOLVEMENT OF THE UBIQUITIN SYSTEM IN CANCER (1) CELL DIVISION ONCOPROTEIN Decreased degradation TUMOR SUPPRESSOR PROTEIN Increased degradation CANCER CAN BE CAUSED BY LACK OF DEGRADATION OF AN ONCOPROTEIN, OR BY TOO RAPID DEGRADATION OF A TUMOR SUPPRESSOR PROTEIN.

  16. VELCADE - A HIGHLY EFFICIENT INHIBITOR OF THE PROTEASOME Proteins linked to ubiquitinchains are degraded by the proteasome Linkage of ubiquitin chain to protein by specific enzymes (E1, E2, E3) Velcade (Bortezomib, PS-341)

  17. VELCADE (BORTEZOMIB) PROTEASOME INHIBITOR • Approved by FDA at 2003 for the treatment multiple myeloma, • a bone marrow cancer • Inhibits the proliferation of myeloma cells and promotes their • apoptosis • Also effective in the treatment of mantle cell lymphoma

  18. SOME THOUGHTS ON THE FUTURE OF HEALTHCARE IN THE 21ST CENTURY. • Life expectancy ~ 90-100 years, accompanied • by prolonged quality of life • Retirement age ~ 75 years • New treatments for currently unsolved, major • health problems: cancer, neudegenerative and • cardiovascular diseases • Molecular medicine • Individualized medicine • Technology-based medicine

  19. Technion lab (1971-present) Dvora Ganoth Hanna Heller Esther Eytan Sarah Elias Judith Hershko Former graduate students Aaron Ciechanover Yuval Reiss Valery Sudakin Shirly Lahav and many others… Collaboration and help Irwin A. Rose Joan Ruderman Michele Pagano Present graduate students Yakir Moshe Shirly Miniowitz Adar Teichman Postdoctoral fellows Ilana Braunstein Danielle Sitri-Shevah Yelena Dumin

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