Download 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,
MRI, US; other technology-related; molecular diagnosis)
• Improvements in treatment of disease (technology-related:
intensive care, pacemakers, etc.; novel drugs: cancer
chemotherapy, AIDS, etc.)
ROLES OF SCIENTIFIC DISCOVERY IN THE IMPROVEMENT
OF HEALTH CARE.
1. 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.).
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.
PROTEIN SYNTHESIS AND DEGRADATION
DNA
RNA
Protein synthesis
Protein
Amino acids
Protein degradation
…
MAIN FUNCTIONS OF PROTEIN DEGRADATION
amino
acids
amino
acids
ABNORMAL
PROTEIN
1. Removal of abnormal
or misfolded proteins
prevents toxicity to cells
NORMAL
PROTEIN
2. Degradation of normal
regulatory proteins stops their
action (“switch off”)
QUESTION:
HOW ARE CELLULAR PROTEINS DEGRADED AT
A HIGHLY SELECTIVE AND REGULATED MODE?
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 energydependent 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
Ubiquitin- a protein that marks other proteins for degradation
PROTEINS ARE TAGGED FOR DEGRADATION BY
LINKAGE TO UBIQUITIN CHAIN
Proteins linked to
Linkage of ubiquitin chain
to protein by specific
ubiquitin chains are
enzymes (E1, E2, E3)
degraded by the proteasome
Goldberg, 2005
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 energydependent 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
THE CELL DIVISION CYCLE
Level
Cyclin E
Cyclin A
p27
Skp2
G0/G1
NON-DIVIDING 
CELLS
Cks1
S
Time
DIVIDING CELLS
Oscillation in levels of proteins that regulate cell division
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
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)
INVOLVEMENT OF THE UBIQUITIN SYSTEM IN CANCER (1)
ONCOPROTEIN
CELL DIVISION
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.
VELCADE - A HIGHLY EFFICIENT INHIBITOR
OF THE PROTEASOME
Proteins linked to
Linkage of ubiquitin chain
to protein by specific
ubiquitin chains are
enzymes (E1, E2, E3)
degraded by the proteasome
Velcade
(Bortezomib, PS-341)
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
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
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