Yosef Shiloh, the winner in 2011 of the Israel Prize for Life Sciences and the Clowes Award of the American Association for Cancer Research, is now on sabbatical and doing work at NYU Cancer Center.
Born in 1949, Shiloh, a human genetics professor at Tel Aviv University, has devoted his career to researching a rare genetic disorder that he found in 1977 in four members of a Moroccan Jewish family in southern Israel. It causes among other things a predisposition to cancer. Shiloh’s work, much of which is funded by the Israel Cancer Research Fund, was considered by Science magazine the medical equivalent of the Rosetta Stone in deciphering a host of biomedical mysteries.
Jewish Week: How would you describe your work in layman’s terms?
Yosef Shiloh: The field I am working in is called maintenance of genome stability. It means that the DNA that defines what we are — its integrity and stability — must be maintained in a very strict manner. DNA is the genetic material that passes from one generation to another, and any mistake in the information that is contained in the DNA — specific alterations in its sequence — could be critical. We call a detrimental change in the DNA sequence a mutation, and mutations can lead to genetic diseases and cancer. Therefore, cells possess a sophisticated system that responds to DNA damage by repairing the damaged DNA and restoring the normal life cycle of the cell.
How do such changes occur?
There are a variety of agents that do that, ranging from environmental like chemicals and radiation to what we call the enemy from within — byproducts of normal metabolism that damage the DNA.
What are you hoping for in your research?
By studying these fortunately rare diseases in which the DNA damage response is defective, like ataxia-telangiectasia (A-T), we can understand better this critical system. Patients with A-T have a propensity for neurodegeneration,
immunodeficiency and radiation sensitivity.
Its understanding is important in the research of many common diseases, such as cancer and aging-associated diseases.
How did you get into this field?
When I was a graduate student in 1977, I met a Moroccan Jewish family in southern Israel and four of its 10 members were affected with A-T. The striking clinical features of the disease made it clear to me that the defective function in these patients is important.
What happens to those with A-T?
Affected children show lack of balance when they begin to walk. This is an early sign of the disease and the beginning of a progressive neuromotor dysfunction that results from the progressive degeneration of a specific part of the brain — the cerebellum that coordinates our movements and maintains balance. It is a progressive disorder and it gets more and more severe with age.
What happens to those who have it?
They are confined to a wheelchair, and they are dependent on others for everyday activities. They also suffer from immune deficiency and recurrent pulmonary infections. They tend to develop leukemia or lymphoma at a rate 1,000 fold higher than the general population. The patients are also very sensitive to ionizing radiation, of the type that is used for radiotherapy of cancer. So it was clear from the start that a very important biological function was missing in these patients.
What has your work on A-T accomplished?
After many years of intensive work in many laboratories, the gene which is mutated in A-T patients was discovered in our lab. This led to the identification of the protein made by this gene and understanding of its function as a cardinal player in the DNA damage response. Our lab has been part of this effort. In parallel, we attempt to understand the various clinical symptoms of A-T based on these insights.
What else have you learned?
Understanding the DNA damage response is also important for refining a main cancer treatment modality — radiation. Doctors need to understand the biology of what happens in the body when tissues are irradiated.
This is an example of how interest in a very rare genetic disease led to important biomedical discoveries with implications in many areas of medicine — not the least of which is cancer treatment.
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