It will eventually be possible to predict which patient will respond well to specific drugs.
By JUDY SIEGEL-ITZKOVICHcancer cells 88(photo credit: )
When John Mendelsohn, an inquisitive sophomore at Harvard in 1956, mulled over what "major" to pursue, he considered a variety of subjects from physics, chemistry and math to literature, political science and history. By chance, Mendelsohn - a native of Cincinnati and the son of a Jewish belt maker - sauntered into the biology department and asked the office assistant if any research opportunities were being offered.
"There's a new professor here," she said. "He's very young, still in his 20s, but he's supposed to be very good. His name is Dr. James Watson."
This serendipitous event occurred three years after Watson, along with Dr. Francis Crick, discovered the structure of DNA. Watson and Crick, working with colleagues Maurice Wilkins and Rosalind Franklin, built the double-helix model that has had as momentous an effect on medicine as Albert Einstein's famous 1905 papers had on physics.
Mendelsohn - now president of America's top cancer research hospital, M.D. Anderson Cancer Center of the University of Texas - became the first undergraduate student to work in Watson's lab. Last week, the 69-year-old received $500,000 for his work, sharing the Dan David Foundation Prize for the Future Dimension at Tel Aviv University with Prof. Joseph Schlessinger of Yale. Although he has received many prestigious awards, Mendelsohn says this is the largest monetary prize he has ever been given.
He is still in touch with Watson, who is about a decade older and has retired as director of New York's Cold Spring Harbor Laboratory, one of America's two leading non-university biomedical research labs. "But he is still teaching, and I see him about once a year," Mendelsohn told The Jerusalem Post in an exclusive interview on campus before receiving the Dan David Prize.
"When I started work in Dr. Watson's lab, we knew only that DNA had the right chemical configuration to carry a genetic code. We didn't know the code or how the code was transmitted into protein; messenger RNA had not yet been discovered. Now we can list hundreds of genes and their proteins that are different in cancer cells compared with normal cells because of mutations or altered expression patterns. This helps us understand how a normal cell works at the molecular level and what's wrong in a cancer cell. It has given us an opportunity to develop rational targets for treating cancer, instead of trying to poison the cancer cells."
Molecular biology, he continued, was a new term in those days. "I wanted this knowledge to prepare me for the study of medicine. Watson impressed me then as a no-nonsense guy, evidence-driven, precise and very knowledgeable and critical. He had not yet received his Nobel Prize. Everybody at Harvard knew about Watson and Crick's seminal paper in Nature explaining the structure of DNA, but nobody knew how vast the implications would be," Mendelsohn recalled.
"We were just beginning to understand how proteins were created. Our Harvard lab played an important role in realizing the information chain from DNA to RNA to protein," he continued.
A year after meeting Watson for the first time, Mendelsohn discussed his career plan with him. Watson "outlined what he thought would happen in the field of molecular biology and genetics in the next decade - accurately, as it turns out. He urged me to get my Ph.D. because the field was going to blossom, which it did. But after much thought I told him that I really wanted to be a physician. I had a tremendous interest in science but liked people; the thought of applying science to the problem of human disease was very appealing."
MENDELSOHN went on to Harvard Medical School, where he received his MD in 1963, and later specialized in oncology. After serving as a research associate at the US National Institutes of Health and a faculty member at Washington University in St. Louis, he joined the faculty of the University of California at San Diego in 1970 and stayed for 15 years, establishing the university's cancer center and heading it between 1976 and 1985. In 1980, Mendelsohn began work with Dr. Gordon Sato on blocking receptors.
"It was a novel approach, like putting gum in the ignition so that you couldn't turn the key, when the key meant allowing cancer cells to grow." The result was Erbitux, a monoclonal antibody known generically as cetuximab and used to extend and perhaps even save the lives of patients with colon, head and neck cancers. The University of California at San Diego sold the rights to ImClone Systems Incorporation, which in turn, granted exclusive rights to Bristol-Myers Squibb in New Jersey and Merck in Germany to develop and commercialize the drug, which is given by infusion.
For many decades, the gold standard of cancer treatment was to remove a tumor if possible, destroy any malignant cells with radiotherapy and give chemotherapy with cytotoxic drugs (that kill off cancer cells along with healthy tissue). However, this technique has major side effects on growing and dividing cells such as bone marrow, the stomach, intestine, hair follicles, ovaries and testes.
But a new and promising technique - one that is the basis of Erbitux and about half of the experimental cancer drugs being developed and tried today for several types of cancer - uses a different approach: customization based on genes that are abnormal and molecular pathways of individual patients' tumors. Cancer-drug researchers aim to target and destroy tumor cells while leaving normal cells untouched. For this, a specific marker identifying a cell as cancerous is required, together with a means of targeting this marker and subsequently destroying the cell. Epidermal growth factor receptor (EGFR) is highly expressed (overactive) in many types of tumors. Its main function, which is normally tightly controlled, is to promote the growth and division of cells, the repair of cellular damage and the movement of cells within surrounding tissue. But in cancer, EGFR's effects are enhanced, leading to the growth of tumors, increased resistance to chemotherapy or radiotherapy and the formation of metastases (small pieces of tumor that break off and invade other parts of the body). Researchers aimed at targeting cells that have EGFR on their surface, and early lab research showed that blocking the activity of this receptor has a potent anti-cancer effect.
THIS MECHANISM is also the basis of the breast cancer drug Herceptin and Avastin, another drug for advanced colon cancer. Blocking the activity of this EGFR has a potent anti-cancer effect, preventing it from becoming active. EGFR with cetuximab attached is drawn inside the cell and destroyed, thus minimizing the amount of EGFR on the cell surface that can be activated. Since it is an antibody, Erbitux has the ability to alert the immune system to the presence of tumor cells so it can kill them.
Other types of cancer may be in Erbitux's crosshairs as well.
"In the coming years, we will take patients' cancer cells to the lab and study their chemical abnormalities. This will eventually make it possible to predict which patient will respond well to specific drugs," he explained.
Avastin and Erbitux have received unusual prominence in recent weeks. A handful of colon cancer patients have been holding a hunger strike outside the Knesset to demand the inclusion in the basket of health services of these expensive (NIS 20,000-NIS 25,000 a month per patient) drugs.
With his wife Anne and their three sons, he then moved to New York, where he became chief of the department of medicine at the Memorial Sloan-Kettering Cancer Center. Then, in 1996, he was named president of M.D. Anderson and moved to Houston. M.D. Anderson ranks as one of the world's most influential centers devoted to cancer patient care, research, education and prevention. This year alone, it will care for more than 70,000 patients, conduct basic and clinical research with more than $104 million in grants and train nearly 2,000 scientists, cancer specialists and health professionals.
Mendelsohn proudly noted that in four of the past six years, M.D. Anderson has been ranked as the top cancer hospital in the US (the other was Memorial Sloan-Kettering) and one of the best 10 to 15 medical centers in America. Although it is one of the first three federally designated comprehensive cancer care centers, only a minority of its funding comes from the US government, with most from health maintenance organizations paying for their members' care and from grants. Mendelsohn is only the third full-time president in M.D. Anderson's 65-year history, and he knows the 41st President of the US, George Bush Sr. well, because he is on the hospital's board.
GRADUALLY, he found it impossible to simultaneously treat patients, teach, run a lab and work as an administrator, but he continues to follow research developments and watch as the antibody approach to cancer spreads.
This was his third visit, since the late 1970s, to Israel. Although he comes from a prominent Jewish family (whose branches include composer Felix Mendelsohn but not philosopher Moses Mendelsohn) that includes a Reform rabbi who had a big influence on his life, he doesn't speak Hebrew.
John and Ann, a photographic researcher and museum chairman, visit their sons all over the globe: Andrew teaches the history of science at The University of London and with his wife Tina has three children; Jeffrey, single and living in San Francisco, "is trying to save the world" by recycling paper, and Eric, an investment banker in New York, is married to Isabel and has three children.
Asked what he will do with the $500,000 award, Mendelsohn notes that he will donate 10% as scholarships, as required by the Dan David Foundation. With part of the rest he will ensure the education of his grandchildren.
He is concerned that fewer young Americans go into science, with the vacuum being filled by foreigners. "I don't know if it's laziness or the desire to make money quickly. Science research is a lifestyle that requires a lot of time in the lab, and the math is difficult. American kids today are not taught that doing science is something wonderful. We must improve the educational system and honor scientists as we honor rock stars and Hollywood actors. In Singapore, I saw school posters honoring children who excel, but you won't see that in the US."
He noted that China has invested a great deal in basic scientific research. "I visited China in 1991 and found the labs were very primitive; I went back a year-and-a-half ago and found they have the same equipment now that we do in the US."
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