To Find Cures for Cancer

 

When asked to predict future trends in cancer research, Prof. Leo Sachs responds resolutely: "Futurology in science has not been very successful. If I knew what would be important in five years time, I would do it now!"

With nearly 50 years of research behind him and still going strong, Sachs, a member of the Weizmann Institute's Molecular Genetics Department, has made fundamental contributions to the fields of hematology, developmental biology, and cancer research, paving the way to clinical treatments applied worldwide.

To find cures for cancer has topped the medical wish list throughout most of the twentieth century. Over one hundred forms of cancer exist, and though induced by diverse factors, all result in changes to the DNA. Now, when some researchers claim that the deciphered human genome may lead to an imminent cure for cancer, Sachs's perspective on this battle is unique -- he's been on the scene since even before the DNA double helix was discovered, back in 1953.

He had actually envisioned things quite differently. Born in Leipzig, Germany, his family moved to England in 1933 following Hitler's rise to power. "My original dream was to help establish a kibbutz in Palestine. I even spent two years as a farm laborer, milking cows," says Sachs. But apparently it wasn't in the cards. The doors to Palestine were virtually closed by the British, so Sachs began studying agricultural botany at the University of Wales, became fascinated along the way by genetics and development, and ended up completing a Ph.D. in genetics at Cambridge University.

He moved to Israel in 1952, where he began to contribute to the fledgling country in the way he knew best -- as a geneticist at the Weizmann Institute. "I wanted to study animal and human genetics, but there were no animals," Sachs recalls. "Nor for that matter, was there a building to work in. The cornerstone for the experimental biology building had just been laid." Given a bench in one of the chemistry departments, Sachs started working on a theory that human amniotic fluid, which bathes the baby in the womb, contains fetal cells that provide information about the fetus. His research proved him right, showing that these cells can be used to determine the baby's gender and other important genetic properties. Sachs's research formed the basis for amniocentesis, the widely used prenatal diagnosis of human diseases.

Eventually, Sachs secured his own laboratory and a supply of mice and began working on a question that would anchor his research throughout. "The question was, what controls normal development and what happens when development goes wrong? Why does the machinery in cancer cells run amok, causing abnormal proliferation? I was convinced at the time, as I am now, that in order to understand 'what's gone wrong' (in cancer), one must first understand 'what's gone right' -- in other words, normal cellular processes," Sachs explains.

Focusing on blood stem cells, a small group of bone marrow cells that produce some 200 billion new blood cells every day, Sachs ended up designing the first cell culture system able to grow, clone, and induce the development of different types of normal blood cells. The year was 1963. Using this process, he subsequently discovered and identified a family of proteins that plays a key role in controlling normal blood cell development. Later named colony stimulating factors (CSF) and interleukins, one of these CSF proteins is now used worldwide in a variety of clinical procedures. These include boosting the production of infection-fighting white blood cells in cancer patients undergoing chemotherapy or radiation, and improving the success of bone marrow and peripheral blood cell transplants.

Sachs also demonstrated, for the first time, that malignancy can be reversed. He showed that the proteins he had identified, and some other compounds, set leukemic cells back on the right track -- inducing them to differentiate into normal-behaving mature cells. This approach, using retinoic acid combined with chemotherapy, is now standard procedure in treating human promyelocytic leukemia, and it has greatly increased survival rates.

Why do cancer cells outlive normal cells? This is another question currently being explored by Sachs. All cells contain a built-in suicide mechanism, known as apoptosis, which is vital for eliminating damaged or surplus cells. However, many cancer cells contain mutations in the key suicide-regulating genes, causing them to live longer. "By 'switching off' these mutated genes and other external factors we may be able to induce cancerous cells to self-destruct," says Sachs.

The research questions have not changed over time, Sachs emphasizes, only the methodologies. "In the past we were able to view the various types of chromosomal abnormalities, but today we can also zoom in and examine the actual interaction between genes. By uncovering the genes involved and how they are expressed in their environment -- in other words, what the neighborhood is like -- we can essentially eavesdrop on 'communication lines' and target weak links. For instance, one approach is to target communication between tumors and new blood vessels that support them. New diagnostic techniques will also improve our ability to determine the therapy likely to be most effective in treating a patient's specific pathologies."

And what about gene therapy -- replacing defective genes with normal counterparts? Sachs believes it may be quite some time before this approach becomes clinically feasible. "But who knows," he says, leaning back on his fifty years of scientific experience. "Remember, the most interesting things in science are the unexpected and unpredictable!"