Mother Nature's pharmacy

The Yeshiva University discoverer of a cancer-stopping chemical derived from a common evergreen is working to improve its efficacy.

evergreen 88 (photo credit: )
evergreen 88
(photo credit: )
In the Beginning, there were diseases with the potential to strike humans, animals and plants. But God also created a "medicine cabinet" full of potential cures and treatments in the form of natural substances - often in the most remote places, and even in organisms such as undersea corals and sponges. It is the task of scientists to find them, and learn which substances work against which disorders. Dr. Susan Band Horwitz, a senior molecular pharmacologist at Yeshiva University's Albert Einstein College of Medicine in New York City, is one of those detectives. She worked for decades on the bark and needles of the Pacific yew tree (Taxus brevifolia) - an evergreen growing in many parts of the world - and found it has a unique characteristic relevant to cell division. As a result of her work, a drug named Taxol was developed, and over one million people with breast, ovarian, head & neck and non-small-cell lung cancer have benefited. She visited Israel recently to attend the convention of the Israel Society of Microbiology at Ben-Gurion University at the invitation of its president and BGU Prof. Bracha Rager, adviser to the Health Ministry's chief scientist. A session of the conference was devoted to the memory of Horwitz's husband, Prof. Marshall Horwitz, a leading physician, virologist and great friend of Israel who died last May, and prizes in his name were distributed to outstanding students. "Small molecules can do big things," the researcher told The Jerusalem Post in an interview during her visit. "What I refer to are drugs from natural products such as Taxol from the yew tree, which I was involved in for most of my professional life. Some scientists argue that one shouldn't bother with natural compounds, but just synthesize new ones, but I say there are so many unique ones ready for picking." But the puzzle must be solved quickly, because many species of potentially life-saving and life-improving pharmaceuticals are becoming extinct. THE SOFT-SPOKEN researcher was herself honored in the autumn of 2004 with New York City's highest honor for achievement in the biological and medical sciences: She was presented the Mayor's Lifetime Achievement Award for Excellence in Biological & Medical Sciences by Mayor Michael Bloomberg at a ceremony in City Hall. Previous recipients have included four Nobel laureates. Horwitz is the fourth Einstein faculty member to receive this prestigious award. The award recognizes Dr. Horwitz's pioneering research that led to the development and approval of Taxol, considered one of the most effective cancer-fighting therapies developed in recent years. Her work influenced both basic and clinical research with antitumor drugs, and she and her 10-person lab are currently focusing on the problem of drug resistance and what other drugs work synergistically with Taxol. Horwitz received her bachelor's degree from Bryn Mawr College and her doctorate from Brandeis University. Recently named to the American Academy of Sciences, she is a fellow of the US National Foundation for Cancer Research, past president of the American Association for Cancer Research, and on the board of scientific advisors for the National Cancer Institute. She also received the $150,000 Warren Alpert Foundation Prize. The outgoing, longtime dean of Einstein, Prof. Dominick Purpura (who nominated Horwitz for this award) said: "One thing Mr. Alpert stipulated when he developed this prize was that it should go to someone who had already made major contributions to helping patients. The impact of Susan's work has been quite extraordinary." BORN AND raised in Boston, Horwitz never wanted to be a physician. "I couldn't stand the sight of blood," she confides. "But I love pharmacology and biochemistry." When her late husband was a hospital intern, she was planning to do post-doctoral study in biochemistry. But then she got pregnant - with twins. "I didn't want a full-time job, but something I could do three days a week." She was offered a research job at Tufts University, and loved it. In the early Sixties, the US agriculture Department and the National Cancer Institute dispatched a delegation to find natural compounds to make new drugs for cancer treatment. "On the last day of the mission, when they were about to go home, a young botanist collected yew tree bark," she recalls. It was then shown that the compound was cytotoxic to cells growing in tissue culture, but over the next decade almost nothing further was gleaned about its biological action. In 1977, Horwitz was approached by the institute to study the biological activity of 10-deacetyl-baccatin III - the original compound that was later converted by chemical synthesis to Taxol in her lab. "I had rejected many other compounds, but was intrigued by this molecule. I quickly saw that it had a unique chemical structure and characteristics. It had a bonding site to the microtubules of cells." Within a few months of receiving her first samples, Horwitz with her then-graduate student Peter Schiff found that the compound inhibited cell division, which is deregulated in cancer, thereby promoting uncontrolled cell growth. In subsequent studies she showed that Taxol interferes with mitosis - the process in which the chromosomes in a cell nucleus are duplicated and then segregated into two daughter cells. It was the only existing drug at the time to function in this way. Microtubules are dynamic polymers - hollow cylindrical tubes that are constantly being remodeled by the addition or removal of tubulin sub-units. During mitosis, microtubules act like long tethers to pull duplicate chromosomes to opposite poles of a cell so they can be incorporated into two new nuclei. To complete the process, the microtubules must become shorter as the chromosomes draw near their final destination. Horwitz discovered that Taxol stabilizes microtubules, preventing them from shrinking and thus blocking the segregation of chromosomes. It is now known that Taxol disturbs cellular growth at various stages including mitosis, which leads to eventual death of the cells. The drug has become a valuable tool in basic cancer research to help delineate the function of microtubules. Taxol, which takes 26 steps to be synthesized and is still expensive even though it's available in generic versions, is made today from the needles of yew trees grown in India. Horwitz notes that it isn't surprising that a compound in a plant species kills dangerous cells, as the bark and leaves protect a tree from pathogens and invaders such as animals. Aspirin, for example, is derived from willow bark. "Susan's discovery that Taxol bound to and stabilized microtubules, thereby blocking cell mitosis meant that Taxol was a prototype for a new class of chemotherapeutic drugs," said Purpura. The discovery of Taxol's unique mode of action gave oncologists a new weapon in the fight against cancer, because unlike many of the cancer drugs approved or under development at the time (such as cisplatin and nucleotide analogs that interact with DNA), Taxol's mechanism of action was not mediated directly by DNA. The drug has become one of the most valuable cytotoxic chemotherapeutic agents available. Marketed by Bristol-Myers-Squibb, Taxol was first approved by the US Food and Drug Administration for the treatment of ovarian cancer in 1992, followed two years later by approval for metastatic breast cancer and seven years ago for non-small-cell lung cancer. More recently, it has been used for head and neck cancer as well. But while it has greatly improved the quality of life for cancer patients, it doesn't actually cure cancer. Indeed, cancer cells may develop resistance to it over time. Horwitz and her team are working out to find why. As it is toxic to rapidly dividing cells, Taxol causes patients to lose every hair on their body, at least temporarily. They are investigating whether the presence of different forms of tubulin might explain why some cancer cells are more responsive to the drug than others. Horwitz, who is associate director for drug development at the Albert Einstein Cancer Center, is also studying a class of compounds called epothilones, which has a completely different structure than Taxol but also binds to microtubules. Such new drugs may offer useful alternatives for Taxol in cases where the drug is poorly tolerated or ineffective. Scientific research today is very different than it was when Horwitz was starting out. "Today, there are almost no native-born Americans going into it," she said, adding that this is also true of American Jews, who in previous decades were leading lights in this field. "Although Jews still go to medical school today, they go into other things. It's a shame, but a growing number of our researchers are immigrants or students from the Far East, from Taiwan, China, Korea and Vietnam. These are the ones who will win Nobel Prizes in the future." The older of her two 41-year-old sons is a professor at Harvard Medical School, while the younger is a lawyer in Washington who is active in the Coalition to End Handgun Violence; Horwitz, who has three grandchildren, visited Israel often with her husband, and even did a sabbatical here. She notes that many cancer patients live with their illness. Many people take Taxol in low doses, often in combination with other drugs to maximize the effect. "I'm sure there will be drugs that completely cure cancer, but probably not in my lifetime. It is a very complex disease, and different in various organs. The next big thing will be chemoprevention - that is, preventing pre-cancerous polyps and other tissue from turning malignant. "If we can get a chemical to do this, it would be fantastic."