Messenger - Vol. 4, No. 2, Page 4 1995 Tackling tumor research with engineering tools When Rakesh A. Jain, Delaware '74M, '75PhD, was growing up in India, his dream was to become a jet fighter pilot. Poor vision kept him from flying, but good judgment gave him a different enemy to attack-cancer. As the head of Massachusetts General Hospital's tumor biology laboratory, Jain fights that enemy daily as he and his colleagues try to find a way to help anti-cancer drugs penetrate solid tumors more effectively. His work in tumor biology also has led to joint appointments as the Andrew Werk Cook Professor of Tumor Biology at Harvard University Medical School and as a professor in the Harvard University-M.I.T. division of health sciences and technology. As part of his doctoral work in chemical engineering at Delaware, Jain worked at the National Cancer Institute with Pietro M. Gullino, who was measuring the consumption of nutrients by malignant tumors in animals. The more Jain worked with Gullino, the more he began to suspect that something in the physiology, or physical makeup, of a tumor might be blocking the spread of blood-borne drugs to all of the cancer cells. "I began to think that my engineering background, including my understanding of fluid and molecular transport, could aid in exploring that possibility," Jain wrote in an article last July in Scientific American. Scientists have had success in developing drugs that kill cancer cells, but those drugs are far more effective in liquid cancers such as leukemia and lymphoma than in solid tumors of the breast, lung and brain, Jain explains. In most cases, the drugs shrink, but do not completely destroy, the solid tumor. Jain looked into the physiology of tumors to identify the path a drug takes through the blood stream to cancer cells. Because this area of cancer research was not in vogue at the time and Jain's engineering credentials were not typical, his first six grant requests were turned down. Ultimately, he and his team were able to show that several characteristics of a tumor can impede the flow of drugs to the cancer cells. First, a tumor is composed of only about 50 percent cancer cells. Forty percent is composed of the area between the cells made up of a collagen-rich matrix called the interstitium. Ten percent is the blood supply system, or the vasculature, which brings nutrients and drugs to the tumor and removes waste. For a drug to reach the cancer cells, it must leave the blood vessel and travel through the interstitium. The interstitium in a tumor is more extensive than in healthy tissue, so it takes drugs much longer to arrive at the cell through the interstitial matrix. Jain and his colleagues found that not only did high pressure in the interstitium interfere with the transfer of drug molecules to cancer cells, but that blood vessels in a tumor are not evenly distributed, causing a lack of flow to certain areas and to the cancer cells in those areas. In 1987, Jain began to test his theory that interstitial pressure in a tumor is unusually high, equal to the pressure within the capillary network from which the drug must flow to reach the cancer cell. Shortly after his move to Boston and Massachusetts General Hospital in 1991, he published a paper in the journal, Cancer Research, detailing the results of a study using seven women who had cervical cancer. The team used small doses of radiation to lower interstitial pressure in the women's tumors, along with the application of therapeutic drugs. In four of the seven women, the tumors were completely eradicated. Those results have led to a larger study. Jain and his team have now tested 30 patients with cervical cancer. "We looked at the six- month survival rate, and we're now looking at the two-year rate. We will probably publish at the end of that period, in a year or so," Jain says. Jain will only say that the results are "very interesting"; he is determined not to overstate the significance of his work. Jain, the person, like Jain, the scientist, doesn't overstate the facts of his life, either. For example, when he was a boy in India and he wanted to drop biology to study Sanskrit, he had to make up three years of Sanskrit to take the course, and he did. And, despite his aversion to the study of biology and the fact that he has never taken a course in either biology or physiology, Jain read and absorbed in one week the classic human physiology book given to him by his doctoral professor at Delaware, James Wei, now dean of the School of Engineering and Applied Science at Princeton University. Jain has received numerous honors, including a Research Career Development Award in 1980 from the National Institutes of Health, a Guggenheim Fellowship and a Humboldt Senior Scientist Award. Most recently, he was awarded an $8.3 million, seven-year Outstanding Investigator Grant from the National Cancer Institute. Despite his overload schedule at Massachusetts General, Harvard and M.I.T., Jain manages to swim twice a week, listen to music, indulge in fine dining and admire art. His tastes are eclectic. "I could listen to Maria Callas for hours, but I also like the Grateful Dead." He met his wife, Janet, in Pittsburgh while he was attending theatre in the round. He spoke to her during intermission, and they discovered they shared a love of cities and other cultures. Janet teaches smoking cessation classes for the American Cancer Society. Jain speaks in superlatives of his time at the University of Delaware. He came to the U.S. to study with UD chemical engineering Prof. Morton M. Denn, now at the University of California-Berkeley, the author of five textbooks, one of which Jain had read. He arrived in the United States with "only $50 in my pocket. One of my professors helped me get my first month's stipend at the beginning, rather than the end of the month, so I was able to survive. I have very fond memories of Delaware," Jain recalls. When asked how he managed to continue his research even when most of the medical community had no faith in it, he responds: "Hope-the hope of finding a better way to deliver cancer-fighting drugs, of building a bridge between the test tube and the patient, the lab bench and the bedside." -Barbara Garrison