Research: Chemical Engineer Leads Multidisciplinary Cancer Studies

Contrary to popular belief, tumors are not merely a collection of cancerous cells they are a whole system of malignant cells, vasculature, and interstitial space. Chemical engineer Rakesh Jain has discovered three barriers to the delivery of therapeutic agents to their targets. First, the blood supply is nonuniform. Some cells have adequate blood supply while others do not. Second, the pressure of the interstitial space is elevated throughout the tumor, causing drugs to be pushed back into the blood vessels or washed out of the space. And third, because of the disruption of circulation, genetically engineered macromolecules must often travel large distances, taking days, weeks, or even months to reach isolated sections of the tumor. Initially, Jain used two animal tumor models for his work. One model is an isolated tumor, pioneered by then-NIH pathologist Pietro Gullino. In this model, the tumor has a single artery and a single vein. This construction allows for easy monitoring of material moving in and out of the tumor, which then can be measured. The other preparation is a thin, transparent tumor, grown in the ear of a rabbit. This model permits examination of physiology in vivo. Now, with links to clinicians at the Pittsburgh Cancer Institute, Jain is able to test his observations in humans. The team is studying oxygen tension and interstitial fluid pressure in various human cancers. In addition, Jain and his colleagues are studying human tumors that can be modified so that they have a single artery and single vein, like the animal model used in the lab. Jain's most recent finding (the article is in press) is that tumor vasculature in addition to cancer cells is the target of a type of killer cells referred to as LAK cells. It was previously believed that only the cancer cells were the target. The long-term goal of the team's research is twofold: first, to modify tumor physiology so that more drugs can be delivered to the tumor; and second, to make the vasculature and the interstitium the target for therapy instead of the cancer cells. --M.T.K. Twelve years ago, Rakesh Jain, a chemical engineer from India, started basic in vivo cancer research not at a medical school, not in a biology department, but in a chemical engineering department of an institution famed for its engineering and computer science schools, Carnegie Mellon University in Pittsburgh. Initially, Jain worked with engineers, and for years his research findings were largely ignored by the cancer research community. What did an engineer have to offer the biological sciences, anyway? Today, Jain's lab has expanded into a multidisciplinary team that is concentrating on the microcirculation of tumors. The team is producing some of the most promising research in the field. In fact, two of Jain's recent articles published in Cancer Research have been attracting attention within the research community: Determination of tumor blood flow: a review, 48 :2641-58, 1988; and Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure, 48 :7022-32, 1988. Jain is the 1990 recipient of the Alexander Von Humboldt Senior Scientist Award (for basic research) and the Abbott Microcirculation Award (given by Abbott Laboratories). He also received the 1980 Research Career Development Award from the National Institutes of Health, as well as a 1983 Guggenheim Fellowship. Apparently, a chemical engineer has a great deal to offer the biological sciences. A key factor in Jain's latest research successes is the team he has assembled. He now has an immunologist, a pathologist, a biomedical engineer, a mechanical engineer, and a M.D./Ph.D student working in his lab, in addition to doctoral and postdoctoral chemical engineering students. And in the past year, Jain has forged alliances with clinicians (radiation, medical, and surgical oncologists), so that the methodology and concepts the team has developed in the lab can be tested on patients. Jain's interest in tumor microcirculation as well as his experience in the multidisciplinary approach began 15 years ago at the National Institutes of Health under his mentor, Pietro M. Gullino, a pathologist. Jain turned to Gullino and cancer research at the urging of his Ph.D. adviser at the University of Delaware, James Wei. Wei gave Jain a textbook on human physiology, a book that Jain a novice in biology and physiology read in one week before joining Gullino at NIH. Jain was curious about why the cancer-killing chemicals known as magic bullets were effective against solid cancer cells in vitro but not in vivo. He suspected barriers to these chemical agents and started investigating the microcirculation of tumors. No one was studying the problem systemically. There are many people developing and manufacturing poisons to kill cancer cells, says Jain, but very few people are investigating how these poisons will reach the cancer cells in vivo in optimal quantities without destroying healthy tissue. Essentially, Jain and his team are using engineering know-how and approaches to examine a typical engineering problem a delivery system (see accompanying story). Only in the case of cancer tumors, the delivery system happens to be vasculature instead of sewer pipes. The engineering influence is evident in the team's development of special devices and equipment to aid research and its extensive use of mathematical modeling. According to his colleagues, Jain is organized and accessible. He allows maximum independence while coordinating all the working parts. And he stresses communication. Rakesh has the big picture, says senior postdoc Bob Melder, an immunologist with a biophysics background. He has an intuitive sense of how things fit together and is able to coordinate everyone so that our efforts become complementary. It can be very difficult when so many people are interested in so many different things. But instead of confusion, he says, Jain makes these differences an asset. It's the classic way lab directors are supposed to function, and he fills his role admirably, says Melder. In addition to a weekly group meeting, Jain meets at least an hour a week with each member of his team. I just think that communication is the most important thing, says Jain. I make sure that everyone knows the work of everyone else. Unless you know the whole picture, you lose sight of what you are doing. The weekly group meetings have another purpose. They provide a forum for presenting ideas and rehearsing presentations of papers. Jain helps his students by giving them first authorship on articles and by encouraging them to present their work at professional meetings. His colleagues say that Jain supports each team member's personal and professional growth and recognizes each member's contribution. Generating the ideas for the experiments takes no time, Jain says of his own role. Carrying them out does. These are very difficult experiments. Some are like nightmares. Jain does not have a second-in-command in his organization. I want each person to feel that he has equal access to me, he says. The minute I have a lieutenant, then I become a manager; I distance myself. There's no way I'll do that. I'll get out of the job first. All the team members find the multidisciplinary approach exciting and helpful. I find I learn something all the time, says Richard Stock, a chemical engineer. Stock says that he enjoys being in a position in which he can learn from others as well as make a contribution to other people's work. A self-described experimentalist, Stock left a well-paying but not very satisfying job in the oil industry in his native England to return to school. He enrolled at West Virginia University to work on his master's degree. There, says Stock, he became involved with the biomedical applications of chemical engineering by sheer accident. He decided to stay on for his doctorate. When he completed his studies, Jain asked him to join the team. Stock is now developing and perfecting a technique of photobleaching to study fluid exchange in tissues and blood vessels. We have done the typical chemical engineering thing, and scaled up the process used by immunologists and cell biologists to study cell membranes, he says. Yves Boucher, an experimental pathologist from Canada, says he finds the approach and way of thinking of the chemical engineers in particular, their way of looking at the transport of molecules very useful to his work on interstitial pressure of tumors. Because animal tumors may be different from human tumors, the methods that the team developed in the lab needed to be tested in humans. It is part of Boucher's task to interface with the clinicians working with patients. It helps to talk to doctors in the hospitals about their problems in therapy, he says. One of the clinicians, William Bloomer, chief of radiation oncology at the University of Pittsburgh, is finding that working with Jain's team is very helpful. Jain has taken a totally different tack than biological researchers, says Bloomer a course that he says is proving to be effective. Bloomer credits Jain's development of microelectrodes, which minimally perturb tumors, as a real breakthrough in the simultaneous study of oxygen levels and interstitial fluid pressures in various human cancer tumors. One reason the team works smoothly is that all the members are aiming at the same goals, says Cliff Eskey, an M.D./Ph.D candidate. Although the team is multidisciplinary, Eskey says, the group's regular meetings to discuss progress aids the team members in communicating with one another. We all work on the same area. We all speak the same language, he says. Eskey is investigating the metabolism of oxygen and glucose and the transport of molecules within tumors. Part of his job is to collaborate with two additional jurisdictions the biology department and the nuclear magnetic resonance lab. The multidisciplinary approach is the wave of the future, says Melder, who is studying the biophysical factors that determine how cells move through vasculature. The nature of the way science is done has changed in recent times, he says. It is no longer possible for one single person to have all the knowledge necessary to solve complex problems. Rakesh recognized this very early. Jain finds the combination of many disciplines very natural. A lot of engineers are developing models, but sometimes they are very idealized systems, he says. Then there are biologists working in the field, but they can't develop the tools or provide the quantitative thinking. The key is the combination of the two. I've brought together people from different fields. They work together like a symphony. Margaret Thomas Kelso is a freelance writer based in Pittsburgh.

Research: Chemical Engineer Leads Multidisciplinary Cancer Studies

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Margaret Thomas Kelso

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October 1990

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