But once technology made it possible to observe living cells under light microscopy, a handful of scientists determined that non-traumatic cell death was both more methodical and more significant than was previously realized. Our current understanding is usually traced to a ground-breaking paper published in the British Journal of Cancer in 1972 by John F.R. Kerr, Andrew H. Wyllie, and Alastair R. Currie, which described a process in which the cell itself seems to control a mechanism for committing suicide (see J.F.R. Kerr, et al., "Apoptosis: Basic biological phenomenon with wide-ranging implications in tissue kinetics,", Brit. J. Cancer, 26:239, 1972)

   Instead of swelling and rupturing, these cells gradually implode, losing their anchorage and falling out of the surrounding cellular matrix like leaves drifting out of trees in autumn. Kerr and his colleagues named this process apoptosis, from the Greek word "apo," for falling away. They also proposed that the aberrant inhibition or activation of apoptosis could be a root factor in cancer, Alzheimer’s, and other diseases

   By 1992, when John Reed arrived at San Diego’s Burnham Institute, apoptosis research was still a relatively unheralded division of cellular biology. Still, the field had been energized by a handful of discoveries. Reed had joined what was then known as the La Jolla Cancer Research Institute as a staff scientist and director of the oncogene and tumor suppressor gene program. He had previously served as an assistant professor at the University of Pennsylvania Medical School, where he had obtained his M.D., graduating in the top one percent of his class. His doctoral work, also at Penn, focused on Interleukin-2 and other immunomodulatory factors.

   In 1995, Reed was named as scientific director of the Burnham Institute, which now employs more than 400 people. It didn't take long for him to find his way to the forefront of apoptosis research–and to the front ranks of research in general. For two years running now, Reed has topped this publication's annual listing of the world's hottest scientists. His latest #1 ranking, featured in the previous issue, was based on the nine high-impact papers that he's published since late 1997 (see Science Watch, 11(2):1-2, January/February 2000).

In his office in La Jolla, Reed spoke with Science Watch correspondent Bruce V. Bigelow.

How did your research come to focus on apoptosis?

   Reed: We were just trying to understand how some of the genes that we had identified were functioning in cancer. Like most people who got into apoptosis, it was a bit of an accident for me. I wasn’t specifically trying to study cell death. But we stumbled onto genes that turned out to regulate cell death and cell life span, as opposed to cell division. Up to that time, all the genes that had been described in tumors had been shown to control cell division in some way. That was consistent with the idea that tumors are composed of rapidly dividing cells that had gone haywire. But what became obvious as we started to pull out some of these genes was that they weren’t affecting cell division at all. Exploring their function led us to figure out that what these genes were affecting was the life span of the cell, by preventing cells from dying and undergoing their normal physiological turnover. The cells essentially live forever and in some ways become immortal. We observed that they would accumulate in the patient’s body without necessarily dividing any faster. So this really opened a whole new window in understanding cancer biology. It’s one event in the past five to ten years that’s really changed the way we think about cancer. Of course, apoptosis dysregulation appears to play a role in other ailments, such as autoimmune diseases, AIDS, and stroke, in addition to cancer.

Why do you think research in this field seemed to explode out of nowhere?

   Reed: There are actually descriptions of the process that go back almost a century to early work in microscopy, where some of the pioneer scientists saw cells that they thought were undergoing some kind of degeneration. Some scientists studied systems where the tadpole lost its tail during morphogenesis and other processes where this programmed cell death occurs as a natural event. They were talking about things along these lines without fully understanding what they were seeing.
   The group that tends to get credit for really establishing this field, as well as coining the term "apoptosis," is Wyllie, Kerr, and Currie in the early ‘70s. Some members of the group, like Andrew Wyllie, were involved in early efforts to characterize some of the biochemical events. The other thing that was happening subsequent to that and somewhat in parallel was that people who were studying development in lower organisms started to find evidence of genetic regulation of cell death. They found they could make mutant worms that had defects in genes which prevented them from experiencing programmed cell death. That solidified the idea that there is a genetic program that controls cell death. That work was pioneered largely by Bob Horvitz at MIT. Eventually, what we began to realize was that this was not simply a situation where cells run out of gas–as if they didn’t have enough nutrients or somehow lost some structure needed to maintain their integrity. We observed that there was something that actively triggers this suicide–an active process that is genetically programmed, genetically determined, and actively regulated.
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