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Biomedicine

Why Cells Die

A Nobel Prize-winning discovery may redefine the way we treat diseases.

For many years biologists have known that cells die at predictable points during development: tadpoles lose their tails and become frogs; human fetuses lose the webbing between their fingers and toes during prenatal development. However, very little was known about the mechanism until Robert Horvitz ‘68 and other researchers identified and described the process of programmed cell death. Their work earned them the 2002 Nobel Prize in Physiology or Medicine.

“At the time [Horvitz began his research], most scientists thought that cells died because they had no choice,” says Craig B. Thompson, chair of the Department of Cancer Biology at the University of Pennsylvania. Scientists believed that cells died when they were deprived of oxygen or damaged by something in their environment.

Building on preliminary work by Sydney Brenner and John E. Sulston, the scientists with whom he shared last year’s Nobel Prize, Horvitz identified specific genes that trigger cell death in the cells of a millimeter-long soil-dwelling nematode named Caenorhabditis elegans. Without the presence of these genes, Horvitz determined, certain cells could live indefinitely. In subsequent studies, he showed that similar genes are present in humans.

“That changed everything,” says Thompson. “It turned out that these cells choose to eliminate themselves.” In essence, they commit suicide. By proving the genetic component, Horvitz was able to demonstrate that programmed cell death is a normal, fundamental, and controlled biological process in cells.

Horvitz’s path to the Nobel was not entirely predictable. As an MIT undergraduate, he majored in mathematics and economics. But, he told the MIT community in a lecture on campus last fall, “it was the late ’60s, and I wanted to do something different.”

To him, “something different” meant moving across town to pursue a PhD in biology in the Harvard University lab of James Watson, who along with Francis Crick had discovered the structure of DNA and confirmed that it carries hereditary information. Watson was collaborating with two other scientists in his lab, Wally Gilbert and Klaus Weber. Horvitz remembers that the troika was “incredibly stimulating. Their combined training left me unafraid to approach any new problem in any context,” he says. Horvitz sustained this mentality throughout his postdoctoral fellowship, which he started in 1974 under Sydney Brenner at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England.

Joining Brenner’s lab was a natural choice for Horvitz. Brenner had been credited with realizing that because of its simplicity, C. elegans provides an ideal model for studying cell differentiation and organ development. The adult nematode comprises only 959 cells; it grows from egg to maturity in only three days; and because it is transparent, it is easy to monitor under a microscope. Horvitz wanted to study the nervous system through genetics. “The prospect of combining genetics and neurobiology in the early 1970s left very few options, and what I’d heard about Sydney and his worms,” he says, “was very appealing.”

John Sulston had joined Brenner’s lab in 1969. Working with Horvitz, Sulston mapped the entire cell lineage-from the fertilized egg to the adult organism-of C. elegans. With the map, Sulston was able to demonstrate that the adult C. elegans always contains precisely 959 cells. Furthermore, every C. elegans generates exactly 1,090 cells over the course of its lifetime. This means that in every nematode, the same 131 cells follow exactly the same pathway and die at exactly the same time of life. Horvitz says that his Nobel work began as a quest to discover how and why those cells die.

In 1978 Horvitz returned to MIT as an assistant professor of biology and continued to build on his early work with the genes of C. elegans. He discovered the genes Ced-9, Ced-4, and Ced-3, and with others in his lab, he determined their core genetic pathway: Ced-3 is the killer; Ced-4 works by triggering Ced-3 to kill; and Ced-9 is a protector gene. When Ced-9 is turned on, it stops Ced-4 from triggering Ced-3. Even more remarkable, Horvitz realized that the programmed cell-death pathway is fundamentally the same in more complex organisms.

Horvitz published his first paper describing that pathway in C. elegans in 1986, but it was in the early 1990s, when his lab was able to demonstrate the existence of human counterparts to the C. elegans genes, that pharmaceutical companies began to examine the therapeutic potential of Horvitz’s research.

“The field has really taken off in the last 10 years,” said Junying Yuan, a former Harvard grad student who was one of Horvitz’s advisees in his lab. Now a professor of cell biology at Harvard Medical School, Yuan says, “When I published my thesis in Bob’s lab in 1993, there were maybe 100 papers published that year on programmed cell death. Now there are more like 100 per week.”

Regardless of the impact his discoveries might have on the treatment of disease, Horvitz’s work has already influenced the way developmental biologists think about cell and tissue development. He has shown that programmed cell death is a fundamental, genetically controlled biological process, and his discovery that programmed cell death follows almost the same process in all sorts of organisms demonstrates the principal of “biologic universality.”

In his lecture on campus last fall, Horvitz, now the David H. Koch Professor of Cancer Biology at the Institute, pointed out that whether the organism is a worm, fruit fly, yeast, or human, “there are genes and gene pathways in all of us that are strikingly similar.”

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