Cells that are damaged or no longer necessary for growth and development routinely commit suicide through a process known as apoptosis, or programmed cell death. Apoptosis is essential to proper tissue and organ development, and defects in this pathway are known to be involved in cancer, autoimmune disorders, and the development of neurodegenerative diseases.
Pioneering studies by H. Robert Horvitz have made him one of the central figures in research on programmed cell death. He discovered key genes that control cell death in C. elegans, a tiny transparent worm made up of fewer than 1,000 cells. (Nearly identical genes have been identified in other animals, as well as in humans.) For this work and for his studies concerning organ development in C. elegans, Horvitz won the 2002 Nobel Prize in Physiology or Medicine, an award he shared with Sydney Brenner and John Sulston, whose studies made important related contributions.
Horvitz's work with C. elegans began during a postdoctoral fellowship in Brenner's laboratory in Britain in the 1970s. There, Horvitz teamed with Sulston, who was also working in the Brenner laboratory, to trace the ultimate fate of each cell in the miniature worm as it developed from an embryo into an adult. Their work revealed that cell division in the worm produces many more cells than survive to make up the mature animal.
In the mid-1980s, as a biology professor at the Massachusetts Institute of Technology, Horvitz identified the first "cell death" genes, called ced-3 and ced-4, demonstrating that their activation is essential for cell death. "Discovering that programmed cell death is specified by particular genes established that programmed cell death is a basic biological process, much like cell division, cell migration, and cell differentiation," Horvitz explained. Later, Horvitz showed the gene ced-9 protects against cell death by regulating both ced-3 and ced-4.
It is perhaps an unlikely success story for a scientist who majored in mathematics and economics in college and did not take a biology course until his senior year. The course, however, proved fascinating, and after only six weeks, Horvitz decided to apply to graduate schools in biology. He ultimately decided upon Harvard, where he worked under the guidance of James Watson, the codiscoverer of the double-helical structure of DNA, and Walter Gilbert, who is known for developing a method to determine the exact sequence of the nucleotide building blocks in DNA. Both men are also Nobel laureates.
"As a graduate student, I came away with two beliefs that have driven my research career ever since," Horvitz said. "First, do the 'doable.' I recognized early on that working on an important but intractable problem would not suit me. Second, it is no harder to work on an important problem than one that is not important; this bit of advice, from Jim Watson, was engraved in me."
Horvitz has also identified many additional genes that act in programmed cell death. His apoptosis studies may also improve the understanding of neurological disorders such as amyotrophic lateral sclerosis (ALS), a disease that killed Horvitz's father in 1989. In collaboration with others, Horvitz identified a gene involved in the inherited form of ALS, and he is also pursuing other genes involved in the disease. "My hope is that my discoveries will one day lead to advances in medicine that alleviate human suffering and contribute to the world in ways that will benefit mankind."
While Horvitz is perhaps best known for his apoptosis research, for many years he has also turned his attention to understanding how genes control other aspects of development and also behavior, again using C. elegans as a model. Horvitz has identified many genes involved in development and behavior, revealing specific pathways shared by both worms and humans that are involved in a variety of human diseases.