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New Nobelist Horvitz explains why we should care about cell death

After his lecture on Friday, newly minted Nobelist Robert Horvitz gets a kiss from his wife, Martha Constantine-Paton, also a professor in biology at MIT.
After his lecture on Friday, newly minted Nobelist Robert Horvitz gets a kiss from his wife, Martha Constantine-Paton, also a professor in biology at MIT.
Photo / Donna Coveney

In H. Robert Horvitz's first MIT lecture as a Nobel laureate, he told a standing-room-only crowd on Friday afternoon that tadpoles lose their tails and pigeons' feet become unwebbed through the same process that is his claim to fame: programmed cell death. In addition to being a normal part of development for humans, programmed cell death gone awry may be implicated in diseases such as cancer and Alzheimer's disease.

Horvitz - the David H. Koch Professor of Cancer Biology, an investigator for the Howard Hughes Medical Institute and for the McGovern Institute for Brain Research at MIT, and a member of the MIT Center for Cancer Research - received the Nobel Prize Oct. 7 for discovering and characterizing the genes controlling cell death in the nematode Caenorhabditis elegans.

In the same lecture hall where as an MIT undergraduate he had taken "Introduction to Electrical Engineering" with Amar Bose of Bose stereo-speaker fame, Horvitz stood at the podium before the hundreds of students, faculty and staff members packing the seats and aisles of Room 10-250 and explained why we should care about dying cells. genes of cell death

"We've known for many years that cells die. What is notable is that in many cases when cells die, it's not because they've been damaged beyond life, but because they've enacted an endogenous process of cell suicide," he said.

From the time that the fertilized egg first divides and continues to divide, creating in humans millions upon millions of cells, the cells take on different characteristics that allow them to become the different parts of the body - arm, liver, brain, etc. Programmed cell death is a necessary part of this process of development.

Cells also die in the course of various diseases. This aspect of the research is particularly alluring to drug companies, who hope to find a targeted approach to halting or accelerating cell death as needed. In diseases such as AIDS, neurodegenerative diseases and cerebral stroke, too many cells die in programmed cell death. In others, such as cancer, autoimmune disease and viral infections, there is too little cell death.

"To me, the interesting aspect of this is that there is a biology of cell death," Horvitz said. If programmed cell death was "a cell fate like any other cell fate, there ought to be genes that control that."

In Horvitz's lab at MIT, specific genes were identified that are responsible in part for programmed cell death. Without the genes they named ced3 and ced4, cells do not die. These C. elegans genes, and others later identified in neighboring cells involved in helping the cell die, turned out to have counterparts in humans. These genes, which block or cause the process of cell death, are potential targets for intervention.

"In many of these disorders, cells may be poised on a knife edge and maybe we could push them one way or the other," Horvitz said.

Horvitz likes to say that this year's Nobel is really recognition for C. elegans.

In this little creature of only 959 cells, "you could see individual cells and follow a cell and its daughters and so on and so forth," he said. The worm's tiny size and short reproductive cycle allowed the researchers to study many organisms in a small amount of time.

Although it was a leap of faith at the time to study roundworms, yeast and fruit flies in the quest for knowledge of human biology, it turns out that the molecular genetic pathway of processes such as programmed cell death in these organisms has similar counterparts in humans.

"If one looks at the major funding in molecular genetics in the last 10 years, what's really striking is that despite the diversity of organisms, we show that genes and gene pathways in worms, people, fruit flies and yeast cells are strikingly similar," Horvitz said.

He thanked his wife, MIT biology professor Martha Constantine-Paton, and others for turning out to hear him, as well as "first and foremost, my lab," and his MIT colleagues. He said that since he came to MIT as a student in 1964, "this has been a spectacularly supportive environment" and the help and friendship of his biology department colleagues "remains a force behind my scientific effort."

Horvitz shares the prize with Sydney Brenner of the Molecular Sciences Institute of Berkeley, Calif., who established the nematode as a model organism for experimentation, and John E. Sulston of the Wellcome Trust Sanger Institute of Cambridge, England, who mapped a detailed cell lineage in C. elegans that showed that specific cells undergo programmed cell death in the process of cell differentiation.

According to the Nobel committee, the three were recognized "for their discoveries concerning genetic regulation of organ development and programmed cell death."

A version of this article appeared in MIT Tech Talk on October 23, 2002.

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