Concepts familiar from grade-school algebra have broad ramifications in computer science.
Although he is "delighted and incredibly honored" to share the 2002 Nobel Prize in physiology with two friends and colleagues, MIT Professor H. Robert Horvitz said Wednesday he would find nothing more gratifying than to have his work lead one day to a treatment for a disease such as cancer or any of the neurodegenerative disorders thought to be tied to a malfunction of programmed cell death.
Horvitz is a busy man. He is the David H. Koch Professor of Cancer Biology at MIT, 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. He also holds appointments at the Massachusetts General Hospital in neurology and in medicine.
Horvitz received the prize for discovering and characterizing the genes controlling cell death in the nematode Caenorhabditis elegans, a roundworm about a millimeter long that lives in the soil. He later showed that these genes interact with each other in cell death, a normal process in every living cell, and that these genes correspond to existing genes in humans.
On vacation in the French Alps, he spoke at an MIT news conference on Monday by phone.
"The wonderful thing about this discovery is that is relevant to all branches of biological science and to the brain," said fellow Nobel laureate Phillip Sharp, director of the McGovern Institute. "Half of Bob Horvitz's lab works in neuroscience." Horvitz is currently analyzing how the nervous system controls behavior and how genes specify the functioning of a neuromuscular system.
"This is a great day for Bob Horvitz, a great day for MIT, a great day for science and a great day for the future of human health," said President Charles M. Vest. He said the Nobel recognition is a boost for research universities, where the bulk of the country's basic fundamental research is accomplished.
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. Sulston identified the first mutation of a gene participating in the cell death process.
According to the Nobel committee, the three were recognized "for their discoveries concerning genetic regulation of organ development and programmed cell death."
"These two men are heroes to me," Horvitz said of Brenner and Sulston. "Each could have received a Nobel prize for something different. It's an honor to be joined with these two friends and colleagues in this way."
Programmed cell death - in which healthy, normal cells kill themselves - is a necessary part of shaping developing tissues and organs and refining the central nervous system. The process also is used by the body in immune cell development and function, and for removing unnecessary or damaged cells.
Horvitz, who grew up in Illinois, did not take a conventional path to this honor in biological science. He came to MIT to major in economics and math. He decided to switch to biology because "the new biology seemed to be very interesting - I was ignorant about it and thought it was something I would try. The nervous system was very interesting to me. So I went into this field of biology out of ignorance and continued on C. elegans because I thought it offered the prospect of studying the nervous system in detail."
At the time, no one was sure how working on a microscopic worm could relate to human disease. It turns out that C. elegans - and other models such as the fruit fly and the zebrafish - are very relevant to humans and the "genetic pathways" in these creatures also show up in people. But before this was established, Horvitz said he had to make a choice about whether to pursue this basic research.
The late Nobel laureate and MIT biology professor Salvador E. Luria helped him decide. Luria studied bacteria and bacterial viruses to understand genes and the process of heredity, even though it was then thought by some that viruses don't have genes. Horvitz decided to concentrate on the roundworm and pursued his own research with the "unsubstantiated bias that what we learned from a nematode would be applicable to human beings," he said.
Programmed cell death is a key mechanism for regulating cell numbers and connections and for sculpting tissues, Horvitz has said. "Its misregulation can play a central role in certain cancers, autoimmune diseases and neurodegenerative diseases. We now know many of the molecules that control programmed cell death." Researchers hope that by fully understanding the mechanism behind programmed cell death, they may be able to develop treatments for cancer and a vast array of other diseases in which misregulated programmed cell death plays a role. In some diseases, cells live that should die, and in others, cells die that should live.
"When we found the gene responsible for the killing process [in C. elegans] we found that a similar protein had been isolated by two pharmaceutical companies in connection with human inflammation. No one had any notion these proteins could be involved with cell death. So now we have [information about] human genes involved in killing cells. If the process is involved in human disease, we could take those genes and attempt to prevent them from working," he said. "That way, one could eliminate the death and, one hopes, the disease. A large number of major pharmaceutical companies and small biotech companies are seeking to use this scientific knowledge to define targets for disease."
A MODEL ORGANISM
Horvitz, known internationally as an expert on the genetic analysis of animal development, is noted for his work on how genes control three aspects of animal development: cell lineage, or how a single fertilized egg undergoes repeated divisions to create the many distinct cell types of an adult animal; cell signaling, or how cells communicate with each other; and programmed cell death, known as apoptosis.
To better understand these processes, Horvitz has made a close study of C. elegans. The tiny worm contains exactly 1,090 cells, of which 131 undergo apoptosis, most during embryonic development.
Research by Horvitz's team has shown that four proteins - EGL-1, CED-9, CED-4 and CED-3 - play a central role in the apoptotic machinery. The worm genes governing cell lineage, cell signaling, and cell death are similar to those found in other organisms, including humans. As a result, studies of the worm have provided insights into human development and disease.
For example, the discovery in Horvitz's laboratory of a nematode gene that causes programmed cell death led to the identification of related human genes. "Knowledge of what makes cells die and of what can block the cell-death process in the nematode may help lead to the identification of agents that can regulate the cell deaths involved in a variety of human disorders, such as cancer and neurodegenerative diseases," Horvitz said. He established that programmed cell death, a major and normal aspect of animal development, is an active biological process, dependent upon the functioning of particular genes.
By identifying and characterizing such genes in the nematode, Horvitz discovered mechanisms of broad significance in biology and medicine. Most recently, his laboratory found that phagocytes, or engulfing cells, believed to be only a cleanup crew that got rid of dying cells so harmful by-products wouldn't hurt the organism, actually play a role in helping cells die.
A separate research team led by Horvitz, with colleagues at Harvard, also discovered a new type of receptor in C. elegans that responds to serotonin. This finding could help explain how drugs such as Prozac, which manipulate levels of serotonin signaling, bring about their therapeutic effects. "We have identified a new mechanism of signaling in the nervous system, whereby serotonin can rapidly turn off, instead of turn on, the actions of nerve cells," Horvitz said.
The nematode is an important organism for research. It is the only animal for which scientists have developed a complete map of its cells (including a complete wiring diagram of its nervous system), a complete sequence of its DNA and a complete cell lineage. The latter was deduced in part through the efforts of Horvitz in collaboration with Sulston of the Wellcome Trust Sanger Institute.
Among Horvitz's many honors are the 1999 Gairdner Foundation International Award, the 1998 General Motors Cancer Research Foundation's Alfred P. Sloan Jr. Prize, the 1996 Ciba-Drew Award for Biomedical Science, the 1995 Charles A. Dana Award for Pioneering Achievements in Health, the 1993 V.D. Mattia Award from the Roche Institute of Molecular Biology, and the 1986 Warren Triennial Prize of the Massa- chusetts General Hospital.
In announcing the Mattia award, Roche Institute Director Hebert Weissbach said that Horvitz has made "fundamental contributions to our understanding of the role of specific genes in the development of an organism. His work on nematodes is a clear example of how research on what some might consider an obscure organism can yield valuable information that is relevant to other species, including man."
In 1993, Horvitz was one of the lead researchers of a collaborative nationwide effort by 32 researchers who found an association between a gene mutation and the inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.
Horvitz is a member of the National Academy of Sciences and a Fellow of the American Academy of Arts and Sciences and the American Academy of Microbiology. He is a member of several professional societies, including the Genetics Society of America (he was president in 1995). He is also a member of the National Advisory Council of the National Human Genome Research Institute and was co-chair of the Working Group on Preclinical Models for Cancer of the National Cancer Institute.
In 2001 Horvitz received the Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience, and in 2000 he won the Paul Ehrlich and Ludwig Darmstaedter Prize (Frankfurt, Germany), the March of Dimes Prize in Developmental Biology, and the Louisa Gross Horwitz Prize for Biology or Biochemistry (Columbia University).
Horvitz was born on May 8, 1947, in Chicago. He received bachelor's degrees in mathematics and economics from MIT (1968) and the master's degree (1972) and Ph.D. (1974) in biology from Harvard University. He was a postdoctoral researcher at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. He joined the faculty of MIT in 1978 and became professor of biology in 1986 and an investigator of the Howard Hughes Medical Institute in 1988.
He and his family live in Newton, Mass. It's a home that really knows its biology - his wife is MIT biology professor Martha Constantine-Paton.
A version of this article appeared in MIT Tech Talk on October 9, 2002.