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Three Win Nobel for Work on Suicidal Cells By LAWRENCE K. ALTMAN An American and two Britons won the Nobel Prize in Physiology or Medicine yesterday for their discoveries of how healthy cells are instructed to kill themselves. The discoveries, made largely in studies of a tiny worm, involved a process called programmed cell death, or apoptosis, which is necessary for proper tissue and organ development but also plays a role in many diseases. The winners are Sydney Brenner, 75, a British citizen who founded the Molecular Sciences Institute in Berkeley, Calif., and who is a professor at the Salk Institute for Biological Studies in San Diego; H. Robert Horvitz, 55, a professor at the Massachusetts Institute of Technology in Cambridge and a Howard Hughes Medical Institute investigator; and Sir John E. Sulston, 60, of the Wellcome Trust Sanger Institute in Cambridge, England. The three, who worked together in Cambridge, England, in the 1970's, will share a $1 million prize. The prize honors their collective work, in the last 30 years, on C. elegans, a 1-millimeter soil worm or nematode. The investigations of programmed cell death have given scientists better insights into cancer and the way some viruses and bacteria invade human cells, according to the Nobel Assembly of the Karolinska Institute in Stockholm, which selected the winners. The body uses cell suicide in immune cell development and function, and for removing unnecessary or damaged cells. Malfunction of cell-death genes is a hallmark of a number of diseases. For example, in AIDS, heart attacks, stroke and degenerative diseases of the central nervous system, cells are lost from excessive apoptosis, the institute said in its citation. Other diseases, like autoimmune conditions and cancer, are characterized by a reduction in cell death, leading to the survival of cells normally destined to die. Biologists who study the development of the embryo were the first to describe programmed cell death. They noted that cell death was necessary for embryonic development, as when tadpoles metamorphose to become frogs, and in the process that eliminates tissue that forms in human fetuses between fingers and toes. Apoptosis also shapes brain development, in that a vast number of neuronal cells present in the early stages is gradually eliminated. The research on the way cells are programmed to die began in the 1970's when Dr. Brenner, a native of South Africa was working in Cambridge, England. Dr. Brenner, who has a trenchant wit and enjoys stirring up the scientific world, had earlier worked on basic principles of how DNA instructs cells to make proteins. Together with his colleague Dr. Francis Crick, Dr. Brenner did basic work on the nature and workings of genes. Looking for new peaks to conquer, he chose the working of the brain but felt the project required a new experimental animal with a simple brain. He chose C. elegans. Its brain turned out to be too complex to analyze, but the worm nonetheless served as a wonderful model to study development of the animal embryo. Dr. Brenner's team could look through a microscope at the translucent worm to follow cell division and other biological processes as it grew rapidly from a fertilized egg to form muscle, blood, heart, the nervous system and hundreds of other tissues. That process requires cells to specialize in a correct manner and at the right time during development in a way that allows the specialized cells to cooperate and make the body function as an integrated unit. The embryo and fetus produce huge numbers of cells. But even an adult human forms more than a thousand billion cells each day. As cells are created, an equal number die through cell suicide both in the fetus and adult. Maintaining the appropriate number of cells in the tissues requires a fine-tuned balance between cell division and cell death. The single-cell organisms like bacteria and yeast that scientists often use in other studies are unsuitable for understanding how the complicated processes of cell suicide are controlled. And the enormous number of cells in mammals make them too complex for such basic studies. Dr. Brenner's worm, multi-cellular yet relatively simple, became the most appropriate model system. In 1974, Dr. Brenner broke ground by using the chemical EMS, or ethyl methane sulphonate, to induce mutations, or genetic changes, in the genome of C. elegans. Additional studies showed that mutations could be linked to specific genes and to specific effects on organ development. In later studies, the three scientists discovered that specific genes control the cellular death program in C. elegans. Other studies showed that the deaths of 131 of the worm's original 1,090 cells are under the control of a particular set of genes. Corresponding genes exist in higher species, including humans. Dr. Sulston was honored for extending Dr. Brenner's work with C. elegans. Dr. Sulston developed techniques to study all cell divisions in C. elegans, from the fertilized egg to the 959 cells in the adult. The process by which a single fertilized egg undergoes repeated divisions to create the many distinct cell types of an adult animal is known as cell lineage. In 1976, Dr. Sulston described the cell lineage for part of the developing nervous system. Dr. Sulston also showed that every nematode underwent exactly the same program of cell division and differentiation, and that programmed cell death is an integral part of the normal differentiation process for certain cells. He identified the first mutation of a gene participating in cell death. These findings led him to the important discovery that specific cells in the cell lineage always die through programmed cell death and that this process could be monitored in the living organism. Dr. Sulston described the visible steps in the cellular death process and demonstrated the first mutations of genes participating in programmed cell death, including a gene known as nuc-1. Dr. Sulston also showed that the protein whose production is governed by the nuc-1 gene is required for degradation of the DNA of the dead cell. Dr. Horvitz, who was born in Chicago, was honored for continuing Dr. Brenner's and Dr. Sulston's work on the genetics and cell lineage of C. elegans. He received the news while vacationing in the French Alps. "It was quite enjoyable to have Champagne before lunch in France," Dr. Horvitz said in a phone call to a news conference at M.I.T. yesterday. In a series of experiments beginning in the 1970's, Dr. Horvitz used C. elegans to determine the existence of a genetic program controlling cell death. In 1986 he published what the Nobel committee called pioneering research that identified the first two bona fide "death genes," known as ced-3 and ced- 4. Dr. Horvitz showed that functional ced-3 and ced-4 genes were essential for cell death. Later, Dr. Horvitz showed that another gene, ced-9, protects against cell death by interacting with ced-4 and ced-3. Dr. Horvitz also identified a number of genes that direct how a dead cell is eliminated. Further, Dr. Horvitz showed that the human genome contains a ced-3-like gene. Dr. Horvitz's team has found a new function for cells known as phagocytes that engulf foreign agents. In the past scientists believed that phagocytes acted only as part of a cleanup crew to get rid of dying cells so that harmful byproducts would not hurt the body. Now Dr. Horvitz's work has shown that phagocytes actually play a role in helping cells die. Working with colleagues at Harvard, Dr. Horvitz has found a new type of receptor in C. elegans that responds to the chemical serotonin. The finding could help explain how drugs like Prozac, which manipulate brain levels of serotonin, work. "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," M.I.T. quoted Dr. Horvitz as saying. Dr. Horvitz said that the body's abnormal control of cell suicide "can play a central role in certain cancers, autoimmune diseases and neurodegenerative diseases." He said better understanding of programmed cell death might lead to development of treatments for cancer and other diseases. "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," Dr. Horvitz said. SOURCE: The New York Times http://www.nytimes.com/2002/10/08/science/08NOBE.html?ex=1034740800&en =e19c23ec4aecbb57&ei=5062&partner=GOOGLE * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn