Research by molecular biologist Sidney Altman (born 1939) has helped unravel many of the mysteries surrounding deoxyribonucleic acid (DNA), the chemical at the heart of the cells of all living things that controls their structure and purpose. For their discovery—in independently conducted studies— that ribonucleic acid (RNA) serves not only as a transmitter of genetic information but also acts as an agent of change in living cells, Altman and Thomas R. Cech in 1989 were awarded the Nobel Prize in Chemistry.
Altman's discovery of catalytic RNA has shaken the very foundations of the biosciences, altering their central principle. Even more significantly, it has had a profound impact on our understanding of how life on earth began and developed. Scientists have known that the flow of genetic information from DNA to protein requires enzymes and other proteins. Altman's discovery has gone a long way toward answering one of the most puzzling questions confronting bioscientists who have long sought to determine which was the first biomolecule-DNA or protein? In light of Altman's research, it now appears that RNA molecules were the first biomolecules to contain both the genetic information and play a role as biocatalysts. His discovery of catalytic RNA has also given gene technology researchers a new tool with the potential for creating a new defense against infection. In 1997 Altman himself experimented with a method to combat bacteria's resistance to antibiotics by inserting artificial genes in bacteria to make them more sensitive to ampicillin and chloramphenicol, two widely used antibiotics.
Altman was born on May 8, 1939, in Montreal, Quebec, the second son of poor immigrant parents. His father, Victor, worked in a grocery store in the city's Notre Dame de Grace neighborhood, where Altman grew up. His mother, Ray Arlin, had worked in a textile mill before marrying Victor but looked after the home and her children by the time Sidney was born. Altman's parents instilled in him an appreciation for the value of hard work. As he wrote in his autobiographical profile on the Nobel Prize Web site, "It was from them that I learned that hard work in stable surroundings could yield rewards, even if only in infinitesimally small increments." As a boy, he liked sports and writing, but his greatest love was reading. An avid reader as a boy, Altman possessed a broad taste in books, including novels, sports books, and books about science. His early interest in science was sparked by two events, "the first being the appearance of the A-bomb," he recalled in his autobiographical profile. "The mystique associated with the bomb, the role that scientists played in it, and its general importance could not fail to impress even a six-year-old. About seven years later I was given a book about the periodic table of the elements. For the first time I saw the elegance of scientific theory and its predictive power… . [W]hile I was growing up, Einstein was presented as a worthy role model for a young boy who was good at his studies. I added various writers of fiction and stars of ice hockey and baseball to my pantheon."
After graduating from West Hill High School in Montreal, Altman headed off to the United States to study physics at the Massachusetts Institute of Technology (MIT). He'd originally planned to attend McGill University in Montreal, but when a high school friend suggested that they apply together to attend MIT, Altman agreed. As it turned out, Altman was accepted, but his friend was not. Although
Altman's father's grocery business had prospered during Sidney's high school years, there was some concern in the Altman household about their ability to meet the expenses of Sidney's schooling at MIT. On top of that, Altman himself was not really sure he wanted to go to MIT. However, after a few weeks at his new college, any doubts he may have had were dispelled. According to his profile in Science.ca, Altman found he enjoyed living away from home, on top of which he was very much impressed by the caliber of his fellow students. During his final semester at MIT, Altman took an introductory course in molecular biology, a subject that by then had begun to generate a great deal of excitement in the scientific community. The course familiarized Altman with nucleic acids and molecular genetics, laying the groundwork for his future encounters with these subjects. In 1960 he graduated from MIT and worked for the next two years as a teaching assistant in the Department of Physics at Columbia University.
In 1962 Altman moved to the University of Colorado Medical School to work as a research assistant under Leonard S. Lerman and to study molecular biology. As an assistant to Lerman, he worked mainly on research into the replication of the T4 bacteriophage, a substance that infects bacterial cells in much the same way that a virus infects human cells. In 1967 Altman earned his Ph.D. in biophysics from the University of Colorado and went to work briefly as a research assistant in molecular biology at Vanderbilt University. Later in 1967 he won a grant from the Damon Runyon Memorial Foundation for Cancer Research that allowed him work as a research fellow in molecular biology at Harvard University. For the next two years, he worked under noted biochemist Matthew Meselson, continuing his research into the genetic structure of the T4 bacteriophage. In 1969, with the help of Lerman, Altman won a fellowship to work in the Cambridge, England, laboratory of Sydney Brenner and DNA co-discoverer Francis Crick.
It was while working at the Brenner and Crick lab that Altman made an important discovery that helped to lay the groundwork for his later discovery of catalytic RNA. While working on mutant cells with malfunctioning tRNA (transfer RNA), Altman tried an experiment to see if he could isolate a special type of RNA called precursor-RNA. He took a glass plate (to which a thin layer of gel had been applied to one side) and put on it a few drops of material that had been prepared from the mutant cells. The glass plate was then placed into a strong electrical field. According to Altman's profile at Science.ca, "This technique, called electrophoresis, is a standard method for separating chemical compounds. The electric field causes different compounds to move across the gel at different speeds." Altman then waited for several hours and laid photographic film on top of the gel. "Tiny amounts of radioactive tracer atoms in the RNA emit X-rays that will leave characteristic bands on the film," his profile at Science.ca continued. When the film was taken to the darkroom to be developed, Altman knew within minutes that he had discovered the first radiochemically pure precursor to a tRNA molecule, the first step on the path to the discovery of catalytic RNA.
Altman stayed on for another year at Brenner and Crick's lab, before returning to the United States in 1971 to accept a post as an assistant professor in Yale University's biology department. A year later, he married Ann Korner, with whom he had two children, Daniel and Leah. In 1975 Altman was promoted to associate professor at Yale. Three years later he attracted wide attention in molecular biology circles when he published the results of an experiment conducted by one of his graduate students. The experiment demonstrated that the RNase P enzyme was at least partially made up of RNA, which meant that RNA played an integral role in the enzyme's activity. This finding contradicted the widely held belief among molecular biologists that enzymes were made up of protein, not nucleic acids.
In 1980 Altman was made a full professor at Yale. A year later, Thomas Cech of the University of Colorado independently published a study with conclusions very similar to those of Altman. Cech reported that his research had shown that the precursor RNA from the protozoan Tetrahymena were reduced to their final size as tRNA without the assistance of protein, suggesting that the precursor RNA catalyzed this transformation itself. Cech's findings lent considerable weight to Altman's earlier conclusions about the role of RNA in the activity of the RNase P enzyme. Further buttressing the findings of both Altman and Cech was research into the catalytic activity of RNase P conducted by Cecilia Guerrier-Takada, a colleague of Altman's at Yale. Guerrier-Takada's studies discovered catalysis even in the control experiments that used the RNA sub-unit of RNase P (the M1 RNA) but which contained no protein. Her findings laid the groundwork for a finding by Altman that the M1 RNA displayed all the classical properties of a catalyst, especially since it remained unchanged by the reaction. This finding by Altman removed any remaining doubt that RNA could function as an enzyme.
In 1984 Altman, who was now chairman of Yale's biology department, became a naturalized American citizen, although he retained his Canadian citizenship. A year later he was named dean of Yale College, a post in which he served for the next four years. As dean, he helped to win an expanded role for science education in all of Yale's curricula. The crowning glory of Altman's career in scientific research came in 1989 when he and Thomas Cech were jointly awarded the Nobel Prize in Chemistry for their independent studies demonstrating the catalytic ability of RNA. It is hard to overestimate the importance of their discovery, which proved conclusively that nucleic acids were the building blocks of life, acting as both genetic codes and enzymes. According to Notable Scientists: From 1900 to the Present, in presenting the award to Altman and Cech, the Nobel Academy described their discovery as one of "the two most important and outstanding discoveries in the biological sciences in the past 40 years," the other being the discovery by Crick and James D. Watson of DNA's double-helix structure. The findings of Altman and Cech about the catalytic properties of RNA have provided geneticists with a strong foundation for research into possible medical applications. It seems reasonable to believe that if RNA enzymes can cut additional sequences of tRNA from a strand of precursor tRNA, medical professionals could possibly use RNA enzymes to cut infectious RNA from the genetic system of someone infected with a viral disease.
A member of the National Academy of Sciences, the American Society of Biological Chemists, and the Genetics Society of America, Altman also received the Rosenstiel Award for Basic Biomedical Research in 1989. In 1991 he was selected to present the DeVane lecture series at Yale on the topic "Understanding Life in the Laboratory." In a 1997 address to incoming freshmen, posted on Yale University's Web site, Yale President Richard C. Levin offered this quote from Altman on the joys of discovery: "When I was a post-doc, I did an experiment that resolved a problem that I had been working on for a year or more. When I saw the result, there was not only the feeling of relief you get when you stop banging your head against a wall, but, more important, I then understood some of the puzzling results that had been published by others in the years before. The feeling of great satisfaction at having solved my problem as well as having illuminated others kept me floating on air for weeks."
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