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The Sol Spiegelman Papers

Biographical Information

[Sol Spiegelman at the Woods Hole Library]. [ca. Early 1940s].
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"It's not the job of scientists to create a universe. It is simply their job to describe it. Scientists are the catalysts of the inevitable. I call this my principle of dispensability."
--Sol Spiegelman, in a 1975 interview

Sol Spiegelman was a pioneering molecular biologist whose discoveries accelerated the study of gene action and laid the foundations of recombinant DNA technology. He was born in Brooklyn, New York, on December 14, 1914, to Max Spiegelman, a teacher of oriental languages and religion at a Hebrew theological seminary, and his wife, Eva. Even as a child, he was deeply interested in biology and wanted to pursue a career in the field. However, when he began undergraduate work at the City College of New York in 1933, he found his biology courses full of "sloppy thinking, soft facts and rather dull professors.'' He majored in math and physics instead, but continued reading biology on his own and taking summer jobs in biological research labs. In 1936 and 1937, Spiegelman took a leave of absence from City College to work as a researcher at the Richard Morton Koster laboratory at Crown Heights Hospital in Brooklyn. There he studied bacterial mutations and produced his first research paper.

In that first paper Spiegelman analyzed a single, regular mutation in Salmonella aertrycke bacteria cultures and suggested that this mutation process was analogous to that in higher life forms. He proposed that the study of rapidly multiplying bacteria cultures might therefore be useful in cell genetics research and even illuminate the cell proliferation that characterized tumor growth. In the mid-1930s, however, the idea seemed preposterous to many experts in the field. The editor of the American journal Genetics declined to publish the study, and noted, "It is well known that bacteria have no nucleus and therefore can have no genetics." The Journal of Bacteriology also returned the paper and added, "We don't know what you are doing, but it is not a proper thing for a bacteriologist to be studying." The paper was finally accepted and published in the British Journal of Genetics, perhaps, Spiegelman guessed, because "the English are so much more tolerant of deviants." Spiegelman's ideas were ten years ahead of their time; by the end of the 1940s, with the discoveries of Joshua Lederberg, Salvador Luria, and others, bacteria and viruses would be accepted and embraced as model organisms for genetic studies.

Spiegelman returned to City College and completed his BS in 1939, then began graduate studies in cell physiology at Columbia University, working with H. B. Steinbach. When Steinbach moved to Washington University in St. Louis in 1942, Spiegelman followed, and completed his PhD work there in 1944. His doctoral and postdoctoral work explored a phenomenon known as 'enzymatic adaptation' or induction, a topic that would occupy him for the next decade. It was known that the ability of a microorganism (e.g., yeast) to manufacture various enzymes--the special proteins that catalyze the thousands of chemical reactions in living systems--could be used to track its genetic changes. Changes in a microbe's repertoire of enzymes would indicate a change in its genes, i.e., a mutation. However, researchers had long observed that microbes sometimes seemed to "adapt" to the presence of novel nutrient substances by producing the enzymes necessary to digest them, without mutating. Spiegelman demonstrated that such an adaptation did indeed occur, and could be induced with simple organic compounds. Thus what was crucial to the synthesis of a new enzyme was not just the presence of the right gene, but activation--induction--by the right nutrient. The expression of genes for making various enzymes could be "turned off and on" by exposing the microbe to various nutrients. This meant that the gene-enzyme relationship was more complex than the one gene-one enzyme theory recently proposed by Edward Tatum and George Beadle: genes controlled not the direct synthesis of enzymes and other cell proteins, but only the potentiality of such synthesis. If a microbe's synthesis of a particular enzyme could be controlled by induction, the mechanisms of gene function could be studied within a constant genetic situation, rather than by tracking mutations. Spiegelman also suggested that adaptation might occur via either partial or complete copies of the gene (which he called "plasmagenes") moving out of the cell nucleus into the cytoplasm to serve as "programs" for protein synthesis. This idea anticipated the influential "messenger" concept developed by French investigators François Jacob and Jacques Monod ten years later, which led to the discovery of messenger RNA as the transmitter of the genetic information in DNA. During this time, Spiegelman and the French team were perhaps the only researchers maintaining that the study of enzyme induction in microbes could lead to a better understanding of gene function. By the mid-1950s, induction had become one of the key systems of genetic studies.

Spiegelman stayed at Washington University until 1948, when he left to take a National Institutes of Health fellowship at the University of Minnesota. In 1949 he joined the faculty at the University of Illinois at Urbana-Champaign. He continued his investigations into microbial enzyme adaptation, but in the mid-1950s, he also began research on the enzymes involved in nucleic acid synthesis. He was intrigued by the "strange biological situation" of certain phages (viruses that infect bacteria) which have RNA, not DNA, as their genetic material. How did these survive in a universe of cells that use DNA as their genetic material and RNA as genetic messages? In a series of elegant experiments over 10 years, Spiegelman solved the problem of how RNA phages exploit cellular information to survive and replicate in a host cell. Spiegelman reasoned first that the injected RNA strand of the virus must serve directly as a message and remain intact during its translation into protein; second, that an enzyme should be found in cells infected with RNA viruses that would allow that RNA to replicate; and third, that such RNA replicases (as the enzymes were soon called) must be specific to the viral RNA, since viral RNA replication occurred within cells containing other cellular RNA molecules.

Working with the MS2 and Q-beta phages that infect E. coli, he confirmed these predictions. He isolated and purified the RNA replicase for each and demonstrated that it was specific to that virus. Further, he found that Q-beta RNA could be replicated indefinitely in a test tube, and that the new RNA was biologically active. Thus, in 1965 Spiegelman became the first to carry out what one science writer called "the dream experiment of modern biology," the test tube synthesis of biologically competent, replicating, and infectious viral nucleic acid. Later work with this synthetic viral RNA (which he called "the little monster") showed that it could even demonstrate Darwinian evolution in response to various pressures imposed upon it. One mutant, for example, had, by its 74th generation jettisoned about eighty percent of its genes, retaining only enough to replicate itself.

Spiegelman is perhaps best known in molecular biology for developing, during the first few years of his nucleic acid work, the formidable technique of DNA-RNA hybridization. This technique takes advantage of the fact that the four nitrogenous bases of DNA always form pairs in the same way: adenine with thymine, and cytosine with guanine. (In RNA, uracil takes the place of thymine as the partner of adenine.) If a given length of DNA is "unzipped" into single strands, then exposed to RNA whose sequence of bases is complementary to it, the RNA will bond to a strand of the DNA. Such hybridization is highly specific, occurring only between genetic sequences that are nearly identical, and thus enables researchers to distinguish between different types and sequences of DNA and RNA, and the DNA sections that constitute individual genes. Molecular hybridization has been a powerful tool in the successful development of molecular biology. It has been essential in analyzing the organization of the genome and in the effective use of recombinant DNA technology.

In 1969, Spiegelman decided to shift his research focus to cancer, a subject that had "hovered in the background" of his work since his undergraduate days. He accepted the position of director at the Institute of Cancer Research at the Columbia University College of Physicians and Surgeons, and started to explore the possible role of RNA tumor viruses in certain human cancers. Such viruses had been shown to cause certain animal cancers and Spiegelman expected that RNA viruses might be found in human leukemia, sarcoma, lymphoma, and breast carcinoma. Using molecular hybridization and other techniques, he found significant homologies (similarities of nucleotide sequences) between some of the animal tumor viral RNAs and the RNAs of several human tumor types. He was then able to develop a reliable test to detect the presence of virus RNA in tissues. Although later researchers found that relatively few human cancers are directly caused by viruses, Spiegelman's work greatly expanded scientific understanding of their mechanisms. In the year before his death on January 21, 1983, he was developing a blood test for breast cancer.

Spiegelman's accomplishments earned him many honors and awards, most notably the Lasker Award for Basic Medical Research in 1974 and the Antonio Feltrinelli International Prize in Biology (the "Italian Nobel") in 1981. He was elected to the National Academy of Sciences in 1965 and to the American Academy of Arts and Sciences in 1966, and was a member of the American Society of Biological Chemists, the American Society for Microbiology, and the Genetics Society of America, among others. Columbia University appointed him a University Professor--one of only three--in 1975. Between 1966 and 1979, he was awarded ten honorary doctorates.

Throughout his career, Spiegelman proved himself an extraordinarily creative and productive scientist, publishing over 350 articles. His research clarified fundamental problems in biology and opened up new pathways for further studies; he devised ingenious new techniques that facilitated major advances in research; and he provided ideas and evidence for practical approaches to cancer prevention and control. He was a gifted and articulate teacher, as well as a mentor to dozens of graduate students. One of them, Nobel laureate Richard Axel, noted, "He was a great teacher and colleague. Hundreds of students and fellows passed through his laboratory, each imbued with a critical sense and a love for science which characterized Spiegelman's own work."

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