Sol Spiegelman, a Pioneer in Molecular Biology
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They Wand 0SS tk Slmsldera of Giants: Sol S@egelman, a Piomer in l$lokcular Biology Number 21 May 23,1983 Science in our century has been Indeed, it is upon his widely acclaimed marked by tremendous upheavals in un- discoveries that much of the framework derstanding, brought about by momen- of the discipline now rests. Sol was still tous discoveries and extraordinary pe~ deeply involved in a number of projects ple. One such upheaval has occurred in when, tragically, he died following a biology. It began in the 1930s, when a brief illness on January 21, 1983.2 This new field, molecular biology, was born essay is dedicated to his memory, and to of the synthesis of five distinct disci- the surviving members of his family: hw plines: physical chemistry, crystallogra- wife, Helen; his daughter, Marjorie; and phy, genetics, microbiology, and bio- hk sons, Willard and George. chemistry.1 I deeply regret that Sol did not have Molecular biologists try to explain the opportunity to read this long biological phenomena at the molecular overdue discussion of his work. I had level. By the mid-twentieth century, planned to do this as part of our series of they had settled several problems that essays on various awards in science—in plagued previous generations of biolo- particular, the Feltnnelfi prize, men- gists. For instance, proteins and nucleic tioned later. Sol was one of the true acids had been known since the nine- giants of modem science. So it is with a teenth century to be very large mole- mixed sense of pain and gratitude that I cules, each consisting of long chains of use thk opportunity to pay tribute to a subunits—amino acids in the case of man whose genius was unique. protein, punnes and pynmidines in the Sol was born on December 14, 1914, case of nucleic acid. But it remained for in New York City to Max and Eva (Kra- molecular biologists to discover the long mer) Spiegelman. Even as a child, he ex- sought after sequence in which these hibited a deep interest in biology.s But subunits occurred. During the 1930s, when he began his undergraduate career however, answers to fundamental ques- at the CoUege of the City of New York in tions involving the structure of DNA, 1933, he found his biology courses so and the processes by which it regulates disappointing that he majored in mathe- cell metabolism, still lay in the future. 1 matics and physics instead. However, he It was during this turbulent, revolu- read biology on hk own. And in 1936 tionary time that my friend Sol Spiegel- and 1937, he interrupted his schooling to man completed his undergraduate train- work as a researcher in the Richard Mor- ing and entered the field of molecular ton Koster Research Laboratory, Crown biology. He would become one of the Heights Hospital, Brooklyn, New York. major figures in the then infant science. There he completed his first research pa- 164 zymes is under direct genetic control,~ Spiegelman felt that knowledge of how the genes themselves are controlled was vital to an understanding of malfunc- tioning enzymes. He began his investiga- tions in the mid- 1940s. The work occu- pied him for a full decade. But in the end, he and his colleagues were able to show clearly that enzymes could be al- tered without necessarily involving an accompanying mutation in the genes controlling them. Spiegelman suggested that changes or abnormalities in en- zymes occurred when critical fractions of genes were inappropriately activated or deactivated—a phenomenon known familiarly today as switching a gene on or off. Sol Spiegelman The implications for cancer research were enormous. During most of the per-an analysis of the mutation of a 1940s, the wild multiplication of some bactenum,q written under the supervi- cells at the expense of others that is so sion of the lab’s dwector, A. Shapiro. He characteristic of cancer had been as- returned to City College in 1938 to finish cribed to genetic mutation. Spiegel- hk undergraduate career, and graduated man’s results, however, made it possible with a bachelor of science degree in to test the idea that the genes of a can- 1939. cerous celf might be intact, but that the Spiegelman went on to begin graduate control mechanism had gone berserk. work in cellular physiology at Columbia And Spiegelman’s suggestion that copies University in 1940. After two years of the information encoded within DNA there, he continued his postgraduate are transmitted into the cefl’s cytoplasm studies from 1942 through 1944 at Wash- for protein synthesisb.T had great signifk ington University, St. Louis, Mksouri. cance for future research into messenger During this time, he also lectured in RNA. physics and in applied mathematics. He During 1945 and 1946, Spiegelman received hm PhD from Washington served as an instructor in bacteriology at University in ceflular physiology and Washington University School of Medi- mathematics in 1944. cine. He was then promoted to assistant In his early investigations, Spiegelman professor of bacteriology, a post he held wanted to describe how cells form their for more than two years, until 1948. He enzymes, and what factors determine became so widely known and admired the types of enzymes a celf has. Enzymes for the elegance of hk experiments that are proteins that stimulate, direct, and the American Cancer Society offered to regulate the complex chemicaf reactions set him up in his own research program underlying the life processes of an or- with an annual budget of S25,000-a ganism. It was suspected that abnormal- sum greater than the budget of the entire ities in certain enzymes involved in the biology department.3 Spiegelman ac- regulation of tissue building played a cepted the offer. In 1948 he left St. role in the development of cancer. Since Louis, taking the grant with him, and it was known that the synthesis of en- went to work with ‘tie US Public Health 165 Service at the University of Minnesota, for an enzyme that would duplicate, or Minneapolis. When the money ran out a replicate, the viral RNA directly. year later, he left Minneapolis for the In 1963, Spiegefman and several col- University of Illiiois, Urbana. There he leagues found the enzyme they were was named professor of microbiology, looking for: one capable of specifically and there he would remain for the next recognizing viral RNA among all the 20 years. other bacterial RNA within a cell. 12 It By the mid- 19S0s, a few years after his was the first of the nucleic acid polymer- arrival at Illkois, Spiegelman began the ases—enzymes aiding in the formation work that eventually led to the discovery of nucleic acid-discovered to possess for which he is best known, While study- such a quality, which was later named ing the synthesis of nucleic acids, he and template spectilcity. IS Spiegelxnan’s an- an associate, Benjamin D. HaLl, found it nouncement of the discovery at a Cold necessary to pair a strand of viral DNA Spring Harbor symposium in New York with a strand of matching viral RNA, B was greeted with skepticism. 14 But This was possibly the most important within two years he demonstrated, technique in molecular biology, then or together with I. Haruna, that an enzyme now—RNAIDNA hybridization. The coded for by still another virus, known new technique led Spiegehnan and hk as phage Q~, was also template specif- colleagues directly to the discovery that ic. 13The enzyme proved relatively easy only one strand of DNAs double helii to isolate and purify. Within the year, transmits the genetic information to the Spiegelman was using Q~s RNA repli- celf’s protein-making machmery. g cating enzyme-or RNA replicase-to In 1961, Spiegehnan turned his atten- manufacture RNA in test tubes. 15 tion to those viruses which contain RNA The “artificial” RNA proved as viable rather than DNA. The central biological and infectious as its “natural” counter- dogma of the time held that the direction part. Spiegehnan used it to observe Dar- of transmission of genetic information winiin selection at the relatively simple was always from DNA to RNA. Thus, it molecular level, a stage removed from was relatively easy to understand how a the complexities of evolution at the DNA virus used a bacterium to repro- cellular level. lb,17 His experiments duce itself: it simply injected the cell culminated in 1966 with the discovery of with its own DNA, which interposed be- a type of RNA that was a fraction of the tween the cell’s DNA and the cellular original Q? phage—a “little” Qfl. l~m It RNA. However, in the case of viruses could do little more than grab the ap- contatilng RNA rather than DNA, the propriate rep ficase enzyme and copy it- problem was to describe how an RNA self. Presumably, this extremely liiited virus completes its life cycle in a celf capacity for simple replication is alf that dominated by DNA. Spiegefman seemed primeval nucleic acid molecules were to confirm the view of RNA as subor- able to achieve. Why, then, had they dinate to DNA when he failed to find ever evolved beyond that capacity, to evidence that viral RNA could somehow the point where they were capable of usurp a bacterium’s genetic machinery directing the synthesis and functioning to produce copies of itself that were of something as complicated as a cell? made of DNA, rather than RNA. 10How- Spiegehnan’s work made possible some ever, as we shall see, just such a reverse hypotheses and further work concerning tmnscription of RNA to DNA would be the environmental pressures that had dwcovered nine years later.