Copyright 0 I996 by the Genetics Society of America Perspectives Anecdotal, Historical And Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove Recollections of HOWARDTEMIN (1934- 1994) John W. Drake* and James F. Crowt *Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 and ‘Genetics Laboratory, University of Wisconsin, Madison, Wisconsin 53706 N 1960 HOWARDTEMIN finished a postdoctoral year ers, MICHAEL(now an attorney) and PETER(now a pro- I at Caltech and moved to the University of Wiscon- fessor of economic history). His father HENRYwas an sin. His brilliance was evident to his Caltech associates, attorney, his mother ANNETTE (nee LEHMANN)was what but as to promise he gotmixed reviews. GEORGEBEADLE we might nowcall a volunteer. Bothwere strong- and RAY OWENboth recognized HOWARD’Sability but minded and voluble. HENRYconducted a diverse one- differed in their assessment of his future. RAY was con- man legal practice; at home he held high expectations fident, BEETSnot so sure. They decided to bet a fifth of those around him. ANNETTE had wanted to be a of whiskey on whether HOWARD woulddo something physicist but found that worldclosed to women. A important within five years of graduation. After five bright and busy person, she founded a Citizens’ Com- years he had a publication record that was respectable mittee for Public Education in Philadelphia and a free but not unusual, and he had kept plugging away at an summer camp for children who would otherwise be heretical idea. RAY was particularly impressed by one of denied that experience. She was active in both Hadas- HOWARD’Spapers and thought his accumulated work sah and the synagogue, where she chaired the School good enough to win the bet, but BEETSdemurred. A Committee. Thus, whatever may have been the genetic few years later he reluctantly conceded and the betwas contributions to his abilities, HOWARDalso benefited paid off (a bottle of Old Crow, we are told). Of course, from an environment in which both analysis and action if they had waited until the discovery of reverse tran- reigned. scriptase in 1970, there would have been no question. As an undergraduate at Swarthmore, HOWARDstud- HOWARDwas honest, strongly individual, and willing ied biology. He quickly became a practicing scientist, to state and stand by his convictions. These traits were participating in two summers of research at the Jackson evidenced at his graduation from Swarthmore, where Laboratory. His first paper, dealing with the genetics of he had had a disagreement with a college policy and congenital anomalies (INGALLSet al. 1953), was based refused to dress for the graduation ceremony. (Years on work done there. His final oral examination in 1955 later, after he became famous, Swarthmore awarded for an honors degree at Swarthmore iswell remem- him an honorary degree; this time he donned cap and bered at that institution, because his thoughtful and gown.) His outspokenness was also evident at the 1975 far-seeing responses elicited a vigorous debate among Nobel Prize banquet in Stockholm, when he shocked the external examining committee that soon subverted the audience by expressing his outrage that the one the examination into a professorial exchange. known major cause of cancer, cigarette smoking, was There have been numerous tributes to and reviews so blithely overlooked, even at the event itself. At a of HOWARD’Slife in science (e.g., COOPERet al. 1995). gathering of Nobel laureates in 1991, one speaker said Here, instead, are personal accounts by two of us who that if the world were more loving, many social prob- knew him well, but at different times and in different lems would be solved and world tensions lessened. ways. The first deals with his virology and his Caltech HOWARD,with AIDS in mind, used his turn to shock an years, the second with his life in Wisconsin. international television audience by saying, “If you love, Caltech and virology (J.W.D.): HOWARDinitiated his use a condom.” Perhaps the most characteristic exam- Caltech graduate work in 1955. He settled first into the ple was his steady belief in and defense of theprovirus laboratory of ALBERT TYLER, a kindly, scholarlydevelop- theory during a time when the transfer of information mental biologist who was interested in fertilization and from RNA to DNA was unthinkable. early development. I had been working in the same lab, HOWARDMARTIN TEMINwas born on December 10, both of us having arrived at Caltech with an interest in 1934, in Philadelphia. He was bracketed by two broth- embryology. We were impatient, however, and saw no (;erwtic\ 144: 1-6 (September, l!)YC,) 2 J.W. Drake andJ.F. Crow exploring this and related retroviruses. At Caltech he promptly engaged in a vigorous collaboration with HARRYRURTN. Their first success was the development of an RSV assay suggested by the then-recent results of MANAKERand GROWPI?(1956). This “focus” assay was a hybrid between a virus-induced plaque ancl a cell col- ony, in which RSV-transformed cells locallyout-prolifer- ate their contact-inhibited siblings (TEMINand RURIN 1958).Just as with the invention of the phage and the animal virus plaque assays, the focus assay brorlght all the analytical power ofquantitation to bear on the ques- tion of virus-induced cell transformation. 1950-1959 was a decade of great excitement in biol- ow.There was much discussion at Caltech about the still mysterious prophage state in lysogenic bacteria. By the middle1950s it had become clear that the prophage was so closely associated with the bacterial chromosome c that it behaved like a bacterial marker. Thus, HOWARD’S mind was soon steeped in the powerful concept of the chromosomal prophage, and he began to imagine “ly- sogeny” by an RSV “provirus.” He later found an RSV variant that produced a variant morphology in trans- formed chicken cells, further strengthening theanalogy with bacterial lysogeny. In 1960 H0W44RDmoved to the University of M’iscon- sin, where he remained for the rest of his life. He con- tinued to probe the natureof the RSV-transformed cell c’ and began to advocate in print the notion that a provi- rus state could be achieved by an RNA tumor virus ( P.R., TEMIN1963, 1964a). He surmised that the RNA of the FI(;I’KEI.-How..\KI> in 197i with his favorite mode of virus would have to be copied into the DNA of the transportation in Madison. provirus and that progeny virus could result from tran- scription of this provirus. However, in addition to as- way to advance the field, the probes of the time often suming a different shape and becoming tumorigenic, being no better understood than their target tissues. most or all RSV-transformed cells continuously release After a while, as word of our frustrations spread, JIM virus without dying. This was very different from the WATSONintervened. He was a visiting scientist at the prophage + phage transition so elegantly elucidated by time, fresh off DNA and anobject of considerable local ANDR~LWOFF a few years earlier in which an occasional curiosity. He decided thatwe might profitably work with cell suddenly bursts, releasing many phage particles. &NATO DULBECCO,a virologist who had recently in- In support of his hypothesis, HOWARD found that vented plaque assays for animal viruses and was about blocking transcription with actinomycin D stopped vi- to apply the attack mode of the Phage School to these rus production (TEMIN1963), whereas transformed previously intractable viruses. DUI.REC<:Oagreed thatwe cells continued to make virus in the presence of inhibi- could work in hislab and introduced us to the members tors ofDNA replication such as fluorodeoxyuridine, of his group who were to become our daily mentors. aminopterin, and cytosine arabinoside (TEMIN1964b). These included MARGUERITE VOGT, whowas in charge Then, using hybridization techniques, he demonstrated of overall operations and was intimately familiar with sequence homology behveen RNA from the virus and the technical procedures involved in the plaque assays. DNA from transformed cells (TEMIN 1964~).However, Another was HARRY RURIN,a senior research fellow, an these studies are more persuasivein retrospect than adventuresome thinker, and a singer and guitar player they were when first described, in part because of com- much in demand at parties. plexities in some of the results and universal uncertain- Probably because of perceived parallels between de- ties inthe interpretation of inhibitor studies, but proba- velopmental processes and the cellular modifications bly more because of the novelty of the hypothesis. wrought by tumor viruses, HOWARDtook up Rous Sar- HOWARD’Sprophage model required thatviral single- coma Virus (RSV), which had been discovered by PEY- stranded RNA be copied into double-stranded DNA TON Rous in 1911 and was the canonical “cancer vi- and that the latter be integrated into the host DNA. rus.” HOWARDspent most of his subsequent career Early attempt5 to find an enzymatic activity to catalyze Perspectives 3 undiscovered, RNA plasmids might have offered an even more compelling (albeit incorrect) hypothesis to explain the carrier state. By standing firm, HOWARD later gained praise for his courage in the face of wide- spread disbelief of his thesis. HOWARDdid a great deal of virology during his de- cades in Madison, publishing some 276 research and review articles on the subject in addition to his Caltech output andtraining several-score graduate studentsand postdoctoral fellows. Starting even before Madison, he repeatedly wrote on the role of virusesin cancer, a vexing question before the discovery ofoncogenes, and he argued for the origins of retroviruses from cellular transposons. HOWARDbecame steadily more interested in the problem of viral variation. Even in the Caltech years it had been obvious that RNA viruses mutate rapidly, frustrating attempts to obtain stable genetic markers.