©2015 AACR/Todd BuchananDavid Baltimore was born on Long Island, NY. His scientific roots began with his work as a graduate student on poliovirus replication, more specifically on how this virus could replicate its single-strand RNA genome. At the time, it was difficult to position this work in the context of the reigning paradigm of DNA-forming RNA, which in turn formed proteins. He was among the small group of researchers whose studies revealed the workings of a nucleic acid polymerase that operated totally independently of DNA—specifically the virus-encoded RNA-dependent RNA polymerase. This interest in viral genome replication led him to propose a method (1971) for categorizing all animal viral genomes based on their genomes and the polymerases that were required to replicate these genomes, often involving virus-encoded replicases.Baltimore’s interest in viral genome replication was greatly strengthened by his collaboration with and ultimately marriage to Alice Huang who had studied the intricacies of the replication cycle of vesicular stomatitis virus (VSV). The puzzle created by VSV, and later by a number of other similarly organized animal viruses, derived directly from the peculiar organization of its genome—negative-strand single-strand RNA. Unlike the situation with poliovirus, which carries a single-strand RNA genome that could serve as an mRNA active on the polysomes of virus-infected cells, VSV and similarly configured animal virus RNA genomes could not be translated upon entrance into host cells by their virions. This logical quandary forced a realization that the VSV virions themselves carried a virus-encoded RNA polymerase that could be carried into an infected cell and thereafter generate the positive-strand, subgenomic copies of the viral genome that could, in turn, serve as mRNA templates for the synthesis of viral proteins, among them the viral RNA-dependent RNA polymerase.This VSV research also depended on an experimental trick that soon served Baltimore well. Given the proposed presence of the viral replicase in the virions of VSV, its actions could be monitored experimentally by permeabilizing its virions, which are wrapped in a lipid bilayer membrane, with low concentrations of nonionic detergent supplied in concentrations high enough to allow ribonucleotide triphosphates to penetrate into the virions but not so high as to entirely disrupt the virion structure.It was then (1970) that Baltimore realized that the use of nonionic detergents to permeabilize the virions of lipid-containing animal virus genomes could be extended in an entirely new direction. He was well aware of the iconoclastic notion proposed by Howard Temin 6 years earlier that viruses like Rous sarcoma virus stored copies of their genomes in the DNA genomes of infected host cells. Temin’s proposal landed him in a scientific wilderness, as there were very few in the research community who could accept the notion that RNA molecules could be copied into DNA. Baltimore himself was more than familiar with Temin’s research. Although still in high school, the two attended together (1955) a summer research program for high school students at The Jackson Laboratory in Bar Harbor, Maine. Their academic trajectories were parallel for a while, with both attending Swarthmore College in Pennsylvania and Baltimore rooming with Temin’s younger brother there. Moreover, as their research careers developed, they became two of the small cadre of animal virologists who were beginning to elucidate the molecular biology of animal virus genome replication.In truth, there is nothing in the organization of viruses like Rous sarcoma virus that dictates that its virions must carry viral polymerases, as the plus-stranded viral genomes carried by these virions could be translated, like the poliovirus genome, by host-cell polyribosomes. Nevertheless, both Baltimore and Temin—Baltimore at MIT and Temin at the University of Wisconsin—essentially simultaneously searched for the viral reverse transcriptase in virions, doing so with permeabilized virions and describing the ability of the virion-bound polymerase to copy RNA into DNA (1970). Temin was welcomed back from the scientific wilderness, and the two, along with their mentor, Renato Dulbecco, were recognized by a Nobel Prize in Physiology or Medicine in 1975. The importance that the discovery of reverse transcriptase played in the subsequent recombinant DNA revolution cannot be overstated. In 1971, Baltimore proposed an overarching scheme for how to classify all animal viruses according to their genomes and strategies for genome replication.MIT recruited him back from New York where he had worked for several years, and he soon worked with Salvador Luria to propose and found the MIT Center for Cancer Research, taking advantage of the federal funds that flowed out from President Nixon's 1971 declaration of a War on Cancer. In fact, at the time, neither Luria, a bacterial geneticist, nor Baltimore, a virologist, were deeply embedded in cancer research. Instead, they proceeded with the bold assumption that expertise and insights flowing from other rapidly developing specialties in biomedical research, notably molecular biology, would accrue to the benefit of cancer research, being useful for understanding the origins of the disease and thereafter generating appropriate cures.In 1975, Baltimore began assuming a leadership position in the American biomedical research community with his organization (together with Paul Berg and Maxine Singer) of a meeting in Asilomar, California, that debated the potentials and perils of embracing the then-recently invented recombinant DNA technology. As it turned out, the perils feared by many did not eventuate, and the research community, having delayed its use of recombinant DNA for a year because of the moratorium proposed at Asilomar, jumped in with both feet to embrace this powerful technology. During these years and soon thereafter, his research group made truly fundamental discoveries, including descriptions of the Abelson murine leukemia virus (1975), the NF-κB signaling pathway (1986), and the RAG enzyme (1990), which enables recombination of immunoglobulin-encoding segments in the genome and leads thereby to antibody diversity.During this spate of productivity, Baltimore persuaded Edwin C. (“Jack”) Whitehead to fund the establishment of the Whitehead Institute for Biomedical Research (1982), affiliated with the Department of Biology of MIT. Its founding represented a bold departure for the then-reigning organization of research conducted in American universities, and accordingly led to much controversy at MIT, as its founding documents specified clearly fiscal independence from MIT together with obligations of the Whitehead’s principal investigators to bear full teaching responsibilities of faculty housed in MIT’s nearby Department of Biology. During this period in the mid-1980s, in light of his fundamental discovery of retrovirus reverse transcription, he headed a committee, appointed under the aegis of the US National Academy of Sciences, that was dedicated to proposing the directions and organization of AIDS research in the United States. Soon thereafter, he was appointed to the presidency of the Rockefeller Institute in New York, a position that he held for a bit more than one year (1990–1991) before stepping down and becoming a member of the Rockefeller faculty, remaining there until 1997 when he was appointed to the presidency of California Institute of Technology/Caltech in Pasadena, California. In the years after, he relinquished the Caltech presidency and continued as a faculty member of Caltech until his death on September 6, 2025.Baltimore remained dedicated to science and was supportive of other researchers. I remember he once told me that he would never want to publish anything with me. Coming from someone else, that comment might have been taken as an insult; then he continued, “If we publish something together, everyone will say ‘look what Baltimore has done again.’” It was an act of generosity toward me and was very like him to give others credit.An overview of his multifaceted career leads to a simple conclusion: It is hard to cite others in American biomedical research whose influence and leadership rival Baltimore’s. By sheer force of personality and intellect, he helped shepherd American biomedical research to the high level that it attained in the half-century after the 1970 discovery of reverse transcriptase.
Robert A. Weinberg (Mon,) studied this question.
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