David Baltimore

David Baltimore

California Institute of Technology

As one of the premier biomedical scientists of the last five decades, he is renowned for the breadth and beauty of his discoveries in virology, immunology, and cancer; for his academic leadership; for his mentorship of prominent scientists; and for his influence as a public advocate for science

The 2021 Lasker~Koshland Award for Special Achievement in Medical Science honors David Baltimore (California Institute of Technology), one of the premier biomedical scientists of the last five decades, who is renowned for the breadth and beauty of his discoveries in virology, immunology, and cancer. He has provided visionary academic leadership at multiple institutions and has mentored trainees who have later become prominent scientists in their fields. Since the beginning of his career, he has worked at the interface of policy and biological research, advocating for science and for ethical conduct. His statesmanship has influenced numerous areas of public interest.

Unanticipated revelations, new biological horizons

As a graduate student in the early 1960s, Baltimore wondered whether mammalian viruses might help scientists understand human physiology the way bacterial viruses had helped them understand E. coli. By following this instinct, he has unearthed a treasure chest of knowledge.

Two years after joining the Massachusetts Institute of Technology in 1968 as a junior faculty member, Baltimore discovered that certain tumor viruses can copy their genetic material, RNA, into DNA. This capability violated conventional wisdom, which held that genetic information flows from DNA to RNA to protein. He tracked this dogma-defying feat to an enzyme, now called reverse transcriptase, and published the work in 1970 back-to-back with the late Howard Temin (University of Wisconsin, Madison), who had posited the idea and independently performed similar work. For this achievement, they won the 1975 Nobel Prize for Physiology or Medicine (Figure 1). Baltimore was 37 years old.

Receiving the Nobel Prize from Swedish King Carl Gustaf in 1975

Receiving the Nobel Prize from Swedish King Carl Gustaf in 1975

This advance delivered numerous practical and theoretical impacts, some of which were not yet known at the time. Eventually, for example, reverse transcriptase enabled the isolation of protein-coding portions of genes, a task that was difficult to accomplish from genomic DNA, which contains long sequences that interrupt the protein template. The enzyme allowed scientists to make a DNA copy of mature messenger RNA, in which these stretches had been spliced out by the cell’s machinery.

Baltimore wanted to use viruses to study cancer in mammals. Toward that end, he began studying the Abelson virus, which causes leukemia in mice and corrupts well-behaving mouse cells in culture dishes, goading them to proliferate wildly. Baltimore and postdoctoral fellow Owen Witte traced its cancer-causing abilities to a previously unknown enzymatic power—the capacity to add phosphate chemical groups to the amino acid tyrosine within proteins. Tony Hunter (Salk Institute of Biological Studies, La Jolla) independently made similar observations in other viruses. Such chemical adornments control signaling systems that regulate a variety of activities, including cellular replication.

This finding led to a cascade of discoveries, some of which have culminated in medical benefits. Most notably, a defective version of a related human enzyme underlies chronic myelogenous leukemia, and scientists developed a compound that blocks its activity. The resulting drug, imatinib (now widely known as Gleevec), has transformed this previously fatal illness into a manageable condition and saved many lives (Lasker Clinical Research Award, 2009).

Baltimore then harnessed numerous other observations about Abelson virus’s effects on cells in culture to expand his studies into developmental immunology. He uncovered a protein, NF-kB, that activates hundreds of genes involved in inflammation and plays key roles in many diseases, particularly numerous cancers.

Later, Baltimore found genes whose products orchestrate one of the most awe-inspiring developmental processes in existence. All B cell precursors contain the same set of genes, yet somehow each mature B cell acquires the ability to make a unique antibody that recognizes a specific foreign peptide. With Baltimore, graduate students David Schatz and Marjorie Oettinger devised and deployed a scheme by which they isolated the two so-called Recombination-Activating Genes—RAG-1 and RAG-2—that rearrange antibody genes to generate an astounding degree of diversity from a constant starting set of genetic information. Baltimore also proposed how an enzyme called terminal transferase might help generate diversity in antibody genes, and this theoretical work opened untilled ground.

Each of these breakthroughs has spawned a new field, yet they represent only a subset of Baltimore’s major findings. He has published more than 700 papers, many of which hold a central place in their discipline.

Training students and postdoctoral fellows has been integral to Baltimore’s research accomplishments. He believes that the best young scientists will flourish if they receive financial and intellectual support as well as the latitude to follow their own ideas. With this philosophy, he has mentored scores of scientists, many of whom are now world renowned. Twenty of his scientific progeny have become National Academy of Sciences members.

Deft institutional leadership

In 1980, a wealthy entrepreneur named Jack Whitehead invited Baltimore to help him build a new biomedical research institute. Baltimore crystallized Whitehead’s general notion into a clear vision, and then made it a reality, thus creating one of the best centers for experimental biomedicine on the planet. Along the way, he convinced Whitehead that MIT would be its ideal home even though the school was known more for mathematical and technical prowess than for health sciences. Then, against much suspicion and skepticism, he convinced MIT to accept it into the heart of the school. He enticed top-flight investigators who were probing exciting questions and melded these personalities into a functioning institution.

In 1982, he became the founding director of the Whitehead Institute for Biomedical Research (Figure 2). Its relationship with MIT became a model for other institutes, and he also conceived a novel—and now emulated—program that offers especially talented recent PhD and MD-PhD graduates the opportunity to pursue independent projects without first apprenticing as a postdoc.

With Jack Whitehead during construction of the Whitehead Institute in 1984

With Jack Whitehead during construction of the Whitehead Institute in 1984

In addition to launching this new institution, Baltimore has led proven and esteemed academic establishments. Even his brief stint as President of the Rockefeller University (1990-1991) left a long-lasting and constructive imprint. He raised the status of junior faculty, unlocking them from a hierarchical model in which they struggled to thrive. In the same position at California Institute of Technology (1997-2006), he raised the largest ever single donation at the time to support science at a US university. This gift provided seed money for imaginative, interdisciplinary initiatives and gave all of the divisions at Caltech the opportunity to imagine new directions for themselves.

For the public good

When the US invaded Cambodia in 1970, Baltimore was pipetting away, performing his reverse transcriptase experiments. Compelled to stand against an immoral and illegal war, he froze his samples and joined the protests. Since then, Baltimore has comingled his intellectual acumen, personality, and moral compass to contribute, away from the bench, to the scientific community and society (Figure 3).

Accepting the National Medal of Science from President Bill Clinton in 2000

Accepting the National Medal of Science from President Bill Clinton in 2000

The recombinant DNA revolution began in the early 1970s and concern immediately emerged about possible hazards. Baltimore felt called to figure out how to respect the ethical issues without halting research. He worked with Paul Berg, Maxine Singer, and others to organize the famous 1975 Asilomar Conference, whose participants produced a strategy for engaging prudently with the new technology while exploiting it to engender knowledge. Baltimore subsequently served on the Recombinant-DNA Advisory Committee of the National Institutes of Health (NIH).

Four decades later, gene-editing tools became available, and his peers again turned to him for leadership as they began to cultivate a discussion about how to navigate this unexplored territory. He chaired the first (2015) and second (2018) International Summits on Human Gene Editing, which grappled with questions that are arising from the impending possibility of manipulating human genes in a heritable manner—a venture that presents enormous benefits, such as correcting genetic disorders, as well as risks.

Baltimore has also helped galvanize the US to tackle a serious medical problem that the federal government was ignoring. In 1986, the HIV/AIDS epidemic was raging, yet no national program existed through which to plan a response. The National Academy of Sciences and the Institute of Medicine asked Baltimore and the late Sheldon Wolff (Tufts University School of Medicine) to co-chair a commission that would study the relevant issues. The resulting report reshaped the country’s approach to the scourge. It injected a sense of urgency into the situation and recommended a monumental research, educational, and public health campaign to learn about the virus and curb the spread of disease. Baltimore had the gumption to call for a $1 billion research program—a tremendous amount of money at the time.

Baltimore shines as a model for all facets of the scientific enterprise. He has made breakthroughs in manifold fields, nurtured rising investigators, grown institutions and programs from scratch, and led with wisdom. His thoughtfulness and integrity have guided colleagues and the public, and his ever-expanding legacy continues to benefit the world of biomedicine and society at large.

by Evelyn Strauss

Selected Publications of David Baltimore

Baltimore, D. (1970). Viral RNA-dependent DNA polymerase. Nature. 226, 1209-1211.

Baltimore, D. (1974). Is terminal deoxynucleotidyl transferase a somatic mutagen in lymphocytes? Nature. 248, 409-411.

Witte, O.N., Dasgupta, A., and Baltimore, D. (1980). Abelson murine leukemia virus protein is phosphorylated in vitro to form phosphotyrosine. Nature. 283, 826-831.

Sen, R., and Baltimore, D. (1986). Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 46, 705-716.

Baltimore, D., (2009). Discovering NF-kB. Cold Spring Harb. Perspect. Biol. https://cshperspectives.cshlp.org/content/1/1/a000026

Zhang, Q., Lenardo, M.J, and Baltimore, D. (2017). 30 Years of NF-kB: a Blossoming of relevance to human pathobiology. Cell. 168, 37-57.

Schatz, D.G., Oettinger, M.A., and Baltimore, D. (1989). The V(D)J recombination activating gene, RAG-1. Cell. 59, 1035-1048.

Schatz, D.G., and Baltimore, D. (2004). Uncovering the V(D)J recombinase. Cell. S116, S103-S106.

Baltimore, D. (2019). Sixty years of discovery. Annu. Rev. Immunol. 37, 1-17.

Perspective

Crotty, S. (2001). Ahead of the Curve: David Baltimore’s Life in Science. University of California Press, Berkeley.

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Acceptance remarks by David Baltimore

As an 83-year-old man, I look back on my long career in science and feel a deep appreciation that I was introduced to the joys of scientific investigation when I was a high school teenager. That came during a summer-long stint at The Jackson Laboratory in Bar Harbor, Maine, where I was mentored by three great mouse geneticists who introduced me to research and to the challenge of understanding the activities of a creature like the mouse. That “me” was a nerdy kid who sensed that dedicating his life to research might just be the contribution to society that would justify taking up space on an increasingly crowded planet. But first I needed to be educated, to learn how the world works. I put that challenge to Swarthmore College and it responded magnificently. In addition to giving me the broad education that prepared me for the many roles of a scientist—investigator, teacher, mentor, administrator, policy wonk, citizen—Swarthmore also used a form of education, learning in small seminars, that provided a forum for grappling with the new perspectives opening in biology.

In the late 1950’s, when I was in college, it had been only a few years since Watson and Crick had changed the whole trajectory of biological research by elucidating the structure of DNA. Biology was now an informational science, but the faculty was trained in the older, mainly observational, aspects of biology. How could I, and a small band of likeminded Swarthmoreans, prepare ourselves for working in the ever-changing world of research that was opening in front of us? The seminars provided the venues, and we took matters into our own hands.

Later I made the fateful decision to start my career working on RNA of animal viruses. I began by examining these relatively simple creatures, which led to the study of cancer, and then built up to research into the adaptive immune system of the mouse. In this trajectory, I tested what could be learned by focusing on nucleic acid enzymology. What convinced me to take on working on the mouse, was the increasingly powerful technology that came from investigators itching to solve some burning questions of their own. In 1975 this resulted in recombinant DNA technology, and that was the apotheosis I had been waiting for. We already knew that the secret of the adaptive immune system was that it scrambled segments of DNA. It seemed evident that the recombinant DNA methods would allow us to answer the questions about how this occurred, and I set out to guide my laboratory in that direction. Thanks to willing post-docs, we did what it took to pivot the laboratory, then located in the MIT Center for Cancer Research, towards immunology. And thanks to two students, we narrowed the focus to a question about enzymology; about how the segments of DNA were put together. They found the RAG genes that encode the enzyme proteins that do the job. We went on to lay out the pathway that a cell takes as it matures from a committed B cell to a functional B cell. The key was transcription factors. The one we stayed with, NF-κB, has proved central to understanding inflammation.

It has been a great ride over the 65-plus years since I was at Jackson Lab. I am most grateful to the many trainees who have contributed to the ride and who deserve to share in this award. Science is a great force in society because, messy as the process is, it finds the truths that underlay the phenomenology of our experience. Nowhere is that more evident than in the history of molecular biology over the last seven decades, and it has been a blessing to be able to play a role in the unfolding story.

2021 Special Achievement Award video

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