How does the immune system work? How does it distinguish between friend and foe—the foreign structures worthy of attack, and the healthy tissues to leave alone? What makes the immune system go haywire and start attacking healthy nerve tissue, causing autoimmune diseases like multiple sclerosis? How does the immune system retain a “memory” to recognize and attack invaders years after an initial exposure?
Nobody really knew.
After working to answer these questions as a graduate student in the 1960s, Hood developed into a leading immunologist over the next two decades—before he became known as the man with the gene machine. “Lee was unquestionably the preeminent molecular immunologist in the world,” said Perlmutter, now president of Merck Research Laboratories. Mark Davis, a former student of Hood’s who himself became a leading immunologist at Stanford, agreed. “Lee was the absolute intellectual leader of immunology from the ’70s through the ’80s,” Davis said.
It was on this work that Hood competed for the top prize in science: the Nobel.
When Hood was a graduate student in the 1960s, his chosen field of immunology was full of mystery. Scientists were groping in the dark, unsure how best to gather data even to start tackling the hard problems. Yet there was action to be had in immunology. The decade before Hood dedicated himself to the field, Jonas Salk developed a vaccine against polio, a disease that crippled and killed young people. This was among the great triumphs of twentieth-century science. Vaccines worked, increasing life expectancy and quality of life. Scientists just didn’t know why they worked, and why some experimental vaccines didn’t provoke an immune response at all.
But it was clear that studying immunology promised significant payoffs for both health and medicine. Millions of people suffered from chronic and debilitating autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and lupus. A deeper understanding of immunology could pave the way for new and better vaccines, new and better drugs. It could improve surgery success rates, because doctors would know how to prevent the body from rejecting transplanted hearts, kidneys, or bone marrow. Especially optimistic researchers went further: Could you “teach” the immune system to turn its killing firepower toward cancer cells, seeking and destroying them just like an invading virus? The research questions were so ambitious that some scientists thought they might never be answerable. The tools to tackle them didn’t exist. Neither did formal departments of immunology at most universities. The jargon of immunology was so thick, it intimidated many people in other biological disciplines.
But Hood could easily foresee an entire career’s worth of grand adventures in immunology. One of his heroes at Caltech, Ray Owen, had done pioneering work in cattle twins that laid the foundation for the concept of “immune tolerance.” Owen was a postdoctoral fellow at the University of Wisconsin in the mid-1940s—the “dark ages” of immunology, as geneticist James Crow later wrote. Owen raised the provocative possibility that the immune system was able to distinguish between foreign invaders to kill and healthy tissue to leave alone, or “tolerate.” Owen’s original manuscript was never published. A short version published in 1945 drew little notice at first, Crow wrote. But progress in immunology soon followed. Like any field of science, success begat more success. Ambitious young scientists like Hood were attracted. He had an opportunity to work with one of the founding fathers of the field. And Owen happened to be a kind soul willing to help students in need of career guidance. Hood was in.
But one couldn’t just dive into the grandiose problems of immunology. Scientists of Hood’s generation realized they first needed an intimate understanding of the structure and function of proteins—the molecules that carry out a lot of basic immune functions. Among the most interesting warrior molecules: antibodies. Antibodies are Y-shaped proteins, secreted by B cells, a type of white blood cell that comes from the bone marrow. Antibodies were fascinating because they appeared to act like heat-seeking missiles against invading pathogens. Each unique pathogen requires a distinct antibody to destroy it. The human body has a finite list of tens of thousands of genes, yet a seemingly unlimited capacity to produce antibodies—billions of them—exquisitely tailored to their killing task. Scientists had some working theories on how this was possible. But mostly they were stumped.
One working hypothesis was that the B cells became genetically altered after conception, in response to a person’s environment. The key to antibody diversity, the thinking went, was through these post-conception DNA alterations, otherwise known as “somatic mutations.” Another working idea was that B cells—some with genes inherited from the mother, and some with genes inherited from the father—swapped DNA with each other as needed and then reshuffled it to form the components of antibodies. These were “germ-line” mutations. “Just as you have 26 letters in the alphabet forming whole libraries of books, or 52 playing cards making up innumerable poker hands,” the cell’s ability to shuffle genes explains how the immune system can mount such an amazingly diversified antibody defense, as Dr. Thomas Waldmann, chief of the metabolism branch of the National Cancer Institute, later explained it in the Washington Post. As a graduate student under Dreyer, Hood helped refine this hypothesis. He worked on showing that two genes could rearrange their DNA to provide instructions for making a novel protein, though he wasn’t the first to definitively prove it. The idea (“two genes, one polypeptide”) challenged decades of dogma that said only one gene is responsible for carrying the instructions for making a distinct protein (“one gene, one protein”). The answer eluded scientists for many years, in part because antibodies are large, complex molecules with subunits made of long peptide chains. These peptides came in a couple varieties, known roughly as “heavy chains” and “light chains,” which come together to give the Y-shaped antibody its structure. Both chains had variable regions, found on the tips of the Y-shaped molecule, and these are the parts that bind with antigens. They were obviously important. It wasn’t obvious, beyond that, where to look for clues to the source of antibody diversity
This mysterious source of antibody diversity continued to fascinate Hood in the early part of his career on the Caltech faculty. Technology was improving in the 1970s, with the advent of manual DNA sequencing methods developed by Fred Sanger and Wally Gilbert, but progress was still slow for Hood’s taste. Lacking bulletproof data, Hood equivocated in a 1978 paper published in Nature. It was titled “Rearrangement of Genetic Information May Produce Immunoglobulin Diversity.” That wasn’t very satisfying. Hard, convincing evidence was necessary to win over skeptical peers.
Hood’s drive to develop the automated protein sequencer, and later instruments like the automated DNA sequencer, were influenced in part by this problem. He understood what could be done with powerful new tools that could throw off large volumes of experimental data. Rather than defensively dig in his heels, like many protein-focused biologists did in the 1970s, Hood was savvy enough to see where the action was heading. He knew he would have to break out of his comfort zone and embrace the new DNA-based molecular biology, or else risk falling into irrelevance. Linking DNA and proteins together—truly connecting the dots—would give rise to a more unified view of biology. Hood’s deep knowledge of immunology and of biology’s big unanswered questions are what enabled him to direct the way new automated protein and DNA sequencing machines should work.
The instruments that resulted were such a significant advance in the field of genomics that people eventually would forget Hood’s reputation as an immunologist. He couldn’t build the machines himself, but that didn’t really matter. As Mike Hunkapiller, the leader on the technology side of the Hood lab, put it:
He wasn’t, and still isn’t, a technologist, despite the reputation. That’s not what he did. His chemistry skills were not that good, in a sense. His experimental skills, I don’t think, were that good. He wasn’t necessarily that close to the details, the practical ways, to get things done. But that’s OK. [He] could bring people in who got the vision, and he could [provide] the guidance to help nudge along what needs to be done. . . .
There wasn’t a history at that point of building automated technology to help solve these problems. Lee’s genius early on was in figuring out that we not only need to deal with the qualitative aspects, in getting enough sample to run an experiment, but we’re going to need to generate a lot of data to solve some of these problems. It wasn’t something that was going to be scalable with just more pairs of hands.
Hood wasn’t the only one thinking about the new tools of biology, and how they might be used to answer the questions about antibody diversity. Through the mid- to late 1970s, it came down to a three-horse race. There was Hood’s team at Caltech, Phil Leder’s team at the NIH, and Susumu Tonegawa’s team at the Basel Institute for Immunology in Switzerland. Each was working independently on different pieces of the puzzle. “Lee Hood wanted to win the Nobel Prize for sure. He worked like hell,” said Bill Dreyer, the Caltech professor, in a 1999 oral history interview. “He had [to do] more and more work on antibodies to build up his image in the field. And he did—he did superb work. This is a wonderful thing, that people are this way.”
Tonegawa wanted the prize, too. Like Hood, Tonegawa had a prodigious work ethic. Members of the Hood lab were fearful of the Japanese scientist they saw as a “samurai warrior.” Apparently, Tonegawa told his first wife they couldn’t have children because it would be a distraction from science. He worked all night and expected his colleagues to do the same.
Besides his drive and intellect, Tonegawa had an advantage the others couldn’t match: location. The United States had banned the use of an important technique, and Tonegawa wasn’t working in the United States. Early recombinant DNA techniques in the mid- to late 1970s created thrilling possibilities—along with ethical concerns. The techniques made it possible to splice DNA from one organism, like a human, insert it into a host cell, like a bacterium, and produce many copies of a functioning human protein. Fears that scientists might end up introducing a cancer-like virus in people led to a moratorium for a couple years, which stalled work in the United States.
No such moratorium existed in Switzerland. The recombinant DNA techniques were precisely what Tonegawa needed to get a jump on the long-standing question about the source of antibody diversity. “He was the smartest of all,” Dreyer recalled in his oral history. “You couldn’t use those tools yet in this country—they were banned—but he went to Switzerland.”
The race was on. Given the importance of antibodies, the scientist who could pin down the source would probably win the big prizes.
The Albert Lasker Basic Medical Research Award was one of the biggest. It’s sometimes called the “American Nobel.” The prize, first granted in 1946, is announced each September. Enough time must pass that a scientist’s contribution can be considered in the proper context. Hood was nominated in 1987.
Hood was excited. At age forty-eight, this would be the most prestigious award of his career. Just as enticing, the winner of the Lasker would be first in line for the Nobel Prize. A total of eighty-six Lasker Laureates have gone on to receive the Nobel.
When the judges’ decision came down, Hood, Leder, and Tonegawa all shared the Lasker Award. Sharing the prize, then and now, was a common way for big prizes to honor the contributions of several scientists without going into the convoluted and often controversial business of determining whose work was truly first, and whose was most important.
The gene-swapping theory turned out to be correct. The theory of somatic mutations—in which antibodies took advantage of DNA variations in response to environmental stimuli after conception—was partly correct, too. “The real answer turned out to be a hybrid of both,” Hood said. Antibody diversity had been solved.
Tonegawa’s tour de force was unmistakable. He took advantage of some of new manual techniques for DNA sequencing and analysis. “In one crucial experiment, Dr. Tonegawa determined the genetic mechanism of antibody diversity and showed that new genes are created through rearrangement of DNA during B-cell differentiation. In further research, Dr. Tonegawa confirmed and determined the details of his discovery by cloning and sequencing antibody genes,” the Lasker Foundation wrote. Years earlier, Bill Dreyer and his plucky graduate student Lee Hood had developed and refined a theory, which is critically important, but Tonegawa had confirmed it with hard data.
Leder was honored by the Lasker jury for “a stunning series of experiments” finding that when antibody-producing B cells perform their genetic rearrangement, it can sometimes lead to a disturbance in the regulation of cell division, giving rise to cancer.
The jury cited Hood for documenting “in elegant detail the immune system’s method of rearranging pre-existing sequences of DNA to make the genes for each new antibody.” As the Washington Post later put it, Hood and Leder “proved that the genes containing instructions for the protein chains that make up an antibody are spliced and shuffled as a B-cell develops, much as a railroad controller uncouples and recouples the cars of a freight train.” The Hood team used molecular biology techniques to study the components—both the “light chain” and the “heavy chain”—that come together to make up antibodies. In describing what happened in the heavy chain, the team found an additional variable that contributes to antibody diversity, according to the Lasker Award jury. Tonegawa had been first and did crucial work on the more complicated genetic rearrangement that occurred in antibody light chains. But that wasn’t the whole story. On the antibody heavy chains, Mark Davis said, “we really made a killing.”
Hood was more than ready to take a victory lap. He flew to New York to accept the award. Eran, then attending Harvard, joined the celebration.
Back at Caltech, the Hood lab was buzzing with speculation. The boss was rumored to be a Nobel contender. If he won, they would all, by extension, bask in some of the glow that makes scientific careers. Which of the three labs had made the most important contribution? It didn’t matter. The Nobel Prize can be shared by as many as three scientists in a given year. Since Hood, Tonegawa, and Leder shared the Lasker, they all could soon be jetting off to Stockholm.
Hood was ready for the fabled early-morning phone call in October 1987. But the phone didn’t ring. While visiting Bell Labs on the East Coast, Hood got the bad news. Tonegawa, alone, had captured the Nobel Prize in Physiology or Medicine. It was only the second time in more than twenty-five years that the committee gave the award to a lone recipient. The Nobel committee citation said Tonegawa “completely dominated this area of research” from 1976 to 1978. “If you are given the Nobel Prize alone, what higher tribute can you be paid?” the immunologist Hans Wigzell of the Karolinska Institute in Sweden told reporters. Wigzell was a member of the Nobel committee that year, and given his expertise in immunology, he was surely an influential voice in the deliberations. When reporters asked Leder and Hood whether they had been unfairly snubbed, both were diplomatic. Both men, in separate interviews, told the New York Times that Tonegawa’s prize was well deserved.
Years later, Hood called the loss “the most disappointing moment in my life to that point.”
Each side had a legitimate argument. And, as with many major prizes—including the Academy Awards, football’s Heisman Trophy and journalism’s Pulitzer Prizes—there’s a long history of behind-the-scenes campaigning and controversy surrounding the biggest award in science. Hood said he never found out why he lost. “The wife of a friend who was on one of the Nobel committees told me at the time that I should have more actively campaigned, and that perhaps would have changed the outcome,” Hood said.
Hood wasn’t that naïve about Nobel Prize politics. It was common knowledge that publishing groundbreaking papers and hosting stimulating seminars were just part of a winning prize campaign. It was also important to find one’s way to Sweden, off the beaten scientific track, and give stirring lectures there. Once the antibody diversity work had wrapped up in the early 1980s, postdoc Mitchell Kronenberg recalled, Hood “made more than the expected number of trips to Sweden.”
Why did Hood fall short? Years later, Wigzell offered some perspective. An immunologist about the same age as Hood, Wigzell said he recalled having “several very early discussions” with Hood about how the immune system recognizes invading antigens while at a Cold Spring Harbor symposium in the late 1960s. “Lee has made several very nice contributions to the question of especially B-cell cognition/recognition of antigen. I remember . . . Lee being profoundly excited via Dreyer’s thoughts.” So that much was clear to Wigzell: Dreyer had the crucial insight that genes might reshuffle their information to form antibodies. Hood, as a graduate student, discussed and refined this theory with his adviser and later, as an independent investigator, ran experiments that shed light on parts of the antibody diversity mystery. His instruments made it possible to drill deeper into fundamental questions of molecular immunology. But Nobel Prizes, at least in the physiology-or-medicine category, typically are not given for inventing technologies. “One important thing to note . . . that is sometimes not given due weight, is that the [Nobel Prize in Medicine] should be given for a DISCOVERY whereas for instance for Chemistry it could be an IMPROVEMENT,” Wigzell wrote to me in 2014.
So if the Nobel Prize for Medicine is discovery-driven, not technology-driven, then the only realistic way Hood could win was for the quality of the results from his experiments in immunology. Looking back, Wigzell said:
It is of course now quite clear that molecular biology tools were drivers in the development of a deeper understanding in immunology. Here, Lee was instrumental in . . . understanding the way biology would move, thus putting great force into the development of pioneering instruments for protein and DNA sequencing and synthesis. This may be his most important contribution to science.
Being an immunologist by training, Lee was also then quite successful in the analysis of the various key molecules in the mammalian immune system, [including] the immunoglobulin molecules and their functions in the immune recognition and specificity. Relatively speaking, his contribution here is truly excellent. But maybe not as equal in consequence to the development of medical science as the technological achievements.
Many other accomplished scientists and inventors never had their moment of glory in Stockholm. Thomas Edison, inventor of the lightbulb; Tim Berners-Lee, pioneer of the World Wide Web; and Stephen Hawking, the physicist who explained the death of black holes, are among the illustrious people who never got the Nobel.
Tim Hunkapiller recalls having dinner with Hood after he flew back to Pasadena. “It was the only time he was shocked at how disappointed he was,” Hunkapiller said. “He didn’t anticipate it affecting him.” Not long after, he was philosophical about it. During a long drive to a scientific retreat, Roger Perlmutter said, “I remember him saying, ‘I didn’t get into this business to win prizes.’” Still, Hood couldn’t help feeling snubbed. “He felt he deserved it, it had been an important problem, and he made seminal contributions,” Perlmutter said. The Hood team respected Tonegawa’s rightful claim to a Nobel. But many thought that he shouldn’t have gotten the prize all by himself.
Antibody diversity was solved. The next great race was on. Two even more mysterious areas of immunology beckoned: T cells and the MHC. T cells, in their various subtypes, performed essential roles in the immune system’s orchestra. The MHC—the major histocompatibility complex—was a series of molecules that bind to the surface of an antigen and display bits of its proteins so that certain T cells can recognize the pathogen for attack. They act sort of like matadors waving bits of red flag in front of charging bulls. Scientists discovered a phenomenon called MHC restriction; it governed when the immune system could recognize a foreign antigen. If you could control that, you could control whether the immune system recognized and rejected an organ transplant. With that, scientists had a richer picture of the immune system. Antibody diversity was only part of the story. If you really wanted to know how the body develops an immune repertoire, then you also had to know how T cells form receptors on their surface that bind with invading antigens.
By the mid-1980s, the Hood team had plowed through the complex genetic underpinnings of antibody diversity, the T cell receptor, and the MHC.
Research on antibody diversity and the MHC was “absolutely pathbreaking,” said Ellen Rothenberg, who became a longtime Caltech faculty member. Irv Weissman called the work, along with the development of the automated DNA sequencer, one of the central achievements of Hood’s career.
Taken together, this work created a deeper understanding of what is now known as the “adaptive immune system.” This system provides the body’s repertoire for learning to fight antigens and remembering how to fight invaders it has seen before. The idea is essentially this: the immune system, through complex genetic rearrangements, evolves to keep up with the relentless and rapid onslaught of invaders that display all kinds of complex structures: microbes, chemicals, and even insurgent cancer cells. Seeing the immune system adapt quickly to stimuli forced many scientists to think deeply about evolution.
Hood remembers this time as a “golden era,” when he was at the peak of his career. He had recruited a cast of young stars in immunology and technology, and they were advancing quickly on both fronts.
Science, of course, isn’t about one triumphant discovery after another. There are a lot of dead ends.
Michael Steinmetz was familiar with that harsh reality. He was Hood’s point man overseeing fast-moving work on the genetics of the MHC. Steinmetz’s team focused on sequencing a genetic region known as the I-J locus, which was widely believed to hold the code that gave T cells their ability to recognize specific pathogens. Labs all around the world were forming hypotheses, gathering data, and refining their hypotheses as part of this quest. Intense scrutiny was being applied to this specific zip code of sorts on the genome. Mark Davis recalls what happened next:
There was this very well-defined locus, called I-J. It was supposed to be there in the middle of the MHC, and was the key to a lot of work on T cells. [Steinmetz’s crew] raced through and found nothing. . . . It was a huge psychological shock to the whole field of immunology. They put a lot of effort into it, because they thought this was going to be it. Then it went away.
Knowing where the code wasn’t was useful, certainly. But where was it? Finding out was important, because then researchers could start to look at commonalities and abnormalities in the code that might provide valuable clues for medicine. “The identification of the complementary DNA encoding these chains was the real Holy Grail yet to be found,” wrote Arthur Weiss, a UC San Francisco researcher, in a 2005 review article. Labs all over the world were pouring millions of dollars into this quest, throwing lots of eager young people at the problem.
Mark Davis was one. As a grad student at Caltech in the ’70s, Davis chafed under his first adviser, Eric Davidson. Looking for a fresh start in 1977, he sought out Lee Hood. The two were a good match. Davis thrived on autonomy. Hood needed self-starters. Hood’s expertise was still confined mostly to protein molecules. Davis had a growing set of skills in nucleic acids—DNA and RNA. Davis’s skills improved, aided in part by the technical chops Caltech imported when Tom Maniatis, a pioneer in gene isolation and cloning, joined the faculty in 1977. Under Hood, Davis finished his PhD work by the end of 1980 and took a postdoctoral fellowship at the NIH. He was poised to apply his genetic engineering skills to the T cell receptor problem.
The theory was that, like antibodies, T cells rearrange genetic material to form receptors that could bind with invading antigens. T cells have thousands of these receptors on their surface. But none was available in large quantities. That made it hard to get enough data to prove the theory with statistical confidence. Davis knew, from his graduate school days working for Hood, that getting the DNA code was going to be essential to getting that Holy Grail.
This was such a hot area of science that Stanford offered a faculty job to Davis in 1983. Until then, he was just a young investigator with a small team at the NIH. But he had devised a novel approach using mice to find the genetic basis for the T cell receptor.
Word began circulating that Davis was onto something big. He began to hear competitive footsteps. Davis learned through the grapevine that Hood was mobilizing resources to beat him in the T cell receptor race. It was not unprecedented in the rough-and-tumble scientific world, for a thesis adviser to try to chase down a former student. But it was unusual. More common would be to give encouragement or attempt to form a partnership. Hood did neither.
Davis thought he had a comfortable lead. He knew that Hood’s lab didn’t have his level of expertise in DNA or his novel method. But he also knew he had fewer resources than Hood, with the limited budget of a newbie, and he couldn’t afford to be complacent. He needed to establish himself as the leader in the field. So in August 1983 at a scientific conference in Kyoto, Japan, he rather brazenly declared—without showing hard data—that he had done it: isolated a messenger RNA that encoded a component of the mouse T cell receptor. What Davis didn’t know was that an obscure researcher at the University of Toronto named Tak Mak was working on the same problem, having come across what he believed to be vital DNA code for making the T cell receptor in human cells. Mak was shocked to hear word of Davis’s presentation in Kyoto. “We were jolted out of our complacency and naïveté,” Mak recalled. He put a second graduate student on his project. Speculation mounted about who had done what. A month or so after Davis gave his talk, Mak called Davis and said he had identified the T cell receptor’s beta chain in human cells. He asked how they might work together. Davis remembered the conversation this way:
I asked, “Does it rearrange?” He said, “I don’t know.” I thought, “Who is this guy? Is this some kind of crank caller?” I thought I was being generous. I said, “If you send me your sequence, I can tell you if it’s the same as ours. He said, “I was thinking you could send me your sequence.” I said, “No dice.”
Davis hung up, wondering whether Mak was bluffing. By December, Davis couldn’t ignore the gossip: Mak was onto something, and he had enlisted the formidable Hood lab as a partner to extend on his initial findings. Then, in January 1984, Irv Weissman asked Davis whether he had submitted his T cell receptor paper to a scientific journal yet. “I’m still fussing with it,” Davis replied. He had wanted to make a grand splash with two papers at once. The exacting brand of scientific perfectionism required for such a tour de force had its merits, but it could also be slow. Lee Hood could eat slow scientists for breakfast. Weissman gave his Stanford colleague a warning: “Now is not the time to get writer’s cramp,” he said.
Davis felt stung. He hadn’t been personally close to his former adviser, but he had done good work for the boss. He didn’t see this coming. Instead of staying out of it and letting Davis have his day in the sun, Hood had partnered with a rival. Was Hood really so fixated on getting wins that he was willing to crush a former student’s career along the way? Hood already had a reputation for picking up ideas from others, assimilating them into his efficient lab, improving them, and gaining the competitive advantage. He sometimes told people in his lab that he didn’t care where the good ideas came from, he just wanted them all. Some joked (or complained) that the Hood lab operated like the Borg alien race from Star Trek: The Next Generation. Their famous line: “We are the Borg. Lower your shields and surrender your ships. We will add your biological and technological distinctiveness to our own. Your culture will adapt to service us. Resistance is futile.”
Loyalists to the Hood lab scoffed at such notions. Davis was hypersensitive about ordinary scientific competition, they said. But even decades later, Davis remembered how rattled he was at the time. Fear of being scooped by the all-powerful Hood, real or imagined, drove him. This was a career-making discovery for a young scientist. He couldn’t afford to finish second. “What’s striking to me is that people would say things like, ‘I hear Lee is getting into this T cell receptor work; what are you going to do now, Mark?’” Davis said in a 2013 interview. “They thought I didn’t have a chance.”
He rushed to finish his two papers by February 1984. He drove them to a DHL office at the airport. He arranged to have a courier pick up the envelope at London’s Heathrow Airport and whisk it to the offices of Nature, the top scientific journal. Eight days later, Davis got a call from an editor. His papers had been accepted. It was an astonishingly quick turnaround; publication typically takes a couple of months as editors wait for peer-reviewed comments and revisions.
Davis showed that T cell receptors have genes for variable, constant, and joining regions—quite similar to the genes that provide the code for making antibodies. It was a critical finding that established how T cell receptors recognize and combat invaders. The same March 8, 1984, issue of Nature also published Mak’s work on the T cell receptor. The editors had been holding Mak’s paper—which contributed key knowledge about human cells—since November. The trio of publications in the same issue from two independent labs made a convincing case.
The discoveries skyrocketed Davis and Mak to international acclaim. Hood’s name didn’t appear on that seminal batch of T cell papers, since Mak had completed the work before his partnership with Hood. But between June and September 1984, Hood and Mak coauthored five papers on T cell receptor genetics in mice and humans, published in Cell and Nature. Davis couldn’t rest. He published five more papers in Nature that year as well. “It was over the top. Lee is famously competitive,” Davis later told the Wall Street Journal. For at least the next three years, Hood’s team on the T cell receptor, led by Mitchell Kronenberg, continued experiments to answer remaining questions. Kronenberg doesn’t recall Hood ever openly expressing a desire to “crush” Davis, despite rumors to the contrary.
Hood’s collaboration with Mak was brief. The agreement was that Mak would work on human cells and Hood would stick to mice. But Hood wasn’t the type to stay in a small sandbox for long. His aggressiveness made many collaborators leery. “He already had a reputation of being someone who would take everything you’ve got and then say ‘See you later.’ He wasn’t looking for a long-term relationship. You might be a coauthor on the paper, if you were lucky,” Davis said.
What’s the old line about nice guys finishing last? After all, many top scientists got to the top because of their sharp elbows. James Watson, the co-discoverer of the DNA double helix, was famously fearful of Linus Pauling and dismissive in his treatment of Rosalind Franklin, a collaborator. As Davis said, “I don’t think it’s the first time it’s ever happened in the universe, but it’s unusual . . . especially when it was your own student.”
The work on T cell receptors had been laborious. DNA sequencing in the mid-1980s was painstaking and prone to human error. One gene might be composed of a few hundred, or a few thousand, base chemical units of A, C, G, T in a unique signature. It might take a graduate student’s entire career to nail down the DNA sequence for just one gene. Sequencing the adrenaline receptor took a full decade. It reminded Hood of his graduate-school days, working on protein extraction and purification. But this was the leading edge. Hood started to turn his attention away from immunology. Some of the big questions had been answered; the others remained far beyond the reach of existing technologies. It was time to focus on a greener pasture: genomics.
For most of a decade, Hood had been dreaming about what he could do if he could sequence DNA with a truly high-speed, large-scale, automated set of instruments. Hood was eager for instruments to handle the drudge work of sequencing and for computers to crunch the data. Biologists would be able to ask bolder, broader, data-rich questions—to imagine hypotheses they never would have dreamed up before. The vision struck many as pure science fiction. The boldest idea was to obtain the first complete human genome, with its staggering row of six billion base chemical units of DNA. Some thought it would take a century.
Even Hood had his doubts about the Human Genome Project the first time he heard about it, in the mid-1980s. It didn’t take him long to change his tune. First, he just needed a better machine.