Book Summary: Hood, Trailblazer of the Genomic Age
“Hood“ is a sympathetic and clear-eyed biography of Leroy Hood, who played a crucial role in the biotechnology revolution by leading the development of several automated biological tools. He came close to winning a Nobel Prize with important work in immunology. He was the chairman of Biology at Caltech for a decade. Most of all, he brought teams of talented people together and inspired them.
His story starts as many eminent scientists do: early signs of intelligence, fascination with science, an influential high school mentor, and some success in the Westinghouse Talent Search. But Hood also had something else: an extreme and frankly superhuman level of energy, akin to Thomas Starzl (The Puzzle People) or Joshua Boger (of Vertex Pharmaceuticals, covered in The Billion Dollar Molecule). From his early teens he was a short sleeper, reading books late into the night and waking early to study. When he meets fellow winners of the Westinghouse competition (renamed Intel, and then Regeneron Talent Search), and later attends Caltech, he realizes that he was reasonably talented even by their standards, but not smart enough to coast.
When I met the fellow winners, I was a bit intimidated by how smart and broadly knowledgeable a lot of these people were. . . . After that, I knew I was good but wasn’t in the upper-upper echelon of really smart people. (Location 508)
Hood wasn't just a science-obsessed monomaniac. He becomes class president at Caltech while maintaining excellent grades. His most exceptional talent probably lies in the inspiration and management of other scientists. Through a combination of extreme personal productivity, ceaseless optimism that bordered on hypomania, and charisma, Hood eventually gathers a mini-department of postdocs and grad students under him, all in orbit around him.
But all that lies in his future. Hood attends medical school at Hopkins after Caltech, then gets his PHD back at Caltech. While in grad school, he works at the National Cancer Institute (NCI) for two years on immunology. There he grows his network, working alongside Tony Fauci (here is an interview between the two of them: very sharp for a pair of 80+ year-olds!) and others who later became the big names in their respective fields. This taste of federal bureaucracy is not to Hood's liking, and his dislike of its slow pace will be a recurring theme in his life.
Hood begins his career in immunology, focusing on the then-mysterious question of how the immune system generates precisely tailored antibodies to novel pathogens. The idea of somatic hypermutation, involving as it does the copying and moving of multiple genes, was somewhat heretical in the 1970's. Tonegawa eventually won the sole Nobel Prize for his work on this, but Hood's mentor, William Dreyer, along with Hood himself, did important work on this question as well.
The central idea that animates Hood after those early years is the idea of enabling inventions. Hood wants to make molecular biology quicker by automating the sheer drudgery of basic lab work.
Lee had a simply stated set of four goals: to enable the automated reading and writing of proteins and of DNA. His greatest contribution to biology was aggregating teams to accomplish these goals. (Location 92)
The idea of advancing biology by advancing technology is one that will sound familiar to any who have studied the history of biology and medicine from the 1980's onward. The biotech revolution which gave us synthetic insulin and many other drugs, and then later, very high throughput DNA sequencing and synthesis, was driven by the rapid improvement in biological technology, and Hood played a key role in that.
The prescience that Hood displayed by seeing that technology would transform biology is a recurring feature of his scientific career:
he had an uncanny ability to recognize a good, but raw, idea when he saw it. As he did many times throughout his career, Hood got on board with a promising original idea, and became an early and forceful advocate for (Location 999)
The other key feature is Hood's ability to lead large group of scientists. Back at Caltech, and as a newly minute associate professor, he immediately begins working at his usual frenetic pace. He meets several young gifted scientists at Caltech, whom he recruits to his lab. Hood's mentorship strategy is best described as "sink or swim", which alienates many graduate students, but some stick around, drawn by his vision and productivity. His big break after his immunology work is the automated protein sequencer, whose development he leads in the late 1970's and early 1980's, and which was subsequently commercialized by Applied Biosystems. One of the key people on that team, Michael Hunkapiller, later co-founded Celera (who raced the government to sequence the human genome), and other companies.
Hood's lab grows as his influence does: with ample funding from federal grants, an endowed chair at Caltech, and some outside money from donors, combined with a hands-off managerial style, Hood had the largest lab at Caltech by a large margin. He was an early TEDTalk-style science educator, traveling around the country to speak to graduate students at seminars to sell them on his vision-- and of course, build his network and recruit along the way. If he liked you, he'd ask you to join his lab, but you'd need to find your way there and elbow your way into some free lab space.
As usual, Hood hadn’t bothered to inform the lab about the new recruit. No space or supplies were set aside to help him get started. Like everyone else, Smith would have to sink or swim. As was often the case, a lab veteran would take pity on the newbie and offer a helping hand. In Smith’s case, that person was Joan Kobori. (Location 2478)
The sheer size of Hood's lab, along with his keen sense for especially talented postdocs and graduate students, makes his lab extraordinarily productive. Hood's talent for public speaking nets him private donor money, his early commercial success with the automated protein sequencer catches venture capitalists' attention, and his generosity with media engagements raises his own public profile.
Hood lab was growing at a startling rate. During just one year, 1988, the lab reported that it worked on an astonishing seventy-four research projects. The next biggest group, led by Davidson, had twenty-three projects. (Location 2918)
Hood's star in the 1980's was ascendant.
In 1980, at the ripe age of 42, Hood became the chairman of the biology department at Caltech, though he only agreed to the job with several conditions:
permission to skip all faculty senate meetings, (Location 1671)…He wanted additional money for the biology department, which he could dole out at his own discretion. Part of the money could be used to give raises to three lieutenants who would share the administrative burden. (Location 1665)
1980 was an important year for other reasons. The Bayh-Dole Act effectively liberated patents made with federal funding from federal control (with many caveats) and an important case, Diamond vs. Chakrabarty, permitted the patenting of living creatures (in that case, an engineered bacterium that could degrade crude oil). Both were big moments in biotech and in university involvement in industry more broadly.
After the automated protein sequencer, Hood dreamt of an automated DNA sequencer. Hood had helped start the company (Applied BioSystems, which had commercialized the automated protein sequencer) that sold the first DNA sequencer, but the biochemist Marvin Caruthers was more central to its invention. Still, this too raised his profile. Hood's lab also collaborated with Tak Wah Mak, and published several high-profile papers on the T-cell receptor, competing with a former grad student of his, Mark Davis, who was working on the same problem.
So the 1980's were a tremendously productive and busy time for Hood. However, the same strengths that made him so tremendously productive became liabilities in the late 1980's. Hood's distant mentorship style and openness to new students swelled his lab, but created pressures on students to be highly productive or risk losing his attention, which culminated in an episode of scientific fraud by Vipin Kumar, a rising star in his group. His vocal dislike of bureaucracy and procedure infuriated Caltech administrators who tried to coordinate their approaches to large donors. On a personal level, Hood's disregard for others' schedules turned many in the department against him.
As chairman, Hood called faculty meetings on short notice, whenever he happened to be in town. Members of the division often couldn’t attend and have their voices heard. (Location 2913)
During the late 1980's the Human Genome Project (HGP) was being conceptualized and debated by the leading scientists and administrators. Hood was an early proponent and organized a series of influential lectures on the ethics of the project, but never became a high-level administrator of it. Some of the ones who did, like Francis Collins and Eric Lander, would later become the most powerful science administrators in the US. Craig Venter, who had managed to outmaneuver Hood by having the first lab to have a working commercial version of the automated DNA sequencer, would eventually lead the private attempt to beat the HGP.
The Venter saga is another demonstration of Hood’s personality being an occasional liability. In short, Hood alienated many scientists by publicly claiming credit for inventing the automated DNA sequencer.
Hood’s grab for credit came with a price. It hurt his relationships at Applied Biosystems, and that created an opening for other scientists. One was J. Craig Venter. Then a little-known scientist at the National Institutes of Health …He decided he wanted the NIH to become the first test site for the Applied Biosystems commercial-grade DNA sequencer, (Location 2658)
To researchers, being the first test site is a coup: it means a crucial competitive advantage over peers. To instrument developers, choosing a beta tester is a critical strategic decision. Companies (Location 2660)
Given Hood’s years of effort in the field, his lab should have been at the top of the list. It wasn’t. His goodwill reservoir was depleted. (Location 2663)
Exit from Caltech
In 1987, Thomas Everhart became the new president of Caltech, and by 1989, had ousted Hood from his position as Chair. The ostensible reason was that a large grant Hood had just been awarded from the National Science Foundation prohibited him from having other administrative responsibilities, but it was really a coup by the biology department against him. To add to his stress, Hood spent much of the early 90’s reviewing the work of his grad students, trying to sniff out other episodes of scientific fraud. His research productivity suffered.
In 1992 his fortunes turned. A former star of Hood's lab, Roger Perlmutter, who had founded the Immunology department at the University of Washington (UW), came up with a plan to recruit Hood away from Caltech. Bill Gates, a Seattle native who had just became a young billionaire, was being wooed by UW as a donor. Hood was hosted at a series of guest lectures at UW where Gates was in attendance, and the two were fast friends:
Hood, fifty-two, and Gates, thirty-five, hit it off. The dinner stretched a full four hours. Gates and Hood found they could speak each other’s language…. (Location 3409) Hood said later: “I think my mind was made up very quickly after that dinner. Bill Gates was an interesting, intellectually challenging person. I’d never met anybody quite like him. There wasn’t anyone on the board at Caltech that was the same dynamic, driving, inquisitive, and intense kind of person. It was terrific. He just got things, and could get to the heart of the matter so quickly.” (Location 3418)
University of Washington
In 1992 Hood became the founding chair of the molecular biotechnology department at UW, as well as the first William H. Gates III chair. He brought 24 lab members from Caltech with him, and also recruited a number of big names in biology away from other institutions. Hood had a productive few years there, but state universities have stricter rules on funding than Caltech and UW (at least back then) had a less practiced technology transfer office. While Hood was friends with a number of university big-wigs, he repeated the mistakes he had made at Caltech of alienating ordinary faculty members and playing loose with funding rules. He also had two high-profile collaborations, one with Monsanto and one with philanthropist Michael Milken, publicly fail.
Institute of Systems Biology
So by 1999, at the ripe age of 61, Hood was ready to start his own private scientific institution. UW had entertained the idea of starting it within the university, but was unwilling to give it the autonomy that Hood desired. The Institute for Systems Biology was born. Unfortunately for Hood, while a number of excellent scientists had decided to join him, he was low on funds. Over the next five years he invested 25 million dollars into the Institute, money he had earned from various biotech stocks and awards over the years. The early 2000's were a mixed time for him:
Money wasn’t materializing, but the institute’s reputation and influence grew. They got papers published in scientific journals, slowly building a serious body of scientific work. They popularized the term “systems biology,” influencing fellow biologists to make it mainstream. (Location 4679).
150+ institutions or centers for systems biology sprung up around the world and lots of NIH money flowed to "systems biology", but his organization remained precariously funded, and Hood was constantly traveling to pitch to donors or countries.
An apparent turn in his fortunes was a 100 million dollar partnership with Luxembourg, but it turned sour when a co-founder at the institute, Alan Aderem, exited around then, along with other scientists.
Alan Aderem had had enough. Not only was he disturbed by the Luxembourg partnership, but he could clearly see that Hood—even at age seventy-two—wasn’t going anywhere. In 2011, Aderem accepted an offer to become the president of the nonprofit across the street: Seattle Biomedical Research Institute, later renamed the Center for Infectious Disease Research. (Location 4995)
The saving grace of Hood's institute was an unusual merger with a newly profitable (but still non-profit!) healthcare system in the Washington area, Providence. Because of Affordable Care Act provisions that started funding many uninsured patients, Providence, which had previously cared for those patients with charity care accounts, was unexpectedly rich in cash. At the same time, many hospital chains were merging, and in this new environment, were using partnerships with research institutions to fund-raise from donors and market themselves to the public. Thus, the ISB would give Providence a sheen of cutting-edge and Providence would supplement the ISB's funding and perhaps allow for more speculative research.
From a history of science perspective, a valuable insight from this book is the radically different funding and institutional environment of mid and late 20th century medicine.
When Hood was starting out, the average age of a first-time NIH grant winner was thirty-five. By 2004, it was forty-two, as federal funding flattened out and a larger pool of scientists had to compete for relatively small pieces of the pie. Many young scientists, especially those with families, found it hard to get started. (Location 1162)
Science Administrators are Older
Though I haven't looked at empirical data on this specifically, my impression is that scientists in Hood's time were obtaining leadership and administrative positions earlier in their careers than is typical nowadays. Hood becomes chairman of Caltech's biology department in his early 40's, whereas the last two chairman's of biology at Caltech took positions in their late 40's and early 50's, respectively. Along those lines, Tony Fauci, a contemporary of Hood's at the NCI, has been in the same role at the NIAID for 35 years, Francis Collins has been director of the NIH for 12 years, and was director of the National Human Genome Research Institute for 15 years before that. Both of those men entered very high-level administrator roles in their late 40's. That seems earlier than is typical nowadays, but I haven't looked at this in-depth.
Eric Lander, the soon-to-be science advisor to President Biden and director of the Broad Institute, is substantially younger than Fauci, Hood, and Collins, but similarly (or more as a cabinet-level position?) influential. Interestingly, instead of working his way up the federal bureaucracy, in 1990 he co-founded the Whitehead Institute/MIT Center for Genome Research (which later became the Broad), when he was only 33. He played a big part in the Human Genome Project as well. My speculation on this is that one of the few ways that a young scientific administrator can obtain very high-level leadership positions is either joining the field when its less established, and growing along with it, or making your own institution, parallel to already established groups.
Reducing Fraud is not costless
One of Hood's recurring complaints is that federal money comes with onerous reporting requirements. It makes me wonder about how much effort is spent by scientists ensuring they don't run afoul of "anti-fraud" laws or similarly well-intentioned but burdensome funding regulations. He often bypassed the traditional hiring requirements at the institutions he worked at so that he could more quickly hire talented postdocs, so that seems like another roadblock in academia. In addition, Hood complains about the unwillingness of federal grant reviewers to be more risk-tolerant and fund less incremental (and more paradigm-shifting) science.
Talented People are Rate-Limiting (?)
A more general theme is the apparent scarcity of highly effective science administrators. Before moving to UW, Hood was getting recruitment offers from many places:
Harvard asked Hood to apply for its presidency. Roche, the enormous health-care company, offered to increase his salary sevenfold. Monsanto beckoned with another lucrative bid for the Caltech star. Always, the answer was no. (Location 2887)
While someone like Hood, with his boundless energy and focus, is quite rare, I'm not sure that nearly as effective managers are that rare. My uninformed speculation on this is that a big filter is that of experience: without previous experience credibly demonstrating talent at science administration, risk-averse institutions won't take a risk on you. And yet, that experience is hard to come by for a younger and early-career scientist because mostly older scientists occupy those administrative roles.
The existence of young tech billionaires in executive and administrative roles (along with occasional standouts such as Eric Lander taking on science leadership roles in his 30's) demonstrates that young people are capable of successfully managing big groups of people in technical fields. I'm not sure how much an aging class of science administrators has to do with how risk-averse federal science funding is, but intuitively it seems related. Here is some data on how the average age of scientists at the time they do Nobel Prize winning work has increased.
Some random closing thoughts:
it is striking that when highly intelligent and motivated people meet each other, even when separated by ~17 years-- like Bill Gates and Leroy Hood-- they can become good friends quite quickly.
mentorship from influential scientists can really positively influence your early career, but since mentors are always searching for exceptionally talented students, selection effects are quite large, and it seems hard to measure what effect mentors have on success.
Bill Gates pivoting his philanthropy away from university donations and systems biology seems like an especially wise and moral decision in retrospect. It is not clear what practical results systems biology has yielded so far (of course, basic research has a huge time lag between discovery and application, so the story may change in another 10 years), but the Gates Foundation's work in developing countries has done a lot of good in the short and medium term. 4
the Matthew Effect seems important for explaining the careers of some highly prominent scientists. Early success gives you a good reputation, which gets you more opportunities, and people knocking down your door to collaborate with you.