Leroy Hood: Discovery Science

Biotech guru Leroy Hood leads researchers in a new direction

Mary Beth Gardiner
Published: February, 2003

Photo by Brian Smale
For his honeymoon, Leroy Hood planned to take his new wife on a 110-mile trek across five mountains. Eager to please, Valerie Logan strapped on her new backpack, a wedding gift from a friend, and fell in step beside him. By the end of the second day, they hadn’t reached the lake where they intended to camp before night began to fall. With only craggy ground as far as the eye could see, Hood made his decision: they would turn off-trail and head uphill, through the woods, to get to the campsite faster. They bushwhacked up the side of the mountain, struggling over rocks and past grasping branches as the darkness deepened.

Considering the events of the lifetime that has unfolded since that honeymoon trip, the decision made by the 24-year-old newlywed on the trail that summer night is vintage Lee Hood. The tenacity of this physician-scientist, called by some the father of biotechnology, is evident in a career marked by ground-breaking innovations in biological instrumentation and analysis, and by his bellwether efforts to shift responsibility for scientific discovery from individuals to cross-disciplinary, interactive groups.

Along the way he has directed a number of large and productive research labs; helped to found 11 companies, Applied Biosystems and Amgen being two of his earlier efforts; and patented a dozen inventions. Hood has co-authored more than 500 scientific articles and textbooks, and won numerous honors – among them the Lasker Award and Kyoto Prize, known, respectively, as the American and Japanese equivalents of the Nobel Prize.

His motivations often misunderstood, Hood’s maverick tendencies have won him both praise and criticism. His detractors see him as solely a technologist, one who has too closely aligned himself with the business world. His colleagues know him as a visionary, but also a realist—a practical man with a practical purpose.

Hood says the inspiration behind his fervor is simple. “I’m interested in making things better for the world.”

The hum of Hood’s ideas and values has reached a crescendo in the Institute for Systems Biology. This innovative research center, established two years ago in Seattle, Wash., is dedicated to the integration of biology, computation, and technology as a means of furthering the fundamental revolution that is taking place in medicine, the move toward predictive and preventive medicine.

Within 10 to 15 years, Hood forecasts, physicians will be able to predict a person’s predisposition for disease based on his or her genetic makeup. And not long after that, they will understand the biological networks within which the defective genes reside, and be able to block the harmful effects.

“The idea is that all the elements of a biological system can be defined and put into a database,” he says. “Sequencing the human genome and placing the sequence in a database is pure discovery science…, which raises the possibility of globally analyzing the behavior of all human genes in, for instance, normal cells versus cancer cells.”

Discovery science, Hood says, stands in contrast to hypothesis-driven science—the tried and true approach that has prevailed for years, where a hypothesis is formulated and experiments carried out to test that hypothesis.

Though his proposed interdisciplinary, systems approach to biological discovery is revolutionary, traditional hypothesis-driven methods have not been abandoned. Rather, they are embedded in the new approach, which advocates figuring out what happens normally within a system—a signaling pathway in a cell, for example—then disrupting that system repeatedly, making note of what changes occur. If you know how the system can break down, Hood says, you should be able to figure out how to fix it.

“Biology is infinitely complicated, so what you have to do is use hypotheses to shed light on global studies of very selected aspects of complexity. Then you can start to sort out what it’s about.”
Leroy Hood, M.D., Ph.D.
Photo by Brian Smale
Supported by both private and public funding, the non-profit institute currently has a staff of 180 employees—about half the ultimate goal—and is engaged in 10 industrial and three academic partnerships. The nine faculty members run the gamut from astrophysicist to immunologist to mathematician to protein chemist to computer scientist, all learning how to speak each other’s language and apply their tools to understanding biology’s complexity.

“At first blush, they all think biology’s easy, and that they all have the ways to help us out,” says Hood. “But in most instances, they are useful only in direct proportion to how well they understand biology.

“These people can develop techniques and computational tools, but the development has to be driven by biological frontiers. There are all sorts of fancy tools that let you measure things, but who cares if the things aren’t relevant? You have to figure out how to measure important things rather than measure anything.”

Hood’s unique take on how technology supports biological discovery is not always well appreciated, especially in academic circles, says George Lake, a founding faculty member at the institute and astrophysicist who is applying his expertise to the study of biological networks and the role of retroviruses in evolution.

“If you’re a technologist at a university, that’s a tough position to be in,” Lake says. “There are very few people with the deep scientific insight that (Hood) has got who so embrace technology.”

Nature as teacher

Hood developed a deep connection to the natural world in his youth. Born in 1938 in Missoula, Montana, a town split by a rapidly flowing river and lying at the convergence of two forested mountain ranges, he began roaming the woods before the age of six, and camping by himself shortly thereafter.

Summers spent at his grandfather’s ranch in the Beartooth Mountains of southwestern Montana shaped his character and his destiny. Hood was the son his grandfather had never had, and from the man, Hood says, he learned “the power of love, commitment and friendship.” On the ranch he learned to ride horses, tend the animals, and climb the rugged mountains, further bolstering his confidence and independence.

Because his high school was small, Hood was able to explore a ragbag of activities, from music to acting to debate to sports. Football’s camaraderie and rough-and-tumble held particular appeal for him.

Another highlight was the chance meeting of Valerie Logan, the woman who would one day become his wife. They lived in neighboring towns, and met at a state speech, debate, and drama meet in the spring of their junior year. They would date, off-and-on, in a cross-country courtship that lasted seven years.

Navigating Montana’s rocky terrain as a child spawned in Hood an enduring love for mountaineering that has since carried him across countless peaks, including the Sierra Nevada Mountains in California (left) and the Swiss Alps (right).
Photos courtesy Leroy Hood, M.D., Ph.D.
Hood excelled in mathematics and science. During his junior and senior years, he took courses in his grandfather’s geology camp, a summer program attended by students and faculty members from a number of Ivy League universities, and was a field assistant for several geology mapping projects in the nearby mountains. One of these projects was the basis of his Westinghouse Science Talent award, the first ever from Montana.

By his senior year, his science teacher, Cliff Olson, asked him to take over the biology classes, which he did, gleaning his lesson plans from issues of Scientific American.

“I enjoyed getting the sophomores excited about biology,” Hood says, “and more importantly, I learned enough to begin to see the enormous potential of biology in the future. I remember being fascinated by one article on the structure of DNA, discovered just three years earlier in 1953. I came away convinced I wanted to go into biology.”

Hood had been leaning heavily toward a liberal arts college in Minnesota. But Olson convinced him to attend his alma mater, the California Institute of Technology (Caltech), because of its elite faculty and students and its outstanding research reputation. After graduation in 1960, Hood went on to medical school at Johns Hopkins University in Baltimore, Md., to get more background in human biology.

“I found it staggering how little we really understood about human biology,” he says. “I remember asking a pediatric intern, a resident, and then a visiting professor, in that order, what caused diarrhea. Each could list organisms and diseases that did so, but could not speak to the pathophysiological mechanisms. It was a descriptive view of biology that was quite different from what I was used to.”

Having developed a keen interest in immunology, Hood returned to Caltech to work with biology professor William Dreyer on theories of antibody diversity. Their work advanced the idea—radical at the time—that antibody chains were encoded by two distinct genes, which became physically rearranged during maturation of antibody-producing immune cells. The theory helped explain the tremendous adaptability of the body’s immune system to a wide range of infectious assaults.

“By my second year of graduate school, I was giving lectures at universities and national meetings,” Hood says. “The general reaction of the scientific community to the two gene/one polypeptide hypothesis was skepticism and even reprobation. I realized for the first time how threatening new ideas are to many scientists.”

Dreyer’s mentorship was pivotal, inspiring conceptual thinking and creativity in his protégé, and providing the two pieces of advice that have colored all of Hood’s subsequent scientific efforts: One, always practice biology at the leading edge, and two, if you really want to change the field, invent new technologies to push the frontiers of biological knowledge.

Hood and Logan married while he was in graduate school. After earning a Ph.D. in biochemistry, Hood served a three-year stint in the Public Health Service, pursuing his research on antibody diversity at the Immunology Branch of the National Cancer Institute. But by far his most memorable experiences during those years, he says, were the births of his son, Eran, and his daughter, Marqui.

A new view of technology

“One of the most important roles of a mentor is to create unbounded environments where people can move in any direction they want, and to give them a problem that is unbounded and will challenge them. Then, just let them do it.”
Leroy Hood, M.D., Ph.D.
Photo by Brian Smale
In 1970, Hood returned to Caltech again, this time as a member of the faculty, his mentor’s imperatives ringing as loudly in his ears as ever. “I went to Caltech with a commitment to split my time between biology and technology,” he says. “The idea was that biology should drive the choice of the technology developed, and that the technology should lift barriers to the deciphering of important biological information.”

Over the next 20 years, Hood’s lab would develop four instruments—a protein sequencer and synthesizer, as well as a DNA sequencer and synthesizer—that allowed scientists to move readily from a protein sequence to its gene sequence and vice versa, and allowed for the synthesis of genes and fragments of proteins.

This suite of four instruments formed the technological foundation of modern molecular biology, opening the door for many new and powerful strategies, including the polymerase chain reaction (PCR). The lab’s work on the automation of DNA sequencing contributed directly to the planning and realization of the Human Genome Project.

The discoveries that were enabled by the protein sequencer in the early 1980s led to a number of key disease-related breakthroughs, including the treatment of chronic anemia with erythropoietin and the implication of prion proteins in mad cow disease and its human variant, Creutzfeldt-Jakob disease.

Hood’s own research was expedited by the technologies developed in his lab, which allowed him to move from an analysis of antibody proteins to an analysis of antibody genes. The combined efforts of Hood’s lab and the laboratories of Susumu Tonegawa and Philip Leder established that the two gene/one protein theory was correct, that there were many antibody genes in our DNA, and that the genes were capable of undergoing adaptive mutation to further increase antibody diversity.

In recognition of these efforts, the three scientists were awarded the prestigious Albert Lasker Award for Basic Medical Research in 1987. That year Tonegawa was the sole recipient of the Nobel Prize. Hood admits he was disappointed not to be selected to share the award. “On the other hand, you do science for the fun of doing science, you don’t do it to win prizes,” he says.

Meanwhile, Hood was getting his first taste of the blossoming biotech industry. Nineteen companies turned down his proposal to commercialize the gas-liquid phase protein sequencer that he and Michael Hunkapiller, a senior research fellow in his lab, developed in the late 1970s, even though it was 100 times more sensitive than current equipment, and capable of sequencing important yet relative scarce proteins like the prion.

A venture capitalist from San Francisco, Bill Bowes, had heard that Hood was shopping his instrument unsuccessfully, and offered up $2 million to start a company to market the sequencer. The result was Applied Biosystems, today part of Applera Corp. and a world-leader in molecular instrumentation.

In the spring of 1985, Lee Hood was one of a dozen scientists who gathered in Santa Cruz, Calif. to discuss whether sequencing the human genome was a good idea. It was the first meeting ever held on the Human Genome Project.

Hood recognized that a new approach to science would come from having this comprehensive cache of biological information. This radical new opportunity, he realized, held enormous promise for human health. With the new tools, it would be possible to identify defective genes, the first step toward understanding their roles in human disease and how to overcome their dysfunction.

His lab at Caltech already had developed a unique cross-disciplinary culture of biologists and technologists, but Hood wanted to go further. So in 1987, he applied for and received funding from the National Science Foundation to transform his lab into “Science and Technology Center.”

During the next five years, the center cut the first turf in the field of proteomics, and helped pioneer the technology for putting oligonucleotides, single-stranded pieces of DNA, on “chips.” DNA chips have greatly accelerated genetic research.

Shaking the Etch-A-Sketch comes at a price, however. When Hood proposed a new Division of Molecular Biotechnology, the Biology Department – which would have been its administrative home -- balked at the technological direction his lab was taking.

Convinced at this point that his cross-disciplinary vision of science was essential to biological discovery, Hood moved his lab to the University of Washington School of Medicine in 1992. With $12 million of support from Microsoft founder and Seattle native Bill Gates, Hood established the Molecular Biotechnology Department.

The new department thrived, deepening and expanding the efforts of the transferred Science and Technology Center. It spawned two of the 16 Genome Centers that worked on the Human Genome Project, and gave rise to a multitude of industrial collaborations. The center also developed ink-jet printer technology for making DNA chips, and a fluorescence-activated cell sorter of unprecedented power.

Body as system

A concept had been marinating in Hood’s mind since the early 1990s—systems biology, the study of the interaction of all the elements in a system, be that a cell or an organism, rather than studying one gene or one protein at a time. Hood’s lab moved increasingly toward a systems approach in its research efforts, using global technologies to study prostate cancer as well as bone marrow stem cells and autoimmune disease.

In 1996, Hood proposed the creation of an Institute for Systems Biology at the University of Washington, to be modeled after the successful Whitehead Institute for Biomedical Research in Cambridge, Mass. Three years of discussion were not enough to clear the path of administrative obstacles, however, so in December 1999, Hood resigned to co-found an independent institute with faculty colleagues Alan Aderem and Ruedi Aebersold.

Originally housed near the University of Washington campus, the Institute for Systems Biology now occupies a new building, not far away, on the shore of Lake Union. The design of the three-story facility consciously reflects the mission.

The open floor plan encourages flow from one work group to the next – cubicles of biologists adjoin those of physicists, mathematicians, computer scientists, engineers, and chemists. Labs are quietly efficient, the din from banks of instrumentation sequestered in windowed rooms across from rows of streamlined workbenches. Walls are painted with the colors of nature – sunflower, olive, burnt sienna, deep lilac – and pools of sunlight fall into nooks furnished with overstuffed chairs.

Lee Hood blends into the background here, though his schedule on any given day is anything but inconspicuous. One recent morning, Hood addressed a delegation of Taiwanese scientists, ministers, and business leaders on cooperative biotechnology ventures. Afterward, he gave a tour of the facility to U.S. Congressman Adam Smith.

As they walked, the two discussed the best way to identify an agent used in a bioterrorist attack and why intellectual property rights are important to the development of drugs. By noon, Hood was across town, addressing the Democratic Leadership Council on the ethical and social consequences of the biotechnology revolution.

Some research efforts, especially the use of embryonic stem cells, have led to calls for greater government regulation over what scientists can do in the laboratory. Hood agrees that the research should be monitored; where he disagrees is at what point. “Our responsibility is not to block the creative discovery process, but to carefully shepherd and control the applications of the technologies for the good of society,” he says. “Technology is going to present society with enormous opportunities and enormous challenges.

“We must educate ourselves so that we can participate in the social decision-making process, balancing these opportunities and challenges,” Hood adds. “Only if we think rationally and analytically, and are at least informed about the basic facts of what biology and biotechnology is about, can we think effectively about these social and ethical issues.”

Hood is inexhaustible and stays perpetually warmed up and ready to speak on any topic, his gears seemingly stuck in drive. A fit man with an intense gaze, only his graying hair betrays his 64 years. His days often start early with a solitary run, a time when he says he does his best thinking. Younger colleagues marvel at his stamina, finding their own energy flagging under the duress of building the infrastructure of the center while maintaining their research.

Though he’s much more likely to pick up the sports page than the business section of the newspaper, Hood understands deeply how industry can serve his vision. The long-term plan, he says, is to launch small start-up companies that can develop the discoveries of institute scientists. Venture capitalists already have committed funding for a new building he calls the Accelerator, where the companies will be housed while they get a foothold.

“The business is just a means to an end for Lee,” says his colleague, George Lake, “a way to get the technology matured to the point that it benefits science. If people in medicine or science have something to do with a company, that is instantly a conflict of interest, something dirty. But the fact of the matter is, if you have something that will actually improve people’s well-being, if you don’t get financial backing it will take years longer to develop, and whatever benefit it has is lost to those people who suffered for those years.”

Hood is quick to give credit to the myriad talented scientists who have populated his large and busy labs over the years, and who are primarily responsible for the technological and methodological innovations.

“Students will often come up with solutions to problems that the mentor would neither have the time nor, in some cases, the specialized skills to solve,” he says. “One of the most important roles of a mentor is to create unbounded environments where people can move in any direction they want, and to give them a problem that is unbounded and will challenge them. Then, just let them do it.”

“His lab works very well for people who are independent and are able to find their own resources for learning,” says Jared Roach, a physician and research scientist at the Institute. “That said, Lee is really there for you when you need him.”

“He’s very open to people having done different things with their life—it’s one of his endearing qualities,” adds Lee Rowen, a senior research scientist at the Institute who has doctoral degrees in biochemistry and philosophy.

Since his days in medical school, when he volunteered to teach science to inner-city high school students, Hood also has been committed to K-12 science education. He and his wife currently are involved in an effort to revise the way science is taught in Seattle public schools.

The goal: to lift science education from the doldrums of rote memorization to a more active, inquiry-based method, one that sparks interest in young minds and instills a long-lasting habit of questioning. The program, supported by a National Science Foundation grant, includes summer workshops for teachers. “You just have to go and see kids getting turned on by hands-on, inquiry-based thinking to realize that this is the way you really want to teach things,” Hood says.

The culmination of a lifetime’s work, the Institute for Systems Biology is Hood’s meridian hour, his greatest chance to make a contribution to society. Through the systems approach to biological discovery, he aims to expedite the move toward personalized medicine. And by grassroots efforts to transform K-12 science education, he hopes to produce a citizenry better able to question and understand the momentous changes ahead.

Asked whether retirement is on the horizon, Hood first says no, then hedges.

“Yes, in the sense that I see myself doing different kinds of things,” he says. “I think I will always stay scientifically and intellectually involved, but in a less demanding way that would give Valerie and me more time to have fun, to do some things in the outdoors while we’re still able. Because there will be a time when we’ll be more fragile.”

Lee Hood fragile? Not a chance.

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