The 46 BRIDGEAcceptance Remarks by Leroy E. Hood 1970, when I came to Caltech as a purchase robust, easy-to-use, auto- young assistant professor, I decided I mated DNA sequencers. would spend half my time trying to The development of the auto- develop technologies for decipher- mated DNA sequencer gave me a ing molecular biological informa- deep appreciation for the power of tion—DNA, RNA and proteins. I cross-disciplinary approaches to bio- spent the other half doing molecular logical problems, which led directly immunology. Over the next 25 years to the second paradigm change— or so, my colleagues and I developed the Human Genome Project. a series of five instruments that cre- ated platforms for modern biological The Human Genome Project analyses—deciphering the mysteries Initially proposed in 1984, the of DNA, RNA, and proteins. Human Genome Project was aboutLeroy E. Hood, president, Institute for Systems Biol- What was instructive in develop- determining the order of DNA let-ogy, and recipient of the 2011 Russ Prize. Photo by ing the automated DNA sequencer ters in the 23 pairs of human chro-Event Digital Photography Inc. was our initial failure. I had per- mosomes (e.g., the genome or the suaded an excellent biologist to source code for creating humans). Receiving the Russ Prize is a undertake this task, but over a Using the sequencing technologywonderful honor. I would like to three-year period, he failed because available at the time, this task mightthank the Russ family who created he did not have sufficient command well have taken 100 years. Becausethe prize; Ohio University, which of four key disciplines—molecular of my interest in automated DNAsponsors the prize; the National biology, chemistry, engineering, and sequencing, I was invited, with 11Academy of Engineering, which computer science—whose integra- other “experts,” to the first meetingmanages the prize; the Russ Selec- tion was necessary for automating on the Human Genome Project attion Committee; and last, but not DNA sequencing. Santa Cruz in May 1985. The groupleast, my colleagues who have made I then assembled a team of four decided that the genome projectit possible over the years for me to scientists who rapidly solved the was feasible, although it would bewin the prize. problem. Lloyd Smith, an outstand- technically difficult. Several of us One of my joys has been to par- ing chemist and laser specialist, spent the next five years convincingticipate in a number of paradigm Mike Hunkapiller, an engineering a very skeptical community of biolo-shifts in biology over the course of genius with superb instrumentation gists that the genome project couldmy career, that is, changes in how we skills, Tim Hunkapiller, a biologist/ transform biology.think about and practice biology. I computer scientist, and I rethought I played an active part in thewill talk about five of these changes, the problem and within six weeks, Human Genome Project: (1) myhow the first led naturally to the had conceived the concept of four- team developed the automated DNAsecond and how the first four were color DNA sequencing (a different sequencer that enabled the project;essential to the fifth. The five para- color for each of DNA base). (2) I was an early advocate for thedigm shifts are: bringing engineer- I founded Applied Biosystems project when 90 percent of biologistsing to biology; the Human Genome Inc. in 1981 to commercialize the were initially opposed (the NationalProject; cross-disciplinary biology; first four instruments my lab devel- Institutes of Health [NIH] aggres-systems biology; and P4 medicine. oped (DNA and protein sequenc- sively opposed it up until the final ers and synthesizers). Lloyd Smith decision was made to go forward);Bringing Engineering pioneered the development of the (3) I was on the National Academyto Biology first prototype instrument, which of Sciences committee that gener- The first paradigm shift was emerged in 1985. By the late 1980s ated a favorable report in 1988-1989,bringing engineering to biology. In the biological community could which led to the initiation of the
SUMMER 2011 47proposed 15-year project in 1990; of small molecules), and pheno- tendency for blood clotting. Aand (4) I directed a Human Genome typic assays. patient with this defect shouldSequencing Center that sequenced Fourth, it pioneered the appli- drink lots of water, should notportions of chromosomes 14 and 15. cations of computer science and sit on an airplane for five hoursThis was one of 16 such centers in mathematics to biology. In fact, without walking and stretching,the United States. the genome project legitimately and may take low doses of anti- The most remarkable thing brought mathematicians and com- coagulants. This knowledge isabout the Human Genome Project puter scientists, and even theo- particularly important for pregnantis that it demonstrated explicitly retical physicists, into biology to women with the defective gene.how the needs of biology can lead think about acquiring and storing, Eleventh, physicians now useto transformational new technolo- analyzing, mining, integrating, and DNA sequencing of tumors to ana-gies that, in turn, can revolutionize ultimately creating predictive and lyze disease-perturbed biologicalbiology—and catalyze the emer- actionable models of complex bio- networks to determine the rightgence of remarkably different logical systems. drug for individual patients.aspects of biology. Fifth, it was the first biological Twelfth, the genome project A narrowly focused article by project with an open source policy created a scientific environment,Nicholas Wade in the New York for all data. It mandated the instan- which, in part, led to the fifth para-Times in 2010 purported to show taneous release of data to the bio- digm change, P4 Medicine, which Ihow the Human Genome Project logical community so everyone will discuss shortly.had failed to live up to its promise. could analyze the new information Thirteenth, the genome projectThe article stimulated my think- immediately as it was produced. changed the sociology of biology.ing about the transcendent benefits Sixth, it created the first rigorous For example, it introduced the con-the project had yielded, which are standards for biological data—and cept of “big science” to biology. Byremarkably broad in scope. Let me project funding depended on meet- big science I mean cross disciplinary,cite briefly 14 accomplishments that ing these standards. hypothesis-driven science that inte-revolutionized both biology and Seventh, it gave us access to the grates different data types to buildmedicine. genomes of plants, animals, and predictive models to help solve diffi- First, the Human Genome Project microbes, and knowledge of those cult problems, such as P4 Medicine.democratized genes, that is, made all genomes has transformed many “Small science” is done by a singlegenes accessible to all biologists. fields of biology. investigator and a few co-workers Second, it delineated, for the Eighth, it revolutionized our and takes on highly focused, discretefirst time, all human genes and, by understanding of evolution in abso- problems.inference, all proteins. This com- lutely magnificent ways. The synergy between big andprehensive “parts list” enabled a Ninth, it transformed how we small science is enormous. Eachnew approach to biology that I think about medicine. It created can take advantage of the strengthscalled “systems biology”—a holistic a new field of medical diagnostics of the other, and they can effec-approach to dealing with biological using biomarkers in tissues and tively operate in an integrated way.complexity. The concept of systems blood, which can actually detect Unfortunately, at NIH today, therebiology is the focus of the work done disease early and stratify complex is a tendency—driven by budgetat my Institute for Systems Biol- diseases into subtypes, making it constraints and supported by manyogy—the first systems biology orga- possible for physicians to do imped- scientists who practice small sci-nization—started in 2000. ance matches against appropriate ence—to do away with big science. Third, the Human Genome therapies. However, eliminating big scienceProject catalyzed the development Tenth, it opened up the possi- would be a tragic mistake, becauseof high-throughput instrumenta- bility of using DNA sequencing to we need it to take on complex andtion, the very effective genera- identify genes that have actionable challenging problems of biology andtion of biological information in behaviors with regard to patients. society. We obviously need a mixedgenomics, proteomics (the study of For example, Leiden factor 5, a portfolio that will enable us to takeproteins), metabolomics (the study gene defect, leads to an increased advantage of the strengths of both
The 48 BRIDGEbig and small science in an inte- environment in the Department of to better diagnoses and therapies;grated way. Molecular Biotechnology. It was and (2) create metrics for assessing Finally, the genome project was time to create a new discipline I the wellness of each individual andthe first project that supported an called systems biology. optimize his or her future wellness.investigation of the social, ethical, P4 Medicine will have four impli-and legal aspects of the genome Systems Biology cations for society. First, over thesequence in a way that presaged In 2000, I resigned from the Uni- next 10 years it will force everyhow we must consider medicine in versity of Washington to co-found, sector of the health care industrialthe future. with Alan Aderem and Ruedi spectrum to reformulate its business Aebersold, the Institute of Systems plans and will thus create enormousCross-Disciplinary Biology Biology (ISB), the first of its kind potential economic opportunities The development of the auto- in Seattle or anywhere. I did this for new and existing companies.mated DNA sequencer gave me a because I found the bureaucratic Second, it will lead to digitizationdeep appreciation for the power of constraints of the university to be of medicine, which will have threeusing cross-disciplinary approaches at odds with the new organizational aspects: (1) analyses of billions ofto address biological problems. structure required for systems biol- digital data points for each individ-Indeed, in 1992 with the help of Bill ogy. A fascinating question is how ual will provide enormous insightsGates, I moved from Caltech to the old organizations can adapt to new into health and wellness; (2) analy-University of Washington Medi- paradigms. This is not easy—it ses of some single molecules, singlecal School to create the Depart- requires leadership, flexibility, and cells, indeed of any quantized unitment of Molecular Biotechnology, a willingness to “change the rules.” of information in humans, will leadthe first cross-disciplinary biology From ISB’s very inception, we to actionable information for thedepartment. That department had began exploring a systems approach patient; and (3) wireless iPod®-a remarkable record of accomplish- to disease, which requires integrating style health devices with unob-ment: it pioneered the field of our cross-disciplinary environment. trusive sensors will enable eachproteomics (the study of proteins); We pioneered new analytic tools and individual to observe and recordprovided the software for data then used them to deal with enor- in real time understandable sum-quality and the assembly of DNA mous amounts of patient data. maries of his or her personal datasequence fragments for the Human relevant to wellness and disease andGenome Project; developed the ink- P4 Medicine to observe how these data changejet DNA array synthesizer (the fifth The integration of these develop- in response to environmental fac-instrument I developed); developed ments led to what I called P4 Medi- tors and lifestyle decisions. Whena novel, very high speed, multipa- cine, a revolutionary new medicine combined with social networkingrameter cell sorter; and housed two that is predictive, personalized, pre- tools and strategies, real-time accessof the 16 U.S. genome centers. ventive, and participatory. P4 Medi- to personalized health data has In the 1980s, I had become con- cine embodies the idea that medicine the potential to engage patients invinced that immunology, my area is an informational science. wellness-optimizing behaviorof biological study, was far too com- My 10-year vision for P4 Medi- modifications in a way that hasplex to be studied in an atomistic cine is that a virtual cloud of bil- never before been possible. Theway—one gene and one protein at a lions of data points will surround digitization of medicine will catalyzetime. I realized we needed a holistic each patient and that we will have transformations in health care com-approach that could analyze how all computational tools to reduce that parable to the changes emerginggenes (or proteins) behaved in this enormous data dimensionality to from the digitization of informationcomplex biological system. After we simple hypotheses about health and technologies and communications.invented the tools for global analy- disease and to sculpt these phenom- Third, P4 Medicine will turnses of genomic data, the genome ena, with exquisite specificity, for around the escalating costs of healthproject had generated a parts list each individual. In so doing, P4 care and bring them down to a pointof human genes and proteins, and Medicine will: (1) demystify the that will essentially solve the fiscalwe had created a cross-disciplinary complexities of disease and lead crisis presently faced by the United
SUMMER 2011 49States, which is caused in substan- technical and societal. The societal A wonderful question to contem-tial part by rising health care costs. challenge is to create legal, ethical, plate is what the paradigm changesMoreover, we will be able to export commercial, and policy structures of the future will be and how theyP4 Medicine to the developing that will enable the emergence of will build on the paradigm changesworld, with the potential for democ- the radically disruptive P4 Medi- of the past.ratizing health care, which was cine paradigm, which will change In closing, let me thank one moreunimaginable even a few years ago. the focus of our health care system person, my wife, Valerie Logan. Her Fourth, P4 medicine will create from reactive to proactive. unwavering support has been anwealth for the countries in which it This societal challenge will essential cornerstone of my chal-is practiced. This wealth will result be far more difficult to surmount lenging career. One fascinatingfrom the enormous savings from than the technological challenge. aspect of the approach my insti-effectively practicing wellness (and Indeed, we recently established a tute—the Institute for Systems Biol-reducing the massive loss of prof- nonprofit institute—the P4 Medi- ogy—has taken to tackling someits due to sickness). In addition, cine Institute—to bring P4 Medi- “big problems” in biology (e.g., P4the economic opportunities from a cine to patients and begin dealing Medicine) has been to create inter-“wellness industry” will soon emerge, with selected societal problems. national strategic partnerships thatas part of the P4-catalyzed transfor- We believe small pilot projects will bring together complementary skills,mation of the conventional health be essential to demonstrating the excellence, and new funding oppor-care industry. Indeed, I forecast that, power of P4 Medicine, and we have tunities. I have to say, however, thatin time, the magnitude of this new initiated two with Ohio State Uni- of all the successful strategic partner-wellness industry will far surpass that versity Medical School—one on ships in which I have participated,of the “disease industry,” that is, the wellness and one on heart failure. the partnership with Valerie Loganhealth care industry of today. Clearly, the first four paradigm has been by far the best—and the The acceptance of P4 Medicine changes described above were essen- whole has far exceeded the sum ofinto the mainstream of health care tial for the emergence of the fifth its parts. Thank you, Valerie.will require meeting two challenges: paradigm change—P4 Medicine.