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Molecular and Systems Biology By Leroy Hood, President, Institute for Systems Biology Dr. Hood (M.D., Johns Hopkins, 1964; Ph.D., Caltech, 1968) began his career at Caltech, where he and his colleagues pioneered four instruments that comprise the technological foun- dation for contemporary molecular biology. In particular, the DNA sequencer revolutionized genomics by allowing the rapid automated sequencing of DNA. While at Caltech, Dr. Hood and others worked with Arnold O. Beckman to organize the Beckman Institute in 1986. In 2000, Dr. Hood cofounded the Institute for Systems Biology in Seattle. He has been honored You need to with numerous academic and scientific awards for his study of immune diversity, continuing development of instrumentation, improvements to diagnostic methods, and efforts to open use frontier doors for new treatments and cures. Dr. Hood is a member of the National Academy of Sciences, the Institute of Medicine, and the American Association of Arts and Sciences. problems in I was at Caltech for 30 years--four years as an undergraduate, four years as a gradu- ate student, and then 22 years as a faculty member. During that time, I participated biology to in four transformational developments in biology: the creation of new technologies, genome biology, systems biology, and personalized medicine. Each of these advances drive the kinds should be seen as nothing less than a paradigm shift in the biological sciences, with all of these paradigm changes driven by changes in technology. of technology When I became an assistant professor at Caltech in 1970, I divided my time equally between biomedical research and the development of new instruments, despite some you want to resistance from the department. However, the two should not necessarily be seen as dis- tinct. You need to use frontier problems in biology to drive the kinds of technology you develop. want to develop. And once you've developed those technologies, they in turn allow you to remove the shrouds of confusion from these frontier areas. One of the first instruments that my colleagues and I successfully developed was a device to determine the amino acid sequence of proteins. With a sensitivity much greater than any previously available instrument, the device allowed us to look at biologically inter- esting proteins that had theretofore been invisible. With University of California, San Francisco, professor Stanley Prusiner, we sequenced the proteins involved in prion diseases--work that helped Prusiner win the Nobel Prize in 1997. We sequenced the pro- tein erythropoietin, a hormone that stimulates the production of red blood cells and was one of the first billion-dollar products in the biotechnology industry. We also sequenced proteins involved in neurotransmission, stem cell development, and immune reactions. 26 INSTRUMENTATION FOR A BETTER TOMORROW

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It was a remarkable time; we had this instrument that let us go out and survey the field of all these things that hadn't been looked at before. We also developed a device to synthesize proteins from their constituent amino acids. This instrument was critical, for example in synthesizing part of an important protein in the AIDS virus, which in turn led to the development of the first protease inhibitor for the virus. The protein synthesizer also played a key role in the development of the poly- merase chain reaction (PCR) because it enabled the construction of the oligonucleotide primers that are essential to the amplification of targeted DNA regions. PCR never would have happened if it had not been possible to synthesize DNA very readily. In the late 1970s, I began thinking about commercializing some of the instruments I was developing. The president of Caltech emphasized that the fundamental role of the university was scholarship and education, not the commercialization of instruments, so I began exploring options on my own. I went to 19 different instrument companies and pre- sented a vision of how instruments were going to transform biology. I was 0 for 19. In fact, I went to Beckman Instruments three times, and the last time a manager said, "We're just not interested." About that same time, Arnold Beckman, who was no longer directing Beckman Instruments, heard me give a lecture, and his reaction was "This is really interesting. This is just what Beckman Instruments needs." I should point out, this raises a really interesting question about companies. What happens when the creative driving force of the company isn't at the helm anymore? Is it really better to start new companies? That's what I did. I participated in the founding of a new company, Applied Biosystems, which commercialized the instruments we were developing and is now a world-leading company in the field of molecular instrumentation. One of the most important instruments commercialized by Applied Biosystems was the automated DNA sequencer, which could determine the sequence of nucleotides in DNA molecules. This got me into the next big adventure of my life, which was the Human Genome Project. Launched in 1990, the project completed an initial draft of the human genome in 2000, and a final draft in 2003. Essential to the project's success was the auto- mated DNA sequencer developed by Applied Biosystems. The development of the instrument began in earnest in 1982 through a multidisciplinary effort involving biolo- gists, chemists, computer scientists, and engineers. I realized that the tools of biology INSTRUMENTATION FOR A BETTER TOMORROW 27

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1986 First automated DNA sequencer 1980 launches the genomics revolution. Frederick Sanger awarded 1990 Applied Biosystems commercializes the Nobel Prize in Chemistry Advances in mass spectrometry the first automated DNA sequencer, for inventing the dideoxy enhance protein identification accelerating the researchers' DNA sequencing method, and characterization. ability to unravel genetic secrets. still used today to identify Time-of-Flight (TOF) MS with the genetic code of organisms. matrix assisted laser desorption ionization (MALDI) is introduced, and becomes an important technique for understanding large biomolecules, including proteins. 1991 1989 1985 GenBank and other public Gene for cystic fibrosis Robert Gallo and databases begin to show 1983 identified. A mutation Luc Montagnier exponential growth Kary B. Mullis develops in the gene sequence independently in sequence information, the polymerase chain creates a protein that publish the DNA as Applied Biosystems reaction (PCR), cannot function properly. sequence of HIV, the automated DNA and a technique that enables virus that causes AIDS. protein sequencers gain scientists to rapidly in popularity. amplify DNA. In 1993, he received the Nobel Prize in Chemistry for his accomplishment. couldn't be developed just by biologists any more; we had to integrate our partners from other disciplines (see Figure 16 for the development of analytic methods). This project convinced me that a cross-disciplinary environment could foster major advances in biology. Such an environment was difficult to establish at Caltech, so in 1992, I moved to the University of Washington to establish a new department of molecular biotechnology. The department brought together faculty members working on proteomics--the global analysis of proteins--cell sorting, protein synthesizers, and other sensitive, high-throughput instruments. We had good tools, a good computational infra- structure, and a cross-disciplinary environment, and the idea of biology as an information science was just beginning to emerge. With the necessary components of a more comprehensive approach to biomedical prob- lems becoming available, I turned my attention to the best way to approach complex bio- medical problems. Systems biology is the idea that we can look at all of the elements of a system. There are two main types of digital information in biological systems. One is the genes that make proteins, and these proteins often create networks that do things like sig- nal transduction of information from outside a cell. The second type of digital informa- tion is the regulatory elements that interact with a class of proteins called transcription factors--they regulate the expression of proteins and help to create networks of physio- logical and developmental order. These two types of information lie at the heart of systems biology. To take advantage of the many new opportunities offered by this perspective, I cofounded the Institute for System Biology in 2000. Instruments now being developed are specifically focused on a systems biology perspective. For example, we are involved in efforts to use nanotechnologies to sequence single DNA molecules, which would eliminate the need to produce a large number of identical DNA 28 INSTRUMENTATION FOR A BETTER TOMORROW

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2002 Next-generation mass spectrometers 1998 further improve accuracy of protein DNA sequencing becomes 2002 identification and characterization. industrial scale. The ABI Systems increase analysis 1994 Mouse Sequencing PRISM 3700 DNA Analyzer speed and provide even higher DNA evidence gains Consortium publishes sequence becomes the primary platform performance for protein and peptide acceptance for use of mouse genome, enabling used to sequence the human identification and analysis of small in criminal cases, and scientists to compare the contents genome, enabling molecule drug is brought to public of the human genome with the project to be metabolites attention in the this important animal. completed years important in O.J. Simpson trial. ahead of schedule. therapeutics. 1995 2002 1994 Craig Venter and colleagues at 1997 John B. Fenn and Koichi Tanaka Term "proteomics" TIGR complete first genome "Dolly," a sheep, 2000 awarded Nobel Prize for coined thrusting protein sequence of a free-living is the first mammal to The Human Genome Project Electrospray studies into spotlight. organism, Haemophilus be cloned from an adult. and Celera Genomics and MALDI ionization. Applied independently complete their Biosystems and Applied Biosystems/ 1993 influenzae, using the novel drafts of the human genome. MDS SCIEX incorporated these Huntington disease "shotgun" sequencing method. In February 2001, Celera award-winning techniques into their gene identified, ending The flu-causing organism Genomics published its results mass spectrometry systems. the decade long search. contains 1.8 million base pairs in Science, and the HGP Genome sequencing of and approximately 1,000 genes. published its results in Nature. a few viruses is complete. molecules for sequencing. My prediction is that within 10 years we will be able to sequence FIGURE 16 A pictorial timeline the complete human genome inexpensively and rapidly. We are also working on instru- illustrating the rapid development of genetic ments that will be able to analyze the individual RNA molecules in a cell (such instruments analysis techniques. would indicate which genes are turned on and making proteins) as well as on an integrat- ed "nanolab" that would subject the contents of a single cell to a variety of diagnostic tests. In turn, these new instruments will make possible the coming era of personalized medi- cine. Patients would have their DNA sequences analyzed and undergo a profiling of the functioning of their cells using material from a simple blood test. We'll look at your DNA and make predictions about your future health. And we'll look at your blood as a window to health and disease. Disease arises as a consequence of modified biological networks. When you modify the network, you modify the patterns of gene expression, which constitutes a molecular sig- nature that differentiates health from disease. We can design a drug strategy that moves a network back toward its more normal behavior. This new approach to medicine will have profound consequences for the health care and pharmaceutical industries, I predict. The medicine of today and the medicine of the future are going to be radically different. For example, I think in the next 10 years big pharma is going to be entirely restructured. I don't think it will be able to respond to the new kinds of medicine we will see. At the same time, the new medicine will have a powerful effect on the lives of individuals. If you put the medicine of the future, which I think is 10 to 20 years off, together with things that are happening in aging and neurobiology, I think we're going to significantly increase the productive lifespan of individuals over the next 20 years. INSTRUMENTATION FOR A BETTER TOMORROW 29