Under Biology's Hood

the multibillion-dollar human genome project’s effort  to detail the entire set of human genes was biology’s moonshot. But it might have never made it off the launch pad without one key piece of technology-the automated DNA sequencer. Labs crammed full of these machines, each rapidly determining the sequence of bits of DNA, were the fuel that made the project feasible. Leading the team that developed the sequencer shortly before the genome project was initiated in the mid-1980s is just one of the achievements that has helped turn Montana native Leroy Hood into a biotech superstar. Now 62, the Caltech-trained biologist has laid the foundations for a string of biotech companies, helped unravel the mysteries of the immune system and mad-cow-disease-causing prions, built-with $12 million from Bill Gates-a molecular biotechnology department at the University of Washington, and left the university behind to found his own institute, Seattle’s Institute for Systems Biology.

Founded in January 2000 with an anonymous $5 million donation, the Institute is a vehicle for what Hood sees as a whole new kind of biology-one that focuses, not on individual genes, proteins and other factors, but on how they come together in complicated systems to make us healthy or ill. Fulfilling this vision of “systems biology” will require that researchers mix lab work with computer modeling and eschew highly focused and hypothesis-driven experiments in favor of the factory style approach typified by the genome project itself. The payoff, Hood says, will be a fundamental transformation of medicine. And he’s eager to develop the  technologies to make it happen.

Doing that, while at the same time trying to build his institute’s endowment, keeps the biologist busy. TR senior editor Rebecca Zacks caught up with Hood this spring in a series of phone calls-5:30 in the morning was convenient for him-to his home, office, and an airport lounge.

TR: You’re perhaps best known for leading the team that invented the DNA sequencer as a young Caltech professor in the early 1980s. But that was just one of four technologies you worked on at Caltech, right?
Hood: We had a deep interest in developing tools that would push biology ahead over the next 15 years. We had a clear vision of four instruments that would change the world: the DNA synthesizer, the DNA sequencer, the protein synthesizer, and the protein sequencer. They allowed one to decipher and synthesize biological information more effectively than was previously possible.

TR: Why are these tools so important?
Hood: The relationship between biology and technology is interesting. Most biologists are indifferent to technology-they use it, but they don’t really see it as a fundamental part of biology. Indeed, it is new or more sensitive technology that can open up new horizons in biology. A great example is the protein sequencer [a device that determines the identity and order of the amino-acid building blocks that make up a particular protein]. The sequencer we developed was about 100 times more sensitive than previous versions. It let us analyze many proteins that were heretofore utterly inaccessible to analysis. We carried out six projects and each of them opened up a new and interesting field. For example, we sequenced a hormone called erythropoietin with Amgen, and that sequence was key to their cloning the gene which led directly to the development of the first billion-dollar drug of the biotech industry.

TR: Still, you didn’t always get an enthusiastic response when you proposed these tools-even with the DNA sequencer?
Hood: I sent in a couple of grants to the National Institutes of Health in the early ’80s when we were just starting to develop the DNA sequencer, and neither was funded. Comments were, “Grad students can do it cheaper,” or “It’s impossible.”

I went to the president of Caltech in ‘78 or ‘79 and said, “Look, we are developing four instruments that will change biology. My colleagues are suggesting that they should be made available to the general scientific community. Hence, we should commercialize them.” And he said, “Caltech isn’t really interested in commercialization. If you want to, you have permission to go out and commercialize them, but we’re not interested in that kind of thing.” Over the next two years I went to about 19 companies and got 19 nos. It was around 1980 when a venture capitalist from San Francisco called me and said, “I’ll put in a couple of million to develop these instruments you’ve been shopping around. Why don’t we start a company?” That company became Applied Biosystems [which merged with scientific instrument maker Perkin-Elmer in a $330 million stock deal in 1993].
 
TR: What other firms did you help found?
Hood: I was in on the beginning of Amgen, and I’ve been involved in founding seven or eight other companies since. I got involved in the biotech revolution in the early days. It was intellectually exciting to be involved as a scientific advisor. One learned an enormous new science and enjoyed the science without any of the responsibility of making money. Companies go through this maturational process where they need founding scientists as scientific advisors for the first few years, and then they mature and function independently. It is a healthy process.

TR: Were you ever tempted to get more involved in the business side?
Hood: Not at all. The key issue always for me was the freedom to approach new problems. With a company, no matter how flexible the opening opportunity seems, in the end you have to make money and subjugate your interests to making money. What is so wonderful about academic research is you can explore what you wish. The other issue is the ability to attack long-term problems. You are not constrained to making money within two or at most three years.

TR: You thought the Human Genome Project was worth long-term investment, but initially not everybody felt that way?

Hood: I went to the first meeting held on the Human Genome Project in the spring of ‘85 at the University of California, Santa Cruz. Robert Sinsheimer, the chancellor, had $35 million and was considering spending it on an institute to sequence the human genome. He invited 10 or 12 scientists to consider this for two or three days. My lab had started working on the DNA sequencer in the early ’80s, and the publication describing the first prototype was in 1986. So the Human Genome Project and DNA sequencing came together.

There were three things that stood out in my mind about that first meeting. One was the enormous technological challenges the Human Genome Project presented, both in sequencing and mapping, but also in computation and analysis. The second thing that was exciting was to see how it would transform biology and medicine. I was an advocate for this project, and was there ever bitter opposition. Hostile, aggressive and negative interactions resulted. And the reason for that, which is the third thing that really impressed me, is the genome introduced to biology a completely new approach, which I’ve since come to call “discovery science.” It’s the idea that you take an object and you define all its elements and you create a database of information quite independent of the more conventional hypothesis-driven view.

What people really resisted in the Human Genome Project were two major things. One, “It’s going to cost too much money-it’s going to take money away from me.” And this was never correct. The project started with a large bolus of new money and has since brought lots of new money to science. The second argument against the Human Genome Project was that it was trivial, it wasn’t really science. It was referred to as a fishing expedition, or a mindless collecting of facts. What they did not realize is how these databases were going to transform how we think about biology and medicine.

TR: Can you describe those changes?
Hood: First, discovery science is now an accepted concept. Second, the human genome has provided us with a genetics parts list for humans and the other model organisms whose genomes have been sequenced. We must do biology to figure out how these parts function, and now we have them-genes, control sequences, etc.-in databases. Third, the Human Genome Project has given us access to human variability, the genetic variations which make humans different from one another-different in physiology and different in disease predisposition. And it’s in this arena that medicine will be utterly transformed over the next 20 years or so.

TR: Do these changes raise ethical issues?
Hood: I think a big issue is how we’re going to educate the public about the revolution that is coming in medicine. What will happen over that 20- to 25-year time period is that we will move from what I call reactive medicine-you get sick, they try to fix you-to what I would call predictive medicine-they look, for example, at your genes and determine whether you have a bad gene for breast cancer, so you will have a 70 percent likelihood that at the age of 60 you’ll have breast cancer. In this stage, you can make predictions, but you can’t do much about it. The final stage will be the preventive stage where we will be able to take defective genes, understand the pathways in which they operate and how to manipulate those pathways so you can circumvent the limitations of the defective gene. Ideally, you would be able to take pills that could reverse those limitations in a preventive fashion.

This preventive medicine is going to wreak enormous challenges for how we educate physicians. The fact is, the physicians we’re educating today are going to be practicing in that era, and most of them do not have the faintest idea about the coming revolution in medicine. Medical schools are, in general, resistant to responding to this certain future. In my experiences, their attitude is, “Well, that is an interesting proposition, but we do not have time to think about it today.” The same will be true of society at large. There are also the ethical issues of genetic privacy, germ-line genetic engineering, and genes that influence human behavior.

TR: Why is the lay public’s knowledge of medicine and science important?
Hood: In the end it is the public that places two limitations on how we do science. One is funding and the second is the regulations that govern how we do science. Accordingly, it is imperative that we somehow reach out to the lay public and educate them about these issues.

TR: In a nutshell, what is systems biology?

Hood: Suppose you wanted to figure out how a car works. The way biology has done it in the past is to create a group of specialists that would study individual parts-the wheels, the brakes and the ignition. Each group of specialists would talk within their own group but not to the members of the other groups. What systems biology does is attempt to use discovery science to define all the elements in the system, all the components of the car. Then it perturbs the car-accelerate, brake, etc.-and attempts to define the relationships of the elements one to another at various levels-mechanical, electrical, etc. Finally, systems approaches integrate these different kinds of measurements and data in a way that one can begin to formulate graphical displays and finally mathematical models that ultimately will give one insight into the structure and functioning of the car.

That is basically what systems biology is about. It is taking a biological system, identifying its elements, perturbing it in a model system, capturing information at the DNA, RNA, protein, protein interaction, informational pathway and informational network levels, and integrating and graphically displaying [that information], and then developing mathematical models that will describe the structure and behavior of the system.

TR: What does that allow you to do?
Hood: It allows you to understand the system and how it functions. If you are a pharmaceutical company, it suggests that there are critical points in these informational networks at which one can begin to attack the system, manipulate it, circumvent the limitations of defective genes. We are at the earliest stages of learning how to do mathematical formulations. Once we do, I think it will transform how one identifies drug targets, how one deals with potential side effects of drugs, and how one determines whether a particular drug that has already been approved might do something else that is even more interesting.

TR: Is all this modeling moving biology out of the wet lab and into the computer-what some call “biology in silico?”
Hood: Not at all. The message is that we have to integrate the computational tools with the data generated from biological tools. The systems-model process is really iterative with data generation, modeling, data quantitation, etc. The first time you go around the loop, you find that your model is not very good, so you have to do more experiments to improve it. This process repeats itself until you get to a place where the predictions you can make with the model are in conjunction with the experimental data you generate. You will never make progress in biology if you believe you can attack biological complexity solely in silico. The heart of biology is complexity, and we are going to unravel complexity only by doing biological experiments. But the integration with modeling and the graphic display of complexity is a central feature of what we’re trying to do at the Institute for Systems Biology.

TR: Why did you start the institute?
Hood: I moved from Caltech to the University of Washington School of Medicine in 1992 to start the Department of Molecular Biotechnology. The vision of the department was to be cross disciplinary; that we were to hire engineers, applied physicists and computer scientists, as well as biologists. By 1995 or so, we had filled all the space we had been allocated. The department was enormously successful. We had terrific people. We had great funding. So I went to the president of the University of Washington and asked to build a new structure to expand the department in keeping with the already apparent opportunities of systems biology. The president said no, that there were eight or nine other projects in line and that I would have to wait 10 or more years before I could get a building. I then decided to start the institute. I spent about four years trying to create it within the School of Medicine at the University of Washington, but in the end, I had to resign and establish an independent nonprofit institute. When all was said and done, I realized that the university culture and bureaucracy just could not have sufficient flexibility for the needs of an institute attempting to respond to the opportunities emerging from the Human Genome Project. The Institute for Systems Biology has been operating for a little more than a year. We have seven cross-disciplinary faculty and have grown from a staff of two to a staff of 160. We’ve established six technology platforms, we’ve been successful in getting grants and industrial support, we’ve established a number of industrial partnerships, and we’ve published a series of exciting papers, including one that is a proof of principle for the Institute.

TR: What technologies are you developing?
Hood: We are working on ink-jet synthesizers that can be used to build oligonucleotide gene chips [stamp-sized wafers capable of analyzing thousands of genes at a time] in a more flexible manner than can be done with the alternative technology-photolithography. We are setting up a very large-scale proteomics production line [to identify and characterize proteins and their functions]. This is a very important technology for the post-genomic era. We’re working on sophisticated cell sorters that will be able to take complex populations of cells and very rapidly separate different cell types. We are working on new ways of determining protein-protein and protein-DNA interactions. These technologies are high throughput and global in nature-they look at all or most genes or proteins. At the same time, we are attempting to develop software that is good for the visualization of biological complexity, software that can automate the process of building and optimizing the models. Obviously, we have to develop computational tools that will capture information from each of these different technologies.

TR: What sorts of biological problems is the institute tackling?

Hood: One area that is important to the institute is human genetic variation and its correlation with physiology or disease predisposition. We are developing technologies for identifying and typing human variation more effectively in large populations. We are also very interested in immunity, stem cell research, and cancer. In addition, we are using yeast as a model system to work out our high-throughput technologies and our strategies for doing systems biology.

TR: Any plans to commercialize this work?
Hood: We are more than ready to spin out intellectual property to industry. We can either license the intellectual property to preexisting companies, or we can spin it out as new companies. Over the past year, we have already spun out two companies: MacroGenics, which uses the tools of genomics and proteomics to discover targets on cancer cells that can be used for immune-system-based therapies; and Cytopeia, which is developing technologies to further multiparameter, high-speed cell sorting and enlarge its applications. The forte of the Institute is not doing short-term research, but rather taking on long-term, challenging problems.

TR: Those long-term problems are the sort you’ve said are best tackled in an academic setting-yet in the past few years you felt you weren’t able to do so at the University of Washington. Do you think the obstacles you encountered there are endemic to universities these days?
Hood: I do. The question is a very interesting one: are universities going to be able to compete in this new world of post-genome biology? The issue is open. As I noted earlier, the issues center around leadership, flexibility, timeliness, resources-and very new ways of doing science. It has been a struggle for me for the last five years. But possibly these changes will come more easily now that we understand the issues and the opportunities that are emerging from systems biology. What is clear is that this approach will transform biology and medicine.