The Bell Labs of Biology

By next year, biologists are scheduled to finish sequencing the entire set of human genes. The Human Genome Project has been a mammoth endeavor involving thousands of scientists and billions of dollars. But for Peter Schultz, the real fun-understanding how all those genes function-is just beginning.

Coming from most people, that would sound like idle boasting. But Schultz has the track record to back it up. Part entrepreneur, part research administrator, part organic chemist, Schultz has always been intent on turning lab advances into real-world technologies. Starting in the late 1980s, he was one of the pioneers of “combinatorial chemistry,” a collection of techniques for rapidly generating huge numbers of compounds and screening them for specific kinds of activity. Many researchers would have been content to stop there.

Not Schultz, who played a pivotal role in turning this seemingly esoteric advance into a revolution in the search for new drugs and materials. Affymax, a combinatorial chemistry startup Schultz helped found in 1989, has changed the way pharmaceutical companies hunt for new compounds, while Symyx, which he co-founded in 1995, has used similar combinatorial technology to revolutionize the discovery of electronic materials and catalysts (“Winning Combination,” TR May/June 1998). In his latest incarnation, Schultz plans to use some of these same chemistry tricks to understand everything from human cognition to human development.

In his office by 5:00 a.m., Schultz maintains a hectic schedule. In addition to heading up the new genomics institute-which began operations last summer-Schultz serves as a director of several startup companies and maintains his presence in academia by running a 40-member lab at the Scripps Research Institute. Senior Editor David Rotman caught up with Schultz early one morning to hear about his plans for the institute and the increasing role of chemistry in biomedical research-and to get an update on the effort to put together the vast jigsaw puzzle of human genes.

SCHULTZ: There are between 100,000 and 200,000 distinct genes in the human genome. The sequence [of the entire human genome] will probably be complete this year or next and be in the public domain in 2002. The most immediate impact the gene sequence will have on the average person is in the development of new diagnostics for disease and new targets for drug development. The question is, what are the cellular and physiological functions of those genes? And how can we modulate those functions to, for example, treat disease?

TR: Answering those questions is the mission of your institute?

SCHULTZ: Yes, we want to deduce the function of a particular gene product [each gene codes for a protein], then learn how that protein interacts with other molecules in an organism and how to modulate the function of that particular protein. We want to understand the function of these proteins and their role in the cell and organism. The result will hopefully be the ability to create small molecules, proteins or genes themselves that act as human therapeutics.

TR: You left the University of California, Berkeley, and Howard Hughes Medical Institute to head the new institute. What was the attraction?

SCHULTZ: The sequence of the human genome is determined once in the history of mankind. It’s a unique time in biology and chemistry-equivalent to the advent of quantum mechanics in physics. The question is-how do we begin to understand and assimilate the huge amount of information encoded in the genome? The other revolution that has occurred during the last 10 years in the biological and physical sciences is in the way in which we carry out experimental science. There’s been a tremendous increase in our ability to design, implement and analyze experiments-to carry them out not one at a time but thousands or millions at a time. That has been made possible by combinatorial technologies, computational tools and advances in engineering and miniaturization-the kind of tools and processes that revolutionized the semiconductor industry are being moved over into the biological and physical sciences. The bottom line is that without that set of tools it would be damn near impossible to deal with the huge amount of information related to the human genome.

TR: Aren’t there a lot of other research groups working in the field of functional genomics these days? In other words, isn’t there a lot of competition out there for the institute?

SCHULTZ: But very few people have attempted to bring together all the tools under one roof and use them synergistically to understand gene function. That’s what we’re trying to do. It’s something that’s difficult in a conventional university setting, because it requires focused efforts and dedicated resources. It’s difficult to do in biotech companies because they usually have one mission or goal. And it’s difficult to do in a big pharmaceutical company because there’s a product focus. I view this place as a new Bell Labs of biology: a tremendous technological infrastructure with small, highly collaborative groups.

TR: What do you anticipate will be the payoff? Will it lead to faster or more efficient drug discovery?

SCHULTZ: The mission isn’t drug discovery. It’s biological discovery and improved technologies for making those discoveries. But the point is that nowadays very little time passes between when an important biological advance is made and when people begin to try and exploit that advance for human therapeutics. If someone makes a discovery involving the underlying molecular basis for Alzheimer’s disease, the next day the pharmaceutical industry will begin implementing drug discovery programs based on that new insight. Likewise, if you discover what genes are important in longevity, or in cognition, that’s a fundamental scientific discovery, but very shortly thereafter those gene products become targets for the development of therapeutics. That fact allows a place like this to focus on biological discovery with the expectation that it’s going to lead to important biomedical advances.

SCHULTZ: Exactly. I think that Paul Herrling [head of research at Novartis] realized there needed to be a place that brought together many of these tools and focused them on the opportunity created by the genome sequence. There weren’t such places in either the academic world or industrial world. We’re somewhere between university and biotech-pharmaceutical research. This is really an experiment. And the reason that the Novartis Research Foundation is willing to support us is their realization that there’s a very thin line between basic research and new opportunities for the development of therapeutics.

TR: You’ve been involved in startup companies and academia, and now you’re associated with a large pharmaceutical company. What are the tradeoffs of each in terms of the innovation process?

SCHULTZ: I retain my “academic” hat at the Scripps Research Institute. But the problem with academia is it’s very hard to focus resources like one can do in industry. On the other hand, companies sooner or later tend to become very product-focused because they have shareholders wanting value. At this institute we have the opportunity to have our cake and eat it too. As we make discoveries or develop tools that have commercial value we can pass on those discoveries through the foundation to Novartis and they can use them to develop drugs; if Novartis isn’t interested, we can spin off startups that can develop and apply the technology at a high level. The institute is free to continue developing new tools and making new discoveries. You just can’t do that in academia. You can’t focus resources like that because it’s a democracy and everyone has a vote.

TR: What are some of the specific technologies that you’re focusing your resources on?

SCHULTZ: We’re developing a range of tools and applying them to the discovery of new biology at the molecular, cellular and organism level. For example, at the molecular level we’re analyzing what genes get selectively expressed during fertilization, aging, learning or in neurodegenerative disease and cancer. At the same time, we’re setting up high-throughput screens for molecules that affect function at the cellular level, for example, the differentiation of stem cells into various cell types and the entry of viruses into cells. We’re also carrying out discovery at the level of the whole organism. For example, we’re setting up a mouse screen in which we’re going to randomly mutate a large number of genes in the mouse genome and carry out high-throughput phenotypic screens. One can screen for fat mice, thin mice, smart mice, dumb mice, mice that are pain-insensitive-or even long-lived mice. One can examine thousands of mutant mice for interesting phenotypes and then use the genomic tools that we and others are developing to map and clone the interesting gene mutations.

TR: You’ve done pioneering work in a number of areas. A few that come to mind are catalytic antibodies and combinatorial chemistry for finding new materials. Is there a common theme in your work?

SCHULTZ: I’m a chemist and am interested in molecules and molecular functions-what molecules do and how that is related to their structures. Chemistry is moving from a focus on the structures of molecules to a focus on the functions of molecules. And if you’re interested in molecular function, you should understand that nature has already solved the problem of making a remarkable array of functional molecules. For example, nature solved the problem of molecular recognition with the immune system and antibodies (a major line of defense against pathogens). Instead of making one antibody, and testing one antibody at a time for its ability to bind to a foreign molecule, it makes billions at a time and tests them all. That’s a combinatorial approach. We’ve taken that idea and used it to search for interesting new catalysts. We’ve even taken that strategy and applied it to making libraries of materials and searching for novel optical, magnetic and electronic materials. I think there’s basically a limitless opportunity in the periodic table. The underlying theme is how you do experiments thousands at a time and analyze the data thousands at a time.

SCHULTZ: It is strange. On the other hand, it’s strange that an organic chemist/biological chemist started a materials science company [Symyx] too. But I think that it’s less strange now that I’m here. Because what genomics, the gene sequence, and all these tools are making possible is an understanding of biology at a molecular level. And as soon as you’re talking about something at a molecular level, it’s chemistry. A chemist is also not a bad choice in the sense that all these tools bridge biology, chemistry, physics, engineering and computation-and a chemist is a scientific jack-of-all-trades. However, it does mean that I’ve spent a lot of my time learning a lot of cell biology over the last year-let’s put it that way.

TR: You’ve been involved in a couple of very successful startup companies. Any future plans?

SCHULTZ: I was a founding scientist at Affymax, then I was a founder of Symyx. Now we’re forming a third company, which we’re spinning out of the institute. Some of the structural genomics tools we’re developing here will be the basis for the startup.

TR: What’s its name?

SCHULTZ: I think it’s going to be called Syrrx. I have good luck with companies that end with an X.

TR: Structural genomics, as opposed to functional genomics?

SCHULTZ: Right. Structural genomics involves the determination of the three-dimensional structures of proteins on a genome-wide scale. The idea we’re pursuing at the institute is to carry out high-throughput protein structure determination and then virtual docking of small molecules to identify compounds that bind and modulate the activity of these proteins. If you can input 200,000 or 400,000 compounds in a computer, and actually dock in silico this entire library of molecules against a particular protein structure, one could, in theory, virtually identify leads for new drugs. We’re developing these new technologies at the institute, but we don’t have the resources to commit 100 people just to structural genomics. With the startup, we can put together the resources necessary to really exploit the technology.

TR: Ten years from now, what kind of research will we be talking about?

SCHULTZ: In 10 years, we won’t be talking about the functions of individual proteins or individual cells but about the functions of networks-how collections of proteins in the cell, and collections of cells in the immune system or in the brain, function together. It’s like in information science-it’s not the individual bit, it’s the integrated circuit. In biology it’s going to be pathways and networks.

TR: And what will that increased understanding of pathways and networks mean in terms of developing therapeutics?

SCHULTZ: For instance, if you want therapeutics for cognition, it may not be good enough to understand the function of an individual protein or even an individual cell; you have to understand how those cells work together. Memory is not associated with one neuron. It’s associated with a network. Once we begin to understand pathways and networks, in theory we can make therapeutics that modulate activities that rationally affect the properties of the entire network. We should become a lot more effective in the development in therapeutic agents.

TR: And gain the ability to take on different types of functions?

SCHULTZ: Exactly. The immune system is another example. If you begin to understand how all the different cells work together in asthma, inflammation or organ rejection, you can become a lot more sophisticated in the development of therapeutics. The same thing is true in cancer. Most of the drugs we use to kill cancer today do so by basically targeting rapidly dividing cells. That’s not a very sophisticated approach. As you begin to better understand how cancer cells are different from a normal cell, you should be able to develop more selective drugs.

TR: I take it from what you say that there’s still a long way to go in understanding these bio-networks.

SCHULTZ: It’s a difficult problem because you have to figure out the function of individual proteins before you can figure out how they work together. If you look at a car and want to understand how it works, you look at the cylinders, the pistons, the valves, the spark plugs-and once you understand what each of those does, then you can begin to see how they all work together. It’s the same thing here. You have to look at the functions of the individual proteins in a cell, and then you can start to understand how they work together.

TR: At this point, it’s still pretty much looking at…

SCHULTZ: …the spark plugs. And the problem is that we don’t even have the whole list of the parts. We’re still collecting the list of all the parts, while we’re trying to figure what they do individually. The next level is to figure out how all the parts work together. That’s the analogy to the cell. And then you go from the individual cell-there are billions of neurons in the brain-to understand how all those cells work together to make an organ. The goal is to understand life at a molecular level. And if that’s the goal, chemists will have to play a key role.