Biochemist Catalyzes Multidisciplinary Biomaterials Research

It's odd to find a biochemist holding a high-ranking management position in the materials sciences division of a major national laboratory. And the team that Mark Alper has assembled at Lawrence Berkeley Laboratory in Berkeley, Calif.--consisting of organic chemists, enzymologists, chemical engineers, and even a journal editor--may seem even stranger. But in the four years since Alper founded the Enzymatic Synthesis of Materials Program at the Berkeley lab, this eclectic collection of investigators has fused into a productive unit. Alper's team is one of only a few groups in the United States focusing on the blending of biotechnology and materials research. They are at the forefront of a very exciting, very promising field--bioderived materials--that can have a variety of applications, including artificial skin, optics, paper production, synthetic spider silk, and custom-made polymers. "After people started asking me, `What's a biochemist doing in a materials division?' I had to come up with some justification," quips Alper. "I figured I'd create a major program so people wouldn't ask me anymore." The mission of Alper's team is to take on a novel challenge: using biological processes to make materials. The group's seven principal scientists are already coaxing enzymes, the super-efficient facilitators of natural reactions, to do their bidding. Creating commercially viable materials through biological processes is by no means unprecedented. In fermentation, for ex- ample, a biological process creates something new--such as beer or champagne, from starting materials like hops and grapes. And for years, explains Alper, naturally occurring enzymes have been used in industrial processes. What Alper's team is doing, however, is attempting to engineer highly stable and functional enzymes that could be used to synthesize new materials for use in products as diverse as pharmaceuticals, electronics, adhesives, and biological sensors (to detect various bacteria and viruses, for example). The group's researchers are working toward this goal in conjunction with approximately 30 postdocs, graduate students, and technical support personnel. Enzymes are attractive because they can generate uniform products at low temperatures and pressures without allowing competing reactions to occur. They can also speed up processes--some by up to 15 orders of magnitude. And according to Alper, improbable though it may seem, some reactions that normally would take 300 million years to complete could be completed in a very short time--as short as one second--with the addition of an enzyme. At the time when Alper got the idea to form the Enzymatic Synthesis program, he was already deputy director of the Center for Advanced Materials (CAM) at Lawrence Berkeley Laboratory (LBL). He is now also associate division head of the lab's materials section. Add in teaching duties at the University of California, Berkeley, and it's clear that he doesn't have time for any hands-on science. But Alper, like the enzymes that are so prominent in his program, is a crucial facilitator of the activities of his diverse group. In some cases, the team leader says, he asks his scientists to look at their work from a new angle. For example, how might their basic research be extended to make it relevant for industrial applications? A major mission of CAM, of which the Enzymatic Synthesis program is a part, is to explore areas in materials science of importance to U.S. industry, such as adhesives, biodegradable materials, computer disk drives, and pharmaceuticals. Organic chemist Mark Bednarski enthusiastically pursues this goal. "I think now it's become even more important for society to really take a look at biotechnology," says Bednarski, "and start using it to really solve problems in materials and synthesis of organic compounds." Along these lines, Bednarski recently received a grant from the California Competitive Technology Program to support the transfer of his research on novel self-assembling materials to a Bay area company. Biocircuits Corp., based in Burlingame, Calif., plans to use Bednarski's technology to develop a device for detecting viruses. Bednarski's laboratory has designed and synthesized multifunctional molecules that can be used in sensors that selectively bind targeted molecular organisms. Another CAM team member is UC-Berkeley chemist Peter Schultz, one of the first scientists to develop catalytic antibodies. Researchers create these antibodies by injecting an animal with a stable molecule that has been designed to mimic the shape of the transition state of a reaction of interest. The antibody acts as an enzyme by forcing the substrate into the transition state shape as it binds to it. "We went to Pete Schultz and said, `You've made a lot of catalytic antibodies and they've all been basically performing biological reactions,'" recalls Alper. "`Why don't we see if we can make a catalytic antibody for a nonbiological reaction?'" They did, and it worked. Using their "abzyme," Schultz and Andrew Braisted, a graduate student in his lab, catalyzed the Diels-Alder reaction, which forms carbon-carbon bonds, in a reaction that is not known to occur in any living organism. Says Alper, "It [this research] demonstrates that the concept of catalytic antibodies can apply to any reaction, whether it's biological or not." The investigators now hope to look at similar nonbiological reactions that would have industrial usefulness and make catalytic antibodies to facilitate those reactions. Schultz is also collaborating with Michael Levitt, a professor of cell biology at Stanford University, Calif., who will use protein modeling to predict what substitutions can be made in order to give an antibody chemical reactivity and stability. Schultz will take these predictions, make the changes, and see if they work. "It's an iterative process of predict, synthesize, characterize, and predict again," says Alper. Collaborative bonds, such as the one between Schultz and Levitt, are initiated and dissolved as appropriate among the members of the Enzymatic Synthesis team. "Whether we function cohesively as a group or not depends on what's going on at a given time," says Jack Kirsch, a professor of biochemistry at UC-Berkeley and a CAM scientist. "You know what everybody is doing, more or less, and when you have a project that fits in with their expertise, you work with them and then go your separate ways." Kirsch, who considers his lab the most biological component of the group, is involved primarily in studies of an enzyme called lysozyme. He has collaborated on and off with chemical engineer Harvey Blanch and with Bednarski. Recently, Kirsch has discovered what may be a general rule that will apply to the redesign of enzymes that remain stable at higher temperatures, a feature particularly attractive to industry. One collaboration that may indeed get industry's attention is a long-distance effort between Bednarski and team member Matthew Callstrom, a chemistry professor at Ohio State University, Columbus. They have succeeded in making new carbohydrate-based materials. With the patent application written and papers soon to be published, these enzymatically derived materials are being considered for applications in protein stabilization and drug delivery. Bednarski and Callstrom's success has attracted the attention of Bruce Novack, a professor in UC-Berkeley's chemistry department with an interest in polymer synthesis. Novack is planning to join the team and work with Bednarski and Callstrom in studying the properties of these new materials. Bednarski credits his collaborative accomplishments and those of other investigators in the program to the energy levels required by the research itself. Working in what he calls "an interfacial science program" requires a lot of stamina, says Bednarski. "People who are normally doing chemistry don't do biology, and vice versa," he says. "You really have to be able to juggle three or four balls at the same time and at least know how to talk to people. This program gives us a context where we can do that." When Alper set out to assemble his team, after raising funds from the Department of Energy's Materials Science Division, he started by merely looking out his window. "When we got the idea for this program, all we did was look west, down the hill, among the hundreds of Berkeley faculty in chemistry, biology, materials science, and chemical engineering," he says. Although a few collaborators in the program are scattered--across the country at Ohio State, downstate at the Research Institute of Scripps Clinic in La Jolla, and across the bay at Stanford University--most of the team is based at LBL and UC-Berkeley, just a four-minute shuttle-bus ride apart. Alper identified those researchers who were working in areas in which he saw an overlap of interest and invited them to join--not in a whole new research project, but in an extension of the work they were already doing. The newest member of the Enzymatic Synthesis program is Daniel E. Koshland, Jr., editor of Science and a noted enzymologist. Koshland, Kirsch, and Alper together teach a biochemistry course at Berkeley. The three had discussed for several years how Koshland might become involved with the program. Recently, Koshland has been investigating what may prove to be an alternative to catalytic antibodies for creating enzyme activity where it did not exist before. His goal is to take an enzyme that catalyzes one reaction and try to genetically alter it so that it catalyzes a different one. Kirsch has done similar work on another system, and their combined efforts are focused on developing sufficient understanding of the process to allow creation of enzyme activities for specific reactions leading to materials synthesis. Alper, unlike the typical manager, doesn't have to motivate the people with whom he works. Bednarski, for example, seems to have taken head-on the challenge of making the program fly. "I think that it's finally now a solid program and you're going to be seeing more of this type of idea," says Bednarski. "I think probably we're a little ahead of our time on it, but I think you'll see more focus on trying to get proteins [instead of just enzymes] really into the use of making molecules for us. And it takes a variety of things to do that. It's not just getting the protein. You have to design a reactor, so you have to put the biotechnology into it. You have to be mobilized, and it's a big job. But once you get going, I tell you, you can't beat it. It's the best way to do things." Even with this kind of enthusiasm and future vision, there are challenges. "Very few of these people saw themselves as being involved with materials," Alper says. "And they still don't see their primary focus as materials. So, there's a lot of energy spent trying to look for overlap of interest and getting people excited about the materials aspects of things. "But, it hasn't been a major battle." Laurel Joyce is a freelance science writer based in Palo Alto, Calif.

Biochemist Catalyzes Multidisciplinary Biomaterials Research

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