Maryland Biotechnology Facility Stimulates Protein Engineering

Consortium's technology for synthetic protein engineering offers access to one of the next hot fields in biotechnology WASHINGTON -- Proteins! That's what his elders would tell Dustin Hoffman to pursue instead of plastics if the 1960s movie The Graduate were set in the 1990s. That's where the next revolution in man-made materials will be. And that's why the federal government, the University of Maryland, and local politicians have invested $8 million to set up a protein engineering laboratory, the Center for Advanced Research in Biotechnology (CARB), in Rockville, Md. They're betting that molecular biologists can tailor proteins to do exactly what they want them to do. One day, scientists hope, these "synthetic" proteins will outperform their natural counterparts, just as polypropylene outdoes wool and cotton in keeping people warm today. As drugs, custom analogs should work at lower doses and cause fewer side effects. They will also be made into industrial enzymes that last longer or work at higher - or lower - temperatures. Eventually, "biotronic" computers may replace electronic machines. To realize these goals, scientists need to know much more about how nature makes and shapes proteins. They must better understand how changes in a protein's chemical makeup affect its properties. Consequently, protein engineering is a high priority for forward-thinking drug and chemical companies. The Japanese and British governments have backed industry-university-government consortia to get a head start. And now, with CARB, so is the United States. CARB is one of six centers that make up the Maryland Biotechnology Institute. The institute employs 250 people and receives $15 million in grants and contracts. Other centers focus on agriculture, medicine, marine biotechnology, public policy, and biomanufacturing. One feature that sets CARB apart from the pack is its state-of-the-art facilities, including a computer and graphics laboratory complete with a minisupercomputer and workstations. Its scientists examine the structure of molecules through X-ray crystallography; soon they will also use nuclear magnetic resonance (NMR) spectroscopy. Officially established six years ago, CARB didn't open its facility until last fall. And its debut has been fairly low key. Scientists at nearby Johns Hopkins University in Baltimore barely know of its existence. And so far just four companies have asked CARB to do work for them, and at least two of the four had personal ties with scientists there. So its reputation is far from established, but CARB does have local industry and academic, county, state, and federal officials rooting for it. "It's one of the best facilities in the metropolitan [Washington] area," says Yasuo Iriye, senior director of Otsuka America Pharmaceuticals Inc., which has its headquarters next door to CARB. "Not very many biotechnology companies can afford this equipment." When Otsuka needed to know more about a protein it wanted to use as a starting point for making a new cancer drug, it turned to CARB for help. "They came to us and, with no questions asked, handed us a bag of protein," recalls CARB Director Tom Poulos. CARB scientists are now making an analog to a natural cytokine. Once the structure of this molecule has been determined, Otsuka hopes to develop it into a drug. Iriye says that his parent company in Japan does not have ready access to such expertise. Instead, the equipment and scientists exist in just two national centers in Japan, and companies must wait their turn to have their products investigated. For one California company, nothing in its home state could offer as good an arrangement as CARB could. "It's something that could be done here with academic collaboration, but CARB understands a corporation's needs," says James Jenson, director of protein chemistry at Triton Biosciences in Alameda, Calif. Jenson's biotechnology firm has been working on a transforming growth factor that promotes healing and also seems to play a role in tumor growth. Jenson says that his company's scientists need to learn more about the growth factor and how to change its shape to make it work better. "Structure is a very important first step," he notes, "and that is something that CARB excels in." For now, CARB is primarily a university-government operation. Scientists either work for the federal government and have a civil service ranking, or they hold tenure-track faculty positions. "Here's a mix of two types of employees working at the same lab bench," says Poulos. He estimates that half of CARB's support will come from the federal government, primarily through the National Institute of Standards and Technology (NIST). For 30 years, NIST has had a similar arrangement with the University of Colorado in Boulder, where NIST and university researchers collaborate in astrophysics. The Maryland center's link with NIST "started with a handshake," recalls Donald R. Johnson, director of technology services for NIST. During the early 1980s, NIST's predecessor, the National Bureau of Standards (NBS), was assessing how it might best serve the nascent biotechnology industry. "It became very clear that biotechnology was an academic-based and research- intensive activity and that it would be advantageous for NBS [NIST] to have a coupling to the academic world," Johnson recalls. "We needed collaboration and a channel for communication." NIST wasn't the only one taking an interest in biotechnology. The University of Maryland, in an assessment of its technological strengths, decided to focus on biotechnology. And Montgomery County, looking toward its economic future, couldn't help noticing that it was home to the National Institutes of Health and other federal agencies, as well as to one quarter of the nation's biomedical scientists. While its industrial strength had been in communications and information technology, the county also contained dozens of biotechnology service companies. The question was how to leverage these biotechnology assets to create economic growth. "They were looking for a research centerpiece," says Johnson, who had served on a local planning board. At the same time, the University of Maryland recognized that an association with NIST would place it a cut above biotechnology centers in other states and might hasten national recognition. Countless presentations and negotiations later, the three-way partnership was forged. The county provided land and helped negotiate the purchase of adjacent private property. NIST provided staff and interim laboratory space. Faculty positions and other support were provided by the University of Maryland. It was a "genuine, unequivocal partnership with industry and all levels of government," says Rita Colwell, director of the Maryland Biotechnology Institute. Thanks to NIST participation, CARB was up and running in record time. For two years, its scientists worked in NIST laboratories. As experts in theoretical chemistry, NIST researchers add another dimension to CARB. Also, their agency has a long history of collaboration with industry. Since the 1970s it has run an automated manufacturing test facility that involves 20 universities and 50 companies. Its own laboratories are host to 1,100 visitors a year, about 200 of whom are company scientists working on their own projects. This staff and their collaborators generate more patents per scientist than any other federal agency. "CARB has been very carefully orchestrated to focus on the very basic underpinnings of biotechnology," says Johnson. "We're in the process of developing a world-class capability of determining the structure and function of a given protein and developing fundamental tools which industry is interested in." One way that CARB hopes to achieve that goal is to have the best possible equipment on hand. "Other major labs have the basic facilities that we have, but they don't have the quantity of things that we have," says Gary Gilliland, a CARB fellow. "It's unusual to have what we have all in one place," adds Poulos. The center also offers what Poulos calls "complementary sets of talent." Within CARB's 40,000 square feet of lab space are crystallographers, molecular biologists, and specialists in nuclear magnetic resonance, working together to probe the secrets of proteins. "The crystal growth of biological molecules is an empirical procedure, a black art," Gilliland explains. Their surfaces are so complex that it is difficult to predict how these substances will crystallize. Even with X-ray crystallography, it can take years to learn one protein's structure. Nuclear magnetic resonance spectroscopy is faster but works just for proteins with fewer than 100 amino acids. The analysis can take one person six months. Call it Maryland's answer to Silicon Valley in California. Or to the Route 128 corridor in Massachusetts. State officials see no reason why they cannot use biotechnology to generate the same type of high-tech booms in their communities that the electronics industry made possible here. Or so CARB's planners and a few of its scientists would like to believe. Already, Maryland ranks second to California in number of biotechnology companies, according to a 1988 survey by the former consulting firm Arthur Young and Associates. The 141 biotechnology firms within its borders fall below California's total of 273, but the number places it well ahead of New Jersey, Massachusetts, and North Carolina, each with about 90 biotech companies. No doubt one attraction is the neighborhood: The National Institutes of Health, the Food and Drug Administration, the U.S. Department of Agriculture, and Johns Hopkins University are all within an easy commute. And proximity breeds success. Each year, for example, about 40 percent of the $500 million that NIH awards for contract research stays in Maryland. These federal agencies also provide a highly skilled labor pool. NIH's 14,000 employees include thousands of leading biomedical scientists, while the FDA has 3,500 scientists in its Maryland laboratories. About one quarter of the nation's biomedical experts - and an estimated 183,000 scientists and engineers overall - reside in the region. Plus, 14 of the 200 largest banks and 33 major venture capital firms are based in the state and can provide backing for new biotechnology ventures. Last year the state sponsored a conference to look at global market opportunities, and it has set up an international trade program to introduce its companies to potential clients. The Maryland Industrial Partnerships Program, operated through the University of Maryland, provides matching funds for research and development. The state is considering a joint effort with its university and the private Johns Hopkins University to set up a pilot plant for making biopharmaceutical grade compounds. They would be made available to local small biotechnology companies that could not afford to set up their own manufacturing facilities. The Maryland Biotechnology Institute is supposed to help shepherd this development and provide the facility with a scientific underpinning. The counties, too, have jumped onto this biotechnology bandwagon. To encourage more growth in biotechnology, Montgomery County set up the 288-acre Shady Grove Life Sciences Center and helped build the Center for Advanced Research in Biotechnology. Howard County, a northern neighbor, offers $4,000 grants to qualified biotech companies. Other efforts include a High Technology Council, set up in 1985 to improve the climate for such companies. The council, in turn, has spawned the Biotechnology Network, which coordinates a monthly meeting of about 75 companies in the field. --E.P. The theoretical challenges are daunting. Genetic engineers are sophisticated enough to make precise, tiny changes in proteins by cutting out, inserting, or rearranging the genetic codes that are the blueprints for these proteins. What scientists cannot yet predict, however, is how these substitutions affect the protein's ultimate shape. The amino acid chain folds in a complex way, forming helixes and plateaus essential in determining the protein's ultimate function and effectiveness. The computer helps scientists make intelligent guesses. For example, Fred E. Coehe, assistant professor of pharmaceutical chemistry at the University of California, San Francisco, uses modeling to work on the folding of interleukin-2. But his computer, at best, provides only 75 percent of the answer. A complete understanding and predictions, he says, could take 20 years. CARB expects to give a boost to the entire field of protein engineering. Gilliland has put together a database with all the details for diffraction studies of protein crystals and about how those crystals are made. Gilliland's goal is to open enough channels of communication to create a synergy that will make protein engineering flourish nationally as well as locally. Toward that end, CARB has sponsored conferences and will soon start a monthly Washington-Baltimore Structural Biology Colloquium. "The main problem is one of trying to get people to sit down and have coffee together," says William F. Harrington, a biologist at Johns Hopkins University. "That provides the stimulation and the creativity." There is potential, for example, for cross-fertilization of ideas between CARB and the University of Maryland Medical Center, the other centers of the Maryland Biotechnology Institute, and Johns Hopkins, where last year Harrington and about 20 other colleagues set up the Institute for Biophysical Research on Macromolecular Assemblies. The new Hopkins institute is trying to understand how proteins work at the next level of complexity - in the context of living systems. Harrington, for example, studies how muscles contract. The institute's scientists rely on some of the same techniques being mastered by CARB scientists, but also must develop new ones that allow researchers to study proteins in action. Overlap of a different sort, between applied and basic research, is common in the field of protein engineering. So CARB's creators expect to develop increasing involvement with local companies. "We're unique in our accessibility," says Poulos. Located in the heart of Maryland's biotechnology corridor, CARB wants to make it easy for companies to link up easily and quickly and avoid the need to have similar labs of their own. Even larger companies could benefit by buying into CARB's collaborative approach, says Dale Oxender, director of the Center for Molecular Genetics at the University of Michigan. Companies like Monsanto, Du Pont, Eli Lilly, and Upjohn have their own setups, he notes, "but there's a lot of reinventing the wheel. If they got together and made one huge facility, then they would advance more rapidly." CARB's Poulos thinks industrial participation will come in time. In the meantime, he's concentrating on building a strong reputation. "What we want to do is establish ourselves as scientific leaders." Poulos says the center is already a leader in cytochrome 450, an enzyme important in detoxification, and beta-lactamase, an antibiotic-degrading enzyme. His scientists have the lactamase structure in hand and hope to use it in rational design of drugs. In the future, he says, "I don't think it will be necessary to solicit business." He hopes CARB will double and add a new building and more chemists who will study biomimetic materials, molecules that act like proteins but are not as easily degraded by the digestive system. Johnson hopes that eventually companies will send their own scientists to CARB, giving them the chance to bounce their ideas off others at the same time they work on their own projects. "In some respects it [CARB] is a model," he adds. "It lets them participate in a research game that requires a critical mass that they could not otherwise achieve. This kind of collaboration can be a very, very fruitful way to work." He recognizes that such arrangements require the working out of intellectual property rights. But he believes that the Technology Transfer Act of 1986 allows federal scientists the flexibility needed for both sides to reach an acceptable agreement. "We would like very much to develop CARB further as a national center," says Colwell. "It's a mechanism to bring the U.S. to the fore [in biotechnology]."

Maryland Biotechnology Facility Stimulates Protein Engineering

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