Biotech Blooms at the University of Georgia

Clifton A. Baile The two-decades-old biotech industry remains largely concentrated in a few epicenters. Now Georgia is about to stake its claim on the biotech map, thanks to an unusual synergy of state government, industry, and academia. Since 1990, the Georgia Research Alliance (GRA) has purchased equipment, erected new facilities, and supported eminent scholars, building on existing infrastructure and scientific talent at its six major research universities. A series of losses in the 1980s to other states--including elusive microelectronics and semiconductor industry bids, as well as the exodus of the homegrown biotech company Amgen--catalyzed the birth of the GRA in 1990. "The effort sees discoveries as a set of mechanisms, with scholars as centerpieces who will assemble integrated teams of experts to ease transition of basic research results to the marketplace," says Clifton A. Baile, an eminent scholar in agricultural biotechnology at the University of Georgia (UGA) in Athens, where he has been the coordinator for the Applied Genetic Technology Resource (AGTEC). With seven new facilities planned, AGTEC has already spawned start-up companies that represent a Noah's ark of possibilities in biotechnology. The coming explosion of genomics information is fueling formation of these commercial efforts, and at the same time uniting them and the traditional fields they represent in novel ways. UGA's new Animal and Dairy Science Complex sets the stage for an impending marriage of agriculture and biotechnology. The labs on the fourth floor, comprising the animal biotechnology resource, look much like any cell and molecular biology facility. They contrast sharply with the growth pens, slaughterhouse, and attached sewage treatment plant and stockyard on the ground floor. Two particular labs symbolize the coming union: a bench facility to study muscle biology linked to a kitchen for taste-testing meat. This first-floor facility in the months before its occupation by nonhuman animals is impressive. State-of-the-art surgical research areas are near a pig farrowing room where pens are designed to monitor feeding and prevent sows from crushing piglets. A "ruminant metabolism room" is a high-tech toilet of sorts, where excrement and urine will be collected for gastrointestinal studies. The ground floor also houses labs for microinjection and embryo implantation, the tools of cloning. Other areas will accommodate rodents, chickens, and fish. Discoveries made at the cell and molecular level on the fourth floor will determine the types of experiments conducted below. The doors upstairs are already marked with the names of the new companies, where work is under way to find more efficient routes to environmental monitoring, enzyme and pharmaceutical production, food improvement, and bioremediation. Richard Winn has introduced mutation-detecting bacterial genes into fish eggs. Mariner Biolabs LLC's first product will be transgenic medaka, a Japanese freshwater fish. Richard Winn, cofounder and associate research scientist in the school of forest resources, has introduced mutation-detecting bacterial genes aboard phage and plasma vectors into fish eggs. After exposure to tainted effluents, the transgenic fish are ground up and these genes scanned for mutations, an environmental indicator. Fish offer numerous advantages over rodents, Winn says, not the least of which is a better image among animal rights activists not as enamored of the scaly as the fuzzy.1 "Fish are easy to grow and manipulate, and they provide a cost-effective, rapid way to look at the same DNA damage that you would use other vertebrates for," says Winn. A fish costs pennies a year to raise, compared to about 20 cents a day per rodent, he adds. GREAT POTENTIAL: Aureozyme Inc. has taken genes from anaerobic fungi that normally live in the bovine rumen and transferred them to E. coli and yeast, for production of hydrolytic enzymes that have eclectic applications. Aureozyme Inc. traces its roots to cow stomachs, where anaerobic fungi produce hydrolytic enzymes that rapidly convert plant cell walls to fermentable sugars, a talent with applications in the detergent, textile, feed, brewing, bakery, pulp and paper, chemical, and remediation industries. But these more economical enzymes aren't very accessible in their natural setting. "So we move the genes to easily cultivated organisms, such as E. coli and yeast, at an industrial scale," says vice president for research and development Xin-Liang Li. The technology is based on the work of Lars Ljungdahl, the Georgia Power distinguished professor in biotechnology and professor of biochemistry and molecular biology at UGA.2 AviGenics Inc. sees chickens in a new light, as living bioreactors to manufacture drugs. Transgenes use the ovalbumin promoter, and are introduced directly into blastoderm cells through holes made in fertilized eggs. "The egg is a wonderful protein delivery platform. Ovalbumin accounts for two grams of the total five grams of protein of an egg. With that expression level, one chicken is the equivalent of 20 to 25 goats," says Andrew Wooten, director of corporate development. The first transgenic chicken, named ALVin, incorporated a vector and passed it to the next generation. UGA recruited scholar Steve Stice from Advanced Cell Technology in Amherst, Mass., where last year he led the team that cloned several cows from fetal fibroblasts.3 Stice arrived in Athens in mid-October, to hold a 51 percent position as university professor and a 49 percent appointment as chief scientific officer of OptiGen Inc., formed by Stice, Baile, and business manager George Murphy to scale-up cloning of hogs and cattle. But unlike Charlie and George, the cloned calves of last year's headlines, the cloning protocol at UGA will use nuclei from adult cells, a la Dolly. The reason is the focus on improving agronomic characteristics, where "it is important to clone from adult cells, because we have to know what the phenotype is," explains Stice. The first goal is the $11 billion domestic hog market, where within four years clients will pay several dollars per animal cloned to include specific characteristics, Stice predicts. "Cloning allows us to introduce genetic change faster than artificial insemination. Although cloning will have a place in agriculture, not all animals will be clones, because we have to use traditional breeding to introduce new variants," he adds. Stice foresees producers raising several different cloned herds, to control traits while maintaining some genetic diversity. The botanical component of AGTEC is in an earlier phase than the companies coalescing from animal biotech. The lag reflects biology--compared to their zoological counterparts, many plant genomes are enormous and peppered with large and complex gene families. Plus, many crop species are notoriously resistant to receiving foreign genes. The first start-up is PhytoWorks Inc., which uses transgenic trees to detoxify heavy metal and organic contaminants. Consider mercury, which taints tens of thousands of sites in the United States. Richard Meagher, chief scientific officer and professor of genetics, and his colleagues have transferred bacterial genes that convert ionic mercury to the less toxic inert form to Arabidopsis thaliana4 and yellow poplar,5 using microprojectile bombardment. The transgenic plants release the mercury as a harmless gas. The ultimate bioremediation target is organic mercury, which forms from the ionic version. "Methyl mercury is biomagnified from a million to hundreds of millions of times in wetlands. Bacteria make methyl mercury in an anaerobic zone one to two inches below the soil surface, and rotifers, crabs, and other organisms concentrate it millions of times, to levels that damage the gastrointestinal and nervous systems," explains Meagher. So far, his transgenic plants thrive amid the toxin. "We can hit them with levels of methyl mercury no plant has ever seen." Farther down the road to commercialization, a nucleus of researchers from arts and sciences, agriculture, and forestry is coming together to identify common applications of genomics, molecular markers, and transgenics. "The vision of AGTEC is to bring to the table technology that is basic on the one hand, and applicable to the field on the other hand. This is a challenge for all of us, because our disciplines until now have evolved separately," explains Roger Boerma, a research professor and coordinator of the center for soybean improvement. And so researchers who typically deal with flats of soybeans or peanuts are now working with investigators more accustomed to DNA sequencers. Boerma, assistant professor of forest resources Jeffrey Dean, director of the plant center Lee Pratt, and professor of crop and soil sciences Wayne Parrott are using genetic markers and genomics to identify and track traits, then they plan to apply transgenesis to create new crop variants. For example, Boerma used markers to reveal why breeding a high-yield but insect-resistant soybean had proven elusive--six genes control resistance. Once they knew that they were dealing with a quantitative trait, Boerma's team was able to design a strain with both desired characteristics. "In traditional breeding, we'd attack a previously intractable trait with selection. But using markers saved us years," he relates. Discovering natural resistance genes also avoids reliance on synthetic insecticides and is cheaper. AWAITING COMPANY: This pig will soon by joined by cloned, transgenic brethren at the University of Georgia if research succeeds. Another technology--vaccine crops--will unite the animal and plant arms of AGTEC. "We are putting genes encoding antigens for three viral diseases of chickens--avian flu, Newcastle disease, and infectious bronchitis--into soybeans, so that we can feed and vaccinate chickens at the same time," explains John Ingle, director of biological resources and biotechnology and associate vice president for research. Vaccine crops will be safer and more effective than existing approaches. "Now chickens are vaccinated by spraying an attenuated virus. But the animals still get sick and don't lay as many eggs. Plus, the virus can mutate back to virulence, or recombine with other viruses," says Parrott. The evolution of corporate biotechnology at UGA is not without controversy. Transferring genes between species transcends the capabilities of traditional agriculture, a long-standing presence at the university. And at a public lecture Stice gave on Feb. 10, sponsored by the student-run Sagan Society, several people questioned his dual role as professor and entrepreneur. But the scientists involved view the symbiosis as a natural step in the evolving relationship between academic life science and commercialization of new types of products that basic discoveries have made possible. And with potential offerings as eclectic as chicken bioreactors, cheaper fungal industrial enzymes, bioremediating trees, and piscine toxin detectors, the possibilities seem limited only by the imaginations of researchers. Sums up Stice: "Companies will work side by side with professors to develop new technologies. This will give students a head start in finding out what industry is about. It is a great idea and it is working well. A lot of good science comes out of industry-supported science." Ricki Lewis (rickilewis@nasw.org) is a textbook author and a contributing editor for The Scientist. J. Wittbrodt et al., "More genes in fish?" BioEssays, 20:511-5, December 1998. W.S. Borneman et al., "Fermentation products and plant cell wall-degrading enzymes produced by monocentric and polycentric anaerobic ruminal fungi," Applied and Environmental Microbiology, 55:1066-73, 1989. E. Pennisi, "After Dolly, a pharming frenzy," Science, 279:646-8, Jan. 30, 1998. C.L. Rugh et al., "Mercuric ion reduction and resistance in transgenic Arabidopsis thaliana plants expressing a modified bacterial merA gene," Proceedings of the National Academy of Sciences, 93:3182-7, 1996. C.L. Rugh et al. "Development of transgenic yellow poplar for mercury phytoremediation," Nature Biotechnology, 16:925-8, October 1998.

Biotech Blooms at the University of Georgia

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