here was a time not very long ago when the men and women of "animal science" toiled at the gritty fringes of academia. Clad in overalls, their boots caked with manure, these sturdy souls knew sheep, cattle, poultry and swine like their colleagues knew laboratory mice, and each new discovery was applied swiftly toward innovations in the real world of the working farm. But as a visitor to Paige Laboratory at the University of Massachusetts Amherst soon discovers, today's picture is quite different. No longer a major agricultural state, Massachusetts is putting more and more of its resident intellects to work in the service of a whole new animal: cutting-edge biotechnology. The University has kept pace by revamping the once-fragmented, applied field of animal science into one Department of Veterinary and Animal Sciences, shifting its focus to animal life at its most mysterious, fundamental level ? the genes. Here researchers are peering inside cells instead of gullets, gaining intimate knowledge of creatures great and small by sequencing the DNA in their lymphocytes. And what they are learning about cancer, infectious diseases and cell death promises to improve the lives of humans as well as domestic animals. Like the forward march of science itself, the transition was halting and gradual. When she joined the department 13 years ago, Barbara Osborne was one of the few faculty with grant support, and as a molecular immunologist groomed at Stanford Medical School and the National Institutes of Health, she wasn't exactly an expert on sheep, cows or chickens. One morning while working in her laboratory Osborne was startled by a man in soiled overalls toting a cardboard box. "He plunks the box on my desk and says 'I want you to take a look at this,'" Osborne recalls. "Inside it was a dead chicken. That's when I learned my lab had been the animal autopsy room. The farmer was very upset with me ? I didn't know anything about chickens, except that this one was definitely dead." Bringing cutting-edge agricultural biotechnology to UMass: the Department of Veterinary & Animal Sciences. All the former dairy, poultry and meat sciences were funneled into the department, which set down specific goals, including the identification of genes crucial to animal health and productivity, locating important genes, demonstrating the importance of gene expression at the cellular level, and applying this knowledge toward generating animals with increased economic value and resistance to disease. With these scientists' new way of seeing, the answer to the riddle of why the chicken died may be as exacting as the genetic code on a gnarled sliver of DNA, and post-mortems are more the domain of the gas chromatograph than the dissecting table. On this previously elusive level, we have far more in common with farm animals than we think. "Now we have people of varied disciplines doing work that can be applied to humans as well," says graduate program director Cynthia Baldwin, Ph.D., a microbiologist who did her postdoctoral research in animal diseases in Nairobi, Kenya. Baldwin is one of a trio of women professors in the department, including Osborne and recent arrival Deborah Good. Though their academic and personal backgrounds vary widely the three are friends as well as colleagues, and their research is enriched by a constant sharing of information and expertise. "It's a small department and we actually know what each other does," says Osborne, who describes herself as the old fogie of the department. If Osborne's an old fogie there's hope for all of us. Here is a woman whose exuberance is as contagious as her smile, someone who can draw a listener into the most arcane details of her science with the wit and grace of Julia Child talking us through a cassoulet. A some-time collaborator with her husband Richard Goldsby, Ph.D., a biology professor at Amherst College, Osborne's chief interests are the immune system and cell death, two of biology's most enduring puzzles with boundless implications. The immune systems of humans ? or mice, the subjects of Osborne's research ? encounter tens of millions of pathogens and crank out antibodies for each one, antibodies encoded by millions of genes. The mechanics defy the imagination, and, like spectators at a virtuoso magic show, biologists are forever asking, how do they do that? "We think that's more genes than humans or mice have," says Osborne. As it turns out, immune systems perform thanks to endless mixing and matching of DNA, and it's this mixing and matching that gives an animal's defenses such dazzling versatility. In pigs, sheep and cattle the process is different from antibody response in humans and mice, whose immune systems are fueled by cells manufactured in the bone marrow. Now that it's feasible to clone genes for particular antibodies scientists can, as Osborne puts it, "muck around" in the immune system. "So many biologists are asking the same questions, so we're always trying to narrow the focus," she says. Though Osborne is captivated by the intricate workings of the immune system, the bulk of her research effort is devoted to answering an even more compelling question: "How and why do cells die?" "Cell death occurs all the time, even during the development of the fetus ? think of the fetal hand developing from a webbed paddle," says Osborne. "Those paddle cells die in a very orderly fashion, up and down, and where you had a paddle, you now have a hand or foot. In other words, cell death shapes and sculpts the developing animal." It's a powerful concept ? death as a crucial thread in healthy development. And it's a concept that has been known to embryologists for centuries. This orderly, benevolent cell death occurs not just in embryonic development, but throughout life ? in the immune system, in the mammary glands, in the lining of the stomach. Osborne is intrigued by cell death in the immune system, which gets the message to kill off critical cells like T-cells after they go from the bone marrow to the thymus gland, which affords researchers a lens through which to make sense ofthe process. "The thymus is a great organ to study," says Osborne. "In the thymus you can actually time cell death and work with pure cells." As with Julia Child, we'll leave the finer techniques and trade secrets to her, but basically Osborne has been able through a process called DNA "subtraction" to set up a "library" of genes expressed only during cell death. "It's led to huge insights into how cells die," says Osborne. "For example, some genes are unique only to the white blood cells called lymphocytes ? if you knock out those genes lymphocytes won't die. And we've found pathways that are private ? directed to individual cells, as well as common pathways, shared among cells," says Osborne, drawing a rudimentary flow chart on the board. Each arrow in the resulting sketch reflects months and months of exacting lab work, but the lay person can grasp the stunning implications: if you use this knowledge to tell cells to die or tell them not to die, you could, say, specifically direct the death of tumor cells while sparing healthy ones, reverse the massive cell death that characterizes Alzheimer's disease, reverse fresh spinal injuries for which there is currently no hope of repair.....the possibilities go on, and they have a way of catapulting Osborne's research into unexpected directions. Most recently, she is looking at cell death in the mammary glands. "Think of the massive proliferation of cells during pregnancy and lactation," she says. "After weaning, 60 to 80 percent of those cells die. It's wonderful to study this process in mice, who have eight mammary glands." Not only is the mechanism of cell death in mouse mammary glands very close to that in humans, but it is also quite similar to cell death in the male prostate, Osborne explains. Her lab recently identified a gene that inhibits cell death in the mouse mammary gland. "It was a serendipitous finding and we want to pursue it," says Osborne, now optimistic about what this gene and related ones might tell us about the causes of and potential cure for breast cancer, the number one cause of cancer deaths in women. Like her colleagues, assistant professor Cynthia Baldwin's research has drawn her into the elusive recesses of cellular immunity. But Baldwin's work focuses on a specific pathogen, the group of bacteria known as Brucella. Affecting cattle, sheep, swine, goats, and the occasional farmer or veterinarian, Brucella wreaks havoc around the world by felling animals in a variety of ways. Brucella abortus, the bacterium Baldwin studies, causes pregnant animals to abort their fetuses, and the infected mother must be destroyed as well. "It's extremely infectious," says Baldwin, who did her postdoctoral work at the International Lab for Research on Animal Diseases in Nairobi, Kenya. Though her time these days is spent more in the classroom and the lab, Baldwin loves going "out to the barn" ? the South Deerfield farm where she draws blood samples from the cows. An animal lover, Baldwin earned her doctorate at Cornell University's veterinary school, where she became acquainted with cows ? and brucella. Brucella affects wild as well as domestic animals and it has plagued the herds of bison that roam the meadows of Yellowstone National Park. But the biggest toll is on dairy cattle. In 1996, 141 herds were infected and 112 herds had to be, in agricultural parlance, "depopulated." Still, the situation is better than it was. There are two Brucella vaccines, but together they protect only 70 percent of animals inoculated, says Baldwin, who shares an office suite with her husband, assistant professor Samuel J. Black. (They met and married as researchers in Africa, where their two children were born.) Baldwin hopes her research will lead to a more effective vaccine, and the U.S. Army is very interested because Brucella is common in the strategically important Middle East, where the bacteria turns up in unpasteurized milk and cheese. Baldwin has known "quite a lot" of people infected with Brucella. It's an occupational hazard, she says, though Baldwin faces little risk from the weakened strain with which she herself works. Like malaria, it's an infection that compromises the immune system for life, announcing its colonization with chills, cyclical fevers, anorexia, and eventual arthritis. "It's not like a strep throat," says Baldwin, shuddering ever so slightly. "Antibiotics can help, but they can't cure it." What Baldwin and her research team hope to develop is an attenuated vaccine, one that's strong enough to trigger an immune response but is unable to survive. "Sometimes you can use pieces of a pathogen, other times the toxin alone," says Baldwin, whose investigations are focused not on the bacterium but on the specific immune response to it by its host (in this case, mice). "If we can understand that immune response, we can alter it," says Baldwin, who is also probing the abundance and role of a specific type of white blood cell called gamma-delta-T-cells, discovered in cattle about 13 years ago. While Baldwin and Osborne are "mucking around" in animal immune systems, department newcomer Deborah J. Good is investigating the role of a particular family of genes in the development of the nervous system. A molecular biologist, Good earned her doctorate at Northwestern University and went on to do postdoctoral work at the National Institutes of Health in Bethesda. A self-described small-town girl from upstate New York, the soft-spoken Good never imagined she'd earn a place among the sharpest minds of her generation, someone who'd acquire her first patent while still in her twenties. "I originally studied to be a medical technician," says Good, who like her colleagues is married to a scientist, albeit one in the private sector who for proprietary reasons must keep his research secret, even from his wife. "I just hadn't set my sights very high." In the lab of NIH senior scientist Ilon Kirsch, Good proved herself a dogged and imaginative researcher. And when Good, whose earlier research focused on genetic factors in a form of leukemia, uncovered the role of two important proteins in the developing nervous system, Kirsch dispatched her to the side of a veteran researcher who proceeded to teach Good everything she knows about mice. "I was excited about my discoveries and thought, this is great it's the decade of the brain," says Good. The only trouble was that Good, by then fluent in molecular biology and cell culture, knew "nothing" about neurobiology, and even less about mice. She set about educating herself, and the result is her creation of so-called "knockout" mice ? mice in whom Good was able, through recombinant genetic techniques, to delete specific genes' coding for the production of the important proteins she hopes to demystify. To establish a colony of recombinant mice, Good spent over a year breeding normal mice to altered "chimera" mice. Her persistence paid off when the first group of mice with altered genes from each parent ? the homozygotes began dying at around 8 months of age, compared with the two-year life span of normal mice. Until their abrupt demise the mice seemed healthy. What is it about their nervous systems that dooms them, all for the lack of two proteins? "I'm very interested in how the nervous system develops," says Good."By studying these two genes I hope to describe their role in central nervous system development." Good is also using knockout mice to uncover clues about reproductive development. What motivates this parallel interest is quite obvious even from a grainy reprint of Good's snapshots of the mice ? the male knockout mice are obese and have tiny underdeveloped gonads. One need not grasp the arcana of Good's research ? a potentially numbing litany of acronyms and codes ? to appreciate how the department nurtures her curiosity and enthusiasm. Sitting at her desk with its mountain of background materials for the grant proposal she's writing, Good has settled into her new home with notable ease. With the department's blessing she is training a molecular biologist's eye on crucial questions in animal science, and her name sums it up for this newcomer as well as her two colleagues good for animals, good for humans, good for science. BACK TO TABLE OF CONTENTS