John Gearhart

File photo It is a sobering time for US stem cell researchers. Just days after a national election set the stage for the possible criminalization of embryonic stem cell research, a popular television program portrayed such cells incubating in patients in coma, ready to be used to treat a wealthy man's Parkinson disease. A video presented at the American Society for Human Genetics annual meeting in Baltimore a month earlier, however, told a very different story--this one real. The video showed rats that had been paralyzed with virally induced spinal muscular atrophy. A few were hobbling about, some dragging their hindquarters or taking halting, stumbling steps, courtesy of human neural stem cells infused into their spinal cords. Doug Kerr, assistant professor of neurology at Johns Hopkins University School of Medicine, provided the spinal cord injury model and protocol, and John Gearhart, professor of obstetrics and gynecology at Hopkins, supplied the stem cells. It's been four years since Gearhart was thrust into the budding stem cell spotlight when he and then-postdoctoral researcher Michael Shamblott described culturing of embryonic germ (EG) cells.1 "John Gearhart's work with primitive mouse and human embryonic germ cells clearly demonstrates the pluripotential nature of these stem cells. His recent experiments showing recovery of neuromuscular function in the hind limbs of adult rats are impressive," says Donald Orlic, an associate investigator with the hematopoiesis section at the National Human Genome Research Institute in Bethesda, Md. Today, stem cell researchers face a public eager for cures yet mistrustful of research involving embryos, while basic understanding is far from complete. Gearhart remains optimistic by focusing on the science. "There's a definite Alice-in-Wonderland quality to stem cell research these days, with unexpected twists and turns and unusual characters. Nothing appears as it seems to be from the point of view of classical embryology," he says, referring to the ability of stem cells to seemingly escape their embryonic boundaries.2 Gearhart is an ex-Drosophila geneticist who detoured into mammalian development. His arrival at Hopkins in 1980 cap-ped an unusual personal trajectory. "My dad was a coal miner in western Pennsylvania who died when I was 3. My mother couldn't take care of three young sons, so when I was 6, I became a ward of the state. I lived in an orphanage in Philadelphia, but I went home on occasion," Gearhart recalls. His mother remarried, and her new husband bought an orchard. Shades of Gregor Mendel, the young Gearhart became fascinated with growing fruits. That interest continued at Pennsylvania State University, where Gearhart studied horticulture. In his second year, he took a genetics course, "and I fell in love." His doctoral work focused on control of gene expression in Drosophila with Bruce Wallace at Cornell University. Along the way, Gearhart interacted with a who's who of biologists. "Barbara McClintock was on my PhD committee. I did a postdoc for four years with Beatrice Mintz at the Fox Chase Cancer Center [in Philadelphia]. And later on, I trained Rudolf Jaenisch and Karl Illmensee," he recalls. At Hopkins, Gearhart has worn many hats, investigating the mammalian embryo, Down syndrome, and running the in vitro fertilization (IVF) clinic under the guises of obstetrics/gynecology, cell biology, basic science, physiology, and the Bloomberg School of Public Health. He is the C. Michael Armstrong Professor of medicine and will soon move to the new Institute for Cell Engineering. Gearhart's interest in embryonic stem cells (ESCs) began in 1992, when he and others, familiar with the cells from mouse knockout technology, began to consider applications in regenerative medicine. Dismissing "IVF leftovers" as a source because the people who donate them have fertility problems, Gearhart turned instead to EG cells, which come from 5- to 7-week-old aborted human embryos. He and Peter Donovan, then at the National Cancer Institute and now at Jefferson Medical College in Philadelphia, began culturing EG cells into stem cells in 1993, with help from Geron Corp., Menlo Park, Calif., in 1995. "John moved from doing imaginative human-disease-directed work with mice, using transgenic approaches, to being one of the pioneers of human stem cell technology. He suffered the problems that all the human ESC/EG original workers had: They could not get government funding. John persevered with industrial support," says Barbara Knowles, director of research at the Jackson Laboratory in Bar Harbor, Maine. In July 1997, at a meeting in Colorado, Gearhart and Donovan unveiled their human EGs,3 but it wasn't until the 1998 publication1 that "all hell broke loose," Gearhart recalls. Today, disapproval of using human prenatal material is dampening some researchers' enthusiasm. "When I talk to graduate students and postdocs, I sense hesitancy. They are thinking, 'Well, if I do this, where will I work?'" Gearhart says. At least one researcher, Roger Pedersen, has left the University of California, San Francisco, for the United Kingdom. Despite the bleak climate, Gearhart remains upbeat. "The power is from what we're going to learn about how cells are programmed, and how they can be reprogrammed. Cell-based therapies will come from this understanding. In the long run, what we learn from stem cell biology will be more important than the cells themselves." Ricki Lewis (rickilewis@nasw.org) is a contributing editor. References 1. M.J. Shamblott et al., "Derivation of pluripotent stem cells from cultured human primordial germ cells," Proceedings of the National Academy of Sciences, 95:13726-31, 1998. 2. R. Lewis, "A paradigm shift in stem cell research?" The Scientist, 14[5]:1, 2000. 3. R. Lewis, "Embryonic stem cells debut amid little media attention," The Scientist, 11[10]:1, 1997.

John Gearhart

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