It was a dream that Schöler, who runs Penns Center for Animal Transgenesis and Germ Cell Research, nursed for nearly a decade, starting with his co-discovery of a tiny molecule he named Oct4. Exclusive to embryonic stem (ES) and early germsperm or egg precursorcells, Oct4 was described by Schöler in 1989 as a transcription factor (protein that guides DNA in encoding other proteins) that confers the hallmark property of an ES cell: pluripotencyor the ability to become almost anything. In practical terms, pluripotency is what allows that little clump of cells that forms after sperm and egg meet to spin off into neurons, heart, liver, kidney cells and build a fetus.
After Gearhart and Donovans landmark harvest of human embryonic germ cellsfrom aborted fetusesin 1998, researchers scrambled to induce these versatile cells to morph into every kind of cell imaginable. But they were stumped because there were two things ES cells refused to become: germ cells and the placenta-forming trophoblasts. For Schöler, now the Marion Dilley and David George Jones Chair and Professor of Reproductive Medicine in the School of Veterinary Medicine, this became a driving obsession.
Schöler sits behind his desk at the Center for Transgenesis, which consists of four major laboratories housed on two levels of the research building at New Bolton Center, Penns large-animal hospital, and another lab in Center City. As he searches for the right words to explain his pursuit, he seems to find speech inadequate to convey his zeal. So Schöler starts to draw. He quickly sketches the three tissue layers that form an embryo. If an embryo can produce its own germ cells to fill up its ovaries and testes, reasons Schöler, as he prods his sketch with a black marker, why then cant ES cells do this in a dish?
Though he had pondered this question while still in his German homeland, he knew that it was not the place in which to seek the answer. In the persistent shadow of the Third Reichs mission to genetically engineer a master race, Germany had turned a cold shoulder to human stem-cell research, strictly limiting the practice even today.
Born in Toronto, Schöler, 50, grew up in his parents native Germany. At the University of Heidelberg, he earned his diploma in biology followed by his Ph.D. in molecular biology. And he developed a keen interest in gene regulation and developmental biology, particularly as they relate to the germ line.
Ive always been interested in what distinguishes body cells from germ cells, he says. Germ cells are fascinating because they link one generation to the next.
After several years in academe and industry, Schöler went to the European Molecular Biology Laboratory (EMBL), to head his own research group in 1991. There, he was rejoined by former colleague Karin Hübner.
Hübner, who grew up on skis and surrounded by animals in the Bavarian Alps, had always had a knack for science. She studied biochemistry, became certified as a laboratory technician, and went to work in the lab of Nobel laureate Feodor Lynen, who was investigating the regulation of cholesterol and fatty-acid metabolism. Hübner then moved on to the fields of cell biology and neurochemistry, and finally molecular biology. She worked with Schöler on the Oct4 protein and shared his gusto for the mysteries and promises of ES cells.
By the late 1990s, Schöler, who currently sits on the stem-cell research advisory board for Germanys conservative Christian Democratic Party, had achieved fame for his accomplishments in the stem-cell field. But with little enthusiasm or funding for his research in Germany, he set his sights on the University of Pennsylvania. Philadelphia was emerging as the international hub of stem-cell research, and Penn offered a sturdy emphasis on the basic sciences.
Penn has more talent in its clinical and basic-science labs than anyone else in the world, says Dr. Glenn McGee, assistant professor of medical ethics at Penns School of Medicine. No other institution can compete with Penn when it comes to answering the question, Whats in the dish?
Most importantly, says Schöler, Penn offered Dr. Ralph L. Brinster V60 Gr64, the Richard King Mellon Professor of Reproductive Physiology at the veterinary school. Brinster, whom Schöler calls the godfather of so many things, is perhaps the worlds premier contributor to the field of genetic modification of the germ line. Schöler welcomed the opportunity to collaborate with him. So in the summer of 1999, he moved with his wifean attorneyand two school-age sons to the Philadelphia suburbs.
Hans Schölers arrival really strengthened stem-cell biology at Penn, says Narayan Avadhani, the Harriet Ellison Woodward Professor of Biochemistry and chair of the animal-biology department at the veterinary school. Avadhani says that the Brinster-Schöler stem-cell tag team propels the veterinary school which, according to officials in its deans office, has invested more than $15 million on stem-cell research thus farahead of other stem-cell powerhouses like Johns Hopkins and the University of Wisconsin to become the world leader in the field.
Hübner, who had spent some time working in Texas, was eager to bring her ES work to the States. She and a few others followed Schöler and, by late summer, Hübner was hooked into a new missionto generate oocytes from mouse ES cells. Though enticed by the idea of pushing ES cells to make this transformation, a notion she and Schöler had discussed for several years, she was not convinced that her microscopic subjects would cooperate.
I cant say I figured, Yes, yes, theyre going to do it, she recalls. It was more like, Lets try it, and lets see.
The key to the project was finding a way to recognize the germ cells, if and when they developed. To this end, Schöler and Hübner had years earlier created a stem-cell marker using green fluorescent protein (GFP). As soon as she began the current endeavor, Hübner transformed her ES linederived from male-mouse embryoswith a tailored Oct4 transgene designed to activate GFP only in early germ cells. Hence, cells in the early germ stage were programmed to glow green.
For months, Hübner toyed with the construct, altering the Oct4 and manipulating the cell densities and culture conditions.
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The Most Amazing Cell