It was a dream that Schöler, who runs Penn’s 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 germ—sperm or egg precursor—cells, 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: pluripotency—or 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 Donovan’s landmark harvest of human embryonic germ cells—from aborted fetuses—in 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, Penn’s 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 can’t 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 Reich’s 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.

“I’ve 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 Germany’s 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 Penn’s School of Medicine. “No other institution can compete with Penn when it comes to answering the question, ‘What’s in the dish?’”

Most importantly, says Schöler, Penn offered Dr. Ralph L. Brinster V’60 Gr’64, 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 world’s 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 wife—an attorney—and two school-age sons to the Philadelphia suburbs.

“Hans Schöler’s 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 dean’s office, has invested more than $15 million on stem-cell research thus far—ahead 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 mission—to 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 can’t say I figured, ‘Yes, yes, they’re going to do it,’” she recalls. “It was more like, ‘Let’s try it, and let’s 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 line—derived from male-mouse embryos—with 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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2003 The Pennsylvania Gazette
Last modified 09/02/03

FEATURE: The Most Amazing Cell
By Joan P. Capuzzi Giresi
Illustration by Julia Vakser

Dr. Hans Schöler: “We now have a tool to get a better understanding of the biology of the oocyte.”

Dr. Karen Hübner: “Even if it’s a weekend, the cells still get hungry.”