Ask any biologist which wish he or she would most like to see granted and almost every one would express a desire to learn how a single fertilized egg “differentiates”–or produces with exquisite precision the more than 200 cell types that ultimately make a human being.
That topped James Thomson’s wish list, too, when as a young, untenured veterinarian and PhD molecular biologist he set out to find human embryonic stem cells, the master keys that could help unlock the great mystery of human development. Embryonic stem cells are among the first cells to be made when a fertilized egg starts dividing. They exist for only a few days, but in that time they give rise to brain, heart, liver and all the other organs in the body.
“How they do it is really the ultimate question in biology,” Thomson said. “To me, it’s a fascinating question. And the basic understanding was something I wanted to devote my career to unraveling.”
Mouse embryonic stem cells had been identified in 1981, sheep stem cells in 1987, hamster in 1988, pig in 1990, and rabbit in 1993. Then, in 1995, Thomson derived the first embryonic stem cells from primates (rhesus monkeys) in his lab at the University of Wisconsin. That put the scientific world on notice: The race was on.
Thomson won it in November 1998 when he reported that five human embryonic stem cell lines with normal chromosomes had been established. He derived them from surplus embryos created at fertility clinics and not only coaxed them to grow but in effect stopped their biological clocks by preventing them from differentiating.
“There was no magic bullet to it, no magic chemical or growth factor,” he said. “It was mostly being extremely careful about conditions in the laboratory and having gained the experience from doing all the steps that led up to it. Rhesus monkeys are a lot closer biologically to people than they are to other primates. Given the conditions that allowed us to culture rhesus embryonic stem cells, we were pretty confident that the same techniques would allow us to derive human embryonic stem cells.”
Since 1998, Thomson and his colleagues have witnessed something that nature has long kept secret–the birth of neurons, insulin-producing islet cells, and heart and blood cells, cells that other Wisconsin researchers already are using to develop new therapies.
Stem cells also hold the promise of not only replacing diseased or damaged tissue to restore people to health, but of revealing the magnificent orchestration that goes on between genes and proteins to make a complex organism. This could lead to ways to prevent disease, construct whole organs and even extend our life span.
“If we understand how development proceeds in a really basic way, we can probably take that program over again and allow the body to regenerate in ways that it doesn’t currently do,” Thomson said.
“When you think about all these cell-based therapies–for diabetes, Alzheimer’s, Parkinson’s disease–it’s a rather crude thing to try to replace the cells after they’re already gone,” he said. “It’s much better to understand at a basic molecular level what destroyed them in the first place. The embryonic stem cell gives you that access in a new way that really changes the way we can do biology now.”
To find the embryonic cells, Thomson had to conduct his research in a secret laboratory somewhere near the University of Wisconsin with money provided by private investors.
Thomson’s unusual route to one of the greatest discoveries in biology illustrates how some areas of science are being held hostage.
The secret location was necessary because of the threat posed by those who oppose human embryonic or animal research. Thomson had to rely on private funding because the federal government, which supports most biological research in this country, wouldn’t pay for work on human embryos.
“Hardly anyone was working on the problem,” said Dr. Douglas Melton, a stem cell researcher at Harvard University and the Howard Hughes Medical Institute. “There were no federal funds available, and that immediately eliminates 90 percent of the nation’s best scientists.”
Getting around barriers
To work around the ban on federal funding, Thomson made a pact with Geron, a biotech company in Menlo Park, Calif. In return for supporting Thomson’s work, Geron was to receive exclusive licenses to commercialize some of the cell types derived from the stem cell lines.
But the most formidable barrier Thomson faced was the scientific unknown.
A few laboratories around the world worked on mouse embryonic stem cells. But deriving similar cells from monkeys or from humans was considered by many to be too daunting.
Thomson grew up in suburban River Forest and received a degree in biophysics from the University of Illinois, Urbana-Champaign. There, in a biology honors course taught by Fred Meins, Thomson became hooked on the great mystery of human development.
“He was a real influence on my life,” Thomson said. “It was an extraordinary program. You didn’t even have a textbook. Everything was taught from the primary literature, and you did real experiments in the lab.”
From Illinois he went to Philadelphia’s Wistar Institute in the late ’80s. It was one of the few places doing mouse embryonic work, and there he learned the arcane science of making mouse embryonic stem cells.
Because embryonic development is significantly different in humans, Thomson realized that mouse research was a dead end and that the search for human embryonic stem cells would have to move to non-human primates that were more like people.
What he didn’t know was that a team of researchers was being assembled in Melbourne, Australia, to take a shortcut and go directly for human stem cells.
The Australians had assembled a formidable team: Ariff Bongso, an IVF specialist from Singapore who was already growing human embryos to the blastocyst stage in hopes of improving pregnancy results; Alan Trounson, an IVF expert and deputy director of the Monash Institute of Reproduction and Development in Melbourne; Dr. Martin Pera, an expert on embryonic cells from Oxford University; and Dr. Benjamin Reubinoff, a clinical gynecologist at Hadassah University in Jerusalem.
They soon found that they could isolate human embryonic cells, but they couldn’t get them to grow more stem cells. Months and years went by and the stem cells either quickly died or differentiated into other cells.
Thomson had been struggling to overcome the same problems. “They are finicky cells to grow.”
Thomson worked 12-hour days, seven days a week. Starting at 5:30 a.m., he worked at his secret laboratory a few hours before going to his other lab at the university’s famed Regional Primate Research Center. All day he would go back and forth between the two to keep tabs on his precious stem cells.
Recalls Ed Golos, a friend and fellow primate researcher: “All of us work really hard. But Jamie was very focused and very dedicated to achieving his goal. He’s had a vision that he’s followed through on that this will be an immense opportunity.”
Diversions and success
Thomson, 42, married and the father of two small children, engages in some of his favorite pastimes: hang gliding, kayaking and playing with his many pets.
When he struck pay dirt in 1995 and was able to derive a stable line of embryonic stem cells from rhesus monkeys, he was buoyed by success. But so were the Australian team members, who gained new hope that they could do the same for human stem cells.
Thomson’s next move was to try to derive human stem cells from discarded human embryos. But he had a dilemma. Some people objected to such research. Was it ethical?
He asked for help from the University of Wisconsin’s Institutional Review Board, which tussles with such ethical questions before allowing experiments to proceed or quashing them.
“We had a lot of discussions about this,” said Dr. Norman C. Fost, a professor of pediatrics and a board member. “We pointed out that government-appointed committees in Canada, Great Britain and the U.S. found that the use of surplus embryos with proper consent was morally and legally acceptable. Finally we concluded that it didn’t violate any clear moral obligations to embryos that otherwise were about to be discarded.”
Meanwhile, the Australian group had doubled its efforts. They still had frustrating setbacks but by 1998 they had two human cell lines growing. These multiplied and filled the petri dishes to overflowing but still retained the powers of stem cells.
But before they could finish writing their paper, the journal Science published Thomson’s account of how he had for the first time grown stable cultures of human stem cells.
Four days later, the Proceedings of the National Academy of Science published a report from John Gearhart of Johns Hopkins University saying that he had derived stable lines that seemed to have all of the powers of human embryonic stem cells. Gearhart, who had obtained his cells from aborted fetuses, had also been funded by Geron.
Thomson’s claim to victory came only after he had watched and waited for six months to make sure that his self-renewing stem cell lines had passed all the tests.
“That’s when we said, `Hey, we’ve got it.’ By then for me it was a feeling of tired relief, more than any kind of ecstasy. We had done a lot of work to try to get them to that point.”
Hurdles still remain. For one thing, little is known about how stem cells differentiate into specialized cells, Thomson said. The scientists hope to find the chemical controls that would allow them to choose what kind of cells to make, such as cells of the liver or of the blood.
What’s been accomplished so far is only the beginning of Thomson’s vision: “It does not mean there will be therapies in the clinic tomorrow. I think stem cells can revolutionize human medicine, but it’s going to be a long, drawn-out process.”
