This article originally appeared in Isthmus on Sept. 8, 2000.
James Thomson's 1998 research paper was short and succinct, with sentences as clipped as his style of speech. But its impact was enormous, reverberating through the world of science and providing the key prod that reversed 20 years of prohibitions on federally funded human embryo research.
The paper, published in Science magazine, said this new technology promised to "provide a potentially limitless source of cells for drug discovery and transplantation therapies."
Two weeks ago, the National Institutes of Health approved guidelines for the use of embryonic stem-cell research that resulted directly from Thomson's pioneering work. The government changed course finally because of the cells' revolutionary potential to cure disease and understand birth defects.
Because of the NIH decision, academic scientists may receive federal money to study these cells, lending more brainpower to the cause and bringing this research out from the private world of biotech.
"It's a great thing," says Thomson, a UW-Madison developmental biologist. "They could well have waited until after the fall elections, but they're committed to moving forward."
To opponents, led by pro-life activists, however, experiments that make use of material from human embryos are as ghastly and objectionable as those conducted by Nazi-era scientists. Even if it leads to discoveries that save human lives, they say this amounts to trading some lives for others.
"The practice of using aborted babies for research purposes is inherently immoral and unethical," says Susan Armacost, legislative director for Wisconsin Right to Life. And while the NIH tried to appease critics by making a distinction between obtaining embryos for research and the research itself, Armacost says "the ethical and moral objections remain."
Arthur Caplan, a University of Pennsylvania bioethicist who's weighed in often on the embryo research issue, says the issue of stem-cell research is clouded by abortion politics: "We're one of the few countries in the West that still battles over the metaphysical status of an embryo."
The NIH ruling does not finally resolve anything. A new Republican administration could reverse it, while a bill sponsored by U.S. Sen. Arlen Specter, a conservative Republican, would go even further in providing federal support for stem-cell research. The pro-life lobby, meanwhile, is determined not to give up the fight.
"Research is becoming something of a god," says state Rep. Mark Gundrum (R-New Berlin), conceding that the pro-life movement is on the defensive. "Even Republicans calling themselves 'pro-life' are starting to believe that quality of life through research is justified. The governor is starting to lean in this direction more than I want to see." He says he "would love to hear a clear statement" explaining where Gov. Tommy Thompson stands on this issue.
Thompson's press handlers did not return repeated calls.
Gundrum plans to introduce legislation that will directly prohibit embryonic stem cell research in Wisconsin. "In my opinion, you can't justify killing human lives in the hope that someday you might improve the quality of some other people's lives," he says. "It sounds like a very familiar argument that was used in Germany several years ago. It's a scary mentality, in my opinion."
Barbara Lyons, Wisconsin Right to Life executive director, supports Gundrum. She says legislation proposed last spring to outlaw trafficking in "fetal body parts," introduced by Rep. Sheryl Albers and supported by Lt. Gov. Scott McCallum, didn't go far enough.
"[Preventing] the 'sale' of fetal body parts does not prevent their use," complains Lyons. "Unfortunately this particular research [on embryos] is going on in Wisconsin."
Man with a mission
The NIH first considered funding research on human embryos in the late 1970s, after the birth in England of Louise Brown, the world's first "test-tube," or in vitro, baby. But for two decades, a vocal anti-abortion movement succeeded in preventing any publicly financed studies, even to prove the safety of fertility procedures. That didn't stop private research on patients desperate for children, and the result is that thousands of embryos now lie frozen in clinic vaults.
These embryos, unneeded and unwanted, are routinely thawed and tossed. But in the mid-1990s, Thomson received permission to take 36 of them from the UW-Madison's in vitro fertility clinic, and dissected them to see what good might come. The result was a breakthrough of the sort that wins Nobel prizes.
What James Alexander Thomson succeeded in doing was to isolate the human body's most primordial cells and prevent them from going their separate ways -- from turning into the more specific cells that become blood or skin or nerves. His achievement, reported in the Science article, made front-page news around the world.
"The development of cell lines that may produce almost every tissue of the human body is an unprecedented scientific breakthrough," Harold Varmus, former director of the National Institutes of Health, told a Senate subcommittee in December 1998. "It is not too unrealistic to say that this research has the potential to revolutionize the practice of medicine and improve the quality and length of life."
Thomson used embryos whose parents planned to discard them and who agreed to the research. He grew each one to a five-day-old ball of cells called a blastocyst -- far too young to implant in a uterus -- and separated the inner mass of cells, called embryonic stem cells, from the outer sphere. Thomson also managed to keep them dividing patiently and endlessly, waiting for a cue, ghostly translucent circles floating in a nutritious pink sea.
Later, that physical separation of cells from sphere would provide a crucial rationale for federal officials hoping to ethically separate themselves from the thorny matter of destroying embryos.
Because of the U.S. government's longtime ban on embryo research, Thomson's work was funded by a biotech firm, Geron, now affiliated with two other biotech powerhouses: Scotland's Roslin Bio-Med, of Dolly the cloned sheep fame, and Celera, which raced to sequence the human genome. Geron paid for an off-campus lab and brand-new equipment, to ensure that no public money tainted Thomson's work.
Thomson, while grateful for Geron's support, thinks there are good reasons for future research to be publicly funded. "If this was put in the public domain, even with a modest level of funding, it would go so much faster," he says. "The corporate funding is appropriate, because they're the ones who get the therapies to the market. But the best minds in medical research are, for the most part, academic."
Thomson, with the chin stubble of a man who clearly has more important things to do besides shaving, is one of those minds. Carl Gulbrandsen, managing director of the Wisconsin Alumni Research Foundation, calls him a "man with a mission."
A native of Oak Park, Ill., Thomson has doctorates both in veterinary medicine and molecular biology from the University of Pennsylvania. He began by studying the embryonic development of mice, later switching to rhesus and marmoset monkeys. His first stem-cell patent, in fact, is on the embryonic stem (ES) cells of rhesus monkeys, which may have given him the edge in the competition to isolate human ES cells.
Thomson, now 41, says his research requires more persistence than brilliance: "It's really a matter of putting [the cells] in the proper culture, the proper environment."
He is private and intense, a rapid-fire speaker who wastes no time on proprieties. "They're dull-looking, like other cells," says Thomson of the microscopic orbs looming so large in the public imagination. But to biologists, the isolation of human ES cells was hardly prosaic. To them, Thomson's achievement, which was followed quickly by a Johns Hopkins scientist, John Gearhart, who found ES cells in aborted fetuses, propelled both biology and medicine into an entirely new realm. Science later dubbed it "Scientific Breakthrough of the Year."
Jokes Thomson, "Nice that John Gearhart and I beat out all those quantum physicists and chemists."
From imagination to cure
A big goal of embryonic stem cell research, as scientists instantly knew, was to make cells change into different body tissues on command, and then direct them to replace cells failed from disease. The idea is far more than theory.
The dead beta cells of a diabetic's pancreas could be replaced with new ones, grown in a lab and injected into a patient's liver. The new beta cells would begin to make insulin and the patient would be cured. Human experiments with such cells taken from cadavers have worked, but limiting factors are immune rejection and the quantity of cadavers and cells.
The useless neurons of a Parkinson's sufferer, no longer able to secrete the transmitter dopamine, or those of an Alzheimer's patient, no longer making acetylcholine, might be replaced. Experiments to achieve these results, done on animals, had worked too.
Embryonic stem cells would also enable scientists to test new drugs and study inherited disorders like cleft lip and cleft palate and the causes of cancer.
Moving so quickly from the imagination to a cure has never before been done, says Thomson. "People have been studying developmental biology for 100 years, and it's all been very theoretical and interesting, but suddenly because of the embryonic stem cells, all that knowledge translates very directly into treating human disease. And if, over the course of my career, embryonic stem cells and the knowledge from them are used to treat a couple of diseases, that would be extremely satisfying, even if I'm not the one doing it all the time."
Scientists around the world are in hot pursuit of the treatments this new technology may bring. They are taking on the next wave of questions: What makes an human ES cell turn into a neuron? Into an islet? Into a blood cell? Can they be deliberately and reliably nudged to change? If they are transplanted into a sick person, how can rejection be prevented?
The latter question is occupying Thomson right now. In a paper published last February in e-biomed, a new Internet research journal, he and fellow UW-Madison scientists Jon Odorico and Dan Kaufman speculated on five ways to solve the problem of rejection of ES-derived tissue transplanted into needy patients, especially those arising from an immune system failure, like diabetes or multiple sclerosis.
"One of the advantages of ES cells is that they can give rise to more than one thing," says Thomson. Not only do embryonic cells mature into cells of specific organs, but they also will turn into blood cells, the ones that produce bone marrow. Since matching marrow is the key to preventing the rejection of transplanted organs, it might be possible to first create the proper immune environment with genetically matched marrow.
"What that does for you, as long as you get the bone marrow to be accepted, you can be off [immunosuppressive] drugs for life," says Thomson. "Now, that sounds good if you say it fast. The trouble is, it's going to be hard to do."
At the UW-Madison, Odorico already has worked out the procedure for making pancreatic cells from primate ES cells, while Kaufman has derived all kinds of blood cells. And that's just one way to use ES cells.
Thomson is optimistic: "I think from a practical point of view, developmental biology is going to go pretty fast. Years, not decades." Especially with dozens of federally funded scientists joining the fray and sharing their insights.
What's ethically appropriate?
The pro-life and Christian lobbies who oppose that financing insist there are valid alternatives, such as research using so-called "adult" stem cells. These are cells found in more mature and specialized tissue like skin and blood, and which serve as a fount of renewal as older cells age. Just this summer, for example, scientists successfully prodded blood-making stem cells into becoming nerve and muscle cells, obviating the need to use embryos, the critics say.
C. Ben Mitchell, senior fellow of the Center for Bioethics and Human Dignity, based in Deerfield, Ill., is among those who think adult stem cells are the solution. Biotech does have its merits, he says, "But if the means of getting there involves killing a human embryo, then we think the cost is too great. If you grant the embryo has any special status, more than a broken fingernail, then you have to talk about what kind of respect that organism warrants."
Thomson is not swayed, for both scientific and ethical reasons. "It's probably wishful thinking," he says of the hope that ES cells aren't needed. They have properties that adult cells don't--most significantly, the apparent ability to divide indefinitely, without maturing or differentiating into other types of cells.
Studying human embryonic cells, says Thomson, will also lead to insights about adult cells, as well as inherited diseases and birth defects. But there's another, even more compelling reason to use them, and here Thomson is emphatic: "The question is, why would we not want to do embryonic cell research? The implication is that it's not ethically appropriate to do, period. I simply disagree with that."
Thomson, the father of a pink-cheeked 2-year-old, has made his peace with the sticky matter of experimenting on what could, if left intact and implanted in a uterus, become another human being. But it's still a minefield, and he knows it.
"If the choice is between basically throwing them out, and doing something that can help people, it'd be ethically...." For a brief moment, he hesitates, then recovers. "It's hard for me to imagine that throwing them out is a better ethical decision."
But the pro-life lobby is strong, so even the National Institutes of Health, in allowing the research, didn't dare dismiss it as a moral issue, but forged a shield instead. In its new guidelines, it created a somewhat clumsy distinction between the process of deriving the cells, and actual research on them. Once that inner blob of cells is separated from the outer sphere, according to this logic, it is no longer an embryo, so the congressional ban on embryo research doesn't apply. How to get the cells, then? That dirty job, according to this peculiar logic, will remain with private labs.
So researchers wanting to study the cells are not guilty of a moral crime, and will be eligible for federal funds. (The Specter bill would go beyond NIH and allow federally financed scientists to derive the cells, too.)
Bioethicist Caplan, who supports embryonic stem cell research, calls the NIH's ruling "a short-term legalistic maneuver." Wisconsin Right to Life employs far stronger language.
"The proposed guidelines are illegal," declares Armacost in a recent press release. "In 1996, Congress voted to ban federal funding for 'research in which a human embryo or embryos are destroyed, discarded or knowingly subjected to risk of injury or death.' Clearly, the new guidelines are meant to circumvent current law...."
Benefits and tradeoffs
The ethical and moral issues surrounding biotech research will not go away. Indeed, it's likely that even greater moral conundrums will follow. At work are powerful influences, not only the profit motive of industry, but the cries of desperately ill people, expressed through national groups like the Patients' Coalition for Urgent Research. Thomson says his lab regularly hears from people seeking miracle cures that science has not yet devised.
It may not be long, though. Thomson's work and the cloning of Dolly in 1997 blasted a hole through one of the last locked doors of biology, and now it's anyone's guess as to where we're going. The irony is that Thomson's home country is the one most skittish about the new ideas.
In the United Kingdom, an idea known as "therapeutic cloning" has been placed before Parliament for a vote. "The potential benefits outweighed some of the concerns," Liam Donaldson, England's chief medical officer, said in a speech accompanying his panel's report. Is cloning something we might want to do here?
The word conjures images of a neighborhood filled with Stepford moms, heads turned in sync as they watch their kids race around on the soccer field. But that's the problem. Just as in the debate over embryo research, the image becomes the reality, and the conversation never gets off the ground.
Dolly's birth was important, but not just because she was a clone. It was the method of her conception that upended scientists' ideas about the limits of biotech. A cell nucleus from a sheep's udder -- not normally involved in reproduction -- was fused with an empty egg cell, and an embryo formed. It was implanted in another ewe, and the result was Dolly. Cloning had been done before Dolly, but nobody had ever used cells that weren't already designed to reproduce.
Now, imagine that the resulting embryo wasn't implanted in a uterus, but was simply allowed to grow for five days -- about as long as Thomson let his embryos grow before he split them apart to pull out the inner cells. You'd have embryonic stem cells, and if you knew how to culture them indefinitely -- the essence of Thomson's discovery -- you'd have ES cells that perfectly matched the genes of the original donor.
The British rejected the idea of letting those embryos mature into adults. In the U.S., no such ban exists, and private researchers are free to do whatever they want. But the U.S. National Bioethics Advisory Commission, considering what research should be eligible for federal dollars, did concede the potential of "therapeutic" cloning in its report to President Clinton last fall. It might be time for the American public to sit up and listen.
In the world of science, one discovery invariably leads to another, with attendant promise and peril. Some people are calling for greater regulations, some sort of overarching body, that would take on the most pressing issues and help the entire nation decide whether some new ideas should be simply put aside, a violation of all we hold dear. Or at least what a majority of us, expressed through our senators and representatives, hold dear.
"I do think there needs to be a healthy dialog on this," says WARF's Carl Gulbrandsen. "What are the ethical issues involved? What are the legal issues involved? What are some benefits of this technology, and what are the tradeoffs? I think that people need to be educated about what this research is about, and they need to make up their own minds as to whether this is proper."
James Thomson, his mind already settled, would just like to return to his work. But he's helped to unleash a genie, and he knows his life will never be the same.
"Although it is nice to see one's work featured on the front page of The New York Times, the thrill wears off quickly," he writes in an e-mail. "What will be very satisfying to me personally is if over the course of my career during the next few decades this work contributes in a meaningful way to new effective therapies for diseases such as leukemia, Parkinson's and diabetes. Few people have a stronger reason to get up in the morning and go to work, so I'm lucky."
