In early November of 1998, when human embryonic stem cells were introduced to the world, the possibilities seemed astonishing.
"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," then-National Institutes of Health Director Harold Varmus told a Senate hearing less than a month after Wisconsin biologist James Thomson reported his stem cell feat in the journal Science.
Varmus went on: "There is almost no realm of medicine that might not be touched by this innovation."
Today, five years after the shy University of Wisconsin-Madison scientist published his succinct but earthshaking paper showing that stem cells—ephemeral, blank slate cells that occur at the earliest stages of human development—could be isolated, cultured and grown in apparently limitless quantities, enthusiasm is tempered.
The public cheerleading of Varmus and others, without a doubt, helped make stem cells a household word and set a high (and unrealistic) expectation that therapies for a host of debilitating cell-based diseases were just around the corner.
There is no doubt among biologists that embryonic stem cells have vast potential. There are no other cells that can perform the same biological feats as embryonic stem cells. They can morph into any one of the 220 types of cells and tissues in the human body. Nurtured in their undifferentiated state, they can proliferate endlessly in culture, and provide a vast supply of cells for research and, someday, therapy. And perhaps most importantly of all, they provide our only window to the earliest stages of human development and, after differentiation, access to more specialized cells that could vastly improve our understanding of the onset of cell-based diseases, and perhaps ways to prevent them.
But as Thomson himself emphasized in 1998, their glitziest application in the clinic—the tantalizing potential of transforming transplant medicine by creating large quantities of cells to treat debilitating diseases such as Parkinson's, diabetes and ALS—would be a decade in the future under the best of circumstances.
"We went through this period of extreme hype and high expectations," recalls Carl Gulbrandsen, managing director of the Wisconsin Alumni Research Foundation (WARF), the private, not-for-profit foundation that holds Wisconsin's patents to stem cell technology. "Things seem to have settled down, but people still expect a lot, and we're still in a tight political environment."
Indeed, the politics of stem cells from the outset have been as far reaching as the technology itself promises to be. Extending from the Oval Office, where stem cells became the dominant domestic issue of the first eight months of the Bush Administration, to the other end of State Street, where a few state legislators remain determined to criminalize the research, the political dimensions of stem cell science have framed a national debate and influenced many aspects of how the research is done and funded.
According to Gulbrandsen, the administration's decision to permit federal funds to be used for research on at least some stem cells lines—a decision heavily influenced by former Wisconsin governor and current Health and Human Services Secretary Tommy Thompson—was a turning point in the debate.
"Bush's decision was a landmark decision," Gulbrandsen says. "A lot of people don't like it, but it was an ingenious political solution. That decision wouldn't have occurred without Tommy Thompson there."
Although wading through a political quagmire was difficult and sometimes painful for the retiring biologist Thomson, it was a necessary exercise.
"The first year or two (after first isolating the cells) were pretty much wasted due to politics," says Thomson. "But since then we've done pretty well" in the lab.
The early flood of publicity, breathless in its descriptions of the medical and research potential of stem cells, Thomson feared, would set unrealistic expectations in the public mind. Lost in the glowing words, he says, are the hard and painstaking realities of basic science.
"It's a new field. It takes time to grow," notes Thomson. "Look at the first five years of mouse embryonic stem cells. It took a while to get going. It is natural that these things take time."
The field would grow much faster, Gulbrandsen argues, if politics did not remain a prevailing force on stem cell science: "Bush's decision was pivotal, but the field is still stuck in the quagmire, and that is evident in the level of research funding by NIH for human embryonic stem cells. Since Bush's decision, NIH has funded approximately $170 million of adult stem cell research, but only $10 million on human embryonic stem cell research."
Despite such imbalance, there has been significant progress on the stem cell research front over the past five years. Many of the most important developments were not the headline-generating feats that would fulfill the promise touted in the early days of stem cells, but they were the steps necessary to bring the field to fruition.
"All of the little technical things have been worked out," says Thomson, noting such achievements in his lab as learning how to manipulate the genes within stem cells, a technique known as homologous recombination and that makes it possible to use the cells to mimic human disease in the laboratory dish. "We've done very well at Wisconsin."
And what started out as a lonely effort in a single lab has mushroomed into a significant industry on the UW-Madison campus. There are now almost 30 UW-Madison faculty engaged in different aspects of embryonic stem cell research.
Timothy Kamp, for example, a UW Medical School professor of medicine and physiology, has used human embryonic stem cells to derive cardiomyocytes, heart muscle cells that can substitute for the animal cells routinely used to study issues of the heart. "It is obviously very difficult to get living human heart cells for study," Kamp says. "We hope that having (these cells) will provide a routine source of cells amendable for detailed investigations."
It may be possible, Kamp adds, to genetically manipulate the embryonic stem cell-derived heart cells to mimic heart disease in the lab dish. "These cells will help us not only understand basic human cardiac cell physiology and biology, but also will likely play an important role in unraveling the basic mechanisms of disease."
In addition to the growing cadre of Wisconsin faculty lining up to explore issues of basic and applied biology with the help of stem cells, there is a growing physical infrastructure on campus as well. There are gleaming and unique facilities at the Wisconsin National Primate Research Center, and the Wasiman Center, for example, where neural stem cells are a research emphasis. Included there is a clinical biomanufacturing facility that could well process the first stem cells that will ever be used in a clinical setting.
In October of 1999, WARF created the WiCell Research Institute, a UW Research Park-based subsidiary devoted to distributing stem cells to qualified academic and industrial researchers, and to conducting basic stem cell science. To date, WiCell has shipped cells from three of the five original stem cell lines identified in the November, 1998 Science paper to as many as 140 labs worldwide. By early next year, Gulbrandsen says, WiCell will be shipping cells from all five lines.
According to Gulbrandsen, there are now other sources of stem cells in the United States that, along with WiCell, ship to as many as 200 labs engaged in embryonic stem cell research. "In five years, that is pretty remarkable and would not happen unless the research were critically important."
But Wisconsin remains the leading supplier of cells for research, notes Thomson.
"We've shipped more cells to more labs than anybody else—by a wide margin," says Thomson, who also serves as WiCell's scientific director.
What's more, WiCell has become a training ground for scientists who travel to Madison from around the world to learn how to grow and maintain the finicky cells. And in late September of this year, NIH named WiCell as one of three Exploratory Centers for Human Embryonic Stem Cell Research in the country, a designation that included $1.7 million in research funding.
"I hope WiCell evolves into an institute that broadly supports research on campus," Thomson says. "WiCell as a research institute is an evolving concept."
On campus, a new infrastructure is taking shape in the form of the Wisconsin Stem Cell Research Program. The mission of the new program, according to its manager, Barbara Lewis, is to provide a framework for UW-Madison stem cell research and training. It will organize seminar series, journal clubs, and an annual retreat for researchers from across the campus to discuss their work and funding opportunities. The program, she adds, will be active in private fund raising for a stem cell training program and basic and applied stem cell research initiatives. In addition to the new Wisconsin Stem Cell Research Program, future initiatives, campus leaders suggest, could bring facilities for both regenerative medicine and a Medical School 'translational facility' where stem cells would gain a more solid clinical footing.
"The university has invested heavily in nurturing the burgeoning area of stem cell biology," says R. Timothy Mulcahy, Graduate School associate dean for the biological sciences and associate vice chancellor for research policy. "We have supported cluster hires in the area of regenerative medicine and stem cell biology and established the Wisconsin Stem Cell Research Program to coordinate and facilitate stem cell research across campus."
Wisconsin, Mulcahy asserts, is well positioned to continue to lead the world in human embryonic stem cell research.
"Thomson's discovery elevated the field to heights previously thought impossible, and has brought within reach all the promise others in the field have long dreamed of," Mulcahy says. "In 20 years we'll be surprised by what stem cell research has delivered. I'd hazard a guess that the biggest pay off will be in areas we haven't even considered."
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