Jeff Miller/UW Communications
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Saul Richman's prospects were not good. In November 2009, after what he thought was the flu turned out to be leukemia, he underwent a week of 24-hour chemo. When that didn't work, more chemo sent the cancer into remission, but with an 80% chance that it would return. Richman needed a bone-marrow transplant and, even then, his prospects were grim.
"Once you have leukemia, it's already kind of too late," says Karen, Saul's wife of 41 years.
In May, an international donor search failed to find a match. The Richmans' time and options were running out. Then something unexpected happened.
"We were referred to UW," Karen recalls. "They said, 'There's one more thing we've been having good results with.' We thought we were going there for a bone-marrow transplant, but they said, 'No, this is something completely different.'"
In July, doctors from the UW-Madison's Bone Marrow Transplant Program infused Saul, 60, with blood drawn from the severed umbilical cords of two different newborns. Doctors hoped this infusion, rich in adult stem cells, would help Saul grow an entirely new blood supply with an immune system resilient enough to destroy the leukemia for good.
So far, the treatment is working. In October, DNA fingerprinting revealed these stem cells now produce 97% of Saul's blood. Karen is mesmerized and grateful.
"Until you're faced with the death of a loved one, you can't fully appreciate this science," she says. "To have my husband's life is an extraordinary gift. It breaks my heart that others might not get this same chance."
Controversy over stem-cell research has raged ever since UW-Madison biologist Jamie Thomson first isolated human embryonic stem cells in 1998. Subsequent discoveries of adult and induced pluripotent stem cells (IPS) have deepened the divisions, with pro-life groups and many Republicans claiming the latter are more promising and ethical alternatives, as they don't necessarily destroy human embryos.
Opponents of embryonic stem-cell research love cases like Saul Richman's, which illustrate the benefits of using other kinds of stem cells. Let's focus on this research, they say, and leave the embryos alone.
Politicians like Gov. Scott Walker wholeheartedly embrace these claims, saying they would rather support research on adult stem cells than the embryonic kind. But scientists in the field balk at what they say is a false dichotomy.
As Thomson puts it, "Embryonic stem cells are really the gold standard in understanding how [other stem cells] work. The main thing we have to do right now is understand the differences."
In August 2001, President George Bush decided that 21 existing embryonic stem-cell lines would qualify for continued federal funding, but any new lines would not. Researchers, citing poor derivation and culture methods in 1998, wanted to create new, uncontaminated lines. In 2005 and 2007, Bush vetoed bills that would have permitted this.
A federal ban on the research has never existed, but six states have banned it, and one greatly restricts it. Twice over the last decade, GOP legislators in Wisconsin have introduced bills to ban embryonic stem-cell research in the state; faced with certain veto by Gov. Jim Doyle, neither advanced.
Now, with the election of Walker and control of the state Legislature, the party is in a position to make this happen.
And while GOP leaders say they'll focus first on economic rather than social issues, researchers are nonetheless on edge.
"Banning embryonic stem-cell research would send a terrible message to the rest of the country and make us look like a scientific backwater," says John Wiley, former chancellor and current interim director of the new Wisconsin Institutes for Discovery, which conducts stem-cell research. "Researchers need an academic environment that isn't hampered by political and religious opinions."
In his campaign last year, Walker told an anti-abortion group he would ban embryonic stem-cell research, but later backpedaled on the statement. Walker didn't respond to requests for comment. And a spokesperson for Senate Majority Leader Scott Fitzgerald says no decisions have been made whether and when to take up this issue.
But on Jan. 3, the first day of the Walker era, state Rep. Joel Kleefisch (R-Oconomowoc) introduced a tax exemption for tangible personal property used for qualified research which "would not apply to those facilities that conduct embryonic stem cell research."
There are three different stem-cell types: embryonic, which are derived from human embryos; adult, which are found in blood, tissue and organs; and induced pluripotent, which are adult stem cells genetically reverted to an embryonic stem-cell-like state. All have unique qualities and differences that aren't fully understood.
At this stage, it's impossible to say what clinical niche these cells will occupy. But pro-life groups have long trumpeted adult stem cells as a better, safer and more ethical avenue of inquiry.
"In the last 10 years, there has been documented clinical success using adult stem cells over a broad range of conditions," says Matt Sande, spokesman for Pro-Life Wisconsin. "Cordal damage, cardiac repair, spinal injury...the list goes on and on; whereas human embryonic stem cells have never demonstrated any success."
Many researchers say they hope adult and IPS cells will prove equivalent to embryonic stem cells, but the science, still in its infancy, isn't there yet. And so, for now, some scientists reject claims that one stem-cell type is better than another.
"Anybody who says that is completely off base scientifically," says Derek Hei, director of the UW-Madison's Clinical BioManufacturing Facility, which produces clinical-grade stem-cell lines for public and private researchers. "They don't understand the issues. They don't know the facts. They haven't worked with the different cell types. They don't understand the logistical issues of manufacturing these cells for potential commercial use."
Differences between stem-cell types are subtle but substantial, and genetic vagaries influence cell behavior in unknown ways. Some lines grow better than others. Some are better at differentiating into certain specialized cells. And adult stem-cell lines have a far shorter shelf life than the embryonic. That has major implications in the number of treatments produced from a single line.
"Understanding why they're different is one of the biggest challenges we face," says Hei. "That's why scientists who work with these cell lines really cringe at any attempt to limit their use, because we just don't know what cell lines will be better for certain clinical applications until we've actually used, grown and tested them."
Embryonic stem-cell detractors tend to overstate clinical successes of adult stem cells. (IPS cells, invented in 2007, again by the UW's Thomson, have no known therapeutic value as of yet.) Dozens of new adult stem-cell populations, derived from various tissues and organs, are being investigated for all sorts of disease applications. But, says one researcher, "We're still waiting to see if they're really helpful."
The anecdotal reports that often crop up in media are stirring but have little scientific merit. Proving a treatment effective requires reproducible effects and comparisons to placebo or control groups. Assigning cause and effect in the majority of these cases is, at this stage, impossible.
To date, the only medically proven adult stem-cell treatments rely primarily on blood stem cells - similar to those used in bone-marrow transplants - for which there is more than 50 years of medical data. But the effectiveness of these cells doesn't extend much beyond treating disorders and cancers of the blood.
Scientists say it's too early to be shutting down whole avenues of research. They note that nearly 30 years passed between the first bone-marrow transplant - technically, the world's first stem-cell treatment - and the adoption of this treatment as routine medical practice.
"Embryonic stem cells were only discovered in 1998," says Tim Kamp, a UW-Madison cardiologist who in 2009 coaxed embryonic stem cells into becoming a specialized type of working heart cell. "We've got 12 years under our belt, and the first clinical trial using an embryonic-stem-cell-derived product started [last] year. That's really pretty fast to get something started down the clinical road."
At present, even adult blood stem-cell treatments, like the cord blood transplant Saul Richman received, are fraught with unknowns. Asked what's left to learn about these cord blood cells, Dr. Mark Juckett, a hematologist with the UW-Madison's Bone Marrow Transplant Program, answers, "a lot."
Treatments involving these cells produce widely varying results. "Patients have to be willing to accept that uncertainty, look forward and hope for the best," says Juckett. "We're big worriers as physicians, so we watch everything very closely so we can anticipate any odd problems that show up."
Meanwhile, the promise of embryonic stem-cell research is only beginning to materialize. Late last summer, a California company began the first FDA-approved clinical trial using a product derived from embryonic stem cells on patients with spinal-cord injuries. And a Massachusetts company recently received approval for a clinical trial using embryonic stem cells to treat a rare eye disorder.
Thomson expects the first stem-cell therapies will be geared toward people who die early for a variety of reasons. "Think about diabetics," he says. "They have a 10- to 15-year less than the average life expectancy, so I think it'll be more about restoring normal productive life."
Political polarization of stem-cell research sometimes obscures the science behind it - difficult and incremental.
"Getting things into the clinic when it's a brand-new technology is something that takes decades, not a couple of years," says Thomson. His company, Cellular Dynamics, makes heart cells that let drug companies forgo the traditional animal models to discern a new drug's toxicity. It's a modest application, not a revolution.
Similarly, adult stem-cell applications are not as visionary as proponents claim. For instance, the stem cells that doctors infused into Saul Richman came from umbilical-cord blood, which has been banked since the late 1990s by various public and private entities.
"These are stem cells that can rebuild the bone marrow, and it just happens to be that in babies there's a ton of them," Juckett explains. "So you squeeze out some blood from the placenta and umbilical cord, and there's lots of cells in that product. These cells can renew the bone marrow in an adult in a long and lasting way."
Cord blood has been used in children since 1988, but only in the last two years have adults, too, benefited from its curative power.
"The amount of blood we get from these units is so small that we've not offered this to adults because the outcome had not been very good," says Juckett. "But what we can do is collect blood from two separate individuals, combine them to make a larger product, and use that as the stem-cell source."
Unlike bone-marrow transplants, which require a precise donor match, cord blood stem cells are able to tolerate areas of mismatch. Traditional markers, like blood type and sex, are irrelevant. In fact, had Richman received female cord blood, his new blood's DNA would type female.
"What happens initially is that both cords will grow, but by three months one cord will dominate, and you get a new immune system," explains Juckett. "Immune systems don't coexist; one always takes over. We're really not sure what determines the dominant cord. That whole process is interesting, but not very well understood."
In September, just two months after the transplant, Saul Richman, a soft-spoken man of few words, grins as he says, "I have brand-new blood."
Indeed, a series of DNA fingerprinting tests performed since July shows one of the cords steadily producing more and more of Saul's blood. Just 3% of his own blood remains.
But while these transplants greatly improve the odds of survival, they aren't a cure-all. Some leukemia is impervious to the new immune system. Sometimes the patient's own blood is the dominant type. And, though cancer-free, Saul Richman now suffers from a peculiar form of graft vs. host disease.
"If you get a kidney, it's your body fighting off the new kidney," says Richman, whose rejection symptoms are managed with medication. "With cord blood, it's the new blood fighting against your body. That's happening to me right now."
It's a small sacrifice for life. "It's very exciting because these baby stem cells have a great capacity to do all kinds of wonderful things," says Juckett. "They give us an opportunity to help people we couldn't help otherwise, and it turns out to be a better option than what we've been doing."
When a sperm and egg combine, each contributes half of the 46 chromosomes necessary to create a complete genetic human. This mass of unorganized, undifferentiated cells is, to biologists, a zygote. But to groups like Pro-Life Wisconsin, it's a human being.
"There's a continuum of human life," says Matt Sande. "First you're an embryo, then a fetus, a newborn, an adolescent, a young adult, middle-aged and then elderly. No matter what stage you're in, the underlying humanity is the same. That never changes."
Five days after fertilization, the zygote, still in transit toward the uterus, becomes a blastocyst, composed of two cell types, one being the inner cell mass, from where embryonic stem cells are derived.
But researchers don't extract live blastocysts from women. Stem cells used in research are derived from surplus embryos created for in-vitro fertilization treatments that would otherwise be discarded.
"The majority of the public, when this is explained, are really supportive," says Thomson. "Of course, there's a very vocal segment that disagrees."
Unlike adult stem cells, embryonic cells can become any specialized cell in the body. This is what makes them the gold standard for research.
In recent years, Thomson's research has shifted focus from embryonic stem cells to induced pluripotent stem cells, which he discovered in 2007. These IPS cells are genetically reverted to an embryonic-like state, making them a very close equivalent.
"The trouble is that they're very similar, but have very subtle differences," he says. "We don't yet understand how significant those differences are."
To reach that understanding, Thomson hopes new embryonic stem-cell lines can be created with federal grants, something now permitted under President Obama's 2009 executive order.
"The ones we were stuck with in the Bush administration were done in 1998, and we didn't really know how to culture them well back then," he says. "They were abused, but now we can finally go back in a limited way and make some more. We're gearing up to do it but actually haven't achieved it yet."
In August, a federal judge issued an injunction halting federally funded embryonic stem-cell research, but it was stayed by an appellate court a few weeks later. The case involves a pair of adult-stem-cell researchers in Boston who sued the government, claiming Obama's easing of restrictions on embryonic stem-cell research put them at an unfair disadvantage in procuring federal grants.
"Unfortunately, only the opponents see the dichotomy between embryonic stem cells and adult forms of stem cells as competitive," says Juckett. "To scientists, the study of all stem cells allows more general knowledge about the mechanics of these cells."
It's unclear when the case will go to trial.
Meanwhile, the Republicans who now run Wisconsin could put the whammy on stem-cell research here - along with the jobs and investment it brings. The UW's Tim Kamp thinks that would be tragic.
"If we don't do it here in Wisconsin, the treatments will be developed elsewhere," he says. "Either we continue to be innovators and leaders in this area or we watch it happen from the sidelines."
Sande has a different take.
"The question is: Are we going to protect embryonic human life in law or do embryos not have any rights and can be experimented on and killed? We need to grant personhood to human beings regardless of what stage of life they're in."
Banning or restricting research would have major economic consequences for the state. A report issued in September by BioForward, an industry trade group, showed that the biosciences have produced 24,000 private-sector jobs with a $7 billion economic footprint. UW-Madison alone has upwards of $19.5 million in federal grants for embryonic stem-cell research.
The university also has an international stem-cell bank, which produces stem-cell lines for researchers around the world. Observes Wiley, "Even if there was no stem-cell research on campus, we still have a big stake in all stem-cell research."
State Rep. Terese Berceau (D-Madison) thinks this should make a difference to the Republicans in charge.
"Even if most of them don't give a damn about the potential benefits, I know that economic consequences do matter to them," she says. "Do they want to accept [responsibility for] devastating our scientific community and chipping away at our state's greatest economic engine - the UW?"
Perhaps they do. Sen. Glenn Grothman (R-West Bend) says that if it were up to him, he'd vote to ban embryonic stem-cell research, claiming adult stem-cell research has greater potential. When asked what informs his decision-making, he replies, "Common sense."
"Some people enjoy creating babies to experiment on, but I don't," he says. "Embryonic stem cells are the pie-in-the-sky for people with a political agenda they want to push."
