Stem Cells Reborn

In the wake of scientific fraud in South Korea, researchers are renewing their race to clone stem cells.

[To check out a six-minute video featuring two eminent researchers and Technology Review’s editor in chief discussing the hows and whys of embryonic stem-cell research – with spectacular color graphics and images – click here. Note: You can pause the video at any time.]

In late 2003, researchers at Advanced Cell Technology, a small biotech startup in Worcester, MA, thought they were about to do something remarkable. They had painstakingly generated cloned human embryos from adult cells and were trying to keep them alive long enough to harvest their inner cell masses, precious balls of cells that give rise to stem cells.

It was one of the most sought-after prizes of biomedical research: a way to grow embryonic stem cells directly from, say, a skin cell taken from a specific patient. It was also one of biomedicine’s most speculative projects; indeed, the scientists at Advanced Cell Technology (ACT) were the only team in the United States actively pursuing it. But Robert Lanza (see “Stem Cell Hope”), who headed the group, says he believes that his team at ACT was on the verge of success. If he’s right, and if the work had continued, the company would almost certainly have had in its hands the key to a revolutionary new set of biomedical tools – and possibly to new treatments for a host of different diseases.

But in February 2004, the ACT scientists’ hopes were dashed. A South Korean stem cell scientist named Hwang Woo Suk of Seoul National University and his colleagues announced in the journal Science that they had created patient-specific stem cells. The achievement vaulted Hwang to scientific stardom. His country named him its “supreme scientist” and honored him with a postage stamp depicting a paralyzed man able to walk again. Patients clamored to be part of his work. Hwang embraced his role as an international stem cell celebrity, announcing plans to create something called the World Stem Cell Hub, where members of his lab would clone and culture stem cell lines for scientists around the globe.

“What had been a terribly risky field that many scientists were loath to venture into now became a possibility,” says Evan Snyder, director of the Stem Cells and Regeneration Program at the Burnham Institute for Medical Research in La Jolla, CA. Many U.S. researchers who had been unable or unwilling to start cloning work themselves began planning collaborations with the Korean scientists. “We knew [cloning] would take a lot of time and money, and the Korean government was willing to throw so much at this one problem,” says Snyder. “When that seemed to have been accomplished, many of us said, Well, that’s a relief. Now we can do the real science experiments.”

However, Lanza and his colleagues, who had been so close to cloning stem cells, watched dejectedly. “It was embarrassing,” says Lanza. “This obscure group announced they had done it.” ACT was already on shaky financial ground, but Hwang’s achievement made its situation even more precarious. The company also abruptly lost its supply of human eggs – a crucial ingredient in cloning research – because clinics that ran donor programs felt no further need to participate in research whose central goal had been achieved. As a result, the scientists literally had to put their work on ice. “We had to freeze down lots of our cells. It shut down that research, and there has been no active research since,” says Lanza. There was, plainly, no glory – or profits – in coming in second.

Only none of it was true. Beginning in May 2004, reports started trickling in that Hwang had used unethical means to obtain eggs for his cloning research and lied about it. By December 2005, it became clear that the deception was much more wide ranging. Hwang’s human-cloning research, it seemed, was a spectacular fraud: investigators from Hwang’s university found no evidence that his team had created cloned stem cell lines at all.

“It was like watching a car wreck taking place in slow motion. The magnitude of the problem was just really horrifying,” says Snyder. “The world had been reset to pre-2004, like when Superman turned the world backwards. If you were pursuing cloning in 2004, you began pursuing it again. If you were sitting on the sidelines, you were back sitting on the sidelines.”

But some researchers couldn’t turn back the clock. In the months since Hwang had made his announcement, ACT’s investors had lost interest in producing patient-specific stem cells, and scientists at the company were now focusing on developing less risky stem cell therapies. “We were perceived as a failure, when in fact we were the furthest ahead,” says Lanza, vice president of medical and scientific development at ACT. “We had lost a year of work and moved on to other things.”

“The real work suffered because this guy was playing some game,” Lanza continues. “I know I will be criticized for saying this, but I truly believe we had a protocol that would have been reproducible and straightforward, and we could have started on therapies by now.”

Six months after the details of the fraud began emerging, Lanza and groups at Harvard University and the University of California, San Francisco, among others, are gearing up to start new programs to clone stem cells from adult donor cells – a process usually called somatic-cell nuclear transfer or therapeutic cloning. Despite the technical and political hurdles, the scientists are convinced that nuclear transfer will have a huge impact on medicine. Most immediately, they believe, cloned stem cells could be used as models in which to study human disease and test new drugs with unprecedented accuracy; eventually, stem cells could be transplanted directly into patients to cure degenerative diseases.

The Korean fraud, while clearly devastating for Lanza, may have inadvertently galvanized the field. “The Hwang episode was very destructive,” says Ronald Green, an ethicist at Dartmouth College. “But Hwang’s claims gave people a glimpse of what would be possible with cloned stem cells, and the consequence was a renewed interest in therapeutic cloning.”

Scientists who had planned to collaborate with Hwang had spent months thinking seriously about what they could do with cloned stem cells, from creating new tools to shed light on the diseases they had studied for decades to investigating new treatments. The excitement those possibilities aroused, along with new influxes of cash from state and private sources, made many unwilling to wait on the sidelines any longer. Snyder, a pediatric neurologist and neonatologist who wants to develop new treatments for his patients, is now considering starting his own cloning program. “There is more of a readiness to get into this area, and I think that will carry over,” he says.

Disease Payoff
In a freezer in La Jolla, CA, is a bank of frozen skin cells collected from patients with a rare and devastating genetic disorder called Lesch-Nyhan disease. Children born with the disease have a genetic error that causes them to produce too much uric acid, which builds up in their tissue. They also suffer major neurological problems in roughly the same part of the brain stricken by Parkinson’s disease, resulting in motor and cognitive problems. “No one understands why a defect in this gene leads to a defect in the brain,” says Theodore Friedmann, a pediatrician and geneticist at the University of California, San Diego, who has been studying the disease for almost 40 years.

About two years ago, Friedmann, an expert in gene therapy, began to consider how stem cells could help his patients. Embryonic stem cells have two valuable properties: under the right conditions, they can regenerate themselves – dividing to create identical new cells – and they are pluripotent, meaning they can develop into almost any type of cell in the body. That magnificent pliancy captivates scientists like Friedmann, who dream of the day they can take stem cells, coax them to become new brain or liver cells, and transplant them into patients with Parkinson’s disease or organ failure.

Scientists have already shown that in animals, stem cells can help treat heart disease, spinal-cord injury, and sickle cell anemia, among other things. Rats with damaged spinal cords regained some mobility after injections of neural precursor cells made from embryonic stem cells. Stem cells transplanted into rats’ heart tissue can help heal damaged heart muscles.

But before similar therapies can be tested in people, scientists will need to resolve the problem of immune rejection. Transplanted stem cells, which are now derived from discarded embryos, are genetically different from their recipients; like donor kidneys, they thus carry the risk of provoking an immune response. That means that even the most advanced treatments are still years away from clinical use. Therapeutic cloning is one way to make stem cells suitable for transplant, since it yields cells that share their recipients’ DNA.

Theoretically, cloned stem cells could help Friedmann’s patients; scientists could fix the genetic defect in the cells before implanting them. The prospect of such revolutionary treatment is what has most captivated both the public and the media. But Friedmann and Snyder are focusing on an application that could have much broader implications – and is closer at hand. Instead of using the cells as a form of therapy themselves, the researchers plan to use them to study Lesch-Nyhan disease and test new treatments. Experts say this type of application could dramatically improve our understanding of how any disease with a genetic component unfolds at the cellular level. “You could make a stem cell line that has ALS or Parkinson’s, using DNA from a patient that really has the symptoms,” says Snyder.

Scientists could prod the cells to develop into the type of cells damaged by a disease, such as dopamine neurons in Parkinson’s, and study the intricate progression of the disease from its earliest stirrings to its final cellular death knell. Because the cells would be genetically identical to the patient’s DNA, they would undergo many of the same molecular changes that underlie the patient’s disease.

Ian Wilmut, the British scientist who helped clone Dolly the sheep, hopes to turn stem cells in a dish into motor neurons, the type of nerve cells ravaged in Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis, or ALS). Creating a stem cell line with the disease would allow scientists to study how these neurons sicken and die and to search for ways to slow or stop the downward spiral of the disease. “I think that disease models, such as the ones we plan to create, will do more in the short term, and maybe the long term, to treat disease than cloning stem cells for tissue transplants,” Wilmut says.

One of the major advantages of cloned stem cells is that they would enable scientists to create accurate models of a disease without first determining the underlying genetics. “With a lot of sporadic diseases, we know there is a genetic component, but it’s not clear what it is or how it contributes to the development of the disease,” says Larry Goldstein, a neuroscientist at UCSD who studies Alzheimer’s disease. “We have a lot of hypotheses, and I think this methodology will put us in a position to test those hypotheses. And if one is correct, we’ll have a direction to go for therapy.”

A stem cell model of Alzheimer’s would also allow scientists to study what the disease does before symptoms appear and perhaps create early-diagnostic tests. By the time an Alzheimer’s patient goes to the doctor with cognitive problems, the brain is significantly – and possibly irreversibly – damaged. “Studying the brains of people who have already died is like studying a plane crash after the plane hit the ground – you’re looking at the wreckage,” says Goldstein. “We want to look at the black box of Alzheimer’s disease. What happens in those cells before the crash?”

To search for early signs of the disorder, scientists could generate stem cells using DNA from an Alzheimer’s patient, then prod the cells to differentiate into neurons, monitoring them for the production of specific proteins or other molecular changes not seen in neurons derived from healthy embryonic stem cells. The same approach might work with cancer, which is characterized by a series of harmful genetic changes. “We want to know what’s the earliest you can detect differences in disease cells,” says Renee A. Reijo Pera, codirector of UCSF’s human-embryonic-stem-cell biology program.

Cloned stem cells may also provide a much more effective way to test drugs. “Very often the animal models that exist for a particular disease really don’t authentically replicate what’s going on in a human,” says Snyder. Using models based on stem cells, scientists could test drugs at different stages of disease, searching for compounds that could prevent a person at risk for, say, Alzheimer’s, from ever developing the disease in the first place, or for compounds that stop or reverse the progression of damage in people who already have the disease.

Snyder eventually hopes to create stem cell models of many different neurodegenerative diseases. His first step, in collaboration with Friedmann, will be to use the frozen skin cells housed at UCSD to create stem cells with Lesch-Nyhan disease. Snyder originally hoped Hwang would teach him the cloning process. But now the scientists plan to embark on the therapeutic-cloning project on their own and are working on getting regulatory approval and state or private funding.

Ethical Eggs?
To generate normal stem cell lines, scientists start with a fertilized embryo, usually discarded from an in vitro fertilization clinic. They collect a specialized ball of cells, called the inner cell mass, from the embryo when it is just five to six days old. Cultured in a dish, the cells develop into a line of embryonic stem cells that can, depending on the conditions, either regenerate itself or differentiate into specialized cell types, such as heart cells, liver cells, or brain cells. Scientists must continually make new stem cell lines, because existing lines may accumulate mutations, making them unfit for therapies and many types of research.

Cloned stem cells, however, are even more difficult to make than regular embryonic stem cells. Scientists take the DNA from a differentiated cell, such as a skin cell, and insert it into an egg that has been stripped of its own DNA. The egg then starts dividing, much as a regular embryo would. If it survives long enough, its inner cell mass can be harvested and used to grow stem cells. Scientists have generated stem cells from cloned mouse embryos but have not replicated that feat in humans. Unlike naturally fertilized embryos, cloned embryos are hard to keep alive long enough – almost a week – that their inner cell masses can be gathered.

Hwang had claimed to do this with remarkable efficiency, using a small number of eggs. Human eggs are a precious resource that is very difficult to obtain, so the frugal use of eggs is critical to making nuclear transfer practical. But subsequent investigations revealed that Hwang and colleagues lied not only about their results but also about the number of eggs they used in their experiments. According to a report from South Korea’s National Bioethics Committee, Hwang used 2,221 eggs in his failed experiments, rather than the 427 eggs reported in his two Science papers. Scientists now have no idea how many eggs are required to successfully clone a line of human stem cells.

When the nucleus of an adult cell is put into an egg, some unknown factors in the egg turn back the clock on it, reverting it to its embryonic state. “It’s like pushing the reformat key on a computer. You reformat it to become some other kind of cell,” says Snyder. “We don’t understand the molecular pathways that do this….As far as we know, the only thing that can do this is the egg.”

According to Kevin Eggan, a molecular and cellular biologist at Harvard who is seeking approval from his university to start nuclear-transfer research, “It’s not clear how many eggs we need or how many women will step forward to donate eggs.” Eggan, who also sits on the ethics review board of the California Institute for Regenerative Medicine (and was a member of the 2005 TR35), says he’s spent much of the last year learning about the ethical and medical issues associated with egg donation. Many scientists say access to eggs will determine the success of therapeutic cloning. “We have a therapy that could have revolutionized medicine like antibiotics, but we have a bottleneck that shoots it down,” says Lanza.

The egg donation procedure is uncomfortable and potentially painful and carries some medical risk. Women must undergo hormone treatments to stimulate ovulation, counseling sessions to understand the risks involved, and a medical procedure in which a needle is inserted into the vagina to remove eggs from the ovary. A small percentage of donors develop ovarian-hyperstimulation syndrome, which in rare cases can cause kidney failure.

Even ardent supporters disagree over the most ethical ways to handle egg donation. Some scientists don’t want to use human eggs at all. “We feel it’s inappropriate to put women through a risky and potentially dangerous procedure when we don’t know what the efficiency is,” says Stephen Minger, a scientist at King’s College London who is planning to apply for permission from the British government to clone human stem cells using animal eggs. Those who do want to use human eggs disagree about whether women should be paid for their donations. Opponents worry that payment could encourage some women to undergo the procedure without understanding the risks. But others think compensation is the most ethical approach. “When ACT did this, we paid egg donors,” says Green. “I continue to think that’s the best way to do it. It’s fair and open and the least likely to lead to evasion.”

According to Lanza, all the women who recently contacted ACT about donating eggs dropped out of the process when they learned how much time was involved. Lanza says he still plans to proceed, as soon as he can get a new source of eggs. “If I were just starting, I probably wouldn’t do it,” he says. “Sometimes I spend more time on the phone with lawyers than I do on the science….But we’ve invested so much time and energy and so much of ourselves that we want to see this to completion. I still feel there is a very important role for [nuclear transfer] in different diseases.”

Lanza suspects that, because of the shortage of eggs and the unknown efficiency of the cloning process, the therapeutic use of cloned stem cells will end up looking more like a kidney transplant than like the ingestion of a widely prescribed drug. “We do recognize it’s not the broad cure we had hoped, but I’m convinced it will save some individuals,” he says. “Perhaps a mother would donate a round of eggs to create stem cells for her sick child.”

Federal Blockage
As American scientists gear up for the new race toward nuclear transfer, they face many of the same hurdles that stranded most of them in the starting block two years ago. Hwang had huge sums of money from the Korean government, an adoring public, and an enormous, albeit ethically unsound, supply of human eggs. U.S. scientists face intense public scrutiny, an administration opposed to embryonic-stem-cell research, and a continuous struggle to get funding from private investors.

In 2001, President Bush limited federal funding for embryonic-stem-cell research to work involving a small number of cell lines already in existence. That policy has exerted a disastrously chilling effect on the field. Scientists who wish to do research on newly derived embryonic-stem-cell lines or to derive new lines themselves – as is necessary in nuclear transfer – must find private sources of funding.

Scientists and university administrators also face the arduous task of separating all publicly and privately funded research. “It means everyone is dragging 10-pound weights on their feet,” says Greg Simon, president of FasterCures, a Washington, DC-based advocacy group that aims to speed development of novel therapies. “We’re spending a lot of wasted time separating government money from private money when we should be spending time doing research.”

The federal blockade also means that the National Institutes of Health, the nation’s largest biomedical-research institute, has forsaken its standard regulatory role, leaving many scientists operating in a vacuum. The National Academy of Sciences has tried to pick up some of the slack, publishing a nonbinding set of guidelines for stem cell research in 2005 and creating a stem cell research oversight committee earlier this year.

Many state governments have felt compelled to step in, both regulating and providing funding for stem cell research. So far, California, Connecticut, Massachusetts, and New Jersey have passed laws that permit embryonic-stem-cell research, including work on cloned embryos. Arkansas, Indiana, Iowa, Michigan, North Dakota, and South Dakota prohibit research on cloned embryos.

In addition, California, Connecticut, and New Jersey have all earmarked state funds to support stem cell research not funded by the federal government. The California initiative, by far the biggest at $3 billion, has encountered pitfalls at every turn, demonstrating the difficulties that arise when states get into the research-funding business. The California Institute for Regenerative Medicine, the oversight entity created by the state’s Proposition 71, has grappled with accusations of conflicts of interest among those who determine the distribution of funds and with controversies over how the state will reap the financial benefits of stem cell research – a promise that was part of the proposition.

Almost all embryonic-stem-cell research in the United States faces funding obstacles and ethical objections, but because nuclear transfer is the most contentious topic in the field – it involves not only the destruction but also the creation of embryos specifically for research – scientists and universities planning nuclear-transfer programs are extracautious. “The spotlight is on anyone doing this kind of research,” says Lanza. For example, Massachusetts law mandates criminal penalties for people who violate laws governing egg and embryo procurement. “If we slip up anywhere, we’ll be crucified,” Lanza says.

Other countries have much more supportive environments for embryonic-stem-cell research, which may give them the lead in the new race to perfect nuclear transfer. In the United Kingdom, for example, stem cell research is more intensely regulated but also much more open. Scientists apply to a central government authority for permission to do research involving human embryos. Summaries of research proposals under review – including those involving nuclear transfer – are posted online for public evaluation, along with an explanation of the criteria for approval. “In the U.K., we have enormous government support, from the prime minister on down,” says Minger, an American scientist who migrated to the U.K. “There’s a stigma associated with stem cells in the U.S. that’s not true here.”

This openness contrasts with the situation at Harvard, where several scientists applied for permission to do nuclear-transfer research more than two years ago. According to Massachusetts state law, the researchers must get their experiments approved by institutional review boards. But whereas the British approval procedure is largely transparent, neither Harvard officials nor scientists proposing experiments would discuss with Technology Review their research plans or the details of the review process until after it is completed.

Across the Atlantic, government support has helped two U.K. groups charge to the forefront of therapeutic-cloning research. Alison Murdoch, Miodrag Stojkovic, and collaborators at the University of Newcastle upon Tyne have probably made more progress in nuclear transfer than any other researchers. Murdoch’s team received permission from the U.K. authority to start experiments in August 2004 and announced that it had cloned an early-stage embryo (it hasn’t yet isolated stem cells) soon after Hwang published his now retracted paper announcing an efficient cloning technology. At the University of Edinburgh, Wilmut also intends to do nuclear transfer. He put his plans on hold after the Hwang scandal, but he is now seeking permission to start a new set of experiments, using animal eggs rather than human eggs.

California’s Haven
In a lab high on a hill overlooking the San Francisco Bay, Renee Reijo Pera sits at her desk listening to the sounds of construction. The space next to her lab has been entirely gutted; ladders and scattered extension cords have replaced the orderly rows of microscopes and freezers. Upon completion in August, the space will become the home of UCSF’s new therapeutic-cloning research program. It will effectively be a replica of Reijo Pera’s current lab, stocked with the same sort of equipment, but purchased with private funds.

UCSF hopes the new facility will help it become a frontrunner in therapeutic cloning. The university was the first in the United States to attempt nuclear transfer, albeit unsuccessfully, in the 1990s. “Now we hope to start again where those studies left off,” says Arnold Kriegstein, director of the university’s Institute for Stem Cell and Tissue Biology.

Reijo Pera and colleagues started cloning experiments at another off-site facility in April, possibly the first U.S. group to try human nuclear transfer since Lanza’s team halted its work in 2004. In the UCSF lab, they will use “fail to fertilize” eggs from an in vitro fertilization clinic, which are much easier to get than donor human eggs. When they have optimized the experimental conditions, they will start using human eggs donated specifically for research.

UCSF’s new program is just one sign of California’s bid to become a haven for therapeutic cloning. The $3 billion in state funding for stem cell research that voters approved in 2004 has been held up in legal disputes; but in the interim, the oversight agency is issuing bonds to raise money for stem cell programs. Many universities that hope to receive some of that money say that nuclear transfer will be a major part of their research agendas.

Two teams of scientists at Harvard with an impressive dossier also plan to start nuclear-transfer experiments. George Daley at Children’s Hospital Boston wants to create patient-matched stem cells for bone marrow transplants for children with blood diseases, such as leukemia. Currently, many of these children cannot find donors whose bone marrow is a close enough match to be suitable for transplant. And sometimes even matched bone marrow transplants can trigger a severe immune reaction. Eggan, an expert in mouse cloning, and Doug Melton, a molecular and cellular biologist at Harvard, want to use cloning to create new models of neurodegenerative disease and diabetes. The Harvard scientists hope to get final approval for their respective projects this year.

Reprogramming the Debate
Tobias Brambrink sits at a microscope, staring at a plate coated with millions of specialized skin cells known as fibroblasts. He hopes to find a clump of cells that glow green, or even better, some cells that have the rounded shape of stem cells, rather than the elongated shape of fibroblasts. Brambrink, a postdoctoral researcher in Rudolf Jaenisch’s lab at the Whitehead Institute for Biomedical Research in Cambridge, MA, is searching for the genetic switches that control reprogramming – a poorly understood transformation that takes place during cloning, reverting an adult cell to its embryonic state.

All cells in an organism share the same genes, but the pattern of a cell’s gene activity determines whether it will become a stem cell or a differentiated cell. During reprogramming, some still-unknown factors in the egg turn off the genes that make a cell, say, a neuron and turn on the genes that are expressed in embryos. To uncover the genes controlling this conversion, Brambrink has engineered adult cells to express the genes that are selectively activated in eggs. If a particular gene expressed by one of these cells is crucial to the reprogramming process, it will activate genes that are known to be involved in the process’s later stages; those genes have been tagged with markers that make the cell glow green. In the best-case scenario, the activator gene might trigger reprogramming itself, creating a clump of stem cells where once sat differentiated fibroblasts.

Reprogramming cells in a dish would be a huge breakthrough for the field of therapeutic cloning. Once scientists understand the process, they can create new technologies to turn adult cells directly into stem cells. Such technologies would eliminate the ethical controversy surrounding embryonic stem cells, because they would not require the creation and destruction of human embryos. They would also eliminate the need for human eggs, which could make therapeutic cloning much more efficient and therefore more broadly useful. Such an advance could truly usher in a new era of regenerative medicine, where a tailored stem cell transplant is available to anyone who needs one.

Scientists have already shed some light on the reprogramming process. In a paper published in September, Rick Young, a biologist at Whitehead, and colleagues identified a set of genes that are kept inactive in undifferentiated stem cells. Researchers theorize that when these genes are turned on, they produce transcription factors that spur the cells along different developmental paths.

Scientists caution that a clear picture of reprogramming – one that would enable the production of stem cells without eggs – is likely decades away. However, the little known so far is already helping scientists develop new, less controversial techniques for creating stem cells. For example, scientists are searching for ways to create genetically altered embryos that no longer have the potential to develop into human beings, thus eliminating some of the ethical controversy surrounding nuclear-transfer research. Markus Grompe, director of the Oregon Stem Cell Center at Oregon Health and Science University in Portland, hopes to create such a technology by forcing donor cells to express genes normally found only in embryonic stem cells (see “10 Emerging Technologies: Nuclear Reprogramming,” March/April 2006).

In fact, nuclear transfer may turn out to be a transitional technology. But even if it is, and for all its controversy, it might still be vitally important as the key to developing newer technologies that are able to finally free embryonic stem cells from ethical quandaries. “Nuclear transfer is the only way we can currently do reprogramming. This is our model and our yardstick to learn what’s important,” says Whitehead’s Jaenisch. Adds Snyder, “If we don’t know how to do nuclear transfer, or we’re not allowed to do it, then this potentially debate-solving technique becomes impossible to pursue.”

Lanza is also working on new reprogramming technologies to get around the shortage of eggs. But like Snyder, he worries that too much focus on uncertain alternatives could derail progress on therapeutic cloning, which scientists know works. “Let’s develop all these technologies and see what works best,” he suggests. He adds that months and years of grappling with the ethical and legal issues surrounding stem cell research, rather than the science, have worn him down. But the thought of stem cell-based therapies pushes him to keep going. “I’ve often gone home and thrown up my hands. But then I say, We can’t give up that easily.”

Emily Singer is the biotechnology editor of Technology Review.

Sidebar: Overcoming Immunity
One of the biggest obstacles to stem cell-based therapies is the possibility of immune rejection, as can happen with donor kidneys. Patient-matched stem cells – derived from a patient-donated skin cell – could present a way around this problem. But as researchers have come to believe that cloning stem cells may be too inefficient for broad use, they have begun developing other ways to overcome immune rejection.

Rather than creating stem cell lines for every patient who needs them, says Stephen Minger, a stem cell scientist at King’s College London, we might do better to create 1,000 stem cell lines representing the most common immune profiles in the population. “You wouldn’t get a perfect match for everyone…but you would be close, and you might only need mild immunosuppression,” he says.

Scientists are also developing ways to use stem cells to deceive the immune system. “If you can knock out [immune response], it’s possible you can have cells sneak under the radar,” says Tim Kamp, a stem cell scientist at the University of Wisconsin-Madison. Preliminary research suggests that turning stem cells into a type of immune cell known as a dendritic cell can trick the host’s immune system into accepting other, related cells. If scientists made both immune cells and whatever cell type was needed for therapy from the same lines of stem cells, they might be able to inject both cell types into a patient without an immune response.

In some cases, doctors may not need to worry about immune rejection. “We’re starting to recognize that stem cells may be better tolerated by the immune system in some areas of the body than we expected,” says Evan Snyder, a neurologist at the Burnham Institute in La Jolla, CA. “Embryonic stem cells seem to be tolerated in the brain, even without immuno-suppression.”

Geron, a California-based biotechnology company developing embryonic-stem-cell therapies, is taking advantage of this fact to develop new treatments for spinal-cord injury. Scientists have spurred injured rats to walk again after injections of neural precursor cells derived from embryonic stem cells; Geron is seeking permission to start human clinical trials of a related procedure next year.

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