Stem cell cures?

The long and winding road


Stem cells. We’ve heard they can cure Parkinson’s disease, patch damaged hearts, replace the pancreas, rewire the spinal cord, cure cancer and restore memories lost in the fog of Alzheimer’s disease.

Jonathon Rosen

Well, not yet they can’t. Encouraged by the potential for breakthroughs like these, in 2004 Californians passed Proposition 71 to create the California Institute for Regenerative Medicine. The measure provides $3 billion over 10 years to support stem cell research in California. Yet despite the infusion of cash, expected to start flowing this year, the path to cures is proving to be more an obstacle course than a cakewalk.

After so much hopeful advertising and with a motto of “Turning stem cells into cures,” CIRM leaders are now under pressure to come through with the cures within the organization’s life span. The announcement made this fall by the agency’s governing board reflects the mood: The Independent Citizens Oversight Committee approved five- and 10-year goals that will guide funding and help keep the organization on track toward meeting voters’ expectations.

Although the plan includes a total of 20 goals, most amount to individual steps all leading to the overarching objective of curing disease — like listing “hire a contractor” and “get permits” as part of the overall goal of building a house. Four of the steps aim at getting more researchers into the field and encouraging those researchers to interact with each other and with industry. Eight additional goals revolve around generating much-needed new cell lines and understanding their biology. These all culminate in the ultimate purpose of testing out therapies on people within 10 years.

“When we set these goals, we were trying to be true to the spirit of Proposition 71, which is to generate cures for disease,” says Patricia Olson, PhD, CIRM’s scientific program officer who led the effort to craft the goals. She says Proposition 71 was intended to fill the funding gap for human embryonic stem cell research. The goals reflect this by primarily encouraging cures based on embryonic rather than adult stem cells. Embryonic stem cells have the potential to become all types of cells in the body. Adult stem cells can develop only into cell types from their tissue of origin — blood-forming stem cells, for example, can become only blood cells. Adult stem cells have broad potential for treating disease, but don’t have the unlimited potential of embryonic stem cells.

Olson says that although CIRM has no real teeth when it comes to enforcing the time line, she and others at the organization are aware of the political consequences of failure. The public won’t notice if, for example, in five years California fails to fill CIRM’s goal of establishing a stem cell bank. However, the consequences of having no cures in the pipeline after 10 years of funding could be politically significant. The credibility loss could hurt public support for science and state funding of research in California and elsewhere. A resulting ripple effect would hurt all researchers, not just those studying stem cells, according to Olson.

Even with CIRM’s focus, Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine (and Stanford medical alumnus, 1965), says the 10-year time line is tight. “We need to realize that there are defined intervals in the long trail from discovery to accepted therapies,” he says. All the intervening steps take at least eight years from discovery to an approved therapy. He says that although the time line will be a challenge, the longer-term outlook is excellent. “By 15 to 20 years there should be a whole lineup of cellular, protein or molecular therapies from pluripotent stem cell research,” he says.

Still, Weissman is optimistic that the organization he campaigned for will help California lead the effort to find stem cell-based cures. Work already under way at Stanford will play a big part in reaching CIRM’s ultimate goal of treating disease, he says.

New cells

The CIRM 10-year goals relating to cures are both specific and a bit vague. They aim to have completed at least one human clinical trial showing that a stem cell treatment works. Other goals are to have early stage clinical trials in progress for an additional two to four diseases, and proof of principle for stem cell therapies in animal models for an additional six to eight diseases. That’s somewhere between nine and 13 diseases that could be in line for a new treatment in the next 10 years.

Theo Palmer, PhD, who is developing treatments for neurodegenerative diseases using stem cells among other methods, calls that number large but doable. “If we think in terms of therapy that treats disease, rather than eliminating the disease entirely, then I think we could easily see those numbers,” says Palmer, assistant professor of neurosurgery.

However, he says researchers face significant obstacles. For starters, none of the embryonic stem cell lines that existed at the time of President Bush’s August 2001 announcement — making them available for federal research funding — are well-suited to treating humans. That’s because researchers originally used mouse cells and cow serum to provide nutrients to these stem cells, which as a result might cause the human cells to carry animal viruses or other contaminants. Now that researchers are learning more about what keeps stem cells happy, they are figuring out how to skip the animal products.

Those federally approved lines have additional problems making them less than ideal for finding cures. First, they haven’t been maintained using consistent, known media, creating a major hurdle for FDA approval. “It’s much easier to convince the FDA that a treatment is safe if you can say that your cell line has been developed and propagated under known conditions,” Olson says.

In addition to regulatory problems, the current cell lines are difficult to handle, requiring 24/7 coddling. What’s more, as the cells age they become more and more crotchety.

A final blow to the existing lines, all of which were derived from discarded IVF embryos, is that they reflect the mostly white population that underwent IVF treatment. Few of those lines will contain genetic variations typical of black, Hispanic or Asian populations. That’s an issue because one great promise of stem cell research is in understanding the origins of disease. If all the stem cell lines come from an ethnically similar background, they are unlikely to represent the wide range of genetic predispositions to disease that exist in other ethnic groups.

“The disease-specific cell lines will really be critical for that kind of discovery,” Palmer says.

Creating such specific cell lines most likely means perfecting a technique called nuclear transfer, in which a researcher places a nucleus from an ordinary cell into an egg. Next a researcher stimulates the egg to divide for five days, creating the ball of cells from which stem cells can be extracted. This is the technique South Korean researchers claimed to have mastered in 2004, but was later proven to be fraudulent. Though researchers have achieved nuclear transfer in many animals, including sheep, cattle and mice, nobody has achieved nuclear transfer in humans.

All of these problems underscore why six individual CIRM goals revolve around making new cell lines for use in research and new treatments. For CIRM, achieving those goals means more than just funding the most promising strategies for generating new cell lines. It also means funding new buildings and equipment. Existing lab space and the tools they contain were built or bought with federal research dollars and therefore can’t be used for work with new embryonic stem cells. Essentially, in order to find new cures, CIRM researchers need a research kosher kitchen with one set of equipment for all things federally funded and one set of equipment reserved for newer cells.

Stanford already has well-equipped laboratory space about 5 miles from campus where researchers can work with and derive non-federally funded stem cell lines. Long-term plans include moving those researchers to a new building on campus. For now, only one lab has begun working with new human embryonic stem cell lines. Postdoctoral scholar Eric Chiao, PhD, has been creating new lines from IVF embryos destined to be discarded by Stanford’s in vitro fertilization clinic. Working with Julie Baker, PhD, assistant professor of genetics, and 64 5-day-old embryos, he’s so far created four lines.

Stanford isn’t alone in developing new lines. Research teams at UC-San Francisco, Harvard, the Biopolis biomedical center in Singapore, the Karolinska Institute in Sweden and companies Cellartis and Geron are all developing additional stem cell lines from IVF embryos.

For now, nobody at Stanford has attempted nuclear transfer to create embryonic stem cell lines, although Weissman says that’s one eventual goal of the Stanford institute. Other teams working to crack the nuclear transfer riddle are at UCSF, Harvard, Biopolis and the University of Newcastle in England.

Theo Palmer

Neural rosettes

Researchers in Theo Palmer’s lab grew these bouquets of neurons from human embryonic stem cells. To get this result, medical student Branden Cord and postdoctoral fellow Katrin Schrenk-Siemens coaxed the stem cells with growth factors over the course of a month.

Making the cells into something

Even if CIRM’s short-term goals of creating and dispersing new stem cells lines come to fruition, that still leaves what Palmer calls the single biggest obstacle to stem cell therapies — gruesome tumors called teratomas. “If we had solved this problem earlier, I think we’d have therapies in trials now,” he said.

In early animal experiments with transplanted embryonic stem cells, those cells quickly formed teratomas bristling with hair, teeth and other cellular productions. These deadly tumors were hardly the tidy cellular Band-Aids the researchers had hoped to produce. It became apparent that for stem cells to treat disease, they first need to be coaxed into becoming the type of cells they’d be replacing.

Embryonic stem cells destined to treat heart disease first need to become heart tissue, and those intended to replace a pancreas must behave in a lab dish like pancreas cells do. What drives stem cells to take on one fate over another is a focus for Micha Drukker, PhD, a postdoctoral scholar working with Weissman. He has started the difficult task of identifying proteins on the surface of cells as they become ever more committed to a given fate. As part of this work, he’s hoping to find out what combination of factors drives cells down a particular path.

“Without knowing these steps, I don’t think it’s possible to develop therapeutics,” Drukker said.

While Drukker works out the big picture of how and why stem cells take on a certain fate, others are taking a more directed approach of trying to push stem cells to become their cell type of choice. As one example, Palmer has two students in his lab working out ways of growing neurons for use in repairing brain tissue after a stroke or irradiation, or in Parkinson’s disease. The challenge of the moment is steering stem cells to become the specific type of neuron that’s needed and in sufficient purity to be therapeutically useful. What’s more, even if the researchers can generate neurons, the brain and spinal cord are complex, three-dimensional structures with a network of neuronal connections. Plopping a new neuron amidst all those existing connections would be like throwing down a new road without any connections to existing streets — it wouldn’t exactly help traffic.

The issue of three-dimensional structures is one reason Palmer believes that diabetes, hemophilia or other diseases in which the replacement cells need not occupy a precise location will be among the first diseases to reach clinical trials.

Seung Kim, MD, PhD, associate professor of developmental biology, has been working on ways of generating insulin-producing cells to replace those lost in type-1 diabetes.

What makes this work a potential front-runner for near-term therapies is the variety of locations in which the cells can reside and still do their job. In his animal models he has transplanted insulin-producing cells called islets, which normally sit in the pancreas, into both the kidney and the liver — a site already used successfully for islet transplants. As long as the cells respond to sugar appropriately and their location provides a blood supply, there’s a chance they’ll thrive.

While researchers like Palmer and Kim are hoping to grow cells for transplantation therapies, others are hoping for ready access to cells for research purposes. As one example, postdoc Chiao is hoping to lure some of his newly created embryonic stem cells into becoming liver cells. He’s doing the work in collaboration with Jeffrey Glenn, MD, assistant professor of medicine, who studies the hepatitis virus in cells from donated livers — cells that can be hard to come by. If Chiao could generate a supply of liver cells, it would greatly speed hepatitis research. Similar work with other tissues could allow researchers to study the causes of disease or to test drugs. Chiao’s liver cells could be a useful tool for screening whether new drugs will be toxic to healthy tissue, also one of CIRM’s goals.

Olson says no one goal is more important than another. Creating new cell lines won’t fulfill voter expectations unless researchers figure out how to work with them. Nor will encouraging new researchers to join the field, if those researchers don’t interact to speed the exchange of ideas. “All of the goals are important contributors to the main goal of finding cures,” she says.

Taken together, the obstacles to cures for brain disease could be disheartening. But recently, after two months of painstaking effort, a student in Palmer’s lab generated a plate of Parkinson’s disease-type neurons out of human embryonic stem cells. Just weeks before, the same student, an ace at creating neurons from mouse embryonic stem cells, had bemoaned the difficulty of working with human cells.

With that hurdle overcome, the group can focus on the next task of repeating and expanding the experiment. To a typical voter, verifying results probably seems all but irrelevant in a quest to cure disease. Palmer, though, finds it breathtaking to have come even this far. SM

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