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Stem-Cell Wonderland

Will cures be affordable to all?

by Ralph BraveSacramento News & Review
October 20th, 2005

Last week, a middle-aged woman from Maryland sat in the Denver airport, reading a story in The New York Times headlined "California Maps Strategy for Its $3 Billion Stem Cell Project." Asked whether she's professionally involved in the life sciences, she said, "No." Why then was she reading this particular article? Without hesitation she replied, "My father died from Parkinson's disease."

So it is around the state, the nation and even the globe: Having launched a major stem-cell venture nearly a year ago, California is being watched and looked to for stem-cell cures for all kinds of chronic diseases and conditions.

But the woman in the airport would not have been encouraged by the tale told in the most recent University of California, Berkeley, alumni magazine of a woman near her own age suffering from Parkinson's. This woman's husband happens to be both a cell biologist and director of Berkeley's stem-cell center. When it comes to the prospect of a stem-cell therapy to save his wife or any other Parkinson's patient, he states his scientific opinion succinctly: "Right now, it's remote."

The tension between the hope for cures embodied in California's big stem-cell adventure and the scientific challenges in meeting those hopes is almost palpable at every stem-cell meeting and conference. The lectures from most scientists almost always include a proviso that stem-cell therapies or cures are a decade or more away. But there is clearly pressure building to find stem-cell cures rapidly, and there's at least one proposal to move toward the first human clinical trials next year.

How to make sense of this? Where is the right balance to be found between cold-eyed scientific rigor and the urgent desire to cure disease and address huge swaths of human suffering?

A glimpse at the current status of California's stem-cell endeavor and recent reflections from stem-cell scientists provide some clues.

Plot twists and tumult
The September 9, 2005, meeting of the California Institute for Regenerative Medicine (CIRM) governing board had the markings of a Hollywood script--but whether it was one written by Frank Capra or Samuel Beckett remains to be seen. On that day, the lead actors in California's $3 billion stem-cell enterprise announced the first grants of $40 million to 16 research universities and institutes. The plot twist was that they didn't actually have a single cent to hand out, as the monies remain tied down by lawsuits challenging the constitutionality of the venture.

This was but the latest scene of tumult during the first year of California's big stem-cell adventure. One year ago this November, a 59-percent majority of California voters approved Proposition 71, embedding the creation of the CIRM in the state's constitution, in order "to realize therapies, protocols, and/or medical procedures that will result in, as speedily as possible, the cure for, and/or substantial mitigation of, major diseases, injuries, and orphan diseases." This includes a constitutional "right to conduct stem-cell research," including stem cells derived from "somatic cell nuclear transfer"--that is, embryo cloning.

No matter one's view on the issues involved, this has to stand as some of the most unusual language in any constitution anywhere in the world: a constitutional right to a particular line of scientific research, directly tied to a prospect for cures that are to come "as speedily as possible." In a way, it's an expression of the ultimate California dream: the right to be cured, quickly.

The passage of Proposition 71 certainly sent a strong rebuke to President Bush and his policy of narrowly restricted support for embryonic stem-cell research. Indeed, Proposition 71's protection of stem-cell research in the state constitution is a direct reflection of how threatened the scientific community felt and still feels by the national Republican neoconservative/religious fundamentalist coalition's attempts to limit biomedical research by executive order and by statute. The Bush policy gave birth to Proposition 71.

With Proposition 71, California was to become the world's epicenter of stem-cell research. The measure's $3 billion budget dwarfed even that of whole other nations. Worries of a "brain drain" of the best and brightest stem-cell researchers and their protégés to the Golden State became rampant in scientific circles.

But the freezing of funds by litigation, and turmoil over the institute's open-meeting policies, conflict-of-interest rules, research-subject protection and intellectual-property guidelines have dominated the first year of the state stem-cell institute. Even state Senator Deborah Ortiz, D-Sacramento, the state legislator who most prominently guided California's stem-cell policy prior to Proposition 71 and avidly campaigned for the initiative's passage, turned an unrelentingly critical eye toward CIRM's policies and process. Only under intense pressure from the legislative leadership was her state constitutional amendment on these issues tabled this year.

While few Californians have the time or interest to follow the intricacies of these complex debates, at some point the state's citizenry will ask whether the CIRM can deliver on its promise of "Cures for California," as the Proposition 71 campaign was called.

"The chances for diseases to be cured from stem-cell research are high," Stanford stem-cell pioneer Irving Weissman assured voters in Proposition 71 campaign ads. "If the promise of stem-cell research comes true, we can hope for a single treatment with the right stem cells to cure diseases every family has," his televised image told us. Ads by other prominent scientists delivered similar messages.

Were these statements to be relied upon? Or was this just a stem-cell sell?

Proof of principle
That no one has ever been cured by stem-cell therapy is a true statement, and one often made by the opponents of embryonic stem-cell research. But at a recent "Stem Cell 101" seminar for doctors and nurses, professor Kent Erickson, chair of the UC Davis School of Medicine's Department of Cell Biology and Human Anatomy, pointed out that bone-marrow transplants, practiced successfully for the past 30 years, are actually a form of stem-cell therapy. Later, his colleague, UC Davis Medical Center liver specialist Dr. Mark Zern emphatically repeated this: "Bone-marrow transplantation is stem-cell biology."

What they meant is that it is the naturally occurring healthy stem cells in transplanted bone marrow that are responsible for reviving a patient's ability to produce the blood and immune cells needed to stay alive. Such transplant operations are responsible, Zern proudly points out, for the complete turnaround in the ratio of cures for childhood leukemia. Where previously 90 percent of such cases died, today 90 percent of such cases live.

For scientists, this is "proof of principle" that stem-cell therapy can work. There are other such proofs of principle for therapies conducted in animal models and in humans for a wide range of diseases, from Parkinson's to diabetes, which serve as the catalyst for much stem-cell research and advocacy. But proofs of principle are not the same as proofs of cure.

Broadly speaking, the most accurate description of the goal of stem-cell research is "cell replacement." The idea is that when a degenerative disease like Parkinson's or Alzheimer's hits, or a chronic injury like spinal-cord injury occurs, the best hope might lie in replacing the damaged cells or tissues with healthy ones. (This is the origin of the phrase "regenerative medicine.") Stem cells, whether they come from umbilical-cord blood, from adult tissues and organs, or from embryos, are the source for generating the needed new particular cells or tissues--not the therapeutic replacement stuff itself.

The moral controversy
Much of the public controversy over stem-cell research has arisen because of two factors: the use of embryos and cloning techniques.

With the first isolation of human embryonic stem cells at the University of Wisconsin in 1998, the dream of regenerative medicine took a huge leap forward. Here indeed was the mother lode for the 226 varieties of human cells making up all human tissue and organs, from our skin to our brains. If the mechanics of these embryonic stem cells could be mastered in the lab, then replacement tissues and even whole replacement organs might be devised for any number of debilitating diseases and conditions that currently have few or ineffective or no treatment options.

But harvesting these stem cells requires destroying the five-day-old embryo from which they come. The moral controversy over this procedure continues to this day. When patient advocate Don Reed, whose son was paralyzed in a college football game, addressed the "Stem Cell 101" seminar on the dire need for embryonic stem-cell research, the first question from the audience was "My life began at conception. When did yours begin, Don?"

On the other side, though, a pro-life scientist such as Stanford's William Hurlburt, who serves on President Bush's Council on Bioethics, is so convinced of the therapeutic potential for embryonic stem cells that he has been working vigorously to find a technical way out of the moral dilemma. His proposal is to genetically alter embryos so they could never develop, never become "life," yet still could supply embryonic stem cells. Just this week, Massachusetts Institute of Technology scientists reported successfully implementing this procedure in mice.

Cloning technology has become joined to the stem-cell debate in the attempt to create cells that will be accepted by a patient's immune system. The idea is to take the DNA from a patient's skin cell, for example, place it in an egg (which has had its own DNA removed), thereby fertilizing it, and allow it to develop until the embryonic stem cells are formed. These embryonic stem cells, and any cells derived from them, then would be a perfect genetic match for that patient. The destruction of an embryo and the proliferation of cloning technology remain dividing-line issues for some.

But they are issues that have been settled in California with the passage of Proposition 71. Here, the question is whether even with utilization of these techniques, the cures can be delivered.

UC Davis' professor Erickson lays out an imposing agenda of stem-cell-research requirements before they can be ready for human trials: learning how to generate and proliferate the cells, learning how to control the cells so that they become the kind needed for each particular use, figuring out how to assure they survive once implanted into a patient, making sure they go to the right place in the patient's body and guaranteeing that they will function properly once there. A lot of work, which includes making sure that the new cells don't kill the patient.

"These are tasks which place targeted cell-based therapies 10 to 20 years away," said the professor. A recent report from the California Council on Science and Technology was even more tentative, calling effective therapies "at least ten to twenty years away."

UC Davis professor of pediatrics Alice Tarantal, who recently received a $6 million National Institutes of Health stem-cell grant, summarized it this way: "It will be several years before we can be confident that the cells are going to do what we want them to do."

The rat walks
But then there's Hans Keirstead's "rat walk" video.

Hans Keirstead is the Hollywood-handsome, Canadian-born scientist based at the Reeve-Irvine Research Center at UC Irvine. Even before Proposition 71, he regularly showed a video of a rat whose spinal cord had been severed in a way to mimic paraplegic human spinal-cord injury. Upon injection of replacement nerve cells, the rat regains significant ability to move its hind legs and some bladder control.

Keirstead's work and video have been immensely influential. Patient advocate Don Reed describes holding that rat in his hand in March 2002 as something close to a religious experience. The rat-walk video was shown at legislative hearings and numerous campaign occasions for Proposition 71.

But the scientist has been widely criticized for showing the video before his research had been accepted within the scientific community. Keirstead also has been accused of giving patients false hope, as the rat stem-cell treatment provided relief only if given within a week of the injury, and many therapies effective in rodents have never worked in humans.

While Keirstead admits that he cannot predict whether stem-cell treatments will work in humans, he justifies his actions based on patients' needs and is unabashed in his desire to move forward. "One of the problems with spinal-cord injury is that there is no chronic treatment," he recently told an industry journal. "Patients get patched up and sent home with no therapy base. ... They go back to lives of tremendous difficulty behind closed doors. It's devastating. I get telephone calls literally every day from patients, and every single story is desperate. These individuals often commit suicide. I've had people say to me, 'What are you going to do to stop me?'"

Keirstead's research demonstrated some intriguing features in stem-cell-based therapies that may be relevant approaching other diseases and conditions. One is that the cells appear to naturally migrate to the place of injury. This seems to be the result of some kind of inherent chemical signals directing the cells to where they are needed. Second is that the therapeutic effects in this case may not come from the cells serving as replacements so much as protecting the functioning of the remaining healthy cells in the damaged area.

Based in part on Keirstead's research, the Geron Corp. of Menlo Park is in active discussions with the Food and Drug Administration (FDA) for permission to proceed with first-phase human clinical trials for stem-cell therapy for spinal-cord injury. Geron's chief financial officer, David Greenwood, told SN&R that top trauma centers around the country are being enlisted to offer the experimental treatment to newly injured spinal-cord patients. Patients enrolling in the trial will need to accept all possible risks from the protocol. Asked whether Geron receives requests from patients to be the first "guinea pigs," Greenwood replied, "Everyday. Everyday."

An FDA spokeswoman said the agency is prohibited from disclosing names of companies applying for trials but confirmed that there are several requests under review for stem-cell therapies.

"Go slow. ... Be very careful"
An even more difficult call will be for diseases in which there are existing treatment options. Type 1 diabetes (often called juvenile or insulin-dependent diabetes) is an example of this close to the heart of the state's stem-cell enterprise. Robert Klein, the driving force behind Proposition 71 and chair of the CIRM board, has not been shy about his motivation to seek a cure for his 14-year-old diabetic son. The Juvenile Diabetes Research Foundation contributed more than a half a million dollars, so intensely does the diabetes patient-advocate community believe in the potential for stem-cell cures.

"Type 1 Diabetes: Low Hanging Fruit for Stem Cell Research?" asked the opening PowerPoint slide in professor Jeffrey Bluestone's presentation at the scientific symposium sponsored by CIRM during the first weekend in October. Bluestone, a University of California, San Francisco, diabetes researcher, who himself does not do stem-cell research, makes the case for the urgency. Sixteen million Americans currently have diabetes; one in 14 will develop it. With a million new cases diagnosed each year, it is the third most common disease in the country.

There are two types of diabetes. The most common, which usually arises during adulthood, is Type 2. Characterized by a growing resistance to the body's own insulin, Type 2 diabetes is often treatable with diet and exercise.

Type 1 diabetes, on the other hand, becomes manifest during childhood or early adolescence. In this form of the disease, the insulin-producing cells of the pancreas actually have been destroyed by the body's own immune system. Daily insulin injections are required in order to live.

Bluestone and others view Type 1 diabetes as an early prime target for stem-cell therapy for several reasons. First, the disease involves only a single type of cell, the beta cell, which produces insulin. Second, experiments have shown that the cells don't necessarily have to be reintegrated with the pancreas in order to function. They can lodge in the liver or other places and seem to do their job just fine.

Third, doctors have succeeded already in performing this kind of cell replacement with hundreds of diabetic patients. Scientists have been able to take the pancreases from organ donors (dead people), pulverize them, isolate and retrieve the beta cells and transplant them into living diabetics. Almost all these patients achieved insulin independence.

But there are problems. Most patients were back on insulin within five years. The transplant procedure costs around $350,000. The patients need to go on a daily complement of drugs to suppress their immune systems so that the body won't reject or destroy the new insulin-producing cells. And, as with other donor organs, there aren't enough cells to go around.

Still, Bluestone and others call this cell transplant "proof of principle" that stem-cell-derived therapy can be achieved. But he concluded his talk with a warning to "go slow" and "be very careful." Among other things he has in mind is that the wrong kind of transplanted stem cell can result in a cancer.

The clinical-trials quandary
Although the Proposition 71 campaign claimed more than 70 diseases that could be treated with stem-cell therapies, each disease will require different approaches. Many believe that stem-cell research will deliver new drugs long before cell replacement itself is possible. The stance of the private sector is one measure of the difficult road ahead: Besides Geron, there is almost no private investment in stem-cell companies.

But with Proposition 71, California's scientific and patient-advocacy communities struck a bargain: The patient groups would deliver the votes and the money for embryonic stem-cell research, breaking the Bush blockade, and the scientists would harness their research in the service of cures, "as speedily as possible."

The patient groups delivered. The state's science, biomedical and biotechnology communities are clearly aware of the obligation and the peril in holding up their part of the deal. Moving toward human clinical trials when so much basic science still remains to be done creates a quandary, one that has some bioethicists expressing concern about "patient-driven" research. But it is a quandary that at least one CIRM board member says is neither unwelcome nor unfamiliar.

"There has to be a balance," said Dr. Claire Pomeroy, dean of the UC Davis School of Medicine and a representative on the governing board of CIRM. "We have to get the basic science right. But we also have to recognize that these patients don't have decades and generations. They need answers now.

"This is a balance which we face every day in clinical research. This is the challenge we face in our cancer center at UC Davis, when we decide whether and when to bring a new therapy up.

"I think there will always be a tension between 'Let's define every single basic scientific fact' and 'Let's go to clinical trial.' One thing I've heard the patient advocates and other patients tell me is 'I'm willing to take some risks.' If that's a truly informed risk, and the appropriate regulations have been followed, then we have to take that into consideration.

"Let me just say one other thing. The use of early stem-cell therapy for incredibly serious fatal diseases, quickly fatal diseases, may have a different balance than, as an extreme example, the use for purely aesthetic corrections. The basic science of hair transplants has to be much safer and much more thoroughly investigated compared to something like end-stage Lou Gehrig's disease, where we really don't have other options for those patients."

Pop a pill and hope
Moving forward under Proposition 71, of course, depends upon CIRM winning the lawsuits in court and finally having the money to pay for all this research. Next month, the court will hear both sides argue that a judgment should be summarily cast in their favor, says a spokesman for the state attorney general's office. If the case goes forward, it could take six months or more to be resolved. In the meantime, Chairman Klein is trying to line up tens of millions of dollars in "bridge financing" from philanthropic investors. These investors will purchase "bond anticipation notes" with the understanding that if the court case is lost, there will be no payback for them.

The financial hurdles and the obstacles to a cure are just part of the package for the representative of Parkinson's-disease groups sitting on the California stem-cell board. Addressing the recent symposium of stem-cell scientists, attorney Joan Samuelson spoke from the perspective of her 18 years of disease difficulty. "Every morning I wake up frozen stiff, pop a pill and hope in an hour I'll be able to function," she told them. When it comes to cures, "are we perhaps living with expectations too high?" Samuelson asked rhetorically. That, she declared, is in "the best tradition of California. Hope is a very pragmatic tool. We believe we can change the world. We believe in the hope we have."



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