The Stem-Cell Controversy: A Three-Sided Coin

But now there is a third side to the stem-cell coin. It is called induced pluripotent stem cells (iPS). These cells might be the solution to both the ethical nightmare and the scientists’ dream; they can be made without going through an embryo-creating/destroying procedure. Maybe, like some sort of strange Twilight Zone flip, the edge-on result changes the game entirely by allowing science to study disease in ways that will be more immediately transferable to human medicine. While the first steps of moving stem-cell therapies out of the lab and into the clinic (from “bench to bedside”) are already in progress, large scale applications might be close at hand.

Here we explore several aspects of stem-cell research which have been discussed in recent publications and at two recent conferences held in San Francisco.

Regenerative Medicine

The body’s tendency to wear down and eventually fail is not unique to humans. The universe as a whole, physicists tell us, is running downhill; decay and death are inevitable. The problem for medical science, and indeed for each of us, is to work out ways to maintain health and vitality for as long as possible against the degenerative pull of nature. Some argue that this will always be a losing battle; others are optimistic. So much so, in fact, that they no longer see physical immortality as a magical, “fountain of youth” fantasy.

Although not life extension per se, the first point of attack is tissue repair. If degenerative diseases such as ALS (Lou Gehrig’s disease), Parkinson’s, Alzheimer’s and diabetes could be cured, many people who now suffer greatly and die prematurely would certainly enjoy a longer and higher quality life. Likewise, if spinal cord and heart injuries could be healed, much suffering could be alleviated.

By combining an understanding of genetics, cell communications and the developmental process that both builds a body and subsequently allows it to degrade, scientists are seeking methods to stimulate the body to both maintain itself and to recover from degenerative disease and injury. Eduardo Marbán at the Cedars-Sinai Heart Institute, for example, has begun testing the capabilities of stem cells to repair the heart. Using heart tissue biopsies from the patient to create a cardiosphere cell culture, Marbán is currently reviewing the efficacy of these cells in restoring heart function following a heart attack. He reported positive results at the First Cedars-Sinai Regenerative Medicine Institute (CSRMI) Symposium in Los Angeles. Marbán noted that this procedure is the “first therapeutic intent of a cardiobiopsy.” Results of this trial are expected soon.

This is the great potential of the stem-cell revolution, the “heads you win” side of the coin. The “losing” side for some ethicists has long included the need to create clones from patient cells via a nuclear transfer/embryo-creating process, as well as the continuing use of IVF “leftover” embryos for further research. Marbán’s method bypasses these drawbacks entirely because the patient’s cells are used directly.

It is the human embryo that has always been at the core of the stem-cell controversy. In terms of potential therapies, because cloned embryonic stem cells shared the patient’s genes, implanting these cells back into the patient to stimulate tissue regeneration seemed like a good route to clinical success. Avoiding immune system rejection is a key concern when foreign cells are injected back into the body.

One company has spent the last decade building a generic stem-cell bank without cloning. Moving forward under the premise that stem cells are “immune-privileged,” the biotech company Geron has manufactured generic nervous system stem cells and has recently received FDA approval to move into phase 1 clinical trials. Technically called hESC-derived oligodendrocyte progenitor cells, they are meant to repair a specific type of spinal cord injury.

The clinical trial is aimed at testing the repair capabilities of these cells in neck injuries such as those sustained in swimming pool or car accidents. The trial requires that the cells be injected into new or acute damage that has not undergone cellular scarring, and as Reuters reported, Geron CEO Thomas Okarma notes that these accidents most often occur in the summer. “This is the high season, if there is such a word that is appropriate, for the frequency of these injuries.” Geron recently reported that the first candidate for the procedure had been found.

Recent mouse studies reported by others indicate that human embryonic stem cells may also be capable of repairing more long-term or chronic spinal cord injury.

If Geron’s trial is successful, and of course one hopes it is for the sake of the patients that could be helped, the business model of creating a kind of off-the-shelf supply of various stem-cell types ready-made—just thaw and inject the product tagline might read—seems to make sense. But other breakthroughs since 2006 may leapfrog this technology: iPS cells are reprogrammed directly from an easily captured patient skin cell. (See Sniffing Out a Cure for Parkinson’s.)

One leader in iPS research notes that the days of much embryo-based work may be waning. Although human embryonic stem cells will be necessary for some time to further medical understanding of stem-cell biology, “My brain has completely switched to iPS,” CSRMI Director Clive Svendsen, Ph.D. told Vision. “Get your stories out quick, because [that] whole era is disappearing.”

A recent issue of the journal Regenerative Medicine focused on iPS cells and their potential in both regenerative therapies and drug discovery. “What is clear is that we are living through a revolution in our understanding of cellular lineage specification, tissue genesis and the epigenetic regulation of our genome,” the issue’s guest editors noted, “and all because of the availability of iPS cells and the reprogramming process.”

Pinball Wizard

How does an iPS cell differ from “traditional” stem cells? Rather than creating a truly embryonic cell, the key idea is to take a differentiated cell from the patient and basically reset the process. Svendsen and colleague Dhruv Sareen at CSRMI cleverly picture the iPS reprogramming process as a ball traveling through a pinball machine. Back in the day when pinball machines were mechanical rather than a screen graphic, the game was played by launching a silver ball onto the inclined field of play. As it rolled toward the bottom and out, the player strategically manipulated various flippers to keep the ball in play and score points.

In their paper “Stem Cell Scientists Play a Mean Pinball” published in Nature Biotechnology (April 2010), Svendsen and Dhruv use the path of the ball around and through the playing field as representative of the cell differentiation process. In other words, during normal development, embryonic stem cells give way to all the different cell types of the body; when finished—once a cell becomes muscle, nerve, blood, skin, etc.—the game is over: the ball has left the field.

Creating iPS cells, however, is like a skillful save—an adroit flip that kicks the ball (differentiated cell) back to the top of the field to a renewed stem-like state. This dedifferentiation is actually achieved through the introduction of various chemical signals. Now the ball/cell may travel or be directed (careful, don’t tilt) down a new path; a skin cell may be thus reprogrammed as another cell type entirely. This is the point of the iPS game. These new cells may be cultured and tested, used as drug-screening platforms, or, at some point in the future, serve as therapies themselves, reintroduced into the patient and able to restore or regenerate the patient’s lost function. In this analogy the flippers represent various transcription factors that scientists actually manipulate or “overexpress” to cause cells to reverse their destinies.

Astounding Progress

This chemical manipulation is the state of the art, the amazing “edge of the coin” that most investigators overlooked or considered improbable if not impossible. Calling the advances “breathtaking,” the Regenerative Medicine editors write, “Never before have we wit­nessed the rapidity with which findings have been duplicated and incremental advances made to refine a methodology. Today finds any number of investigators worldwide able to direct the reprogramming of somatic cells to pluripotency, using cells obtained from a wide variety of anatomical sources and species, and all manipulated with relative ease.”

They continue, “This was an unthinkable task 5 years ago where practitioners of nuclear transfer perhaps stood alone in the hope that such technology might one day be a practical tool to study disease, generate large numbers of defined cell types for use in screening platforms and, that ultimate objective, create patient-matched cells and tis­sues for clinical transplantation.”

Cedars-Sinai’s Svendsen has been actively involved on the iPS front for many years. “We can now replay the disease over and over again in the culture dish and begin to ask questions about how this happens, and perhaps find drugs to prevent it. It's revolutionary science,” he says.

Prior to his appointment at CSRMI, Svendsen and colleagues at the Waisman Center and the Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, successfully reprogrammed cells from a patient suffering from spinal muscular atrophy. Patient skin cells converted back to neurons that grow in culture, show the chemical signature of disease, and can be used to screen the effectiveness of new drug therapies. “This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease,” they reported in Nature, in January of 2009.

“This is, to our knowledge,” they continue, “the first report to observe disease-specific effects on human motor neuron survival and drug-induced increases in protective proteins, thus validating that the iPS model can recapitulate at least some aspects of this genetically inherited disorder.”

Thus, indeed, great progress is being made; it is setting the foundation for future work just as pilings form the footings for skyscrapers. Nevertheless, there is dissatisfaction with the pace of progress. Just as there has been a perceived lack of progress following the completion of the Human Genome Project—many recent articles have questioned the pace of developing new medical applications from that work—there remains the sense that stem-cell progress has also been lagging. In a time of “stimulus spending” around the globe, it is easy to be trapped by the idea that all discovery translates immediately into human treatments.

Stem-Cell Tourism

Stem-cell hype leads to much stem-cell hope. Unfortunately, there are sharks in the stem-cell waters. As always, there is a danger to the overeager consumer when it comes to seeking out stem-cell-based cures to disease. For every legitimate endeavor, there is a snake oil offer as well. For a decade or so, almost concurrent with the Human Genome Project, potential stem-cell therapies have been oversold by politicians, legitimate scientists as well as stem-cell charlatans. It is therefore easy for the ill or injured to imagine medical timelines as much shorter than they actually are. Observers of the history of the “bench to bedside” transition note that 20 years is the usual time frame from initial discoveries to clinical efficacy.

We are just now coming over the horizon to view a stem-cell-driven regenerative medicine world on the valley floor below. “Are we there yet?” We are not; some “therapies” have assumed commercial status prematurely, if not falsely. Irving Weissman, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and president of the International Society for Stem Cell Research (ISSCR), scolded the 3,000+ assembled in San Francisco for the Annual Meeting of the ISSCR in this regard. “Some of your names are on these sites,” he said, pointing to the explosion of Internet offers for stem-cell cures that lead patients “into the hands of predators” who hawk unproven stem-cell cures. They “treat your wallet but not you: [they are] a pernicious group and they are all over the place.”

“The FDA [the U.S. Food and Drug Administration, which oversees clinical trials and drug safety] protects us all,” he noted, and then echoed the reasoning given in ISSCR documents outlining the need for more consumer information. “These [untested] practices could place individual patients at risk and jeopardize the progress of legitimate stem cell clinical translation.”

Toward the goal of consumer advocacy and warning, Weissman announced that the ISSCR will devote more effort to providing informative videos and blog posts to help the lay person evaluate possible stem-cell therapies. He warned that “smoking out the charlatans” is a goal of the ISSCR. When Vision asked if other sanctions might be in store for ISSCR members associated with questionable practices, Weissman said, “No, [his address] was the warning.”

Another Edge

Even as well-regulated, peer-reviewed trials proceed, the debate over how much we need to know before offering desperate patients treatment is unsure. Commenting on Marbán’s heart stem-cell injections, Svendsen told Vision, “Eduardo is edging on, moving ahead a little quicker than some would. However, he is getting things done. There are some basic core scientists who actually see this as a bad thing because they have been trained to understand mechanism. So they don’t think it is valid to move forward to a clinical procedure until you understand mechanism. My argument to them is that if we had said that about diabetes, we never would have started using insulin. We did not understand how insulin worked for 10 years, yet we saved millions of lives long before the discovery that insulin regulates sugar.”

In “Brave Pioneers or Clinical Cowboys,” published in Cell Stem Cell (June 4, 2010), George Daley says that “the field is bound to move forward prior to us having a really good sense of the range of the risks and rewards.” Daley, director of the Stem Cell Transplantation Program at Children’s Hospital Boston, aligns with the ISSCR when he says, “There are some people out there who think they know more than they do.” Finally, he notes, just as gene therapy seemed to offer many answers but also presented unforeseen challenges, really making stem-cell therapy work for human patients may be more grueling than imagined. “We’ve not yet faced the reality of how difficult it’s going to be.”

Even with the advent of iPS cells, the revolution of the stem-cell “coin” may finally come to rest here: How much information is enough to move forward? The discovery that promised to solve a dilemma has its own dichotomy. Heads: enough knowledge to move ahead with human subjects. Tails: too little.