Embryonic stem cell research: accepting the knowledge and applying it to our lives.

Parkinson's disease slowly robs its victims of their independence and dignity. Symptoms include jerky movements and shaking of limbs and head as the disease disrupts motor function and mobility. More than 1 percent of the human population has Parkinson's. The disease progressively restricts movement and communication. It is eventually fatal. Muhammad Ali and Michael J. Fox have Parkinson's, and the disease hastened the death of Pope John Paul II.

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While successfully evading researchers' efforts to understand why and how it starts and progresses, Parkinson's disease has shown scientists what it does to the brain-it kills the neurons that control the release of dopamine, a chemical which is important in controlling movement. When dopamine production stops, the pathological symptoms of Parkinson's appear. There is no effective treatment for the disease, but more and more researchers are pinning their hopes on embryonic stem cells for solutions. Hopes stalled as the debates about the ethical uses of these materials are weighed and judged.

Heralded as the salvation for a host of human ills, stem cells have become a growing presence in our lives. Embryonic stem cells are particularly attractive to researchers because they have more potential than adult and fetal stem cells. Embryonic stem cells are the first cells to emerge in a fertilized egg, or blastocyst, of an organism. It is from these that all the other cells, which become the tissues and organs of a living organism, develop as the embryo matures. Scientists learned how to extract stem cells from mammalian embryos over 20 years ago. Now, they are learning to coax them into becoming cells of various organs, brain cells, and blood cells in culture dishes. Their results, good and bad, continue to stir passions, and to raise hopes for cancer and organ transplantation and for new treatments for paralysis and neurodegeneration leading to Parkinson's or Alzheimer's diseases.

Although embryonic stem cells, or ES cells, hold the greatest potential for medical research, they also awaken the greatest fears about the direction of medical research. The debate about whether to use embryonic stem cells, or ES cells, draws on religious and humanitarian insights--often touching on subjects about the origin and the quality of life. The discussions are far reaching, affecting national and international research policy and commercial development. Amid the on-going ethical debates a key area of discussion is missing: What are the costs of having, or not having, a solid stem cell research program for nation and for life? And as these discussions rage, people wait.

Working quietly in Kyoto, removed from these debates, Japanese researchers recently cleared another hurdle to a viable embryonic stem cell therapy for Parkinson's. These scientists successfully reversed Parkinson-like symptoms in monkeys by transplanting monkey embryonic stem cells, without rejection or causing tumor development. If reproduced, they have found a promising, if controversial, avenue to effective treatment for humans with Parkinson's. The finding is significant, not simply for its therapeutic promises. It also quietly announces that embryonic stem cell research has advanced to where national research funding, moral positioning, and private interests begin to intersect.

Parkinson's disease, mobility and dopamine

Next to spinal cord injury, Parkinson's disease is the most likely candidate for a viable stem cell therapy. Unlike the more general brain damage found in other degenerative disorders like Alzheimer's and amyloid lateral sclerosis (Lou Gehrig's disease). Parkinson's is localized, causing the loss of neurons in the region of the brain called the substantia nigra. Situated in the basal ganglia, this region regulates voluntary movement and produces dopamine.

Dopamine is a neurotransmitter, a chemical in the brain that mediates emotional and physical responses and is associated with "runner's high" and learning. The loss of dopamine neurons is a symptom of Parkinson's. It is not the primary cause of the illness, but it is the most visible and debilitating early effect of the disease and the main target for therapeutic treatments. Researchers suspect that stem cells might be able to replace the neurons that produce dopamine and thereby stop or retard the progress of Parkinson's.

The drug L-dopa converts to dopamine in the brain. It is currently the most widely used treatment for Parkinson's. However, it is not perfect. It produces side effects, does not halt the disease's progress, and is not always effective. It simply masks the symptoms and enables mobility. In addition, L-dopa introduces dopamine in the absence of the regulating factors that would accompany dopamine release and removal in a healthy brain. Replacing lost dopamine neurons with newly grown ones from embryonic stem cells is currently the most promising direction for therapeutic research for Parkinson's.

Embryonic Stem Cells: From Mice to Humans

Led by Kyoto University's Jun Takahashi, a team showed that embryonic stem cells could be a viable route to therapy for complex degenerative disorders by successfully guiding the development of monkey embryonic stem cells into monkey dopamine neurons that, when implanted, removed the signs of Parkinson's-like illnesses in primate subjects. Even 14 weeks later, no common side effects, such as tumor growth, were found.

The challenge in stem cell research, according to Dr. Takahashi, is to be able to recreate in a culture dish the same environmental conditions that the stem cells would require in the developing organism to trigger specific cell fates.

"The right balance of chemical signals is needed," he explained. "Inhibitory signals block certain development cascades and excitatory signals enable others." The trick is to reproduce the right setting for the right result, and it is harder to pull off in less developed stem cell treatments.

Embryonic stem cells taken in the earliest days of development are undifferentiated cells, or pluripotent cells. Unlike adult and umbilical cord blood stem cells, which have more restricted cell destinies, embryonic stem cells offer the most versatility and have the most potential for research. The insights into development processes and disorders that ES cell research would provide would be profoundly beneficial. But for the moment, it is harder to work with ES cells.

Dr. Takahashi and his team worked in stages. Using mouse embryonic stem cells, a collaborating laboratory first learned how to cultivate neural progenitor, or precursor, cells. From these cells the scientists then teased out dopamine cells in a stable culture system that was later transferred into mice. But mouse cells are neither human nor monkey cells.

The same culture feeding system, explained Dr. Takahashi, needed tweaking for other animal cells to reproduce the same results. The researchers first cultured pluripotent monkey stem cells for a week to develop into multi-potent neural progenitor cells. These multi-potent cells are partially differentiated. Using a cocktail of enzymes, they further cultured these progenitor cells into precursor dopamine neurons and later new dopamine neurons. They transplanted these cells into the brains of monkeys whose dopamine neurons had been killed. Before the operation, the monkeys exhibited many of the same mobility symptoms as humans with Parkinson's, but these were noticeably reduced after the transplant.

"This was the first step," said Dr. Takahashi. Before human therapy can be attempted, scientists need to learn how to entice human embryonic stem cells to become dopamine neurons. They were able to grow monkey stem cells on a mouse-based feeder, but they know that this same system will not work on humans. When asked when an effective human feeder system might be expected, Takahashi demurred.

From Monkeys to Humans?

Aside from a thirty-minute discussion on "Science Friday," a National Public Radio (NPR) program in the United States, the Kyoto team's finding received little attention. This is odd, especially considering that this finding indicates Japan will rival Korea as leader in stem cell research and plays into the hype surrounding the benefits of stem cell research. The work is scientifically sound, but whether or not it will have practical application is difficult to predict.

Both Jun Takahashi and his new supervisor, Dr. Ryosuke Takahashi, shed some insight into why. "We saw no tumor growth in monkeys after fourteen weeks, but a longer study is needed," explains Jun Takahashi. This would verify that no tumors were formed.

Dr. Ryosuke Takahashi, Chair of Neurology and Clinical Research at Kyoto University and a leading researcher in motor neurodegeneration, also commented on his colleagues' findings. "It is interesting as a potential treatment for my patients." Then he noted concerns about the primate model in studying Parkinson's for therapy. "The research team created Parkinson's-like symptoms in their monkeys by chemically killing all the dopamine neurons in the animals. They did not recreate the actual pathology of the disease." In effect, the Kyoto-based researchers performed a cell-to-cell transplant. Without knowing the actual causes for the dopamine neuron loss, the potential for treatment remains unknown. Stem cell transplants may simply be masking the symptoms just like L-Dopa. Replacing dopamine neurons in Parkinson's patients is not likely to cure them.

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But would Ryosuke Takahashi suggest this therapy for his patients with Parkinson's disease? Yes, he hastily replied, echoing a point made on "Science Friday."

The radio program focused less on the actual therapeutic potential of the finding than on the political and moral implications of the primate study. It did, however, express sympathy for Parkinson's patients. On the program, Dr. J. William Langston, of the Parkinson's Institute, commented on the Japanese study. He argued that many of the moral issues surrounding the progress of stem cell research in the United States are not present internationally and that success outside of the United States would effectively nullify many of those questions.

"People with Parkinson's disease do not care nor do they want to wait for treatments," Langston said. They will want help now, and at any cost, regardless of the ethical debates. Demand by Parkinson's sufferers will fuel research. A recent NHK program on the ethics of fetal stem cell research for medical purposes highlights this too. As Japan debates the morality of the issue, Japanese are now seeking treatment in China, which allows the use of aborted fetal cells (also called embryonic germ cells) for transfer--regardless of scientific merit, legitimate medical evaluation, or moral positioning.

Without open and realistic investigations, medical therapies that incorporate stem cells cross into pseudoscience and alternative medicine. Worse, they run risk of betraying public hope. These are legitimate concerns. According to Dr. R. Takahashi, the extent to which expectations for cures based on embryonic stem cells have been inflated and whether they will be met will impact research, funding and public trust. What penalty will be exacted for failure to deliver?

Stem cells and a future for research

Embryonic stem cells are the blueprints, the raw materials, and the laborers that build life. Embryonic germ cells are the next stage of development and are found in fetuses. Their fates have already been partly determined but can still develop into a subset of organs. Adult stem cells are highly specified and the least flexible.

Research using adult stem cells and embryonic germ cells from aborted fetuses has advanced significantly, but most researchers agree that studying embryonic stem cells from humans is essential. These hold the keys to understanding our development. Scientists can learn much simply by discovering how these first cells transform into all the other cells, but this work is time consuming and still risky.

Nearly 25 years after work on mouse stem cells began, researchers have only just learned how to develop mouse embryonic stem cells into neurons for higher brain functions, where cognitive processing takes place, at RIKEN Center for Developmental Biology. This advance is technically more important than its promises for therapeutic treatments, as it provides insights into mammalian brain formation. Extrapolating the findings for human treatments, however, may be premature.

These Japanese advances, combined with Jun Takahashi's suggestion that human cultures of ES cell differentiation in dopamine neurons will be possible, indicate that more researchers are stepping up to the line: they want to explore the potential of human embryonic stem cells. These findings, and two Korean reports on human embryonic stem cells, show that moral debate may undermine national research efforts in the short run. Korea has taken the lead in human somatic cell transfers of stem cells (cloning). The potential benefactors of these therapies are put forth to show the moral need to pursue work on embryonic stem cells.

Nevertheless, as Ryosuke Takahashi and most degenerative disease researchers admit, these are only treatments. With the possible exception of certain types of spinal cord injury, where the damage is clearly isolated and non-progressive, the hope of stem cell treatment is not in preventing the disease. These solutions do not cure the diseases. Research pursuing the source of diseases must continue if real solutions are to be developed. Using these techniques with human embryonic stem cells is a next logical step.

Fears of cloning and the creation of human--non-human hybrids using embryonic stem cells have made these next steps difficult. Japan narrowly approved the use of human embryonic stem cells late last year while maintaining a ban on fetal cell use, but even this decision is tenuous. While moral debates on the ethics of fetal and embryonic-stem-cell research grab attention, international, practical, economic and environmental issues of ultimately broader impact on social well-being are being ignored. These, too, need to be included in any discussion of national stem-cell-research policy.

More than our definition of human life is at stake. What are the practical benefits of taking a leading role in stem cell research? Who benefits? Who loses? Japan's government council only narrowly agreed to approve embryonic stem cell research after a team of Korean researchers announced that they had successfully cloned human embryonic stem cells in February 2004. Actively pursuing human stem cell research will affect science, medicine and business. Attention to these questions might prove more beneficial in developing an ethical policy for Japan that enhances its role in life sciences than debates about quality of life, definitions of humanity, and morality.

Researchers are also pushing to ease stem cell regulations for their own survival; they need funding. If given the green light, funding and support will pour in and leave other projects under funded. Right now Ryosuke Takahashi and other researchers investigating the causes of Parkinson's disease favor stem cell research in answer to patients' requests for these treatments. With finite resources, investigation into the causes of diseases like Parkinson's would take a back seat to clinical research into stem cell treatments.

Jun Takahashi's team is exploring the therapeutic potential of embryonic stem cells, not its clinical applications. If his work becomes more important than the understanding of Parkinson's pathology, it would mark a shift from basic research to applied research with shorter, less complete visions.

Dr. Jun Takahashi's research is highly collaborative and involves laboratories undertaking various aspects of research; however, Dr. Takahashi should move cautiously. Human embryonic stem cell research in Japan should be pursued with an eye to understanding human development and to discovering therapeutic treatments for many degenerative diseases (brain or otherwise). Its goal should be to protect and expand basic research foundations without jeopardizing the drive for core knowledge.

The fear is that money will pour into stem cell research with inflated expectations detrimental to science in the long run. The NHK program is an example of how rapid adoption of embryonic stem cell findings will invite pseudoscience and quack medicine, and inflame the debate on life, the cost of life, and the right to life. Medically embracing Dr. Jun Takahashi's work or other stem cell findings before understanding their limitations and realistic benefits would be a waste of good research. As stem cell research on embryos advances, the true question is how do we choose to accept the knowledge and apply it to our lives.