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Getting Stem Cells Right

Fri, 01 Feb 2008 00:00:00 -0500

A true, no-cost resolution of a conflict, where the interests of all parties are served without compromise, is an exceedingly rare thing. Yet just such an unlikely resolution may be in hand for one of the most acrimonious conflicts of recent times: the debate over human embryonic stem cells.

Research groups in Japan and the United States have shown that ordinary human skin cells can be converted to stem cells with all the important properties of human embryonic stem cells by a process termed direct reprogramming. Like embryonic stem cells, reprogrammed cells are pluripotent, able to generate all the cells of the body, and so they have been named induced pluripotent stem cells (IPSCs). Unlike human embryonic stem cells, however, IPSCs are genetically identical to patients and are generated without destroying human embryos or using either human or animal eggs.

Producing IPSCs is remarkably simple. First, adult skin cells are removed by a biopsy procedure similar to a blood draw. The skin cells are treated in the laboratory with gene-therapy viruses that contain four reprogramming factors. Over approximately two weeks, the reprogramming factors convert some of the adult skin cells into IPSCs. No embryos are produced and no embryos are destroyed; the skin cells simply transform into cells that are the functional equivalents of human embryonic stem cells.

Direct reprogramming is one of the most exciting scientific discoveries of modern times, and it significantly alters both the political and the scientific landscape of stem cell research. The availability of an ethically and scientifically uncompromised source of pluripotent stem cells should be warmly embraced by all parties as a truly win-win resolution to the long-standing controversy over embryo-destructive research.

Or so one would think. Despite the initial euphoria with which both scientists and ethicists greeted these remarkable findings, the stalwarts of unrestricted stem cell research almost immediately began the solemn chant of “research must go forward on all fronts.” The International Society for Stem Cell Research, one of the largest professional associations of stem cell biologists, issued a press release the day the studies appeared cautioning that “these findings do not obviate the need for research using human embryonic stem cells; rather the different avenues of human stem cell research should be pursued side by side.” This sentiment was echoed even more strongly a week later by the editors of Nature magazine, who stated “this is exactly the wrong time to constrain research on human embryonic stem cells.”

It is important to ask whether the interests of science and of society are indeed served by allowing research to move forward using all sources of pluripotent stem cells: from human embryos, from direct reprogramming, and from (as yet theoretical) human cloning. Studies of pluripotent human stem cells will undoubtedly advance our understanding of human biology. Patients may someday benefit from new therapies based on stem cell research. These are noble purposes. Yet do we really need to continue research on pluripotent stem cells derived from human embryos when we can obtain cells with the same properties in an ethically uncompromised way? Do we need to pursue human cloning as a means of generating patient-specific stem cells when we can produce them so readily from adult skin?

Regardless of how one views the ethical status of human embryos, the existence of an alternative source of pluripotent stem cells radically undermines the justification for human embryonic stem cell research. Even President Clinton’s bioethics commission concluded that embryo destruction posed a moral problem and was justifiable only if there were no alternatives, stating in the 1999 report entitled “Ethical Issues in Human Stem Cell Research ” : “In our judgment, the derivation of stem cells from embryos remaining following infertility treatments is justifiable only if no less morally problematic alternatives are available for advancing the research . . . . The claim that there are alternatives to using stem cells derived from embryos is not, at the present time, supported scientifically. We recognize, however, that this is a matter that must be revisited continually as science advances.”

Clearly, the advent of direct reprogramming warrants a serious revisiting of the contention that “no less morally problematic alternatives are available.” In all relevant practical terms, IPSCs are functionally equivalent to stem cells from embryos. James Thomson, the first person to isolate human embryonic stem cells and the author of one of the two studies on direct reprogramming, notes in his paper that IPSCs “meet the defining criteria” for embryonic stem cells “with the significant exception” that the cells “are not derived from embryos.”

Although direct reprogramming is still in its scientific infancy, there are already a number of important reasons why IPSCs are superior for scientific research”reasons that have nothing to do with ethical concerns over destroying human embryos. First, the ability to generate patient-specific stem cell lines for research on human genetic diseases is a tremendous scientific advantage. IPSCs are available now, compared to the merely theoretical prospects of obtaining patient-matched stem cells from human embryo cloning. Moreover, direct reprogramming can generate multiple stem cell lines from an individual patient without any additional cost or effort”an enormous scientific advantage. Thus, scientists can begin studying human diseases immediately using these cells, and this is likely to be the most significant early application of this technology.

In addition to these important scientific advantages, direct reprogramming offers a number of practical advantages. IPSCs are simpler to produce than stem cells from human embryos, and they are ethically uncompromised and therefore fully eligible for federal funding. These features make the cells attractive to scientists who have avoided embryo-destructive research from technical, ethical, or financial concerns. Direct reprogramming also does not involve human embryos or human eggs and is therefore subject to simpler regulatory requirements, another practical advantage that will attract more scientists to this area and speed the pace of discovery.

These practical advantages do not merely reflect current federal policies that might be altered by the next presidential administration. They reflect the intrinsic superiority of IPSCs on a practical front.

IPSCs also offer a significant ethical advantage, even for those who do not consider destruction of human embryos to be an ethical problem. Because direct reprogramming does not use human eggs, research can be conducted without subjecting women to the medical risks associated with egg donation. The difficulty of obtaining human eggs has been a serious problem for research on both human embryonic stem cells and human cloning. A recent New York Times editorial noted that, despite a $100,000 advertising campaign mounted by “respected stem cell researchers at Harvard,” not a single woman has stepped forward, a situation the editorial refers to as “the vexing egg donor problem.” The dearth of egg donors is not terribly surprising in light of the medical risks associated with this procedure. A significant percentage of women who donate eggs experience serious complications that include both sterility and death.

In a seemingly last-ditch effort to justify a line of research that is clearly compromised on scientific, practical, and ethical fronts, advocates of human embryonic stem cells are quick to assert that the direct-reprogramming breakthrough was based on information obtained from the study of human embryonic stem cells”therefore proving that human embryo research is critical to scientific advancement.

What this argument fails to point out is that IPSCs were first produced from cells of an adult mouse, using information from studies of mouse embryonic stem cells. The factors identified in these animal studies proved sufficient to reprogram adult human cells as well. Research on human embryos may have contributed to the development of IPSCs, but it can hardly be seen as critical.

The destruction of human embryos is no more critical for advancing research on direct reprogramming. While it will be interesting to compare pluripotent stem cells derived from direct reprogramming to those derived from human embryos, scientists have twenty-one lines of human embryonic stem cells available for federal funding to make these comparisons, and there is no scientific justification to clone and destroy human embryos to obtain new human stem cell lines.

Despite the astonishing scientific advance of direct reprogramming, it is important to remain realistic about the possibility of developing pluripotent stem cell therapies. Direct reprogramming will not be a panacea for treatment of all human medical conditions. Because of problems with immune rejection, safety (cancer risk), and efficacy (ability to produce clinically useful cells), there are currently no medical treatments using pluripotent stem cells. Direct reprogramming resolves the significant problem of immune rejection by producing patient-matched cell lines. The serious issues of safety and efficacy, however, remain for IPSCs, just as they do for embryonic stem cells.

Indeed, the risks associated with IPSCs may be greater at this time because of the use of gene-therapy viruses for reprogramming, though the need for such viruses is likely to be eliminated as the technique is further refined. The risk of tumor formation, common to all pluripotent stem cells, can theoretically be addressed by converting stem cells into mature cells. Yet despite considerable effort, efficient conversion of pluripotent stem cells into clinically useful cells has not been accomplished. Because of these remaining hurdles, no immediate therapies should be expected from human pluripotent stem cells, whether they are derived from embryos or from direct reprogramming.

The final argument of those still supporting research on human embryos is that freedom of scientific inquiry demands that research be unrestricted”that science and society will be harmed by placing limits on what scientists can investigate.

Yet science, like all human endeavors, must operate within the constraints of ethical values. No one seriously believes that freedom of scientific inquiry should trump all other considerations. Good science does not demand that all avenues of inquiry be pursued. The Tuskegee experiments on African American men with syphilis and the Nazi experiments on Jews and disabled persons were not legitimate avenues of scientific investigation and were not justified by the useful information they yielded.

Many Americans consider research on human embryos to be fundamentally wrong. Even some who do not share this conviction are nonetheless uneasy with using human embryos as research material. James Thomson recently remarked in an interview with the New York Times , “If human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough.” Good research, research that truly advances our knowledge, enhances our lives, and ennobles our culture, must respect both scientific and ethical standards. IPSC research meets the highest standards of science, and it respects the ethical standards of many Americans who object to human embryonic stem cell research as deeply immoral.

Maureen L. Condic is associate professor of neurobiology and anatomy at the University of Utah School of Medicine and conducts research on the development and regeneration of the nervous system.

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What We Know About Embryonic Stem Cells

Mon, 01 Jan 2007 00:00:00 -0500

Back at the beginning of 2002, there was considerable optimism regarding the promise that embryonic stem cells were said to hold for millions of people suffering from fatal or debilitating medical conditions. Stem cells derived from human embryos, it was claimed, provided the best hope for relief of human suffering. Despite the profound ethical concerns regarding the use of human embryos for medical and scientific research, many Americans embraced this promise and the seemingly miraculous hope it offered.

The challenges facing embryonic stem cells were formidable. First, there was the concern that the cells and their derived tissue would be rejected by the patient’s immune system, requiring the patient to undergo lifelong immune suppression. The three proposed solutions to this incompatibility problem (generating large banks of stem cell lines, cloning human embryos to provide a source of cells that perfectly match the patient, or genetically engineering stem cells to reduce immune rejection) were either socially, scientifically, or morally problematic (or all three). Second, there was the serious problem that embryonic stem cells form tumors when transplanted to adult tissues, and the tumorogenic capability of these cells is difficult, if not impossible, to control. Finally, there was the disturbing fact that science had thus far provided essentially no convincing evidence that embryonic stem cells could be reliably differentiated into normal adult cell types, as well as the disturbing possibility that overcoming this barrier would prove a difficult scientific endeavor.

Despite these concerns, many continued to regard embryonic stem cells with hope, believing that further research would overcome these difficulties and harness the power of embryonic stem cells for the benefit of mankind. Such optimists asserted that it was simply a matter of investing sufficient time, money, and research.

Since 2002, considerable resources have been devoted to just such research. A recent query of the grant database maintained by the National Institutes of Health (NIH) indicates that more than eighty research projects investigating human embryonic stem cells have been funded over the past five years. A research effort of this size represents millions of dollars in public money invested in the medical promise of embryonic stem cells. Indeed, the NIH reported to Congress in September of last year that anticipated spending on human embryonic stem cell research in 2006 was “just $24,300,000.” Since 2002, approximately nine hundred research papers have been published on investigations of human embryonic stem cells, with more than a thousand additional papers investigating the properties of embryonic stem cells derived from animals. Clearly, research on embryonic stem cells has advanced considerably over the past five years, and it is therefore important to revisit the promise in light of current findings.

Stem cell-based therapies propose to treat human medical conditions by replacing cells that have been lost through disease or injury. Unlike an organ transplant, where a damaged or diseased tissue is removed and then replaced with a comparable organ from a donor, stem cell therapies would involve integration of replacement cells into the existing tissues of the patient. The dispersed integration of the transplanted cells throughout the targeted organ (indeed, throughout the entire body of the patient) would make it impossible to remove the stem cell derivatives surgically should any problems arise. Thus, the problem of immune rejection is of particular concern—if transplanted cells are attacked by the immune system, the entire tissue in which the foreign cells reside becomes the target of a potentially disastrous immune attack.

Over the past five years, the scientific community has focused almost exclusively on somatic-cell nuclear transfer, or cloning, as the best resolution to the problem of immune rejection. During somatic-cell nuclear transfer, the genetic information of an unfertilized human egg would be removed and replaced with the unique genetic information of a patient. This would produce a cloned, one-cell embryo that would mature for several days in the laboratory and then be destroyed to obtain stem cells genetically matched to the patient. Based on the success of animal cloning, human cloning was optimistically predicted to be a simple matter. Once we were able to clone human embryos, those embryos would provide patient-specific stem cell repair kits for anyone requiring cell-replacement therapies.

Human cloning has proved to be more challenging than anticipated. Human eggs, as it turns out, are considerably more fragile than eggs of other mammalian species, and they do not survive the procedures that were successfully used to clone animals. Multiple attempts by several research groups worldwide have been unsuccessful in generating human clones. The few reports of the successful cloning of human embryos were either unverifiable press releases or clear chicanery promoted by a quasi-religious group for its own publicity.

The elusive prize to generate the first human clone appeared to be won in March 2004, when a South Korean group led by Hwang Woo-Suk reported in the prestigious professional journal Science that they had generated a human stem cell line from a cloned human embryo. A year later, in June 2005, this same group sensationally reported that they had successfully generated eleven patient-specific stem cell lines from cloned human embryos and had dramatically improved their success rate to better than one in twenty attempts, bringing cloning into the realm of the possible for routine treatment of human medical conditions. Hwang was hailed as a hero and a pioneer, and his reported success evoked an almost immediate clamor to remove the funding restrictions imposed by the Bush administration on human embryonic stem cell research, lest America fall hopelessly behind South Korea in developing therapies.

By fall 2005, however, the cloning miracle had begun to unravel. Colleagues of Hwang raised serious concerns about his published studies, launching an investigation into possible scientific fraud. By December, it was conclusively shown that all the claimed cloned stem cell lines were fakes. To date, no one has successfully demonstrated that it is indeed possible to clone human embryos, and, based on the failed attempts of Hwang and others, human cloning is not likely to be a simple task, should it prove possible at all.

The scandal surrounding Hwang’s audacious fraud raised multiple concerns about the ethics of embryonic stem cell research. Investigations revealed that Hwang had used thousands of human oocytes for his unsuccessful attempts, not the hundreds as he had originally claimed. The medical risks associated with egg donation (the potential complications include both sterility and death) raise serious questions about the morality of conducting basic research on human cloning. Given that Hwang pressured junior female colleagues into donating eggs for his research, how can the interests of female scientists be protected from such professional exploitation? Given that thousands of human eggs from more than a hundred women were used by Hwang and not even a single viable cloned human embryo resulted from this research, how can the medical risks to women entailed by this research possibly be justified?

The technical challenges encountered by Hwang are not particularly surprising. Experience from multiple laboratories over the past decade confirms that it is extremely difficult to clone any animal. Cloned embryos are generally quite abnormal, with those that are sufficiently normal to survive to live birth typically representing between 0.1 and 2 percent. The problems do not end with the technical difficulty of somatic-cell nuclear transfer itself. Extensive evidence indicates that even the cloned animals that make it to birth are not untarnished success stories. Following Ian Wilmut’s production of Dolly the sheep, the world’s first cloned mammal, it was almost immediately evident that Dolly was not normal; she experienced a number of medical problems that resulted in her being euthanized, due to poor health, at the age of six years, about half the lifespan of a healthy sheep. Dolly was the only clone to survive to live birth out of the 277 cloned embryos Wilmut’s group generated, yet this success did not prove that cloning can produce a normal sheep. Dolly was merely normal enough to survive to birth.

In the past five years, a number of studies have carefully examined patterns of gene expression in mice and other cloned animals that survived to birth. Not one of these animals is genetically normal, and multiple genes are aberrantly expressed in multiple tissues. Both the severity and the extent of these genetic abnormalities came as a surprise to the cloning field, and yet, in retrospect, they are not surprising at all. The fact that most cloned embryos die at early stages of development is entirely consistent with the conclusion that somatic-cell nuclear transfer does not generate normal embryos, even in the rare cases where clones survive to birth. Thus, the optimistic contention that “therapeutic cloning” would fix the immune problem facing potential embryonic stem cell-based therapies for humans seems thus far entirely unsupported by the scientific evidence.

The dwindling numbers of therapeutic-cloning supporters defend this procedure by asserting that the genetic abnormalities are only a problem if you are attempting to produce a live birth. Thus, in a 2004 New York Times article, George Daley, a stem cell researcher at Children’s Hospital in Boston, acknowledged that cloned animals show multiple genetic abnormalities, yet optimistically asserted, “Cloned tissues are not likely to have the same problems.” In light of the mounting evidence that cloned animals experience severe genetic disregulation, such tentative reassurance is wearing thin, with even Daley admitting that his optimistic prediction that cloned tissues will prove normal enough for medical purposes has “yet to be proven.”

The question of how normal cloned tissue needs to be is not merely a detail that needs to be worked out. It is, in practice, a fundamentally unanswerable question. If cloned human embryos are to be used as a source of stem cells, we will be faced with this simple question for every single patient: How normal is this particular cloned embryo, the one we are going to use to generate stem cells to treat this particular patient? Without allowing that embryo to develop and observing precisely how abnormal it proves to be, it is simply impossible to know whether it is normal enough for medical use. Every patient will be an experiment with no quality control. Perhaps the particular cells will be normal enough to cure this particular patient, but then again perhaps they will be so grotesquely abnormal that they will create a condition worse than the one they were intended to treat.

The limitation in our ability to determine which cloned embryos are of sufficient normalcy to generate medically useful replacement tissue is one that no research can address unless scientists develop some kind of test to determine in advance which cloned embryos are normal enough. Developing such a test would almost certainly require the horrific scenario of growing human embryos to a sufficient state of maturity that the normalcy of their developing tissues could be empirically determined. This would mean implanting cloned embryos into surrogate wombs and then aborting them at specific times to examine the embryo’s development. Based on this information, it might be possible (although difficult) to identify features of very early embryos that predict whether they are capable of generating therapeutically useful tissue. Whether Americans are willing to accept the unknown (yet potentially large) risk of being treated with stem cells of undetermined (and essentially undeterminable) quality or whether we would prefer to accept the kind of experimentation on human embryos and fetuses that would be required to ensure embryonic stem cell safety are questions of profound social and moral importance.

It was unambiguously clear five years ago that embryonic stem cells robustly form tumors (teratomas) when transplanted into adult tissues, and this remains the case today. Teratomas are benign tumors that contain a variety of differentiated cell types (hair, teeth, muscle, etc.). These tumors can often prove fatal because of their rapid growth, but they are not malignant or cancerous tumors, which metastasize into multiple locations within the body. Embryonic stem cell advocates were well aware of the tumor-forming potential of these cells. (Indeed, teratoma formation following injection of embryonic stem cells into adult mice is still today the test of whether a researcher has successfully generated a bona fide embryonic stem cell line.) Embryonic stem cell advocates dismiss the threat of these tumors, however, claiming this would prove a problem only for undifferentiated embryonic stem cells.

These optimistic predictions have not held up to scientific experimentation. The tumor-forming potential of embryonic stem cells has proved a significant problem that does not show signs of being resolved any time soon. More than a dozen papers over the past five years (five papers within the past year alone) have shown tumor formation in animals treated with differentiated embryonic stem cell derivatives. In several of these studies, a shocking 70 to 100 percent of the experimental animals succumbed to fatal tumors. In all cases, tumors were believed to be derived from embryonic stem cells that either failed to differentiate or from cells that somehow de-differentiated once transplanted. Although experimental approaches designed to reduce tumor formation from differentiated embryonic stem cell derivatives are under investigation, it is not clear whether these approaches will ever prove successful, especially if the tumors are due to uncontrolled de-differentiation of the embryonic stem cell—derived tissues back to a more primitive state once they are transplanted to an adult environment.

Even more alarming than formation of benign (albeit, fatal) tumors, several studies over the past five years have raised concerns that the longer embryonic stem cells are maintained in the laboratory (or, presumably, in the tissues of adult human patients), the more likely they are to convert to malignant cancer cells. Embryonic stem cells spontaneously accumulate the genetic abnormalities associated with embryonal carcinoma (a form of testicular cancer). Embryonal carcinomas are believed to be the cancerous equivalent of embryonic stem cells and are a highly metastatic form of cancer. Although the finding that embryonic stem cells spontaneously convert to cancer cells over time remains contested, it is clear that some, if not all, embryonic stem cells undergo this conversion, and the factors controlling the transition are not well understood.

The assertion that embryonic stem cells in the laboratory can be induced to form all the cells comprising the mature human body has been repeated so often that it seems incontrovertibly true. What is missing from this assertion remains the simple fact that there is essentially no scientific evidence supporting it. Experiments have shown that embryonic stem cells are able to participate in normal embryonic development, an observation that is also true of cancerous embryonal carcinoma cells. When injected into early mouse embryos, both embryonic stem cells and embryonal carcinoma cells randomly contribute to every tissue of the developing body.

Even more dramatically, when embryonic stem cells are injected into mouse embryos under specific experimental circumstances (a procedure known as tetraploid complementation), they can be induced to form all the cells of the postnatal body. These experiments prove that embryonic stem cells (and embryonal carcinoma cells) remain capable of responding appropriately to the developmental signals that regulate tissue formation in the embryo, and from these results we can conclude that if embryonic stem cells were intended to provide cell replacement therapies for embryos, they would represent a very promising therapeutic approach. The problem, of course, is that embryos are not the intended targets of stem cell therapies, and there is little reason to believe that the capabilities of embryonic stem cells in an embryonic environment are relevant to their therapeutic potential for non-embryonic patients.

Five years ago, most scientists working in the field of embryonic stem cell research confidently predicted that we would soon determine the precise recipe of molecular factors required to replicate in the laboratory the mysterious inner life of the embryo. David Anderson, a stem cell researcher at Caltech, boldly asserted in a New York Times opinion piece that once science had figured out the factors required to replicate embryonic development, specific molecules could simply be “thrown into the bubbling cauldron of our petri dishes,” where they would transform embryonic stem cells into an unlimited source of replacement cells for any tissue we chose to produce.

Skepticism regarding this claim was well warranted. While there have been hundreds of papers published over the past five years that stridently claim “cell type X produced from embryonic stem cells,” under closer inspection these successes have all been less miraculous than they appeared. It is relatively easy to generate stem cell derivatives in the laboratory that have at least some of the properties of normal, mature cell types. But the test of whether an embryonic stem cell—derived brain cell, for example, is indeed a normal adult brain cell is to put it into the brain of an adult animal and determine whether it survives and contributes to normal brain function. In addition, if laboratory-generated cells are to be therapeutically useful for the treatment of human disease and injury, they must be shown to have therapeutic value in adult animals: It is not sufficient that embryonic stem cell—derived cells merely survive in adults; they must also be able to repair the underlying disease or injury. It is precisely this kind of test that embryonic stem cell—derived tissues have proved unable to pass.

When cells derived from embryonic stem cells are transplanted into adult animals, their most common fate is to die. Indeed, most such transplanted tissue does not survive beyond a few weeks in an adult environment (the only exception is blood cells, where small numbers of cells survive long term in mature animals). The rapid death of transplanted embryonic stem cell-derived cells stands in striking contrast to the robust survival of bona fide adult cells when transplanted to adult tissue. Typically, even the most promising experiments involving the transplant of embryonic stem cell derivatives have reported modest positive effects that persist for only a few weeks. In the few cases where tiny fractions of the transplanted cells survive for months (rather than weeks), this straggling band of survivors typically provides no therapeutic benefit.

The failure of embryonic stem cell-derived tissues to survive when transplanted to adult tissues strongly suggests that science has not yet determined how to generate normal adult tissue from embryonic stem cells. Why then do some studies show modest, short-term benefits from transplantation of such tissues? In many cases, the authors of these studies speculate that embryonic stem cell-derived transplants are not providing benefit because of replacement of lost or damaged cells but rather because the transplanted cells are supporting the survival or function of damaged adult tissues by secreting generic survival factors. Thus, the modest and transient benefits reported for embryonic stem cell-derived cell transplants over the past five years do not appear to require stem cells at all and are likely to be replicated by simply identifying the beneficial factors produced by the transplanted cells and supplying these factors directly.

In light of the serious problems associated with embryonic stem cells,— I noted in 2002, “there is no compelling scientific argument for the public support of research on human embryos.” Serious scientific challenges are, by definition, problems that have stubbornly resisted the best attempts of science to resolve them. Over the past thirty years, hundreds of billions of dollars and countless hours of research by dedicated professionals worldwide have been devoted to solving the problems of immune rejection and tumor formation, yet these issues remain serious scientific and medical challenges. The mysteries of embryonic development have been plumbed for more than a hundred years by some of the most brilliant biologists of history, and yet, despite the clear progress we have made, we are nowhere near the point of having a “recipe book” for cooking up cellular repair kits to treat human disease and injury. Immune rejection, tumor formation, and embryonic development have proved themselves to be profoundly serious scientific challenges, and they are likely to remain so for decades into the future.

The hubris of scientists in the field of embryonic stem cell research who confidently asserted “Give us a few years of unrestricted funding and we will solve these serious scientific problems and deliver miraculous stem cell cures” was evident in 2002, and it is even more evident today. For the past five years, researchers have had completely unrestricted funding to conduct research on animal embryonic stem cells, and yet the serious scientific problems remain. They have had every conceivable tool of modern molecular research available to them for use in animal models, and yet the serious scientific problems remain. Millions of dollars have been consumed, and hundreds of scientific papers published, and yet the problems still remain. The promised miraculous cures have not materialized even for mice, much less for men.

In June 2004, Ron McKay at the National Institutes of Health acknowledged in a Washington Post interview that scientists have not been quick to correct exaggerated claims of the medical potential of embryonic stem cells, yet McKay justified this dishonesty by stating: “To start with, people need a fairy tale. Maybe that’s unfair, but they need a story line that’s relatively simple to understand.” Isn’t it time Americans recognize the promise of obtaining medical miracles from embryonic stem cells for the fairy tale it really is?

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Stem Cells and Babies

Mon, 01 Aug 2005 00:00:00 -0400

Positions on human embryonic stem-cell research tend to fall into two camps: Either anything goes, or nothing goes. Proponents of the anything-goes position assert that the potential scientific and medical benefits of embryonic stem-cell research override all other considerations”and therefore restrictions on the funding and scope of this research are unwarranted. Proponents of the nothing-goes position assert that no amount of potential medical and scientific usefulness can justify the intentional creation and destruction of nascent human life.

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Whose View of Life? Embryos, Cloning, and Stem Cells

Sun, 01 Aug 2004 00:00:00 -0400

The question of when human life commences is one of longstanding philosophical and scientific interest. In our day it has been thrust into the realm of immediate urgency by advances in embryonic stem cell and cloning technologies. The question is taken up by Jane Maienschein in Whose View of Life? The book examines the matter principally from a historical perspective, asking how scientific, secular, and (to a lesser extent) religious views about the onset of life have changed over time as the scientific understanding of embryonic development has expanded.

Maienschein is a well-published writer in the history of science, and this book has been warmly welcomed by many. Publishers Weekly says the “book should be required reading,” Garland Allen calls it “essential reading,” Jonathan Weiner describes it as “timely, sensible, and clearheaded,” and in a very friendly interview with the author posted on the New York Academy of Sciences website she is praised her for a perspective that “casts doubt on the certainties of anti-research thinkers.” In her introduction, Maienschein declares that she will take a balanced and neutral look at “how to define when a life begins and what the appropriate boundaries and constraints on human embryo research should be.”

This is a worthy goal, but one finds that balance and neutrality are not evident in the product of her efforts. Though she is an historian of science, there are serious problems with her presentation of both history and science, and in the end she settles the question of her title by appealing to the self-evident correctness of her own preferred answer: we are to resolve the question of when life begins by rejecting the “extremism and absolutism” of those who believe life begins at conception, and by cleaving instead to the “wisdom” of “meta-experts” (these are apparently academic historians of science). Such meta-experts will help us to “forge a compromise explicitly responding to our best science and our best moral thinking.” The reader will note that it is a curious sort of “compromise” that explicitly denies any role for the “extremism and absolutism” of those who reject Maienschein’s own viewpoint.

The majority of the book deals with the history of thought about human embryonic development, beginning with the views of Aristotle and proceeding in rough chronological order to the present day. The presentation of historic viewpoints is at times inexplicably disjointed. (Why, for example, are topics as divergent as Mendel’s genetic experiments with pea plants, the eugenics movement of the early 1900s, and the cloning of frogs all covered in a single chapter?). Yet the text is still reasonably informative and entertaining. A major theme that emerges from Maienschein’s historical studies is that two opposing opinions on the origins of human life have coexisted since ancient times. One is the “preformationist” view, which asserts that life is present in some form from the earliest stages of development (the modern form of this view being the belief that life begins at conception). The other is the “epigenesist” view, which asserts that life comes into existence gradually over time. Maienschein would have us believe that these two views have come down more or less intact to the present and that understanding the changing historical preeminence of one position versus the other enables us to see that the question of when life begins is finally unresolvable.

Yet Maienschein’s historical presentation is flawed in important ways. While maintaining ostensive neutrality regarding the relative merits of the preformationist and epigenesist views, Maienschein indulges in a less than even-handed characterization of these two positions. Modern-day preformationists (those who believe life begins at conception) are “absolutists” who hold “extremist” views that are “vague and unsustainable” but who advance these views as “immutable, without possibility of compromise or accommodation,” and thereby contribute to “the politics of hate.” By contrast, even highly dogmatic statements by proponents of the epigenesist view are not similarly condemned. For example, Michael West, the president and CEO of Advanced Cell Technology, is quoted as saying: “You can’t say that making and destroying a pre-implantation embryo is the destruction of a human. Because it isn’t. If it was a human life, I wouldn’t touch it. Absolutely not. A human individual does not begin at conception. It begins at primitive-streak formation.” (The “primitive streak” forms approximately fourteen days after fertilization and marks the beginning of a period during which cells of the embryo organize into three primary tissue types.)

Clearly, an opinion as strong as West’s could be fairly described as “immutable, without the possibility of compromise or accommodation,” but Maienschein presents this statement without qualification and goes on to laud West for his conviction that “the research must go forward.” Similarly, the inflammatory advice of Nobel Prize“winner James Watson about embryonic stem cell research”“We’ve got to go ahead and not worry whether we’re going to offend some fundamentalist from Tulsa, Oklahoma””is presented without comment; Watson is not charged with advancing “the politics of hate.” This is hardly a balanced and neutral look at today’s debate.

Maienschein’s exposition of scientific information (particularly modern findings) is similarly biased. Considerable factual inaccuracy and distortion arise from Maienschein’s selective omission of scientific findings that cast a less than kindly light on embryonic stem cell and cloning research. It is notable, for example, that despite devoting an entire chapter to the topic of cloning, Maienschein glosses over the well-established and significant fact that the vast majority of cloned animals either die before birth or are physically and genetically abnormal. This fact certainly calls into question the wisdom of using such abnormal cells for the therapeutic treatment of human disease. Similarly, despite the promisingly even-handed title of her final chapter, “Hopes and Hypes for Stem Cells,” Maienschein fails to discuss the well-established drawbacks of using embryonic stem cells for therapeutic purposes (See my article, “The Basics About Stem Cells,” FT January 2002). The effect of these omissions is to present embryonic stem cell and cloning research as therapeutically promising technologies that are uncompromised by significant scientific limitations. The best that can be said for such a presentation is that it is disingenuous.

Maienschein’s portrayal of history also suffers from a number of conceptual flaws. Maienschein paints a picture of the historic debate over when life begins as a series of inconclusive battles between the preformationist and epigenesist views, a continuing controversy in which neither position has achieved clear victory. She goes on to argue that, because the available science has sometimes favored one view and sometimes the other, science will never resolve the debate. She concludes that while we must take scientific information into account, science itself cannot define the beginning of life.

This picture is interesting, but it is also profoundly inaccurate. Maienschein’s argument explicitly denies the possibility of real advance in science and falsely suggests that the question of when life begins is simply beyond the realm of scientific inquiry. On the contrary, the historical facts strongly argue that although there were limitations in scientific understanding and method that precluded a clear resolution of this question in previous eras, such limitations no longer exist. While the inability to “look inside” the womb may have led early scientists to favor the epigenesist view that life gradually comes into existence from inanimate matter, we simply know better today. Once we came to understand that embryos arise from the fusion of living sperm and egg cells, the debate over spontaneous generation of embryos from inanimate seminal and vaginal fluids was forever closed to serious scientific discussion. Real and substantive progress has been made, and in no circumstances will further research prove capable of causing our understanding to revert to a disproved concept.

Suggestive comparisons may, of course, be made between earlier epigenesist-preformationist controversies and our current debate over when life commences, but such comparisons do not “inform” the current debate in any meaningful sense. Indeed, they have no bearing on the real issue, which is whether our current scientific understanding substantively and permanently resolves this question. The modern discussion of when life commences must proceed from the answer to following question: Given what we know with certainty, what type of new information is it currently possible for us to discover”and could such information substantively change our present understanding of early embryonic development?

What we know with certainty, despite Maienschein’s insistence that the “jury is still out,” is that the facts inarguably support the preformationist view she so vehemently rejects. We know, for example, that single-cell embryos are unambiguously organisms, for the defining feature of an organism, as compared to a simple collection of cells, is that it is “organized” to accomplish a “purpose” that exceeds mere cellular life. Talking about “purpose” may make some readers (including some scientists and perhaps some historians of science) nervous, yet in the context of developmental biology, an organismal “purpose” means nothing more than the playing out of a game plan that we know, by observation, results in the formation of increasingly complex, integrated structures, all of which work together for the continued life and health of that organism as a whole. Embryos manifestly behave as organisms and as nothing other than organisms from the single-cell stage onward. This conclusion is true today, will be true forever in the future, and will at no point be subject to substantial revision by further scientific research or discoveries.

Maienschein, like many other proponents of using stem cells from embryos as research material, denies the organismal nature of single-cell embryos by simply asserting the opposite. However, such denial is contrafactual. Maienschein states, for example, that single-cell embryos only function as “cells dividing into other cells that are just like them.” This assertion is patently absurd; single-cell human embryos ultimately produce babies, not merely multiple copies of themselves. Early embryos can be destroyed to yield embryonic stem (ES) cells that do indeed simply reproduce themselves, yet once the embryo is destroyed, the cells that once composed it lose their organismal character. If early embryos are nothing more than ES cells, and if human organisms “spontaneously” come into existence at some later developmental stage (the primitive-streak stage, for example), then embryos and ES cells should be interchangeable. That is to say, it should be fully possible to aggregate ES cells together and reconstitute an embryo that will develop into a normal baby. The fact that embryos cannot be “made” from ES cells alone demonstrates that ES cells are qualitatively different from em-bryos. ES cells are “organized” to the purpose of maintaining and replicating cellular life, but not to the purpose of generating a baby.

Aristotle, of course, knew nothing of single-cell embryos or ES cells, but an Aristotelian distinction between the two can be made quite clearly: the single-cell embryo fully possesses a substantial form that is organized toward the generation of increasingly complex systems, ultimately culminating in an adult individual, whereas the ES cell possesses a qualitatively different substantial form that is organized toward the maintenance of cellular life and generation of other cells like itself. (Maienschein’s apparent confusion of accidental form and substantial form causes her to erroneously assign Aristotle to the epigenesist side of the debate, thus lending that side a somewhat more distinguished pedigree than it deserves.) The radical difference in kind between ES cells and embryos exists from the earliest stages of embryonic development and does not magically come into existence at the primitive-streak stage”regardless of how convenient such a mystical event might be for the argumentation of those who favor doing research on early human embryos.

The ultimate issue for Maienschein is not so much when life begins; it is, rather, when do we as a pluralistic society choose to value and defend life? Maienschein believes that human life is worthy of defense at some point and that our definition of when human life begins should be informed by scientific evidence. Yet she also believes that research on human embryos is valuable and should therefore be allowed to proceed. To reconcile these beliefs, Maienschein ultimately rejects the scientific facts regarding when life begins and resorts to the purely utilitarian argument that human life is valuable and worthy of protection so long as some other goal (in this case the hope of curing human disease by destroying human embryos) does not exceed the value she personally chooses to assign to human life at a given developmental stage. The answer to her question “Whose view of life?” turns out to be “Maienschein’s.” Society’s interests will be better served by answering the question of when life begins by appealing to scientific fact.

Maureen L. Condicem is an Associate Professor of Neurobiology and Anatomy at the University of Utah; she is currently conducting research on the regeneration of embryonic and adult neurons following spinal cord injury.

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Life: Defining the Beginning by the End

Thu, 01 May 2003 00:00:00 -0400

What defines the beginning of human life? This question has been the topic of considerable legal and social debate over the years since the Supreme Court’s Roe v. Wade decision”debate that has only been intensified by the recent controversies over human embryonic stem cells and human cloning. Answers to this question run the full gamut from those who argue that life begins at conception (the view of more than one major world religion) to those arguing that babies are not to be considered fully human until a month after birth (the position of Princeton Professor of Bioethics Peter Singer).

The range of dissent and disagreement on the question of when human life begins has led many to believe it cannot be reasonably resolved in a pluralistic society. Courts have ruled that the diversity of opinion on the topic precludes a judicial resolution, requiring instead that the matter be addressed in the political arena, where accommodation of divergent views can be wrought through debate and compromise. Many Americans appear equally unwilling to impose a single interpretation on society, preferring instead to allow decisions regarding the beginning of life to be largely a matter of personal choice.

While reluctance to impose a personal view on others is deeply ingrained in American society, one must question the legitimacy of such reluctance when the topic of our “imposition” is a matter (quite literally) of life and death. Few beyond the irrationally obdurate would maintain that human embryos are anything other than biologically Homo sapiens and alive, even at the earliest developmental stages. Equally few would contest the fact that, at early stages of embryonic development, human embryos bear little resemblance to anything we easily identify as “human.” For most people, reconciling these two facts involves the uncomfortably fuzzy process of drawing a line somewhere during the continuously changing process of human prenatal development and asserting: “There. That’s when human life begins”at least for me.” It is precisely the subjectivity and inaccuracy of this decision that fuels our discomfort at “imposing” it on others.

In contrast to the widespread disagreement over when human life begins, there is a broad social and legal consensus regarding when human life ends. Rarely has the point been made that the definition of human death can be applied to the question of when life commences with compelling symmetry. The definition of when life ends is both scientific and objective, and does not depend on personal belief or moral viewpoint. The current medical and legal understanding of death unambiguously defines both when human life ends and when it begins in a manner that is widely accepted and consistent with the legal and moral status of human beings at all stages of life.

Death is something most people readily recognize when they see it. People express very little confusion about the difference between a living person and a corpse. Surprisingly, however, the distinction is not as clear from a medical and scientific perspective. There is very little biologic difference between a living person in the instant before death and the body of that person an instant after death. Yet some property has clearly departed from the body in death, and that property is precisely the element that defines “human life.” What, then, is the difference between live persons and dead ones? How is death defined medically and scientifically?

The question of when and under precisely what conditions people are viewed as “dead” has itself been the subject of considerable debate. Traditionally, the medical profession considered a person dead when his heart stopped beating”a condition that rapidly results in the death of the cells of the body due to loss of blood flow. As the life-saving potential of organ transplants became increasingly apparent in the 1960s, the medical community undertook a reexamination of the medical standards for death. Waiting until the heart stops beating results in considerable damage to otherwise transplantable organs. After a long and contentious debate, a new standard of death was proposed in 1968 that defined “brain death” as the critical difference between living persons and corpses, a standard that is now widely (although not universally) accepted throughout the world.

Brain death occurs when there has been irreversible damage to the brain, resulting in a complete and permanent failure of brain function. Following the death of the brain, the person stops thinking, sensing, moving, breathing, or performing any other function, although many of the cells in the brain remain “alive” following loss of brain function. The heart can continue to beat spontaneously for some time following death of the brain (even hearts that have been entirely removed from the body will continue to beat for a surprisingly long period), but eventually the heart ceases to function due to loss of oxygen. The advantage of brain death as a legal and medical definition for the end of life is that the quality of organs for transplant can be maintained by maintaining artificial respiration. So long as oxygen is artificially supplied, the heart will continue to beat and the other organs of the body will be maintained in the same state they were prior to death of the brain.

Defining death as the irreversible loss of brain function remains for some a controversial decision. The fact that the cells and organs of the body can be maintained after the death of the individual is a disturbing concept. The feeling that corpses are being kept artificially “alive” as medical zombies for the convenient culture of transplantable organs can be quite discomforting, especially when the body in question is that of a loved one. Nonetheless, it is important to realize that this state of affairs is essentially no different from what occurs naturally following death by any means. On a cellular and molecular level, nothing changes in the instant of death. Immediately following death, most of the cells in the body are still alive, and for a time at least, they continue to function normally. Maintaining heartbeat and artificial respiration simply extends this period of time. Once the “plug is pulled,” and the corpse is left to its own devices, the cells and organs of the body undergo the same slow death by oxygen deprivation they would have experienced had medical science not intervened.

What has been lost at death is not merely the activity of the brain or the heart, but more importantly the ability of the body’s parts (organs and cells) to function together as an integrated whole. Failure of a critical organ results in the breakdown of the body’s overall coordinated activity, despite the continued normal function (or “life”) of other organs. Although cells of the brain are still alive following brain death, they cease to work together in a coordinated manner to function as a brain should. Because the brain is not directing the lungs to contract, the heart is deprived of oxygen and stops beating. Subsequently, all of the organs that are dependent on the heart for blood flow cease to function as well. The order of events can vary considerably (the heart can cease to function, resulting in death of the brain, for example), but the net effect is the same. Death occurs when the body ceases to act in a coordinated manner to support the continued healthy function of all bodily organs. Cellular life may continue for some time following the loss of integrated bodily function, but once the ability to act in a coordinated manner has been lost, “life” cannot be restored to a corpse”no matter how “alive” the cells composing the body may yet be.

It is often asserted that the relevant feature of brain death is not the loss of integrated bodily function, but rather the loss of higher-order brain activities, including consciousness. However, this view does not reflect the current legal understanding of death. The inadequacy of equating death with the loss of cognitive function can be seen by considering the difference between brain death and “persistent vegetative state” or irreversible coma. Individuals who have entered a persistent vegetative state due to injury or disease have lost all higher brain functions and are incapable of consciousness. Nonetheless, integrated bodily function is maintained in these patients due to the continued activity of lower-order brain centers. Although such patients are clearly in a lamentable medical state, they are also clearly alive; converting such patients into corpses requires some form of euthanasia.

Despite considerable pressure from the medical community to define persistent vegetative state as a type of brain death (a definition that would both expand the pool of organ donors and eliminate the high medical costs associated with maintaining people in this condition), the courts have repeatedly refused to support persistent vegetative state as a legal definition of death. People whose bodies continue to function in an integrated manner are legally and medically alive, despite their limited (or absent) mental function. Regardless of how one may view the desirability of maintaining patients in a persistent vegetative state (this being an entirely distinct moral and legal question), there is unanimous agreement that such patients are not yet corpses. Even those who advocate the withdrawal of food and water from patients in persistent vegetative state couch their position in terms of the “right to die,” fully acknowledging that such patients are indeed “alive.” While the issues surrounding persistent vegetative state are both myriad and complex, the import of this condition for understanding the relationship between mental function and death is clear: the loss of integrated bodily function, not the loss of higher mental ability, is the defining legal characteristic of death.

What does the nature of death tell us about the nature of human life? The medical and legal definition of death draws a clear distinction between living cells and living organisms. Organisms are living beings composed of parts that have separate but mutually dependent functions. While organisms are made of living cells, living cells themselves do not necessarily constitute an organism. The critical difference between a collection of cells and a living organism is the ability of an organism to act in a coordinated manner for the continued health and maintenance of the body as a whole. It is precisely this ability that breaks down at the moment of death, however death might occur. Dead bodies may have plenty of live cells, but their cells no longer function together in a coordinated manner. We can take living organs and cells from dead people for transplant to patients without a breach of ethics precisely because corpses are no longer living human beings. Human life is defined by the ability to function as an integrated whole”not by the mere presence of living human cells.

What does the nature of death tell us about the beginning of human life? From the earliest stages of development, human embryos clearly function as organisms. Embryos are not merely collections of human cells, but living creatures with all the properties that define any organism as distinct from a group of cells; embryos are capable of growing, maturing, maintaining a physiologic balance between various organ systems, adapting to changing circumstances, and repairing injury. Mere groups of human cells do nothing like this under any circumstances. The embryo generates and organizes distinct tissues that function in a coordinated manner to maintain the continued growth and health of the developing body. Even within the fertilized egg itself there are distinct “parts” that must work together”specialized regions of cytoplasm that will give rise to unique derivatives once the fertilized egg divides into separate cells. Embryos are in full possession of the very characteristic that distinguishes a living human being from a dead one: the ability of all cells in the body to function together as an organism, with all parts acting in an integrated manner for the continued life and health of the body as a whole.

Linking human status to the nature of developing embryos is neither subjective nor open to personal opinion. Human embryos are living human beings precisely because they possess the single defining feature of human life that is lost in the moment of death”the ability to function as a coordinated organism rather than merely as a group of living human cells.

What are the advantages of defining the beginning of human life in the same manner that we define its end, based on the integrated organismal function of human beings? To address this question, the alternative arguments regarding when life begins must be briefly considered. While at first inspection, there appear to be many divergent opinions regarding when human life commences, the common arguments are only of three general types: arguments from form, arguments from ability, and arguments from preference. The subjective and arbitrary nature of these arguments stands in stark contrast to the objective and unambiguous definition that organismal function provides for both the beginning and end of human life.

Of all the arguments regarding when human life begins, the most basic, and perhaps most intuitive, is that to be human, one must look human. Early human embryos are often described as “merely a ball of cells,” and for many, it is difficult to imagine that something that looks more like a bag of marbles than a baby could possibly be a human being. Fundamentally, this argument asserts that human life is worthy of respect depending on appearance. When plainly stated, this conclusion is quite disturbing and also quite problematic. What level of malformation are we willing to accept before we revoke the right to continued existence? How are we to view children whose mature form will not be completely manifest until puberty? Form alone is a profoundly trivial and capricious basis for assigning human worth, and one that cannot be applied without considerable and obvious injustice.

The superficiality of equating worth with form is sufficient for most to reject this argument and retreat to a functional definition: form per se is not the issue; rather, it is the ability to function as a human being that defines the beginning of human life. Human beings are capable of a number of distinctive functions (self-awareness, reason, language, and so forth) that are acquired gradually over prenatal life as development proceeds. Therefore, the argument goes, human worth is also gradually acquired, with early embryos being less human than more developed fetuses.

A number of seemingly independent arguments regarding when life begins are in fact variations on this argument from ability. Thus, the proposal that human life begins when the fetus becomes “viable,” or capable of surviving outside of the womb, is a subset of the ability argument that gives conclusive weight to the suite of abilities required for survival independent of the mother. Similarly, the common argument that embryos are human when they are in the womb of the mother (where they can develop into babies), while embryos generated in the laboratory are not, is also a variation on the ability argument that equates developmental ability with human life and worth.

While the argument from ability is less superficial than the argument from form alone, it is no less problematic. As noted above, functional definitions have been repeatedly rejected as a legal basis for the definition of death, in part due to their arbitrary nature. One can certainly identify any number of elderly and disabled people who are less functionally adept than newborn infants”and perhaps even late-term fetuses. While Western culture has a strong tradition of meritocracy, providing greater economic and social rewards to those who demonstrate greater achievement, basic human rights are not meted out according to performance. Unless we are willing to assign “personhood” proportionate to ability (young children, for example, might be only 20 percent human, while people with myopia 95 percent), the limited abilities of prenatal humans are irrelevant to their status as human beings.

The final and perhaps the most emotionally compelling argument for assigning human status to a developing embryo is the extent to which parents desire a child. Yet the argument from being wanted, which equates status as a human being with the desire of a second party who has the power to confer or deny that status, essentially reduces the definition of a human being to a matter of preference. You are human because I choose to view you that way. The fact that human status can be positively conferred for “wanted” embryos as well as denied for the “unwanted” illustrates the fundamental arbitrariness of this argument. The preferences of individuals who possess the power to impose them on others are hardly a compelling basis for legislation on human life.

Despite the apparent diversity of views regarding when human life begins, the common arguments thus reduce to three general classes (form, ability, and preference), all of which are highly subjective and impossible to reconcile with our current legal and moral view of postnatal human worth. It is, in fact, the subjectivity and inconsistency of these views, rather than their diversity, that makes them so unsatisfying as a basis for legislation on human life.

Unlike other definitions, understanding human life to be an intrinsic property of human organisms does not require subjective judgments regarding “quality of life” or relative worth. A definition based on the organismal nature of human beings acknowledges that individuals with differing appearance, ability, and “desirability” are, nonetheless, equally human. It is precisely the objective nature of such a definition (compared to vague “quality of life” assessments) that has made organismal function so compelling a basis for the legal definition of death.

Once the nature of human beings as organisms has been abandoned as the basis for assigning legal personhood, it is difficult to propose an alternative definition that could not be used to deny humanity to virtually anyone. Arguments that deny human status to embryos based on form, ability, or choice can be readily turned against adult humans who have imperfect form, limited ability, or who simply constitute an inconvenience to more powerful individuals or groups. Indeed, such arguments can be quite protean in their ability to deny rights to anyone not meeting an arbitrary criterion for humanity. Abraham Lincoln made this very point regarding arguments based on form, ability, and choice that were put forth in his day to justify the institution of slavery:

It is color, then; the lighter having the right to enslave the darker? Take care. By this rule, you are to be slave to the first man you meet with a fairer skin than your own.

You do not mean color exactly? You mean the whites are intellectually the superiors of the blacks, and, therefore, have the right to enslave them? Take care again. By this rule, you are to be slave to the first man you meet with an intellect superior to your own.

But, say you, it is a question of interest; and, if you can make it your interest, you have the right to enslave another. Very well. And if he can make it his interest, he has the right to enslave you.

Postnatal humans run very little risk that embryos will someday organize politically to impose restrictions on the rights of “the born.” However, once society has accepted a particular justification for denying rights to one class of individuals, the same justification can readily be applied to other classes by appealing to the simple argument: “Society has already determined that form, ability, or preference defines human life and thereby restricts human rights. Why should the same standard not be applied in this case?” In American society and jurisprudence, arguments from accepted precedent carry great emotional and legal force. Society must determine whether it is willing to accept the current subjective and arbitrary basis for determining the status of prenatal human beings as a legitimate precedent for future legislation on human rights.

Embryos are genetically unique human organisms, fully possessing the integrated biologic function that defines human life at all stages of development, continuing throughout adulthood until death. The ability to act as an integrated whole is the only function that departs from our bodies in the moment of death, and is therefore the defining characteristic of “human life.” This definition does not depend on religious belief or subjective judgment. From the landmark case of Karen Ann Quinlan (1976) on, the courts have consistently upheld organismal function as the legal definition of human life. Failure to apply the same standard that so clearly defines the end of human life to its beginning is both inconsistent and unwarranted.

The conclusion that human life is defined by integrated (organismal) function has wide-reaching implications, both political and moral. While the public domain has limited authority to promote morality, it does have both the power and the responsibility to prevent harm to individuals. A consistent definition of what constitutes human life, both at its beginning and at its end, requires that current legislation dealing with prenatal human life be considered in light of both biological fact and accepted legal precedent regarding the definition of human life. If current legislation enables and supports the killing of human beings based on a scientifically flawed understanding of human life, laws can and should be revised. Clearly, such a revision would not be without political cost. Yet allowing life-or-death decisions to be based on arbitrary or capricious definitions is also a course of action that is not without considerable social and moral cost.

Dr. Maureen L. Condic is an Assistant Professor of Neurobiology and Anatomy at the University of Utah, currently conducting research on the regeneration of embryonic and adult neurons following spinal cord injury.

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Stem Cells and False Hopes

Thu, 01 Aug 2002 00:00:00 -0400

We have all witnessed the transforming power of hope—the focus and sustenance hope provides when strength and reason fail to pull us through a difficult situation. Facing tragedy and loss, hope is often the only thing standing between us and the void. Life-threatening illnesses or injuries provide some of the most poignant occasions for hope. We hope that a loved one will survive a critical surgery. We hope that cancer will respond to chemotherapeutic drugs. We hope, often against all odds, that this time, for this one precious and irreplaceable person, death will be thwarted and life will go on.

When medical science offers no legitimate hope for a cure, desperation and grief can drive people to grasp at any straw that might offer hope to them or to their loved ones. For many, herbal medicine or other “alternative” therapies become the vehicle for hope when medical science has done all it can do. For others, hope comes from beyond the realm of medicine. Faith often takes up at the limits of hope, to turn the eyes of the desperate to the source of all life, all hope, and all salvation. Facing death with dignity requires us to accept our mortality and find peace beyond the hope possible in this world.

It is precisely the power of hope, the ability of hope to provide solace and motivation in the most desperate situations, that makes the manipulation of hope such an appalling offense. The selling of false hope is a contemptible exploitation. Whatever comfort a false hope temporarily offers, it is far offset by the damage that is caused when the illusion is crushed by reality. Not only do bitterness and resentment replace the optimism a false belief once supported, but for the terminally ill it is often too late to go beyond bitterness and arrive at any kind of peace. To die an angry death, betrayed by hope and cursing those who have lied to you, is a fate few would wish on even their worst enemies.

It is difficult to imagine anyone so hardened by malice that he would intentionally mislead the desperate merely for the pleasure of watching a false hope deflate when it collides with the truth. Yet desperation is a powerful motivator, and the ranks of the desperate have more than once been exploited for the political, social, and economic gain of the unscrupulous. People with nothing to lose, who view a contest as a matter of life or death, tend to make formidable combatants. Marshaling armies of such “desperados” has been a strategy employed to great effect throughout history. No less so today in some fields of medical science.

Patients suffering from incurable medical conditions have been repeatedly used to influence the public and legislative debate over embryonic stem cell research. Setting aside the significant moral objections to experimenting on human embryos, there are very real problems with embryonic stem cell research on purely scientific grounds. As I recently discussed in these pages ( The Basics About Stem Cells , January), employing embryonic stem cells as a therapeutic treatment for human illness faces the serious challenge of immune rejection by the patient. One of the proposed resolutions to this problem has been to replace the genetic information of the stem cell with that of the patient to generate a copy or “clone” of the patient that could be used as a source of replacement tissue.

In the face of strong public opposition to human cloning, proponents of embryonic stem cell research have advanced a tried-and-true tactic from the realm of product marketing: when people reject a product, repackage it and sell it under a different name. Thus human cloning has been effectively reborn as “somatic cell nuclear transfer” (SCNT), in the hope of selling a failed product under a different brand name to a public that is understandably hesitant to endorse the cloning of people for spare body parts. The contemptible aspect of this particular marketing scheme is the nature of the target audience and the role of false hope in the sales pitch.

I recently had a series of conversations with a woman dying of multiple sclerosis (MS). MS is a particularly cruel and painful disease that progressively robs a person of the ability to walk, to talk, and eventually even to swallow and breathe. The woman, by all measures a bright and well-educated person, was still in the early stages of her illness and was highly motivated to devote every last shred of her energy to promoting the “cure” offered by embryonic stem cell research. In a very real sense, this was to be her life’s work, her legacy. The rage and frustration she expressed at those opposed to human cloning was intense. How, she asked, could people deny her and others in her situation their last, best, and only hope for a cure?

How, indeed. In the face of such an emotional attack, many are driven to accept the imagined “need” for human cloning. The tragic irony, of course, is that the cure so many desperately hope for is based on nothing more than bald assertion. Proponents of embryonic stem cell research and human cloning have enlisted the ranks of the terminally ill not only to lend credibility to their claims, but to provide the valuable emotional trump-card of “How can you deny me a cure?” Those opposed to human cloning can be readily vilified as standing in the way of a cure—a cure that exists only in the hopes of the desperate and the speculations of a small number of scientists.

Perhaps the most distressing aspect of the current turn in the embryonic stem cell debate is that there are few constraints on where emotional exploitation can lead us. A year ago, the American public was asked to accept federal funding of research on human embryonic stem cells, based on the unsupported assertion that such research would cure human disease. Less than one year later, we are now being told that generating human clones is required in order for the true therapeutic potential of embryonic stem cells to be realized. At both junctures, patients with debilitating medical conditions were brought before the public to provide highly emotional testimony regarding their hope for a cure, and many Americans, swayed by compassion, reluctantly stomached their reservations.

What will the next twelve months bring? Will we next be asked to accept the need to “culture” therapeutic clones in artificial wombs for a few months until tissue-specific stem cells can be obtained from growing embryos? Perhaps the cloned embryos will need to be grown even longer, until usable organs for transplant can be “harvested.” While these scenarios may seem implausible (and would undoubtedly be dismissed as “preposterous” by embryonic stem cell advocates), the generation of human clones in the laboratory appeared to be equally preposterous one short year ago. The point is simply this: in the absence of credible scientific evidence documenting precisely how embryonic stem cells and cloned human embryos will cure disease, one can assert anything one chooses and all things can be equally justified by hope.

Proponents of embryonic stem cell research and human cloning are well aware that the future of this research cannot be debated solely within the realm of science policy. They have not succeeded in garnering public support on the basis of the scientific evidence, largely because there is no compelling evidence in support of their assertions. Even if strong scientific evidence existed, the equally strong moral objections to this research would undoubtedly persist. Advocates have also not succeeded in defining the matter solely in terms of scientific freedom and the pursuit of knowledge; the history of the last century amply illustrates the need to restrict scientific inquiry in some circumstances. In the face of these failures to recruit the public to their cause, advocates of human cloning and embryonic stem cell research have attempted to recast the issue as one of compassion and hope by marshaling the ranks of the desperate. The strategy appears to be: when you can’t win on legitimate grounds, win by any means possible. Such a strategy does not preclude outright deceit and emotional manipulation, all in the name of “hope.”

To offer false hope to the desperate as a means of advancing a political, social, or economic agenda is worse than merely cruel, it is objectively evil. Valuable resources are being diverted from other, perhaps more promising, areas of research, and, in the meantime, patients and their families are serving as pawns in a political arena. People facing the prospect of suffering and death deserve better than this. As patients, they deserve the best that science and medicine can offer. As human beings, they deserve honesty. No amount of false hope can alter the fact that after more than twenty years of unrestricted research on animal embryonic stem cells, this field has failed to yield a single cure for any human illness .

Embryonic stem cell research and human cloning go to the heart of how we view human life, both at its earliest and its final stages. As is the case for all matters of life and death, this research raises issues that are both painful and profound. Resolution of these issues should certainly not be based on unfounded speculation and emotional exploitation of those desperately hoping for a cure.

Maureen L. Condic is Assistant Professor of Neurobiology and Anatomy at the University of Utah, working on the regeneration of adult and embryonic neurons following spinal cord injury.

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The Basics About Stem Cells

Tue, 01 Jan 2002 00:00:00 -0500

In August of last year, President Bush approved the use of federal funds to support research on a limited number of existing human embryonic stem cell lines. The decision met with notably mixed reactions. Proponents of embryonic stem cell research argue that restricting federal funding to a limited number of cell lines will hamper the progress of science, while those opposed insist that any use of cells derived from human embryos constitutes a significant breach of moral principles. It is clear that pressure to expand the limits established by the President will continue. It is equally clear that the ethical positions of those opposed to this research are unlikely to change.

Regrettably, much of the debate on this issue has taken place on emotional grounds, pitting the hope of curing heartrending medical conditions against the deeply held moral convictions of many Americans. Such arguments frequently ignore or mischaracterize the scientific facts. To arrive at an informed opinion on human embryonic stem cell research, it is important to have a clear understanding of precisely what embryonic stem cells are, whether embryonic stem cells are likely to be useful for medical treatments, and whether there are viable alternatives to the use of embryonic stem cells in scientific research.

Embryonic development is one of the most fascinating of all biological processes. A newly fertilized egg faces the daunting challenge of not only generating all of the tissues of the mature animal but organizing them into a functionally integrated whole. Generating a wide range of adult cell types is not an ability unique to embryos. Certain types of tumors called teratomas are extraordinarily adept at generating adult tissues, but unlike embryos, they do so without the benefit of an organizing principle or blueprint. Such tumors rapidly produce skin, bone, muscle, and even hair and teeth, all massed together in a chaotic lump of tissue. Many of the signals required to induce formation of specialized adult cells must be present in these tumors, but unlike embryos, tumors generate adult cell types in a hopelessly undirected manner.

If a developing embryo is not to end up a mass of disorganized tissues, it must do more than generate adult cell types. Embryos must orchestrate and choreograph an elaborate stage production that gives rise to a functional organism. They must direct intricate cell movements that bring together populations of cells only to separate them again, mold and shape organs through the birth of some cells and the death of others, and build ever more elaborate interacting systems while destroying others that serve only transient, embryonic functions. Throughout the ceaseless building, moving, and remodeling of embryonic development, new cells with unique characteristics are constantly being generated and integrated into the overall structure of the developing embryo. Science has only the most rudimentary understanding of the nature of the blueprint that orders embryonic development. Yet, recent research has begun to illuminate both how specific adult cells are made as well as the central role of stem cells in this process.

The term “stem cell” is a general one for any cell that has the ability to divide, generating two progeny (or “daughter cells”), one of which is destined to become something new and one of which replaces the original stem cell. In this sense, the term “stem” identifies these cells as the source or origin of other, more specialized cells. There are many stem cell populations in the body at different stages of development. For example, all of the cells of the brain arise from a neural stem cell population in which each cell produces one brain cell and another copy of itself every time it divides. The very earliest stem cells, the immediate descendants of the fertilized egg, are termed embryonic stem cells, to distinguish them from populations that arise later and can be found in specific tissues (such as neural stem cells). These early embryonic stem cells give rise to all the tissues in the body, and are therefore considered “totipotent” or capable of generating all things.

While the existence of early embryonic stem cells has been appreciated for some time, the potential medical applications of these cells have only recently become apparent. More than a dozen years ago, scientists discovered that if the normal connections between the early cellular progeny of the fertilized egg were disrupted, the cells would fall apart into a single cell suspension that could be maintained in culture. These dissociated cells (or embryonic stem cell “lines”) continue to divide indefinitely in culture. A single stem cell line can produce enormous numbers of cells very rapidly. For example, one small flask of cells that is maximally expanded will generate a quantity of stem cells roughly equivalent in weight to the entire human population of the earth in less than sixty days. Yet despite their rapid proliferation, embryonic stem cells in culture lose the coordinated activity that distinguishes embryonic development from the growth of a teratoma. In fact, these early embryonic cells in culture initially appeared to be quite unremarkable: a pool of identical, relatively uninteresting cells.

First impressions, however, can be deceiving. It was rapidly discovered that dissociated early embryonic cells retain the ability to generate an astounding number of mature cell types in culture if they are provided with appropriate molecular signals. Discovering the signals that induce the formation of specific cell types has been an arduous task that is still ongoing. Determining the precise nature of the cells generated from embryonic stem cells has turned out to be a matter of considerable debate. It is not at all clear, for example, whether a cell that expresses some of the characteristics of a normal brain cell in culture is indeed “normal””that is, if it is fully functional and capable of integrating into the architecture of the brain without exhibiting any undesirable properties (such as malignant growth). Nonetheless, tremendous excitement accompanied the discovery of dissociated cells’ generative power, because it was widely believed that cultured embryonic stem cells would retain their totipotency and could therefore be induced to generate all of the mature cell types in the body. The totipotency of cultured embryonic stem cells has not been demonstrated and would, in fact, be difficult to prove. Nonetheless, because it is reasonable to assume embryonic stem cells in culture retain the totipotency they exhibit in embryos, this belief is held by many as an article of faith until proven otherwise.

Much of the debate surrounding embryonic stem cells has centered on the ethical and moral questions raised by the use of human embryos in medical research. In contrast to the widely divergent public opinions regarding this research, it is largely assumed that from the perspective of science there is little or no debate on the matter. The scientific merit of stem cell research is most commonly characterized as “indisputable” and the support of the scientific community as “unanimous.” Nothing could be further from the truth. While the scientific advantages and potential medical application of embryonic stem cells have received considerable attention in the public media, the equally compelling scientific and medical disadvantages of transplanting embryonic stem cells or their derivatives into patients have been ignored.

There are at least three compelling scientific arguments against the use of embryonic stem cells as a treatment for disease and injury. First and foremost, there are profound immunological issues associated with putting cells derived from one human being into the body of another. The same compromises and complications associated with organ transplant hold true for embryonic stem cells. The rejection of transplanted cells and tissues can be slowed to some extent by a good “match” of the donor to the patient, but except in cases of identical twins (a perfect match), transplanted cells will eventually be targeted by the immune system for destruction. Stem cell transplants, like organ transplants, would not buy you a “cure”; they would merely buy you time. In most cases, this time can only be purchased at the dire price of permanently suppressing the immune system.

The proposed solutions to the problem of immune rejection are either scientifically dubious, socially unacceptable, or both. Scientists have proposed large scale genetic engineering of embryonic stem cells to alter their immune characteristics and provide a better match for the patient. Such a manipulation would not be trivial; there is no current evidence that it can be accomplished at all, much less as a safe and routine procedure for every patient. The risk that genetic mutations would be introduced into embryonic stem cells by genetic engineering is quite real, and such mutations would be difficult to detect prior to transplant.

Alternatively, the use of “therapeutic cloning” has been proposed. In this scenario, the genetic information of the original stem cell would be replaced with that of the patient, producing an embryonic copy or “clone” of the patient. This human clone would then be grown as a source of stem cells for transplant. The best scientific information to date from animal cloning experiments indicates that such “therapeutic” clones are highly likely to be abnormal and would not give rise to healthy replacement tissue.

The final proposed resolution has been to generate a large bank of embryos for use in transplants. This would almost certainly involve the creation of human embryos with specific immune characteristics (“Wanted: sperm donor with AB+ blood type”) to fill in the “holes” in our collection. Intentionally producing large numbers of human embryos solely for scientific and medical use is not an option most people would be willing to accept. The three proposed solutions to the immune problem are thus no solution at all.

The second scientific argument against the use of embryonic stem cells is based on what we know about embryology. In an opinion piece published in the New York Times (“The Alchemy of Stem Cell Research,” July 15, 2001) a noted stem cell researcher, Dr. David Anderson, relates how a seemingly insignificant change in “a boring compound” that allows cells to stick to the petri dish proved to be critical for inducing stem cells to differentiate as neurons. There is good scientific reason to believe the experience Dr. Anderson describes is likely to be the norm rather than a frustrating exception. Many of the factors required for the correct differentiation of embryonic cells are not chemicals that can be readily “thrown into the bubbling cauldron of our petri dishes.” Instead, they are structural or mechanical elements uniquely associated with the complex environment of the embryo.

Cells frequently require factors such as mechanical tension, large scale electric fields, or complex structural environments provided by their embryonic neighbors in order to activate appropriate genes and maintain normal gene-expression patterns. Fully reproducing these nonmolecular components of the embryonic environment in a petri dish is not within the current capability of experimental science, nor is it likely to be so in the near future. It is quite possible that even with “patience, dedication, and financing to support the work,” we will never be able to replicate in a culture dish the nonmolecular factors required to get embryonic stem cells “to do what we want them to.”

Failing to replicate the full range of normal developmental signals is likely to have disastrous consequences. Providing some but not all of the factors required for embryonic stem cell differentiation could readily generate cells that appear to be normal (based on the limited knowledge scientists have of what constitutes a “normal cell type”) but are in fact quite abnormal. Transplanting incompletely differentiated cells runs the serious risk of introducing cells with abnormal properties into patients. This is of particular concern in light of the enormous tumor-forming potential of embryonic stem cells. If only one out of a million transplanted cells somehow failed to receive the correct signals for differentiation, patients could be given a small number of fully undifferentiated embryonic stem cells as part of a therapeutic treatment. Even in very small numbers, embryonic stem cells produce teratomas, rapid growing and frequently lethal tumors. (Indeed, formation of such tumors in animals is one of the scientific assays for the “multipotency” of embryonic stem cells.) No currently available level of quality control would be sufficient to guarantee that we could prevent this very real and horrific possibility.

The final argument against using human embryonic stem cells for research is based on sound scientific practice: we simply do not have sufficient evidence from animal studies to warrant a move to human experimentation. While there is considerable debate over the moral and legal status of early human embryos, this debate in no way constitutes a justification to step outside the normative practice of science and medicine that requires convincing and reproducible evidence from animal models prior to initiating experiments on (or, in this case, with) human beings. While the “potential promise” of embryonic stem cell research has been widely touted, the data supporting that promise is largely nonexistent.

To date there is no evidence that cells generated from embryonic stem cells can be safely transplanted back into adult animals to restore the function of damaged or diseased adult tissues. The level of scientific rigor that is normally applied (indeed, legally required) in the development of potential medical treatments would have to be entirely ignored for experiments with human embryos to proceed. As our largely disappointing experience with gene therapy should remind us, many highly vaunted scientific techniques frequently fail to yield the promised results. Arbitrarily waiving the requirement for scientific evidence out of a naive faith in “promise” is neither good science nor a good use of public funds.

Despite the serious limitations to the potential usefulness of embryonic stem cells, the argument in favor of this research would be considerably stronger if there were no viable alternatives. This, however, is decidedly not the case. In the last few years, tremendous progress has been made in the field of adult stem cell research. Adult stem cells can be recovered by tissue biopsy from patients, grown in culture, and induced to differentiate into a wide range of mature cell types.

The scientific, ethical, and political advantages of using adult stem cells instead of embryonic ones are significant. Deriving cells from an adult patient’s own tissues entirely circumvents the problem of immune rejection. Adult stem cells do not form teratomas. Therapeutic use of adult stem cells raises very few ethical issues and completely obviates the highly polarized and acrimonious political debate associated with the use of human embryos. The concern that cells derived from diseased patients may themselves be abnormal is largely unwarranted. Most human illnesses are caused by injury or by foreign agents (toxins, bacteria, viruses, etc.) that, if left untreated, would affect adult and embryonic stem cells equally. Even in the minority of cases where human illness is caused by genetic factors, the vast majority of such illnesses occur relatively late in the patient’s life. The late onset of genetic diseases suggests such disorders would take years or even decades to reemerge in newly generated replacement cells.

In light of the compelling advantages of adult stem cells, what is the argument against their use? The first concern is a practical one: adult stem cells are more difficult than embryonic ones to grow in culture and may not be able to produce the very large numbers of cells required to treat large numbers of patients. This is a relatively trivial objection for at least two reasons. First, improving the proliferation rate of cells in culture is a technical problem that science is quite likely to solve in the future. Indeed, substantial progress has already been made towards increasing the rate of adult stem cell proliferation. Second, treating an individual patient using cells derived from his own tissue (“autologous transplant”) would not require the large numbers of cells needed to treat large populations of patients. A slower rate of cell proliferation is unlikely to prevent adult stem cells from generating sufficient replacement tissue for the treatment of a single patient.

The more serious concern is that scientists don’t yet know how many mature cell types can be generated from a single adult stem cell population. Dr. Anderson notes, “Some experiments suggest these [adult] stem cells have the potential to make mid-career switches, given the right environment, but in most cases this is far from conclusive.” This bothersome limitation is not unique to adult stem cells. Dr. Anderson goes on to illustrate that in most cases the evidence suggesting scientists can induce embryonic stem cells to follow a specific career path is equally far from conclusive. In theory, embryonic stem cells appear to be a more attractive option because they are clearly capable (in an embryonic environment) of generating all the tissues of the human body. In practice, however, it is extraordinarily difficult to get stem cells of any age “to do what you want them to” in culture.

There are two important counterarguments to the assertion that the therapeutic potential of adult stem cells is less than that of embryonic stem cells because adult cells are “restricted” and therefore unable to generate the full range of mature cell types. First, it is not clear at this point whether adult stem cells are more restricted than their embryonic counterparts. It is important to bear in mind that the field of adult stem cell research is not nearly as advanced as the field of embryonic stem cell research. Scientists have been working on embryonic stem cells for more than a decade, whereas adult stem cells have only been described within the last few years. With few exceptions, adult stem cell research has demonstrated equal or greater promise than embryonic stem cell research at a comparable stage of investigation. Further research may very well prove that it is just as easy to teach an old dog new tricks as it is to train a willful puppy. This would not eliminate the very real problems associated with teaching any dog to do anything useful, but it would remove the justification for “age discrimination” in the realm of stem cells.

The second counterargument is even more fundamental. Even if adult stem cells are unable to generate the full spectrum of cell types found in the body, this very fact may turn out to be a strong scientific and medical advantage. The process of embryonic development is a continuous trade-off between potential and specialization. Embryonic stem cells have the potential to become anything, but are specialized at nothing. For an embryonic cell to specialize, it must make choices that progressively restrict what it can become. The greater the number of steps required to achieve specialization, the greater the scientific challenge it is to reproduce those steps in culture. Our current understanding of embryology is nowhere near advanced enough for scientists to know with confidence that we have gotten all the steps down correctly. If adult stem cells prove to have restricted rather than unlimited potential, this would indicate that adult stem cells have proceeded at least part way towards their final state, thereby reducing the number of steps scientists are required to replicate in culture. The fact that adult stem cell development has been directed by nature rather than by scientists greatly increases our confidence in the normalcy of the cells being generated.

There may well be multiple adult stem cell populations, each capable of forming a different subset of adult tissues, but no one population capable of forming everything. This limitation would make certain scientific enterprises considerably less convenient. However, such a restriction in “developmental potential” would not limit the therapeutic potential of adult stem cells for treatment of disease and injury. Patients rarely go to the doctor needing a full body replacement. If a patient with heart disease can be cured using adult cardiac stem cells, the fact that these “heart-restricted” stem cells do not generate kidneys is not a problem for the patient.

The field of stem cell research holds out considerable promise for the treatment of disease and injury, but this promise is not unlimited. There are real, possibly insurmountable, scientific challenges to the use of embryonic stem cells as a medical treatment for disease and injury. In contrast, adult stem cell research holds out nearly equal promise while circumventing the enormous social, ethical, and political issues raised by the use of human embryos for research. There is clearly much work that needs to be done before stem cells of any age can be used as a medical treatment. It seems only practical to put our resources into the approach that is most likely to be successful in the long run. In light of the serious problems associated with embryonic stem cells and the relatively unfettered promise of adult stem cells, there is no compelling scientific argument for the public support of research on human embryos.

Maureen L. Condic , a new contributor, is assistant professor of neurobiology and anatomy at the University of Utah, working on the regeneration of adult and embryonic neurons following spinal cord injury.

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