• Open Access

Impedance of Novel Therapeutic Technologies: The Case of Stem Cells

Authors

  • David G. Zacharias B.A.,

    1. Harvard School of Public Health, Harvard University, Boston, Massachusetts, USA
    2. Mayo Medical School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Timothy J. Nelson M.D., Ph.D.,

    1. Division of General Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Paul S. Mueller M.D., M.P.H.,

    1. Division of General Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    2. Program in Professionalism and Ethics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • C. Christopher Hook M.D.

    1. Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    2. Program in Professionalism and Ethics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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C. Christopher Hook (hook.christopher@mayo.edu)

Abstract

Embryonic stem cell (ES) technology has advanced considerably within the past three decades and has gained prominent distinction within the emerging field of regenerative medicine. As it now enters the nascent stages of clinical application, many hopes and expectations arise along with questions as to where the technology will go. This paper evaluates the technical and practical obstacles that must be overcome before it can fully translate into the clinical context, the existence of strong opposition to the technology, political and legal barriers that have impeded its progression, and the role of healthcare reform in creating new social and economic priorities. In contrast to the technological imperative, a driving force seeking to implement the most recent scientific advances into medical practice, we refer to such translational obstacles as “technological impedance.” Rather than expending inordinate effort to preserve existing systems that continue to possess major hurdles, we advocate fostering interdisciplinary approaches in the development of new generation platforms and embracing disruptive innovations that create solutions to technological impedance and move us forward in healthcare delivery. Clin Trans Sci 2012; Volume 5: 422–427

Human embryonic stem (hES) cell technology has advanced for more than a decade and has come to be regarded as “the gold standard” in the stem cell field.1,2 These cells have met the most stringent standards for pluripotency and demonstrate immense promise for diagnostic and therapeutic capabilities.3 Nevertheless, hES research has given rise to social conflict and nations remain divided regarding its regulation.4 We aim to distinguish between the scientific and clinical realities of hES technology and highlight the ethical, legal, and social issues concerning its use in the United States (US). In light of obstacles that impede the progression of these technologies, we consider what the future may look like for stem cell research.

Scientific and Clinical Applications of hES Cells

Since isolation in 1981, nonhuman embryonic stem (ES) cells have proven sufficient to give rise to all tissues of the adult organism across all three embryological germ layers.5–8 Twenty-seven years later in 1998, the first hES cells were isolated from frozen embryos and have since contributed enormously to our understanding of cellular pluripotency.3,9 Although no hES treatments are available for clinical use in nonstudy settings in the US, the first FDA-approved Phase I clinical trials for hES technology are underway assessing the safety of hES cell-derived oligodendrocyte progenitor cells in patients with spinal cord injury and retinal pigmented epithelial cells in patients with age-related macular degeneration and Stargardt’s macular dystrophy.10–14 Despite these advances, several practical contstraints impede translation of hES technology into clinical practice.

Because of the plasticity and unrestricted growth potential of hES cells, one major concern of using transplanted hES cells in humans is the risk for teratoma formation and tumorigenesis, a challenge faced by all pluripotent stem cell platforms.15–17 As recently reviewed, a number of animal studies have shown an increased risk for tumor formation arising from transplanted hES cells.18 Clearly, such an adverse effect must be addressed before hES technology can be offered as an approved therapeutic product. Another risk inherent to allogeneic stem cell transplants is immune rejection.19,20 Because hES cells are not “self” tissue, recipients would require immunosuppressive therapy similar to a patient receiving an organ transplant. For example, the Geron Phase I clinical trial stipulates that patients undergoing allogeneic hES cell transplants must receive immunosuppressive therapy for at least 4 months and be monitored for 15 years thereafter to evaluate for rejection.21

Another concern for hES technology is resource availability. Given the absence of FDA-approved treatments based on hES cells, this topic has yet to be fully addressed. But as the research now shifts from the laboratory to the clinic in hopes of curing hundreds of diseases that affect millions of people, we will need to assess practically whether embryos derived from in vitro fertilization (IVF) will be numerically sufficient to meet this demand. Notably, researchers currently must abide by NIH guidelines that “…allow for funding of research using hES cells derived from embryos created using in vitro fertilization…”22

One patient survey revealed that about half of respondents (totaling 1,020 families) stated they would be somewhat (27%) or very (21%) willing to donate their IVF embryos for research.23 Looking at the total supernumerary (left over with no plans for reproductive use) frozen embryos at IVF clinics in the US and using conservative estimates concerning actual donation, freeze-thaw survival, successful growth to the blastocyst-stage, and successful derivation of hES cells, this group estimated about 2,000–3,000 hES cell lines could be procured.24 This small number of hES cell lines may well be grossly insufficient to meet the needs of the hundreds of millions of genetically and immunologically diverse people afflicted with various diseases who might benefit from hES cell technology. Hence, researchers and clinicians must come up with solutions from collection to processing in order for the supply to meet the demand.25 In 2005, the Committee on Guidelines for Human Embryonic Stem Cell Research stated,

“Billions of dollars will be committed to hES cell research from public and private sources in the coming years. It is not yet clear exactly what specific therapeutic benefits will emerge from this investment, but there is reason for concern they will not be equitably distributed in our current health-care system. … The therapeutic possibilities inherent in hES cells can mean vastly improved lives for millions of disease sufferers … The hES cell research community should ensure that there is sufficient genetic diversity among cell lines to allow for potential translation into health-care services for all groups in our society.”26

Taking into account governmental regulation, a phenomenological incidence of an aging population with an increased disease burden and inability for embryo donation, and a massively expensive healthcare system, we seem to have a Malthusian stem cell deficit emerging. Given the current circumstances, it would appear that this charge simply cannot be met. To be sure, policy can evolve to better meet the need, but one can see how it will be difficult.

In regard to donors, surveys reveal that a majority of couples do not reach a disposition decision regarding their left-over frozen embryos and nearly half find such a decision to be emotionally distressing.27,28 Similarly, reproductive clinicians, many of whom are investigators, perceive a conflict of interest in trying to discuss the donation of embryos for research with their patients.29 Embryo and gamete donation tends to be a more delicate subject and coercing the patient toward a decision could arguably become a breach of patient autonomy and the patient–physician relationship.30 And though certain types of tissue donation are socially permissible, the incentivizing of egg and embryo donation to meet the potential stem cell demand would surely raise concern regarding financial resources, patient safety, and reproductive exploitation.31, 32

None of these concerns, however, are insurmountable. But given 30 years of continued research in this area, it would be wise to assess fairly the prospect of hES technology as a future clinical reality. In addition to practical, technical, and economic limitations, other questions must be explored to help guide our decision making. Specifically, the scientific and medical community has failed to ask, “How does the ethical, legal, and social context shape the scientific debate of when (or whether) hES technology should become a clinical priority?” In other words, is the medical context sufficient to address whether societal resources should be committed to pursue this technology?

Ethical Concerns Regarding the Human Embryo

More often than not, notions of personhood are constructed from a “hybrid continuum” of biological facts balanced with religious, moral, and juridical values.33 In regard to embryonic moral status, the question “When does human life begin?” has not been the focus of controversy. The question truly being addressed is “When does human life become worthy of moral consideration?” In essence, the task is to determine “…whether a being is the kind of entity to which moral principles or other moral categories can and should be applied and, if so, based on which properties of the being.”30

Drawing on insights from the fields of neurogenesis and cognitive psychology, some assert that rationality and sentience should dictate moral status.34 In line with this, a number of proponents maintain that harm occurs only if an embryo suffers.35 In the famous words of utilitarian, Jeremy Bentham, “The question is not, Can they reason? nor, Can they talk? but, Can they suffer?”36 One member of the President’s Council on Bioethics, Michael Gazzaniga, stated:

“These are entities that do not possess a single neuron and are ready to go and can create tens of thousands of cell lines. Put another way, a piece of DNA is not a human being. A human being is an entity with a functioning brain consisting of billions of neurons with trillions of synapses that develops over time and with crucial interactions with the environment.”37

Others recognize that the potentiality of an embryo to mature into a fully developed organism may be an important consideration,38 but some point out that leftover embryos derived from IVF will die anyway.39 One common view is the concept of the embryo as a person in and of itself, articulated by two former members of the President’s Council on Bioethics:

“A human embryo is a whole living member of the species Homo sapiens in the earliest stage. … Human embryos possess the epigenetic primordial for self-directed growth into adulthood. … We were then, as we are now distinct and complete. … As humans they are members of a natural kind—the human species. … Since human beings are intrinsically valuable and deserving of full moral respect in virtue of what they are, it follows that they are intrinsically valuable from the point at which they come into being.”40

Religious worldviews also weigh in heavily on the hES debate. Polls consistently reveal that 85% of Americans feel that religion is important to their lives.41 Traditionally, Judaism and Islam have supported hES research while many from Christianity (e.g., Catholics and certain Protestants) have opposed it with eastern religious worldviews such as Hinduism and Buddhism being divided.42,43 The Vatican condemns the use of human embryos for stem cell research because the Church believes that human life possesses moral value at conception.44 One Protestant theologian writes:

“…This is not an understanding shaped chiefly in the fires of recent political debate; rather, it has very deep roots in the Christian tradition. … In honoring the dignity of even the weakest of living human beings—the embryo—we come to appreciate the mystery of the human person and the mystery of our own individuality.”45

Our purpose here is not to resolve these social conflicts nor provide an editorial appraisal of the arguments. We simply think it is important to recognize that research requiring the destruction of human embryos is controversial.46 If the past few decades have taught us anything, it is that these sentiments are deeply rooted in the moral and religious consciences of many and prudence would dictate that they not be underestimated nor brushed aside lightly. This conflict, which the authors believe is not resolvable, has led to several contentious legal and political developments in the US.

Political and Legal Controversy in the United States

In 1994, a report by the NIH Human Embryo Research Panel stated that although embryos could not be created for research purposes, supernumerary embryos from IVF could be utilized.45 President William Clinton and the Republican-led Congress passed the Dickey-Wicker Amendment in 1996, which forbade the use of federal funds to support the creation of human embryos for research or “…research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death. …”47 Two years later in 1998, Thomson and colleagues isolated the first hES cells through private funding.48 Soon after, influential people began advocating for hES research on Capitol Hill including Mary Tyler Moore, Christopher Reeve, Michael J. Fox, and Nancy Reagan. In August 2001, President George W. Bush signed a bill allowing the use of federal funds for research on all previously derived hES cell lines so as not to support further embryo destruction.4 In both 2006 and 2007, Congress tried to pass bills allowing the use of federal funds to support research of newly isolated hES cell lines; both were vetoed by President Bush.47

Soon after inauguration, President Barack Obama issued Executive Order 13505 for the NIH to formulate new hES research guidelines to reverse those of his predecessors. Yet, two days later, he signed the Omnibus Appropriations Act of 2009, which included the Dickey-Wicker Amendment.48 In July 2009, the NIH announced permission of funding for hES research on newly derived cell lines, but not for the creation of those lines.22 This resulted in many new hES cell lines available for federally funded research.49,50 However, the next month a group of plaintiffs filed a lawsuit against the NIH and the Department of Health and Human Services arguing that the new guidelines were illegal under the Dickey-Wicker Amendment.47 After a case dismissal and subsequent appeal, Chief Judge Royce Lamberth of the U.S. District Court in Washington, D.C. temporarily blocked federal funding for hES research in August 2010 until the case was decided.51 After a storm of controversy and filings that resulted, the District Court of Appeals overturned the ruling on September 9th, 2010 to allow funding for the time being.52

Judge Lamberth had ruled that the distinction between deriving hES cells and using them is invalid: “If one step or ‘piece of research’… results in the destruction of an embryo, the entire project is precluded from receiving federal funding.”51 However, the 2009 NIH hES guidelines state:

“…hES cells are not embryos as defined by Section 509. … These guidelines therefore recognize the distinction, accepted by Congress, between the derivation of stem cells from an embryo that results in the embryo’s destruction, for which federal funding is prohibited, and research involving hES cells that does not involve an embryo nor result in an embryo’s destruction, for which federal funding is permitted.”22

The court battle continued for nearly eight months as a three-judge panel of the appeals court evaluated the case.53,54 Eventually, the court ruled 2–1 in favor of the NIH, accepting their distinction between hES cells and human embryos.55 The case was returned to Lamberth who agreed with the ruling and dismissed the case. The plaintiffs stated they would review their options for appeal, but it is uncertain whether it will go any further.56,57 Regardless of the decision, Congress would need to repeal the Dickey-Wicker Amendment in order to remove definitively any potential legal obstacles to government-funded hES research.58 However, many remain skeptical the Dickey-Wicker Amendment will be repealed and wonder about renewed vulnerability under future political administrations.59 Due to the threat of funding loss during the 11 month case, a number of scientists left the hES field altogether shifting their focus instead to researching involving bioengineered pluripotent stem cells.60–62

Social and Economic Considerations

As for stem cell policy, it is understandable why many have written extensively about the way things ought to be. Although some advocate for science to progress unchecked by the larger societal context,63–65 it is important to come to terms with the fact that societal values regarding healthcare are not shaped solely by the potential for scientific discovery and therapeutic breakthrough. The expense associated with expanding personalized medicine is particularly poignant in light of the current economic crisis and need for healthcare reform.66 Paradoxically, despite the highest per capita expenditures for healthcare worldwide, Americans have poorer health and lower life expectancy than citizens of most developed nations.67,68 In the US, it appears that “the invisible hand of the marketplace” cannot achieve equilibrium when presented with higher healthcare costs, shrinking resources, a morbidly unhealthy population, and an insatiable demand for premium healthcare. These problems are exacerbated by pressure on the scientific community to expend resources on the development of all potential treatments.69 Unrestrained technological advancement, including that related to stem cell technologies, is antagonistic to the ideal of affordable, equitable, accessible, and community-based healthcare.70–72 Indeed, medical professionalism of the new millennium is calling for physicians to “provide health care that is based on the wise and cost-effective management of limited clinical resources.”73,74

Putting it All Together: Impedance and the Future of Stem Cells

Nevertheless, personalized medicine offers significant advantages over conventional medicine and thus, remains a vision for the future of healthcare delivery, particularly in the field of regenerative medicine.75 The desire to develop stem cell technology is fueled partly by a “technological imperative” in US healthcare; that is, a public fascination with technology that creates a driving force seeking to implement as soon as possible the most recent scientific advances into medical practice.76,77 However, there are other factors to be considered when assessing the feasibility of translating bench research to bedside care of patients. This paper has highlighted the fact that individuals seeking to develop hES technology continue to deal with significant obstacles including (1) multiple technical and practical challenges that must be overcome before achieving clinical utility, (2) strong ethical and religious opposition among various groups in the US and elsewhere, (3) political controversy creating legal barriers to its development, and (4) healthcare reform and social/economic priorities that impose stringent demands on this technology. These barriers create resistance that acts as an opposing force to the technological imperative, which we will simply call technological impedance (Figure 1).

Figure 1.

From Bench to Bedside. Successful clinical translation requires not only enhancing demand for a given medical technology, but also addressing or circumventing barriers to its development. By way of analogy, we can borrow from Ohm's Law and note the inverse relationship that exists:inline image

Unfortunately, a historical overview would reveal that these barriers have remained largely unaddressed (and perhaps unrecognized) by the scientific and medical communities in their pursuits of developing new technologies. This is not surprising, however, given that technological impedance commonly arises out of a context outside the purview of science. Consequently, as we evolve into a society of hyperspecialization, it becomes increasingly paramount that we move away from professional isolationism and develop into a culture that fosters interdisciplinary collaboration and collective effort.78–81 Only in this kind of environment can disruptive innovation flourish and lead to creative solutions which overcome technological impedance and move us forward in healthcare delivery.82

It is unlikely that hES technology will overcome the translational impediments it faces. Even if an approved hES therapy reaches the market, many of these factors (predominantly economic, ethical, and social) will continue to hinder its widespread use and clinical efficacy. Nevertheless, out of this first-generation pluripotent stem cell platform novel technologies are emerging.83 In the past five years, nuclear reprogramming technology of human somatic cells has advanced rapidly. Numerous reports from the literature conclude that induced pluripotent stem (iPS) cells demonstrate promise for patient-specific therapies, diagnostic tools, and research models for both normal development and human disease.84–95 Though recognizing a long road of maturation with many unknowns and inherent problems, some speculate that this embryo-independent stem cell technology has the potential to replace many, if not all, pluripotent stem cell applications.96–99 However, while iPS does address many issues pertaining to resource availability, genetic diversity, and concerns regarding embryo destruction, many in the scientific community call attention to the fact that iPS is yet insufficient to meet all the challenges faced by hES.58,97,98,100–102

Ultimately, iPS cells may not be the complete answer; it may require a third, fourth, or even fifth generation pluripotent stem cell platform to achieve practical clinical feasibility and widespread acceptance. But the important summary message is that we recognize apparent steps forward and utilize them to evolve and advance the science in order to meet the needs of our patients, rather than expend inordinate effort to preserve existing systems.103,104 We should be realistic about hES technology in regard to the inherent ethical, cultural, and political controversy it creates, recognize practical barriers of technological development and resource availability that lie ahead, and allow patient-centered objectives to guide our decisions as we pursue personalized and regenerative medicine in a healthcare environment necessitating reform.

Financial Support and Disclosures

Member, Boston Scientific Patient Safety Advisory Board (PSM)

Associate Editor, Journal Watch General Medicine (PSM)

This work is supported by Mayo Clinic and a generous gift from the Todd and Karen Wanek Family Foundation.