A 56-year-old man with severe angina pectoris visits a cardiac specialist for a consultation. During the course of the examination, the patient excitedly describes a story from the news about an experimental gene therapy that aims to stimulate new blood vessel growth in patients with coronary artery disease. He feels that such therapy could dramatically improve his condition and expresses a strong desire to enroll in the clinical trial. The clinician has some familiarity with the details of the trial and wonders how she should counsel her patient.
A 24-year-old woman with abnormal bladder development and function resulting from spina bifida visits her physician for a routine check-up. The patient would also like to discuss a new therapy she has heard about that involves the growth of a replacement bladder for transplantation using the patient’s own cells. This therapy has been successfully applied in a number of other patients with spina bifida. Her physician wonders how to approach the discussion with his patient.
Regenerative medicine has been the focus of substantial funding and research efforts worldwide (Attorney General of California, 2004; Greenwood et al., 2006). Additionally, it has engaged public attention through highly publicized political debates (Press, 2006; Wagner, 2006), media accounts of “miracle” cures (Kuntzman, 2004), and strong lobbying from voluntary health organizations (Perry, 2000). As a newly emerging and evolving field, there is to date no consensus definition of regenerative medicine (Mironov et al., 2004). For the purposes of this discussion, we define regenerative medicine as follows:
Regenerative medicine is an emerging interdisciplinary field of research and clinical applications focused on the repair, replacement, or regeneration of cells, tissues, or organs to restore impaired function resulting from any cause, including congenital defects, disease, trauma, and aging. It uses a combination of several technological approaches that moves it beyond traditional transplantation and replacement therapies. These approaches may include, but are not limited to, the use of soluble molecules, gene therapy, stem cell transplantation, tissue engineering, and the reprogramming of cell and tissue types.
Regenerative medicine can be thought of as the next phase in the evolution of organ transplantation and replacement therapies (Haseltine, 2003; Daar, 2005). Instead of simply replacing cells, tissues, and organs, however, regenerative medicine aims to provide the elements required for in vivo repair, to design replacements that seamlessly interact with the living body, and to stimulate the body’s intrinsic capacities to regenerate (Greenwood et al., 2006). Disciplines contributing to this field include genetics and molecular biology, materials science, stem cell biology, transplantation, developmental biology, and tissue engineering (Haseltine, 2001; Greenwood et al., 2006). In the realm of tissue engineering, for example, researchers aim to design and grow new tissues and organs using cells, scaffold material, and soluble molecules to guide growth. Such developments could help to overcome challenges facing traditional transplantation, such as immune rejection and shortages of donor material (Cortesini, 2005).
It has been estimated that stem cell-based therapies, one aspect of regenerative medicine, could potentially benefit over a hundred million patients in the USA alone for conditions such as diabetes mellitus, autoimmune diseases, cardiovascular disease, cancer, and neurodegenerative diseases (Commission on Life Sciences, 2002). Though still in the early stages of development, regenerative medicine has produced several therapies currently available on the market. These include the tissue-engineered skin substitute Apligraf (Petit-Zeman, 2001) and the adult stem-cell-containing bone regenerating therapy Osteocel (http://www.osiristx.com/products_osteocel.php).
Given the new therapies that regenerative medicine is likely to produce, the high level of media and public attention the field is receiving, and the experimental nature of many of the regenerative medicine therapies currently available, how should clinicians respond to patients’ inquiries and what ethical issues does this field raise?
Regenerative medicine raises a number of ethical issues, some of which, such as the moral status of the embryo, are relevant at the broad societal and policy levels. This section focuses specifically on ethical issues that are likely to be encountered in everyday clinical practice: informed consent, decision-making capacity, therapy versus enhancement, and transplantation ethics. Each of these four issues will be discussed in turn.
Firstly, regenerative medicine presents new challenges to the process of informed consent. This is partly the case because many regenerative medicine therapies are currently available only through clinical trials, and clinicians will, therefore, face the question of whether or not their patients should enroll in such trials. In these cases, extra weight is placed on the importance of proper informed consent because the potential risks associated with such experimental therapies are largely unknown (McKneally and Daar, 2003; Kimmelman, 2005). Certain regenerative medicine therapies, such as gene therapy, are associated with a higher degree of uncertainty than traditional therapeutics because they are not backed by a long history of pharmacological data that can provide a degree of predictability (Kimmelman, 2005). It is also the case that patients, particularly severely ill patients, can inaccurately perceive the purpose of a trial as one designed to provide direct therapeutic benefit rather than to produce generalizable knowledge (Lo et al., 2005). Clinicians, therefore, must be particularly alert to their obligation to fully disclose and explain potential risks, benefits, and areas of uncertainty in order to allow their patients to give true and full informed consent to treatment.
Regenerative medicine also presents challenges to the informed consent process because of its innovative nature. As an innovative technology, regenerative medicine raises questions regarding a patient’s ability to consent fully to treatment given that the therapies are often complex and unfamiliar (Lo et al., 2005). Simplifying complex material so that patients can appropriately comprehend potential therapies can be challenging. Clinicians, however, have an ethical obligation to provide clear and reliable information to patients and to verify that the patient has fully understood this discussion (Lo et al., 2005). The duty to inform patients accurately and thoroughly is of particular relevance in the face of media attention and hype, which may lead to unrealistic expectations of potential therapeutic outcomes.
Secondly, regenerative medicine can raise issues related to a patient’s capacity to consent to treatment. This relates primarily to therapies targeted at the brain, and it takes on particular importance with respect to regenerative medicine because of the newness of the technology, the complexity of the organ being targeted, and because many of the patients receiving such therapies will be suffering from neurodegenerative diseases that could compromise their decision-making capacity (Glannon, 2006).
Thirdly, clinicians could face issues regarding the appropriate application of regenerative medicine therapies given their potential dual use; that is, given their ability to be used as a therapeutic tool but additionally as a method of enhancing normal function (Daar, 2005). Precisely what constitutes “impaired” versus “normal” function, and thus what constitutes therapy or enhancement, remains undefined and will most likely be addressed on a case-by-case basis. Carrying out an intervention purely for enhancement purposes does not necessarily mean that it is unethical (Miller and Brody, 2005). Enhancements can, however, raise concerns that concepts of normalcy may be shifted, that the autonomy of children will not be respected, and that a person’s sense of self may be affected, particularly when considering neurological enhancements (Wolpe, 2002; Sandel, 2004). One emerging neuroregenerative treatment, for instance, involves injecting self-assembling synthetic peptides into the brain, which form nanofiber scaffolds in vivo to stimulate brain tissue and nerve regrowth. This technique has been successfully used to restore sight in hamsters with severed optical nerves (Ellis-Behnke et al., 2006).
Finally, given that the application of many regenerative medicine therapies will involve the transplantation of cells, tissues, organs, or bioartificial constructs into the body, ethical issues similar to those faced by the field of traditional transplantation are raised. These issues include the ethics of procuring donor materials and compensating donors, respect for different cultural perspectives on organ transplantation, as well as protecting patient safety, particularly with respect to non-human animal-derived materials (Rizvi, 1999; Abouna, 2003). Unlike traditional transplantation, where organ procurement and transplantation occur within a relatively short time frame, it may be the case that cells donated for regenerative medicine therapies are preserved and used many months or even years after the time of donation. This raises the question of whether donors should be re-contacted to update their family history in the interests of protecting the safety of the recipient. Such re-contact would, however, need to be weighed against the donor’s right to privacy and confidentiality (Lo et al., 2005).
The law relevant to regenerative medicine is primarily focused on the regulation of stem cell research. This legislation will affect the extent to which physicians will encounter regenerative medicine therapies in practice, and the kinds of therapy that are at their disposal. There is currently no international consensus on the regulation of stem cell research (Isasi et al., 2004). As such, legislation varies broadly worldwide, from permissive, to flexible, to restrictive policies (MBBNet, 2007).
Countries with permissive policies on stem cell research include China, India, and the UK (Human Fertilisation and Embryology (Research Purposes) Regulations, 2001; Greenwood et al., 2006). In these countries, stem cells may be derived from a wide variety of sources, including the derivation of human stem cells from embryos created specifically for research purposes through somatic cell nuclear transfer. Somatic cell nuclear transfer, also called therapeutic cloning, is a process in which the nucleus of an oocyte is removed and replaced with the nucleus of a somatic cell, and the oocyte is stimulated to divide. Once cell division has reached the blastocyst stage, approximately four to five days later, stem cells can be harvested from the inner cell mass of the embryo (Lanza et al., 1999).
Countries with flexible legislation limit the methods of acceptable stem cell procurement. In countries such as Canada (Assisted Human Reproduction Act, 2004) and Brazil (Biosafety Law of 2005 [Nelson, 2005]), human embryonic stem cells may be derived from unused embryos created for the purposes of in vitro fertilization given that proper consent procedures are followed. Embryos may not, however, be created specifically for research purposes using somatic cell nuclear transfer.
Countries with restrictive stem cell legislation vary widely. The USA, for instance, restricts federal funding for embryonic stem cell research to stem cell lines already in existence at the time of the Presidential announcement on stem cell research in 2001. The ban on creating new embryonic stem cell lines, however, does not apply to research funded by private or state funding. A motion to loosen federal funding restrictions on human embryonic stem cell research, the Stem Cell Research Enhancement Act of 2005, passed both the House of Representatives and the Senate but was vetoed by President George W. Bush in July 2006 (Congress of the United States of America, 2006). In Italy, by comparison, all embryonic stem cell research is banned under legislation that regulates assisted human reproduction. A June 2005 referendum to amend this legislation failed because voter turnout was below the 50% required for quorum (UK Department of Health, 2005).
Distinct from legislation enacted to define what is and what is not legal with respect to regenerative medicine, several government agencies are creating policies to guide the development and use of regenerative medicine therapies. From a policy perspective, regenerative medicine presents new challenges in regulating emerging products to ensure quality control and patient safety (Daar, 2005). The case of tissue engineered products illustrates these challenges particularly well.
Traditionally, the regulatory route of a product depends on its principal purpose or mode of action. The primary mode of action of drugs is via chemical means, while medical devices act primarily through physical means (Jefferys, 2003). Tissue-engineered products, however, often integrate these two functions. A physical scaffold serves as the framework on which cells are seeded. Growth factors stimulate the growth of the cells on the scaffold, and the scaffold itself may release soluble molecules to encourage regeneration in vivo (Koh and Atala, 2004; Sohier et al., 2006). Many countries are still striving to create policy that can accurately and effectively regulate the development and application of tissue-engineered products (Jefferys, 2003). The European Union Commission to Regulate Tissue Engineering Technologies released draft regulations for public comment in May 2005 (European Commission, 2005). In the USA, the Food and Drug Administration (2004) has created the Office of Combination Products to coordinate the regulation of tissue engineered products. Additionally, the current Good Tissue Practices Final Rule, released in the USA in May 2005 (US Food and Drug Administration, 2005), strives to regulate cell- and tissue-based products by focusing primarily on safety and the potential for communicable disease transmission rather than on product identity standards (Preti, 2005).
Empirical studies on the ethics of regenerative medicine largely focus on public opinions regarding the appropriateness of embryonic stem cell research and their understanding of stem cell issues (Perry, 2000). These studies may provide some guidance for clinicians regarding the beliefs they are likely to encounter when discussing regenerative medicine therapies with their patients and the level of comprehension they can expect their patients to have.
A recent study of nine countries in the European Union, for example, showed that the majority of those surveyed supported using spare embryos from in vitro fertilization for stem cell research but not embryos derived via somatic cell nuclear transfer (Solter et al., 2003). Results released in a study involving 2212 Americans showed that two-thirds of respondents either approved or strongly approved of embryonic stem cell research (Hudson et al., 2005).
Public understanding of stem cell research has also been evaluated through empirical work. A study found that 60% of Americans surveyed felt that they had a “good understanding” of stem cell-related issues (Nisbet, 2004). A follow-up study, however, asked Americans to identify specific kinds of stem cells that came to mind when discussing stem cell issues. More than half of the respondents replied that they did not know, and only 17% identified embryonic stem cells (Nisbet, 2004). The Genetics and Public Policy Center in Washington DC tested public understanding of stem cell and cloning issues among Americans and revealed incomplete or incorrect knowledge among Americans regarding stem cells and cloning; 45% of the 4834 Americans surveyed believed that is was currently possible to clone a human baby (Burton, 2005).
Regenerative medicine will present issues for a range of clinicians, including family physicians, transplant surgeons, neurologists, and other healthcare practitioners providing care to patients seeking and undergoing regenerative medicine therapies.
Clinicians faced with the question of whether they should recommend patients for clinical trials of regenerative medicine therapies should take extra care to ensure that informed consent is a top priority. Clinicians should disclose all areas of potential risk, including any cases in which unforeseen risks have occurred (Kimmelman, 2005). Any areas of uncertainty with respect to emerging therapies should be openly acknowledged. Time for in-depth discussion with patients should be allotted and should include the specific purpose of the clinical trial in order to avoid any therapeutic misconception on the part of the patient (McKneally and Daar, 2003; Kimmelman, 2005). Clinicians should also inform the patient of any standard treatments available (McKneally and Daar, 2003). Throughout this process, clinicians should be sensitive to the fact that patients seeking experimental therapy may be particularly vulnerable because of severe illness or because they have exhausted all other treatment options.
The high level of media attention around regenerative medicine may result in clinicians facing frequent requests for information from patients about specific regenerative medicine therapies. Clinicians should attempt to provide a reliable source of information independent of what their patients may have heard through the media. The complexity of emerging treatments along with potential preconceived ideas based on media hype will require that they take extra time to engage in in-depth discussions with their patients regarding potential therapeutic options. They should attempt to explain treatment options clearly and simply, asking frequent questions of the patient to ensure full comprehension of the risks and benefits of treatment. Asking patients what they have heard regarding a particular therapy and what their expectations are will help clinicians to ascertain their level of understanding, their source of knowledge, and any assumptions and beliefs regarding regenerative medicine that they may hold.
Patients under consideration for neuroregenerative therapies should be carefully monitored to assess their capacity to consent for treatment. In cases of uncertainty, a formal decision-making capacity assessment should be undertaken. It may be the case that a substitute decision maker will be required to consent to treatment for the patient. A more detailed discussion of these issues is contained in Ch. 3.
The clinician should obtain a full explanation from the patient in the first case of what he has heard about the therapy in order to assess his preconceived assumptions and expectations regarding new blood vessel growth. She should clearly explain the nature of clinical trials, emphasizing that participation does not necessarily entail placement in the treatment group and that many trials are not testing for direct therapeutic benefit to the patient. The clinician should clearly explain the details of the trials, openly acknowledging any information of which she is unclear. Given that the treatment is experimental, the clinician should take extra time to explain in detail the risks and benefits, emphasizing that they are currently unknown and that there have been cases where gene therapy has resulted in unforeseen consequences. Throughout this discussion, the clinician should take steps to verify that the patient has fully understood the information and that he is properly informed of standard treatments available. As a final step, the clinician should refer the patient to the coordinators of the clinical trial to receive additional information and clarification.
The clinical problems of spina bifida are well known to clinicians and the potential regenerative medicine application is easy to comprehend. Literature that has already been published on the outcomes of a few patients can help to inform the clinician’s discussion with his patient. In seven patients with spina bifida aged 4 to 19 years who received tissue-engineered autologous bladders, clinical outcomes were excellent and renal function was preserved. No adverse side effects such as metabolic consequences, urinary calculi, or abnormal mucus production were noted. Upon biopsy, the engineered bladders showed adequate structural architecture and phenotype (Atala et al., 2006). Given that the results for this therapy are early and few, clinicians will have an ethical obligation to keep abreast of the current literature in order to monitor the relative risks and benefits of the procedure and to communicate these to their patients. By the time of publication of this book, there are likely to be additional studies on which clinicians can base their advice. The importance of this breakthrough and the media attention surrounding it could lead to many more patients who wish receive such therapy.