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ddn Editorial Roundtable: Ethics and stem cell research
Since the first derivation of embryonic stem cells (ESCs) in mice in 1981 and subsequent discoveries involving human ESCs (hESCs), this form of stem cell research has been the subject of much ethical, moral and social controversy. In fact, in an attempt to resolve some of these concerns and ensure that important medical discoveries continue to progress, the last three American presidents and their government colleagues have set policies impacting ESC research in various ways. Where ambiguity exists in this debate on a federal level, some states have drawn a clear line in the sand about which forms of stem cell research may be conducted and publicly funded. And while legislators may lack the appetite to tackle this debate, plaintiffs in lawsuits filed at every court level are seeking the last word on the use of embryos in stem cell research.
In this, the second installment of our three-part series on trends in stem cell research, we brought together three individuals engaged in various forms of stem cell-related research to discuss some of the controversies surrounding this burgeoning scientific field. Their views on the use of different types of stem cells, the promise they hold for patients and some of the public concerns about them are diverse and insightful.
Participating in this roundtable discussion were the following researchers:
Dr. Theresa Deisher, founder, CEO and chief scientific officer of AVM Biotechnology, a Seattle-based company "dedicated to the discovery, development and commercialization of safe, effective and affordable pro-life medicines." After earning her Ph.D. in molecular and cellular physiology from Stanford University in 1990, Deisher went on to discover adult pluripotent stem cells isolated from the heart, which she patented and assigned to ZymoGenetics in 1998, six months before Jamie Thompson patented the first human embryonic stem cell lines. She also discovered FGF18 (which she also patented and assigned to ZymoGenetics), a very potent mesenchymal stem cell growth factor currently in clinical trials for osteoarthritis and cartilage repair. Deisher also derived embryoid-body like structures from umbilical cord blood, a discovery which she patented and assigned to Amgen. Deisher is also one of the named plaintiffs in the Sherley, et al. v. Sebelius, et al., lawsuit challenging federal funding of embryonic stem cell research.
Dr. Verna McErlane, director of commercial operations at Sistemic Ltd., a Glasgow, Scotland-based firm that provides miRNA-based products to the drug development, cell therapy and bioprocessing markets. McErlane earned her Ph.D. in preclinical cancer drug development and spent time working at the Gray Cancer Institute in London, where she was involved with the formation of SPEAR Therapeutics Ltd. prior to moving to the University of Dundee, Scotland to pursue evaluation of prodrug anticancer strategies. Subsequently, she was chosen to take part in the Saltire Foundation fellowship program and moved to Boston and attended Babson College before working with Genzyme on its new business initiatives. She also held an international market development position with Axis-Shield in Dundee, Scotland. McErlane was the recipient of the Galen Pharmaceutical Prize in 1999.
Dr. Mark Pittenger, CEO and chief scientific officer of Pearl Lifescience Partners LLC, a firm in Baltimore, Md., that develops vaccines against infectious enveloped viruses using bioengineered cell lines. Pittenger is also a consultant to the Department of Surgery in the Division of Cardiac Surgery at the University of Maryland School of Medicine. After earning his Ph.D. from Johns Hopkins University School of Medicine, Pittenger worked on mesenchymal stem cells (MSCs). He spent more than 10 years at Osiris Therapeutics, including more than two years as the firm's vice president of research. In 1999, he and his colleagues were the first group to provide strong data on the characterization of human mesenchymal stem cells and show their differentiation to multiple lineages. They later showed that the MSCs interact with different immune types of immune cells to down-modulate the inflammatory immune response. Much of his work was translational, performed for the purpose of using these adult stem cells in patients.
ddn: Describe your current stem-cell related work.
Deisher: My work is focused on non-invasive small molecules and biologics to block unintended stem cell sequestration, enabling significantly increased stem cell delivery and retention in target organs.
McErlane: I had a keen interest in the therapeutic potential of stem cells from a targeting perspective during my post-doctorate work with cytochrome P450-1B1 prodrugs, which was further developed during my project work with Genzyme working on a cell therapy initiative in new territories. I am delighted to be able to extend and build on this work at Sistemic, where by aiding the development of safe and effective cells for therapy, I believe the field can really begin to fulfill its immense potential. Recently, I was requested to write an editorial review for this quarter's European Biopharmaceutical Review focusing on the state of the cell therapy industry, and Sistemic's technology at the International Society for Stem Cell Research in Toronto and the Stem Cell Europe meeting in Edinburgh this year.
Pittenger: We are trying to improve the engraftment of stem cells, most notably in the infarcted heart. While the MSCs have multiple abilities that may be beneficial in tissue repair, the low early engraftment limits their potential. Any improvements we find for the engraftment of MSCs will likely be useful for other types of stem cells as well.
ddn: What types of cell lines do you use and why? How do you obtain them?
Deisher: We tend not to work with stem cell lines, although we do periodically work with culture-expanded mixed stem cell populations. We predominantly work with primary mononuclear cell fractions containing multiple stem cell types from bone marrow and whole blood, or with mixed stem cell populations including HSCs, MSCs and VSELs positively selected from mononuclear fractions from bone marrow and whole blood. Additionally, we work with culture-expanded mixed stem cells derived from mononuclear cell fractions from bone marrow and whole blood. We typically obtain fresh cells for each experiment since the types of mixed populations of adult stem cells described above are the stem cells that are bringing the most benefit to patients. This does necessitate long experimental days from start to finish, as the isolation procedures require four to six hours of work.
McErlane: The SistemQC approach we have developed is applicable to all cell types, so we work on somatic cells and also stem cells. Within stem cells, we have worked with iPSCs, hESCs and of course adult stem cells. We obtain cells from our collaborators and/or clients. Our collaborators and clients are a mixture of companies and academic institutions that are focused on using stem cells to develop therapeutics or to develop biologically relevant cell line models for drug discovery and development screening.
Pittenger: We isolate mesenchymal stem cells (MSCs) from bone marrow. They can be isolated by a minimally invasive procedure without sacrificing other healthy tissues, and their expansion in the lab yields millions to billions of stem cells. These MSCs have very reproducible characteristics and differentiate to multiple lineages. We harvest bone marrow from rats, pigs or sheep, and we can order the human bone marrow from commercial sources.
ddn: What are the advantages of using adult stem cells? Embryonic stem cells? Induced pluripotent stem cells?
Deisher: The advantages of using adult stem cells to treat patients, particularly using mixed stem cell populations within mononuclear cell fractions, are: 1) demonstrated effectiveness; 2) availability; 3) patient specificity; 4) lack of immune rejection; 5) affordability; and 6) safety.
Pluripotent stem cells, both embryonic and induced, provide advantages for basic research in the laboratory since they grow irrepressibly and provide ready source material that enhances scientific convenience.
Additionally, induced pluripotent stem cells provide the opportunity to study disease using patient- specific stem cell lines.
McErlane: The advantage of using embryonic stem cells over adult stem cells is their level of ability to differentiate into all cell types of the body due to their pluripotency. Adult stem cells are limited to differentiating into different cell types of their tissue of origin. Another advantage of using embryonic stem cells is that they can be grown easily in culture, in comparison to adult stem cells, which are rare in tissues, making the isolation and expansion of these cells challenging. Since it is likely that large numbers of cells will be required to produce cell therapies for patients, embryonic stem cells have the advantage due to their growth and volume characteristics.
An advantage of using adult stem cells over embryonic stem cells lies in the fact that there is a question of whether embryonic stem cells, once implanted, will cause rejection. Adult stem cells are thought to be less likely to cause rejection. For example, a patient supplying his or her own adult stem cells can be expanded in the laboratory and then re-introduced back to the patient, where the new cells would be unlikely to be rejected by the immune system as they originated in the patient. Not being at risk of immune rejection is a great advantage, as it abolishes the need for taking immunosuppressive drugs over the lifetime of the patient.
iPSCs and ESCs are very similar in many respects, and the comparison between adult and ESCs hold true for iPSCs also.
Pittenger: Adult mesenchymal stem cells have few ethical arguments against their use. They can be easily grown ex vivo, characterized in many ways and formulated for use in tissue repair therapies or limiting immune responses. They are normally found in the adult tissues that need repair, but in insufficient numbers. They have now been safely implanted in more than 1,500 patients. Although embryonic stem cells and iPSCs may provide stem cells for more cell types than MSCs, both form teratomas in vivo, and this problem needs to be carefully solved before they are likely to be safe for clinical therapies.
ddn: Are induced pluripotent stem cells a good alternative to human embryonic stem cells? Why or why not?
Deisher: Induced pluripotent stem cells are a superior choice over embryonic stem cells for studying disease development since they can be disease-specific.
McErlane: An advantage of iPSCs over ESCs is the fact that since the cells will be a near-identical match to the cell donor, rejection by the immune system is thought to be unlikely. A similar potential disadvantage of both iPSCs and ESCs is the fact that both cell lines have the ability to produce teratomas—unlike adult stem cells—and this is of major concern to the people working in the field, as at the end of the day, we all want to bring only effective and safe treatments to patients. The iPSC strategy creates pluripotent stem cells that, together with studies of other types of pluripotent stem cells, will help researchers learn how to reprogram cells to repair damaged tissues in the human body.
Pittenger: The iPSCs are a good alternative to ESCs and have many properties of ESCs, but producing them efficiently is still difficult. The iPSCs can be made without the need for integrating vectors, but the process is not optimal. The iPSCs may have limitations on their differentiation owing to their tissue of origin or the adult nature of the starting cells.
ddn: Scientifically speaking, what are the disadvantages or risks of using each of these types of cells?
Deisher: Pluripotent stem cells, including embryonic and induced pluripotent stem cells, form tumors by their very nature, and this tumor formation cannot be eliminated or removed completely either by cell culture differentiation or manufacturing techniques. Pluripotent stem cells also present economic risks as the price of these types of treatments, when they have been publicly estimated, are placed at just under $500,000 (according to a press release by Thomas Okarma, CEO of Geron Corp.).
Additionally, embryonic stem cell therapies present issues of immune rejection. Drugs to counter immune rejection themselves pose risks of diabetes, hypertension and osteoporosis.
In the United States, horses, dogs, cats and donkeys are being treated with adult stem cell treatments. For instance, instead of a $12,000 knee or hip replacement, dogs can receive $1,800 stem cell therapy with equivalent results. If one asked a veterinarian why they are not treating their animal patients with embryonic stem cells, they would tell you that embryonic stem cells are prohibitively expensive, and present dangers of tumor formation and immune rejection.
McErlane: There are some major differences between iPSCs and ESCs worth noting. The genetic manipulation at present that is required to produce iPSCs, and the long-term consequences of this manipulation after transplantation to the patient, is a big unanswered question of the moment. In addition, there are queries around iPSCs maintaining the genetic memory of their origin, and the long-term consequences have also yet to be understood.
Pittenger: Today, I would say that for adult stem cells such as MSCs, the largest disadvantage is the limited engraftment and their limited differentiation potential to certain lineages. For ESCs and iPSCs, the major disadvantage is the formation of teratomas, that is, the lack of control over their growth and differentiation.
ddn: What is your position on some of the current moral and ethical questions surrounding embryonic stem cell research? Has this debate impacted your work? If so, how?
Deisher: Science should never be removed from ethical and moral oversight. History has taught us this too many times for us to now believe that science is above morals and ethics. The Sherley vs. Sebelius lawsuit, of which I am a plaintiff, asks the courts to uphold the laws of Congress and the intent of Congress in passing the Dickey- Wicker Amendment each year since 1996.
McErlane: I personally believe that there are misconceptions surrounding the moral and ethical questions that surround hESC research, especially in the area that not all ESC research causes the destruction of embryos. In fact, there any many other research techniques available now to produce ESCs that do not harm or destroy the embryo, such as single cells from a blastocyst, dead embryos, non-embryo sources of stem cells created using altered nuclear transfer, parthenogenetic stem cells and germ-cell-derived stem cells. It is my belief that it is our job as scientists to educate the wider public on the alternate sources of ESCs, which I believe to some degree would dispel some of the currently popular beliefs held in this area.
Pittenger: I am not insensitive to the issues, but to me, the fertilized egg is not an individual, and in vivo, many embryos do not implant or develop. To me, the ethical and moral questions about undeveloped human embryos pale in comparison to the moral questions of life and death of children and adults everywhere. I believe any embryos that were created for in-vitro fertilization and are in freezers but unused eventually will be destroyed by letting them thaw and then discarding them. I would rather see this resource used for helping others.
ddn: How have these moral and ethical concerns impacted the overall progress of stem cell research?
Deisher: Adult stem cell clinical progress has been impeded in the United States because the polarizing moral debates have hijacked the discussion away from the true interests of patients. Objective analysis, regardless of one's views about the stage at which human life deserves protection, concludes that adult stem cells are the preferred stem cell to treat patients. Effectiveness, safety, availability and affordability criteria all place adult stem cells as the preferred stem cell therapy.
McErlane: These public concerns have impacted the overall progress of stem cell research in some countries more than others, and at the end of the day, it goes back to us educating the public about the types of cells we use, how they are generated and the potential of these types of treatments to improve and even cure patient diseases, as well as lessening the economic burden of healthcare on our economies.
Pittenger: Certainly, this topic has been debated broadly, and could be debated even if stem cells were very successful at repairing tissue and relieving pain and suffering. I think there are technical hurdles that have been difficult to overcome that have delayed progress more than the moral debate, but one never knows if the next dollar spent on the next experiment can solve the problem, and certainly there was a multi-year ban on ESC research.
ddn: How can those who are pro-embryonic stem cell research and anti- embryonic stem cell research find common ground? What discussions must we have?
Deisher: We can find common ground if we place the true interests of patients first and if we have full disclosure about present and future research intentions. If the real goal of embryonic stem cell research is human cloning, and this is not honestly disclosed, then many discussions are seriously hampered.
McErlane: It is all about basic communication, where everyone understands at a basic level the issues we are discussing. Perhaps as scientists, we need to become more adept at translating the theories in our laboratories out to the general public so there is a better understanding of what we do without misconceptions.
Pittenger: The moral and ethical issues may not be easily agreed upon, but there are many scientific questions that can be posed equally for adult and embryonic stem cells. Some of these questions are the practical issues, such as can the cells be grown to large numbers in reproducible manner to provide a well-characterized reliable source for tissue regeneration needs?
ddn: What should the government's role be in funding stem cell research (in any form), or legislating and regulating what types of stem cell research can be conducted?
Deisher: Stem cell research that involves the destruction of human embryos or that promotes human therapeutic or reproductive cloning is justifiably regulated by our elected officials, locally and federally, and by open public debate and votes of the people.
Pittenger: The government is deeply involved in healthcare and therapeutics at all levels: research, development, safety assessment, regulatory aspects, efficacy assessment and recommended best practice. The government should assure the safety of potential cell therapeutic products, and therefore needs to fund research at many different levels. Unfortunately, the government often operates as a non-scientific, political body that reflects views of politicians, rather than scientists and doctors trying to improve healthcare.
ddn: To what extent has the controversy associated with human embryonic stem cell research impacted the public's understanding of science? How can we improve this understanding?
Deisher: As Dr. Art Caplan, an embryonic stem cell proponent, stated in December 2010, "Embryonic stem cell research was completely overhyped, in terms of its promise. And people knew it at the time. I tried to say so myself at different times myself, even though I support embryonic stem cell research. But this notion that people would be out of their wheelchairs within a year if we could just get embryonic stemcell research funded was just ludicrous. Just simply silly. Yes, those saying it had to know it at the time. The scientists had to have known that."
The public's understanding of science might be improved by clearer and more truthful statements from scientists, and by less biased coverage of science by the media, which at times reaches the level of untruthful reporting.
Pittenger: The public's interest in science is very important to assure funding of research and development. Controversy in science leads to more available information on both sides of the arguments, and individuals will then need to become better informed and make their own decisions. Clear, concise information from reliable sources needs to be available.
ddn: In your view, what is the biggest misconception about stem cell research, and what can be done to change that misconception?
Deisher: The biggest misconception is that pluripotent stem cells (which includes both embryonic and induced pluripotent stem cells) are the magic potion for patient therapy. Stem cell treatments to date that have helped patients have all used adult stem cells, predominantly mononuclear stem cell fractions taken from various sources within the patients themselves. Pluripotent stem cells are fraught with safety problems and are years behind adult stem cells, and they may never help patients because of their safety problems.
This misconception will be changed when media and other agents that disseminate stem cell news correctly and truthfully identify the source of the positive stem cell results they are reporting as adult stem cells. Unfortunately, when the news covers stem cell success stories, the word adult is commonly dropped, leading the public to think that the progress was made with embryonic stem cells—when in fact, embryonic stem cells have not helped anyone. Accurate reporting is not too much to ask of the media, particularly as patients' lives and health are at stake.
Pittenger: I think the first misconception is that it is a long way off; it's not, at least not in every field. The second misconception is that success in applying stem cells to health issues will be "all- curing"—it will not. Rather, it will be another powerful tool for treating a variety of health problems.
ALSO FROM OUR AUGUST ISSUE SPECIAL REPORT:
Root to stem
In new survey, we try to get to the bottom of perceptions on stem cells and other R&D efforts
By Jeffrey Bouley, ddn Managing Editor
Editorial: Embryonic stem cell research: A Dickey-Wicker of a situation
Isn't it about time Congress revisited what is essentially an afterthought on a 15-year-old appropriations bill, clearly articulated the facts and concerns about hESC research and put forth a specific policy on the matter?
By Amy Swinderman, ddn Chief Editor
To view all of the content from our three-part series on stem cell research, click here.