ddn Editorial Roundtable: Ethics and stem cell research

Researchers discuss the ethical, moral and scientific concerns associated with stem cell research

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Since the first derivation of embryonic stem cells (ESCs) in mice in1981 and subsequent discoveries involving human ESCs (hESCs), this form of stemcell 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 thatimportant medical discoveries continue to progress, the last three Americanpresidents and their government colleagues have set policies impacting ESCresearch in various ways. Where ambiguity exists in this debate on a federallevel, some states have drawn a clear line in the sand about which forms ofstem cell research may be conducted and publicly funded. And while legislatorsmay lack the appetite to tackle this debate, plaintiffs in lawsuits filed atevery court level are seeking the last word on the use of embryos in stem cellresearch.
 
In this, the second installment of our three-part series on trends instem cell research, we brought together three individuals engaged in variousforms of stem cell-related research to discuss some of the controversiessurrounding this burgeoning scientific field. Their views on the use ofdifferent types of stem cells, the promise they hold for patients and some ofthe public concerns about them are diverse and insightful.
 
Participating in this roundtable discussion were the followingresearchers:
 
 
Dr. TheresaDeisher, founder, CEO and chief scientific officer of AVM Biotechnology, aSeattle-based company "dedicated to the discovery, development andcommercialization of safe, effective and affordable pro-life medicines." Afterearning her Ph.D. in molecular and cellular physiology from Stanford Universityin 1990, Deisher went on to discover adult pluripotent stem cells isolated fromthe heart, which she patented and assigned to ZymoGenetics in 1998, six monthsbefore Jamie Thompson patented the first human embryonic stem cell lines. Shealso discovered FGF18 (which she also patented and assigned to ZymoGenetics), avery potent mesenchymal stem cell growth factor currently in clinical trialsfor osteoarthritis and cartilage repair. Deisher also derived embryoid-bodylike structures from umbilical cord blood, a discovery which she patented andassigned 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. VernaMcErlane, 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. inpreclinical cancer drug development and spent time working at the Gray CancerInstitute in London, where she was involved with the formation of SPEARTherapeutics Ltd. prior to moving to the University of Dundee, Scotland topursue evaluation of prodrug anticancer strategies. Subsequently, she waschosen to take part in the Saltire Foundation fellowship program and moved toBoston and attended Babson College before working with Genzyme on its newbusiness initiatives. She also held an international market developmentposition with Axis-Shield in Dundee, Scotland. McErlane was the recipient ofthe Galen Pharmaceutical Prize in 1999.
 
Dr. MarkPittenger, CEO and chief scientific officer of Pearl Lifescience Partners LLC, afirm in Baltimore, Md., that develops vaccines against infectious envelopedviruses using bioengineered cell lines. Pittenger is also a consultant to theDepartment of Surgery in the Division of Cardiac Surgery at the University ofMaryland School of Medicine. After earning his Ph.D. from Johns HopkinsUniversity School of Medicine, Pittenger worked on mesenchymal stem cells(MSCs). He spent more than 10 years at Osiris Therapeutics, including more thantwo years as the firm's vice president of research. In 1999, he and hiscolleagues were the first group to provide strong data on the characterizationof human mesenchymal stem cells and show their differentiation to multiplelineages. They later showed that the MSCs interact with different immune typesof immune cells to down-modulate the inflammatory immune response. Much of hiswork was translational, performed for the purpose of using these adult stemcells in patients.
 
 
 

 
ddn: Describe your current stem-cell related work.
 
 
Deisher: My work isfocused on non-invasive small molecules and biologics to block unintended stemcell sequestration, enabling significantly increased stem cell delivery andretention in target organs.
 
 
McErlane: I had a keeninterest in the therapeutic potential of stem cells from a targetingperspective during my post-doctorate work with cytochrome P450-1B1 prodrugs,which was further developed during my project work with Genzyme working on acell therapy initiative in new territories. I am delighted to be able to extendand build on this work at Sistemic, where by aiding the development of safe andeffective cells for therapy, I believe the field can really begin to fulfillits immense potential. Recently, I was requested to write an editorial reviewfor this quarter's EuropeanBiopharmaceutical Review focusing on the state of the cell therapyindustry, and Sistemic's technology at the International Society for Stem CellResearch in Toronto and the Stem Cell Europe meeting in Edinburgh this year.
 
Pittenger: We aretrying to improve the engraftment of stem cells, most notably in the infarctedheart. While the MSCs have multiple abilities that may be beneficial in tissuerepair, the low early engraftment limits their potential. Any improvements wefind for the engraftment of MSCs will likely be useful for other types of stemcells as well.
 
 
 

 

ddn: What types of cell lines do you use and why? Howdo you obtain them?
 
Deisher: We tend notto work with stem cell lines, although we do periodically work with culture-expandedmixed stem cell populations. We predominantly work with primary mononuclearcell fractions containing multiple stem cell types from bone marrow and wholeblood, or with mixed stem cell populations including HSCs, MSCs and VSELspositively selected from mononuclear fractions from bone marrow and wholeblood. Additionally, we work with culture-expanded mixed stem cells derivedfrom mononuclear cell fractions from bone marrow and whole blood. We typicallyobtain fresh cells for each experiment since the types of mixed populations ofadult stem cells described above are the stem cells that are bringing the mostbenefit to patients. This does necessitate long experimental days from start tofinish, as the isolation procedures require four to six hours of work.
 
McErlane: The SistemQCapproach we have developed is applicable to all cell types, so we work onsomatic cells and also stem cells. Within stem cells, we have worked withiPSCs, hESCs and of course adult stem cells. We obtain cells from our collaboratorsand/or clients. Our collaborators and clients are a mixture of companies andacademic institutions that are focused on using stem cells to developtherapeutics or to develop biologically relevant cell line models for drugdiscovery and development screening.
 
Pittenger: We isolatemesenchymal stem cells (MSCs) from bone marrow. They can be isolated by aminimally invasive procedure without sacrificing other healthy tissues, andtheir expansion in the lab yields millions to billions of stem cells. TheseMSCs have very reproducible characteristics and differentiate to multiplelineages. We harvest bone marrow from rats, pigs or sheep, and we can order thehuman bone marrow from commercial sources.
 
 

 
ddn: What are the advantages of using adult stemcells? Embryonic stem cells? Induced pluripotent stem cells?
 
Deisher: Theadvantages of using adult stem cells to treat patients, particularly usingmixed stem cell populations within mononuclear cell fractions, are: 1)demonstrated effectiveness; 2) availability; 3) patient specificity; 4) lack ofimmune rejection; 5) affordability; and 6) safety.
 
Pluripotent stem cells, both embryonic and induced, provide advantagesfor basic research in the laboratory since they grow irrepressibly and provideready source material that enhances scientific convenience.
 
Additionally, induced pluripotent stem cells provide the opportunity tostudy disease using patient-specific stem cell lines.
 
McErlane: Theadvantage of using embryonic stem cells over adult stem cells is their level ofability to differentiate into all cell types of the body due to theirpluripotency. Adult stem cells are limited to differentiating into differentcell types of their tissue of origin. Another advantage of using embryonic stemcells is that they can be grown easily in culture, in comparison to adult stemcells, which are rare in tissues, making the isolation and expansion of thesecells challenging. Since it is likely that large numbers of cells will berequired to produce cell therapies for patients, embryonic stem cells have theadvantage due to their growth and volume characteristics.
 
An advantage of using adult stem cells over embryonic stem cells liesin the fact that there is a question of whether embryonic stem cells, onceimplanted, will cause rejection. Adult stem cells are thought to be less likelyto cause rejection. For example, a patient supplying his or her own adult stemcells can be expanded in the laboratory and then re-introduced back to thepatient, where the new cells would be unlikely to be rejected by the immunesystem as they originated in the patient. Not being at risk of immune rejectionis a great advantage, as it abolishes the need for taking immunosuppressivedrugs over the lifetime of the patient.
 
 
iPSCs and ESCs are very similar in many respects, and the comparisonbetween adult and ESCs hold true for iPSCs also.
 
Pittenger: Adultmesenchymal stem cells have few ethical arguments against their use. They canbe easily grown ex vivo,characterized in many ways and formulated for use in tissue repair therapies orlimiting immune responses. They are normally found in the adult tissues thatneed repair, but in insufficient numbers. They have now been safely implantedin more than 1,500 patients. Although embryonic stem cells and iPSCs may providestem cells for more cell types than MSCs, both form teratomas in vivo, and this problem needs to becarefully solved before they are likely to be safe for clinical therapies.
 
 

 
ddn: Are induced pluripotent stem cells a goodalternative to human embryonic stem cells? Why or why not?
 
 
Deisher: Inducedpluripotent stem cells are a superior choice over embryonic stem cells forstudying disease development since they can be disease-specific.
 
 
McErlane: An advantageof iPSCs over ESCs is the fact that since the cells will be a near-identicalmatch to the cell donor, rejection by the immune system is thought to beunlikely. A similar potential disadvantage of both iPSCs and ESCs is the factthat both cell lines have the ability to produce teratomas—unlike adult stemcells—and this is of major concern to the people working in the field, as atthe end of the day, we all want to bring only effective and safe treatments topatients. The iPSC strategy creates pluripotent stem cells that, together withstudies of other types of pluripotent stem cells, will help researchers learnhow to reprogram cells to repair damaged tissues in the human body.
 
 
Pittenger: The iPSCsare a good alternative to ESCs and have many properties of ESCs, but producingthem efficiently is still difficult. The iPSCs can be made without the need forintegrating vectors, but the process is not optimal. The iPSCs may havelimitations on their differentiation owing to their tissue of origin or theadult nature of the starting cells.
 

 
ddn: Scientifically speaking, what are thedisadvantages or risks of using each of these types of cells?
 
 
Deisher: Pluripotentstem cells, including embryonic and induced pluripotent stem cells, form tumorsby their very nature, and this tumor formation cannot be eliminated or removedcompletely either by cell culture differentiation or manufacturing techniques.Pluripotent stem cells also present economic risks as the price of these typesof 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 treatedwith adult stem cell treatments. For instance, instead of a $12,000 knee or hipreplacement, dogs can receive $1,800 stem cell therapy with equivalent results.If one asked a veterinarian why they are not treating their animal patientswith embryonic stem cells, they would tell you that embryonic stem cells areprohibitively expensive, and present dangers of tumor formation and immunerejection.
 
McErlane: There aresome major differences between iPSCs and ESCs worth noting. The geneticmanipulation at present that is required to produce iPSCs, and the long-termconsequences of this manipulation after transplantation to the patient, is abig unanswered question of the moment. In addition, there are queries aroundiPSCs maintaining the genetic memory of their origin, and the long-termconsequences have also yet to be understood.
 
 
Pittenger: Today, Iwould say that for adult stem cells such as MSCs, the largest disadvantage isthe limited engraftment and their limited differentiation potential to certainlineages. 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 currentmoral and ethical questions surrounding embryonic stem cell research? Has thisdebate impacted your work? If so, how? 
 
Deisher: Scienceshould never be removed from ethical and moral oversight. History has taught usthis too many times for us to now believe that science is above morals andethics. The Sherley vs. Sebeliuslawsuit, of which I am a plaintiff, asks the courts to uphold the laws ofCongress and the intent of Congress in passing the Dickey-Wicker Amendment eachyear since 1996.
 
McErlane: I personallybelieve that there are misconceptions surrounding the moral and ethicalquestions that surround hESC research, especially in the area that not all ESCresearch causes the destruction of embryos. In fact, there any many otherresearch techniques available now to produce ESCs that do not harm or destroythe embryo, such as single cells from a blastocyst, dead embryos, non-embryo sourcesof stem cells created using altered nuclear transfer, parthenogenetic stemcells and germ-cell-derived stem cells. It is my belief that it is our job asscientists to educate the wider public on the alternate sources of ESCs, whichI believe to some degree would dispel some of the currently popular beliefsheld in this area.
 
Pittenger: I am notinsensitive to the issues, but to me, the fertilized egg is not an individual,and in vivo, many embryos do notimplant or develop. To me, the ethical and moral questions about undevelopedhuman embryos pale in comparison to the moral questions of life and death ofchildren and adults everywhere. I believe any embryos that were created for in-vitro fertilization and are infreezers but unused eventually will be destroyed by letting them thaw and thendiscarding them. I would rather see this resource used for helping others.
 

 
ddn: How have these moral and ethical concernsimpacted the overall progress of stem cell research?
 
 
Deisher: Adult stemcell clinical progress has been impeded in the United States because thepolarizing moral debates have hijacked the discussion away from the trueinterests of patients. Objective analysis, regardless of one's views about thestage at which human life deserves protection, concludes that adult stem cellsare the preferred stem cell to treat patients. Effectiveness, safety,availability and affordability criteria all place adult stem cells as thepreferred stem cell therapy.
 
 
McErlane: These publicconcerns have impacted the overall progress of stem cell research in somecountries more than others, and at the end of the day, it goes back to useducating the public about the types of cells we use, how they are generatedand the potential of these types of treatments to improve and even cure patientdiseases, as well as lessening the economic burden of healthcare on oureconomies.
 
Pittenger: Certainly,this topic has been debated broadly, and could be debated even if stem cells werevery successful at repairing tissue and relieving pain and suffering. I thinkthere are technical hurdles that have been difficult to overcome that havedelayed progress more than the moral debate, but one never knows if the nextdollar spent on the next experiment can solve the problem, and certainly therewas a multi-year ban on ESC research.
 
 

 
ddn: How can those who are pro-embryonic stem cellresearch and anti-embryonic stem cell research find common ground? Whatdiscussions must we have?
 
Deisher: We can findcommon ground if we place the true interests of patients first and if we havefull disclosure about present and future research intentions. If the real goalof embryonic stem cell research is human cloning, and this is not honestlydisclosed, then many discussions are seriously hampered.
 
 
McErlane: It is allabout basic communication, where everyone understands at a basic level theissues we are discussing. Perhaps as scientists, we need to become more adeptat translating the theories in our laboratories out to the general public sothere is a better understanding of what we do without misconceptions. 
 
Pittenger: The moraland ethical issues may not be easily agreed upon, but there are many scientificquestions that can be posed equally for adult and embryonic stem cells. Some ofthese questions are the practical issues, such as can the cells be grown tolarge numbers in reproducible manner to provide a well-characterized reliablesource for tissue regeneration needs?
 

 
ddn: What should the government's role be in fundingstem cell research (in any form), or legislating and regulating what types ofstem cell research can be conducted?
 
 
Deisher: Stem cellresearch that involves the destruction of human embryos or that promotes humantherapeutic or reproductive cloning is justifiably regulated by our electedofficials, locally and federally, and by open public debate and votes of thepeople.
 
 
Pittenger: Thegovernment is deeply involved in healthcare and therapeutics at all levels:research, development, safety assessment, regulatory aspects, efficacyassessment and recommended best practice. The government should assure thesafety of potential cell therapeutic products, and therefore needs to fundresearch at many different levels. Unfortunately, the government often operatesas a non-scientific, political body that reflects views of politicians, ratherthan scientists and doctors trying to improve healthcare.
 

 
ddn: To what extent has the controversy associatedwith human embryonic stem cell research impacted the public's understanding ofscience? How can we improve this understanding?
 
 
Deisher: As Dr. ArtCaplan, an embryonic stem cell proponent, stated in December 2010, "Embryonicstem cell researchwas completely overhyped, in terms of its promise. And people knew it at thetime. I tried to say so myself at different times myself, even though I supportembryonic stem cellresearch. But this notion that people would be out of their wheelchairs withina year if we could just get embryonic stemcellresearch funded was just ludicrous. Just simply silly. Yes, those saying it hadto know it at the time. The scientists had to have known that."
 
 
The public's understanding of science might be improved by clearer andmore truthful statements from scientists, and by less biased coverage ofscience by the media, which at times reaches the level of untruthful reporting.
 
 
Pittenger: The public'sinterest in science is very important to assure funding of research anddevelopment. Controversy in science leads to more available information on bothsides of the arguments, and individuals will then need to become betterinformed and make their own decisions. Clear, concise information from reliablesources needs to be available.
 
 

 
ddn: In your view, what is the biggest misconceptionabout stem cell research, and what can be done to change that misconception?
 
 
Deisher: The biggestmisconception is that pluripotent stem cells (which includes both embryonic andinduced pluripotent stem cells) are the magic potion for patient therapy. Stemcell treatments to date that have helped patients have all used adult stemcells, predominantly mononuclear stem cell fractions taken from various sourceswithin the patients themselves. Pluripotent stem cells are fraught with safetyproblems and are years behind adult stem cells, and they may never helppatients because of their safety problems.
 
 
This misconception will be changed when media and other agents thatdisseminate stem cell news correctly and truthfully identify the source of thepositive stem cell results they are reporting as adult stem cells. Unfortunately, when the news covers stem cellsuccess stories, the word adult iscommonly dropped, leading the public to think that the progress was made withembryonic stem cells—when in fact, embryonic stem cells have not helped anyone.Accurate reporting is not too much to ask of the media, particularly aspatients' lives and health are at stake.
 
 
Pittenger: I think thefirst misconception is that it is a long way off; it's not, at least not inevery field. The second misconception is that success in applying stem cells tohealth issues will be "all-curing"—it will not. Rather, it will be another powerfultool for treating a variety of health problems.



ALSO FROM OURAUGUST ISSUE SPECIAL REPORT:
 
Root to stem

In new survey, we try to get to the bottom of perceptions on stem cellsand 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 anafterthought on a 15-year-old appropriations bill, clearly articulated thefacts and concerns about hESC research and put forth a specific policy on thematter?

By Amy Swinderman, ddn Chief Editor
 


To view all of the content from our three-part series on stem cellresearch, click here.

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