factor in these cases is how much legitimate promise the treatment offers, versus the cost in human suffering. Again, potential systemic failures during early research into iASC has led some to be concerned that the efficacy of stem cell therapy may be overstated and improperly coercive to patients facing terminal illnesses.
Efficacy of iASC Therapies
Because stem cell therapies of all types are still in their infancy, it is difficult to ascertain a statistical basis for efficacy. In vitro (laboratory) tests and animal studies have shown great promise for both embryonic stems cell (ESC)- and iPSC-based therapies; however, this promise often fails to materialize when transitioned to human studies. Speculation about differences between controlled and uncontrolled manifestations of illness, age, and compliance of participants, and environmental factors are being examined to explain these discrepancies.
The trend in current literature seems to be that while stem cell therapies occasionally show statistically significant improvements in patient pathology, the benefit is often clinically insignificant (not powerful enough to elicit a noticeable improvement for the patient). This is scientifically encouraging but emphasizes ethical questions such as whether the patient benefit warrants the risks—especially considering that patients may bypass traditional therapies to participate in a study. There is the added conundrum that information about the efficacy of stem cell therapies will not be available until more clinical trials are performed.
When deciding whether to participate in an experimental treatment, patient and doctor must together determine if the study serves the patient’s best interests. This requires realistic analysis of risk to benefit, and some are concerned this analysis is not presently feasible due to undue scientific and media excitement over early SCT trials that may have been “over-hyped.” Of particular concern in critics’ eyes is what has come to be called the Bezwoda fraud. In the early 1990s, Werner Bezwoda of the University of the Witwatersrand, South Africa, conducted research using iASC in the treatment of breast cancer. His results were strongly positive, lighting a firestorm in the media and leading to heavy legislation to encourage SCT in the United States and elsewhere.
In 2000 it was discovered that Bezwoda had falsified much of his data. Some ethicists believe the lingering excitement and residual legislation his research spawned creates a false sense of efficacy for SCT, while others feel the scandal broke trust between patient and researcher, making it difficult to find enrollees for new studies. Ironically, both could lead to ethical concerns as pressures mount to fill studies and inadvertently making rational decisions about risk to benefit difficult.
Safety in iASC Therapies
Due to the relative newness of stem cell therapies, safety information is difficult to come by. Challenges by study coordinators on how to best assess benefit and harm have led to problems with statistical meta-analyses (comparisons of one study to another). Participants in all clinical trials endure increased risk with the hope of it being outweighed by benefit; however, iASC (and stem cell therapies in general) may be particularly risky due to the inherent manner in which stem cells function.
Tumorigenesis
The most readily identified potential for harm with SCT is that of tumorigenesis (secondary cancerous growths), since the cell’s inherent “stemness” is directly related to oncogenes such as cMyc, Rb, and ARF. In fact, a cell’s potential for tumorigenesis in the lab correlates directly to the cell’s stem viability ranking. While some consider it definitively impossible to separate the stem and tumorigenic character of iASC, there has been success in creating less tumor-prone mesenchymal stem cells as well as inducing adult stems cells after removal of the volatile oncogenes. Nonetheless, the possibility of secondary neoplasts remains significant. Theory suggests that iPSC/iASC might have a lesser tendency for tumor formation than embryonic stems cells; however, studies to date show both to be at roughly equal risk.
The most common tumors formed are teratomas, a generally benign encapsulated tumor resembling a normal derivative germ layer. Because teratomas are benign, risk can be mitigated based on transplant location, that is, tumor growth in cartilage is significantly less concerning than tumor growth in the central nervous system (CNS). However, recognized deaths resulting from SCT tumorigenesis have been documented, though it is unclear whether there is a generally increased mortality risk in SCT compared to other studies. Two famous cases involving the death of three Filipino legislators (treated out-of-country) and an infant treated at a private German clinic have drawn publicity to this concern; however, definitive evidence linking the congressmen’s deaths to SCT has not yet been found and the baby’s death was due to internal hemorrhaging from the procedure. The widespread proliferation of unapproved, medically unsupervised SCT may be skewing this data.
Genetic Mutation
Another risk specific to iASC therapy is genetic mutation or contamination. A benefit of using pluripotent iASC is the dramatically reduced incidence of adverse immune reaction; however, using an adult patient’s own cells also increases the risk that the aged cells contain activated oncogenes or other naturally occurring deleterious mutations. As these cells proliferate, the mutations are carried into progeny cells and the newly formed tissues.
In addition to natural genetic changes, contamination by the lab or hosting environment (in the case of SCNT or animal hosts) can lead to genetic contamination. Animal proteins in culture or animal hosts can contain viruses, which may incorporate into the cells ultimately transplanted. It is estimated that up to 30 percent of polio vaccine given in the late 1950s was contaminated by simian virus 40, a theretofore unknown virus found in the monkey kidney used for culturing the vaccine and which has since been associated with human cancers. It is important to note that although it can be difficult to monitor for unknown pathogens and contaminants, the modern laboratory protocols surrounding both research and tissue culture for implantation is far more rigorous than it was then.
Infertility
There has been some concern about infertility as a result of stem cell therapies. While this has been seen as an adverse event in studies, it appears to be the result of associated chemotherapies in conjunction with a cancer treatment, during “participant conditioning” prior to cell implantation, or from the subsequent immunosuppression. Since it appears not to be from the SCT itself, further discussion is not appropriate in this article.
Financial Considerations
An ethical consideration for all clinical trials is the financial well-being of participants. Individuals suffering from significant medical conditions are a “vulnerable population,” many of whom are willing to entertain even the most outlier treatments for the hope of returning to a normal life. Many insurances do not cover the experimental treatments of clinical trials, or will only cover them when other traditional treatment options are foregone. Clinical trials do frequently offer free or reduced-price treatments; however, costs can still place a significant burden on patients and their families. These factors must again be included in the risk/benefit analysis by patients as there is a tendency to underestimate costs, especially for innovative new procedures.
Commercialization of stem cells, stem cell processes, and SCT can add to both the financial burden of patients and their access to treatment. U.S. law allows for the patenting of both laboratory processes and stem cell lines, enabling patent holders to control who may use the products and at what expense. While it is arguably in their financial interest to allow patented items to be used in clinical trials (and thus advancing potential commercial use), this is entirely up to the patent owner and is not mandated. Prices resulting from companies hoping to recoup development expenses can make the cost of participation in trials prohibitory.
