January 27, 2014 | Posted By Michael McNichol and Zubin Master, PhD

Since the discovery of human embryonic stem cells in 1998, many promises have been made by individuals and groups about the potential of stem cell research to revolutionize the practice of regenerative medicine. Yet to date, very little has been seen in terms of novel therapies in the clinic. Because of the substantive economic investments made in stem cell research in order to realize the promise they can offer, greater efforts to translate stem cell research into medicines has ensued. However, many factors might impede the clinical translation of stem cell research. In this blog, we briefly highlight the ethical and scientific issues surrounding the successful translation and commercialization of stem cell research.

The process of clinical translation begins with preclinical research using in vitro systems and animal models to show proof-of-principle and demonstrate safety and efficacy of a potential therapeutic. For example, if a stem cell is to be transplanted into a patient to treat a degenerative disease, then the type of stem cell that is being used must show that it can successfully treat a similar disease in animals prior to testing the product in humans. There are many reasons for using appropriate animal models that mimic human diseases: low cost, reproductive cycle, number of offspring, genetic similarity, similarity in the manifestation of the disease in humans, and ease of handling. However, there are many limitations to animal models that do not result in direct translation in humans, meaning what may work in animals may not at the end of the day be effective in people. While we choose animals as models to mimic human disease, the biology of animals is still significantly different than humans and thus may simply not translate 100%. This issue is difficult to get around. Typically, rodent models (mouse and rat) are used in biomedical science experiments to mimic human disease. The International Society for Stem Cell Research notes that rodents used in stem cell research may not necessarily translate successfully in humans. Some suggest that the use of more evolved animal models would be better for preclinical studies, but using mammals such as non-human primates poses a series of issues including ethical issues of animal research, higher costs, and reduced number of offspring. Moreover, there is no guarantee that studies done in non-human primates are likely to tell us any better whether the intervention will work in humans.

Yet despite the biological differences between rodents and humans, some of the issues to successful translation have to do with the design and appropriate methodology used in preclinical research. Several studies have shown that researchers are not randomizing animals, have low or inappropriate sample sizes, and use inappropriate or underpowered statistics that might result in false positive results where researchers observe an effect that is not truly there. Statistical power is the ability of a study to determine an effect when one truly exists. Many factors affect the power of a study, including the sample size, effect size, variance of the sample population, and the threshold for statistical significance. It has been shown that the mean statistical power of any given animal study is between 18 and 31%. Moreover, selective reporting contributes to the positive publication bias that is well-documented in biomedical science. Here, researchers might publish only positive results and underreport negative ones creating a bias into the effectiveness of certain stem cell research studies. Given reports of the increased pressure on researchers to translate science, this might contribute to the positive publication bias. To circumvent these issues, some have argued that journals should adopt animal research reporting guidelines similar to ones used for clinical studies using humans to ensure that scientists are performing and reporting experiments appropriately.

A second scientific issue affecting the translation and commercialization of stem cell research is noted by the term “valley of death.” The valley of death is the phase(s) between preclinical science research (predominantly NIH funded occurring in colleges and universities) and translation into clinical research to test effectiveness (generally performed by industry). The valley of death can be thought of as the phase after showing proof-of-principle in preclinical research and before phase 2 clinical trials where scientists begin to test the effectiveness of a therapy in humans. The valley of death notes the failure of research to effectively translate into humans. Many scholars have outlined a range of factors that contribute to the valley of death including gaps in research funding, training clinical scientists, partnering academia with industry, and the differences in reward system in the ethos of science between academia and industry. It remains unclear if measures to circumvent any of these issues that contribute to the valley of death will solve the problems as they relate to translational stem cell research.

A third issue that could hamper successful translation of stem cell research relates to public perception studies on science done with a commercial agenda. Several social science studies have shown that patients and the general public trust research done in the public sphere (e.g., publically funded universities and colleges), and are less trustworthy of research performed in private and commercial institutions e.g., pharmaceutical or biotech industry. While these same studies also indicate that the public is more than willing to participate in stem cell research by donating tissues, some still don’t like the idea of a company making profit and the volunteers not seeing any direct benefit from their participation in research. This might mean that for stem cell research (e.g., the donation of cells to create induced pluripotent stem cell), people might be more hesitant to donate if they know the researchers will commercialize the stem cell products. Certainly methods to increase transparency and inform the public are likely to help foster trust and increase participation.

We previously mentioned that researchers report that they feel an increase in the pressure to translate and commercialize science. Scholars have reported that an ethos of translation and commercialization may cause researchers to cut corners, underreport negative or conflicting data, exaggerate positive findings, delay publication to satisfy possible patenting and commercialization interests, and possibly limit the free and open sharing of data and reagents. While there is no clear correlation that a translational ethos means that the science is of poorer quality or faulty, or that scientists perform research with less integrity, the pressure to translate may negatively impact research integrity.

A final issue that plays on the hype about the promises of therapies from stem cell research is regarding stem cell tourism – a form of premature translation where clinics around the world offer stem cell interventions as bonafide therapies where there is no data or testing of safety and efficacy of the intervention. Several reports have been shown that patients receiving unproven stem cell interventions get cancers, lesions, tremors and some have died. Because the public expects stem cell therapies to be present here and now and might not know the difference between legitimate stem cell research and fraudulent therapies, if several tragedies continue to result and receive negative press, it might create distrust in legitimate stem cell research. The distrust could result in the loss of support for stem cell research and a decrease in the participation of patients as subjects for clinical trials. Thus the practice by some unscrupulous physicians and researchers to offer unproven stem cell interventions for financial gain may harm legitimate stem cell research and also impede successful translation.

Translating stem cell research into effective treatments is a long process and we are still in early phases of clinical research while much of stem cell research is still done preclinically. Several scientific and ethical issues could slow down the successful translation of stem cell research. Many scholars recognize these limitations and several proposals are being implemented to circumvent these limits in order to get translate stem cell research.

The Alden March Bioethics Institute offers a Master of Science in Bioethics, a Doctorate of Professional Studies in Bioethics, and Graduate Certificates in Clinical Ethics and Clinical Ethics Consultation. For more information on AMBI's online graduate programs, please visit our website.

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BIOETHICS TODAY is the blog of the Alden March Bioethics Institute, presenting topical and timely commentary on issues, trends, and breaking news in the broad arena of bioethics. BIOETHICS TODAY presents interviews, opinion pieces, and ongoing articles on health care policy, end-of-life decision making, emerging issues in genetics and genomics, procreative liberty and reproductive health, ethics in clinical trials, medicine and the media, distributive justice and health care delivery in developing nations, and the intersection of environmental conservation and bioethics.