Does the possibility of regenerating your diseased body tissues intrigue you? Do you think it is worth exploring the use of healthy parent cells of your own body or of a suitable donor, to rebuild your ailing organs? Is your attention captivated by the proposition of not merely managing a disease through drugs, but curing it by regenerating lost normal function and biological structure?
If yes, then “stem cell therapy” could be a panacea to your medical problems. Stem cell therapy is indeed a bright ray of hope emerging from the horizon of regenerative medicine. It offers medical promise to patients suffering from a host of diseases that are difficult to cure or manage, particularly in their advanced stages.
Diabetes, myocardial injury, Parkinsonism, neurological disturbances, muscular disorders, neoplasms and malignancies, orthopaedic injuries, autoimmune hypersensitive reactions, infertility, baldness, dental disorders and spinal cord injury are a few indications wherein stem cell therapy has been investigated with positive outcomes. However, these are just a handful of conditions wherein stem cell therapy has been studied or applied. Its clinical scope extends far beyond these indications.
Stem cell therapy vs pharmacological and surgical interventions
The growing acceptance of stem cell therapy within the fraternities of medicine and research, inculcates an inquisition to understand the clinical advantage that stem cell therapy provides, as compared with other routine treatment modalities. Routine pharmacological interventions may achieve symptomatic amelioration of disease and often fail to address the underlying pathological process at a cellular level. Surgical interventions too, involve excision of the diseased tissue which often compromises the overall organ function post surgery.
In stark comparison, stem cell therapy is not merely about abating symptoms or severing affected tissues. It takes the concept of medical cure a step ahead by regenerating the functional cells damaged by disease and targets restoration of the lost normal structure and function. This mechanism of action is perhaps the most cardinal unique selling point of stem cell therapy that singularizes it from its other therapeutic counterparts. Given this backdrop, it is not surprising that in the past decade, there has been an exponential rise in the number of clinical studies involving stem cell therapy, across the globe. On www.clinicaltrials.gov alone, merely 70 stem cell based studies were registered between 1990 and 2000. However, in the past decade, i.e. from the year 2000 to 2010, this number has got escalated to a whopping 1286 studies!!
The roadblocks
However, history stands testimony to the fact that scientific advancements have often been in conflict with socio religious ideologies; stem cell therapy not being an exception. Several social and religious groups have objected to the propagation of stem cell therapy as a mode of treatment.
The religious view point presented against stem cell therapy is that the power and authority to recreate tissues and cells rests with the divine. If human mortals make any such attempt, religious fundamentalists consider it to be transgression of divine authority and blasphemy. Also, since human embryos are commonly used for isolating stem cells, several social groups across the globe object to this on grounds that destruction of a human embryo for stem cell research can be equated to loss of life and thus should be upheld as a heinous crime. On the other hand, research enthusiasts have vehemently counter argued that the intention of stem cell research is neither to overrule the divine nor to indiscriminately use human embryos.
Stem cell research aims at opening up new vistas for treating teeming millions of ailing lives across the globe. Nevertheless, the rebuttal between socio-religious fundamentalists and stem cell researchers is ongoing even today and these two lobbies continue to be at loggerheads with each other. In addition to socio-religious dogmatism, stem cell research has been grappled with clinical safety concerns pertaining to antigenicity, mutagenicity, hypersensitivity, teratogenicity, carcinogenicity and genotoxocity. However, several scientific experiments have shown that under various clinical settings, the benefits of stem cell therapy far outweigh its risks. Researchers the world over are striving relentlessly to further minimize the known adverse effects of stem cell treatment so that it gains a wider acceptance within the global community of patients and clinicians.
Regulatory landscape: A bird’s eye view
Given the backdrop of these socio-religious and clinical concerns; stem cell research has come under the scanner of stringent regulatory oversight. Regulators in different parts of the world have thus set up separate divisions, committees and guidelines for conducting stem cell research. The US-FDA’s Centre for Biologics Evaluation and Research regulates stem cell research as per 21 CFR part 1270 and 1271 which describes the conduct of research on human cell, tissue, and cellular and tissue-based products.
In UK, the EMEA has set up a separate division called the Human Tissue Authority and the Human Fertilization and Embryology Authority which regulate non embryonic and embryonic stem cell research respectively. Likewise in India too, the ICMR has laid down special guidelines for the conduct of clinical studies involving stem cells and has authorized the institutional committees and the national apex committee for stem research to regulate stem cell based studies.
Delving into the finer nittigrities of guidelines promulgated by regulators across the globe is certainly beyond the scope of this write-up. However, the crux of most of these guidelines is to ensure that researchers address the clinical concerns regarding the known side effects of stem cell therapy. The guidelines also emphasize on exercising special caution in the sensitive area of embryonic research. Quality control, safety lab testing and preclinical investigations are cornerstones of most regulatory guidelines governing stem cell research.
Stem cell studies: Methodological challenges
The very conduct of stem cell based clinical studies, presents several methodological challenges. Since stem cell research is a relatively new domain within regenerative medicine, there are very few suitable animal models for conducting pre clinical experiments. Currently, a major chunk of pre-clinical stem cell studies are being conducted on the same animal models as those used in drug research. However, very often these animal models often do not seem as efficient in stem cell research as they are in routine pharmaceutical research. This situation thus presents a need of newer pre-clinical animal models that are customized to the requirements of stem cell based investigations.
Over the years, randomized controlled clinical studies have become the gold standard for conducting clinical research. However, it is practically difficult to design randomized controlled studies in the area of stem cell research, owing to the lack of suitable comparators. This is because; the choice of a comparator is obviously limited to either a placebo or an active comparator, which in most cases will be a drug.
Manufacturing a placebo to resemble stem cell infusions presents technological challenges. Besides, since the mechanism of action and treatment goal of stem cell therapy is completely different from that of a placebo or a routine drug; whether or not comparisons of stem cell therapy with a placebo or active drug are scientifically justifiable, is a long standing clinical puzzle.
Hence, randomizing and double blinding of stem cell clinical studies presents a scientific predicament. Consequently, most studies conducted on stem cells are open-label single arm, prospective studies. However, this compromises the robustness of stem cell research since an open label single arm study design is much more vulnerable to human error and methodological biases as compared with its randomized double blinded counterpart.
Stem cells once infused into the human body, undergo a process of “differentiation” into a specific cell type. The differentiation of stem cells into one specialized form of cells is dictated by the in vitro manipulation of these cells prior to infusion. However, the process of differentiation, within the human body occurs under certain natural signals and biological triggers. This process of a manipulated stem cell differentiating into the desired target specialized cell may take variable periods of time depending upon the indication and patient’s health status. Detectable restoration of lost cellular structure and function post differentiation; may take even longer. Therefore, stem cell studies need to be of a much longer duration as compared with other pharmaceutical studies.
Another peculiar feature of the design of stem cell studies is that the intervention period is short followed by a considerably long follow up period. Since the demonstration of efficacy takes longer in this case, it is the follow up period wherein patients are closely monitored for improvement in function, tissue regeneration and any safety concerns as well. This implies that for any stem cell based clinical study, the most critical and decisive efficacy and safety data is gathered during the follow up period.
Stem cell research
In view of these facts, a stem cell based product development programme can be best designed by beginning with determining the source of stem cells, whether embryonic or non embryonic; bone marrow being the most common non embryonic source. Again, researchers need to choose between using the patient’s own stem cells (autologous) or of another donor (allogenic).
This choice will be dictated by the availability of stem cells and the therapeutic indication in point. Following isolation from a determined source, laboratorial quality controlled processes need to be devised for cell manipulation. Then pre-clinical studies can be planned and conducted encompassing routine toxicological examinations as well as the detailed carcinogenicity, antigenicity and mutagenicity testing on animal models.
This can be followed by small exploratory studies, open label in design, on a smaller sample size to check preliminary efficacy and safety in humans. Upon obtaining satisfactory results, larger, longer randomized studies with a greater sample size and a reasonably long follow up can be planned.
Crystal gazing into the future
Banking of cord blood cells of the mother has become a common medical practice in urban India. In the West, this has been a long standing routine which has now got percolated into clinical practice in South East Asia as well. Several large stem cell banks are functional in Indian cities. So much so that, researchers have confirmed the growth of lost teeth through implantation of stem cells in dental sockets. Crystal gazing into the universe of regenerative medicine, one can predict with good reason that the era of grandpas regrowing their natural teeth through stem cells is not very far. Are dentures on their way to becoming dinosaurs?
( Dr. Faisal Khan is Senior Medical Writer and Dr. Navneet Sonawane is Senior Manager, Clinical Operations, Vedic Lifesciences)