GUEST EDITORIAL
Is ‘Stem Cell Therapy’ Becoming 21st Century Snake Oil?
Historical Viewpoints
It is commonly assumed that modern medicine is superior to that practiced in years gone by. Whether true or not, an associated danger is a non-critical acceptance of new advances because of a complacent assumption that previous mistakes regarding poor medical regulation will not be repeated in the modern world. In the ‘bad old days’ we know that the general public were widely duped into believing that all kinds of patent medicines – notoriously ‘snake oil’ – could be ‘wonder cures’ for a wide variety of maladies.1 We think, superiorly, that this couldn't happen nowadays … but the possibility should not be overlooked. Indeed, there is a line of argument to suggest that the process has already begun and, unfortunately, the veterinary profession, often under pressure to emulate human medicine, appears to be at the forefront.
Science of Medicine
The scientific basis for medicine is axiomatic to most modern day veterinarians and homeopathy, for instance, is widely derided for its non-scientific approach. Instead, reductionist science, which posits that discovery of underlying biological truths will then lead to a rapid unraveling of medical problems, is the dominant philosophical approach. Thus, we now implicitly accept that discoveries in laboratory science will, almost inevitably, lead to further and spectacular progress in medicine.
The emergence of stem cell therapy (SCT) – notably that applied to the central nervous system (CNS) – provides a good example of how this process may be expected to work. Less than 20 years ago it was almost universally believed that the CNS was incapable of regenerating cells that had been destroyed. However, a series of experiments in the 1990s (which, incidentally, replicated results that had previously been thought ‘unreliable’) demonstrated that there were stem cells in the CNS which were able to differentiate into many different types of adult cell, including neurons.2 Of course, this finding led to widespread optimism regarding the possibility of reliably repairing the damaged nervous system – a ‘holy grail’ of neuroscience.
Many experiments have now demonstrated a beneficial effect following transplantation of stem cells of various types into the damaged CNS of laboratory rodents.3, 4 The results have been promising – although not spectacular – and, more interestingly, seem not necessarily to depend upon maturation of the stem cells into replacement cells in the CNS, but more often to result from neuroprotective or immunoregulatory effects.5 Indeed, after transplantation, descendants of transplanted stem cells are often difficult to find in host tissue.
Breakdown in Translation
Nevertheless, if a functional improvement has been observed in a laboratory experiment the obvious next step is to determine whether a useful response could similarly be obtained in real-life CNS injury – indeed, it could be argued that this is a prime motivation behind much of the original research. The finding that stem cells can be obtained from many different tissues (adipose, bone marrow, skin etc) has also increased the feasibility of translating SCT from lab to clinic.
However, there are many steps that must be made to convert a successful laboratory intervention into an effective and useful clinical therapy. This final process is critical to the development and acceptance of a novel therapy – and one which, unfortunately, is often poorly managed in veterinary medicine. The crucial element in acceptance of a novel therapy should be a demonstration that this new therapy is clearly superior to the previously available options, which may simply be non-specific supportive care or consist of a demonstrably efficacious intervention. Evaluation of novel therapies for CNS injury requires particular caution because there is a general trend towards spontaneous recovery. This may be spectacular, for instance the return to near-normal function often observed following peracute ischemic events in the spinal cord (such as fibrocartilaginous embolism). Therefore in preliminary ‘open label’ studies an apparent beneficial effect of a novel therapy is often reported and it is easy to be seduced into thinking that the outcomes in such ‘trials’ are superior to those observed in historical cases (sometimes erroneously referred to as ‘historical controls’).
The key tool in defining the real value of a novel therapy is the randomized clinical trial (RCT). RCTs provide the best evidence of an effect of an intervention by eliminating, as far as possible, potential sources of bias. The critical components of a RCT are: 1) Randomization plus allocation concealment: because the treatment is allocated at random and investigators do not know which treatment the next eleigible patient will receive patients cannot be selected based on favorable pre-entry characteristics; 2) Blinding: the outcome is assessed by observers that do not know which treatment has been given to each patient (it is also preferable that the patient [or for veterinary patients, the owner] is blinded too); and 3) Large patient numbers: which allow estimates of effect to be precise. Estimations of effect are affected by bias at all stages in other types of clinical studies (which are usually classified as ‘observational’).
PROBLEMS WITH VETERINARY STEM CELL THERAPY IN 2012
Apparently beneficial effects of SCT in basic science laboratories are generally reported widely in the mass media, with little critical appraisal, and exaggerated claims are often tacitly encouraged by laboratory scientists needing to secure their next grant. For this reason the general public now has an expectation that SCT will be successful, and some owners will request it for their animals. It therefore becomes easy to sell to owners as a respectable treatment, even in the absence of rigorous proof of efficacy. This ready acceptance by owners, together with the tendency for spontaneous functional recovery after CNS trauma makes for an explosive combination in which unproven therapy can thrive.
In recent months a number of studies involving SCT for CNS lesions in dogs – either experimental or clinical cases – have been submitted and published in a variety of journals. However there are a number of impediments to accepting many of the study conclusions at face value. For instance, in many reports the transplanted cell populations are poorly characterized, leaving open the possibility that they may not truly contain stem cells at all. In some studies, there is confusion between the aims of examining safety and demonstrating effectiveness, which each require different study design. A ‘beneficial’ effect of some type has been described in some reports, which may include improved function or histologic endpoint, but often without a control group comparison.
The second issue is that of small trials. Small patient numbers imply a greater risk of more extreme outcomes – such that a very good or very bad effect of the new treatment is more likely to occur than in a large scale trial. If ALL such studies were eventually published, this would not present a problem, since it would mean that the full range of outcome effects would be available for analysis. Unfortunately, because of the unwarranted importance attached to significant P values, authors, reviewers and journal editors tend to obstruct publication of small studies in which there is no demonstrated effect of a new treatment. This publication bias can lead to an overall impression of a useful effect of therapy even when this is not, on balance of all possible evidence, true.
The common feature of the veterinary clinical reports published so far is that they do not comply with the requirements of a RCT in demonstrating an effect while minimizing bias. For this reason, most claims of benefit must currently be regarded as highly insecure. This is not to say that stem cell therapy cannot be effective, simply that we are at a very early stage of the painful and prolonged process of its evaluation; it will likely be many years, or even decades, before the potential benefits or drawbacks have been properly evaluated.
Is Stem Cell Therapy Uniquely Poorly Reported?
Whilst stem cell therapy has rapidly achieved high profile in medicine and therefore even misplaced claims for efficacy are noteworthy it is not the only therapy in veterinary medicine or surgery for which there is insufficient evidence of benefit to support widespread implementation. Novel interventions for common conditions are published frequently in veterinary journals, including Veterinary Surgery. Whilst it is undoubtedly important that new interventions are explained through publication, it is essential that they should subsequently be subject to critical testing of their effectiveness before being widely accepted. This is currently not standard practice in veterinary medicine and surgery: how many commonly used interventions have undergone rigorous testing as described above? Untested conventional interventions therefore frequently have no more objective evidence for effectiveness than homeopathy. Strict testing of novel interventions must become the norm for veterinarians to be able to maintain our view of ourselves as a ‘science-led’ profession. For progress to be made we must learn to form ‘consortia’ of clinicians to pool cases so as to be able to properly test new interventions.
