Stem cell therapy has been held as a promising avenue to restore tissues lost to chronic diseases of aging, including those of the brain. However, despite reports using animal models, no therapeutic advance associated with neural stem cells has reached the clinic, since no advance has been reproducible or effective. However, many think that the only obstruction to our ability to cure diseases such as Alzheimer's and Parkinson's result not from failure of stem cell therapy but from regulatory impasse. There was wide and rampant speculation that when this impasse is lifted, cures for chronic diseases of aging shall be immediately available. Many individuals called for an end to the ban on embryonic stem cell research. In large part, this call stems from the failure of adult stem cells to reach the promise stem cell investigators held out a decade ago and from early demonstrations that embryonic stem cells could apparently mend a severed spinal cord. If embryonic stem cells could effect this result, it would be logical to assume that they may be beneficial in chronic diseases of the brain. While stem cell therapeutic advances judged in animal models has now for the most part been attributed to the release of cytokines and growth factors, there is no reason to conclude that stem cells, embryonic or otherwise, restore functional neural tissues or connections of the central nervous system. However, many believe that they do. The questions are why this belief is strongly held, one, and second, do the facts and passions provide any rationale to deliver now that the ban on embryonic stem cell research is thing of the past?

First, we postulate that embryonic stem cell research holds potential problems that transcend religious, ethical or moral principles. Changing the fundamental components of life as we know it may end life as we know it. While science has enjoyed a very liberal scope through the years, certain items perhaps should not be altered by investigation. Nature has a way of ensuring its own survival and the survival of nature was in fact threatened by our exploration of atomic nuclei, an exploration that resulted in the discovery of ways to unleash unimaginable energy that was first used for destruction. While no living being or component thereof is immortal, the fundamental law of nature holds mankind to be immortal, and in this, we survived eminent termination as nature must have known we would and always will. In doing so it allowed us to develop nuclear destructive devices, if only to illustrate their potential to immortalize mankind, an accomplishment Nature shall never allow. But while Nature may well have considered our ability to release the forces of atomic nuclei, and our wisdom in keeping these forces at bay, it is not at all clear that Nature similarly anticipated our drive to understand the basis of life itself would lead to our ability to alter its fundamentals. Embryonic stem cells may well represent an item with which we should not alter; because if we do, we have no idea of the forces we may release or our ability to contain them. Yet we persist, and scientists demand cloning of engineered nuclei of life, an undertaking that could surpass the threat of atomic extinction and to which Nature did not anticipate. Before this research reaches a state that is essentially irreversible, we should contemplate the results, and what we may attain in further studies. Diseases of aging are part and parcel to Nature's grand design. No one lives forever, and no one ever shall, but mankind will unless we put a premature end to our own existence. Stem cells of the embryonic kind fuel concern that we may be approaching that goal, if indeed this is the goal.

This report shall offer two diverse perspectives on the reported success of stem cell therapy for neural reconstitution. I shall provide evidence that no neural reconstruction has been achieved in any system while Dr. Akshay shall provide evidence that reconstruction has been achieved. In addition, this report shall provide a historical perspective of the hype that has driven many to accept the notion that CNS repair can (and has) been achieved with stem cell therapy. The history of the field is unprecedented in Science and has led to dogma prematurely assumed to be correct, while therapy has not been available for patients with neural disorders.

Although the primary goal of medical research has been to alleviate suffering, immortality has never been the espoused objective of either evolutionary biologists or stem cell researchers. Understanding the complexity of life, particularly unmasking of the mechanism of rescue of function effect of stem or progenitor cells remains a challenge that, many believe, will take time, hype (read hope) and multidisciplinary effort to resolve. The hype that has been created in hope of stem cell therapy reminds one of the hype that once existed when the prospects of gene therapy were being debated several decades ago. The era was characterised by a similar overexcitement of physicians who went ahead and carried out an FDA approved clinical trial which led to the death of an 18 year old volunteer, Gelsinger. The whole pack of cards came crashing down, threatening future funding and research in gene therapy. The incident also killed, in a way, not only the hopes that had been kindled by the prospects of gene therapy but also the 400 planned clinical trials at that time. However, it taught us several lessons, one, that clinical trials should be funded and planned with active involvement of basic scientists and not until proof of principle has been reasonably well established. The enormous publicity received by stem cells is partly due to controversies of regulating (or not) stem cell research and partly due to the publicity given to cloning of Dolly. The success of current stem cell trials being carried out today hinges on dominant role of basic scientists. In this context, it is worth contemplating that every jump in technology takes time and incremental advancements before it settles down successfully, for instance it almost took more than a century for an antibiotic like Pencillin to be discovered and enter the market¹ and another half century for insulin to hit the clinics.² While a few may term stem cell therapy hype as dangerous, many counter argue that it is very good for raising the expectations and delivery standards from stem cell investigators. There have been several controversies that marked the launch of antiepileptic drugs,³ but these could not deter the researchers from abandoning their plans for further advancement. Today, there are half a dozen variants of such drugs available in the market. Similarly, the lack of visible clinical benefit from stem cells should not serve to discourage the scientists. On the contrary, it should catapult them to intensify their efforts further until the incremental advances in the field lead to fulfillment of hopes held by the hype.

The prospect of repairing the damaged brain has provoked excitement, controversy and conflicting scientific claims. The brain was considered unchangeable as postulated by Cajal several decades ago. Altman later showed that neurons can regenerate by H thymidine incorporation studies.^4,5 Many reports have provided interesting leads using disease models where satisfactory functional recovery of cultured neurons has been shown.⁶ There have also been several reports demonstrating the functional revival of damaged brain when embryonic stem cells, including neural stem/progenitor cells were implanted in various animal models of neurological disorders. These reports have demonstrated that the stem cells not only repair the damaged portion of the rodent brain but they also promote survival and delay neuronal cell death.⁶

There are populations of proliferating progenitor cells which are now believed to give rise to new neurons in sub ventricular zone (SVZ) of the lateral ventricles^{7, 8} and in subgranular layer of hippocampus^9,10 raising hopes of curing degenerative diseases. The group of Alvarez-Buyla¹¹ has shown that GFAP positive astrocytes are the source of neurogenesis in SVZ and sub granular region of hippocampus, the seat of spatial memory. Such advancements are critical in laying the road map for ultimate goal to repair the damaged or degenerate brain. Nakatomi et al even showed that infusion of epidermal growth factor (EGF) and fibroblast growth factor2 (FGF 2) into the lateral ventricle of the rat model of ischemia, in which CA1 neurons are selectively lost, leads to recovery of memory and learning function with concomitant regeneration of pyramidal neurons due to neurogenesis.¹² This has facilitated the discovery of factors that would enable desirable neurogenesis. For example, Gage's group even showed that enriched environment and exercise improves neurogenesis and learning^11,11 lending credence to the hope that environment can greatly influence the rate of neurogenesis. From the time when neurological disorders were left with limited treatment we are entering an era where cellular therapy may finally be able to reverse the disorders of brain. Similarly, there are reports that discuss the functional recovery of animals models when dopamine neurons derived from ES cells were implanted,^14,15 however, a very detailed analysis and further investigations can only lead to mapping of the cues that influence incorporation and differentiation of stem cells. In another development, Harris et al recently showed that intravitreally injected CD 133 progenitor cells from bone marrow can even regenerate retinal pigment epithelium (RPE) cells and improve retinal function, as evaluated by ERG, providing functional recovery of the visual cycle.¹⁶ This is one of the findings that has implications for treatment of age related macular degeneration. One of the challenging tasks confronted with researchers today is the problem of translating the stem cell technology to clinic. As bulk of stem cell translation is happening in the Eastern part of the world, it is important to understand the socio-cultural factors which influence the dimension of scientific output. Most of the countries such as Korea, Japan, Singapore, China or India do not have MD-PhD programs in their Institutes or Universities. Many argue this to be one of the key determinants of stem cell translation to clinic. The lack of scientifically designed trials or absence of double blind placebo controls in such important studies may have consequences that can irreversibly alter the pace of clinical translation. Sandhya Srinivasan argues about the state of stem cell clinical trials in Indian subcontinent, in her article, 'Rogue research in the guise of Stem cell therapy' citing the experience of former Chief Minister, Mr Jogi from Chhatisgarh, who noted 'significant improvement' upon stem cell transplantation after his spinal injury.¹⁷ Even though no conclusive evidence of such therapy was previously available, such small commercial clinics are openly endangering the hope stem cell therapy holds for us today. Even though there has been concerted effort to reconstruct the neurons using stem cell therapy, such unregulated trials such as those happening in one of the top medical institutes such as AIIMS, New Delhi¹⁸ have the potential to create the same fear that gene therapy trial once did several years ago. Maintaining linkages with basic scientists is thus an urgent requirement, no longer a choice, in order to avoid unscientific trials, achieve homogeneity in the quality of stem cells to be implanted, maintaining the correct doses and devising the best route of administration to be followed. Only when these issues are addressed by parallel animal experimentation, the leads can be consolidated by clinical studies. It is being increasingly felt among scientists that there is rampant and sudden urge among the physicians to glorify themselves in the name of providing stem cell therapy to patients even though the studies are only at experimental state. People have suggested several ways of curbing this, one of which is to employ the skilled researchers who are trained to understand the value of a common transplantation SOP, one who understands the value of bench work and the drivers of biotherapeutics. This problem has been well addressed in US, where, despite the ES cell research being under scanner, the scientific community is replete with clinical-scientist entities. There are some who believe that it is the difficulties in intellectual property of stem cells which is actually hindering the pace of clinical translation than the stem cells themselves.

Therefore, one can argue that the failure of stem cells to quickly yield desirable clinical end points may not necessarily be a result of failure of stem cells to deliver. Instead, this could be due to the inability to plan the animal studies in a reproducible and meticulous manner coupled with lack of blinding of researchers when the experimental groups are planned. Infact, the generality of need to urgently address such problems in any animal and clinical study can determine the pace of discovery. It is pertinent to note that the lackadaisical approach in translation of neural stem cell therapy is conspicuous when compared to fields such as physics, material science, space science or chemistry where the progress is more visible and rapid. It is possible that a large number of animal models often do not simulate the disease being investigated and extrapolation of results therefore becomes difficult. The appropriate translation dynamics for validating therapies in patients requires rational scaling from rodents-primate-humans, an approach that is abysmally deficient in collaborative effort amongst clinicians and scientists. The regulatory impasse in the use of non human primates coupled with unregulated exploitation of stem cells in the name of patient benefit may not bode well for terminally ill and unsuspecting patients; this has the potential to derail the tremendous impact that the stem cell research is worthy of making.