A Roundtable Discussion on Regenerative Medicine
Last month at the World Stem Cell Summit in San Antonio, TX, GEN’s editor-in-chief John Sterling moderated a panel discussion on “Regeneration Medicine: A New Era of Discovery and Innovation.” The following Q&A is based on some of the responses of several panel members.
The panelists included Marie Csete, M.D., Ph.D., CSO, Huntington Medical Research Institutes; Aubrey de Grey, Ph.D., CSO and co-founder of SENS Research Foundation and editor-in-chief of Rejuvenation Research; Jeanne F. Loring, Ph.D., professor of developmental neurobiology and director of the Center for Regenerative Medicine, Scripps Research Institute (California); and Graham Parker, Ph.D., assistant professor (research), department of pediatrics, Wayne State University School of Medicine and editor-in-chief of Stem Cells and Development.
GEN: What is and is not regenerative medicine?
Dr. Csete: My sense is that the advent of human embryonic stem cells (1998) focused regenerative medicine too narrowly on stem cells and generating replacement organs from them. Recent years have provided a reality check on just what a difficult process this is. Stem cells cannot go it alone. They need structure (tissue engineering) and protection from a host’s diseased environment. From that recognition, new research areas have been revitalized, and regenerative medicine is seen as much more expansive—therapies that can slow down normal and disease-related degeneration, or provide enhanced recovery from injury or disease.
Dr. de Grey: It may be useful for researchers to think further out of the box regarding regenerative medicine than the areas that the term conventionally encompasses. Stem cell therapies are, in essence, a form of damage repair: they restore the number of cells of a given type that have been depleted, thus leading to ill-health. But tissue engineering restores not only cell number but also the structure of the extracellular matrix, among other things. Emerging technologies, often utilizing gene therapy or immune stimulation, powerfully complement these approaches. For example, in many cases they act to remove superfluous cells or detritus that the body is unable to eliminate naturally. The potential combined benefit of these therapies and classic regenerative medicine far exceeds the sum of its parts so there is considerable value in viewing the entire arsenal as facets of the same kind of medicine and thereby promoting cross-disciplinary thinking and research.
Dr. Loring: The definition of regenerative medicine is evolving, since this is an energetic field with a great deal of active research and development. The basic premise is to restore or repair cell or tissue damage that is caused by disease or injury. The regenerative therapies can be adjuncts to more traditional drug-based treatments. Some scientists focus on stimulating the healing power of endogenous tissue-specific stem cells, but since I study pluripotent stem cells, I tend to think of regenerative medicine in terms of what we can do with these cells. This is not limiting, since the power of pluripotent stem cells comes from their vast potential to differentiate into hundreds of different cell types. Uses for these cells in regenerative medicine range from replacement of dead or dying cells to screening drugs for toxicity and efficacy. The fact that we can make these cells from anyone makes them ideal for personalized medicine.
Dr. Parker: Medicine is the diagnosis, treatment, and, increasingly, hopefully, the prevention of what ails us. Most people’s experience of medicine is likely focused on diagnosis and, unfortunately, the treatment of symptoms, the mitigation of the condition, with time bringing an amelioration of the problem. The excitement of regenerative medicine is the ability to replace or regenerate cells, tissues, or organs. So instead of a lifetime of taking injections, tablets, or using prostheses, patients actually become healthy again. Looking at tissue engineering, the classic approach is cells + scaffold = restored functionality.
However, there is an acknowledgement of the importance of the recipient environment. To this end, the use of acellular tissue matrices as the scaffold is a terrific example, as seen in work to rebuild or replace bladders. Looking at stem- cell based regenerative medicine, progress can fairly be said to have not developed as quickly as first anticipated. However, the creation of genomic editing tools for in vitro manipulation of cells for developing models and more precise controls will pay huge dividends in achieving the rigor and standardization necessary to advance regenerative medicine.
GEN: How well can regenerative medicine be made to work in the elderly?
Dr. Csete: Clearly, heterochronic parabiotic studies have shown that the aged environment is hindering normal regenerative processes. How much these results can be recapitulated in humans is up for grabs right now. Anyone who works with rodents and humans knows that rodents are much more forgiving in terms of recovery from injury than humans. Our loss of regenerative capacity with aging probably evolved as a protection against cancer in a long-lived organism [cellular copying mistakes become more frequent as people age]. So, growth factor therapies in aged humans will likely run the risk of increased cancer potential.
Furthermore, studies in various disease processes from Parkinson’s to cancer show that simply dumping in antioxidants doesn’t do the trick. I suspect that arming cell therapies before transplanting them will be more effective than systemic adjuvant treatment, but this is obviously a complex issue. Most of the diseases of interest to us involve complex traits and then, with aging added on, we are feeling our way in the dark.
It will be important to characterize the disease microenvironment phenotype in human diseases. This is needed for regenerative as well as drug therapies—part of the personalized approach to medicine. Clearly, macular degeneration in one patient is not the same disease as in the next patient. Regenerative therapies will have to address these differences to be broadly effective. Animal models of disease simply do not recapitulate the heterogeneity of disease we see in humans (and of course aged animals are prohibitively expensive to develop as a model).
Dr. de Grey: The foremost challenge of geriatric medicine is the complexity of aging, i.e., the simultaneous presence of multiple derangements of cellular and tissue function. In the case of stem cell therapies, many investigators have encountered the dispiriting phenomenon that intrinsically competent cells underperform in the aged patient, somehow inactivated or overwhelmed by the milieu into which they have been transplanted. But there is highly encouraging progress in this regard. In particular, circulating factors have been identified (and the search for more of them continues) whose abundance changes with age, to the detriment of cell function. Being so readily accessible, including to extracorporeal manipulation, the molecular and cellular composition of the circulation is in principle highly amenable to rejuvenation by a range of treatments, and we can expect thereby to transform the efficacy of regenerative medicine generally.
Dr. Loring: If the disease is one of aging, like age-related heart disease, macular degeneration, Alzheimer disease, or Parkinson's disease, we have no choice but to develop therapies that will work for older people. The common theme among multiple degenerative diseases regardless of age is local or systemic inflammation. We should consider whether inflammation is a negative or a positive for cell therapy. Arguments for both views, which remain hypothetical, are viable, and will continue; the answer may be different for different diseases.
Dr. Parker: What is regenerative medicine if not the treatment of an event or condition that is increasingly likely to occur with years lived? To flip the question on its head, organ replacement in a pediatric population has the added complications on accommodating issues such as subsequent organ growth, as well as the individual’s growth, puberty, desire for parenthood, etc. However, I can see that if the treatment depends for its success on the mobilization of an endogenous stem cell population then the efficacy might be predicted to lessen with age. I suspect the problems of dealing with diseased, dysfunctional, or absent recipient tissue are more likely to be hindered by comorbidities or concerns of undergoing an invasive procedure than issues of tissue plasticity or presence or absence of growth factors.