I am a developmental biologist and professor of Neurosurgery and Cell Biology at the University of Virginia Medical School, where I conduct basic and applied research into several types of stem cells including those from embryonic, fetal and adult sources. My major funding source is the National Institute of Dental and Craniofacial Research at NIH.
The opinions expressed by me are those of a scientist and individual, and not official positions of the University of Virginia or the National Institutes of Health.
The rapid advances in stem cell science in recent years are the most exciting I have witnessed in my 31-year career as a biologist. The new science of regenerative medicine has been born from a convergence of stem cell biology, gene therapy, tissue engineering, and materials science. We will be able to repair and replace diseased and defective cells and tissues, and deliver genes and drugs in ways we could scarcely imagine 10 years ago. I believe regenerative medical therapies will be standard within the lifetimes of some of those present today.
The important studies that have fueled the progress were conducted with the support and review of the National Institutes of Health, with the exception of the pioneering human embryonic stem (ES) cell research.
This work could not be done under federal support. Many scientists in this country, myself included, wanted to work with embryonic and fetal human tissues in the past, but simply could not find a way to do so without federal support. There is little doubt we would be much closer today to employing the technologies for repairing and replacing human tissues using stem cells had this not been the case. As we attempt to realize the great promise of regenerative medicine, we can accelerate the rate of discovery by making many more lines available and by increasing the funding available to study the new lines.
This area of science is attractive to many of the best students training for careers in medicine, engineering and scientific research. My four brightest students of the past few years have all chosen to pursue careers in stem cell research. As educators, we can train outstanding young scientists anxious to devote their careers to regenerative medicine, but it is critical that they have the tools-including adequate numbers of independently derived human ES lines -for their graduate and post-doctoral training as well as for establishing their own laboratories.
While scientists in this country are constrained by limited numbers of cell lines, it is clear that many scientists in European and Asian countries are not. China, for one, is making ES cell research the cornerstone of their biotechnology industry. We must maintain our position of leadership in biomedical research for educational and economic reasons as well as the scientific ones.
As a scientific issue, clearly researchers need to be able to study many more human embryonic stem cell lines than are currently available. The larger the number of individual lines studied, the greater the statistical significance of the results. We must study a large enough sample size to account for individual variation in genetic make-up or polymorphisms in genes that control differentiation of stem cells. The population of the United States is diverse genetically, and our heterogeneous genetic background is a serious confounding factor in studying gene expression and the interaction of genes and environment.
We know from population studies of birth defects-many of which are caused by mutations in genes that are the same ones controlling differentiation in ES cells-these genes act differently in distinct genetic backgrounds. Although we do not yet know what variability exists among the genes governing developmental processes in the cells isolated from different embryos, it is reasonable to assume such is the case.
While it is gratifying that to date, there has been excellent concordance in the results obtained with distinct human ES lines in the laboratories of Drs. Thomson at Wisconsin and Gearhart at Johns Hopkins, having so few lines under examination is of concern. Each cell division carries some possibility of acquisition of genetic mutation. Cells in culture lack some of the protective mechanisms afforded those in vivo. Culture of such rapidly growing, virtually immortal cells can rapidly amplify a genetic trait selected for by accident. Working with but a few lines carries the risk of characterizing cells that no longer reflect the properties common to most embryos.
We cannot use the many mouse ES cells available to compensate for the limited number of human ES cells. Human cells differ from other animal cells in important ways, thus there really is no substitute. Human ES cells cannot be cultured in the presence of antibiotics while mouse ES cells can. The cellular structures that move chromosomes during cell division are different and more "fragile" than those of animals-a fact that has been suggested to be a major barrier to nuclear transfer technology. There is a different complement of chromosomes in human and mouse cells, and undoubtedly other significant differences in human and other ES cells that we have yet to discover.
In my laboratory we seek methods to regenerate bone and nerve. I feel the most prudent approach to determine the optimal cells to use is casting a broad net, therefore, we are comparing stem cells isolated from human liposuction procedures-true adult stem cells; cells we have discovered in the dura mater, the lining of the brain and spine, which will probably be harvested from human fetal tissues; and human ES lines obtained from the University of Wisconsin. We are delivering undifferentiated stem cells along with those induced to become precursors of bone cells to rodent models to determine the optimal methodology to engineer new bone. In other studies we have succeeded in coaxing the fat-derived and dura mater stem cells to become true neurons and Schwann cells, critical cell types in the regeneration of nerve. We are currently testing the injection of both cell types to regenerate peripheral (sciatic) nerve, and hope to use a similar approach for regeneration of spinal nerve fibers in the future. Very preliminary studies suggest under some circumstances the cells may be able to ""home" to the sites of tissue injury upon injection, which if true, will greatly facilitate this regenerative technology. We have drawn greatly on advances in culture and differentiation of ES cells in our study of the adult and fetal stem cells. Even though it appears likely that adult stem cells will find clinical applications before ES cells, progress in the ES research will clearly advance adult stem cell research. Advances in biology always come with surprises, so it would be foolish to not conduct rational experimentation, including comparisons of the stem cell types so there will be no doubt that the foundation of our new discipline is sound.
There are other reasons we must study all stem cell types including ES cells. Different types of stem cells may work in concert to repair tissues. As discussed above, we hope injected Schwann cells will release factors that signal nerve cells to extend new axons, thereby repairing severed nerves. One recent study using the Johns-Hopkins cell line showed that injection of neural cell progenitors derived from ES cells into the spinal canals of paralyzed rats restored motion. The actual cells effecting the repair were probably endogenous, "adult" stem cells-perhaps the dura mater cells discovered in my laboratory, which were stimulated to act by factors released from the injected cells. There are also preliminary reports in the past week of a European study in which similar cells were injected into animals with demyelination similar to that of humans with multiple sclerosis. The differentiated stem cells were reported to stimulate replacement of missing myelin of the nerve sheaths. These studies underscore the fact that we cannot assume that support of research using only or primarily adult stem cells will suffice to meet our goals in advancing basic science and regenerative medicine.
Looking to the near future, a reasonable goal might be to assemble an "immunotype library" of human ES cells. Such a cell library would contain at least one or more founder cell lines of each of the major human histocompatibility categories. Then the true advantages of the ES cells-unlimited potential to replicate and total developmental plasticity-- might be realized. Perhaps advances in immunosuppression and transplantation will make this unnecessary. In any case, we stand to uncover many of the mysteries of early development by having a larger and more diverse set of cells, which are readily available to qualified researchers.
In summary, I believe that providing both increased funding and many more cell lines for human ES cell research as soon as possible is critical to the future of healthcare, science, education and the biotechnology industry in the United States. It is hoped that the federal government will be involved in contracting and establishing standards for the process of isolating and distributing additional ES lines. There are reported to be many human embryos in the United States, which are frozen and would be donated for research purposes if allowed or otherwise destroyed. While ethical debates continue on creation of embryos for research, can we not make use of those no longer needed for reproduction?
