In recent times an area of great interest in medicine has been the potential of regenerative therapy as a treatment modality. In that context a very high degree of hype has also been created that stem cells transplantation could be the real answer for a large number of acute and chronic disease conditions for which modern medicine has little to offer. How soon can we expect the practical applications of this frontier technology to become a routine part of modern medicine? What are the real concerns that need to be addressed?
In the post-genomic era, the Biotechnology industry is redrawing the contours of its growth pattern from the traditional development and production of recombinant proteins in microbial, animal and plant vectors, to newer areas of therapeutic modalities, including gene therapy and customised drug development, based on genomics and proteomics. For example, pharmacogenomics has the potential to target specific genes for drugs , thus assisting the development of tailor-made therapies. The recent developments in the field of Single Nucleotide Polymorphisms (SNPs) and DNA chip technology have made it possible to detect errors in gene expression and genetic disorders in individuals, groups of individuals or families. A whole new field of regenerative medicine is opening up as a result of newer advances in areas such as stem cell research.
History of Stem Cell Transplants & Therapy
Considering that the first bone marrow transplant in animals exposed to lethal radiation doses, was carried out in the early fifties, progress in this area has been relatively slow. The first transplant of cells collected from peripheral blood by apheresis was performed only in the eighties, while the first transplant of umbilical cord blood was done in France on a 5 year old boy with Fanconi's anaemia in 1988. Since that time, the National Marrow Donor Programme (NMDP) in the U.S. has enabled over 20,000 stem cell therapies on patients, of which a vast majority was bone marrow, with only smaller numbers of peripheral blood stem cells and Umbilical Cord Blood transplants.
Stem Cell Research
Embryonic Stem Cells are the parent cells of all tissues of the human body. The first successful report on the collection and culturing of the human embryonic stem cells was reported by scientists at the University of Wisconsin, Madison on November 6, 1998, under a project sponsored by the California-based Biotech Company, Geron Corporation. While to-day Stem Cells and their potential applications are taken for granted, it is important to realise that Thomson's discoveries were the culmination of a 17 year international race to capture and cultivate the first human embryonic stem cells. The initial experiments showed that the stem cell colonies included a core of undifferentiated cells (surrounded by a margin of differentiated cells), which had the capability to differentiate into three types of cells, the endotherm, ectotherm and mesoderm, which in turn, can produce special cell types for the gut, bone marrow, cartilege, muscle. kidney, liver etc. The challenge is to direct such differentiation from a random process to one that is pre-planned to produce specific cell types.
While the most talked about and potentially the most rewarding application for embryonic stem cells may be for treating a wide range of human diseases, such as cancer, diabetes, heart diseases, Parkinson disease etc, which are generally caused by death, degeneration or dysfunction of the concerned tissues, such treatments are unlikely to be realised for several years for a variety of reasons. However, of more imminent application is their use for understanding the developmental biology of the embryo, which may have implications in birth defects, infertility etc. In addition, these cell lines have the potential for developing screening models for new drug discovery, for which the animal models available are not truly representative or relevant.
Issues on Stem Cell Research
There are several important issues which impinge on the future of stem cell research, which are not only of a scientific or technical nature, but are related to ethical and moral issues on the use of human embryonic or adult cells, intellectual property rights and the sharing of the accompanying reward systems between the inventors and the donors and financial supports and funding. National and International Guidelines and Policies for stem cell research, are all in early days of drafting and implementation. In addition, it has been recently shown that the belief that adult cells are incapable of differentiation and hence are not useful is indeed a myth. In studies in mice, adult cells from certain parts of the body could transform themselves to other cell types. The significance of these observations is that this technique of using adult cells could be more useful for repairing of tissues damaged by injury or disease .
The recent propensity for injecting autologous Stem Cells to patients , for example suffering from Coronary Heart Disease, has raised a number of new issues. Many of these , including in India have been carried out without any approvals from any agency by investigators and institutions ill-equipped to conduct such experiments. The evidence of their usefulness has been ambiguous and the results have not been subjected to authentic peer reviews.
Funding of Stem Cell Research
The August 9th announcement of President Bush that U.S. Federal funding for stem cell research will be restricted to the 64 cell lines known around the World at that time and no more, has raised a number of issues as well as major concerns. Presumably, all these 64 'approved' cell lines were harvested from fertility clinics around the World. It is not certain as to how many of them are viable and functionally useful, since much work needs to be done before this question is answered. In addition only 16 of the cell lines known at that point in time were derived by U.S. institutions, 5 of them from the original work at the University of Wisconsin. Two laboratories in India, the Reliance Life Sciences Laboratory in Mumbai and the National Centre for Biological Sciences at Bangalore , have seven and three stem cell lines, respectively, Bresa Gen, an Australian company has five, Goteburg University in Sweden nineteen, the Karolinska Institute, five and Technion Institute in Haifa, Israel, four. All in all, institutes in five countries in the World control the 64 stem cell lines included in the NIH list.
Technical Problems
One of the major issues impinging on the future of stem cell research is related to the quality of the available cell lines or even of those which are yet to be harvested. They may be subject to mutations which may decrease their viability for extended manipulation or replication. According to Don Cramer of the University of Southern California Keck School of Medicine, "all cell lines have a limited life span, even cell lines which are considered to be able to proliferate indefinitely die out".
There are also concerns regarding the contamination of the cell lines and their effects on the hosts at the time of implantation. This is primarily because most of the cell lines have been cultured with animal cells or serum, which could be carriers of infective organisms including bacteria and viruses.
Yet another major technical hurdle is the propensity of the human body to reject transplanted stem cells. Fundamentally new methods to prevent such rejection need to be developed if stem cells are to be useful as therapies.
Ethical and Moral Issues
Most countries including those in the forefront of stem cell research, are bogged down by serious considerations of an ethical and moral nature , particularly since the use of embryonic stem cells involves the destruction of the human embryo. While disputes and debates continue, the U.S., a potential leader in biological research on stem cells and their translation into viable products, has taken a "principled stand" in response to public pressure on federal support for such research. In countries such as India, where assisted reproduction techniques are legally permitted, wasted embryos available from fertility clinics are allowed to be used by researchers, subject to obtaining informed consent from the donors. The proprietary rights of the donors on the results of R&D and on the products which emanate from them are still not clear.
The least controversial from an ethical point of view is the use of umbilical cord blood stem cells which are derived from discarded tissue.
Patenting of Cell Lines
Right from the early days of work on embryonic stem cells by James Thomson at Wisconsin, patents for stem cells, as well as for the methods of their production and replication have been applied for and granted by the U.S. Patent Office. The patents issued to Aastrom Biosciences protect several of the fundamental technologies based on stem cells and ex-vivo gene therapy for the repair and replacement of damaged tissues.
These patents also cover replication and genetic modification of human stem cells, as well as processes for growing human hematopoietic stem cells, the source of all blood and immune cell types.
Indian Scene
By choice, chance or by coincidence, India too is into stem cell research. The two Institutes, the Reliance Life Sciences Laboratories in Mumbai and the National Centre for Biological Sciences in Bangalore have been listed by the NIH, U.S.A. as Centres which have recognised stem cell lines. The Department of Biotechnology (DBT), has launched three major R&D programmes on stem cell research, aimed at Blindness, CNS disorders as well as genetic diseases such as beta thalassemia. The Draft Guidelines issued by the Indian Council of Medical Research, stipulate stem cell research to be restricted to discarded embryos and aborted foetuses. At the L.V. Prasad Eye Research Institute in Hyderabad, a project sponsored by DBT will use stem cells harvested from the normal eye tissue to treat blindness in the donor patients other eye. The National Brain Research Institute in New Delhi plans to work extensively on neural stem cells and their use in several congenital and acquired CNS disorders, including Parkinson's disease.The National Centre for Cell Sciences in Pune, which is developing a Repository of cell cultures and cell lines is working on cryo-preservation technologies for bone marrow, development of artificial skin for burns and vitiligo cases, bio-compatible liver devices for liver disorders etc. The Reliance Life Sciences group has ambitious plans to fully utilise their stem cells to transform them into viable products, perhaps through net-working R&D collaborations with international research groups.
Around half a dozen private umbilical cord blood stem cell banks are operative in India which provide preservation facilities for individuals who seek to use these as an insurance against any future need for therapy for their children and their siblings.There is no Public banking and donor and transplantation facilities available as of now.
Indian position on patenting of stem cells or even of products developed from them is not clear, as in the case of patenting of genes, under the new Patent Act. In view of the fact that U.S. and many western countries allow patenting of stem cells, notwithstanding the Indian position, laboratories in India have an opportunity to protect their stem cells based discoveries in those countries.
While all these efforts are at an early phase even from an R&D perspective, it will be prudent to consider even at this stage the multitude of problems that this emerging technology will face in the coming years, before therapeutically useful products for at least some of the underserved medical problems are developed.
(The author is a leading pharma consultant based in Chennai, India. He can be reached through: mdnair@vsnl.com)