Regenerative medicine is being increasingly recognized as an effective treatment modality, particularly for end stage intractable diseases for which modern medicine as practiced to dayhas little to offer. Even if current reports have created a high degree of undeservedhypeand hope that stem cells transplanations couldbe the real answer for many chronic diseases affecting a variety of organs, its potential cannot be underestimated. How soon can we expect the practical applications of this frontier technologyto become a routine part of modern medicine? What are the real concerns that need to be addressed?
Biotechnology in modern medicine
Inthe post-genomic era, the biotechnology industry isredrawing the contours of managing healthcare using therapeutic and prophylacticrecombinant proteins produced in microbial, animal and plant vectors. Further down the line in the developmental phase are newer areas of therapeutic modalities, including gene therapy and customised drug development, based on genomics and proteomics. Understanding the genes responsible for health and/or disease, their expression patterns to produce proteins, determining their functions are all of great application for the development of new drugs. In addition, 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, families, select communities or even among ethnic groups.
Apart from gene therapy which will eventually be an important part of regenerative medicines, the use of stem cells as valuable sources for regeneration of cells, tissues or even organs is being extensively investigated.
Historyofstem cell therapy
Consideringthat 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.
The most complex issue which is yet to be answered is the mechanism by which undifferentiated cells become differentiated. While it is known that genes are primarily responsible, an understanding of the signals that turn specific genes off and on and thereby effect differentiationis still lacking
Since that time, the NationalMarrow Donor Programme (NMDP) in the US has enabled an estimated 20,000 stem cell therapies on patients, of which a vast majority was bone marrow, with only smaller numbers ofperipheral blood stem cells andumbilical cord blood transplants.
Stemcellresearch
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. Whiletodaystem cells and their potential applications are taken for granted, it is important to realise thatThomson'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.
Potential uses
While the most talked about and potentially the most rewarding application for embryonicstem cells may be for treating a wide range of human diseases, such as cancer, diabetes, heart diseases, Alzheimers disease, Parkinson disease etc, which are generally caused bydeath, depletion, degeneration or dysfunction of the concernedcells or 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 theanimal models available are not truly representative or relevant. While cancer cell lines are routinely employed for screening candidate anti-tumour drugs, availability of pluripotent stem cells could yield a much wider range of cell types for screening.
The most complex issue which is yet to be answered is the mechanism by which undifferentiated cells become differentiated. While it is known that genes are primarily responsible, an understanding of the signals that turn specific genes off and on and thereby effect differentiationis still lacking.Such knowledge would be essential before the specific cell types can be developed for drug screening.
The potential to develop cell based therapies is often mentioned as the most important contribution that stem cell researchcan yield in the coming years. The current practice of using donated organs and tissues to replace diseased organs has the inherent problems of mismatches and availability. These problems could be handled by the generation of healthy tissue cells from undifferentiated stem cells in the laboratory. For example, generation of healthy heart muscle cells, or pancreatic beta cells for production of insulinby directing differentiation of human embryonic stem cells in cell culture to specific cells is a distinct possibility.
Issueson stemcellresearch
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 arerelated 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, the donors and the funding agencies. 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 thatthebeliefthat adult cells areincapableof differentiation and hence are not usefulis 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 ordisease.The relative merits of the various sources of stem cells such as cord blood, embryos, bone marrow etc are being studied in detail in many laboratories .
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 approvalsfrom 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 causing concerns to the regulatory agencies and even to patients.
1) US Ban On Federal Funding
The August 9th announcement of President Bush that US 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. The ban was a sequel to widespread opposition to the use of embryonic cells use, since it was deemed by the anti-abortion group in the USthat destruction of the embryo for whatever purpose was equivalenttodeliberate destruction of life itself. Presumably, all these 64 'approved' cell lines were harvested from fertility clinics around the world which had produced the embryos to create life and not for destroying life. Attitudes in other countries have ranged from selective bans and controls, with the majority averring that embryos could be usedfor creating organs and tissues, but not for cloning of humans.
While work on embryonic stem cells particulary those which have not been useful for in-vitro fertilization are on-going, and large inventories are being established in countries outside USA, apart from the 64 already identified in 2001, it is not certain as to how many of them are viable and functionally useful. Of the 64 lines approved for use by the US authorities, only 16 of the cell lines known at that point in time were derived by US institutions, 5 of them were fromoriginal work at the University of Wisconsin,seven and three from two laboratories in India, the Reliance Life Sciences Laboratory in Mumbai and the National Centre for Biological Sciences at Bangalore, respectively. An Australian company had five, Gotenburg University in Sweden, nineteen, the Karolinska Institute, five and Technion Institute in Haifa, Israel, four. All in all, institutes in five countries in the Worldcontrolled the 64 stem cell lines included in the NIH list.
2)The Korean Scandal
It has now been established beyond doubt that the two 'landmark publications' in the prestigious journal, Science by Hwang Woo-Suk from Koreacontained faked data claiming the creation of stem cells specifically tailored for individual patients from cloned human embryos. The outright lies and fraud which was exposed has indeed set back research on stem cellsand emphasized the need for more transparency and clarity on all suchclaims. Nevertheless as mentioned by various authorities on the subject 'it has not dimmed the promise this technology offers for the treatment of a host of diseases including Alzheimers, Parkinson's, spinal cord injuries, diabetes, cardiac diseases apart from some of the established conditions of leukemia, thalassemia etc'.
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 whichmay decrease their viability for extended manipulation or replication. According to Don Cramer of the University of Southern California Keck School of Medicine, "all cell lineshave a limited life span, even cell lines which are considered to be able to proliferate indefinitely die out".
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, USA as Centres which have recognised stem cell lines
There are also concernsregarding the contamination of the cell lines and their effects on the hosts at the time of transplantation. 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.
In general, for this technology to succeed, it should be possible to generate sufficient quantities of the appropriately differentiated cells and tissues which can survive and integrate in a new environment and remain functional during therecipient's life.
Ethicalandmoral 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 US, 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 arederived from discarded tissue. There is a strong case for investments into use of cord blood stem cells since they are not within the purview of such criticisms.
Patentingofcell 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 US Patent Office.The patents issued to Aastrom Biosciences protect several of the fundamental technologies based onstem 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.
Indianscene
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, USA 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 LV Prasad Eye Research Institute in Hyderabad, a project sponsored byDBTuses 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-workingR&D collaborations with international research groups.
Around half a dozen private umbilical cord blood stem cell banks are operative inIndia 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 transplantationfacilities availableas of now.
The concept of public banking centres around the concept of banking stem cells from the public, typing for HLA compatibility and providing the matching cells to patients who need them. A National facility for collection, storage, typing and supply like the National Blood Donor Programme in the US would clearly be the answer.The availability of appropriate stem cells has to be matched by the ability to carry out successful transplants and follow up.
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 PatentAct. In view of the fact that US and many western countries allow patenting of stem cells, notwithstanding the Indian position, laboratories in India have an opportunity to protect theirstem cells based discoveries through patenting in those countries.
All these efforts are at an early phase even from an R&D perspective and therefore it will be prudent to be cautious since while the promise is attractive, the risks involved are equally daunting. The real answer lies in ensuring that every step to progress in the area is based on sound scientific evidence and diligent monitoring of the risk to benefit ratios and outcomes.
(The author is a leading pharma expert based in Chennai. He can be contacted through:mdnair@vsnl.com)