|
|
Why Stem Cells Make for Risky Business - The many difficulties separating scientific hope from technical reality |
By Dr A A Pucci AO FTSE
This article appeared in the review section of The Australian Financial Review, 23 August 2002.
The stem-cell debate has touched on issues that can be grouped into broad categories: bio-ethical, moral, political, legal and philosophical. Concerns have been expressed at the use of spare embryos from IVF clinics as a primary source of stem cells and of aborted foetuses as feeder cells.
International and Australian thinkers have contributed to the debate with either troubling or supportive arguments. Fears of loss of humanity, belief in the great promise, inequity concerns, scepticism about decision-making in legislative procedures, doubts about commercial motives and calls to leave stem-cell research alone have all been heard.
However, very little has been said about the technical difficulties these new procedures will encounter. Deputy Prime Minister John Anderson has alluded to the difficulty of finding matching embryonic tissues and the practical problems that this search will encounter. But the difficulties are not just in the numbers. Technical risks in such ventures have frequently been underestimated and have usually been subordinated to financial and marketing concerns. In the recent history of modern biotechnology, say the past 25 years, I have witnessed directly or vicariously this subordination and have formed broad views on technical fallacies.
By way of example, consider two technologies that have generated great hopes in that time span: monoclonal antibodies and gene therapy. Both were invented in the mid-1970s, but their applications to human therapies have met very different fates.
When I founded Australian Monoclonal Development in 1981, monoclonal antibody technology was already seven years old, but it took a further four years before our first diagnostic product reached commercial reality. Therapeutic applications succeeded in the late 1990s and only now have billion dollar revenues become a reality for the companies concerned 1. In the process, new therapeutic avenues have opened up for patients with cancer, transplantation problems, cardio-vascular and autoimmune diseases. Uses of monoclonal antibodies also abound in diagnostic testing, both in vivo and in vitro. Time, resources and appropriate research have made this possible.
Not so for gene therapy. This technology was touted as a lifesaver for many congenital and/or inheritable diseases. Genes would be introduced to make up for faulty or lacking genes in children and adults. Massive funding was directed at these developments. While living in France in the early 1990s, I was astonished to watch how hundreds of millions of dollars were raised in television appeals to support gene therapy research. Worldwide, billions poured in to fast track the technology to the clinic. Yet to date the results have been poor.
Technical and clinical problems surfaced aplenty, mostly related to the use of viral vectors to deliver the therapeutic genes, and very few patients were ever cured by this technology 2. Yet the same timespan applied and more funds were spent than with monoclonal antibodies. Why this failure?
The informed view is that interventions that work in the clinic have to be transient, act effectively on the site(s) of the disease and then be cleared by the organism. This is how monoclonal antibodies, and for that matter any successful drugs, work in treating disease. Permanent implants work only if made of inert material and used for structural, fixed repair. Any other implant will find resistance and/or generate reactions that are adverse for the patient.
Inserting a gene, even stripped and bared down to just DNA, will induce recognition from the immune system and then defence mechanisms will try to eliminate the implant. The immune defence aims at maintaining the self clear of active foreign material 3.
In the course of its development, our organism has devised ways to restrict its defence mechanisms, sparing its own organs from immune attack. This provides a demarcation between self and non-self. Immune identity is already solidly established in each of us at birth, but continues to strengthen as we are challenged by foreign molecules, whether from surrounding bugs or from implants.
So the first line of resistance to an implanted gene will be the immune system, which is always wary to maintain our immune identity. Of course there are ways to make the body accept foreign parts, but the consequences of using immunosuppressive drugs can be debilitating. This state of affairs is acceptable, however, in the case of terminal illnesses where everything else has failed.
Even if the implant is matched, other reactions at the molecular level may occur because the new gene, and the expression of the relevant protein, may overshoot, thus interfering with some of the numerous biochemical pathways and feedback mechanisms each cell uses in a fine, continuous balance.
Having noted that the implantation of genes in gene therapy has worked so poorly in the past 20 years, what are the odds that cellular therapy, the one proposed by stem-cell researchers, will succeed?
Here the difficulties are greater, both because the implants are more complex (and therefore the potential reactions stronger) than in gene therapy, but also because their putative use in neurodegenerative diseases involves another major organ and another level of identity, that of the brain. Developments in the nervous system start early and continue throughout life. This is the most plastic organ in our body, continuously building connections between neurons, learning and unlearning, and accumulating an enormous number of individual structures.
The neurological identity is otherwise known as the ‘sense of self’ because in this case, as opposed to the immune identity, the organism has a conscious knowledge of it. The neurological self is a system in its own right and one that has established core functions, among which memory has a special place. According to leading neurologist Rodolfo Llinas 4, this self has its own intrinsic structure and dynamics and is not a detached, higher-order monitor for other sensory or cognitive systems. In this self, motor control is a crucial component, as is memory. The self is the locus of agency, the choice and control of action. This pervasive, intimate moment-to moment ‘sense of self’ that we all enjoy is a functional prerequisite for the deliberate control of action.
In neurodegenerative disease, at least in Alzheimer’s, this self may be destroyed to a large extent, with memory as the main target. But even in Parkinson’s disease, where most of the stem-cell research is directed, the loss of motor control cannot be detached from the structure and dynamics of the patient’s neurological identity. So it’s not just a matter of transplanting dopamine-producing stem cells to restore motor control. We need also to understand how those cells will be integrated, if at all, in the previous neurological self.
Difficulties abound as the obstacles of immune and neurological identities have not yet been addressed successfully. But the problems are not limited to the need to break down immune identity and to overcome the loss of neurological identity. Other risks remain in the transformation step of embryonic stem cells and are of a serious nature: tumour formation and viral use.
The most successful experiment so far, at least judging from peer-reviewed journals, has enabled the implant in rats of embryonic stem cells which were shown to be functional. That is, the implanted stem cells produced in vivo dopamine, the hormone lacking in Parkinson’s patients, and the rats started to recover normal movements 5. In this experiment, Kim et al. transformed undifferentiated stem cells into dopamine-producing cells. To make the differentiation effective - failure in transforming even a few stem cells would result in tumour formation - they used a virus vector, a cytomegalovirus.
Would this be an acceptable procedure for human patients? I doubt it. The potential for tumour formation and the use of viral vectors present real risks.
No clinical trial using embryonic stem cells in humans has yet been reported. Most groups are still at the in vitro stage and have not yet commenced animal model trials. So we are a long way away from the cure, even if everything goes according to the scientists’ plans and they are able to overcome the main technical problems just described.
Where are the signs of hope then? A number of peer-reviewed studies have shown the possibility of using pluripotent adult stem cells from blood, bone marrow and neonatal cord to replace blood and epithelial cell types 6. Depending on the site of implant, these stem cells grew to become specialized in the tissues surrounding them, including neurological tissue. The possibility of using one’s own stem cells circumvents identity issues. The Australian Cord Blood Bank is very active in ensuring a steady supply of cells for children awaiting stem-cell transplants.
In other research, brain cells called astrocytes were shown to be capable of stimulating the process of adult neuron generation 7.
Apart from adult stem-cell therapies, which benefit from fewer technical and bio-ethical problems, there are other promising studies. One deals with spinal cord recovery from injury by enzyme treatment 8. Other technologies like electronics and nanotechnology are converging with life sciences to provide solutions for this kind of patients.
As for embryonic stem-cell research, while not the ‘last frontier’ of hope for patients and their families, it has nevertheless its uses.
If rigorously applied, it can uncover many of the still mysterious mechanisms of cell differentiation and help to provide (in the long-term) solutions that will correct certain errors of nature. Stem-cell research should go on with the available surplus embryos.
Commercialisation, though, and the use of embryonic stem cells in the clinic, should be curbed by a moratorium of at least three years. In light of the adverse effects of gene therapy, this is the minimum period of time required to address the technical problems and associated risks described above.
References
- T. Gura Nature 6 June 2002:584
- N. Boyce Nature 13 Dec.2001:677; Z. Le et al. Science 296, 497:2002
- R.H.Schwartz. Fundamental Immunology. Ed. Paul. Philadelphia 1999
- R. Llinas. I of the Vortex: From Neurons to Self. MIT Press, 2001
- J-H Kim. Nature 4 July 2002:50
- Y.Jiang. Nature 4 july 2002:41; I.L.Weissman. Science 287/2000:1442; D. Clarke. Science 288, 2000:1660
- H.Song. Nature 2 May 2002:39; H.van Praag. Nature 28 Feb.2002:1030
- E.J.Bradbury. Nature 11 April 2002:636
|
|
Dr A A Pucci AO FTSE
ATSE Focus is a non-refereed publication. The views expressed in the above article are those of the author(s) and do not necessarily represent the views of the Academy.
|
|
