Select Committee on Stem Cell Research Report


CHAPTER 3: POTENTIAL ADVANTAGES AND LIMITATIONS OF ES CELLS AND ADULT STEM CELLS

3.1 We have received much evidence on the relative advantages and disadvantages of ES cells compared with adult stem cells for the development of stem cell-based therapies. The main scientific considerations are summarised in the following paragraphs.

ES cells

3.2 A great deal of research has been undertaken on ES cells from animals, particularly mice, over many years. In the last three or four years researchers around the world, including in Australia, India, Singapore, Sweden and the United States, have used similar methods to establish human ES cell lines from blastocysts. Three research licences have been granted by the HFEA (for purposes permitted by the 1990 Act) which could result in human ES cell lines being derived in the United Kingdom, but we were told that at the time of writing none had yet been derived.

POTENTIAL ADVANTAGES

3.3 Research on mice has shown that it is possible to isolate pluripotent ES cells from the blastocyst, culture and multiply them in the laboratory, in principle indefinitely, and induce them to differentiate into a wide range of different cell types. Cultured ES cells from some mouse strains are routinely re-implanted into a blastocyst, and then into a mother, to give rise to normal offspring. This demonstrates that ES cells, at least those from mice, can be grown and manipulated safely in culture, and that they can generate all cell types in the body.

3.4 This research has shown that ES cells have significant potential for developing new therapies. First, they are at present the only stem cells that can be readily isolated and grown in culture in sufficient abundance to be useful. Secondly—at least for mice—they can be used to generate a normal animal, which indicates that they are unaltered and potentially safe for therapeutic use. Thirdly, ES cells have the potential to regenerate all normal cell types in the body—the only cell type currently known to have this potential (see paragraph 2.3). Finally, because ES cells are undifferentiated it is not necessary to dedifferentiate ES cells prior to differentiation into a new cell type.

POSSIBLE LIMITATIONS

3.5 The most significant potential scientific limitation on the therapeutic use of ES cells is the problem of immune rejection. Because ES cells will not normally have been derived from the patient to be treated, they run the risk of rejection by the patient's immune system. Three main approaches to overcoming this problem were described in paragraph 2.15.

3.6 It has been argued that, because ES cells have the potential to differentiate into all cell types, it might be difficult to ensure that, when used therapeutically, they did not differentiate into unwanted cell types; or undergo chromosomal alterations which generated tumours. It is clearly essential to guard against these risks, but there is no reason to believe that this is a significantly greater risk for ES cells than for other stem cells.

3.7 Current methods for growing human ES cell lines in culture are adequate for research purposes, but the requirement for co-culture of human ES cells with animal materials necessary for growth and differentiation would preclude their use in therapy. This problem, which applies to all cells grown in culture, is unlikely to be insoluble.

Adult stem cells

3.8 The potential of adult stem cells for therapeutic application is illustrated by the use of haematopoietic stem cells to treat leukaemias and other blood disorders. As discussed in paragraph 2.8, this type of whole tissue transplant probably has limited general applicability. However, recent studies suggesting that various adult stem cells have much greater potential for differentiation than previously suspected (see Box 3) have opened up the possibility that other routes to adult stem cell therapy might be available.

POTENTIAL ADVANTAGES

3.9 The developments referred to above suggest that adult stem cells may have greater therapeutic potential than had previously been thought. Their most significant potential scientific advantage is that, at least for some disorders, they might be isolated from the individual to be treated and therefore avoid rejection by the immune system when transplanted back into that same individual for therapeutic purposes.

POSSIBLE LIMITATIONS

3.10 Even if much of the potential of adult stem cells is realised, there are circumstances where they are unlikely to be useful. The isolation of some types of adult stem cells for therapy, for example the isolation of neural cells from a patient's brain, would be impractical. Similarly, where a person suffers from a genetic disorder or some types of cancers, adult stem cells isolated from that individual will retain the damaging genetic alterations underlying the disease and so be of little therapeutic value.

3.11 If adult stem cells are to be of general utility, it will be necessary to learn how to isolate them, grow them in culture and differentiate them into new cell types. The isolation and growth of adult stem cells have to date proved very difficult. Stem cells generally represent a very small proportion of cells in adult tissues. Unambiguous identification is difficult as their presence in a tissue or mixture of cells is generally inferred from a research observation rather than indicated by any specific biochemical marker which might aid their purification.[23] Although there are several reports of "enrichment"[24] of adult stem cells, there are few, if any, reports of adult stem cells being purified to homogeneity (i.e. where no other cell types are present). It has been suggested that some adult stem cells retain many of their characteristics only as a result of the presence of signals from other surrounding cells, and that maintenance in culture may therefore be difficult.

3.12 Current understanding of the potential of adult stem cells for redifferentiation is still very limited. Although many studies suggest that such processes occur, there is often a degree of ambiguity, for example whether or not the multiple new cell types arise directly from a single adult stem cell with increased potential for differentiation, or from several different stem cells each with a limited but different potential for differentiation. Moreover, it is not yet known whether adult stem cells give rise to cells of different tissue types by transdifferentiation, or by dedifferentiation to a pluripotent cell, which then differentiates into the new cell types (see Box 2).[25] The control and safety of dedifferentiation is a major challenge and one about which little is yet known (see paragraph 3.18).

3.13 The efficiency of differentiation of transplanted adult stem cells is, to date, very poor. For example, although transplantation of bone marrow into mice suffering from muscular dystrophy can lead to new, repaired muscle fibres, the efficiency is several orders of magnitude below that which would be therapeutically useful. Much research is still required to determine whether the efficiency can be enhanced.

3.14 In their natural location in the body adult stem cells do not exhibit great potential for differentiation into new cell types but have evolved to give rise only to specific cell lineages. Indeed, if they exhibited increased potential or plasticity in their natural position in the body this would have disastrous consequences: the "wrong" cell types might develop into the "wrong" tissues. The feasibility of manipulating adult stem cells to undergo dedifferentiation and redifferentiation along pathways which they do not normally exhibit, and the consequences of doing so, are as yet uncertain.

Do developments on adult stem cells make research on ES cells unnecessary?

3.15 Research on adult stem cells is at a very early stage. Without a great deal of further research it will not be clear to what extent their therapeutic potential will be realised, or for what type and proportion of potential applications adult stem cells will be applicable. Although almost all the scientists who gave evidence to us were excited by recent studies on adult stem cells, most sounded a note of caution: many of the published studies are still open to multiple interpretations or require replication; and there are many crucial scientific issues to be resolved.

3.16 We received evidence from a number of individuals arguing that recent developments in research on adult stem cells demonstrated their therapeutic potential and made research on ES cells unnecessary.[26] However, the evidence from the great majority of scientific and medical research organisations, and the experts on adult stem cells whom we consulted, did not support that view. They did not see adult stem cells and ES cells as alternatives but as complementary pathways to therapy. They argued that relatively little is yet known, and that substantially more research on both adult and ES cells is needed before the best routes for therapies can be ascertained; that, despite increasing optimism, it is still not known to what extent it will be possible to exploit adult stem cells therapeutically and in the meantime other avenues should not be closed off; and that, even if much of the potential of adult stem cell-based therapies is realised, it is unlikely that adult stem cells will fulfil all therapeutic needs.

3.17 Although adult stem cells may ultimately fulfil many therapeutic needs, the strong weight of evidence is that the full potential of adult stem cell research and its therapeutic application is unlikely to be realised without research on ES cells. This is because, apart from CNR, ES cells provide the only realistic means at present of studying the mechanisms and control of the processes of differentiation and dedifferentiation. If stem cell therapies (whether using ES or adult stem cells) are to be of clinical benefit and of demonstrated safety, a much clearer understanding of these processes is required. The utility of ES cells for studying them is clearly demonstrated by advances made from animal studies. Most future studies probably can and will be undertaken using mouse (or other animal) ES cells rather than human ES cells. Nevertheless, if safe and reliable therapies are to be developed, a comparison with human ES cells must eventually be made.

3.18 ES are needed for this purpose, partly because of the relative ease with which they can be isolated, maintained in culture and differentiated into other cell types; and partly because they are the only fully undifferentiated pluripotent cell type available for study. If scientists are to dedifferentiate adult stem cells to pluripotency, prior to redifferentiation into a new cell type for therapeutic purposes, they must know whether they have done this correctly and whether the process is safe. Differentiation involves "marking" the genetic material in a number of ways. These "markings" (including chemical changes to the DNA and the interaction of specific proteins with it) are "remembered" during cell division. If an adult stem cell is to be dedifferentiated prior to redifferentiation for therapeutic purposes, these markings must be correctly erased. In fact it is not fully established that CNR produces complete differentiation and erasing of these markings, as recent discussion of Dolly the sheep illustrates.[27]

3.19 It may be that, in time, scientific understanding of the processes involved and developments in the manipulation of adult stem cells will make research on ES cells redundant. The Committee is not convinced that this point has yet been reached or will be reached in the near future. These issues were exhaustively considered in the United States last year by the National Institutes of Health. Its comprehensive report reviewed the state of the science as at 17 June 2001.[28] Emphasising that ES and adult stem cells are different, its concluding paragraph reads:

    Predicting the future of stem cell applications is impossible, particularly given the very early stage of the science of stem cell biology. To date, it is impossible to predict which stem cells—those derived from the embryo, the foetus, or the adult—or which methods for manipulating the cells, will best meet the needs of basic research and clinical applications. The answers clearly lie in conducting more research.

3.20 Because of the importance of this issue we also asked a number of internationally renowned adult stem cell experts for their views. We received replies from Professor Helen Blau, of the Stanford University School of Medicine, Dr Jonas Frisen, of the Karolinska Institute, Stockholm, Professor Nadia Rosenthal, of the European Molecular Biology Laboratory, Monterotondo-Scalo, and Professor Angelo Vescovi, Director of Research at the Stem Cell Research Institute, Milan. They are published in the volume of evidence (pp 472-478). They were unanimous that there was a need for research on both adult and ES cells. Dr Frisen expressed his view as follows:

    My opinion is that adult stem cells are clearly different from ES cells, and that there are no scientific data suggesting the opposite. Although I believe everyone would agree that it would be very good if adult stem cells had the same potential as embryonic, this is unfortunately today only wishful thinking. I find it very important today to work on both embryonic and adult stem cells. This will ensure that potential therapies are not delayed.

3.21 Of all the scientific issues relevant to our inquiry we have given more attention to recent developments in adult stem cell research than to any other. Scientific developments in this field are so rapid that it is difficult to make any firm predictions with confidence. This in itself suggests that avenues of research should not be closed off prematurely.

Conclusions

3.22 Based on the evidence we have heard our conclusions on the research and therapeutic potential of ES cells and adult stem cells are as follows:
(a)stem cells appear to have great therapeutic potential for the treatment of many disorders that are both common and serious and for the repair of damaged tissue;
(b)until recently most research on stem cells has focussed on ES cells from animals and the derivation of ES cell lines from them; cell lines from human ES cells have the potential to provide a basis for a wide range of therapies;
(c)recent research on adult stem cells, including stem cells from the placenta and umbilical cord, also holds promise of therapies; and research on them should be strongly encouraged by funding bodies and the Government;
(d)to ensure maximum medical benefit it is necessary to keep both routes to therapy open at present since neither alone is likely to meet all therapeutic needs;
(e)for the full therapeutic potential of stem cells, both adult and ES, to be realised, fundamental research on ES cells is necessary, particularly to understand the processes of cell differentiation and dedifferentiation;
(f)future developments might eventually make further research on ES cells unnecessary. This is unlikely in the foreseeable future; in the meantime there is a strong scientific and medical case for continued research on human ES cells.


23  
For example, when an adult tissue is transplanted from one individual to another (normally carried out using mice), the transplanted tissue is observed to give rise to cells of a type not present in the original tissue. From this observation it is inferred that the transplanted tissue contains adult stem cells with the potential to differentiate into new cell types, but the stem cells themselves have not necessarily been identified or isolated. Back

24   Increasing the proportion of stem cells in a sample by removing some of the non-stem cell material. Back

25   Research by Dr I S Abuljadayel has been cited on several occasions, including in the Debate in the House of Lords on the Regulations (22 January 2001, Col 37) as supporting this proposition. As Dr Abuljadayel's work has not been published, we invited her to submit it to the Committee as evidence, which she kindly did (pp 296-306) along with other supporting material. Briefly Dr Abuljadayel claims that blood cells can be induced to dedifferentiate to a pluripotent stem cell (a process she calls "retrodifferentiation") which can then be directed to redifferentiate into different cell lineages. If this claim were borne out, it would be a major breakthrough. We have taken advice on Dr Abuljadayel's work and we are satisfied that it does not lead us to modify our conclusions. We note that her manuscript was submitted for publication to four of the leading scientific journals, but was not accepted for publication. Back

26   Notably from Dr Elizabeth Allan, who submitted a memorandum comprehensively documenting research studies involving adult stem cells (pp 306-359). Back

27   Dolly was created by dedifferentiating an adult cell nucleus by inserting it into an egg from which the original nucleus had been removed. It is remarkable that this can be achieved at all, although it is still not known whether this dedifferentiation was "perfect". It has been suggested that some of the properties of the differentiated cell have not been fully erased and that the biological age of Dolly might therefore be greater than her birth age. The same caveats could be applied to dedifferentiation of adult stem cells. Back

28   Report on Stem Cell Research, National Institutes of Health, 2001. Back


 
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