Select Committee on Stem Cell Research Report


CHAPTER 2: STEM CELLS

2.1 In this Chapter we seek to explain what stem cells are, and assess the potential of stem cell research to generate new therapies. We then examine in Chapter 3 the relative scientific advantages and disadvantages of research on ES and adult stem cells.

What are stem cells?

2.2 In the human body new cells are generated by cell division. Most specialised cells do not themselves divide but are replenished, often via intermediate less specialised cell types, from populations of stem cells. Stem cells have the capacity to undergo an asymmetric division such that one of the two "daughter" cells retains the properties of the stem cell while the other begins to "differentiate" into a more specialised cell type (see Box 1 below). Stem cells are thus central to normal human growth and development, and are also a potential source of new cells for the regeneration of diseased or damaged tissue. Stem cells are found in the early embryo, in the foetus, in the placenta and umbilical cord, and in many (possibly most) tissues of the body. As stem cells from different tissues have different physical properties, they are difficult to identify by their physical characteristics alone. Stem cells from different tissues, and from different stages of human development, vary in the number and types of cells to which they normally give rise.

Box 1

  
Differentiation

  
In the course of human development a single cell, the fertilised egg, ultimately gives rise to more than 200 cell types (blood cells, neural (brain) cells, liver cells etc) which make up the human body. This process, whereby less specialised cells turn into more specialised cell types, is called "differentiation". As all cells in the body have (with few exceptions) the same genes, differentiation occurs, in large part, by switching on ("expressing") or switching off ("repressing") different subsets of these genes. Thus, differentiated cell types express different subsets of genes. For example, red blood cells express the gene making haemoglobin (the protein which carries oxygen around the body) but neural cells do not. In general as cells become more specialised (differentiated) the subset of genes that they can express becomes more restricted.

2.3 We describe in Chapter 4 the process of human embryonic development. At the earliest stages after fertilisation (up to about the eight cell stage) all the cells are "totipotent" (i.e. they have the capacity to develop into every type of cell needed for full human development, including the extra-embryonic tissues such as the placenta and umbilical cord). After about five days the blastocyst stage is reached. Within this ball of 50 to 100 cells there is the inner cell mass comprising about a quarter of the cells, from which a unique class of stem cells, embryonic stem cells (ES cells), can be derived. Unlike any other type of stem cell yet identified, ES cells have the innate capacity ("potential") to differentiate into each of the 200 or so cell types which make up the human body, and are described as "pluripotent". The potential of different types of stem cells is described in more detail in Box 2.

2.4 As development proceeds beyond the blastocyst, stem cells comprise a progressively decreasing proportion of cells in the embryo, foetus and human body. However, many, if not most, tissues in the foetus and human body contain stem cells which, in their normal location, have the potential to differentiate into a limited number of specific cell types in order to regenerate the tissue in which they normally reside. These stem cells, described as "multipotent", have a more restricted potential than ES cells, in that they normally give rise to some but not all the cell types present in the human body. Extra-embryonic tissues such as the placenta and umbilical cord also contain multipotent stem cells with the same genetic makeup as the cells of the embryo.

Box 2

  
The potential of stem cells

  
Stem cells from different sources differ in their potential for differentiation, i.e. in the number of cell types to which they can normally give rise. Stem cells which can give rise to all the cells required for human development, including extra-embryonic tissues, are described as "totipotent". Stem cells which can give rise to multiple, but not all, cell types are generally referred to as "multipotent". For example, haematopoietic (blood) stem cells from the bone marrow are multipotent as they give rise to the several different cell types present in blood but do not normally develop into e.g. neural cells. Sometimes the term "pluripotent" is used interchangeably with "multipotent" and this can cause confusion. We use "pluripotent" to refer to a stem cell which can give rise to every cell type in the human body, in contrast to "multipotent", which refers to stem cells which give rise to many, but not all, cell types in the body. As pluripotent cells cannot give to the extra-embryonic tissues they are not totipotent.

2.5 ES cells are a very specific class of stem cell which can be derived from the blastocyst. Other stem cells from later in the development of the early embryo or foetus, sometimes also (confusingly) referred to as embryonic stem cells, are not known to be pluripotent. Indeed, other embryonic, foetal and extra-embryonic stem cells are more akin to adult stem cells than to ES cells. (It has been suggested that it is more appropriate to refer to all stem cells in the body, whether embryonic, foetal or adult as "somatic" to distinguish them from ES cells.[20]) The use of different definitions, both in the scientific literature and in the evidence we received, can be confusing but is perhaps inevitable in a rapidly moving scientific field where hard and fast boundaries cannot always be drawn.[21]

The potential of stem cells for developing new therapies

2.6 Because of their ability to reproduce themselves, and to differentiate into other cell types, stem cells offer the prospect of developing cell-based treatments, both to repair or replace tissues damaged by fractures, burns and other injuries and to treat a wide range of very common degenerative diseases, such as Alzheimer's disease, cardiac failure, diabetes, and Parkinson's disease. These are some of the most common serious disorders, which affect millions of people in the United Kingdom alone, and for which there is at present no effective cure. Stem cell treatments, unlike most conventional drugs treatments, have the potential to become a life-long cure.

2.7 This potential has given stem cell research a high profile and is leading to significant interest and investment in academic, medical and commercial research throughout the world. The main funding bodies gave evidence on the level of their investment in stem cell research (much of it in work on animals):

    (a)  the Biotechnology and Biological Research Council has invested about £17 million in stem cell research over the last ten years (p 230);

    (b)  the Chief Executive of the Medical Research Council (MRC), Professor Sir George Radda, told us that the MRC gives stem cell research a very high strategic priority and supports it to the tune of about £4.5million a year (Q 128); and

    (c)  since 1995 the Wellcome Trust has awarded some 15 project and programme grants specifically for stem cell research, totalling about £4.5million. Although this is only just over half of one per cent of the total Trust spend, the Director of the Trust, Dr Mike Dexter, envisages many more applications in the future (Q 334).

Although the amounts so far invested are relatively modest, all the funding bodies saw this as a major growth area.

2.8 The simplest way of using stem cells for therapy is by implanting a tissue which contains appropriate stem cells into an individual in whom that tissue is diseased or damaged, so that the transplanted stem cells regenerate the various cell types of that tissue. This type of therapy is in routine clinical use for treating patients with leukaemia and other blood disorders by introducing haematopoietic stem cells, for example by bone marrow transplants. Despite the fact that such treatments have been successfully applied for about 20 years, few other examples of this type of approach have been developed. This is because the haematopoietic system is unusual in its accessibility and in the fact that it has evolved specifically to continuously replenish cells in the blood at high rates.

2.9 Recent scientific advances have opened up the possibility of treating a much wider range of disorders by isolating and growing stem cells in the laboratory. In some cases it may be possible to administer stem cells directly to an individual, in such a way that they would migrate to the correct site in the body and differentiate into the desired cell type in response to normal body signals. However, currently it seems more likely that stem cells will be grown and induced to differentiate into a defined cell type in the laboratory prior to implantation. In the longer term it may also be possible to induce stem cells to differentiate into several cell types, generating whole tissues, prior to implantation. For these approaches a much greater understanding of differentiation and developmental "signals" will be required.

2.10 None of our witnesses seriously questioned the therapeutic potential of stem cells for a wide range of disorders. There were differences of view as to when such therapies might be realised. Most witnesses believed that the introduction of effective stem-cell based therapies would be a gradual process over the next five to twenty years, requiring much basic and clinical research prior to clinical application. This is a normal time-span for the development of any new treatment. Even "conventional" drugs therapies take five to fifteen years and several hundred million pounds of investment to reach the patient.

The research path to therapeutic application

2.11 Any potential new treatment for disease requires a great deal of scientific and clinical research before it can be made available to patients. Three necessary steps can be distinguished. First, basic scientific research is required to establish what may or may not be possible, and to identify the best approaches to take and any pitfalls to be avoided. (The types of research questions which must be answered if stem cell therapies are to be developed effectively are set out in paragraph 2.13 below.) Secondly, pre-clinical studies in animals (normally mice) and small-scale clinical studies in human volunteers must be carried out to gain "proof of principle" for each new therapy and to ascertain whether it is safe and whether or not there may be significant side-effects. Thirdly, large-scale clinical trials are required to determine whether the therapy is of real clinical benefit and to further assess and assure safety. In the development of most therapies there is an iterative process between the first and second stages, during which blind alleys are eliminated and the best approaches refined. The great majority of potential stem cell-based therapies are still at the first stage of this process, basic scientific research.

2.12 Stem cell research is currently subject to very rapid change and our report can reflect only the current state of knowledge. From the evidence we have received we are clear that over the next few years most studies on stem cells, whether adult, foetal or embryonic in origin, will be basic research. This research will not in itself be therapeutic, but will be undertaken with the aim of gaining the understanding necessary if stem cells are to be used widely for therapeutic benefit. The potential for stem cell therapies to last the life of the individual patient makes it particularly important to ensure that any safety issues are identified and resolved satisfactorily. Only after considerable advances in understanding processes such as the control of differentiation will it be possible fully and safely to exploit stem cells to treat or cure individuals.

2.13 There is unlikely to be a single approach to the use of stem cells in therapy: different disorders are likely to require different types of stem cell and different therapeutic approaches. For example, for some treatments it may be possible to transplant whole tissues without isolating stem cells (as with bone marrow transplants), whereas for others it may be more effective to purify and grow stem cells in the laboratory prior to differentiation and reimplantation. In order to exploit stem cells to the full it is likely to be necessary to:

    (a)  identify and characterise the specific stem cells to be used. Currently stem cells are primarily defined only by their biological function; if stem cells are to be isolated and purified for therapeutic purposes, scientists must be able to identify unique characteristics which will allow them to be isolated routinely, efficiently and reliably from amongst the millions of cells in a tissue;

    (b)  isolate and purify the required stem cells in sufficient numbers to be useful. Stem cells often form a very small proportion of cells in a tissue.

    (c)  grow stem cells in the laboratory under "clean" conditions so that they (or cells derived from them) can be transplanted back into patients; doctors must be certain that the properties of the cell have not changed in the laboratory, and that there are no contaminants that might cause harm if used to treat patients;

    (d)  show that stem cells, once isolated from their normal location and grown in the laboratory, do not undergo unwanted changes in their properties. For example, all stem cells have the potential to divide, and it is therefore important to ensure that any manipulation does not alter the control of this division process and create a risk of generating cancerous cells;

    (e)  "direct" stem cells to differentiate efficiently into specific cell type(s) required for therapeutic purposes, and ensure that this process does not give rise to any inappropriate cell type. Scientists still know little about the signals which direct differentiation;

    (f)  understand the differentiation process so that when a stem cell has been induced to differentiate into a specific cell type, scientists can be sure that that cell is indistinguishable from normal cells of the same type in the body and will integrate properly with them;

    (g)  understand the dedifferentiation process so that, if an adult stem cell is dedifferentiated to enhance its normal potential, scientists can be sure that this has been achieved accurately and that the signals it originally acquired during differentiation have been erased;

    (h)  understand how stem cells get to and remain in their proper location in the body, so that when they (or cells derived from them) are transplanted into the body they do not migrate to inappropriate locations;

    (i)  avoid immunological rejection of any implanted cells.

2.14 Until recently it has generally been considered that in mammalian cells the process of differentiation is irreversible. However, it has been demonstrated in animals that it is possible to reprogramme ("dedifferentiate") the genetic material of a differentiated adult cell by CNR (see Chapter 5). Following this seminal finding, many studies have also suggested that adult stem cells may have greater "plasticity"[22] than previously suspected: they may be reprogrammed to give rise to cell types to which they do not normally give rise in the body. The potential of specialised cells to differentiate into cell types other than those to which they normally give rise in the body is little short of a revolutionary concept in cell biology. It has significantly increased the possibilities for developing effective stem cell-based therapies.

Box 3

  
Increased plasticity of adult stem cells

  
Recently it has been observed that some relatively specialised stem cells can be induced (at least under some conditions) to give rise to a wider range of cell types than had been expected. For example, it has been reported that stem cells from blood, which in the body normally give rise only to blood cells, can be induced to differentiate into neural cells. This process might occur in one of the following ways:
     (a)  the original stem cell might dedifferentiate to pluripotency and then be reprogrammed to generate the second cell type; or
     (b)  the original cell might change into the second cell type without going through a dedifferentiated intermediate stage, a process sometimes called "transdifferentiation".
Little is known about such increased "plasticity", which is based on observations from which plasticity is inferred rather than on an understanding of the processes involved.


Immunological rejection of stem cell-based therapies

2.15 Immunological rejection is a particularly important consideration for stem-cell based therapies. The human body possesses an immune system which recognises cells that are not its own and rejects them. The immune system has evolved primarily as a protection against micro-organisms that cause disease. However, the body also rejects human cells or tissues that do not belong to it. Immune rejection is one of the major causes of organ transplant failure and is one of the problems which will need to be overcome for any stem cell-based therapy to be effective. There are three main ways of avoiding or repressing immune rejection of transplanted cells or tissues:

    (a)  The use of immuno-suppressant drugs. These drugs have been refined over many years, as part of organ transplantation research. However, they are not always effective; they must normally be taken over the lifetime of the patient; and they leave the patient open to infection.

    (b)  Using "matching" tissues. Sometimes during transplantation it is possible to get a matched tissue type, usually from a near relative. This is often sought for bone marrow transplants. Finding a matching donor is unlikely to be a useful approach for most cell-based therapies. However, because stem cells can, in principle, be cultured indefinitely, it might be possible to establish stem cell banks of sufficient size to comprise stem cells with a reasonable (though never perfect) match to the majority of individuals in the population. If this proved possible, the appropriate matching stem cell from the bank could be selected and differentiated into the cell type required for therapy. Several thousand stem cell lines would be needed to obtain matches to the majority of the British population comparable with those achieved with matched bone marrow transplants.

    (c)  Using the individual's own cells or tissues. This would be the surest means of avoiding immune rejection. Adult stem cells isolated from an individual, and then used to treat him or her, offer one possible way of achieving this, although not in all circumstances. Alternatively CNR could be used to generate cells or tissues that match those of the patient, although it is generally thought that this approach is unlikely to provide the major therapeutic route (see Chapter 5).


20  
See memorandum by Professor Angelo Vescovi (pp 473-475). Back

21   This is exemplified in recent debate over the efficacy or otherwise of stem cell transplants for Parkinson's disease. A study in 2001 (reported in the New England Journal of Medicine (344:710-719)) suggesting that such a treatment had unwelcome side-effects has been cited by some as grounds for concern about the safety of embryonic stem cells. However, although these experiments were carried out with stem cells from an embryo, they were in fact from 7-8 week embryos and were therefore foetal and not ES cells. Back

22   The capacity of a cell to develop into different cell types. Back


 
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