CHAPTER 5: CELL NUCLEAR REPLACEMENT AND
CLONING
The additional purposes
in the Regulations
5.1 As described in Chapter 1, the 2001 Regulations extend the
purposes for which research on early embryos may be undertaken
from purposes connected with reproduction and treating infertility
to certain purposes concerned with understanding the development
of the embryo and increasing knowledge of, and developing treatments
for, serious disease. The possibility of an extension was foreshadowed
in the 1990 Act, which provides (in Schedule 2) for the original
purposes to be extended by regulation.
5.2 In the debates on the Regulations one of the
issues on which there was disagreement was whether the change
effected by them was a matter of degree or such a substantial
change that, as some argued, it should have been introduced by
fresh primary legislation.
5.3 We asked all our witnesses if they saw the additional
purposes as raising new issues of principle. Some—mostly
(but not exclusively) those opposed to research of any kind on
early embryos—contended that new issues of principle did
arise, in so far as the original purposes were strictly limited
to reproductive research, while the new purposes were much more
widely drawn. In their view the purpose of understanding the development
of the embryo entailed basic research rather than research directed
at specified desirable objectives. The All-Party Parliamentary
Pro-life Group, for example, argued that "the regulations
allow 'pure' research on human embryos, without reference to clinical
goals, for the first time" (p 213). In his memorandum Lord
Habgood said: "they [the Regulations] are much too open-ended
and are thus in danger of destroying the broad ethical consensus
on which the original regulations are based" (p 390). It
was also argued that under the Regulations the embryo would be
used instrumentally, as a means to an end, whereas under the original
purposes, the research, although it could not benefit the embryo
that was the subject of it, was at least intended to benefit the
class of embryos as a whole by improving reproductive techniques.
On the other hand, the view was also put to us by the Society
for the Protection of Unborn Children that there was no difference
in principle because all destructive research on embryos is unethical
(p 111).
5.4 The majority of our witnesses, however, did not
see the additional purposes as raising new issues of principle.
They regarded treating serious disease as at least as worthwhile
as promoting advances in the treatment of infertility, and we
find that a persuasive argument. In our view it is difficult to
maintain that the embryo is being used instrumentally under the
new purposes but not under the original purposes, one of which
is developing more effective techniques of contraception, which
can hardly be said to benefit the class of embryos. We accept
that, as we explained in Chapter 2, at least initially, some of
the research carried out under the Regulations is likely to be
basic research, designed for example to understand the process
of cell differentiation. Basic research is a necessary step
to developing treatments and facilitating the potential use of
adult stem cells and should be permitted under the Regulations
in the same way as more directly applied research to which it
is designed to lead, provided that it is subject to strict regulation.
Cell nuclear replacement
5.5 If the extension of the purposes had been the only point at
issue in the Regulations, it is unlikely that they would have
attracted the degree of attention that they did. What underlay
anxiety about them was the perception that they would permit the
creation of embryos by the technique of CNR—popularly described
as cloning. That was seen as objectionable for two main reasons:
first, because it would be one way of creating embryos specifically
for research or therapeutic purposes; and, secondly, because it
would be a step on the slippery slope to "reproductive cloning",
that is the production of a baby by implanting the embryo generated
by CNR in a woman's uterus and allowing full development. It was
also seen as contrary to the spirit of the 1990 Act, section 3
(3)(d) of which prohibits "replacing a nucleus of a cell
of an embryo with a nucleus taken from a cell of any person, embryo
or subsequent development of an embryo", the only form of
cloning known at the time.
5.6 CNR is the process of inserting the nucleus of
an adult cell into a donated egg from which the original nucleus
has been removed. Following CNR, if the recipient egg is induced
to divide, an embryo can be produced. CNR was the first step in
the process by which Dolly the sheep was created.
5.7 CNR is, potentially, a way of producing compatible
tissues for patients which will not be rejected by their immune
systems. It would involve creating a zygote by CNR using a nucleus
from an adult cell of the individual to be treated, and growing
it to the blastocyst stage. ES cells would be isolated from the
blastocyst (which would be destroyed in the process) and differentiated
in vitro to produce cells or tissue for implantation. The
process is illustrated in diagram 1 The use for therapy of ES
cells produced in this way has a potential advantage over the
use of ES cells isolated from early embryos created by IVF, because
the genetic material would be derived from the individual to be
treated and so would not be rejected by the host immune system.
5.8 The procedure described in paragraph 5.7 is often
referred to as "therapeutic cloning", to reflect the
fact that it is envisaged only as a means of generating ES cells
for direct application in treatment and therapies: the embryo
itself is grown only to the blastocyst stage and is not implanted
or allowed to develop further. This is in contrast with "reproductive
cloning", in which the blastocyst would be implanted in a
woman's uterus with a view to producing a baby. Thus, the distinction
between "therapeutic" and "reproductive" cloning
is based on the steps following CNR, and reflects the purpose
for which it is undertaken. The initial process (to the blastocyst
stage) is identical. Under the Human Reproductive Cloning Act
2001 the implantation in a woman of a CNR embryo is now a criminal
offence. In this report we refer simply to the technique—cell
nuclear replacement—by which a blastocyst is produced by
CNR for non-reproductive purposes.
5.9 The majority scientific view presented to the
Committee was that for practical reasons CNR is unlikely to provide
a general basis for therapies in the foreseeable future. We were
told that individualised treatments using the patient's own cells[36]
would be difficult and expensive and would require a continuing
supply of human eggs, which is unlikely to be forthcoming on a
large scale. Some medical charities and patients' support groups
argued that female members of a patient's family would be prepared
to donate eggs for altruistic motives, and this is no doubt true
in some cases. Opponents of CNR argued that it would be difficult
to avoid pressure being brought to bear on potential donors, although
that is a problem that has up to now been dealt with successfully
in the United Kingdom by strict regulation of gamete donation,
including a prohibition on payment. As a response to these problems
it has been suggested that CNR might be used to generate a bank
of ES cells from which the best "match" with the patient
could be selected to minimise the risk of immune rejection. Several
thousand ES cell lines generated by this process would be required.
Whether this is a realistic possibility remains to be seen.
5.10 However, even if CNR does not become a general
basis for therapies in the foreseeable future, it still has significant
potential as a research technique since it would provide a powerful
approach to studying the process of dedifferentiation. In producing
Dolly the sheep CNR has shown that dedifferentiation of adult
cells is possible and gave a major impetus to research into that
process. The biochemical signals which control the process of
dedifferentiation and maintain the genetic material in a pluripotent
state are contained in the oocyte (female egg). CNR research at
present provides the only realistic means of identifying these
factors and establishing how to reverse the signals that "mark"
the DNA during differentiation and must be erased during dedifferentiation.
5.11 The Regulations make no direct reference to
CNR. The 1990 Act did not specifically prohibit the creation of
embryos by CNR—the technique had not been used successfully
on mammals at that time, and was not until Dolly the sheep was
created in 1996; and the Regulations did not specifically authorise
it. When CNR became a practical possibility the Department of
Health was of the opinion, on the basis of counsel's advice, that
the definition of "embryo" in the Act would include
CNR embryos so that research on them—whether under the Act
or the Regulations—would be regulated by the HFEA in the
same way as research on fertilised embryos. This view has now
been upheld by the Court of Appeal (although, as noted in Chapter
1, there is the possibility of a final appeal to the House of
Lords).
5.12 No application has been made to the HFEA for
a licence to create embryos by CNR for research related to the
original purposes in the Act. As long as the purposes were limited
to reproductive purposes, there was little reason to seek to create
embryos by CNR. However, it is generally accepted that extending
the purposes to understanding the causes of (and by implication
developing treatments for) serious disease is likely to stimulate
applications to do research involving CNR embryos.
5.13 The 1990 Act already allows embryos to be created
for research, although as noted in Chapter 3 only 118 have been
created for research purposes since the Act came into force. A
few of our witnesses drew a distinction between the creation of
an embryo (for research) by IVF and by CNR on the ground that
the latter represented a further step away from natural means
of creating embryos. But the main ground of opposition to the
creation of embryos by CNR was that it would increase the likelihood
of such embryos being implanted in a woman. We discuss this "slippery
slope" argument later in this Chapter. Although there
is a clear distinction between an IVF embryo and an embryo produced
by CNR (or other methods) in their method of production, the Committee
does not see any ethical difference in their use for research
purposes up to the 14 days limit.
5.14 The Committee concludes that, even if CNR
is not itself used directly for many stem cell-based therapies,
there is still a powerful case for its use, subject to strict
regulation by the HFEA, as a research tool to enable cell-based
therapies to be developed. However, as with embryos created by
IVF for research, CNR embryos should not be created for research
purposes unless there is a demonstrable and exceptional need which
cannot be met by the use of surplus embryos.
Oocyte nucleus transfer
5.15 Oocyte nucleus transfer, a process akin to CNR, may have
the potential for treating mitochondrial diseases. Mitochondria
are small energy-producing structures present in every cell. They
were described by one of our interlocutors as filling the role
of batteries or a power pack. Most of a cell's DNA[37]
is contained in the nucleus, but a very small amount (less than
one per cent) is found in the mitochondria. Alterations in the
mitochondrial DNA result in a number of relatively rare but very
serious diseases. Mitochondria are present in the female egg,
but are not transferred from the male sperm during fertilisation,
so the mitochondria of the embryo are derived exclusively from
the mother and mitochondrial diseases are transmitted only through
the maternal line.
5.16 If a woman is a carrier of mitochondrial disease,
oocyte nucleus transfer might offer the possibility of preventing
its transmission to her children. Using this technique, the nucleus
would be extracted from the woman's egg and transferred to a donated
egg from which the nucleus had been removed. The egg could then
be fertilised by IVF and implanted in the mother. The procedure
is illustrated in Diagram 2. The resulting embryo would receive
the vast majority of its genes from the mother and father in the
normal way—it would not be a clone—but the small number
of mitochondrial genes would come from a third person, the woman
who donated the egg. This is sometimes characterised as the resulting
baby having two genetic mothers.[38]
5.17 The Donaldson report noted that very little
research has been carried out on this procedure, and that it would
need extensive testing in animal models, and with human eggs,
before it could be used therapeutically in humans. [39]
5.18 It has been suggested that oocyte nucleus transfer
would constitute a breach of the prohibition on germ-line gene
therapy.[40]
Because of the transmission of mitochondrial DNA, the procedure
would involve a (relatively small) modification of the human genome.[41]
However, this issue does not arise at the research stage, which
is the extent of our remit, and should not therefore be a barrier
to research.
5.19 A further objection that has been raised is
that the procedure would breach the 14 days limit for human embryo
research. We do not see that research into oocyte nucleus transfer
would breach the 14 days limit any more than it does with CNR.
The Human Genetics Advisory Commission and the HFEA concluded
in their 1998 Report that CNR would not breach the 14 days limit.[42]
They said, "whether the nucleus to be replaced in an enucleated
oocyte is taken from an adult or from another embryo, the clock
is put back to the beginning, embryonic development starts over
again and the primitive streak stage specified in the Act would
still not be reached within the 14 day time limit".
5.20 The Regulations with which we are concerned
relate only to research. There is no doubt that mitochondrial
diseases are serious diseases and oocyte nucleus transfer may
have great potential for treating them. There is a strong scientific
and medical case for further research into it and we conclude
that if CNR is permitted in certain limited circumstances,
oocyte nucleus transfer should also be allowed for research
purposes.
"Reproductive cloning"
5.21 The question of human reproductive cloning is not central
to our terms of reference, since it was never envisaged that it
would be permitted under the Regulations. However, we have examined
the issues surrounding it because of the argument that the use
of CNR for research purposes represents a slippery slope to reproductive
cloning.
We set out our analysis in more detail in Appendix 6. In summary
the Committee's conclusions are that:
(a) given the high risk of abnormalities,
the scientific objections to human reproductive cloning are currently
overwhelming;
(b) there are further strong ethical objections
in addition to those based on the risk of abnormalities, although
not all the arguments deployed against reproductive cloning are
equally valid. The most powerful are the unacceptability of experimenting
on a human being and the familial and child welfare considerations
arising from the ambiguity of the cloned child's relationships;
and
(c) the Commitee unreservedly endorses the
legislative prohibition on reproductive cloning now contained
in the Human Reproductive Cloning Act 2001.
5.22 Is there then a risk that allowing the use of CNR for research
purposes would make reproductive cloning more likely? In so far
as the starting point is the same, there is no doubt that developing
the CNR technique would in technical terms facilitate reproductive
cloning. But the fact that a technique developed for a worthwhile
purpose may be used for different, unacceptable, purposes is not
a conclusive argument for prohibiting it. Both the potential benefits
and disadvantages and the level of risk and possible safeguards
need to be taken into account.
5.23 Some pronouncements give the impression that it would be
a simple matter to produce a cloned baby. This is far from the
case. Apart from the practical problems referred to in Appendix
6, it would require a well-equipped fertility clinic and the services
of a number of different specialists. Any clinic participating
in this work would lose its licence from the HFEA, and the personnel
involved would now be at risk of committing a criminal offence
punishable with ten years' imprisonment.
5.24 The HFEA has an excellent record in ensuring
that IVF clinics comply with the law, and we are satisfied that
its regulatory powers, now reinforced by a specific statutory
prohibition, provide sufficient protection against the development
of CNR leading to reproductive cloning in the United Kingdom.
5.25 The regulatory system in the United Kingdom
cannot, of course, prevent attempts to undertake reproductive
cloning in other countries. We discuss in Chapter 7 the case for
seeking to negotiate an international ban on reproductive cloning.
36 i.e. using CNR to produce cells or tissue genetically
identical to the patient's. These considerations would not apply
to the same extent if CNR were used to create stem cell lines. Back
37
Deoxyribonucleic acid-the cell's and the body's genetic material. Back
38
An alternative approach to preventing the transmission of mitochondrial
disease would be simply to use a donated egg for fertilisation
by the father's sperm, but the resulting embryo would not, of
course, then contain any of the mother's genetic material. Back
39
Paragraph 4.25. Back
40
A modification of the human genome in which a person's genetic
material (DNA) is altered in the germ cells such that the alteration
can be passed to the next generation. Back
41
The complete genetic material of an individual. Back
42
Cloning Issues in Reproduction, Science and Medicine, December
1998. Back
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