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Therapeutic
use of human cloning techologies
A Genetic Interest Group Policy Paper
It is two and a half years since the possibility of using
cloning technologies on humans for therapeutic ends was put
firmly on the agenda by the cloning of Dolly the sheep at
the Roslin Institute in Edinburgh. Progress has been rapid
since then. Geron Corporation, the American company which
now owns the commercial spin-off of the Roslin Institute,
has combined its own expertise in stem-cell research with
Roslin's expertise in nuclear transfer technology to lay the
basis for beginning work in this area. Another American biotechnology
company, Advanced Cell Technology, is also up and running.
It is safe to say that many other private sector companies
and academic researchers are keenly interested in this area.
It was against this background that the Human Genetics Advisory
Commission and the Human Fertilisation and Embryology Authority
(HFEA) issued a joint recommendation in December 1998, following
a period of consultation and study, that the Government should
give the go ahead for the work. To the surprise of both supporters
and critics of therapeutic use of cloning technologies, this
June the Government delayed taking a decision on the matter;
instead it set up an expert advisory group under the chairmanship
of the Chief Medical Officer, Professor Liam Donaldson, which
is to seek the views of a range of experts from across the
world and then report early next year. But while both sides
might have been surprised, there seems little doubt that it
is the opponents of the new technology who have taken most
comfort from the decision. Mark Nicholls of MATCH (Movement
Against The Cloning of Humans) said: "We're obviously delighted…
this is one battle won, but the war is certainly not over."
Conversely, the biotechnology companies at the forefront of
the work expressed their disappointment, and Lord Winston
condemned the Government's decision as "immoral".
The purpose of this paper is to present an outline of the
science and its possible applications, before moving on to
a discussion of GIG's approach to the ethical and regulatory
issues.
Therapeutic Use of Cell Nucleus Replacement
As the attentive reader will notice, the phrasing in the above
sub-heading differs from the wording of the paper as a whole,
although it means the same thing. The Human Genetics Advisory
Commission / HFEA report preferred 'therapeutic use of cell
nucleus replacement' to 'therapeutic use of human cloning
technologies', or 'therapeutic cloning', in part for reasons
of clarity but in particular because the word 'cloning', especially
when attached to 'therapeutic', conjures up entirely the wrong
mental image of the research that might be undertaken. This
is an understandable concern. The novel Spares is built around
a 'farm' where rich people keep clones of themselves in a
permanent childlike state, so that their organs can be 'harvested'
as and when needed for transplant. Author Michael Marshall
Smith has the clones living in tunnels, 'waiting to be whittled
down'. The tunnel is the butcher's shop, the clones the meat.
Suffice it to say that nothing of the sort is being proposed!
Once this is understood, the occasional use of such terms
as 'therapeutic cloning' shouldn't cause too much harm, and
is hard to avoid at times because the starting point for many
of the possible new therapies is the nuclear transfer technology
pioneered by the team that made Dolly the cloned sheep.
Dolly is a clone in the popularly understood sense of the
term. In precise scientific terms she is not an identical
copy of another sheep, but she is very close. Dolly was formed
by inserting the nucleus taken from the cell of an adult sheep
into an egg of another sheep which had had its own nuclear
material removed. The egg was then induced to begin the process
of division and implanted in another sheep. In the normal
process of fertilisation half the genetic complement of the
fertilised egg comes from the mother and half from the father.
In the creation of Dolly, the full complement came from the
original adult sheep. In this sense Dolly is a copy. But she
will differ by a small amount genetically—the part that is
not contained in the nucleus of the cell—from her progenitor,
and by a further amount biologically due to different environmental
experiences.
When Dolly was cloned it was already understood that the same
technology could be used therapeutically for humans. In transplants
one of the major problems is tissue rejection—the body recognises
the donor tissue as foreign and mounts an immunological response.
But if cell nuclear transfer could be used to make cells with
the same genetic make-up as the patient's, the problem of
rejection could be overcome. Unlike in a cloned adult, the
cloned cell nuclei would be true identical copies, making
the cells the perfect replacements for the damaged or diseased
originals.
A major step towards realising this possibility was made at
the end of 1998, when scientists working in collaboration
with Geron Corporation announced that they had succeeded in
establishing cell culture lines of human embryonic stem cells.
Karen Lebacqz and colleagues on the Geron Ethics Advisory
Board give this summary of the significance of the work: 'because
these cells are considered pluripotent (capable of being the
precursors to a variety of human cell types) and immortal
(sustainable in culture and reproducing themselves indefinitely),
they represent a major breakthrough in scientific research,
with potential for significant advances in tissue transplantation,
pharmaceutical testing, and embryology.' John Gearhart of
Johns Hopkins University was one of the pioneers of this work.
It is worth quoting his groundbreaking paper at length on
the potential of the cell lines having these properties:
'It is exciting to speculate on how human ES lines could be
used in tissue transplantation therapies. Obvious clinical
targets would include neurodegenerative disorders, diabetes,
spinal cord injury, and hematopoietic repopulation. In addition
to possibly providing large numbers of pure populations of
cells for transplantation, ES cells would also lend themselves
to several strategies for the prevention of immunological
tissue rejection after transplantation, including (i) banking
of multiple ES cell lines representing a spectrum of major
histocompatability complex (MHC) alleles to serve as a source
for MHC matching; (ii) creation of universal donor lines,
in which the MHC genes could be genetically altered so rejection
would not occur, an approach that has been tried with moderate
success in the mouse; (iii) customization of ES cells through
transgenesis and gene targeting so that a potential recipient's
MHC genes are introduced into ES cells through homologous
recombination; and (iv) production of ES lines containing
the genome of the prospective recipient. Blastocysts obtained
through nuclear transfer would be used to generate ES cells,
which could then be differentiated to specific lineages for
transfer to the nuclear donor. Because EG [embryonic germ]
cells have been shown to reprogram adult nuclei after cell
hybrid formation, it may eventually be possible to do nuclear
transfers into pluripotent stem cells, which could then be
expanded and differentiated.'
All the areas outlined by Gearhart contain great potential—it
is no wonder that Harold Varmus, director of the National
Institutes of Health, recently described stem cell research
as having the 'potential to revolutionise' the practice of
medicine. For our purposes, it is Gearhart's fourth category
that is of most direct interest. As he points out, the marriage
of nuclear transfer technology and stem cell research promises
ES cells 'which could then be differentiated to specific lineages
for transfer to the nuclear donor.' This would not involve
creating carbon copies of people as depicted in Spares, nor
even fetuses with differentiated organs: all that would be
required would be to create a very early embryo in the lab
using nuclear transfer technology, from which ES and then
differentiated cells could be produced.
The next stage in the research is to do what Gearhart suggests:
work out how to develop specific lineages from ES cells. This
would then open up the possibility of new treatments for degenerative
diseases of the heart, liver, kidneys and cerebral tissue.
Further into the future, if such lines of stem cells could
also be modified to repair genetic defects carried by the
patient, the treatment of diseases such as leukaemia and many
rarer genetic disorder, of the skin for example, could be
revolutionised. ES cells also offer many avenues for basic
research. For example, studies of stem-cell differentiation
could provide valuable information about the mechanisms of
ageing or the causes of cancer.
In its consultation, the Government asks whether there is
an identified need for research on human embryos and involving
cloning techniques for therapeutic purposes. It also asks
whether there are alternatives that do not involve the creation
of human embryos in vitro. For GIG the need is clear. But
it is unfortunate that the Government feels the need to ask
the field to justify itself in such a way. It is creating
a hurdle, which could be interpreted as ruling out basic research.
As Professor David Latchman, vice-chairman of the medical
advisory panel of the Parkinson's Disease Society put it:
'there is a paradox in this announcement. The Government says
we need to see if this therapeutic research is likely to be
valuable, but it's going to be quite hard to find that out
without carrying out the research.'
GIG does not feel that the creation of cloned cell lines for
use in the treatment of disease, or similar possibilities
which might result in improvements in human health, poses
any additional ethical dilemmas over and above those which
are created by existing aspects of genetic medicine and assisted
conception. Indeed, the possibility of undertaking research
and development in this area and choosing not to do it is
not ethically neutral, in that such a decision would leave
families to be affected by disease or disability that might
otherwise have been treated.
When the Human Fertilisation and Embryology Act was passed
in 1990, the conservative philosopher Roger Scruton penned
an article entitled 'Embryo Farmers: the children of Mengele'.
The case against using cloned embryos in research made from
this quarter today is essentially the same as the argument
made against the use of all embryos in research and IVF procedures
back then. And in a sense, the argument for it is also very
similar, a point the Government should note. As the philosopher
John Harris puts it: 'If it is acceptable to produce spare
embryos in pursuit of successful pregnancy then it must be
justifiable to produce them in pursuit of something plausibly
of the same moral magnitude. Saving a life-in-being surely
comes into that category.'
Looking beyond the research stage, GIG believes that the development
and applications of the outcomes of research using nuclear
transfer technology does not raise any additional ethical
implications. Use of derived cells would have to meet safety
and efficiency requirements. But assuming these can be met,
it must follow on from the successful completion of research.
Legal and Regulatory Issues
It has been determined that both human reproductive cloning
and therapeutic cloning are currently illegal in the UK. The
former is ruled out because, among other things, the implantation
of experimental embryos is forbidden. Research on therapeutic
cloning is ruled out because it does not fall within the permitted
reasons for the creation and maintenance of embryos outside
of the human body as laid down in the Human Fertilisation
and Embryology Act. Under the terms of the Act a specific
HFEA licence is required for any research that involves the
creation, keeping or use of human embryos outside the body.
The HFEA cannot grant a licence unless it is satisfied that
the use of human embryos is essential for the research, which
must be for one of the following purposes:
- to promote advances in the treatment of infertility
- to increase knowledge about the causes of congenital
disease
- to increase knowledge about the causes of miscarriages
- to develop more effective techniques of contraception,
or
- to develop methods for detecting the presence of
gene or chromosome abnormalities in embryos before implantation.
In their joint report of December 1998, Cloning: Issues in
Reproductive Science and Medicine, the HFEA and the Human
Genetics Advisory Commission recommended that the purposes
for which human embryos may be used in research under UK legislation
should be extended to include research to develop methods
of therapy for:
- mitochondrial diseases
- diseased or damaged tissues or organs
GIG supports this proposal. Both areas suggested would involve
cell nucleus transfer. We feel this would be consistent with
the spirit of the HFE Act, which was framed so as to allow
research into genetic disease.
Winning Hearts and Minds
Shortly after Dolly's existence was announced in early 1997,
her creator Ian Wilmut lamented that 'here we have a remarkable
achievement, a world first, and there are people who seem
to make a living out of spreading angst'. His team's work
was published in Nature on Thursday 27 February. But the story
broke the Sunday beforehand, leading to near hysteria in the
press and among politicians. In America Bill Clinton called
for a national commission to review what the White House called
the 'troubling implications' of cloning. In the UK, the issue
was raised at Prime Minister's Question Time on the Tuesday.
The Vatican called for a worldwide ban. Joseph Rotblat, the
physicist recently awarded the Nobel Prize for peace after
a lifelong campaign against nuclear weapons, argued that genetic
engineering could pose a greater threat than the Bomb 'because
of these dreadful developments that are taking place there'.
And in an unprecedented move, a Harvard academic e-mailed
Nature to demand that they pull the article from their journal,
on the grounds that such material should not be in the public
domain at all.
The cause of most of the unease was simple: the prospect of
human reproductive cloning. While forswearing any interest
in the idea, and pointing out that it would be illegal in
the UK and many other places, Wilmut freely acknowledged that
his work brought the possibility a lot closer. All of a sudden,
science fiction was nearly scientific possibility, and despite
attempts by Wilmut and others to focus on the benefits of
what they had done, everybody was determined to discuss human
cloning and its dangers.
The passage of time has hardly quelled interest in human reproductive
cloning. There is a consensus that it should not be attempted
at present. GIG shares this view. Many others want a permanent
ban and can foresee no reasons for its use. But one of the
interesting things about the debate over the past two and
a half years is that when gut feelings against human cloning
have been committed to print, many serious commentators have
found the arguments wanting. No wonder David Shapiro was moved
to comment: 'perhaps it is just as well that human cloning
is not yet feasible. We need better arguments for banning
it.' Steve Jones, who has just published his update of Darwin's
The Origin of Species, sees no reason for an all-time ban.
Indeed, it is the arguments for such a ban that he finds objectionable:
'Many find the idea of human cloning shocking. I do not. The
objections turn on genetic essentialism, the idea that a clone
would be stigmatized, treated as a second-class citizen, with
fewer freedoms than an organism produced by sex—in other words
that rights reside in genes rather than people. In the 1930s,
the Nazis took this "DNA über alles" argument to its logical
extreme. A Nazi who received a transfusion of Jewish blood
was thrown out of the party. In the old South Africa, blood
could not be moved across the racial divide, because biological
purity was considered compromised. That attitude is disgraceful,
but it is essentialism—humans as products of DNA—in its purest
form.
GIG sees no need for a permanent ban. The strength of regulatory
and legal restriction should be kept under review in line
with advances in scientific knowledge. It seems likely that
at some point in the not-too-distant future a human clone
will be created; but equally it is difficult to foresee a
significant demand for it.
Steve Jones went on to argue: 'the main danger in the essentialist
panic is restriction of the chance of copying tissues or organs.'
This is GIG's primary concern. But thankfully, after the initial
knee-jerk reactions to Dolly, the therapeutic possibilities
of nucleus replacement are beginning to be appreciated. And
when they are appreciated, there is support for them and the
research that might deliver them. A poll commissioned by the
newly-formed Patients' Coalition for Urgent Research found
that after having been read a statement that "researchers
believe that stem cells can be developed into replacement
cells to cure diseases such as diabetes, Parkinson Alzheimer's,
Cancer, heart disease and others", three out of four Americans
were willing for the American government to fund stem cell
research.
Winning over hearts and minds to the benefits of human therapeutic
cloning, and building upon the support for new therapies that
already exists, will help to foster a supportive climate for
the science to proceed. A legislative delay to consider the
issue is understandable if there are new issues to address
or support to be won. The danger must be that unnecessary
delay will merely encourage the view that there is something
deeply troubling about this kind of work. From scientists,
patients and supporters of the therapeutic uses of cloning
technologies the message is clear: therapies for many previously
untreatable disorders are a real possibility if scientists
are allowed to get on with their work.
NOTES
Karen Lebacqz et al, 'Research with Human Embryonic Stem Cells:
Ethical Considerations', The Hastings Center Report, 29(2):
31.
Gearhart, J. (1998), 'New Potential for Human Embryonic Stem
Cells', Science: 282: 1061-1062. Available at http://www.dti.gov.uk/hgac
Ian Wilmut outlines his objections to human cloning in Prometheus
2. In the same issue molecular biologist Lee Silver and philosopher
Dan Brock question absolutist arguments against cloning. For
another debate, see The New England Journal of Medicine, 1998,
339. John Harris challenges the full range of arguments against
human cloning in '"Goodbye Dolly?" The ethics of human cloning',
Journal of Medical Ethics, 1997, 23: 353-360. Raanan Gillon
does a similar job in 'Human reproductive cloning—a look at
the arguments against it and a rejection of most of them',
J. R. Soc. Med., 1999, 92: 3-12. In his piece, 'The Confusion
over Cloning' (The New York Review of Books, October 23 1997),
Richard Lewontin accuses the critics of cloning, in particular
the US National Bioethics Commission, of rationalising a deep
cultural prejudice. But it is also impossible to understand
their view, he adds, 'without taking account of the pervasive
error that confuses the genetic state of an organism with
its total physical and psychic nature as a human being.' 'Think
before you Squawk', New Scientist, August 2 1997.
'Common Sense About Cloning', International Herald Tribune,
March 16 1998.
'Ethicists urge funding for extraction of embryo cells', Nature,
399, 1999: 292. |
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