Submission from Dr Neville Cobbe, University
1. If one believes everything that one reads
in the recent press, apparently a hybrid embryo ban "hits
hopes of Alzheimer's sufferers" and "would cost patients'
lives" since cloning "can beat disease" and will
offer "the first effective treatments". As I have previously
stated in evidence submitted to Parliament in 2004, I consider
any suggestion that cells from mixed-species cloned embryos might
be used in treating patients to be both naive and irresponsible.
However, I note that the current focus is on research rather than
direct use in therapies, even if this distinction often fails
to be conveyed by the media, so I will restrict my subsequent
comments accordingly. Indeed, I can at least welcome the fact
that the current demand to use eggs from other species may reflect
growing recognition of concerns regarding potential risks to women
if eggs are required for research on such a large scale. Furthermore,
such newfound recognition of risks would also be consistent with
apparent trends towards minimal stimulation IVF and elective single
embryo transfer. Nevertheless, one may be left wondering how feasible
it is to model various non-congenital and late-onset conditions
simply by studying cells from embryos in vitro, never mind
the additional complications due to disrupted gene expression
associated with nuclear transfer and questions of how such complications
would not be exacerbated by the use of eggs from more distantly
related species. I therefore hope that anyone wishing to make
strong claims about the purported promise of such research should
also be willing to publicly provide the fullest possible explanation
of the underlying rationale, supported by appropriate reference
to available evidence.
2. On 10 January 2007, The Times published
a letter signed by 45 individuals in which the following was stated:
"There are clear potential benefits to human
health from, for example, being able to grow stem cells with specific
genetic abnormalities, improving the efficiency of therapeutic
cloning techniques and establishing cell lines for the testing
of new treatments for diseases such as motor neuron disease, Alzheimer's
disease and spinal muscular atrophy. All this can be done without
having to rely on the use of human eggs which are in very short
supply and are needed for treatment of patients with infertility."
It is particularly interesting to note that
Professor Alison Murdoch of the Newcastle Fertility Centre is
among those who have added their names endorsing this statement,
whilst she is described in this letter not as a clinician but
rather as a "stem cell researcher". This inevitably
begs the question as to why Professor Murdoch should be so keen
to recruit additional women to provide her with as many eggs as
possible in attempts to clone human embryos, as clearly revealed
by the minutes of HFEA Research Licence Committee meetings, if
she believes that the use of human eggs for such research is unjustified.
This becomes all the more curious when the same person is engaged
in the direct treatment of patients from whom eggs are obtained
for such research and yet this individual now appears as a signatory
to a statement acknowledging that women's eggs are in very short
supply and are needed first and foremost for infertility treatment.
One would therefore expect that anyone signing such a statement
should also be quick to voluntarily relinquish any licence facilitating
the recruitment of as many women as possible to provide eggs for
3. Alternatively, such discrepancies between
expressed views and apparent practices might raise questions regarding
how much time was available to others to read the final draft
of a letter to The Times before adding their names. On
discovering that the person primarily responsible for this letter
was Dr Evan Harris MP, I wrote to him by e-mail on 12 January
2007, also asking who was responsible for drafting the exact wording,
how many actual members of the entire scientific community were
approached concerning this letter and how many of these became
signatories, or else what motivated the choice of particular individuals
whose signature was solicited. Unfortunately, no direct answers
to these questions have yet been forthcoming. Nevertheless, Dr
Harris did manage to reply within just over 10 minutes from a
computer at Westminster (IP address: 10.136.10.10) and offered
to make a telephone call ("from a train!") but apparently
would not provide answers in writing.
4. Regarding the ethics of research involving
human/non-human entities, Dr Jason Scott Robert has recently pointed
out how there may be an important tension when some studies that
might be more questionable scientifically could also be those
that are less likely to pose significant ethical concerns and
vice versa1. To date, most attempts to clone mammals using
eggs from distantly related species (such as those belonging to
separate mammalian orders) have apparently only permitted limited
embryonic development as far as the blastocyst stage2-10 whilst
development to this stage (in order to derive embryonic stem cells)
is not necessarily equivalent to full reprogramming even when
performing nuclear transfer with eggs from the same species11.
The species status of the resulting entity may also be open to
question, despite the frequently quoted refrain that such embryos
would be more than 99% human in terms of DNA content. Such a figure
deals only with relative numbers of unique protein coding genes
and assumes that each is present in the cell with an equal copy
number. However, when the number of mitochondria typically present
in an unfertilised egg is also taken into account12-15, estimates
of the nuclear fraction of total DNA in the resulting product
of nuclear transfer may drop to under 70% or so and estimates
of the nuclear fraction of protein coding gene copies may be less
than 2%. In light of issues concerning developmental potential
and overall proportions of DNA from different species, how might
such a presumably non-viable entity be classified as a human using
either Ernst Mayr's biological species concept16 or complementary
use of an evolutionary species concept17?
5. Even in the absence of the aforementioned
empirical data concerning cross-species cloning attempts, it is
doubtful how long most such mixed-species embryos and any cells
derived from them would survive since it appears that host mitochondrial
function is not properly supported by donor nuclei from more distantly
related species18-25. This is especially relevant since oocytes
with lower mitochondrial numbers seem to have lower developmental
potential12-15, indicating the importance of adequate functioning
mitochondria for subsequent embryonic development. Although reports
differ regarding the preferential replication of donor or recipient
mitochondria8, 21, 26-31, it is nonetheless possible that supplying
more donor mitochondria may alleviate some incompatibility problems26.
However, known differences in the reprogramming of gene expression
during the earliest stages of embryonic development in different
mammalian genera32-34 and similarities between defects in cloned
animals and interspecific hybrids35-39 together suggest that use
of eggs from more distantly related species would lead to even
more defects in reprogrammed gene expression. Whereas one research
group has reportedly derived embryonic stem cells following transfer
of nuclei from human skin cells into rabbit eggs40, a report in
the journal Nature barely a year ago described how doubt
remains within the research community regarding the feasibility
of this approach41, possibly aggravated by fraudulent claims about
the derivation of stem cells from cloned human embryos.
6. Consequently, if viable offspring of
particular species are extremely unlikely to be obtained when
using eggs and donor nuclei from distantly related mammals, then
there may be a tension between the purported scientific benefit
of transferring human nuclei into eggs from various species and
the moral status of the resulting entity. For example, would this
mean that there are fewer ethical concerns about the use of what
would seem to be intrinsically non-viable embryos of dubious species
status, compared to the destruction of potentially viable human
life? Conversely, would the need for more accurate reprogramming
lead to subsequent demands for eggs from more closely related
species, perhaps even chimpanzees? As it happens, I have already
raised the question of using primate eggs in conversation with
Professor Ian Wilmut. Although both of us felt that the Home Office
would presently be far less likely to endorse this anyway, it
may still be worth considering whether it would be wiser to also
address this specific issue in current legislation before potentially
raising additional public concerns. After all, if the use of numerous
eggs from women for cloning research is presently considered unjustifiable
due to the risks involved and the lack of personal or guaranteed
benefit42, then how would the use of eggs from non-consenting
members of any sentient and endangered primate species be considered
7. On the other hand, it is conceivable
that the use of eggs from less closely related species might be
used in more basic research to advance understanding of the factors
in an egg required for reprogramming gene expression43, though
a host of preliminary data also suggest that much of the desired
information concerning early developmental potential can already
be obtained without actually cloning embryos at all44-46. However,
if it is therefore acknowledged that the transfer of human nuclei
into cow or rabbit eggs is simply basic research with no clearly
predictable or uniquely guaranteed clinical benefits, then questions
may remain as to how this can be accommodated by the present wording
of either the Human Fertilisation and Embryology Act or Statutory
Instrument 2001 No 188. This is not so much a question of whether
such research with mixed-species entities is necessarily illegal
at present, but rather a question of whether or not it might lie
outwith the scope of current regulations and how the HFEA might
be qualified to handle this.
8. Aside from the questions above, more
challenging issues may be raised through the creation of some
chimeric animals in which distinct populations of cells are derived
from human embryos and those of other species, especially where
this involves neurons and a risk that any resulting creature might
exhibit characteristics that would be considered ethically unacceptable
to find in an experimental animal. There is not the space here
to explore this adequately, so I would refer those interested
to recommendations by the National Academy of Sciences in the
U.S.A. 47 and a previous "Policy Forum" in the journal
Science48. In considering the objectives of such experiments,
one should consider whether a 14 day limit for chimeric embryo
experimentation would necessarily be satisfactory from a scientific
perspective and also examine how decisions in this area might
expose inconsistencies if the termination of life may be considered
by some to be more justifiable when increasingly human qualities
are observed, rather than according increasing respect and rights
with increasing signs of humanity in a chimera, as would seem
more ethically sensible.
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