Examination of Witnesses (Questions 40-59)|
31 JANUARY 2007
Q40 Dr Iddon: Chris Mole and I would
like to direct a series of questions now to Professor Shaw and
Dr Armstrong. Can you convince us that this line of research will
be effective in producing embryonic stem cells. What evidence
Dr Armstrong: There is the evidence
from the Chinese Group that I mentioned earlier and, although
their experiments have never been repeated, the publications that
they have produced are reasonably convincing to my mind that we
would be able to produce embryonic stem cells from these lines.
Although I have never attempted this in humans obviously, we have
some very encouraging data from my laboratory for interspecies
embryos between mouse and cow and mouse and rabbit which suggest
very strongly that it will be possible to derive embryonic stem
cell lines of those species using this model system. We are in
the process of proving that the foreign genome which you introduce
into these cells is actually becoming active in expressing all
of the genes from, say, a mouse as opposed to the cow genes and
we believe very strongly that that is happening, that the genome
is becoming active and that we will be able to derive embryonic
stem cell lines from those.
Q41 Dr Iddon: So, you are relying
really on the work of one group.
Dr Armstrong: No, not on one group,
there are several other groups in China with whom we are in contact,
Professor Smith: One of course
has to acknowledge that this is research. If we already knew that
it could be done, we would not be debating Of course, we cannot
be certain but it is a real possibility and people like Lyle should
be entitled to investigate this and make progress.
Q42 Dr Iddon: As you know, those
people who are concerned about this line of research, which includes
the pro-life groups, of course, who will be opposing you in your
requests, know that researchers in Japan have been able to wind
back adult cells and make them pluripotent. Why is this proposal
and the research more advantageous than that claim, if it is true?
Dr Armstrong: We should really
become involved in both of those angles of research. My group
in particular are very interested in finding chemical means of
inducing pluripotency in somatic cells and I also have some very
interesting data looking at how we can interfere with several
enzyme systems which are responsible for maintaining what is called
the epigenotype of a somatic cell, and that is essentially what
we are resetting when we do a nuclear transfer experiment. The
trouble is that nature does it so much better than our very clumsy
attempts to interfere with that system so far and the work you
referred you from Japan from Professor Yamanaka's group has shown
that the expression of certain genes which are involved in maintaining
the identity of an embryonic stem cell are capable of reprogramming
it to an extent but, in order for that reprogramming to be stable,
they always have to keep expressing these genes in a very particular
format which would be fairly useless from a medical standpoint
because you would never be able to transplant cells derived from
those cells into a human patient. So, we need to understand what
is the actual process that those cells are going through either
by the nuclear transfer or cloning process or the reprogramming
ideas that Professor Yamanaka was developing or the ideas that
I am developing in my group before we can ever start to produce
embryonic stem cells on an industrial scale, if you like. It is
not the only angle that we can use but it is a very good and very
adaptable technical system that we can use to investigate these
Professor Shaw: There are two
points. One is that we fully support adult stem cell research
and would be delighted if we could take somebody's skin cell and
turn it into the neurons that we are interested in studying in
terms of the diseases of interest. If you look at where we are
at the moment, that line of adult stem cell research has been
very poor. People have been working on this for a very long time,
from much more accessible tissues and adult stem cells have been
available for much longer. Very few nerve cells can be grown from
adult stem cells. Nobody has ever made a specific sort of nerve
cell such as a motor nerve cell. We know the chemical composition
that is required to make a motor nerve cell from embryonic stem
cells, so embryonic stem cell technology is working. Adult stem
cell technology is way behind that and is not currently working
in the same way. I think that both tracks should be pursued but
certainly I think the fact that adult stem cell research may show
potential is not a good reason to inhibit embryonic stem cell
Q43 Dr Iddon: When we have a cow's
embryo being inserted with human material, we are told that that
embryo is more than 99% human. Would you all agree with that?
Professor Shaw: Absolutely.
Dr Armstrong: Yes.
Professor Shaw: The mitochondria
genome is tiny. There is only 13 polypeptides in the human mitochondria
genome that make proteins. In a mitochondria itself, there are
probably something like 1,500 different proteins. So, even you
want to call these cow/rabbit mitochondria, 99.9% of that mitochondria
is actually human and most of the protein that makes up that entity
is actually human material.
Q44 Dr Iddon: The other day we had
a seminar with some of your colleagues who work in this area and
I was quite surprised because I did not know that in the human
embryo that is created, the nucleus can put out into the cytoplasm
some of its own mitochondria. I thought that cytoplasm just carried
the mitochondria that had come from the donor, be it a cow. Is
that accurate or am I mistaken?
Professor Shaw: Most nuclear transfer
that is done is to put the whole cell into the enucleated egg.
So it takes with it not only the nucleus, carrying the chromosomes,
but also the mitochondria that sit in the cytoplasm. So the human
mitochondria are going to be in there as well as the recipient
rabbit or cow mitochondria.
Q45 Dr Iddon: So, in the cytoplasm,
there is going to be some interaction between the two, the mitochondria
derived from the two sources, and everybody says that the mitochondria
and the cytoplasm are the energy producers of the cell but are
we sure about that? Can the mitochondria not affect the development
of this cybrid embryo in some way and affect the chromosomal behaviour
in the nucleus? Are we sure about the role of mitochondria or
do we need to do more research?
Professor Shaw: We cannot be absolutely
sure that animal mitochondrial genes will not influence cell function
so I think that we should be doing those experiments. I think
they are important to do. If you have functioning human chromosomes
and you have functioning human mitochondria, most of the machinery
will work. You are asking a question as to whether the animal
mitochondria would interfere with that process but, until you
have actually asked that question biologically, it is difficult
to answer. There are experimental ways of attacking that and I
think we should be doing that. Because we do not know the answer
is not a justification not to use these cells.
Q46 Dr Iddon: To make a statementand
let us be quite sure about thisthat mitochondria are not
important in the production of the embryonic stem cells that were
producing stem cell lines might not be an accurate statement.
Professor Shaw: I do not think
that anybody said they were not important. It is whether it is
a critical issue, this will tell us whether these cells will be
of use or not.
Dr Armstrong: Just to get back
to that, I think that the comment I made earlier that they are
not critical to the formation of embryonic stem cells is probably
true because, at the stage of development we are talking about,
the cells are not relying so heavily on the energy generated by
the mitochondria, they tend to rely on another process known as
glycolysis. It may become an issue when you ask those cells to
differentiate into something which does require large amounts
of energy derived from mitochondria such as a muscle cell or a
nerve cell, but we will not be able to answer those questions
unless we perform the experiment in the first place.
Q47 Chris Mole: Professor Shaw and
Dr Armstrong, some of the written evidence we have had has raised
concerns about risks associated with this work. Have you carried
out an assessment on what those risks might be?
Professor Shaw: What sort of risks
are you talking about?
Q48 Chris Mole: I am asking you what
you consider they might be. Some of the evidence we have received
raised concerns about new diseases and diseases crossing the interspecies
Professor Shaw: All cells that
have been derived from humans are treated in a very special way.
All the manipulation done on these cells is done in a protective
hood so that the people doing the experiments are not exposed
to the cells of and animal origin. That is part of routine laboratory
practice. I think that these cells will never be used to be implanted
into anybody, which means that there is no risk of any cross-species
contamination. We are not using these cells for transplantation
and they would not be appropriate for transplantation. They would
never be legally allowed to be used for transplantation and that
is not the purpose of our experiments. I think that the risk is
extremely low in that context. All the risk is as using any human
cell, we have to take precautions that we do routinely in the
laboratory. We use human cell lines all the time.
Q49 Dr Spink: I would like to come
in on that. Some of the groups have argued to me that this will
not work, that it will not give us useful information because
it is a hybrid and therefore we should not be doing it, to which
I argue back, "If it does not work, then you have nothing
to worry about, have you?" How would you answer that?
Professor Shaw: There is no obvious
biological reason why it should not work. Cells with defective
mitochondria are present in many different conditions and indeed
there are people who carry mitochondrial defects who are perfectly
healthy. I see patients who do have mitochondrial-based diseases
and that is when the majority of their mitochondria have this
gene defect and certain cell populations fail because of that.
It is a very, very different situation if the vast majority of
mitochondria are defective. I think that is a very clever misinterpretation
of the facts.
Chairman: I want to finish this session
by 10.40, so I ask that we all try to be as succinct as we can
be with our questions and I ask that you try to be as succinct
as possible with your answers.
Q50 Dr Harris: Would you explain
to us what a chimera test of pluripotency is.
Dr Armstrong: A chimera test is
something that we cannot do with human embryonic stem cells because
it would involve putting a pluripotent ES cell into the blastocyst
of the remaining species such as a mouse and seeing if those cells
can contribute to the development of that organism. Typically,
we would look for coat colour changes in the mouse to see how
pluripotent those ES cells were. We could dissect the mouse to
see if the cells derived from those embryonic stem cells were
present in all of its internal organs or tissues, but we do not
do that with human ES cells. That is the one test we cannot make
because it involves mixing a chimera between an animal and a human.
It is something we would restrict only to mice.
Q51 Dr Harris: If you have a stem
celland I think this applies to a stem cell derived from
an adult cell as much as it does to an embryonic stem celland
you want to check whether it is capable of contributing to all
the potential tissue types, that it has that potential before
you direct it to one particular tissue type, isn't what you would
like to do in a chimera test of totipotency and pluripotency is
to put that cell into an animal model which has the same gestational
timeframe in order to give the embryonic human cell chance to
show what it can do and then see whether it does give rise to
those different cell types.
Dr Armstrong: We can test total
potency or pluripotency in a much simpler way simply by injecting
embryonic stem cells either into the kidney capsule or into testes
with immuno-deficient mice and then specialised types of tumours
called teratoma will grow and those can be sectioned and stained
for various different types of cells and tissues, and that is
the standard we use for determining pluripotency in human embryonic
Q52 Dr Harris: It was suggested to
us in the examples from some of your colleagues that at some point
you would want to go beyond the teratoma testing towards chimera
testing in order to demonstrate totipotency. I definitely remember
it being said that that would be a useful step. Do you dispute
Dr Armstrong: To determine total
potency is an entirely different matter.
Q53 Dr Harris: Or pluripotency?
Dr Armstrong: Because we would
have to then determine that the cells were capable of germ-line
transmission which I do not think we would want to do in a mouse.
A mouse producing human eggs or human gametes would be a little
odd, I think.
Q54 Dr Harris: Professor Shaw, are
Professor Shaw: It is not my area
of expertise and it is not my area of interest and I would not
want to comment.
Q55 Dr Harris: We were told that
it might be useful to have this chimera test of some kind. If
that is the caseand I can see that you are not agreeing
with that and we can go back to our source to check, but let us
accept that it might be useful in order to test these ES cellsdoes
that create a problem for the 14 day limit?
Dr Armstrong: The embryo would
not be grown in culture, it would have to be implanted into the
uterus of some mammalian species in order for it to develop beyond
the 14 day limit and then, if such entities did successfully implant
and were allowed to grow to term, then we would expect to see
contribution from human cells to those developing foetuses, but
what that would tell us . . . I do not know that it would really
add to the current pluripotency test information that we have.
We are developing much better systems from assessing pluripotency
on purely chemical bases looking at the biochemistry of these
cells. The test which is traditionally being applied today for
human cells, as I have said, is the formation of a teratoma and
that has satisfied most of the scientific community to date. I
am not sure I can see what additional data we could gain from
making a chimera between a human ES cell and a mouse blastocyst,
Professor Smith: I would like
to comment on that. I am really very surprised that scientists
have apparently argued that that would be a valuable experiment.
I cannot see that there is any useful knowledge to be gained from
it. I personally would not defend such an experiment. I think
it would be very problematic in terms of public perception. This
is to make a primary chimera where you are trying to make a whole
animal that is essentially half human and half animal. That is
the risk you would take by doing that kind of experiment.
Q56 Dr Harris: I do not think it
was proposed to be half and half, I think they argued that one
could introduce stem cells at the blastocyst stage and you would
see in uterine development without necessarily going to birth
what the contribution was to all the tissue types.
Professor Smith: But it would
still be half and half. I would not rule out that you should never
do that experiment, that there might not conceivably be at some
point something that you can learn, but I cannot see any question
at the moment, and the barrier should be very high for that kind
of experiment and you certainly should never let it go much beyond
Q57 Dr Harris: Do you think that
barrier should be created by primary legislation or by the regulator
saying we need to have scientific use for this, and even then
we would look at it very closely?
Professor Smith: I would say regulation.
One does not know what might happen and how things might change.
Q58 Adam Afriyie: I want to look
at some of the controversy surrounding the ethics and morality,
preferably confined to this area of chimeras, hybrids and so on,
and, secondly, the controversy surrounding the HFEA's decision
to postpone or delay their decision making. In the evidence we
have received, the Scottish Council for Human Bioethics said that
for those who believe that an early human/non-human embryonic
combination is not a person there are no further ethical considerations
about the work that is being done. We have had lots of other evidence
as well from people saying things like an embryo is a human being
from conception, and then of course in this area of hybrids, chimeras,
et cetera, there is the question raised by CARE that because these
would be unnatural entities created, the barrier between human
beings and other species would be blurred. A whole interesting
area of morality and ethics has opened up here. Dr Armstrong and
Professor Shaw, how would you respond to those ethical and moral
objections or considerations in this context?
Professor Shaw: I think I can
understand the origin of the concerns, and obviously human life
is extremely important. What is important to do is to put it in
the context of what people currently accept as being the role
and what is acceptable in dealing with embryos. Many embryos are
generated through normal sexual activity, and many contraceptive
devices work not by preventing conception but by preventing implantation.
The intrauterine device, for instance, prevents implantation,
as do many oral contraceptives. There are possibly hundreds and
thousands of embryos being created every week that are being destroyed
for social reasons. Society thinks that is acceptable and I agree
with them. We are able to create embryos for the purpose of deriving
cell lines. We create embryos that are not for implantation but
are frozen down as part of in vitro fertilisation. If you are
going to say that life begins from conception, then the law should
apply to all those other embryos and clearly it does not. My feeling
is if it is legal to have contraception in this way, and to derive
stem cells from very early embryos, then this work falls within
that remit. It is almost exactly the same entity as the embryos
that are used to derive human cell lines.
Q59 Adam Afriyie: What about the
blurring of the distinction between human beings and other animals
or other entities?
Professor Shaw: I would then revert
to the comment that the cells we hope to derive are more than
99.9% human. They are essentially human cells. The embryo that
is being generated is essentially a human embryo. I would give
you, as an example, the fact that we use animal tissues in many
medical contexts, heart valves being the most common one. If you
have your aortic heart valve replaced by a pig heart valve, a
very common procedure which has happened in this country for more
than 20 years, that person does not become a chimera or a hybrid;
they are a person with a pig heart valve. These cells are human
cells but also have some animal mitochondria.