Submission from Professor Sir Martin Evans
There is a confusion of the use of terminology
and I attempt to provide a clarification of the use of the terms
chimaera (chimera) and hybrid (with cybrid) as currently used
in the context of mammalian cell biology.
Human embryos and human cells in cultureincluding
human embryonic stem cellsneed to be clearly distinguished.
Experiments involving chimaerism of experimental
animals (including embryos) with human cells will be an essential
tool in advancing the possibilities of stem cell based tissue
therapy. These studies will be mainly with stem and precursor
cells which are not embryonic stem cells although they may or
may not have been derived from them. "Reach-through"
regulation from HFEA is undesirable and probably impractical.
In the White Paper "Review of Human
Fertilisation and Embryology act December 2006" paragraphs
2.79 to 2.83 consider embryos combining human and nonhuman material.
I consider that there is a lack of clarity in definition, which
adds to the amount of concern being expressed.
1. Biological experiments which combine two
distinct cells or their components fall into at least three categories
Two or more distinct, intact cell lines are
combined to contribute to a structure. An example would be a chimaeric
mouse made by aggregating two early embryos. This mouse (sometimes
called tetraparental) has in most if not all its tissues and organs
cells from both sources. These cells interact and cooperate, but
do not combine or exchange genetic material. (As an exception,
in certain tissuesmost noticeably, the skeletal musclebecause
there is a natural process of cell fusion during development the
cells in the tissue contain genetic material from both the original
embryos.) Such chimaeric mice are also made by adding embryonic
stem cells to an early mouse embryo and here, the resulting mouse
has tissues containing cells originating from the embryonic stem
cells. Thus a chimaera in this usage of the term does not imply
chromosomal or genetic mixing. Although most experimental mammalian
chimaeras have been made from embryos or cells of the same or
closely allied species one series of experiments inadvertently
used mouse ES cells to make mouse-rat chimaeras.(1) These, in
contrast to mouse-mouse chimeras, had a very small contribution
from the foreign component. Earlier experiments to make rat and
mouse chimaeras using early embryo manipulation also failed to
produce extensive chimaerism in viable offspring.(2)
Two or more distinct cells are fused togethercell
hybridisation. This is usually an in vitro procedure and has been
used extensively between species to derive cell lines with partial
chromosomal contributions from one of the partners in order to
carry out somatic cell genetics. It has also been used between
cells of diverse differentiated type in order to study the controls
of differentiation. These hybrid cells, whether or not grown into
a cell line contain an admixture of the genetic material from
both original partners.
Components (less the nucleus) of one cell are
fused into another cell with its nucleus. Conversely, the nucleus
may be added back to the cytoplasm (without the nucleus) of another
cell. In vitro, the product of this technology has been termed
a cybrid (cytoplasm hybrid) and experiments of this sort have
been largely used to attempt to study controls of differentiation.
This is also the technique used in SCNT of a somatic cell nucleus
into an enucleated oocyte. Thus this technique is essentially
making a cybrid. The cell, contributing the cytoplasm (ie the
oocyte) provides no chromosomal genetic material.
2. Necessity of regulation
2.1 I would also like to submit that legislation
and regulation should seek to permit and indeed promote scientific
progress, but must prevent misuse. In this context, the only area
for foreseeable serious misuse of experiments which combine human
and animal material, particularly in an embryo, are those which
involve allowing development in vivo.
2.2 There are several problematic scenarios.
The one which would involve development of an experimentally manipulated
embryo in a human is, and should be, outlawed. The other is allowing
development of an extensively humanised embryo in vivo in another
species. This needs to be tightly regulated. Regulated, but not
outlawed because there are potentially very important studies,
which will be needed if and when embryo produced cells approach
3. Distinction between ES cells and embryos
3.1 In this context, I believe that it is
very important to differentiate between human embryos and human
embryonic stem cells, and between their use entirely in vitro
and in embryo manipulation. Tissue culture cellsno matter
their developmental potentialare not embryos. I consider
that the attempt to regulate the use of entirely properly derived
cells and cell lines by a "reach-through" from the HFEA
regulations is misguided. Regulation is entirely appropriate at
the stage of use of human embryos. Regulation will also be entirely
necessary at the stage of human therapeutic application of the
products of stem cells. Between the two the UK could benefit by
using the lightest possible touch. It is also pertinent to observe
that cell cultures intended for therapeutic applications in tissue
therapy will not be ES cells but populations of precursor cell:
their differentiated derivatives. These cells may or may not have
arisen from human embryos at their effectiveness will need to
be tested in animal modelsie in chimaeras.