APPENDIX 76
Memorandum from Peter W Andrews, Centre
for Stem Cell Biology, University of Sheffield
EMBRYONIC STEM CELLS—THERAPEUTIC APPLICATIONS
OVERVIEW
There is little doubt that human embryonic stem
(ES) cells can be derived and maintained in long term culture,
while retaining their potential for differentiating into a very
wide range of cell types. Currently, at least eight lines have
been derived in the UK and are in various stages of initial characterisation,
prior to their submission to the UK Stem Cell Bank. Worldwide,
a much greater number have been derived; at present 72 are "enrolled"
in the International Stem Cell Initiative (ISCI) that is undertaking
to provide baseline characterisation and comparison of these lines.
These lines have been isolated by research groups in Australia,
Czech Republic, Denmark, Finland, Israel, Singapore, Sweden, UK,
and USA. These countries are all members of the International
Stem Cell Forum (ISCF), which is sponsoring the ISCI. Other human
ES lines have been derived in countries outside the Forum, including
China, South Korea, India and Iran.
As far as I am aware, most of currently existing
human ES lines have been derived from embryos that were produced
for "Assisted Conception" of infertile couple but were
excess to clinical requirements. One human ES cell line has reportedly
been derived in South Korea by an embryo formed following Somatic
Nuclear Transfer ("therapeutic" cloning, or SNT).
Various groups in the UK and abroad have begun
research to discover means for controlling the differentiation
of human ES cells into a variety of cell types that could be used
in tissue replacement therapies (regenerative medicine) in the
future. Cell types under study include nerve cells, liver, pancreatic
islet cells, and cardiac muscle. Although it is evident that these,
amongst other, cell types can be formed by differentiation of
human ES cells in culture, considerable research is required to
optimise these differentiation protocols and to demonstrate that
the derivative cells express all the functions expect of them.
While there can be little doubt that these goals will be achieved,
it is important not to underestimate the challenge and the time
that it will take to develop the necessary techniques.
CHALLENGES FOR
DEVELOPING ES
CELL BASED
THERAPIES
1. Optimise culture techniques for maintaining
undifferentiated stock cultures of human ES cells, to:
(i) eliminate the use of undefined animal
products to support their growth (and so minimise the risks of
transfer of disease causing micro-organisms);
(ii) reduce their spontaneous differentiation
in order to have robust methods for delivering homogeneous cultures
of undifferentiated ES cells into specific differentiation protocols;
and
(iii) minimise or eliminate the appearance
of genetic variants upon prolonged culture.
2. Develop techniques for inducing and,
ideally, directing the differentiation of human ES cells to form
specific fully functional cell types, suitable for transplantation.
This requires detailed understanding of the signalling pathways
that control the behaviour of pluripotent stem cells.
3. Establish techniques for purifying the
differentiated derivatives and eliminating undifferentiated progenitor
cells that might contaminate such preparations.
4. Develop techniques to avoid the problems
of immune rejection of transplanted cells by prospective patients.
Various approaches are possible, but it remains unknown which
will prove most practicable and effective:
(i) Establish a large panel of lines covering
all tissue types.
(ii) Use of SNT to produce hES cells with
a genotype identical to that of the prospective patient.
(iii) Develop "stealth" lines in
which key genes that elicit immune rejection are eliminated.
(iv) Develop "chimeric" haematopoietic
approaches whereby a patient is made tolerant to hES cell derived
cells by first introducing haematopoietic stem cells derived from
the same hES cell line.
(v) Develop new techniques for manipulating
the immune system to elicit specific types of tolerance so avoiding
immune rejection.
5. Develop techniques for scaling up the
culture and controlled differentiation of human ES cells to produce
material to treat large numbers of patients, once clinical trials
have demonstrated the viability of ES cell-based therapies.
Beyond work with the stem cells themselves to
find means for converting them into clinically useful cell types,
in sufficient numbers to be useful, a major clinical challenge
will be to work out techniques for delivery of these living cells
in a way that will provide maximum benefit to patients.
REGULATORY ISSUES
AND OTHER
HURDLES
Much of the basic biology needed to underpin
the development of therapeutic applications of hES cells can now
be conducted in the UK under the existing legislation and rules.
Generally, the regulatory arrangements in the UK, overseen by
the Stem Cell Steering Committee, are working well. Nevertheless,
it is important to avoid overburdening this area of science with
unnecessary bureaucracy. In this regard it maybe useful to re-emphasise
several key points:
1. Once a line of hES cells has been established
in culture, it is just that—namely a group of cells, and
it is no longer an embryo. At that stage, most work that responsible
researchers would wish to undertake is not controversial and,
given that the cell line exists, there are no special ethical
issues that pertain to most experiments in culture that may be
performed. At this stage, the major ethical milestone, namely
whether or not to use an embryo to derive an ES cell line, has
been passed. It is important for maintaining the research momentum
with established lines that regulation and oversight are kept
to a minimum.
2. Discussion of the regulation of human
ES cell lines has often made the tacit assumption that one embryo
gives rise to one ES cell line. While this is true for the initial
line derived from an embryo, research with that line will undoubtedly
lead quickly to the formation of a large number of sublines with
special features for continued research, and even eventual application.
For example, variants may be produced by the introduction of specific
genes by genetic modification. Such techniques and resulting distinct
sublines will be of great importance as tools for taking stem
cell research forward. Any rules concerning the use, registration
or other disposition of human ES lines must be framed in a way
that will be workable given the very large number of "lines'
that might emerge from research with a small number of initial
lines.
3. Research with human ES cell lines, like
research with any other cell lines or biological tools, will involve
collaborations between different research groups, and also the
need for independent groups to verify the findings made by any
one team. Therefore it is important that human ES cell lines,
and especially variant sublines, are easily transferred from one
research team to another. There is a danger that inappropriately
framed rules could hinder the rapid and timely transfer of lines
between labs, and this must be avoided in any drafting of future
rules if research with human ES cells is to be vigorously pursued.
OTHER MATTERS
Much discussion about human ES cells focuses
upon their use in therapies for serious disease. However, it should
also be recognised that they offer potential for assisting drug
screening and toxicology screening, in ways that will provide
significant advances over current methods. Thus, the use of established
human ES lines will allow the development of standardised human
target cells for many of the assays that are currently required.
At present such assays must be performed with animal cells (which
may differ in their response from their human counterparts), or
with established human cells (which are often tumour cells and
may differ significantly from normal cells), or with clinical
samples of tissues (which are increasingly difficult to acquire
and are, in any case, quite variable from batch to batch).
November 2004
|
