The production of a sheep clone, Dolly,
from an adult
somatic cell(1) is a stunning achievement of
British
science. It also holds great promise for human medicine. Sadly, the
media have sensationalised the implications, ignoring the huge
potential of this experiment. Accusations that scientists have been
working secretively and without the chance for public debate are
invalid. Successful cloning was publicised in 1975,(2) and
it is over eight years since Prather et al published
details of the first piglet clone after nuclear transfer.(3)
Missing from much of the debate about Dolly is recognition that she
is
not an identical clone. Part of our genetic material comes from the
mitochondria in the cytoplasm of the egg. In Dolly's case only the
nuclear DNA was transferred. Moreover, we are a product of our nurture
as much as our genetic nature. Monovular twins are genetically closer
than are artificially produced clones, and no one could deny that such
twins have quite separate identities.
Dolly's birth provokes fascinating questions. How old is she? Her
nuclear DNA gives her potentially adult status, but her mitochondria
are those of a newborn. Mitochrondia are important in the aging process
because aging is related to acquired mutations in mitochondrial DNA,
possibly caused by oxygen damage during an individual's
life.(4) Experimental nuclear transfer in animals
and in
human cell lines could help elucidate mechanisms for many of these
processes.
Equally extraordinary is the question concerning the role of the
egg's
cytoplasm in mammalian development. Once the quiescent nucleus had been
transferred to the recipient egg cell, developmental genes expressed
only in very early life were switched on. There are likely to be
powerful factors in the cytoplasm of the egg that make this happen. Egg
cytoplasm is perhaps the new royal jelly. Studying why and how these
genes switch on would give important information about both human
development and genetic disease.
Research on nuclear transfer into human eggs has immense clinical
value. Here is a model for learning more about somatic cell
differentiation. If, in due course, we could influence differentiation
to give rise to targeted cell types we might generate many tissues of
great value in transplantation. These could include skin and blood
cells, and possibly neuronal tissue, for the treatment of injury, for
bone marrow transplants for leukaemia, and for degenerative diseases
such as Parkinson's disease. One problem to be overcome is the
existence of histocompatibility antigens encoded by mitochondrial
DNA,(5) but there may be various ways of altering
their
expression. Cloning techniques might also be useful in developing
transgenic animals-for example, for human xenotransplantation.
There are also environmental advantages in pursuing this technology.
Mention has been made of the use of these methods to produce dairy
herds and other livestock. This would be of limited value because
animals with genetic diversity derived by sexual reproduction will
always be preferable to those produced asexually. The risk of a line of
farm animals prone to a particular disease would be ever present.
However, cloning offers real prospects for preservation of endangered
or rare species.
In human reproduction, cloning techniques could offer prospects to
sufferers from intractable infertility. At present there is no
treatment, for example, for those men who exhibit total germ cell
failure. Clearly it is far fetched to believe that we are now able to
reproduce the process of meiosis, but it may be possible in future to
produce a haploid cell from the male which could be used for
fertilisation of female gametes. Even if straight cloning techniques
were used, the mother would contribute important constituents-her
mitochondrial genes, intrauterine influences, and subsequent nurture.
Regulation of cloning is needed, but British law already covers this.
Talk of "legal loopholes"(6) is wrong.
The Human
Fertilisation and Embryology Act may need modification, but there is no
particular urgency. A precipitate ban on human nuclear transfer would,
for example, prevent the use of in vitro fertilisation and
preimplantation diagnosis for those couples at risk of having children
who have appalling mitochondrial diseases.(7) Self
regulation and legislation already work well. Apart from any other
consideration, it seems highly unlikely that doctors would transfer
human clones to the uterus out of simple self interest. Many of the
animal clones that have been produced show serious developmental
abnormalities,(8) and, apart from ethical
considerations,
doctors would not run the medicolegal risks involved. Transgenic
technology has been with us for 20 years, but no clinician has been
foolish enough to experiment with human germ cell therapy. The
production of Dolly should not be seen as a moral threat, but rather as
an exciting challenge. To answer this good science with a knee
jerk political reaction, as did President Clinton
recently,(9) shows poor judgment. In a society
which is
still scientifically illiterate, the onus is on researchers to explain
the potential good that can be gained in the laboratory.
References
1 Wilmut T, Schnieke A K, McWhir J, Kind A J,
Campbell K H S. Viable offspring derived from fetal and adult mammalian
cells. Nature 1997;385:810-3.
2 Gurdon J B, Laskey R A, Reeves O R. The
developmental capacity of
nuclei transplanted from keratinised skin cells of adult frogs.
J Embryol Exp Morph 1975;34:93-112.
3 Prather R S, Simms M M, First N L. Nuclear
transplantation in
early pig embryos. Biol Reprod 1989;41:414-8.
4 Ozawa T. Mitochondrial DNA mutations
associated with aging and
degenerative diseases. Exp Gerontol 1995;30:269-90.
5 Dabhi V M, Lindahl K F. MtDNA-encoded
histocompatibility
antigens. Methods Enzymol 1995;260:466-85.
6 Masood E. Cloning technique "reveals
legal loophole."
Nature 1997;385:757.
7 Winston R M, Handyside A H. New challenges in
human in vitro
fertilization. Science 1993;260:932-6.
8 Campbell K H S, McWhir J, Ritchie W A, Wilmut I.
Sheep cloned by
nuclear transfer from a cultured cell line. Nature
1996;380:64-6.
9 Wise J. Sheep cloned from mammary gland cells.
BMJ
1997;314:623.
Robert Winston
Professor of fertility studies
Institute of Obstetrics and Gynaecology,
Hammersmith Hospital,
London W12 0HS
