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CLONING
ISSUES INREPRODUCTION, SCIENCE AND
MEDICINE.
(ISSUED JANUARY 1998) Link
to Original HGAC Paper
Section 1
INTRODUCTION
1.1 In 1997, Dolly the sheep, the first
vertebrate cloned from a cell of an adult animal,
generated considerable interest. Although hailed as
a remarkable scientific breakthrough, concern was
raised both nationally and internationally about
the future evolution of this technology,
particularly in the context of the cloning of human
beings.
1.2 The Human Genetics Advisory Commission
(HGAC), which reports to Ministers on issues
arising from new developments in human genetics
that can be expected to have wider social, ethical
and/or economic implications, and the Human
Fertilisation and Embryology Authority (HFEA),
which has regulatory responsibility for the Human
Fertilisation and Embryology Act 1990, decided to
hold a consultation exercise on cloning. A working
group, consisting of members of both bodies, was
established to take this forward.
1.3 This consultation paper has identified
different potential uses of cloning technologies,
as this will help to identify the various ethical
issues involved. For the purposes of this
consultation we draw the distinction between two
types of cloning: on the one hand, human
reproductive cloning, where the intention is to
produce identical fetuses or babies; and, on the
other hand, what may broadly be called therapeutic
cloning, which (although not coterminous with
conventional scientific usage) includes other
scientific and medical applications of nuclear
replacement technology. For example, studying cell
development or creating stem cell lines with the
aim of developing therapeutic applications. In
order to make this consultation as comprehensive as
possible, some of the ethical questions raised
relate to practices which are illegal in the United
Kingdom. Some embryo research proposals would
require regulations to be made by the Secretary of
State for Health before they could be carried out.
Further details of the UK’s legal framework
are given at Section 5. This paper also discusses
whether current science raises new questions about
more abstract concepts such as individuality and
human dignity. It seeks the views of the community,
including specialists drawn from organisations with
scientific, legal, clinical or ethical interests.
It is envisaged that this paper will be revised in
the light of comments received, and form the basis
of advice from the HGAC and HFEA to Ministers.
Section 2
DOLLY AND POLLY
2.1 Dolly is the first example of an adult
vertebrate cloned from another adult by any
technique. She was cloned using a nuclear
replacement technique, where the nucleus from a
cell, which had two chromosome sets, was fused with
an unfertilised egg from which the nucleus had been
removed. This experiment was the first time that a
fully developed animal had been born following
transfer of a somatic cell nucleus from an adult
animal. A major motivation for the work was to
improve methods for the genetic improvement of
livestock. The technology could also be used to
improve the efficiency of production of transgenic
livestock. This could have potential benefits, for
example, in increasing production of human proteins
in the milk of transgenic animals (e.g. proteins
used to treat blood clotting disorders such as
haemophilia).
2.2 Dolly was the result of a collaborative
experiment between the Roslin Institute and PPL
Therapeutics PLC to test the suitability of
different sources of cells for nuclear replacement.
She was derived from cells taken from the udder of
a 6 year old Finn Dorset ewe which were then
cultured in the laboratory. 277 of these cells were
then fused with 277 unfertilised eggs, from which
the nucleus had been removed, to create
“reconstructed eggs”. This process
resulted in 29 viable reconstructed eggs, each with
a nucleus from the adult animal, which were then
implanted in surrogate Blackface ewes. One gave
birth to Dolly(1).
2.3 However, Dolly was not the first sheep to be
created using nuclear replacement technology. In
1996(2),
it was reported that sheep embryos had been cloned
using nuclear replacement and had resulted in the
birth of two genetically identical sheep, Megan and
Morag. The difference between Dolly and Megan and
Morag is the nuclear donor source: Dolly is derived
from an adult sheep, Megan and Morag from a sheep
embryo.
2.4 Recently, the Roslin Institute and PPL
Therapeutics PLC announced the birth of Polly. She
is a transgenic sheep produced by transfer of the
nucleus of a cultured fetal fibroblast. She carries
a human gene for blood clotting Factor IX, which is
used for treatment of
haemophilia(3).
Section 3
WHAT IS CLONING?
3.1 The birth of Dolly aroused interest and
controversy all over the world, especially focusing
on the possibility of human reproductive cloning,
namely the production of genetically identical
human beings.
3.2 The term “cloning” applies to any
technique used to produce clones. The etymology of
the term “ cloning” is the Greek for
“twig”. Considerable confusion was caused
because the term “cloning” has been used
in both loose and conventional ways for many years
to describe a number of entirely different
concepts. It is important that stringent
definitions be adopted and that the precise context
be defined on a consistent basis to avoid such
confusion. As mentioned in the introduction, for
the purposes of clarity in this document we will
use two distinct meanings of
“cloning”.
3.3 Firstly, “reproductive cloning”,
that is, where an entire animal is produced from a
single cell by asexual reproduction. The creation
of Dolly falls into this category, although this
paper does not consider the implications of animal
cloning. Our concern is with “human
reproductive cloning”, which would involve the
creation of a human being who was genetically
identical to another.
3.4 Secondly, there are scientific and
therapeutic applications of nuclear replacement
technology, which do not involve the creation of
genetically identical individuals. These activities
are also sometimes referred to as
“cloning”, and may broadly, (although not
coterminous with conventional scientific usage) be
referred to as ”therapeutic
cloning”. These applications may include
therapy for human mitochondrial disease and
research which might lead to the replacement of
damaged or diseased tissues or organs, without the
risk of rejection reactions. For example, skin
tissue to treat patients suffering from burn
injuries (see Section 7).
3.5 In addition, there are some routine
techniques long practised by the scientific and
medical communities, which are not the subject of
this consultation:
- generating multiple identical
copies of genes or gene fragments (the chemical
nucleotide sequences of nucleic acids DNA and
RNA). These techniques have been used for over
20 years.
- cultivation in the laboratory of single cell
organisms such as bacteria and fungi, or
individual animal or human cells to produce
multiple identical single cells. For example,
industrial fermentation processes for the
production of bread, beer, wine. These
techniques have been used extensively in
biomedical research for over 50 years.
- The production of entire plants from a
single cell or several cells by asexual
reproduction e.g. the taking of cuttings which
has been practised in horticulture for
centuries.
3.6 Sexual reproduction (whether plants,
micro-organisms, animals or humans) involves the
mixing or recombination of genetic material derived
from two donors. For example, the fertilisation of
an egg by a sperm to produce a progeny with a
unique identity. Genetically identical individuals
can still arise, however, from sexual reproduction
under circumstances in which an early stage embryo
created by natural fertilisation (or in vitro
fertilisation) undergoes division to form two or
more identical births. This is a natural form of
cloning, which resembles the experimental
production of animal clones by embryo splitting
described in 4.1 below.
Section 4
ARTIFICIAL CLONING TECHNIQUES
4.1 The prefix “artificial” has been
adopted in the title of this section to emphasise
the role of scientific and/or clinical intervention
in producing the cloned progeny. Two distinct
methods have been used to clone animals and could
thus, in theory, be used to clone human beings:
- Embryo splitting
The artificial division of a single embryo
replicates the natural process which can give
rise to identical twins. In this case, both the
nuclear genes and the small number of
mitochondrial genes would be identical. This is
done by separating embryonic cells at a very
early stage of development before they have had
a chance to differentiate. However, there are
very few cells at this stage - usually less than
eight - so this method can only give rise to a
few clones.
Nuclear replacement
This process involves the introduction of
genetic material (in the form of an individual
cell nucleus removed from either an embryonic, a
fetal, or an adult cell) into the cytoplasm of
an unfertilised egg or embryo, whose own genetic
material (nucleus) has been removed. The nuclear
genes of clones produced by this technique would
be identical, although the mitochondrial DNA of
such clones would be different. However, unlike
the embryo splitting technique, nuclear
replacement has the potential to create a clone
of an adult organism, as well as the potential
to produce many more clones.
4.2 The nuclear replacement technique to clone
animals is relatively new. The first evidence that
it was possible to clone vertebrate animals using
nuclear replacement was in
1952(4),
using frogs. The more recent developments of
nuclear replacement technology have brought with
them the potential to contribute towards the
genetic improvement of livestock. Annex C discusses
in more detail the experiments which led to Dolly
and subsequent developments.
4.3 The uses of animal reproductive cloning,
including the multiplication of those with
desirable characteristics and the creation of
animals with new characteristics by genetic
targeting, are not considered in this paper. The
Ministry of Agriculture, Fisheries and Food’s
(MAFF) policy on the cloning of farm animals has
been guided by the Report of the Committee to
Consider the Ethical Implications of Emerging
Technologies in the Breeding of Farm Animals (the
Banner Committee) which reported in 1995. MAFF has
since asked the Farm Animal Welfare Council to
consider the implications of cloning for the
welfare of farmed livestock. A consultation
exercise was recently held.
Section 5
LEGAL FRAMEWORK
5.1 The creation, use and storage of human
embryos outside the body is regulated under the
Human Fertilisation and Embryology Act 1990 (HFE
Act) by the Human Fertilisation and Embryology
Authority (HFEA). The regulatory framework
encompasses, among other things, in vitro
fertilisation (IVF), donor insemination, and
research involving the creation or use of human
embryos. Anyone undertaking, without an HFEA
licence, an activity governed by the HFE Act may be
guilty of a criminal offence.
5.2 The nuclear substitution of an embryo, or
any cell whilst it forms part of an embryo is
expressly prohibited by the HFE Act. Embryo
splitting and nuclear replacement of eggs are not
expressly prohibited, but as both involve the use
or creation of embryos outside the body, they fall
within the HFE Act and therefore come under the
jurisdiction of the HFEA.
5.3 The HFE Act allows, under a licence from the
HFEA, research involving human embryos within
strict limits which must not exceed the fourteenth
day of their development. Embryos used for research
must not be replaced in a uterus. The HFEA can
license the use of human embryos only where it
considers their use to be necessary for the
research; therefore animal studies must often have
been carried out before research involving human
embryos will be permitted. In addition, any such
research must appear to the HFEA to be necessary or
desirable for one of the following
purposes(5):
- to promote advances in the treatment of
infertility;
- to increase knowledge about the causes of
congenital disease or about the causes of
miscarriages; or
- to develop more effective techniques of
contraception or methods for detecting the
presence of gene or chromosome abnormalities in
embryos before implantation.
This list may be extended by the Secretary of
State for Health in regulations, provided the new
categories are established with a view to
increasing knowledge about the creation and
development of embryos, or about disease, or with a
view to enabling such knowledge to be
applied(6).
5.4 The HFEA’s policy is that it will not
license any research which has reproductive cloning
as its aim. However, it would consider licence
applications for other types of research involving
embryo splitting or nuclear replacement in eggs,
provided that the research falls within one of the
purposes specified by the HFE Act, or any
regulations, which may be made by the Secretary of
State for Health as described above.
5.5 The Warnock Committee
(1984)(7),
whose report eventually led to the HFE Act, made
clear its view that human reproductive cloning
should not be permitted. In its deliberations on,
“The Cloning of Animals from Adult
Cells”(8),
the House of Commons’ Science and Technology
Committee, was concerned that the law needed to be
reviewed to take account of scientific developments
since then.
5.6 In its response to the
Committee(9),
the Government has indicated that, while human
reproductive cloning cannot take place in the UK,
it will consider carefully, in the light of
developments, whether the legislation needs to be
strengthened in any more specific way. It has said
that, in respect of cloning, it will take into
account the views of Members of Parliament, the
HGAC, HFEA and responses to any general
consultation on the broader issues.
Section 6
REACTIONS TO THE ANNOUNCEMENT OF THE CLONING
OF DOLLY
6.1 There was extensive and mixed press coverage
of Dolly. Most of the reporting focused on the
prospect of human reproductive cloning and the
issues raised by such a possibility.
6.2 The UK Government confirmed its position
that work which would create cloned human beings
should not and cannot lawfully be carried out.
Tessa Jowell, Minister for Public Health, made the
position clear: “We regard the deliberate
cloning of human individuals as ethically
unacceptable”(10).
6.3 President Clinton called on the US National
Bioethics Advisory Commission (NBAC) to investigate
the ethics of such procedures. He also gave
instructions to the heads of executive departments
and agencies that “no federal funds shall
be allocated for cloning of human beings”.
The NBAC, publishing its report on 9 June 1997,
concluded that using nuclear replacement technology
for the purposes of creating a child was unsafe,
and recommended legislation to ban research into
the cloning of “complete people”.
The proposed legislation should have a five year
“sunset” clause to allow review on the
continued desirability of prohibition. President
Clinton accepted this and has sent the
“Cloning Prohibition Bill 1997” to
Congress for consideration. In doing so he stressed
the potential benefits of nuclear replacement
technologies and pointed out that the Bill did not
seek to stop these from being realised. The Bill,
as of January 1998, is still being considered by
Congress.
6.4 Dolly caused a global sensation and since
her announcement a number of international
instruments have been developed. The UK has been
closely involved in a number of initiatives which
call for the reproductive cloning of human beings
to be banned:
- EC draft Biotechnology Patents
Directive(11)
which forbids the issue of a patent on work
leading to deliberate cloning of human beings.
- A protocol forbidding the cloning of human
beings has been developed under the Council of
Europe Bioethics
Convention(12).
- A UNESCO Declaration on the Human Genome and
Human Rights, adopted on 11 November
1997(13),
of which Article 11 states that “Practices
which are contrary to human dignity, such as
reproductive cloning of human beings, shall not
be permitted”.
6.5 Annex D contains brief details of laws in
some countries in respect of human cloning.
Section 7
POTENTIAL RESEARCH AND THERAPEUTIC BENEFITS:
ETHICAL IMPLICATIONS
7.1 The creation of Dolly represented a further
step in the development of nuclear replacement
technology. It showed that a nucleus taken from an
adult animal could be reprogrammed to allow the
full range of gene expression needed to produce a
complete animal, so called gene totipotency.
Although this research is still in its early stages
and has not been reproduced it is a significant
scientific breakthrough and offers a number of
basic research applications of human relevance.
7.2 Nuclear replacement research can improve our
knowledge about physiological processes and the
genotype. For example, it is hoped that this work
will offer a greater insight into the origins of
cancer and other cellular development processes
such as ageing and cell commitment. It may also
offer the potential to produce better animal models
for human disease which would aid research into new
or improved therapies. Many of these important
questions will be difficult to study unless the
procedure shown in livestock animals can be
extended to mice, for example.
7.3 In humans, the possibility
of using nuclear replacement technology for
reproductive cloning has been raised. However, it
could also be used as a means to avoid the
transmission of inherited diseases derived from the
mitochondria. This possible application need not
involve human reproductive cloning. It could
involve, for example, taking an enucleated egg from
a donor containing normal mitochondria, which would
then receive the nucleus from an unfertilised egg
taken from the individual with mitochondrial
disease. The reconstructed egg could then be
fertilised. This type of therapy would not involve
the production of a genetically identical
individual or fetus.
7.4 It is important to make the distinction
between human embryo research, which may be
permitted under licence under the 1990 Act and
reproductive cloning, where an embryo is implanted
into a woman’s womb. The Warnock Committee
concluded in 1984 that, “the embryo of the
human species ought to have a special status”,
which should be enshrined in legislation. The
Committee stated that this special status should
not afford the human embryo the same status as a
living child or an adult, but did mean that human
embryos should not be used frivolously or
unnecessarily. The Committee went on to conclude
that the special status of the embryo would permit
some embryo research up to the fourteenth day of
development provided the research was strictly
controlled and monitored. The recommendations of
the Warnock Committee were included in the
provisions of the Human Fertilisation and
Embryology Act 1990, which allows research to be
carried out on embryos up to 14 days development
under licence from the HFEA within certain
restrictions. Would the use of nuclear
replacement techniques or embryo splitting to
create embryos raise any new issues in relation to
the special status of the human embryo?
7.5 Embryo research which involved nuclear
replacement technology or embryo splitting in the
UK would not be allowed to lead to any fetuses or
babies being produced. A non-reproductive
application of this technology would be to use the
nuclear replacement technique to create in-vitro
stem cells. Are there any medical or scientific
areas that might benefit from research involving
the creation of a cloned human embryo? Would embryo
research involving nuclear replacement technology
raise any new issues in respect of what may
ethically be done within the 14 day period?
7.6 Research which might generate in-vitro stem
cells and cause them to differentiate into specific
cell types could provide insights into how to
induce regeneration of damaged human tissue without
risk of rejection reactions. For example: neural
tissue for sufferers of Parkinson's Disease; skin
tissue to treat patients suffering from burn
injuries; and muscle tissue to treat patients
suffering from heart damage. Under the HFE Act
1990, limited human embryo research may be licensed
for specific purposes as defined in the Act.
However, the Secretary of State does have the power
to broaden the scope of this research, which would
permit the HFEA to consider proposals to conduct
human embryo research for some therapeutic purposes
(see paragraph 5.3). Would any of the potential
applications of nuclear replacement, some of which
are exemplified above, that would not result in
cloned fetuses or babies raise any new ethical
concerns?
Section 8
HUMAN REPRODUCTIVE CLONING: THE ETHICAL
IMPLICATIONS
8.1 The use of either embryo splitting or
nuclear replacement deliberately for the purposes
of human reproductive cloning, to produce
genetically identical human beings, raises serious
ethical issues, concerned with human responsibility
and instrumentalisation of human beings.
8.2 Cloning by embryo
splitting would artificially reproduce the natural
process by which monozygotic (identical) twins, who
make up approximately one third of twins in the UK,
are produced. World-wide, there are approximately
3-4 monozygotic twinnings per 1000 births. Such
naturally occurring twins show that genetically
identical individuals are far from being identical
people: they may differ from one another
physically, psychologically, in personality and in
life experience. The intrauterine environment may
cause lasting differences. It is reported that some
monozygotic twins have problems in establishing
their identity and experience delayed language
development and problems forming other
relationships. It is also reported that these
difficulties usually arise when the children have
been treated as an indistinguishable and
inseparable pair. If individual humans were cloned
by nuclear replacement from an adult cell, they
would, of course, be even more different from their
donor, since their mitochondria, their age, their
environment, both before and after birth, and their
upbringing would differ. The experience of natural
identical twins suggests that a unique genetic
identity is not essential for a human being to
feel, and be, individual(14).
Therefore what is meant by the assertion that
individuals have the right to their own genetic
identity? What does this mean for identical
twins?
8.3 There are a number of
situations where it has been suggested that cloning
technology could be applied to make a
“copy” of another human being. As
explained in Section 5 none of the activities
suggested in these scenarios are permitted in the
UK. Such scenarios envisage single or multiple
“copies” of a living or dead fetus, baby,
child or adult. For example:
- Parents might wish to “replace” an
aborted fetus, dead baby or child killed in an
accident. A grieving woman whose husband and
daughter have been killed in the same car crash,
may wish to use the DNA from one of her
daughter’s cells and insert it into an egg
supplied by another woman. The child born would
be a clone of her dead daughter. However, the
mother would not be “getting back” the
same child that had died.
- In the case of a child dying of kidney
failure and where neither parent can donate a
compatible organ, parents might wish to have a
further sibling, produced by cloning, to be a
compatible organ donor, as this would avoid a
rejection reaction. One of this child's kidneys
might then be transplanted to save the life of
their older sibling.
- An individual might seek to use cloning
technology in an attempt, as that individual
might see it, to cheat death.
There are moral arguments to support the claim
that human dignity forbids the use of human beings
only as a “means”, holding that they are
to be treated as an “end” in their own
right. What implications do these considerations
have for the ethics of human reproductive
cloning?
8.4 There are many general questions about
intervention and reproductive technology, which are
not unique to cloning. For example, what limits are
there on the role of prior choice of
characteristics in offspring, where this is
scientifically made possible. These presumably
apply equally to cloning and include the obvious
need for safety issues to be addressed fully.
8.5 A potential application of human
reproductive cloning by nuclear replacement might
be to assist human reproduction. A lesbian couple
might wish to have a child. Here the cell nucleus
from one woman could be inserted into an enucleated
egg from the other. The resulting embryo might then
be implanted in the uterus of the woman who donated
the egg. Another scenario might be where both
individuals of a couple are infertile or where the
prospective father has non-functional sperm. In
this case, cloning one member of the couple to
create offspring might be envisaged. Would the
use of nuclear replacement techniques be beyond the
limit of what is ethically acceptable to resolve a
couple’s infertility problem?
8.6 Irrespective of whether it
would be desirable, there is considerable doubt
about whether it would even be possible to clone
humans using the techniques used to produce Dolly
the sheep. The nuclear replacement technology used
to produce Dolly is still in its early stages. We
do not yet know whether the work which created
Dolly is repeatable in animals, nor is it known
whether it can be replicated in humans. We should
bear in mind that Dolly was the only normal lamb
born from 276 similar attempts. Only 29 resulted in
implantable embryos, all of which, except the one
leading to Dolly, resulted in defective pregnancies
or grossly malformed births. Similar procedures
aimed at human cloned reproduction might be
associated with similar “wastage” rates
and uncertainties about malformations. The age of
Dolly’s DNA may be the same as the original
sheep, of which she is a clone. She may have a
shortened life-span or a greater susceptibility to
cancer. Even though she appears to be fertile, her
progeny may show an increased abnormality rate,
owing to the accumulation of damage to the DNA.
This raises safety issues about the development of
nuclear replacement for therapeutic purposes. Any
attempt to develop this technology in humans would
be expensive and would require a large amount of
human experimentation. Do these considerations
make experimentation in humans involving the
implantation of cloned embryos ethically
unacceptable? How does this case differ from the
experiments that first led to successful in vitro
fertilisation (IVF) procedures?
8.7 IVF and embryo splitting
are technological interventions that mimic natural
physiological processes (i.e. fertilisation and the
natural creation of monozygotic twins or triplets).
In contrast, there is no apparent known natural
counterpart for the transfer of genomes by nuclear
replacement. IVF is currently used to promote the
creation of human beings that could not be brought
into being under natural conditions. Is there a
distinction between different artificial
technologies according to whether they have natural
counterparts or not? Should society adopt a graded
scale of “unnaturalness” with some
variation from the natural regarded as being
unacceptable?
Section 9
YOUR COMMENTS
9.1 The HGAC and HFEA would very much welcome
your general comments on how the technology might
actually develop, the opportunities and problems
that would be raised by human reproductive cloning
and other applications of nuclear replacement
technology. We are also interested in your views on
the priorities for the future and the ethical
setting in which these scientific developments are
taking place, including any additional ethical
issues raised by human cloning that you have
identified. It would be helpful if your response
could be structured around the questions set out
below:
Any new issues in 14 day period
(paragraphs 7.3 - 7.6)
Q1 Would research using nuclear replacement
technology raise any new ethical issues in relation
to what is permitted in work with embryos in the 14
day period?
Q 2 Are there any medical or scientific areas
that might benefit from research involving human
nuclear replacement?
Own genetic identity (paragraph
8.2)
Q3 To what extent can a person be said to have a
right to an individual genetic identity?
Instrumentalisation (paragraph
8.3 -8.5)
Q4 Would the creation of a clone of a human
person be an ethically unacceptable act?
Experimental human beings
(paragraphs 8.6)
Q5 Would the likely cost in terms of failures
and/or malformations inevitable in developing a
programme of human reproductive cloning be
ethically acceptable?
Natural/Unnatural (paragraph
8.7)
Q6 What ethical importance might be attached to
the distinction between artificial processes for
which there are parallels in natural processes and
those for which there are not?
9.2 We will also be advising Ministers on ways
to build public confidence in and understanding of
new developments in genetic techniques. We would
welcome any suggestions you may have on what this
advice might be in respect of the implications of
human cloning.
9.3 We are grateful to you for taking the time
taken to read and respond to this consultation
paper. Please send your replies, by 30 April
1998 to :
- The HGAC Secretariat
c/o Office of Science and Technology
Albany House
94-98 Petty France
London SW1H 9ST
We may wish, in the future, to publish some of
the views expressed in this paper or those arising
from this consultation exercise. Should you wish
your views to be treated in confidence, please make
this clear in any paper you submit to us.
Further copies of this paper are available
on request from Chris Hepworth (faxed requests
preferred - FAX: 0171 271 2028)
This paper can also be located on our Web
Site location: www.dti.gov.uk/hgac
Annex A
HGAC/HFEA CLONING WORKING GROUP
Terms of reference:
to consider the planning, drafting, distribution
and analysis of a joint HGAC and HFEA consultation
paper on the issues for human genetics arising from
advances in mammalian cloning, and advise the HGAC
and HFEA.
Membership
CHAIRMAN - Revd Dr John Polkinghorne KBE
FRS
Chairman - Advisory Committee on Genetic
Testing, HGAC member
Professor Christine Gosden
Professor of Medical Genetics, University of
Liverpool, HFEA member
Dr Anne McLaren DBE FRS
Principal Research Associate, Wellcome/CRC
Institute, HFEA member
Dr George Poste FRS
Chief Science & Technology Officer,
SmithKline Beecham,, HGAC member
THE HUMAN GENETICS ADVISORY COMMISSION
(HGAC)
The Human Genetics Advisory Commission (HGAC)
was established in December 1996 to take a broad
view of developments in human genetics and advise
on ways to build public confidence in the
application of the new science.
The terms of reference of the HGAC are to:
- keep under review scientific progress at the
frontiers of human genetics and related fields;
- report on issues arising from new
developments in human genetics that can be
expected to have wider social, ethical and/or
economic consequences, for example in relation
to public health, insurance, patents and
employment;
- advise on ways to build public confidence
in, and understanding of, the new genetics.
Membership
HGAC is chaired by Professor Sir Colin Campbell.
Other Members are: Professor Cairns Aitken, Dr
Michaela Aldred, Professor Martin Bobrow, Mrs Doris
Littlejohn, Dr Onora O’Neill, Dr George Poste
and Ms Moira Stuart. Professor Norman Nevin and Rev
Dr John Polkinghorne, the Chairmen of the Gene
Therapy Advisory Committee and the Advisory
Committee on Genetic Testing, respectively, are
also members.
HUMAN FERTILISATION AND EMBRYOLOGY AUTHORITY
(HFEA)
Terms of reference
The HFEA is a statutory body whose major function
is to license all fertility treatments involving
the use of embryos created outside the body (IVF)
or donated eggs or sperm (e.g. donor insemination).
The Authority also licenses the storage of eggs,
sperm and embryos and all research on embryos.
The HFEA was established by the Human
Fertilisation and Embryology Act 1990 and took up
its powers on 1 August 1991. In addition to its
licensing role, the HFEA has several other
responsibilities including:
- to publish the Code of Practice giving
guidance to centres on how they should carry out
licensed activities;
- to keep a confidential register of
information about donors, patients and
treatments;
- to publicise its role and services which
licensed centres provide;
- to give advice and information to licensed
centres;
- to give information and advice to people
seeking fertility treatment, to donors, to
people who may need to store sperm, eggs or
embryos for medical reasons and to the general
public; and
- to keep the whole field of fertility
treatment and research under review, whether the
activities are licensed or not, and make
recommendations to the government if asked to do
so.
Membership
HFEA is chaired by Mrs Ruth Deech. Other members
are: Dr Gulam Bahadur, Professor David Barlow,
Professor Ruth Chambers, Mrs Jane Denton, Ms Liz
Forgan, Professor Christine Gosden, David
Greggains, Professor Andrew Grubb, Professor Martin
Johnson, Richard Jones, Professor Stuart Lewis, Dr
Brian Lieberman, Dr Anne McLaren, Dr Joan Stringer,
Professor Allan Templeton, Professor Anthony
Thiselton, Julia Tugendhat, John Williams.
Annex B
GLOSSARY
Cellular cloning: the process by which
cells derived from the body (“soma”) and
are grown in tissue culture in a laboratory. The
genetic makeup of the resulting cloned cells (the
“cell line”) is identical to that of the
original cell.
Chromosomes: nucleic acid-protein
structure in the nucleus of a cell. Chromosomes are
composed chiefly of DNA, the carrier of hereditary
information. Chromosomes contain genes, working
lengths of DNA that carry the genetic code for
specific proteins, interspersed with large amounts
of DNA of unknown function. A normal human somatic
cell contains 46 chromosomes; a normal human gamete
cell contains 23 chromosomes.
Cloning: copying and propagation without
altering the nuclear genome.
Cytoplasm: the contents of a cell other
than the nucleus. Cytoplasm consists of a fluid
containing numerous structures e.g. mitochondria
that carry out essential cell functions.
Diploid: a cell such as a somatic cell
having two chromosome sets, as opposed to the
haploid situation of eggs and sperm which have only
one chromosome set.
DNA: Deoxyribonucleic acid, found
primarily in the nucleus of cells (some DNA is also
found in the mitochondrion). DNA carries the
instructions for making all the structures and
materials that the body needs to function.
Egg: the mature female germ cell; also
called the “ovum” or
“oocyte”.
Embryo: the developing organism from the
time of fertilisation until significant cellular
differentiation has occurred, when the organism
becomes known as a “fetus”.
Enucleated egg: an egg from which the
nucleus has been removed.
Fertilisation: the process whereby male
and female gametes unite, beginning when a sperm
contacts the outside of the egg and ending with the
formation of the zygote.
Fetus: the term used for an embryo after
the eighth week of development until birth.
Gene: a working length of a chromosome
composed of DNA. Each of the body’s 100,000
genes carries the instructions that allow the cell
to make one specific product such as a protein.
Genome: the complete genetic make up of a
cell or organism.
Genotype: the genetic make up of an
individual.
Germ cell: a cell all of whose surviving
descendants will form sperm or eggs. All other body
cells are known as “somatic” cells.
Human reproductive cloning: the creation
of human beings genetically identical to one
another or to any other human being.
Haploid: the single chromosome set
carried by the sperm and egg cells which are
recombined after fertilisation to create the
diploid chromosome set present in every cell of the
body except sperm and eggs.
In Vitro Fertilisation (IVF): eggs and
sperm are collected and put together to achieve
fertilisation outside the body.
Mitochondria: cellular organelles that
provide energy to the cell. The mitochondrion
contains some of its own genes.
Monozygotic: formed from a single
fertilised egg.
Nuclear replacement: a technique which
involves fusing the nucleus from a diploid cell or
another egg, with an egg from which the nucleus has
been removed. The DNA of the transplanted nucleus
thus directs the development of the resulting
embryo, or egg.
Nucleus: the cell structure that houses
the chromosomes, and thus the genes.
Oocyte: the mature female germ cell; the
egg
RNA: Ribonucleic acid
Somatic cells: any cell of an embryo,
fetus, child or adult not destined to become a
sperm or egg cell.
Stem cell: an undifferentiated cell which
is a precursor to a number of differentiated cell
types.
Therapeutic cloning: medical and
scientific applications of cloning technology which
do not result in the production of genetically
identical fetuses or babies. These techniques may
be undertaken to advance fundamental research and
therefore not all such applications will lead to
immediate therapeutic utility.
Transgenic: containing a gene or genes
introduced from another individual.
Zygote: the single-celled fertilised
egg.
Annex C
EXPERIMENTS WHICH LED TO DOLLY AND SUBSEQUENT
DEVELOPMENTS
The first evidence that it was possible to clone
vertebrate animals using nuclear replacement was in
1952. The first series of experiments, using cells
from tadpoles as the source of donor nuclei,
produced adults but at a very low efficiency.
Although the cells used were highly specialised,
they were not derived from adult frogs, so the
cells might not have been fully differentiated.
Later, clones of tadpoles were obtained by nuclear
transfer from differentiated adult frog skin cells
to an enucleated egg establishing that
differentiation of cells involving selective gene
expression does not require the loss or
irreversible inactivation of genes. No viable adult
frog developed from these tadpoles.
In contrast, cloning by embryo splitting, from
the 2-cell up to the blastocyst stage, has been
extensively used in sheep and cattle to increase
the yield of progeny from genetically high grade
parents. Embryo splitting was first used to produce
genetically identical sheep ten years ago at
Cambridge. This technique has been used extensively
in sheep since then. Because of the different
pattern of early development, embryo splitting is
much less successful in mice. From a scientific
point of view, it would probably not be very
effective in the human, although monozygotic
(one-egg) twins and higher multiples occur
naturally at a low incidence.
The Ministry of Agriculture, Fisheries and Food
(MAFF), the Biotechnology and Biological Sciences
Research Council (BBSRC), industry and the European
Union have funded research at the Roslin Institute
on the development of nuclear replacement
technology since 1991 because of its potential to
contribute towards genetic improvement of
livestock. In announcing the birth of two
genetically identical normal lambs (Megan and
Morag) in 1996, the Roslin Institute reported a new
method of cloning sheep embryos, which involved
first establishing cell cultures from single
embryos. Nuclei from the cultured cells were
transferred to enucleated unfertilised sheep eggs,
particular attention being paid to the cell cycle
stage of both donor and host cells, and the eggs
were then artificially stimulated to develop. More
recently, in creating Dolly, the Roslin Institute
transferred a nucleus from a cell culture of adult
sheep cells. Dolly appears to be the first and only
example of an adult vertebrate which has been
cloned from another adult. However, it has yet to
be established whether the transferred nucleus was
from a differentiated mammary gland cell or from a
stem cell. It is not clear whether Dolly is normal
or whether she could have subtle problems that
might lead to serious diseases. Concern has been
expressed that the use of an adult donor cell will
have effects on ageing and could perhaps lead to
increased incidence of diseases such as cancer.
Dolly appears to be a normal healthy animal and her
development will continue to be closely monitored
as she grows older.
There have also been major developments since
Dolly’s announcement. News of
“Polly” was released by PPL Therapeutics
in July 1997. This project is part of a PPL
programme which aims to develop technology which
will allow large amounts of proteins of therapeutic
value to humans to be produced economically. In
creating Polly, PPL for the first time combined
existing techniques of nuclear replacement and
transgenics. The nuclei in cultured fibroblast
cells from a female sheep fetus were first modified
through the addition of the human gene for factor
IX (a blood clotting protein), by a process known
as transfection. The modified nucleus was then
introduced into the sheep’s egg from which the
DNA had been removed - the nuclear replacement
step. In this way, Polly has been transgenically
modified to enable her to produce therapeutic human
proteins in her milk, and was created using nuclear
replacement technology. The ability to clone
transgenic sheep offers the prospect of the
economically viable generation of flocks of sheep
which are of particular benefit to humans.
Nuclear replacement has also been used for
cloning in various mammalian species (mice,
rabbits, cattle), but until recently only nuclei
taken from very early embryos were effective, and
development was often abnormal, for reasons that
are not fully understood. Recently, in the United
States, ABS Global Inc. have cloned a Holstein
Bull, Gene, by transfer of a fibroblast nucleus
from a male Holstein fetus. This was the first calf
to be born from a non-embryo-derived cell.
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