THE PROJECT to map the human genome is still in its infancy. No one
knows how scientists will tackle the exercise, what they will find or, perhaps
most importantly, how they will apply the knowledge they gain. These three
facets of the project are intricately linked, not only to each other, but
also to myriad legal and ethical issues.
To discuss the ramifications of knowing more about the human genome,
a small group of scientists, philosophers and specialists in law, ethics
and theology met last week in Bern in Switzerland. The symposium, entitled
Human Genetic Information: Science, Law and Ethics, was organised by the
Ciba Foundation, in celebration of its 40th anniversary, together with the
Academic Commission of the University of Bern.
The most immediate problem facing scientists is how to go about determining
the sequence of the base pairs that make up the genetic code. James Watson,
the director of the American programme to map the human genome and co-discoverer
of the double helix, has suggested that individual countries should take
responsibility for particular chromosomes.
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Some scientists at the meeting strongly disagreed, however. Sydney Brenner,
the director of the Molecular Genetics Unit of Britain’s Medical Research
Council in Cambridge, said it would be wasteful to make a complete map now.
He argues that it is necessary to sequence only 2 per cent of the human
genome: the part that contains coded information. The rest of the human
genome, Brenner maintains, is junk. He suggested that it might be possible
theoretically to delete all the junk sequences from the genome of a mouse
and still have a mouse, or at least a ‘mini-mouse’.
Some scientists have argued that, as no one knows what is in the junk
DNA, they cannot dismiss it. The only way to find out whether the junk is
important would be to sequence the entire genome. But Brenner told the symposium
that the counter to this argument is ‘to look on the sequencing of junk
like income tax; it cannot be evaded but there are ways of avoiding it’.
In any case, he added, it is one of the problems that today’s scientists
should leave for their successors.
The mapping of the human genome will undoubtedly take more than a generation
to complete. Even if a machine were available that were capable of producing,
in one day, the sequence of a strand of DNA containing a million pairs of
nucleotides, then it would still take about 20 years to sequence both strands
of the human genome, Brenner said.
He believes that one way to identify the important 2 per cent of the
genome is to look at the sequences of the messenger RNAs of genes that scientists
know contain information important to the organism. Although, initially,
the map showing these sequences would be sparsely populated, eventually,
with more information, the coding sequences would join up.
Brenner said that if some people wanted to sequence the human genome
chromosome by chromosome, then they should be allowed to do that. But he
warned that: ‘We (in Cambridge) do not intend to be assigned a part of a
chromosome by some Politburo somewhere. That’s no way to do genetics.’
When governments are contemplating spending millions of dollars on the
project, the question of whether it is practicable to sequence the entire
genome now is bound to come to the fore. Some researchers at the symposium
warned of the dangers of putting too much emphasis on the benefits that
the project would have for medicine: basic biology would also profit, they
said. But several others said they had no doubts that the justification
for the work would be the medical benefits.
One immediate gain will be the identification of genes responsible for
many inherited diseases. There are several thousand human diseases caused
by mutation of a single gene, which are inherited in a simple Mendelian
fashion. These so-called monogenic diseases include, for example, thalassaemia,
cystic fibrosis, Huntington’s disease and Duchenne mus- cular dystrophy.
In most of these cases, scientists do not know which gene has mutated, or
what its normal product is.
Once that information is available, doctors will be able to offer tests
to couples planning to have children, to determine whether they both carry
a recessive gene for a disease such as cystic fibrosis, for example. Prenatal
diagnosis will also be available for a wide range of genetic diseases. In
the case of monogenic diseases that do not become apparent until late in
adult life, such as Huntington’s disease, there will be simple tests available
to tell people in affected families whether they carry the mutant gene.
The business of prediction will be more complicated for most other diseases
that affect adults, such as coronary heart disease, cancer, diabetes, arthritis
and mental illness. There is often a genetic component to these ‘polygenic’
diseases, but they are not inherited in a simple and predictable way. In
addition, environmental factors such as diet, smoking and lack of exercise
may play a role, or even be entirely to blame for such diseases.
Nevertheless, it may be possible to define the increased risk that individuals
suffer by virtue of their genetic make-up. Bob Williamson, of St Mary’s
Hospital Medical School in Paddington, London, pointed out that about 20
genes determine the levels of cholesterol that people have in their blood
and so their risk of falling early victims to coronary artery disease.
He said that the main use of working out which genes contribute to the
risk of polygenic diseases would be to identify those at high risk. Doctors
could then advise these people on ways of reducing that risk, by giving
up smoking, for example, or other appropriate measures.
The wider availability of techniques to diagnose diseases with a genetic
component will raise difficult legal and ethical issues. Diana Brahams,
a specialist in the law relating to medicine, said it might be possible
in future to identify people likely to develop a serious disease, long before
the symptoms appear.
Such information could be ‘of considerable interest and value to any
prospective employer, insurer, marriage partner or family member and would
be of serious concern to the individual,’ she said. People will have to
tackle the question of how far sensitive genetic information should be made
available to the patient, or to other interested parties.
The people on the Clapham omnibus probably harbour much greater fears
about how scientists could use the information they obtain about the human
genome for treatment, rather than diagnosis. Once geneticists know which
genes are responsible for monogenic diseases, the prospect looms of being
able to carry out some kind of gene therapy. One way to do this would be
to introduce a normal copy of the faulty gene into the cells of the body,
or somata.
While this approach might work for cells that can function anywhere
in the body – cells that produce hormones might be one example – it would
not help with most inherited diseases. In cystic fibrosis, for example,
the defective gene alters the function of membranes in many different organs,
from the lungs to the sweat glands.
For such monogenic diseases, the alternative would be to insert the
copy of the normal gene into the fertilised egg (zygote), following in vitro
fertilisation. Once the embryo was back in the uterus, all its cells would
have a copy of the normal gene and, according to theory, be capable of functioning
normally.
Charles Weissmann, of the Institute for Molecular Biology in Zurich,
Switzerland, pointed out that even if the technology to perform such gene
therapy successfully were available, it would first be necessary to establish
whether the zygote carried the defective gene. Rather than proceeding with
gene therapy on such zygotes, it would be much simpler, he said, just to
replace unaffected embryos in the woman’s uterus.
Gustav Nossal, chairman of the symposium, from the Walter and Eliza
Hall Institute of Medical Research in Melbourne, Australia, put it more
bluntly. ‘We have decided to skin the cat another way,’ he said. He felt
that the mood of the meeting was one of extra- ordinary caution on germ-line
gene therapy. ‘There is more acceptance of the limitations of what we can
do,’ he told New Scientist. This contrasted with the hubristic mood of some
geneticists a few years ago.
Bernard Williams, of the University of California at Berkeley, agreed.
He said there was now a clear distinction between interventions designed
to cure or treat diseases and those aimed at creating more beautiful, intelligent
or otherwise more desirable people.
Speaking after the symposium, he said that the idea that people could
rewrite the human genome to suit themselves ‘was a notion which was treated
with the most profound mistrust by everybody at this conference’.
Part of the reason for this attitude, he said, is that attributes such
as intelligence are highly polygenic: they are the result of the interaction
of many genes with each other and the environment.
The idea that you could find a gene for intelligence and replace it
with one which would make the person into which the embryo would grow ‘cleverer’
is, Williams said, ‘just a fantasy’.
Several of those attending the conference pointed out that there is
no scientific definition of intelligence. Any scientist setting out on a
programme of eugenics to ‘improve’ the human race would first have to make
enormous value judgments about which were ‘good’ characteristics and which
were ‘bad’. Williams said: ‘The idea of intelligence as an unqualified,
unambiguous human good which it would be nice to bring about if you could’
is a concept which most scientists nowadays treat with suspicion.
That may be true, but some speakers pointed out that sequencing the
human genome might uncover a gene contributing greatly to athleticism, for
example, or height. Bernard Davies, of Harvard Medical School, said: ‘Even
if we find such uses trivial or repugnant, a world that accepts cosmetic
surgery and the injection of silicone to enlarge breasts, and that cannot
prevent use of hormones by athletes, may find it difficult to limit nonmedical
uses’ of genetic manipulation if there is a market for them.
The question of who should regulate the application of the new-found
knowledge about the human genome is a taxing one. Brahams pointed out that
the law tends to respond to past events. ‘But when you try to legislate
for some time ahead for things which have not yet happened, you usually
get it wrong,’ she said. Overregulation would suffocate research but, ‘on
the other hand, if you are too liberal, people can do unpleasant experiments’,
as history has shown.
Is it possible to legislate for events which have not yet happened?
For example, should the law ban scientists from doing certain types of research
for fear of what they might find? Davies said: ‘The view that some areas
may be so dangerous that you should stop them early is based on the assumption
that we can see their bad uses more clearly than we can see their good uses.
But history tells us that it is impossible to predict what the distribution
of their uses will be.’ Williams added that you cannot know, before the
event, what you may want to ban. Brenner likened the human genome project
to a journey of discovery through a new country, in which scientists would
label everything. But no one at the meeting, he said, had expressed the
idea of forbidden knowledge, ‘the idea that there should be parts of that
country where no one should ever go’.
Anne McLaren, of the Mammalian Development Unit at University College,
London, said she thought that, in most cases, it was possible to separate
the pursuit of knowledge from its application. She added: ‘Scientists do
not operate in a social vacuum. If society decides that there are areas
they do not wish scientists to explore, then most scientists I know would
go along with that.’
Some societies have already set limits to research. Brahams said that
Denmark has banned all research on embryos, apparently to allow time for
thorough consideration of all the issues involved. The West German Ministry
of Justice is also drafting a law that would make it a criminal offence
to conduct any research on embryos that would be harmful to them. In Australia,
the law bans all research on embryos after the stage where the nuclei of
the sperm and the egg have fused.
There was clear concern among scientists at the meeting that inflexible
laws would interfere with research. Williams, summarising the meeting, said
there was a high measure of agreement about the desirable ways of regulating
the research. Governments should set up regulatory agencies (similar to
the Voluntary Licensing Authority which oversees embryo research in Britain)
that could monitor research and react swiftly to new discoveries. Williams
said: ‘The great virtue is that it stops some arbitrary limits being built
into the law which then become difficult to change.’
As Brahams said, much of the unease about the future scope of genetic
manipulation may have its roots in ignorance. ‘Much needs to be done,’ she
said, ‘with regard to the education of journalists, members of parliament,
lawyers and religious leaders – and, of course, the public at large.’