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Next week in London, 700 scientists will gather to discuss their progress
in mapping the human genome. The meeting – the eleventh international workshop
since 1973 – will almost certainly be the last of its kind. As the project
gathers momentum, its principal workshop is creaking at the joints, a victim
of its own apparent success. There is simply too much material to handle.

In future there will instead be separate meetings devoted to each chromosome
and even these are likely to be overloaded, says Victor McKusick at the
Center for Medical Genetics at Johns Hopkins University, Baltimore, who
has been closely involved in the project from the start.

This year’s jamboree, meanwhile, looks as if it will try to tackle more
than ever before. Not content with the human genome, the organisers have
devoted a whole session to comparing the genomes of other organisms. The
menu includes the pig, the mouse and a weed, thale cress, as well as fruit
flies and the worm Caenorhabditis elegans.

As the volume of information on the human genome grows, so too have
questions over social and ethical issues, such as how best to safeguard
people from misuse of the data. And there is still confusion about how the
research is set up, who should pay and who should be in charge.

The human genome project is a blanket term to sum up the efforts of
hundreds of scientists around the world, to ‘read’ the entire library of
genetic information that is stored on the 23 pairs of human chromosomes.
It includes the various national programmes, such as the US’s with a budget
of $3 billion over 15 years and Britain’s, with £11 million over
three years. The current emphasis is on locating landmarks along each chromosome
and mapping genes that cause hereditary disorders. But the ultimate goal
is to map and sequence all human genes. So far, about 2000 of a total of
about 50 000 genes have been mapped.

The Human Genome Organisation, or HUGO, which is behind next week’s
meeting, brings a degree of international coordination to these efforts.
Set up in 1988, its first president was McKusick, who was succeeded by Sir
Walter Bodmer, head of the Imperial Cancer Research Fund in London. However,
HUGO is not a grant-making body; it has very little money. Bronwen Loder,
scientific administrator of HUGO Europe says the organisation exists to
provide coordination ‘at the level of the practising scientist’. Funds for
the researchers come from their respective governments, from other sources
within participating countries, and from the European Commission.

HUGO’s critics say that without money, it has little to offer. To influence
the project, says Peter Little at Imperial College, London, ‘you need a
pile of money and HUGO doesn’t have it’.

How then does the whole project hang together if there is no single
body to pay the pipers and call the tune? The key is information stored
in the Genome Database, set up at Johns Hopkins, which has been designated
by HUGO as the project’s official data repository. It contains records of
all the genes and landmarks mapped so far, together with information on
the DNA probes that locate the gene and who holds those probes.

Since the database went on line last September, it has grown fast. It
already contains around 170 million bytes of information and boasts 3700
users, nearly 500 of whom are in Britain. A new transatlantic computer service
means that by October, scientists will be able to consult the database from
their own terminals. This facility, says Loder, will reduce the need for
the workshops, which were originally designed for researchers to add new
information to the database.

The Genome Database has come to symbolise the outwardly heroic vision
of the human genome project, of geneticists selflessly sharing technology,
reagents and information in pursuit of a common goal. The assumption is
that all researchers will use the database for the common good. But how
realistic is this? Who, for instance, will vet the information on the database?
And, will researchers release results or hold them back to get ahead of
competitors or to patent their work?

The job of policing the database falls to the chromosome committees
set up by HUGO. Nobody can add information without it being checked by the
committees. But, there is no simple way of ensuring that genome researchers
share data and reagents: it runs against the grain of ‘fast track’ science.

Researchers such as Little, who works on chromo-some 11, see competition
as inevitable because genome research is still ‘disease-led’. ‘There are
a large number of geneticists chasing a rather small number of disease genes,’
he says. Of the 30 or so groups working on chromosome 11, only a handful
are interested in mapping it completely, maintains Little. For most genome
researchers, the holy grail is not a fully mapped chromosome but a single
disease gene. At its worst, says Little, ‘human genetics is a nasty, uncooperative
mess in which people are scared of competition’. Yet some researchers do
not see competition as a big problem. Bob Williamson, of St Mary’s Hospital
Medical School in London says: ‘The idea that teams spend much time worrying
about competing is science fiction.’

Williamson was involved in the hunt for the cystic fibrosis gene in
the 1980s. He says his group and the Toronto team that finally isolated
the gene in 1989, were swapping data up to the last minute before the gene’s
discovery was announced. He is optimistic about the gene mapping project,
which, he says, has engendered a ‘very rapid exchange of data’.

The discovery of a disease gene can lead to fame and virtually guarantees
funds for future projects. For example, Francis Collins of the University
of Michigan, one of the discoverers of the cystic fibrosis gene, has recently
been awarded $500 000 a year by the US National Institutes of Health to
set up a human genetics research centre. Another incentive – for adding
to research funds – is the possibility of patent royalties. Most teams which
discover DNA markers for disease genes will want to patent them as diagnostic
tools although some argue that this could prevent the markers becoming immediately
available worldwide.

Whether an individual, institute or company can patent sequences of
human DNA remains the subject of intense debate (see Talking Point, 27 July).

‘In principle, I don’t see why one can’t patent a DNA sequence; it’s
a chemical,’ says Norman Carey, a consultant in intel-lectual property rights
who was formerly director of scientific affairs at Celltech. He sees parallels
between DNA sequences and antibiotics, because both have no therapeutic
use in their natural state, but immense worth when packaged correctly. Opposing
opinion says natural DNA molecules are not invented but discovered; and
discoveries cannot be patented.

Meanwhile, researchers in the US have already patented DNA. Collins,
for example, has patented the sequence of the principal mutation that causes
cystic fibrosis, because it is the basis of the test for potential carriers.
As yet no one has challenged these patents.

Whatever their position in this debate, most protagonists agree that
scientists should have the right to exploit their work. Yet, some fear that
this right could conflict with healthy running of the Genome Database.

‘This is quite definitely a problem area,’ says Carey. But he also hopes
it can be resolved. ‘I think people are very keen that the information be
rapidly exchanged.’ HUGO has set up a committee on intellectual property,
of which Carey is a member, to discuss the issues and resolve the problems.
In contrast to these efforts, HUGO has yet to tackle the broader ethical
issues posed by genome research. ‘The problem is not the monster scenario
that papers write about,’ says Bodmer.

Many geneticists argue that our knowledge of the genome should not pose
new problems, but raise old questions on a new and larger scale: will individuals
be refused life insurance because they carry a gene that predisposes them
to disease? Will an employer be able to reject a job applicant who carries
a gene that predisposes to (say) mental illness?

But, says Carey, since insurance companies already ask about family
history, blood pressure and smoking, they already make crude assessments
of people’s genetic and lifetime ‘risks’. Knowledge of the genome will merely
make this assessment more accurate.

But the fact that these questions are repeatedly asked, underlines the
need for more debate, the researchers admit. HUGO is ideally placed to tackle
these issues says McKusick. But not everyone agrees. When HUGO was asked
recently to take on the role, the response was lukewarm. ‘Sir Walter was
a little cool to the idea,’ says McKusick.

An international panel of genetics experts, brought together last June
by the Wisconsin Biotechnology Center, the USSR Academy of Sciences and
the Japanese Science and Technology Agency, concluded that an international
body should coordinate and guide research on ethical and social issues raised
by genome research.

After the meeting, HUGO was encouraged to fill this central role, by
making a proposal for funding from the US government’s genome budget. The
offer to HUGO’s leadership came from representatives of the NIH and Department
of Energy, the main channels for government genome research money. To turn
down such an offer could mean rejecting a share of millions of dollars earmarked
for bioethics research.

Liz Evans, who shares the job of scientific administrator of HUGO Europe
with Loder, says the proposal from the Wisconsin meeting was not satisfactory,
but that HUGO was willing to discuss ways to firm up the plan. She argues
that ethical and social differences vary so much from one part of the world
to another that it is ‘almost futile’ to try to discuss them at a global
level. ‘There needs to be a much more regional discussion first,’ she says.
In cases where the issues were of universal interest, HUGO is setting up
workshops.

Some researchers in Britain support HUGO’s hesitation. Sir David Weatherall,
professor of clinical medicine at the University of Oxford, says that with
an international ethical council, we may be trying to run before we can
walk. There have been enough difficulties, he says, even setting up a national
debating forum – which Britain now has in the Nuffield Council on Bioethics.
‘Maybe our first aim should be to work towards a national policy,’ he says.
The issue of HUGO’s role in discussing the social and ethical issues of
genome research is still open. McKusick says no final decision has yet been
made. The issue is on the agenda for HUGO’s council meeting at the workshop.

* * *

Strategies shift to targeting genes

As laboratories gear up to explore the human genome, views on the best
way to tackle the job are changing. Gone, it seems, are the days when researchers
envisaged sequencing vast tracts of uncharted DNA. The emphasis now is on
targeting the estimated 3 per cent of the genome that contains useful information
– the genes themselves (‘In the beginning was the genome’, ¿ìè¶ÌÊÓƵ,
21 July 1990). As a consequence, genome research is losing its image as
a ‘high-tech’ venture. The emphasis on developing faster, cheaper sequencing
machines, which dominated the early days of the US genome project, is fading.
‘The notion that this is big science that only big labs can do is wrong,’
says Sir Walter Bodmer, president of HUGO.

The best way of locating genes is still under discussion. The main line
of attack is gene mapping, which involves locating a gene indirectly with
easily identifiable DNA markers or probes. Bodmer predicts that gene mapping
will identify the positions and sequences of most human genes by the turn
of the century. The sequence of the whole genome, he argues, will then ‘fall
out’ as a by-product.

Others are less confident. At present the global genome effort is driven
primarily by the search for a relatively small number of disease genes.
Once these are found, interest in gene mapping will wane, says Peter Little
of Imperial College in London, and there will be shift towards the ‘technology-based
approach’ of DNA sequencing. Little also stresses that some parts of the
genome have been ignored because, as yet, they have no obvious medical links.
In the end these will have to be sequenced with no knowledge of their function
or value, he says.

The issue then will be whether this ‘blind’ approach actually works.
Last year Craig Venter and his colleagues, at the US National Institutes
of Health in Maryland, tried sequencing, blind, a chunk of chromosome 4.
They soon gave up, unable to make sense of the DNA code they saw.

The main rival to blind sequencing is a strategy called the ‘cDNA approach’.
The idea here is to identify genes from the messenger RNA molecules they
produce in cells. These molecules are the half-way stage between the genes
and the proteins they code for. Researchers reverse this process, copying
the RNA back into DNA which is stored in a ‘library’. They can then use
the library to make gene probes.

This approach, proposed by Sydney Brenner of the Laboratory of Molecular
Biology in Cambridge, was recently put to the test by Venter and his colleagues.
The results, published earlier this year in Science (vol 1, p 651), provoked
a storm of interest. The group managed to identify 337 ‘new’ genes expressed
by one type of brain cell. ‘The strategy turned out to be between 100 and
1000 times more efficient than we thought,’ says Venter. He predicts that
a small laboratory, using the approach, could identify as many as 10 000
human genes a year.

Additional reporting by Christopher Joyce in Washington, Elisabeth Geake
and Jeremy Webb in London