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the DNA in all 24 chromosomes – has gone from the stuff of dreams to
a massively funded program in the US. If this effort proceeds as expected,
within the next five years it will be possible to pinpoint any region on
this vast genetic landscape: this is the map. And within a further 10 years
it will be possible to read from beginning to end virtually every one of
the 3 billion genetic letters that make up the genome: this is the sequence.
It will cost about $3 billion and tens of thousands of man hours. The Human
Genome Program is, unquestionably, biology’s first ‘big science’ project.

Compared with the huge amounts of money that governments have traditionally
poured into physical science projects – $30 billion for the Space Station
and nearly $8 billion for the Superconducting Supercollider, for instance
– the $3 billion price tag for knowing everything there is to know about
the genetic make up of Homo sapiens seems modest. Still, this is heady stuff
for biologists, many of whom are exhilarated by the prospect, while many
others are fearful of what it might do to traditional or ‘small science’
biology.

The speed with which tentative suggestion was transformed into a multi-million-dollar-a-year
programme, indicates that it was an idea whose time had come. Technically,
it was on the cusp of feasibility. More important still, it captured the
imagination of those American legislators who are extremely keen to boost
their country’s competitiveness in the burgeoning field of biotechnology.

But a key element in the rapid implementation of the project was the
early enthusiastic lobbying in its favour by Jim Watson, who in 1963 shared
the Nobel Prize for Medicine with Francis Crick and Maurice Wilkins, for
elucidating the structure of DNA. Watson’s appointment as head of the National
Institutes of ÎçÒ¹¸£Àû1000¼¯ºÏ (NIH) genome effort in the summer of 1988 undoubtedly
added credibility to the project and helped to loosen the government’s purse
strings and so satisfy an ambitious budget. For the fiscal year 1991, more
than $150 million are allocated to the genome programme, twice that for
the previous budget year. In Europe the total sum of national and community
spending is nearly $20 million.

Although all the talk naturally centres on the potential benefits in
molecular biology and medicine, the idea for the project came originally
out of a multi-million-dollar programme to build the world’s largest optical
telescope. Late in 1984, the University of California received a handsome
$36-million gift towards the construction of a 10-metre telescope at the
Lick observatory. This project was overseen by the chancellor of the Santa
Cruz campus, the molecular biologist Robert Sinsheimer. ‘Through a complex
series of events, the University of California was at the time obliged to
return the funds,’ remembers Sinsheimer. ‘A confluence of ideas then emerged
as the thought that this money might instead be used to launch an Institute
to Sequence the Human Genome at Santa Cruz.’

Important to that confluence of ideas was the fact that as Chancellor
at UC Santa Cruz, Sinsheimer frequently came into contact with ‘big science’.
As well as being involved in the effort to raise $80 million for the Lick
telescope, Sinsheimer was part of the team trying to lure the Superconducting
Supercollider to California. And two of the Department of Energy’s weapons
laboratories – Los Alamos and Livermore – were managed by the University
of California, each having an annual budget of nearly a billion dollars.

‘It was thus evident to me that physicists and astronomers were not
hesitant to ask for large sums of money to support programmes they believed
to be essential to advance their science,’ says Sinsheimer. ‘Biology had
always been ‘small science’, and it occurred to me to wonder if there were
scientific opportunities in biology that were being overlooked, simply because
we were not thinking on an adequate scale.’

As a molecular biologist, Sinsheimer was then excited by the advances
being made in molecular genetics, but he was also frustrated that a much
greater knowledge of the human genome would be required if the field were
to move more rapidly. Link this with his desire to bring Santa Cruz up to
the same academic standing as the Berkeley and Los Angeles campuses, and
the prospect of having a major new biological facility – the Institute to
Sequence the Human Genome – on campus became very attractive indeed. ‘The
basic idea seemed right,’ recalls Sinsheimer, ‘but I needed a rational plan
of attack.’

In May 1985, Sinsheimer pulled together a dozen or so top molecular
biologists to discuss what such a project should aim to do and how it might
be achieved. ‘As we analysed the problems to be solved and the likelihood
of progress toward their resolution, the mood of the participants swung
from extreme scepticism to actual confidence in the feasibility of such
a program,’ recalls Sinsheimer. Although his dream of a genome institute
at Santa Cruz was never fulfilled, from this point on the drive to secure
what Harvard biologist Walter Gilbert calls the ‘grail of human genetics’
was essentially unstoppable.

A second element in the building momentum was that, unknown to Sinsheimer
at the time, similar ideas were being hatched at the Department of Energy’s
Office of ÎçÒ¹¸£Àû1000¼¯ºÏ and Environmental Research (OHER), just outside Washington
DC. Although part of the department’s mandate encompasses human genetics
because of a need to understand the impact of radiation on human genes,
the DOE has never been particularly visible in the world of conventional
molecular biology. Charles DeLisi, head of OHER, wanted to change that.
Almost single-handedly, he conceived of and promoted the idea of major DOE
involvement in the burgeoning future of human genetics and molecular biology.

‘I saw it as a natural outgrowth of the department’s responsibilities,’
he said at the time. ‘Our involvement would be on a scale not matched previously,
but then the scale of the project itself was unprecedented in biology. I
thought that, because the DOE was well used to handling big projects, it
would be well placed to handle this one.’ And the amounts of money involved
in the project’s early years – a few tens of millions of dollars – would
be spare change for the DOE’s big spenders.

The first concrete step DeLisi took to secure a place in biological
history for the DOE was a major scientific gathering in Santa Fe, New Mexico,
in March 1986. Organised by Lawrence Livermore researcher Mark Bitensky,
the aims of the Santa Fe meeting directly paralleled Sinsheimer’s earlier
workshop, but on a much grander scale: that’s the way the DOE likes to do
things. The meeting concluded that ‘the objective was meritorious, obtainable
and would be an outstanding achievement in modern biology’. This was the
same conclusion that the Santa Cruz meeting reached. ‘The excitement at
Santa Fe came as a surprise to nearly everyone, including the participants,’
says DeLisi. ‘It was reminiscent of those rare moments in the early phase
of major new ventures, such as the Manhattan project at Los Alamos, or explorations
of outer space, that capture the collective imagination of a community.’

Here, then, was launched a bold new venture in biology, but from two
separate planks: on the one hand, from conventional molecular biologists;
on the other, from the DOE. For many reasons, these two initiatives ran
in parallel for some time, but with the DOE taking an early and impressive
lead, mostly because it had easy access to major funding. The conventional
molecular biology plank would eventually become represented by the NIH,
which seemed at first confused and uncertain about how to proceed. In the
longer term, the development of the genome programme in the US was to be
played out as a tussle between these two agencies over which would be the
leading authority. Eventually, stimulated into concerted action by Watson
and others, the NIH exerted itself and emerged as the undisputed winner.

The first that many biologists heard about the genome initiative was
three months after the Santa Fe meeting, at Cold Spring Harbor’s summer
symposium, which just happened to be on ‘The Molecular Biology of Homo sapiens’.
By this time, says Watson, ‘it was clear that the project was inevitable,
and the symposium was a good forum to discuss it widely’. The response was
extremely mixed, with a divide between enthusiastic established researchers
and fearful younger scientists. Nevertheless, some prominent voices urged
caution too, including that of Nobel prizewinner David Baltimore. ‘The idea
is gaining momentum,’ he conceded, ‘and I shiver at the thought.’

Baltimore’s concern, like that of many others, was that here was a project
of such major proportions that technology and infrastructure would swamp
the science. Biochemists and molecular biologists who were used to teasing
apart the functions of specific genes, piece by piece and in the context
of other elements of the cell’s activity, looked askance at the prospect
of a monster sequencing machine that would just roll through the genome
mindlessly churning out sequence data. ‘An approach that included mapping,
genetics and biochemistry makes a lot more sense,’ observed Maxine Singer,
then at the National Cancer Institute, Bethesda.

But of even more concern, especially among the younger people, was that
the dollar-hungry project would divert funds from traditional molecular
biology. Walter Gilbert, who had shared the 1980 Nobel Prize for chemistry,
for inventing DNA sequence technology, estimated that the job might be done
for about $1 a base, which gives a bill that might in the end top $3 billion
over 15 years. Clearly, the project would need entirely separate funding,
or existing research avenues would indeed be squeezed. David Botstein, then
at the Massachusetts Institute of Technology, said of the prospect: ‘It
endangers all of us, especially the younger researchers.’

Indeed, so concerned was he about the safety of his and others’ future
funding that Daniel Koshland, editor of Science, wrote an editorial suggesting
that it might be best if the DOE were to run the whole venture, thus preserving
intact NIH monies. However, other prominent scientists, particularly Watson,
were even more concerned about the DOE’s competence at running a major biological
programme than they were about the dangers of the genome project sucking
funds from other research. Getting the NIH decisively involved soon became
one of Watson’s principal goals.

Later that summer the nation’s most authoritative body on scientific
issues, the National Research Council (NRC), met in Woods Hole, Massachusetts,
to discuss how it might contribute to the debate. It was decided that a
committee should be set up to study the problem and to recommend how to
proceed. It was to be a star-studded panel, chaired by Bruce Alberts, a
biologist at the University of California, San Francisco. ‘Bruce was chosen
because of his publicly proclaimed distrust of big labs,’ says Watson. ‘He
could talk to other biologists and be on their side. People could trust
him. That was important. He also knew the science very well.’

The Colossus of committees

The NRC committee was just one of several that were pondering the genome
project, others being at DeLisi’s OHER, the Office of Technology Assessment,
and the Howard Hughes Medical Institute. In the end, however, it was the
NRC committee’s report that was decisive in the genesis of the project.
There were several reasons, not least of which was that the committee was
‘one of the most powerful scientific groups ever got together’, according
to Norton Zinder of Rockefeller University. ‘And Jim Watson was standing
astride it all, like a Colossus.’

For Baltimore, the NRC’s intervention was crucial, because it put the
venture into proper perspective. ‘The climate of opinion about the project
had been one of euphoria in the early stages,’ he recalls. ‘The NRC committee
recognised that there were problems, both in the science and in the organisation.
It developed a more rational plan of attack, and broadened the scope beyond
just the human genome, by recommending that genomes from a series of other
species should also be sequenced.’ The argument had been that obtaining
the sequence of the human genome would be a great achievement, but unless
the sequences of other genomes were also known, the information would be
less valuable. Watson claims credit for this extension of the project’s
scope, and describes it as ‘my most important contribution to the project
as a whole’.

During 1987, the year it took the NRC committee to review the evidence
and come up with recommendations, the NIH was reluctantly moving towards
becoming involved. With the DOE declaring that $20 million of new money
would be made available for its march toward the ultimate genome goal, the
NIH at first acted petulantly, saying that it already topped that. Ruth
Kirschstein, a prominent voice at the agency, declared that the ‘NIH is
already spending $300 million a year on mapping and sequencing the genome’.
She even went as far as saying that ‘we see no need for a targeted programme’.
For a while Kirschstein seemed to have the ear of Jim Wyngaarden, director
of the NIH, because he, too, publicly voiced argument. But not for long.

‘Eventually we convinced Wyngaarden that a new, separate program was
essential for the genome project,’ says Zinder. ‘It would have been disastrous
otherwise.’ Apparently contributing to the NIH’s inaction was a good deal
of in-house squabbling over which part of the agency might be responsible
for the genome work: what Wyngaarden now characterises as ‘an attitudinal
problem’. He was also waiting to see how some of the prominent critics in
the community – notably David Baltimore – would eventually turn. There was
a great deal of uncertainty, and, says Wyngaarden, ‘If we had put it to
a vote early on, it wasn’t clear how it would have come out.’

Finally, and with speed, Wyngaarden acted. In February 1988, he organised
a meeting in Reston, just outside Washington DC, to be chaired by Baltimore.

‘It was a brave move by Wyngaarden to have me head the committee,’ says
Baltimore, ‘because he knew I was still not one hundred per cent enthusiastic
about the project.’ Highly respected in the scientific community, Baltimore
therefore had an opportunity to help to shape the project at this crucial
stage. On the agenda was a proposal to establish an Office of Human Genome
Research, to be headed by a new associate director of the NIH. The chorus
of voices – led by Watson – urging NIH involvement had at last prevailed.

The Reston meeting coincided with the publication of the NRC committee’s
report, which laid out a sober plan of how to proceed: mapping the genome
should be the first goal, with sequencing being initiated on a large scale
only when technological development had reduced the cost and time required
to more manageable levels. Other reports had been pointing in this direction
too, but the thoroughness and authority of the NRC’s report finally transformed
what had once been the Human Genome Sequencing Initiative into the Human
Genome Mapping and Sequencing Initiative.

The NRC’s report also indicated that the project should be controlled
by a single lead agency, and it implied strongly that NIH should be that
agency. The timing was right. Both the NIH and the DOE had then appropriated
about the same amount of funds – around $15 million – for targeted genome
research that year. That symmetry was soon to change.

At the end of the Reston meeting, most of the group dispersed, including
Watson. Unknown to him, however, his fate was being sealed in his absence.
Wyngaarden had asked a few people to stay behind to discuss who might be
the Associate Director in the genome office. ‘We came up with two lists,’
says Wyngaarden. ‘One had Jim Watson’s name on it, and the other had three
or four other names. We thought that if we could persuade Jim, he would
be ideal.’ There was no need for recourse to the second list.

Watson had repeatedly and cogently argued that whoever led the NIH venture
must be an active scientist. ‘I had been impressed with the way the high-energy
physics community builds and manages its major projects – the Supercollider,
for instance,’ says Watson. ‘They always have a scientist, not just a manager.
They have a scientist who is a strong advocate of the project and a good
manager too.’ Watson had effectively talked himself into a job.

When the Office of Genome Research was first established it had two
staff in addition to Watson and was within the orbit of General Medical
Sciences, which administered genome funds. Now it has a staff of 30, is
an autonomous centre, and can therefore disperse directly the $108 million
that will probably be at its disposal in the next fiscal year. The DOE’s
genome effort, meanwhile, amounts to $46 million, not insignificant, but
small enough to ensure that the DOE would no longer be a major player in
the game.

The conception and birth of the genome project in the US did not take
place in complete isolation, of course. From the beginning European researchers
took part in the committee meetings and seminars that helped nurture the
developing ideas. Prominent among these were British researchers Sydney
Brenner and Walter Bodmer. Bodmer now heads the Human Genome Organisation
(HUGO), whose role is to coordinate the venture in the international arena.
Nevertheless, the drive to go from proposal to established programme was
fuelled largely by the resources that could quickly become available within
the US system – and by Watson’s energy and charisma in making it work politically.

* * *

What is the human genome project?

THE GOAL of the Human Genome Program is nothing less than a complete
understanding of the genetic basis of Homo sapiens, including the genetic
basis of disease.

The human genetic blueprint – the human genome – contains an estimated
100 000 genes, which encode information in DNA for making a human individual
in the first place, and for maintaining the individual in his/her daily
life. These genes are distributed among 23 pairs of chromosomes (22 pairs
of so-called autosomes and a pair of sex chromosomes, X and Y). Each chromosome
contains a long DNA molecule combined with various protein molecules, which
determine the overall structure of the chromosome. The DNA molecule is composed
of just four units, known as nucleotide bases, linked together in varying
combinations of order like beads on a string. There is a total of 3 billion
bases in the human genome.

Only 2 per cent of human genes have so far been pinpointed to specific
chromosomal locations; and only a handful of some 4000 genetic diseases
are understood at the molecular level. The Human Genome Program aims to
locate the position of all these genes, and to read the genetic information
encoded in them, including the aberrant information in disease genes. Several
levels of attack are planned: first the genetic map, secondly the physical
map and thirdly the complete DNA sequence.

The genetic map. By studying the inheritance patterns of certain characteristics
– including disease, physical traits and arbitrary genetic markers – geneticists
are able to build up a picture of which genes are located close to which
other genes. For instance, the genes for characteristics that are always
inherited together must be located close to each other on the same chromosome.
Genes for characteristics that are inherited together frequently but not
always are probably located on the same chromosome, relatively close together.
Coinheritance of characteristics at levels no better than chance probably
indicates that the genes are on different chromosomes. Extensive analysis
of this sort produces a map that shows the general – but not absolute –
location of the genes for these characteristics, as they occur on the chromosomes.
Genetic mapping has long been an established activity among human geneticists,
but is being boosted under the Human Genome Program.

The physical map. A physical map is a description of the genome in which
the distance between certain landmarks has been worked out in terms of actual
length of DNA, not inferred indirectly from inheritance patterns. The existence
of a physical map will allow researchers to be able to pinpoint precisely
the position within the genome of any piece of DNA in which they are interested.
Physical maps are established by breaking up the genome into manageable
fragments of DNA, identifying the fragments in some way, and then determining
how the different pieces physically relate to each other: it is like assembling
the pieces of a jigsaw back together, to get a picture of the whole. Genome
mapping of this sort is a relatively new enterprise, and the goal of the
Human Genome Program is to have a complete physical map of some kind within
five years.

The sequence. A read-out of the order of the nucleotide bases that constitute
the DNA molecules in the 24 chromosomes – the genome – is known as the sequence.
In principle, every element of the genome – genes, control regions, other
regions – will be visible and identifiable and the instructions they contain
interpretable. Of all the parts of the Human Genome Program, obtaining the
sequence is the greatest challenge, with a target date set at 2005.

In addition to work on the human genome, mapping and sequencing of a
series of other genomes – from ‘model organisms’ – will also be undertaken.
The idea here is to provide a base of comparative data against which human
genome information can more effectively be interpreted. A crucial part of
the entire program is the development of new technology to do the job, particularly
sequencing, and devising ways of handling the huge quantity of data that
will begin to flow from it. The boldest biological endeavour ever undertaken,
the Human Genome Program will cost about $3 billion over a period of 15
years.

* * *

The man with credibility and charisma

JIM WATSON contributed to the elite catalogue of great opening lines
when he wrote the following of his friend and co-discoverer of the structure
of DNA in The Double Helix: ‘I’ve never seen Francis Crick in a modest mood.’

The same can surely be said of Watson, who for more than two decades
has been the always-inspiring and frequently discomfiting leader of the
Cold Spring Harbor Laboratory, New York, one of the world’s great centres
for molecular biology. It is also true that Watson’s immodesty is matched
only by his penchant for speaking his mind, a combination you don’t expect
to find in a government bureaucrat, which, as head of the National Institutes
of ÎçÒ¹¸£Àû1000¼¯ºÏ’s National Center for Human Genome Research, is what he is.

Since being appointed as an Associate Director at the NIH, Watson has
divided his time equally between running the Cold Spring Harbor laboratory
and promoting the genome project.

Watson’s unique brand of outspokenness frequently has his allies curling
their toes in embarrassment and his enemies frothing with rage. ‘People
are always running to me and asking, ‘Does Jim really mean what he says?’,’
comments Norton Zinder, a biologist at Rockefeller University and chairman
of the NIH’s advisory committee on the human genome project. ‘And the answer
usually is, ‘Yes, Jim really means what he says, but not quite in the way
he said it’.’ Jim Wyngaarden, who as head of the NIH appointed Watson to
the genome job, says that Watson can get away with being outrageous, because
of who he is: namely, one of the world’s most famous living scientists.
‘Besides,’ says Wyngaarden, ‘he’s learning to be more tactful. The politicians
love him.’

So why would a scientist of Watson’s stature wish to be a part-time
bureaucrat? ‘I had no choice, because if I hadn’t done it the whole thing
would have collapsed,’ Watson says. He likens the importance of the project
to President Kennedy’s 1961 initiative to send a man to the moon, but suggests
that ‘the implications for human life are likely to be far greater’.

Given such a possibility, Watson simply felt he couldn’t turn his back
on the offer. And on a personal level, he noted recently, ‘I also realised
that I would only once have the opportunity to let my scientific life encompass
a path from double helix to the three billion steps of the human genome.’
That, surely, is a giant leap – for mankind.

Watson was a quick convert to the notion of launching an assault on
mapping and sequencing the human genome on a ‘big science’ scale. He first
heard about it from Renato Dulbecco, who had gone up to Cold Spring Harbor
in the autumn of 1985 to give a speech at the dedication of a new laboratory.
‘He spoke glowingly about the prospects for cancer research if we knew the
sequence of our own DNA,’ remembers Watson.

A couple of months later Watson was engaged in a spirited debate with
a biologist from the Lawrence Livermore Laboratory, who had announced at
Cold Spring Harbor that ‘the Department of Energy is going to sequence the
human genome’. Not if Watson has anything to do with it, was the tenor of
the response. ‘I wasn’t arguing that it shouldn’t be done, but that it was
too important for the NIH not to be involved,’ says Watson.

And this was the beginning of what many perceive as Watson’s publicly
insulting the DOE and its ways of doing science. ‘It doesn’t have the best
biologists and its science is not peer reviewed,’ he says. ‘The DOE simply
cannot be trusted to run a project of this sort successfully.’ While many
of Watson’s colleagues will agree in private that he is right, few put it
quite so bluntly in public. That’s Watson’s approach: an apparently loose
cannon that nevertheless usually hits the right targets.

‘You only have to look at the history of the project to see Jim’s impact,’
says Zinder. ‘The DOE was the major player to begin with, but now NIH is
in the driving seat. He was right on that one.’

Physically, Watson is the archetypal absent-minded professor: with tousled
hair, distracted expression, not the best-dressed man in town (except when
visiting Congress to give testimony, and that’s a clue to his way of doing
things). ‘People think I’m crazy, but I’m not,’ he snorts. ‘Everything I
do is carefully thought out.’ Like the time he rounded up a couple of the
top researchers from his lab, told them to don their suits, and hauled them
off to a local mansion on Long Island, the estate of a potential benefactor.
‘Just as we got to the door, Jim messed up his hair, bent down and untied
his shoe laces, and – looking now like the eccentric scientist – rang on
the door,’ remembers one of his besuited companions. ‘That’s calculated.’
Oh yes, the benefactor came up with the goods.

How well his calculated forays into sensitive avenues of the genome
project worked remains to be seen. For instance, he caused consternation
everywhere when in 1988 he suggested that the most effective way to proceed
would be to divide out the chromosomes among different countries and laboratories.

Who is Jim Watson to tell us which part of the genome we will work on
and which part we won’t? was the tenor of the outraged reaction. ‘People
haven’t thought it through properly yet,’ says Watson. ‘When they have they’ll
see it will have to work that way. No question.’

This was one of those occasions where Watson’s sometimes glib manner
overstated what he really meant, explains Zinder. ‘It’s true that the chromosome
is the natural unit of management, and that’s the way it will naturally
develop. But when Jim mischievously said at a press conference, ‘Oh well,
chromosome one’s the biggest, so we’ll give that to the Soviet Union,’ no
one understood.’

Loose cannon he may seem, but Watson insists that he not only thinks
things through carefully but also consults his colleagues widely before
saying anything. This was the case with the idea of parcelling out the chromosomes
and, he says, the little bombshell he dropped amid American/Japanese scientific
relations last year. Irritated that Japan is being slow in providing funds
for the Human Genome Organization, the international arm of the genome effort,
Watson wrote to Kenichi Matsubara, of Osaka University, and told him effectively
that either Japan coughs up the dough or it can expect to be excluded from
quick access to sequence data produced in the US.

Watson’s argument is reasonable: ‘The sequence data are likely to contain
interesting commercial possibilities, so it is only right that those who
contribute to the effort should have first crack at those possibilities.’
Those who have seen the letter to Matsubara – which went through several
drafts as colleagues tried to soften the tone – say, however, that it is
couched in less than diplomatic language. Matsubara accuses Watson of ‘Japan
bashing’, to which Watson responds: ‘You don’t get anywhere by being a wimp.’

The fact that Watson also chose to remind Matsubara that the Japanese
ought to be grateful for the way the nation was treated by the Americans
after the war betrays a very personal element in these exchanges. ‘They
keep saying that we should remember their sensitivities,’ says Watson. ‘But
they should remember that we remember Pearl Harbor. I’m old enough to have
lived through it.’ At root, Watson simply doesn’t trust Japan to be open
and generous in a scientific project as commercially important as the genome
program. ‘Everyone agrees with me in private, but they won’t say so in public,’
he says.

Coming at a time when America is increasingly uncertain about its continued
stature as an economic superpower, particularly in relation to Japan, Watson’s
championing of American rights finds eager listeners in Congress. ‘They
just lap it up,’ says a prominent colleague. ‘But I’m not sure in the end
it’s a good thing.’

Watson has been in control of the greatest biological science venture
of all time for a little less than two years, and already he has achieved
his major objectives: to make it effectively the NIH’s project, and to establish
the infrastructure within which the science will unfold. What now? ‘After
a year or two the job will become just one of micromanagement, and I’m not
interested in that. So, I’ll leave.’ And he plans then to write another
book.

Next week: Britain’s contribution to the human genome project.