IT TOOK more than a decade of effort, but Monday 26 June 2000 will be
remembered as the day when humankind learned, in a sense, what it is to be
human. Heads of government and Nobel laureates came together to hail the arrival
of a 鈥渨orking draft鈥� of the human genome: the set of genetic instructions which
governs the assembly and function of all human beings.
There may still be some holes to fill in, and the raw genetic information
presented this week may take decades to decipher fully, but for researchers
across the globe Monday was a day for celebration. 鈥淭his is the most wondrous
map ever produced by mankind,鈥� Bill Clinton told a press conference at the White
House. In another, video-linked press conference in London, Tony Blair called
the sequencing of the human genome 鈥渁 breakthrough that opens the way for
massive advancement in the treatment of cancer and hereditary diseases, and that
is only the beginning鈥�.
The scale of this triumph of biological science is awesome. The 24 different
human chromosomes may be too small for the eye to see, but each set contains 3.1
billion base pairs: a code written in 3.1 billion 鈥渓etters鈥�. This amount of data
is equivalent to the contents of 200 telephone directories, each 500 pages
long.
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Reading that code took the combined efforts of thousands of researchers, and
countless hours of work by hundreds of state-of-the-art robotic sequencing
machines humming quietly around the clock in pristine laboratories. Each machine
prepares DNA samples, runs them through electrophoresis gels, and reads off the
results into a database, only requiring the help of a human once every 24 hours.
In deciphering the human genome, biology became a truly industrial process.
But staggering statistics and engineering feats were not the only things
drawing attention to the human genome effort in recent months. This was amply
demonstrated by the fact that Francis Collins, director of the National Human
Genome Research Institute near Washington DC and head of the Human Genome
Project, was not the only person standing next to Clinton on Monday. At the
President鈥檚 other shoulder was Craig Venter, the maverick gene entrepreneur who
two years ago formed the sequencing company Celera Genomics and set out to be
the first to sequence the human genome.
Before Venter鈥檚 dramatic intervention, the $300 million, publicly
funded sequencing effort, which began in 1990, had set itself a completion date
of 2005. Venter upped the stakes by saying that Celera, based in Rockville,
Maryland, would sequence the lot by 2001 using a whole-genome 鈥渟hotgun鈥�
sequencing technique (快猫短视频, 23 May 1998, p 4).
Fearing that Venter would keep the data secret and attempt to monopolise it
by patenting genes, the publicly funded researchers redoubled their efforts and
maintained their policy of putting sequence data onto the Web the moment it was
obtained, with free access to all. As a result, the human genome effort became a
race.
Last autumn, with completion within sight, the two groups held talks about
collaborating and merging data, but this dialogue broke down amid bitter public
accusations from both sides. In the spring, however, there was another attempt
at reconciliation. Collins says that in late April he called Ari Petrinos, head
of the US Department of Energy鈥檚 human genome programme, and asked him to try to
broker a meeting with Venter. Petrinos invited the two geneticists over to his
house on the night of 7 May for beer and pizza. That first secret meeting
quickly led to three more, the last of which was held a week ago. Collins jokes,
鈥淐raig鈥檚 wife is beginning to suspect that something is going on because we鈥檙e
spending so much time together in the evening.鈥�
But this time the deal on the table was merely for the groups to make a
simultaneous announcement and submit separate papers for simultaneous
publication. 鈥淭here are several scientific journals that have been wooing us,鈥�
says Venter.
Speaking on Monday, Venter and Collins even played down the idea that a race
to sequence the genome had taken place. 鈥淲e felt it was important for us to rise
above the squabbles that you鈥檝e read about,鈥� said Venter. Collins agreed: 鈥淚t
seemed absolutely the right moment to sit down together.鈥�
Others in the public team were more candid about the effect of Venter鈥檚
efforts. John Sulston, director of the Sanger Centre near Cambridge, which
provided one-third of the sequence data, said at a press conference in London:
鈥淚 don鈥檛 want my genetic information to be under the control of any one entity
or corporation. We had to fight, I regret that, and it hasn鈥檛 been easy.鈥�
Sulston adds, however, that the competition 鈥渟harpened people鈥檚 desire to
produce something鈥�. But he says, 鈥渋t only accelerated it by a year鈥�.
After publication later this year, the two groups will hold a meeting to
review the data generated by the different sequencing approaches adopted by the
two teams鈥攊nformation that may aid efforts to sequence other genomes. That
meeting is going to be 鈥渋ncredibly interesting and a lot of fun鈥�, says Collins.
He describes the two approaches as 鈥渄ifferent but complementary鈥�. Each approach
will serve to validate the other.
The research groups were excited, for example, by the fact that they came up
with strikingly similar figures for the total number of base pairs in the
genome. The public project estimates that the human genome comprises 3.15
billion base pairs or 鈥渓etters鈥�, while Celera鈥檚 assembled genome has 3.12
billion. 鈥淥ur numbers are so close,鈥� says Eric Lander, director of the Whitehead
Institute Center for Genome Research in Boston, who claims the two groups didn鈥檛
even check their figures against each other until the morning of the
announcement.
Those numbers will remain estimates for some time to come as stubborn gaps
remain in the genome. Jane Rogers, project manager of human sequencing at the
Sanger Centre, says that 97 per cent of the gene-bearing regions of the genome
have now been posted on the Internet as overlapping clones. However, 12 per cent
of that remains unsequenced, and only 24 per cent has been checked as being
fully accurate. 鈥淲e鈥檇 always said when the rough draft was ready, it would be
released,鈥� says Mike Dexter, director of the Wellcome Trust, the London-based
charity which pumped $120 million into the public project. 鈥淎lso, there鈥檚
been intense media interest and it was right to put it out鈥攖he timing was
fine,鈥� he says.
What makes the publicly funded working draft 鈥渞eady鈥� is the fact that the
gene fragments overlap to form a rugged gene map reaching from tip to tip of
every chromosome. 鈥淚t鈥檚 allowed us a view over the whole genome, from end to
end,鈥� Rogers says.
The next job is to continue sequencing and fill in the gaps to complete what
will become a 鈥済old standard鈥� reference genome by 2003. Interpreting this vast
store of raw genetic data remains a huge task, however. Collins says that in the
past six months, scientists have identified a dozen different disease-related
genes using the public database on the Internet. The current total of known
genes is 38 000.
While some estimates for the final total put the figure at well over 100 000,
Lander says the 鈥渂est guesses are more in the 50 000 to 60 000 range鈥�. A group
of 200 genome researchers have set up a betting pool on the Internet to guess
the final number. 鈥淎ll of those in the betting pool under 38 000 have to give up
their $1 bet,鈥� says Collins, who has his money on 48 011.
Other genomes, vital for working out the function of the newly sequenced
human genes, are now in the works. Celera plans to have the mouse genome
sequenced by the end of the year. The public genome project is working on the
genomes of another strain of mouse, the rat and the zebrafish. 鈥淣ot very many
years from now, people will be sequencing individual humans, every organism on
the planet,鈥� says Lander.
