杏吧原创

EXPECTATIONS are high among the pioneers of the gene revolution. 鈥淢ore will
happen in biology in the next 10 years than in the past 50,鈥� says Craig Venter,
the entrepreneur whose company shared the glory for sequencing the human genome
at a White House ceremony on 26 June.

His main rival is just as enthusiastic. 鈥淲e should be able to uncover the
major hereditary contributions to common illnesses like diabetes and mental
illness, probably in the next three to five years,鈥� says Francis Collins, head
of the publicly funded Human Genome Project, which celebrated the completion of
its 鈥渨orking draft鈥� at the same White House ceremony. Bill Clinton crowned the
event, describing the human genome as 鈥渢he most wondrous map ever produced by
尘补苍办颈苍诲鈥�.

Why all the excitement? Because genome research looks set to transform
medicine beyond recognition. Modern medicine has hardly advanced since the
butchery of Victorian times, according to Peter Goodfellow, a leading geneticist
at SmithKline Beecham鈥檚 pharmaceuticals research centre at Harlow in Essex.
鈥淪urgery is still very primitive,鈥� he says, and drugs are seriously flawed, too.
鈥淭here aren鈥檛 enough of them, the drugs we have don鈥檛 work that well and there鈥檚
a significant proportion of patients who don鈥檛 benefit,鈥� he told a recent
conference on health care and genetics at the Royal Society in London. In
support, he displayed a table showing how few patients respond to today鈥檚
medicines (see Diagram).

Master plan

What about the medicine of the future? Can the successful sequencing of the
human genome usher in a golden age of medicine? What鈥檚 the pay-off for patients,
now that we have the genome laid out before us? And when can we expect
revolutionary new treatments that cure the hitherto incurable, without spilling
a drop of blood?

What we鈥檙e talking about is the genetic master plan for assembling and
maintaining a human being. All our cells, except red blood cells, carry copies
of the master plan. Written with an alphabet of just four letters鈥攖he
nucleotide bases adenine (A), guanine (G), cytosine (C) and thymine (T)鈥攁
single set of the code is some 3.1 billion letters long. There are 24 different
chapters, or chromosomes. We get duplicates of 22 of them鈥攐ne copy from
each parent鈥攑lus two sex chromosomes. Girls inherit an X chromosome from
each parent, whereas boys receive an X from their mother and a Y from their
father.

The instructions for assembling human tissue and the cellular machinery that
keeps it in good order appear in 鈥渟entences鈥� called genes. Faulty genes can
cause disease. The haemophilia which cursed Europe鈥檚 royal families, for
example, was caused by a defective gene which messes up the manufacture of a key
blood-clotting protein. By decoding the genome scientists expect to discover
exactly how genetic misprints cause disease. It should then be possible to
produce a drug or therapy to compensate, just as insulin is given to diabetics
and clotting factor to haemophiliacs.

Already, researchers working on the Human Genome Project have discovered
scores of genes linked with disease
(see New 杏吧原创, 20 May, p 14).
But the tools are now becoming available to accelerate the haul
(see 鈥淓nigma variations鈥�).

Finding the gene is just the first step. 鈥淵ou can have all the genes in the
world, but what you need is to find the link between them and disease,鈥� says
Allen Roses, director of genetics at drugs giant Glaxo Wellcome. The roots of
diseases like haemophilia, which result from a single faulty gene, are
relatively easy to spot by studying family medical histories. But finding the
origins of more common killers鈥攈eart disease, say, or cancer鈥攊s more
difficult because in most cases no single gene is to blame. Instead, people
inherit labyrinthine patterns of genes which somehow interact to raise the risk
of disease. To complicate things further, the risk may only materialise through
subtle interplay with the environment, such as breathing polluted air, drinking
too much booze or smoking cigarettes.

Despite all these confounding factors, the gene sleuths are pressing ahead,
teasing out links between genes and disease by studying real human subjects. One
of the best-known efforts is taking place in Iceland, pioneered by the company
deCODE Genetics. The company claims that genes are easier to spot in the
Icelandic population of around 270,000 because medical records and family
histories have been meticulously recorded. They also claim that the population
is relatively 鈥減ure鈥� because it sprang from a small number of original settlers,
although some Icelandic researchers dispute this. But deCODE claims to have made
breakthroughs already, announcing last month for example that it has discovered
a gene linked with schizophrenia.

Another way to figure out what role defective genes play in diseases is to
use what鈥檚 called an 鈥淪NP map鈥�
(see 鈥淐lose cousins鈥�). SNPs, or single
nucleotide polymorphisms, are the variants in genes that make each of us a
distinct individual. Although 99.9 per cent of our genes are identical to anyone
else鈥檚, the 3 million SNPs that occur about once every thousand bases account
for the remaining 0.1 per cent that makes us unique.

Locating where the most common SNPs lie on each chromosome provides gene
sleuths with an invaluable set of signposts for disease-related genes. To this
end, a group of 10 pharmaceuticals companies, five academic institutes and the
Wellcome Trust medical charity set up the SNP Consortium in April 1999 to
compile an SNP map, to be made freely available to all. In September, the
consortium published its first map, showing the positions of some 800,000 SNPs.
But as with the genome itself, the public SNP effort faces keen competition from
Venter. Earlier the same month, Venter鈥檚 company鈥擟elera Genomics of
Rockville, Maryland鈥攁nnounced that it has compiled an SNP map of 2.8
million bases. The Celera map is available only to paying subscribers.

As well as signposting disease genes, SNPs could also provide patients with a
more immediate benefit鈥攄istinguishing those who can benefit from a
particular drug from those who can鈥檛. For example, some people might have a
variant of a liver enzyme which destroys the drug before it can do any good. If
GPs could screen your blood for the crucial SNPs, they could select drugs that
are guaranteed to work for you and avoid giving you ones that don鈥檛. Such tests
could save lives, says Goodfellow. 鈥淎dverse drug reactions in 1994 were the
fourth highest cause of death in the US.鈥� Companies such as Affymetrix of Santa
Clara, California, aim to produce 鈥済ene chips鈥� capable of reading thousands of
SNPs at once from a single patient. They hope these will make SNP testing
affordable.

Meanwhile, Venter believes the most direct way to uncover a gene鈥檚 function
is to see what its counterpart does in other creatures. 鈥淐omparative genomics
will be the single most important tool for analysing genes,鈥� he says.

Among the creatures that have already been sequenced or are now being
sequenced are fruit flies, nematodes, yeasts, pufferfish, zebrafish, frogs and a
host of disease-causing microorganisms. By disabling individual genes through
mutation and seeing what happens to the creature, geneticists can work out the
functions of the animal genes, and then check whether there are defects in
people鈥檚 genes that tally with those in the sick animal.

More ambitious are the bids to sequence the genome of the mouse, which
closely matches the human genome. Speaking in Britain in July, Venter boasted to
a conference on genetics in Birmingham that Celera will have sequenced the mouse by December
(New 杏吧原创, 22 July, p 14). This has triggered another
public-private race. A consortium that includes the Wellcome Trust and the US
National Institutes of Health responded last month with a 拢39 million
drive to achieve the same goal by next February. Venter promptly announced that
95 per cent is already done.

Meanwhile, the new flavour of the month is proteins鈥攅ach one the
product of a different gene recipe. Genes may carry the master plan, but it鈥檚
the proteins that make up the stuff of life鈥攕ome 200 types of living
tissue in humans as well as hundreds of thousands of enzymes that keep our
tissue ticking over.

Grand venture

Never one to rest on his laurels, Venter has launched an ambitious project to
automate the exploration of the human 鈥減roteome鈥�, the protein equivalent of the
genome. 鈥淎t best, our gene code will tell us the increased risk of disease,鈥� he
told delegates in Birmingham when announcing his grand venture. 鈥淚t鈥檚 only by
understanding protein function that we can truly understand and predict medical
辞耻迟肠辞尘别蝉.鈥�

Proteomics pioneers hope to spot disease-causing proteins through a type of
identity parade which compares the protein profiles of healthy and diseased tissue
(see 鈥淗igh in protein鈥�). Venter announced in Birmingham that he is
linking up with 44,000 cancer surgeons in the US to chart protein profiles.
Similar public initiatives have been set up, such as the Cancer Genome Project
at the Sanger Centre near Cambridge. But protein profilers have their work cut
out, because some genes create their proteins in several sections, which can
then be spliced together in any order, so a single gene can generate many
different proteins. Proteins can also have their functions altered or be
switched on and off simply by adorning them with sugars or phosphate groups.

But combined study of genes and proteins will take researchers closer to the
ultimate goal of the genome project鈥攗nderstanding the molecular causes of
disease and devising drugs which intervene at just the right point. A particular
faulty protein might, for example, be the crucial switch that sets off a
catastrophic chain reaction leading to cancer. Once researchers understand the
protein 鈥渨iring diagrams鈥� in cells, they can spot the faulty wiring and
short-circuiting which causes disease. Make a drug that hits the protein
鈥渇allout鈥� from the chain reaction and you鈥檙e only treating the symptoms. Hit the
鈥渕aster protein鈥� or the gene that makes it and you might be able to stop the
cancer in its tracks, or prevent it in the first place
(see 鈥淜now your enemy鈥�).

Even after researchers have worked out the biology and where to intervene to
prevent or cure disease, they still need a drug to do the business. Fortunately,
companies have worked out ingenious methods for making and screening millions of
potential drugs simultaneously, selecting which ones bind to the critical
protein to block it, activate it or do whatever it takes to cure the disease.
For instance, NeoGenesis, a company in Cambridge, Massachusetts, has devised a
system for testing novel chemicals on key disease proteins at a rate of 300,000
a day.

Then when you鈥檝e found a chemical that does the trick, you have to make sure
it isn鈥檛 too toxic to give to patients. Lab tests on colonies of living cells
give a preliminary answer. But prospective drugs are then tested in animals,
before they are finally tested on people. There are plenty of drugs that look
good in early trials but fail abysmally at the final fence鈥攚hen tested
against a dummy or existing drugs.

It takes at least a decade for new drugs to clear these hurdles. 鈥淭he
completion of the full sequence and the SNP map are important milestones, but
only signify the end of the beginning,鈥� says Arthur Holden, chairman of the SNP
Consortium. The first pay-off鈥攖he potential for personalising treatments
with existing drugs鈥攊s already in sight. New wonder drugs to treat
currently incurable diseases will have to wait longer.

Still, the genome, the SNP map and the proteome will provide a mighty boost
in the fight against disease. For the first time, all the culprits causing human
disease鈥攚hether genes or proteins鈥攚ill have been rounded up in one
place.

Expect progress to accelerate. At the end of his talk in Birmingham,
Venter pointed out that he spent 10 years cloning and working out the DNA
sequence of the human receptor for adrenalin. Now, using the equipment at
Celera, the same task would take 15 seconds. Similarly, Roses says that linking
a gene to part of the genome would have taken five years in 1995 and 6 months in
1999. By 2001, with the SNP map and enough data from patients, it could take as
little as a week.

鈥淢y dream is the eradication of common diseases,鈥� says Holden. Society may
have to be patient, and wrestle with some weighty moral and ethical questions to
reach these goals, but most people would sooner face that than the surgical
butchers of Victorian days.