A
plague on our planet... for ever
The Sars epidemic is just the first of
many health scares waiting for us in a highly mobile, densely
populated 21st century, say scientists. It is vital that we learn
all we can about managing such outbreaks as well as fighting them
with technology. Roger Highfield reports
Severe Acute Respiratory Syndrome is only the
beginning. We are set to see many more epidemics sweep across
the planet in the coming decades, turning the 21st century into
the era of the quarantine and face mask.
At risk: one reason deadly pathogens will become more common is
that the world is truly a global community, so that air travel
can spread a disease in a day or two
A number of factors have conspired to make the
world increasingly susceptible to pandemics, according to Prof
Roy Anderson, of Imperial College, London, a leading epidemiologist
who is currently working on the Sars epidemic with colleagues
in London and Hong Kong.
"One reason that these pathogens will become
more common in the coming century is that we are better able to
detect them and reveal, by detailed genetic analysis, if an agent
is truly new as in this case," he said. Another is
that the world is truly a global community, so that air travel
can spread a disease in a day or two.
"The world population is also growing and
pathogens love dense communities," said Prof Anderson. "Perhaps
most important of all, the majority of the world's population
is in Asia - India, Indonesia and China particularly - where there
has been a phenomenal growth of megacities of more than 10 million.''
Sars is an "important rehearsal to see
how the global community can respond," he said. Perhaps the
key lesson is that draconian public health measures have to be
taken if there is any chance of snuffing out an epidemic before
drugs, tests and vaccines are available.
That means: quarantine of patients before they
spread disease; quarantine or close monitoring of all the people
they have come into contact with; and a clampdown on social gatherings
and travel. Sars is likely to become endemic in China, unless
further action is taken.
As one example of the insights that science
can offer into an emerging disease, Prof Christl Donnelly, Prof
Anderson and Dr Azra Ghani, working with Prof Tony Hedley of the
Department of Community Medicine, University of Hong Kong, and
colleagues in the HK Department of Health, and HK Hospital Authority,
publish the first detailed epidemiological analysis of the Hong
Kong Sars outbreak in The Lancet today.
They have concluded, somewhat chillingly, that
the virus kills about half of those aged over 60 and between seven
and 13 per cent of those under 60. This is significantly worse
than the original estimates of about five per cent, based on the
cumulative number of Sars deaths divided by the cumulative number
of admissions.
"These were inevitably going to be underestimates
because the eventual outcome for many admitted patients was unknown
at the time the estimate was made," said Prof Donnelly, explaining
that the virus can hospitalise patients for weeks, not days, making
it harder to track its overall impact as well as placing huge
strain on a health service.
The time from infection with Sars to symptoms
is variable but can be several days, longer than influenza, said
Prof Donnelly. The good news is that the disease seems to be harder
to transmit than 'flu, though the analysis has revealed how "superspreading"
events can accelerate the epidemic.
One insight into superspreading came from the
Amoy Gardens apartment complex in Kowloon where, by the end of
April, 131 cases had been confirmed among residents of Block E.
A "blow back" in the plumbing had
deposited virus from a single infected individual into wash basins
throughout the block. The virus is also transmitted in droplets
so that a sneeze in a lift could be enough to spread the disease
from one person to many others.
If newly infected Sars patients infect, on average,
fewer than one person each, fewer and fewer people will be infected
with each round of infection. If this basic reproductive number
is less than one, an outbreak cannot sustain itself and will burn
out. If the number exceeds one, however, the disease involves
ever increasing numbers.
The Imperial team will publish its verdict on
the risk that the disease will sweep worldwide in a forthcoming
paper.
The good news is that the first global pandemic
of the 21st century has seen an unprecedented effort that has
already set the stage for scientists to develop a range of ways
to curb Sars. Crucially, scientists have identified the cause
- a new human virus - in record time.
The sequence of letters that spells out the
genetic recipe of two strains of the deadly virus has been published
by American and Canadian teams in the current issue of Science,
revealing it to be a new member of the human coronavirus family,
so named because they look like the corona that surrounds the
sun.
In common with other "enveloped viruses"
the Sars coronavirus consists of a sliver of genetic material
wrapped in an overcoat of fat that is spiked with finger-like
proteins that are used to invade host cells.
The strains, one from a patient in Toronto and
the second the "Urbani strain", do not look much like
any other coronavirus seen so far, obscuring the origins of the
pneumonia-like illness, said Dr Mark Pallansch of the Centres
for Disease Control and Prevention, Atlanta.
Coronaviruses are "written" in a more
primitive genetic code RNA rather than DNA so they
mutate more easily. The reason for this mutability is that, to
replicate itself, the genetic information must be copied by a
viral enzyme called polymerase, a notoriously poor RNA "speller".
Being the biggest of all the RNA viruses - with
about 30,000 letters - coronavirus recipes can vary greatly, even
in a single patient, presenting a trickier moving target for drugs
and vaccines.
The genetic code, which differs by only 10 letters
or so in the two strains in the published analyses, will be crucial
for developing tests, drugs and vaccines, also shedding light
on why it can be deadly, said Dr Pallansch. "This can be
used as a tool for these other important efforts.''
There may be a hard core of relatively unchanging
genes in the virus, those that are crucial for its normal functioning
and that, if identified, will offer opportunities to develop vaccines
and treatments.
To search for them, Affymetrix, a company in
Santa Clara, California, is providing tools to scientists that
can give them a unique snapshot of the range of mutations that
can invade a patient.
Perlegen Sciences used "next generation"
Affymetrix technology developed to read the code of entire chromosomes:
it consists of glass wafers covered with up to 60 million genetic
probes: the probes are laid down using microchip manufacture technologies
and consist of sequences of genetic letters. These only bind to
complementary genetic sequences, revealing whether a known sequence
is present or not.
A gene chip has now been designed to detect
the Sars virus, said Dr Stephen Fodor, chairman of Affymetrix
and Perlegen and inventor of the technology. "What is really
exciting is that the genetic code of the virus, at about 30,000
letters, can be represented on a chip no larger than a dime.''
Other insights could come from human genetic
variations. The technology - 220 five-inch gene chips of human
DNA akin to a "CD of the human genome" - has been used
to produce a full genetic analysis of 25 people in 18 months.
The task revealed three million common genetic variations that
play a role in disease, side effects and behaviour - and that
could influence how badly someone will be affected by Sars.
These genetic insights are gold dust for scientists
who already have experience with coronaviruses, such as those
that cause Feline Infectious Peritonitis, the leading infectious
cause of cat death in which the sac that lines the abdominal cavity
- the peritoneum - is infected.
Prof Peter Rottier, of the University of Utrecht,
has taken two approaches to fighting cat coronaviruses: in one,
he has created an "attenuated" GM feline coronavirus
by deleting some of its genes. The GM virus is safer than the
wild type, yet still able to function. Tests suggest that this
can be used to infect cats without causing illness, yet create
immunity to the disease.
There is unease about using "live vaccines"
on people, since they can in theory mutate and evolve to become
lethal again. There are, however, ways to improve safety. For
instance, "judicious rearrangement of the gene order",
as demonstrated for a mouse coronavirus, will minimise the risk
that such a virus would generate viable offspring when it mixes
with a wild type Sars virus, said Prof Rottier.
The second approach to fighting Sars, an anti-coronavirus
drug, exploits the spikes used by a coronavirus to stick to and
invade cells. Prof Rottier has developed small protein fragments,
called peptides, that can attach to these "spike proteins",
blocking the entry into cat cells of feline coronavirus. In a
forthcoming publication, "we will describe these peptides
for coronaviruses for the first time".
From cat and mouse coronaviruses, his group
has now started to extend the work to the human Sars variety.
However, Prof Rottier said that it would take some time to come
up with candidate drugs and vaccines, which will require tests
on animals although that should take him less time than
other groups because he can build on his experience with cats
and mice.
Another key development is an animal model of
Sars. Prof Albert Osterhaus, at Erasmus University, Rotterdam,
has introduced the Sars virus to monkeys to create a similar illness
to that seen in people. This model could be used to test vaccines
and drugs, though Prof Rottier said these experiments could take
"years rather than months''.
In the short term, the worldwide scientific
effort will focus on developing simple and reliable tests for
Sars that can be used by hospitals to check patients with suspicious
symptoms. A British coronavirus expert, Prof Stuart Siddell, of
Bristol University, has been supplied with Sars genetic material
by the Health Protection Agency to help develop a practical test
for hospitals that could identify symptom-free carriers - detection
of silent infections is critical.
In the wake of the release of the viral genetic
code, the US Centres for Disease Control and Prevention have already
developed a gene test for the virus by using a technology called
PCR that can amplify known genetic codes to levels at which they
can be detected.
But hospitals would prefer a blood test and
now Prof Siddell is trying to find what immune response is provoked
by the virus in the body, as part of a network of laboratories
collaborating worldwide. "We need a robust and sensitive
serological test," he said.
He hopes to develop a test for blood antibodies
within weeks, one that does not produce false positives, by cross
reaction with coronaviruses that cause the common cold, and that
does not produce false negatives, missing some infected people.
However, in the longer term he is interested
in the response to Sars of white blood cells, called T cells,
not only as the basis of a test but also because it provides insights
into how to develop an effective vaccine. But even when a vaccine
is available, some mutated viruses may survive and thrive to develop
into a resistant strain.
"It is likely that you get these
so called escape mutants, viruses that mutate and are selected
for resistance, which could be a problem," said Prof Siddell.
"The same goes for an antiviral drug."
The ability to make an endless supply of human
eggs for post-menopausal women - even for men - could emerge from
a breakthrough in reproductive science published today.
Scientists have found a way to mass produce
eggs from embryos, even male embryos, a technique that could scrap
the "biological clock" of women, end the shortage of
eggs for infertility treatments and remove one of the reasons
given by maverick doctors for cloning babies.
However, the American research also makes it
feasible for men to make eggs too so that it will be possible,
in theory, for a homosexual male couple to have children that
are genetically their own, with the help of a surrogate mother.
Although it seems likely a similar approach
could also help infertile men to make sperm, the technique will
not enable women to make sperm because they lack a Y chromosome,
the "maleness" chromosome (men do have one X chromosome,
the sex chromosome possessed by women, so they can make eggs).
One professor of theology called the work "a
cannon ball fired across the bow of Christian bioethics. Many
still operate with the assumption that babies require a mummy
and a daddy."
Prof Ian Wilmut, of the Roslin Institute, near
Edinburgh, is excited by the implications for cloning because
it undermines claims that it could be justified for infertility
treatments.
"If the method can be adapted for use with
human embryo stem cells, and to produce sperm from embryonic stem
cells, this would be the end to calls that cloning should be used
to overcome infertility," he said yesterday.
Instead, cloning would be used to create an
embryo from an infertile person and then an egg or sperm as required,
which in turn could be used for IVF treatments.
"In this way, both man and woman would
contribute their genes to the child as they do normally,"
he said. The possibilities are raised today by Prof Hans Scholer's
team at the University of Philadelphia which removed cells from
early male and female mouse embryos, placed those stem cells in
Petri dishes and grew them into eggs and then into embryos.
Reported in the journal Science, the work shows
that, even outside the body, embryonic stem cells remain "totipotent,"
that is capable of generating any of the body's tissues, said
Prof Scholer.
"Most scientists have thought it impossible
to grow gametes (egg and sperm cells) from stem cells outside
the body since earlier efforts have yielded only somatic (body)
cells."
But his team found that not only can stem cells
from mouse embryos produce eggs but also those eggs can then divide,
recruit adjacent cells to form structures similar to the sacs
- follicles - that surround and nurture natural mouse eggs and
develop into embryos.
The American team now plans to test whether
those eggs can be fertilised.
In the early 1950s, the American psychologist
Solomon Asch performed an experiment to determine just how easily
people cave in to peer group pressure. Those taking part sat alongside
five other people, and were asked to judge the length of a line.
Unknown to them, the five others were all accomplices of Asch,
instructed to give a patently absurd answer. Yet such was the
power of the peer group that 70 per cent of individuals taking
part went along with the majority view.
Having endured yet another week of ballyhoo
about the Human Genome Project, DNA and the double helix, my only
doubt about Asch's findings is that his figure of 70 per cent
may be too low. Certainly in the case of DNA, I doubt if one scientist
in a hundred would dissent from the view that James Watson and
Francis Crick discovered the Secret of Life in the double helix
structure of DNA. Yet they didn't, and it isn't.
I should confess that until recently I too believed
the scientific fairy story of James and Francis and the Secret
of Life. What woke me from its spell was an article in the recent
Nature supplement marking the 50th anniversary of the discovery
of the double helix. It was written by Dr Maclyn McCarty, of the
Rockefeller University, New York, the sole surviving member of
a team led by Oswald Avery, the biochemist. By the end of the
article, it was clear that Avery and his colleagues have been
the victims of a truly shocking miscarriage of academic justice.
To explain why, consider this question: what
led Watson and Crick to work on DNA in the first place? Since
1869 this rather boring molecule had been known to lurk in the
central nucleus of cells, and was still regarded as boring when
Watson and Crick began focusing on it 80 years later. The consensus
was that the key to the Secret of Life - the rules governing all
living cells - took the form of far more complex cellular chemicals
known as proteins.
So what made Watson and Crick think otherwise?
As both freely admitted in their biographies, it was the experiments
of Avery and his colleagues. Working with strains of pneumonia
bacteria, Avery's group found that it could extract a substance
that compelled one bacterium to take on a trait of another - and
then pass it on to its offspring. Whatever this substance was,
it seemed to possess the attributes of "genes", the
long-sought carriers of the instructions for life itself. But
was it a protein or DNA?
In 1944, after years of careful work, Avery
and his group published the first hard evidence that genes are
made from DNA. If they were right, the group could claim to have
identified the key to the Secret of Life. Not surprisingly, their
results were given a very tough time. Critics pointed out that
only one trait had been changed; others suspected that the DNA
was contaminated. Clearly, more work was needed before Avery and
his colleagues could be credited with having cracked the Secret
of Life.
This is where Watson and Crick come in. With
characteristic self-confidence, they ignored all the hand-wringing
over Avery's results, decided he was right, and set about showing
that DNA possessed the molecular structure suitable for the carrier
of genetic information. As everyone knows, the double helix was
triumphant vindication of their confidence in Avery's findings.
Others also found evidence to back Avery's claims
for DNA. They included Alfred Hershey at the Carnegie Institute,
New York, who used a clever radioactive labelling method to distinguish
between protein and DNA in bacteria infected by viruses. Though
much less compelling than Avery's original work or the double
helix, Hershey's findings supported those from Avery's group -
whose place in scientific history seemed assured.
At this point, however, the story of the Secret
of Life takes a bizarre turn. Despite being vindicated by the
brilliant work of Watson and Crick, the work of Avery and his
colleagues was still treated with deep scepticism by the Nobel
Committee - and by the time the quibbling stopped, Avery was dead.
Being denied a Nobel is one thing; the fact that all those who
confirmed his group's key insight - including Watson, Crick and
Hershey - won Nobels leaves no doubt about the importance of Avery's
original work.
The real scandal is the way Avery, who
died in 1955, and his colleagues are still being denied their
rightful claim to be the true discoverers of the Secret of Life
by a Hollywood-style story about two wise guys called Watson and
Crick and a pretty-looking molecule.
7 May
2003

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