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