Science: Return of the plague

Scientists are in a race against time to stop the spread of a new strain of the Black Death. Charles Arthur reports

EVEN THE name inspires a shiver: bubonic plague, also known as the Black Death, still commands respect. You might have thought that it had its heyday, at least in Britain, in the 17th century, when 70,000 people died, before the Great Fire of London in 1666 wiped out the rats and the conditions that let it thrive. But the bubonic plague is making a comeback - and scientists are taking it so seriously that earlier this month, a project began which, by the end of the year, should have unravelled the entire genetic sequence of this ancient bacterium.

The renaissance of Yersinia pestis, as the killer is formally known, was signalled last September by a team of French scientists, who called it "clinically ominous". In a report published in the New England Journal of Medicine, they described the discovery of a drug-resistant strain of Y. pestis in specimens taken from a 16-year-old boy who developed plague in Madagascar in 1995.

Though the boy finally recovered after treatment with streptomycin injections, he had not responded to the cocktail of antibiotics that is the classical therapy for the disease; and another antibiotic mix, containing sulfonamides and tetracycline, which is usually given to people who have been exposed to the disease, also had no effect.

How has this new strain developed? Rather like the multi-resistant strains of TB that are now troubling the industrial world, it has almost certainly evolved from our overuse of conventional antibiotics. By using them at levels insufficient to actually finish off the bacteria, people have created newer and more lethal strains of the bacteria.

The French scientists noted that the danger could have gone unnoticed for some time, because many diagnostic laboratories fail to make routine tests to find out if plague victims are drug-resistant. However, a new project which began this month will seek new holes in the bacterium's defences. The Wellcome Trust is funding work by the Sanger Centre to begin sequencing the 4.38 m nucleotide bases of one strain of Y. pestis. With that, new treatments could be developed.

One of the team who will be in charge of that is Dr Brendan Wren, at the department of medical microbiology at St Bartholomew's Hospital, London. "We don't want to be scaremongering," says Dr Wren. "But this disease is slightly re-emerging in the developing world. And rather like TB, the treatment regimes could be made more difficult for the future."

The Sanger Centre, based in Hinxton, Cambridge, is one of the centres taking part in the enormous Human Genome Project to sequence human DNA. By contrast, bubonic plague is a tiny challenge, a million times smaller than human DNA. "They will get about 99 per cent of the plague DNA sequence within eight weeks. It's getting the last one per cent and putting the pieces together which poses the problem - that will probably take another four months," says Wren. "But it's an appealing idea, to have every piece of the genome."

Using the genomic information, the Bart's team will determine what functions the different genes play by homology - comparing them with other, known genes in comparable organisms. Every difference and similarity gives a clue about how the bacterium does its work. The version being sequenced is not the drug-resistant one, but it is a virulent form which has been widely studied. It actually comes from the US. "People do still get it there, through contact with prairie dogs and so on," says Wren. "In fact, the strain we're investigating [called CO-92 Biovar Orientalis] comes from a cat in the US - it was spread when the cat sneezed."

Using the full genome, the project might be able to develop 20 or 30 candidates for vaccines. "We're looking for improved versions," says Wren. "At the moment, the vaccine against bubonic plague gives a bad response, and isn't always effective." By reading the genome, he and his colleague Michael Prentice aim to determine the weak spots of the bacterium: "By seeing what things make it invasive, we could delete those genes and make a less harmful version for use in immunisation. It would give the appropriate immune response, but would be less harmful."

Alternatively, by identifying the elements of the bacterium which provoke the immune response, they could extract those and put them into a different, harmless organism. That would produce a vaccine which would produce immunity without taking any risks involving the original bacterium.

The plague is not the only disease coming under attack from gene scientists. A similar project, due to start in the summer, will try to unravel the genome for whooping cough (which weighs in at roughly 3.9 million nucleotide bases). There is already a vaccine against whooping cough, a contagious throat infection that mostly affects children, but it is not always effective and some parents are concerned about side effects. Even food poisoning is being studied: the Sanger Centre will soon sequence the Campylobacter jejuni bacterium, which presently causes the majority of food poisoning cases in Britain.

All three projects are being funded under the Beowulf Genomics initiative - which aims to decipher the genetic constituents of bacteria which cause infectious diseases, to develop more effective treatments. A separate project to sequence the TB bacterium has nearly been completed, and should report its results later this year.

It may only just come in time. Developing vaccines using genetic weapons, rather than simple antibiotic ones, looks increasingly like the only feasible path. Antibiotics have kept the death rate at 10 per cent, with most of those infected surviving if the illness is diagnosed early on. But with the rise of resistant pathogens, and given the fact that no new antibiotics have been discovered for decades, we may otherwise find ourselves in a Red Queen's Race against such ancient killers - running as fast as we can just to stand still.

In fact, we are already losing ground: the number of cases reported to the World Health Organisation by 24 countries in Africa, the Americas and Asia has increased recently. From 861 annually during the Eighties, the average number reported annually in the Nineties has grown to 2,025 cases. Without Beowulf, there is only one likely direction for that number.

Information on the genetic sequencing work in the project will be available on the Internet at http://www.beowulf.org.uk.