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• Natural Cures for Antibiotic Resistant Superbugs 8 April 2000

Under surveillance
Ns 8 April 2000

Suppose a deadly new disease emerges in the tropics. Is it natural, or an escaped bioweapon? The WHO wants to set up labs to identify it with funds from a surprising source

HERE'S a story. Deep in the tropics lies the poverty-stricken city of Bisfara. Outbreaks of fever are common enough here, but last summer a new, more deadly variety emerged. The first cases were scattered all over the city. Doctors had no mechanism for reporting them, and it was a week before public health authorities realised they had a new problem. But what exactly were they dealing with? Symptoms included fever, aches, sometimes a cough. The death rate was alarmingly high. Was it flu? Dengue fever? Pneumonic plague? A hantavirus? Something completely new? Standard diagnostic techniques were inconclusive. What happened next? Scenario one: By the time local laboratories had tried and failed to name the pathogen, it had spread widely. The govemment finally allowed in a team from the US Centers for Disease Control and Prevention (CDC) in Atlanta. The researchers mapped the spread of the infection and took blood samples home. The culprit tumed out to be a more virulent version of the dengue strain common in Bisfara, for which there is no treatment. Officials sprayed pesticides to kill the mosquitoes that carry the virus. But until the insects had been controlled, people continued to die and the death toll eventually reached a thousand. Rumours spread of American germ warfare experiments. The US embassy was attacked. Scenario two: In a city near Bisfara, a laboratory equipped to diagnose not only common local diseases but also new ones received reports from regional doctors and quickly realised a new infection had struck. Tests showed the infection was dengue. Its similarity to strains common in Bisfara showed that it was a natural variant (making it improbable that it was a bioweapon created in a lab). Maps of the epidemic were distributed to spray teams. Within a week, the outbreak was over, with fewer than a hundred dead. And the terrifying spectre of a bioweapons attack had gonefor the time being. Bisfara is fictional. But achieving the second scenario is a very real goal for an emerging coalition of public health specialists, epidemiologists and the World Health Organization, who want to remedy one of the biggest deficiencies in world health: disease monitoring. They have found an unlikely ally in a new protocol to enforce the 1972 Biological and Toxin Weapons Convention, which entered its final phase of negotiations last month in Geneva. They hope that if the deal helps ftmd non-military agencies to keep track of changing patterns of infection in poor countries, it could help conquer a bigger dueat than pathogens developed for biological weapons-natural diseases. But clinching the deal will require some skilled diplomacy. Developing countries don't take kindly to Westem interference. Western politicians and senior WHO figures realise that any direct links between the bioweapons protocol and any diseasemonitoring network will be unacceptable to many Third World govemtnents. "Some fear it could be veiled spying," says Antonio Patriota, Brazil's ambassador to the Geneva talks. He strongly supports public health investment through the protocol, and says most developing countries agree. "But some say, would you want Richard Butler setting up your diseasemonitoring system?" Butler headed the UN effort to unearth Iraq's clandestine efforts to make weapons of mass destruction, which some developing countries found unduly intrusive. A country with an outbreak caused by its own illicit bioweapons development can ask the WHO or other intergovernmental agency to keep investigations confidential. The agencies agree, fearing that if their presence leads to a bioweapons investigation, countries will never let them in again. The bioweapons inspectors might have to wait until information leaks out other ways-for example, over ProMED, an Internet fonim on emerging disease. But countries on the receiving end of bioweapons attacks would welcome help with monitoring. And the simultaneous boost to monitoring natural infectious disease could make a huge difference to world health. More than 13 million people die prematurely of infectious diseases every year. As trade, migration, urbanisation and ecological change introduce pathogens into new situations, diseases are evolving apace (New Scientist, 1 April, p 16). Over 30 new diseases have been identified in humans since 1980. Inadequate disease monitoring in many poor countries means outbreaks such as that in the fictional Bisfara are all too common.

Missing monitors

Demissie Halite of the World Bank, former head of the Intemational Centre for Diarrhoeal Disease Research in Bangladesh, recalls how a foreign-funded laboratory in Uganda identified 30 new viruses between 1930 and 1970, but was then abandoned. "One wonders what the outcome would have been if the laboratory had survived and recognised the AIDS virus early in its spread," he says. The WHO's secret weapon-which it hopes will allow better surveillance of pathogens, whether natural or artificial, without alienating governments-is the newly formed Alliance Against Infectious Diseases (AIIAID). This is a coalition of the WHO, the Intemational Centre for Genetic Engineering and Biotechnology in Trieste, Italy, and various public health organisations. AIIAID wants to build a dozen laboratories that, like the fictional laboratory near Bisfara, will diagnose outbreaks, collect disease information and develop new tools to detect and control local pathogens. AUAID figures it needs $50 million over five years to launch 11 labs, probably located in India, South East Asia, China, the Middle East, North Africa, francophone and anglophone sub-Saharan Africa, Amazon, one or two other regions in Latin America, and Russia. These are developing regions with a relatively high likelihood of disease emergence and weak monitoring capabilities. The WHO hasn't got the cash, but senior WHO figures say Western governments have already indicated a willingness to divert money ffimugh the Bioweapons Convention to this end. In fact, when the Bioweapons Convention was signed in 1972, it called for the transfer of biomedical technology to poor countries, partly as an incentive for them to join. The verification protocol to the treaty, due to be signed next year, calls for various declarations and inspections aimed at controlling weapons. But it also contains measures that could finally channel real investment into conventional disease monitoring. Without that, poor countries may not join, and as an incentive, AIIAID plans to locate its labs only in countries that sign the protocol. "Most developing countries aren't worried about biological weapons," says Mark Wheelis, bioweapons spokesman for the Federation of American Scientists. Africa has been almost entirely absent from the talks, but the continent would benefit most from investment in disease monitoring. Most of the major disease outbreaks the WHO investigates in the recent years have been in Africa, notes David Heymann, head of communicable diseases at WHO (see Diagram). The planned Organisation for the Prohibition of Biological Weapons (OPBW), which will enforce the bioweapons treaty, will still investigate 'unusual" outbreaks suspected of being attacks or pathogens that have escaped from clandestine weapons labs. To do this it will need to use the kind of epidemiological data gathered by AIIAID. "You can't know what is unusual until you know what is usual," says Wheelis If an outbreak is caused by a pathogen that is very different from local strains, for example, foul play might be suspected. If it is similar to local strains, bioweapons use might be ruled out. But as Patriots, the Brazilian ambassador to the talks, notes, the association between epidemiology and bioweapons verification is making some countries wary of using the protocol to fund public health monitoring. He says developing countries will therefore need safeguards to ensure that money spent through the protocol to improve public health actually does so. Negotiators are trying to build those safeguards. Proposals to include an epidemiological monitoring network in the OPBW have been scrapped, and instead AIIAID will do monitoring. A proposed clause in the protocol calls for rich countries to "develop a framework ... to support an intemational system for the global monitoring of emerging diseases". Tibor Toth, chair of the protocol negotiations, in New York last month, said AUAID was the way to achieve this. Debora MacKenzie

Natural Cures for Antibiotic Resistant Superbugs
Ns 8 April 2000
FROM the lush forests of Costa Rica and the farming heartlands of Wisconsin come two possible weapons in the fight against the antibiotic-resistant superbugs prowling the wards of hospitals the world over. One hopeful bulletin comes from the Guanacaste Conservation Area in northern Costa Rica, where researchers have isolated fungal extracts which kill the two most feared superbugs, methacillin-resistant Staphyloccocus aureus (MRSA) and vancomycin-resistant enterococci. The other source of hope comes from the University of Wisconsin in Madison, where a promising antibiotic in frog skin has been engineered to make it more potent and less prone to breaking down in patients'bodies. Jon Clardy and his colleagues in the department of chemistry at Cornell University in Ithaca, New York, named the new fungal substances guanacastapenes after the place they were found in Costa Rica. "They've been collected under a programme set up by the US government," explains Clardy. If the substances do turn out to be lucrative pharmaceuticals, Costa Rica will receive a cut of the profits. Clardy and his team isolated the new substances from fungi thriving in branches of the Costa Rican tree, Daphnopsis americana. The filamentous fungi live in cells of the plant's fluid circulation system, and produce the substances to ward off rival microorganisms. "It's a tough world out there," says Clardy. In lab tests, guanacastapene was lethal to MRSA and VRE, he says. However, it also ruptured red blood cells in animals in later tests by collaborators at Wyeth-Ayerst, the pharmaceuticals giant in Pearl River, New York. This might mean that the extract is too dangerous to use as an antibiotic. But Clardy's team has since isolated a further dozen variants from the same fungus which, they hope, will be just as lethal to superbugs without the side effects. "We're purifying them until we have enough to test," he says. Meanwhile, at the University of Wisconsin in Madison, Sam Gellman and colleagues have made artificial versions of magainins, an emerging class of natural antibiotics. Derived from the skin of Xenopus lupus, the African clawed frog, magainins could become the first of a new class of antibiotics derived from animals rather than micro-organisms (New Scientist, 22 June 1996, p 20). Gellman created hardier, artificial variants of natural magainins by replacing the usual amino acid building blocks of the peptide molecules with artificial "beta" amino acids which don't exist in nature. He and his colleagues in the chemistry department hope that the revised versions will make more robust antibiotics because they cannot be broken down in the body by digestive enzymes, unlike their natural counterparts. Also, the structure is more stable. "Conventional peptides are floppy pieces of spaghetti," says Gellman. "Ours has a much more regular structure," he says. Michael Zasloff of Magainin Pharmaceuticals in Pennsylvania, says that the beta amino acids could provide new tools for recrafting magainins. And John Cola, a microbiologist at the Western General Hospital in Edinburgh, welcomes the developments, but wams: "There's a long way between finding a substance with antibiotic action and making it into a drug." Andy Coglhan

Sources: Nature (vol 404, p 565) Journal of the American Chemical Society (vol 122, p 2116)