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New Scientist 30 sept 2000

Vultures face oblivion New Scientist 30 sept 2000
Catching birds for breeding may be their only hope

THE mysterious illness that is killing vultures across India is spreading. Researchers sav that unless the Indian overriment does more to help them pinpoint the cause, birds such as the griffon vulture could die out all over the world. White-rumped and long-billed vultures, and other species of the Gyps genus which includes European griffons, are dying off across India, and are already extinct in some areas. Initial investigations point to a viral infection (New Scientist, 5 August, p 20 and p 33). But the disease seems to be spreading. Last week Munir Virani of the Peregrine Foundation, a conservation group based in Boise, Idaho, told a meeting in New Delhi that he has seen Gyps vultures in Nepal and in regions of Pakistan bordering India with the same drooping heads as sick Indian birds. Numbers of vultures in these areas are falling. Peter Wood of Britain's Royal Society for the Protection of Birds warns that the birds are mobile enough to spread the disease throughout their range, which extends from Spain to South Africa and Thailand. The researchers called on the Indian government to allow them to collect more birds, and set up captive populations of vultures to stop them becoming extinct. Andrew Cunningham of the Zoological Society of London told the meeting that not enough sick or dead vultures have been examined to confirm the cause of the epidemic. Local wildlife officers have been reluctant to let researchers collect dead birds, although four central states have now agreed. "A healthy captive population may be the only hope of keeping the birds going," says Wood, who was also at the meeting. At first the birds would simply be studied, but some hope they might eventually repopulate the wild. Debora MacKenzie

Blood feud Native Canadians want to reclaim their genetic material

MEMBERS of an indigenous people in westem Canada who donated blood as part of a genetics study nearly 20 years ago are demanding that the samples be retumed. They say that the scientist who took the samples, now an Oxford professor, has since used them without their consent for entirely different research. "I signed a paper releasing my blood for arthritis research. Nod-dng else. There was no mention of any other kind of researdi. I want it back," says Larry Baird, chief of the Ucluelet First Nation, whidi is part of the Nuu-chah-nulth people. "This is a major issue around informed consent, when you tell people one thing and you do something different," says Michael McDonald of the Centre for Applied Ethics at the University of British Columbia (UBC). "This is a serious problem with indigenous populations around the world. They're very, very angry." The researcher who took the samples, Ryk Ward, head of the department of biological anthropology at Oxford, says in a written statement: "It is common practice to retain samples for potential further research use, however, all those who donated blood samples ... at any stage they may withdraw their consent to participate in this research." He offered to destroy any samples or hand them to another repository. Ward, then at UBC, took samples from 883 members of the group during the early 1980s to look for genetic markers for an unusual form of arthritis. But in work pubhshed during the 1990s Ward used some of the samples to analyse genetic diversity in the Nuu-chah-nulth in relation to how and when humans populated the New World. In the Proceedings of the National Academy of Sciences (vol 88, p 8720), he says the material he used was collected 'as part of a biomedical study" between 1984 and 1986. Several months ago, David Wiwchar of the Nuu-chah-nulth Tribal Council newspaper Ha-Shilth-Sa published an article partly based on Ward's research. Members of the community, recognising Ward as the person who took samples for arthritis research, took the matter up with the Tribal Council. The council has shown New Scientist a copy of one of Ward's consent forms, signed in 1983, which mentions only arthrifis and other rheumatic diseases. Council officials say Ward never asked for further consent. Richard Spratley of UBC's office of researdi services says that based on the original consent form, the university would have required Ward to get further permission to conduct other studies. But by the time Ward embarked on the genetic diversity research he had moved to the University of Utah. Arthur Caplan, an ethicist at the University of Pennsylvania, can't see the problem as long as no one is identified. "Unless you can show that it harmed, hurt, or disenfranchised someone, legally nothing is going to happen," he says. Baird says the tribal council will decide what action to take at a meeting this week. 'Maybe a small delegation of First Nation people on his doorstep at Oxford may help," he says. Kurt Kleiner

Magic sponge Sea creatures could be a goldmine for powerful drugs

SELF-defence chemicals produced by a sponge could be used as anti-fungal drugs, say researchers in Florida. They hope the chemicals could be used against the growing army of drug-resistant infections. Peter McCarthy of Harbor Branch Oceanographic Institution in Florida and his team scoured the seas for new antifungal drugs. They collected samples of sponges and other invertebrates from waters down to depths of 1 kilometre. "Once you get to deep water, you're dealing with a lot of organisms that have never been seen by science," says McCarthy. After identifying the samples, McCarthy and his team prepared chemical extracts which they sent to Denver-based company Myco-Logics for analysis. The extracts were tested on two notorious human pathogens: Candida albicans, which causes skin infections and thrush, and Aspergillusfumigatus, which causes dangerous lung infections in people with weakened immune systems. After screening more than 3500 extracts, MycoLogics identified 101 interesting candidates. The most promising of these were a completely new class of anti-fungal agents called cyclic peroxy acids, which killed off both species in the test tube and act differently from many antifungals. The animal that makes the compounds is Plakinistrella, an unassuming black sponge that lives in the seas off the Seychelles. T'he team has yet to measure the efficacy and toxicity of the compounds in people. However, McCarthy says that spotting a new Achilles' heel in fungi is a rare and valuable insight. Claire Ainsworth

Odd Bases and Novel Proteins and the Origins of Life

Several researchers have tweaked existing bases to avoid disrupting the overall structure of the DNA chain. Such modifications can upset the normal base pairing, so they are useful for introducing mutations. But the first real success at creating completely new bases that actually increase the coding power of DNA came from Steve Benner, now at the University of Florida, Gainesville, when he devised a new base pair, which he dubbed iso-C and iso-G. He created derivatives of the bases guanine and cytosine by switching the chemical groups involved in forming hydrogen bonds. These bonds form when electrons are shared between bases. They hold the DNA double helix together, and guide the assembly of DNA by forming temporary attachments within enzymes called polymerases. To his surprise, rather than shunning these base impostors, Benner found that some polymerases were able to accept them. He used his creation to make what he calls "the 65th codon": iso-C, A and G. Given a TRNA carrying an iso-G, the ribosome would correctly read this codon and insert an unnatural amino acid. In fact, his imaginary base works so well it raises the question of why it wasn't picked by evolution. "If we found life on Mars using iso-C, iso-G and C and G, it wouldn't really surprise me," says Benner. However, for life on Earth, iso-G does pose a slight problem. It pairs with T (the DNA version of the RNA base U) as well as iso-C, making it a little too promiscuous to be faithfully replicated inside a natural cell. More recently, Floyd Romesberg at the Scripps Research Institute has found a totally new way to expand the code, by creating bases that can pair only with themselves-and he has done it by playing with large greasy molecules that barely look as though they could fit into a DNA double helix.

Back to bases

ln a flurry of papers over the past year, he has announced ever more reliable versions of these bases. He dubbed one of the earlier models PICS. Unfortunately this base is incorporated into DNA roughly a hundred times less specifically and rapidly than a natural base. But his latest invention, called 3MN, is incorporated just ten times less efficiently than a natural base (journal of the American Chemical Society, vol 122, p 8803). Romesberg says this shows rapid progress. "A couple of years ago, we wouldn't have behev6d we could be that close to a natural base," he says. And while one new base may seem like a minor accomplishment, Romesberg points out that in a three-letter code it would allow the creation of 61 completely novel codons for new amino acidsenough to satisfy the curiosity of most chemists for a long time to come. But, just as Liu found problems with unnatural tRNAs, getting real cells to accept the new bases will be the next big challenge. Other researchers think that the most productive way to investigate new forms of life isn't simply to pump up the coding power of DNA and RNA, helping them manufacture a greater range of proteins, but to allow nucleic acids to bypass proteins entirely. The modem genetic code allows a division of tabour, where RNA and DNA hold the code for proteins, but proteins ultimately do the ceu's chemical work. But many biologists believe that early in life's development there would have been no proteins. In the primordial world, so the theory goes, something rather like RNA would have been both code and chemical powerhouse rolled into one. For more than a decade, biologists have been performing test-tube versions of evolution that attempt to recreate this 'RNA world". While nucleic acids have emerged with some interesting powers, such as the ability to chop up their neighbours, so far they have failed to develop the ability to replicate themselves, or even the ability to build their own precursors. Bruce Eaton, president of the company Invenux in Denver, Colorado, thinks this is because the primitive RNAs probably had many more chemical variants than the four modern bases. "Everything now in proteins was probably once available in RNA," he says. To reconstruct one of these primitive and more powerful RNAS, he added a new chemical group called a pyridine to the RNA base uracil. Pyridines are known to bind metals and accelerate chemical reactions. He then looked for modified RNAs that performed a reaction to create molecules with carbon rings like those found in bases. RNAs capable of this reaction had never been found before, but experts think they may have played a vital role in developing life. In 1997, he reported finding not one, but five different families of these new "super" RNAs capable of creating carbon rings. Carlos Barbas at the Scripps Research Institute has pulled off a similar trick with a DNA base, giving it the same side chain as the amino acid histidine. This has allowed him to create one of the smallest DNA enzymes known, a 12-base sequence that can cleave molecules of RNA (fournal of the American Chemical Society, vol 122, p 2433). Barbas has already created DNA bases that carry the side I chains of nearly all of the 20 natural amino acids. Using these, he thinks it should eventually be possible to create a self-sustaining "ecology" of DNA molecules that work just like proteins. Throw a membrane around that, he says, and you have something that looks very much like a living cell. How much further can these soupedup codes be pushed? If evolution taught DNA and RNA to encode protein, and if biochemists can coax them to carry out catalytic reactions, why can't they be taught to encode-and evolve-something entirely different? Liu thinks they can. His idea is to use DNA as a templatecum-assembly platform for entirely new chemicals-in essence, to write a new genetic code for plastic, paint or penicillin. The scheme Liu envisions is attaching a skeleton structure for some interesting chemical-say, a P-lactam antibiotic, the family to which penicillin belongs-to one strand of DNA. Then a series of tRNA-like molecules will bind to codons in that strand, each one bringing in chemical groups, in place of the usual amino acid, that react with and "decorate" the skeleton (see "A ' rtificial translafion", left). The TRNA molecule would then fall away, leaving the newly modified drug, still attached to the DNA, which can then be tested for its antibiotic abilities. And because the DNA code determines exactly which TRNA modified the skeleton, each drug can be resynthesised simply by DNA replication, attaching the skeleton again, and putting in another mix of tRNAs. The drug can then undergo another round of testing without first determining its structure-an enormous time-saver for medicinal chemists. Furthermore, by bringing in enzymes to mutate and reproduce the DNA molecules, a simplified version of evolution can be re-enacted in a test tube. In this way, Liu hopes that one successful drug in a million could easily be plucked out. Eaton's company is working on a scheme that is arguably even more ambitious. It is also using tRNA-like molecules attached to drug synthesis reagents, but this time the skeleton is attached to one of his modified, catalytic RNAS. In this scheme, the RNA not only encodes the new drug, it also acts as an enzyme to aid in its synthesis. So rounds of in vitro evolution will not only create new molecules and enzymes, but a very simple one-step drug synthesis. This process might mimic the early days of evolution, says Eaton. "This is a new way of looking at this. RNAs might have carried around the molecules they produced." That, he speculates, may be how amino acids first became attached to tRNAs-they were part of the molecules that had created them. But even as the work zooms along, researchers in this field realise that once news gets out some people will worry about these wonder molecules or super-bacteria escaping into the environment. "The concern is that if we make these superbugs, we'll soon be living on the Planet of the Apes," says Romesberg. But he points out that unlike natural-born killers such as HIV or Ebola virus, this brave new life-for all its unusual powers-will be remarkably fragile outside the safety of biology laboratories. On this planet at least, it will always be completely dependent on chemicals that only humans can provide. Life as we know it is not about to be outdone. 11