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Genetically engineered fungus bites back at the crops it's meant to save

FOR the first time, a fungus has been genetically modified to be more deadly to the weed it blights. The snag is that the GM fungus kills crop plants as well. While the modified fungus will not be released as a result of the findings, the case shows how genetic modification can have unintended consequences. It is also proof, were any needed, that biotechnology could be harnessed to create weapons that attack crops (see page 4). The fungus was modified to attack velvetleaf weed (Abutilon theophrasti). As it is a close relative of cotton, most weedkillers that target it destroy the crop as well as the weed. "Herbicides don't work, and that's where you have to head in with biocontrol," says Jonathan Gressel, a plant physiologist at the Weizmann Institute of Science in Rehovot, Israel. In theory, diseases are ideal for biocontrol, because many infect just one plant species. The US, for example, is testing funguses that target coca plants or opium poppies. But diseases such as the fungus that causes anthracnose in velvetleaf tend not to make good killers, as any that eradicates its host is itself doomed. So Gressel's team decided to give the anthracnose fungus (Colletotrichum coccodes) a killer punch by adding a gene for a toxin from another fungus, Fusarium. The modified fungus was indeed much more lethal to velvetleaf seedlings in greenhouse experiments, they report in NatureBiotechnology (DOI: 10 .1038/nbt743). "This puts it over the brink to something that would be useful," says Gressel. But the enhanced fungus also killed off tomato and tobacco seedlings, neither of which would normally be affected by the anthracnose fungus. This is exactly the kind of unexpected consequence of a genetic modification that opponents of GM have been warning about, although the case also shows that such effects can be detected at an early stage. "This business of putting in a toxin raises a red flag," says lane Rissler of the Union of Concerned Scientists in Washington DC.

"This is exactly the kind of unexpected consequence that opponents of genetic engineeringwarn about"

To allay these fears, Gressel suggests further "fail-safe" modifications to any such fungus before it is tested outside a sealed greenhouse. Removing the genes for sexual reproduction would prevent it passing on any added virulence genes to related fungi that attack other plants. And removing the genes for spore formation would prevent it spreading via the air, and ensure it died out completely each winter. Even these measures, however, may not be foolproof For example, the fungus may survive without spores, especially in moist tropical regions, says plant pathologist Alan Watson at McGill University in Montreal. There may be other, safer ways to boost the killing power of biocontrol agents. Watson has patented a mixture of anthracnose fungi and low doses of ordinary herbicides for weed control. The herbicide interferes with the weed's normal defences against disease, allowing the fungus to get the upper hand. It has yet to be tested on cotton fields, however. Bob Holmes 0

Body gets a healing boost from its inner electric fields

THE body's ability to heal itself partly depends on natural electric fields, it has been proved for the first time. The work could lead to the development of drugs that speed up healing by enhancing these natural fields. Cell migration and division plays a key role in development and healing. Most research in this area is on chemical factors, but several studies have shown that applying electric fields can affect migration and division as well. After successful trials in animals, for example, a team in the US is trying to encourage the healing of spinal cord injuries by applying an extemal field. To discover whether the body's natural electric fields play a role in healing, Colin McCaig's team at the University of Aberdeen in Scotland looked at rat corneas. In an undamaged cornea, cells pump positively charged ions into the comea and push negatively charged ions out, creating an electrical potential Of 40 millivolts. But in damaged areas this voltage disappears, setting up an electric field between damaged and intact areas that stretches for half a millimetre along the surface of the injured cornea.

The researchers used a variety of chemicals to nullify or enhance this natural field. Dividing cells tended to line up at right angles to the field. But when the fields were nullified, the cells aligned randomly, they report in Proceedings of the National Academy ofsciences (DOI:10.1073/ pnaS202235299). McCaig says that the electric field may attract positively charged proteins or lipids in the membranes of cells. What's more, the team found that healing was faster when the field was boosted, and slower when it was decreased. Stronger fields also encourage cells to divide, though how they do this isn't clear.

McCaig says the work is the first demonstration that the body's natural electric fields play a key role in healing. "It's a big step forward to help biologists believe that the fields are important.' It's possible that drugs could be developed that enhance the natural field around wounds, boosting healing. This may prove more effective than applying an external field that doesn't have the same shape as a natural field. Jon Copley and Michael Le Page

Saving up Mutations

Evolution is a slow, painstaking process. But have plants and animals found a way of seizing the throttle to get them out of a tight spot? BobHolmes reports

DESPITE its universal role in biology, evolution still poses some pretty perplexing questions. Take changes in body form. Every tree or beetle or mouse looks the way it does because thousands of genes turned on at exactly the right time and place to guide the organism from single cell to adulthood. But if body plans are the product of such intricately orchestrated programs, how can evolution ever conjure up new ones? Any slight perturbation would surely send a species tumbling from its evolutionary peak into the barren valleys beneath. Plants and animals may have hit on an ingenious solution - bottling up evolution for times when they really need it. By squirrelling away genetic mutations, the raw material of evolution, and releasing them all at once, species may be able to leap from peak to evolutionary peak without ever having to slog through the valleys between. This happy knack increases their odds of surviving stressful conditions - nothing less than evolution on demand. On the face of it, the idea sounds like biological heresy. Plants and animals couldn't have that sort of control over the random process underlying evolution, could they? Surprisingly, they could. Over the past few years, a handful of lab experiments have thrown up convincing evidence that organisms really can save up mutations for a rainy day. If the same thing happens in nature, then plants and animals have hit on a way to 9-9 seize the throttle of evolution, accelerating it when necessary and slowing it down when not. Their storehouse of mutations may also prove to be a treasure trove of new genes for drug hunters to plunder or, equally, the time-bomb that helps explain the diseases of old age. The lead actor in this iconoclastic drama is a so-called "chaperone" protein called hspgo. one of the most abundant proteins in animals, plants and fungi, hspgo's job is to bind to unstable proteins and help them maintain their correct shape. In this role, hspgo is rather like a valet, tidying up proteins that would otherwise become dishevelled by environmental insults such as high temperatures. Hence the chaperones'other name, "heat shock proteins". But hspgo is also a crucial regulator of development. As a way of silencing proteins until their services are required, cells deliberately make some proteins unstable, especially certain ones that regulate developmental pathways. One of hspgo's jobs is to hold some of these proteins in the "standby" position. "it works on just about every [developmental] pathway you can imagine," says Susan Lindquist, director of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. The first hint that hspgo's job gives it unusual leverage over evolution came four years ago, when Lindquist and her team mate Suzanne Rutherford were working at the University of Chicago. They noticed that fruit flies carrying a mutant copy of the hspgo gene sometimes had offspring that looked very weird indeed. "We had eyes that grew out from the head in a stalk-like pattem, we had bristles in the wrong places, wings with different venation pattems and shapes, abdomens that were partly folded over, legs that were different shapes - virtually every structure in the adult fly was affected," says Lindquist. The same abnormalities showed up in normal flies doped in the larval stage with geldanamycin, a drug that interfere@@th the action of hspgo (Nature, vOl 396, P 336). That wasn't too surprising, given hspgo's pivotal role in development. But when the researchers looked more closely at their abnormal flies, they saw something much more interesting: each set of parents tended to produce offspring with a distinctiv6 set of abnormalities, different from those in unrelated fly lineages. One might have deformed legs, another strangely positioned eyes and stunted wings. If the flies'bizarre body plans were simply down to a shortage of hspgo playing havoc with their developmental pathways, then the defects should have been scattered randomly throughout the whole fly population. But they weren't. There was something else going on, and the researchers thought they knew what it was. They suggested that the familial abnormalities were caused by "cryptic" genetic defects that had lain hidden for generations and only showed up when hspgo stopped doing its job. That would explain Why each lineage sported a different set of abnormalities: each one had its own, unique collection of hidden defects.

This makes sense given hspgo's way of working. When all is well, the researchers proposed, hspgo goes about its usual business of keeping unstable proteins in working order. it does this so efficiently that it can even tuck into shape proteins with minor mutations that would otherwise alter their shape and, therefore, their functions. In effect, hspgo papers over the flaws in an organism's genome by keeping mutations hidden harmlessly away - including mutations in the genes that regulate development. Over the generations, a lineage of flies can accumulate many minor mutations that never see the light of day. in times of stress, though, this patina of orderliness breaks down. High temperatures, noxious chemicals, and a host of other stresses can cause an epidemic of protein misfolding. Faced with a dramatically increased workload, hspgo can no longer keep up and, as a result, malformed proteins go unrepaired. That means stress can lead to the sudden unmasking of hidden mutations. If it happens during larval development or metamorphosis, hidden mutations in developmental genes can produce abrupt changes in shape and form. Remarkably, then, hspgo acts as both a capacitor for storing genetic variation and the trigger that releases it. It therefore gives evolutionary biologists a convincing molecular explanation for evolutionary change. "This looks like something that's going to put evolutionary theory on a firmer ground in terms of mechanism," says Massimo Pigliucci, an evolutionary ecologist at the University of Tennessee in Knoxville. Earlier this year, Lindquist's team announced that hspgo performs the same trick in the thale cress, Arabidopsis thaliana - making it likely that many other organisms store variation in this way, too.

"This is almost too good to be true. Justwhen you need variation - the raw material of evolution - its there?"

Once again, drugs that interfere with hspgo caused some seedlings to develop abnormally. "We had roots that grew up instead of down, changes in the number of root hairs, leaves that developed almost like pine needles, leaves that curled up or down, leaves that became pigmented - all sorts of things," says Lindquist. Many of the variants looked as if they might be helpful to plants trying to adapt to new environments - more or fewer root hairs, for example, might be appropriate for different soil types and moisture conditions - though the researchers did not test this directly. Again, different inbred lines of the plants produced seedlings with different sets of abnormalities, and they showed the same characteristic abnormalities when grown at higher temperatures, even without the drug (Nature, vel 417, p 6i8). Hspgo seemed to be concealing cryptic mutations in plants, too. What's more, once these new variants come out of the woodwork, the useful ones are likely to stick around even after the environmental stress has disappeared. When Lindquist'i team bred fruit flies while selecting for certain abnormalities, after just a few generations the flies hung onto their new shapes even when hspgo was at full function again. Lindquist believes that selecting for these traits, which are the result of many genes working together, prompts the selected lines to accumulate more and more of the desirable gene variants, until eventually the flies exceed a threshold where the trait becomes independent of hspgo. That's important, because it means organisms won't lose useful mutations once the stress evaporates. The upshot of this is that species seem to have a mechanism for delivering variation - the raw material of evolution - just at the time they need to adapt to a changing environment. "It's almost too good to be true. just when you need variation, it's there," says Charles Knight, an evolutionary physiologist at the Max Planck Institute for Chemical Ecology in jena, Germany. Maybe so, but Lindquist's results actually sit quite snugly with existing theories of evolution and development. As early as the 1940s, British biologist C. H. Waddington suggested that organisms must have ways of buffering mutations that could disrupt their development. Though Waddington had some experimental evidence, many biologists remained sceptical, because no one knew how such buffering could arise. Lindquist's work provides the first molecular explanation. "The hspgo work came as a real surprise," says Brian Hall, an evolutionary developmental biologist at Dalhousie University ih Halifax, Nova Scotia. "Here's this molecule we've known about for quite some time that could play this really fascinating role." Hspgo's ability to store and release mutations also helps resolve a long-standing evolutionary puzzle - how species can make the transition from one body plan to another when intermediate forms would seem to be dangerously maladapted. By storing genetic variation and releasing it all at once, a species may be able to muster the raw material for big evolutionary leaps. These larger leaps could increase a species'chances of finding a design that's better adapted to its new conditions, says Lindquist. It may even have been one of the driving forces behind some of the bursts of rapid diversification found in the fossil record - the so-called "punctuated equilibrium" model of evolution popularised by the late palaeontologist Stephen Jay Gould. For all the advantages of such a system, though, Lindquist has backed away from the suggestion - which she and Rutherford hinted at in their first paper - that this storage-and- release mechanism might have been shaped for that purpose by natural selection.

"This looks like somethingthat's going to put evolutionary theory on firmer ground in terms of mechanism"

"We're not by any means saying that it evolved for the sake of evolvability," she says now. Most other researchers agree. "It's actually very difficult to think up cases in which systems evolve in order to make evolution more efficient," says Nicholas Barton, an evolutionary geneticist at the University of Edinburgh. "It's not impossible that that sort of thing can happen, but it takes careful argument to justify it.' Instead, hspgo's buffering ability most likely arose as an incidental by-product of its main role in protecting proteins against environmental stress. But buffering you from genetic mutation may in the end have a less desirable side effect too: one researcher suggests that overloading your chaperone system as you get older may be one cause of the diseases of ageing (see "The shock of the old"). While Lindquist's experiments have focused on hspgo, it is unlikely to be the only protein playing this evolutionary game. "I think this is the tip of the iceberg. There are going to be many things that buffer genetic variation," says Lindquist. Hspgo is just one of a whole platoon of heat shock proteins, and other molecules may also act in similar ways. Earlier this year, for example, researchers at the University of Valencia reported that an hsp dubbed GroEL can repress harmful mutations in the bacterium E. coli (Nature, vol 4i7, P 398). Though even sceptics say her experiments are impeccable and the buffering mechanism she describes is fascinating, Lindquist herself wouldn't claim organisms necessarily enjoy these payoffs in the real world. "For actual long-term evolution to occur, first of all one of the phenotypes that's uncovered needs to be beneficial," says University of Chicago biologist Martin Feder. Then it has got to hang around long enough to shed its dependency on hsp and become abundant in the population. That means the organism expressing it must find a mate whose genes allow this trait to appear. "While not impossible, these events are fairly improbable," Feder concludes. Then, too, fruit flies and thale cress are hardly typical of most species in the wild. Besides their many generations of adaptation to life in the lab, these two species became geneticists'favourites partly because of their unusually short life cycles, which means they accumulate mutations more quickly than other plants or animals. More sedate species might never gather enough hidden mutations for this mechanism to be important. "It's possible that the role of heat shock proteins may be overestimated in organisms that reproduce that fast," says Pigliucci. Nor is it clear that providing more variation will actually prompt organisms to evolve faster. Most natural populations already express ample genetic variation to support evolution, argues Barton: "Even if heritable variation were much lower than it really is, we would be able to account for evolution. You don't have to suppose that organisms are sitting around waiting for variability to come up.' As evidence, he notes that if you select organisms for almost any trait you choose, they'll respond - and faster than you usually see evolution proceed in the fossil record. These will remain open questions until someone can use the hsp system to produce useful adaptations. Feder says he and Lindquist have talked about trying this critical experiment on yeast, but their plans got pushed aside during Lindquist's recent move from Chicago to Massachusetts. No matter how important hspgo's masking of mutations turns out to be in real-world evolution, Lindquist's experiments seem certain to provide other scientists with a valuable tool. Plant breeders, for example, may be able to expose the hidden variation within a crop species as an altemative to costly and time-consuming techniques such as genetic engineering and cross-breeding with wild relatives. Developmental geneticists may be able to use a similar approach to pick apart the evolution of development. Hall, for example, plans to see whether he can uncover hidden variation in a vertebrate, the dwarf African frog. If so, he hopes to use drugs to block hspgo at different stages of the frog's life cycle to gauge the variation at each stage. Such a snapshot, he thinks, would reveal which developmental stages allow the most leeway for innovation and which are most conservative. All in all, Lindquist's results have evolutionary biologists buzzing. "This could open the floodgates to a lot of follow-up," says Pigliucci. Not a bad yield from a bunch of deformed fruit flies.