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Gene therapy gets the body to attack cancer ns 21 dec 02

AN ARmy of Immune cells that can punch thmugh the defences of tumours has been cr eated by generic engineering. The method could soon be tested in people. Of course, there's a big leap between mice and human but it seems logical that this would work for people too." most researchers trying to use the immune system to beat cafkw focus on bowdng the Immune That can hmm a dramatic effect But even if the body produces a vast amri of immune cells against a cancer, can still be foiled. That's because mariy cancers release a slew of protecive proteins, lnduding a vital one called transforming factor beta. 76F-P binds to Immune cells and tells them to stop attacking their quarry. It forms an Invisible fortress around tumours. "Cancer's best weapon is 76F-P," says Lee. To breach this fortress, Lee's team added a mutated gene fbr a TGF-P receptor to cells from mouse bone marrow. The mouse marrow produced Immune cells that still bound to TGF-P but did not respond to its message to stop attacking. The bone marrow was implanted into mice, which were then injected with cancer cells. Of 10 mice injected with melanoma cells, seven were still alive after six weeks and had few signs of tumours. And all but one of five treated mice given prostate cancer cells were still alive after nine weeks. The untreated animals all died within three or seven weeks respecdwly, the team report in CancerResearch. The survival differences are striking, says cancer expert Judah Folkman of Harvard Medical School. "A few years ago immunologists would have said there was no way you could get immune cells to see tumours in a sea of TGF-P," he says. "Now fbr the first time there's a potential lbr transrerring a similar technique to the bedside." There is a catch, of course. TGF-5 is also used by heathy cells to fend off the immune system, so breaching this defence greatly increases the risk of autoimmune diseases - as indeed happened to some of the mice that survived cancer, Lee reports. But the problem is not insurmountable. A Ils6idde gene" could be added to the marrow cells alongside the altered TGF-P receptor, for Instance. Then, when the altered cells have done theirjob, patients could be injected with a substance that triggers the suidde gene and kills them off. Aftematively, all the bone marrow could be destroyed and replaced with unmodifled cells ftm the padenl The @nique Is also likely to be expensive, as cells ftm each patiertt would have to be @cted, modified and then re-implanted. But Lee thinks it should be work against all cancers. And it could be combined vi(ith other immune therapies, or with conventional chemotherapy and surgery, he says. "We'll spend a year doing further studies, and then we'll aggressively pursue human trials.11 Nicola Jones, Boston 0

Bolivia says nuts to the' hunt for the grandaddy of all peanuts-

FRED PEARCE

AS YOU grab a handful of peanuts this festive season consider this. A decision by Washington bankers has wrecked plans to search for the ultimate peanut, reputedly hiding somewhere deep within a remote Bolivian forest. Without it, the future of the world's most ubiquitous nut looks bleak. Last week, the Inter-American Development Bank approved a $132-million loan for a natural gas pipeline through the Chaco forest on the border between Bolivia and Paraguay. The pipeline's promoter is the Bolivian national gas carrier Transrede, which is controlled by Shell and US energy giant Enron. The forest is home to many rare species, including, researchers believe, the genetic grandparent of all modem domesticated peanuts, known as the Bienome parent. Finding it "is the holy grail of peanut evolution" says David Williams of the Intemational Plant Genetic Resources Institute in Cali, Colombia. Over thousands of years, farmers and scientists have bred peanuts to taste good and yield bumper crops, but along the way the peanuts have lost most of their natural ability to fight pests and disease. As a result, peanuts served at parties this year will have been soaked in pesticides. Many poor farmers can barely afford to grow peanuts at all. But, says Williams, if he can track down the ultimate peanut, he will uncover the lost genes for pest and disease resistance. They could then be added to modern peanuts via conventional breeding. The B-genome parent is one of two wild species of peanut thought to have been originally crossed to produce those that are cultivated. Each collecting expedition to the heart of the Chaco forest has produced new peanut species. That, and a climate analysis of the region, suggests 15 tO 20 species have yet to be found, the ultimate peanut among them. "We think it is out there, and it is sure to be endangered. I just hope we can find it in time," says Williams. But those hopes now appear to have been dashed by the decision to push through the Yabog gas pipeline against the vehement opposition of indigenous fishing communities. Chaco has been effectively off-limits to scientists for several years as the local communities fought against the building of one pipeline, completed in 1999, and the settler farmers that have followed in its wake. Fearful of exacerbating the conflict, the Bolivian government has refused to issue the permits that scientists need to remove wild peanuts for safekeeping and research. It is likely they will now be excluded for years. "We cannot expect the ban on collecting to be lifted anytime soon," says Williams.

How we got our backbone JAMES RANDERSON

THE genome of the sea squirt, a distant cousin of animals with backbones, has been sequenced. It is helping reveal how the genome of vertebrates like us evolved. Sea squirts, with their leathery, filter-feeding tubes, do not look much like long-lost relatives. But the larval form of sea squirts reveals their true ancestry. These free-swimming tadpoles have a stiffened rod, or notochord, running down their back, which in a developing vertebrate is the forerunner to the backbone. They also have a simple brain and heart. The creature that gave rise to both sea squirts and vertebrates appeared on the planet during the Cambrian explosion, an orgy of evolutionary experimentation about 550 million years ago. And as modern sea squirts are thought to be similar to this common ancestor, comparing their genome with our own reveals how the vertebrate genome evolved. The species sequenced, Ciona intestinalis, has about 17,000 genes - about half as many as us - according to the joint American and Japanese sequencing team. But the sea squirt genome is just a twentieth of the size of ours, with i6o million letters (Science, VOI 298, p 2157). Our extra genes are mostly duplicates of ones that already existed as single copies in Ciona. No one was sure when these genes were duplicated, but thanks to this study we now know that it probably occurred in an early vertebrate. The extra functions that the duplicated genes can take on may be what allowed vertebrates to become more complex than other animals. "if your genome is big and floppy, maybe you have more flexibility," says team member Dan Rokhsar at the US Department of Energy Joint Genome Institute in Walnut Creek, California. One surprise is that Ciona seems to have stolen at least one gene from bacteria: a gene that enables it to make a cellulose-like compound. It uses the tough substance, not found in other animals, to make a leathery tunic. "It's the most dramatic example of gene transfer into an animal," says Rokhsar. When the human genome was published, it was claimed we had acquired about 200 genes from other organisms, but later research has suggested this is not the case. Genomes are now coming in thick and fast. Ciona is the seventh animal to have its genome sequenced, along with the mouse, fruit fly, mosquito, nematode worm, pufferfish and human.

Pieces of the gravity puzzle fall into place

GRAVITY is a slippery beast. We don't know how strong it is, how it works or how fast its effects move. But this year we made progress. October saw the most accurate measurement yet of Newton's gravitational constant, 6, a measure of the strength of the gravitational interaction between tINo objeCtS. A Swiss team calculated 6s value by measuring how the gravitational pull of two huge tanks of mercury affected the weights of test masses. However, there are discrepancies betNeen measurements (yf 6 made in different labs. This year a highly contentious explanation fbr this was proposed. A group of string theorists proposed that gravity is subtly affected by magnetic fields, and that s 6 should be larger near Earth's poles where the magnetic field is stronger. Sure enough, this fits with the measurements sofar. So Gs varying values mightjust be the first pmof of the hidden dimensions predicted by stringtheory. Equally tantalising is possible evidence for the existence of gravitational waves, the ripples in space-time supposedly caused by abrupt, violent cosmic events. An Italian team reported that two massive aluminium bars, one at CERN near Geneva, the other in Italy, had once vibrated in unison - perhaps as a result of a passing gravitational wave, they suggest.

Gene battle goes south

MICHAEL LE PAGE

THE great debate on genetically modified crops shifted to developing countries this year. While the European Union looked set to introduce tough labelling regulations and US farmers moaned that no one wanted to buy their food, India took the plunge and embraced GM crops. Mexico was one country determined to stand firm against the tide and preserve the purity of its many native maize strains. But its efforts seem futile. The crops in many fields have interbred with GM maize, because grain from the US has been spilt or planted. India discovered some farmers were already growing pest- resistant Bt cotton, after a seed company illegally sold them the GM strain, unwittingly it claimed. In March, the government gave the company conditional permission to sell the cotton. India's decision may well have been spurred by a report revealing how rival China is racing ahead. Scientists there are creating a wide range of disease and pest-resistant plants. Many Chinese farmers are already growing GM rice and wheat, and getting higher yields and suffering less from pesticide poisoning as a result, it's claimed. Similar benefits are being reported in South Africa. But even with millions facing starvation, South Africa's neighbours didn't want to accept GM maize donated by the US. Zimbabwe decided to mill the grain before distribution, to prevent it being planted, but Zambia rejected it altogether. It turns out that GM grain has been part of food aid for the past six years, as the US, one of the biggest donors, doesn't segregate its supplies. So it's quite possible that Mexico isn't the only anti-GM country with contaminated fields. Does it matter? There's no evidence that any existing GM food crops harm those who eat them. However, several studies this year proved that GM crops could interbreed with wild relatives to produce fitter hybrids. So there is a risk of "superweeds" emerging, although few think they will be as serious a problem as normal exotic invaders.

Back in the West, attention turned to "pharming": GM crops designed to produce drugs. In July, New Scientist revealed that many experts were concerned about loopholes in US regulations intended to keep pharmed plants separate from food crops. Theoretically you should simply digest toxic proteins if you accidentally ate such crops. But it's not an experiment anyone wants to try. The food industry in the US has been quietly trying to persuade pharming companies to use only non-food plants. Then GM corn that produces an undisclosed protein was found growing in soybean fields in Iowa. As the latest in a long line of such bungles and mix-ups, it hardly inspires confidence. The coming years could see the release of a whole range of new GM organisms. Australia is developing a virus that makes rabbits sterile. And US company AquaBounty wants to sell its fast-growing salmon. It says they will all be sterile - but if just one escapee bred with wild salmon, it could wreak havoc.