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NS 13 jul 02
The people vs patents
The drugs industry is taking us where nobody sensible wants to go
THERE'S something unsettling about corporations making huge profits from people's suffering. No matter how often healthcare companies insist that they make our lives better, the balance between commercial success and the public good is a difficult one to find. In the past, countries as diverse as Spain, Italy, Turkey, India and Argentina chose to restrict or prohibit the patenting of pharmaceuticals. Now these unilateral solutions are being stamped out by the World Trade Organization (WTO), which lays down rules that all member countries and all sectors of industry have to follow. But this still leaves us with a problem. We see it in its starkest form in the growing controversy over gene monopolies: companies such as Myriad Genetics of Salt Lake City in Utah. Myriad owns a series of patents on the BRCAI and BRC42 genes, which are used to assess a woman's chances of developing breast and ovarian cancer. A company owning such patents could eam lucrative royalties from university labs - and, possibly, other companies - that develop tests for the patented genes. But instead, Myriad wants to be the world's sole provider of comprehensive tests on these genes, and is trying to stop anyone else carrying them out. This approach has been widely criticised in itself. Even more worrying is what could happen if pharmaceuticals companies follow Myriad's lead. Their patent claims are growing ever wider, covering not only genes and proteins that are important in common diseases, but also modes of action of those proteins. If such a patent is awarded, the lucky company would gain exclusive rights not just to an individual drug but to a whole class of drugs. (see page 28). This is worrying indeed. It takes healthcare to a place no sensible person - or industry - would want to go. So, how do we stop thi s situation arising? The mechanisms we would normally tum to for support seem far from promising. Most Western countries have procedures for lodging challenges with patent offices and monopoly (anti-trust) authorities. But these tend to be used by large companies with deep pockets and a financial interest in stopping a rival. As this magazine has said before (i8 May, P 3), patent examiners could make this issue disappear at a stroke if they'd only nail down the uses to which patented genes and proteins can be put. Companies should be limited to specific applications they have shown can work, and not given rights over speculative uses they think genes and their proteins might be good for. But don't hold your breath waiting for this to happt!n. Another place one might tum for help is academia. But universities tum out to be part of the problem. These days, many of them patent everything that's discovered in their labs. They then insist on selling patent rights to a single company, laying the foundations on which monopolies grow. They're unlikely to stop doing this so long as it fills their coffers. Nor can we expect much help from governments. Most Westem goverrunents avoid interfering with the business of big drugs companies for fear that they will decamp to another country. Indeed, there's every sign that in the WTO negotiations designed to give poor countries access to cheaper drugs, Westem governments are backpedalling like fury. They've chosen to support the drugs giants rather than the needs of the poor. So is there nowhere to find help? There is one glimmer of hope, in the form of a group of medics and researchers who are challenging Myriad's patent in Europe. Part of the challenge is ethical - that Myriad's use of its monopoly win hold back healthcare and research. We wish their campaign every success. But there's more to be done. It would be good to see more research gauging the effect of gene patents and monopolies on the pace of research. One study has shown clearly that researchers shy away from working on patented genes, but there's plenty of scope for further investigation here. Another difficulty will be to give people employed by the state or charities enough time to build their cases. Convincing hard-pressed universities and hospitals or charities to provide the backing to mountachaRengeremainsahugestumblingbiodL Political trends wax and wane. The European challenge to Myriad was backed by the old left-of- centre governments in the Netherlands and France. It will be interesting to see if their right-of- centre successors carry on that support. But certainly in other Westem countries, until official attitudes swing back from supporting business towards the public good-there's only one way for biologists and medics to safeguard the freedoms they enjoy, and that's to act themselves.
African fisheries on brink of collapse
THE waters off West Africa were once among the richest fishing gmunds in the world. But fish stocks there have crashed by 80 percent and the area is now as depleted as the North Atlantic. What's more, just a day before researchers raised the alarm at a meeting in Brussels, Eumpean Union fishery officials signed new deals allowing them to take more fish than before off the coast of Angola. Similar deals have also been recently struck with Senegal and Maudtania. 'Fisheries In West Africa will go the way of the 6rand Banks if something doesnl change," says Daniel Pauly of the University of British Columbia, a member of the team. ft is exactly 10 years since the Grand Banks cod fishery crff Newfoundland, once the world's tidiest, was closed fbr two years to allow depleted stocks to recover. But the moratorium didn't work. The fishery today contains even fewer cod than it did in 1992. Pauly and his team have devised a way to estimate the total biomass of commercial fish in a large region. First they take figures for the number of creatures at every level of the food web, from plankton to top predators, and how these numbers change over time. They then use detailed ecological models to recreate the total biomass of fish living across the whole area. Their models have already shown that acmss the whole North Atlantic, the biomass of fish caught for eating fell by more than 80 per cent between 1950 and the late 1990s (New Scientist, 23 February, p 11). Now Pauly's colleague Villy Chdstensen has found a similar average drop in fish stocks off West Africa (see Graphic).
The EU is the biggest fisher in the region, and pledged to agree to fairer fishing deals with poor countries when it proposed its revised Common Fisheries Policy in May. But it seems that despite the dire situation in West Amca, it now plans to catch yet more fish. Last week, the Eumpean Commission signed a deal with Angola increasing the tonnage of EU vessels allowed to catch valuable bottom-dwelling or "demersal" fish such as hake by 12 per cent for the nexttwoyears. Last year, Mauritania, which owns the region's biggest fishery, agreed that between 2001 and 2006, the tonnage of EU squid boats in its waters could increase by 31 per cent, while the valuable black- hake fishery will remain the same as the previousfiveyears. Mauritania did force a slight dmp in quotas for other bottom-dwellingfish. And in June, after a hard-fought battle, Senegal forced the EU to cut the tonnage of demersal fishing vessels in Senegal waters by 30 per cent. But these agreements limit only the tonnap of fishing boats, not the actual amount of fish taken. A more powerful boat can catch more fish than a less powerful one, even though it weighs the same. So tonnage limits mean little. 'It's like letting someone into the grocery store for an hour, and not charging fbr what he takes," says Pouly. If the Grand Banks are anything to go by, the effect will be catastrophic. Ten years ago, cod stocks fell to I per cent of 1950 levels. At the same time, overall fish stocks in the North Atlantic fell to just 20 per cent of what they were. The same is now happening off West Africa. But that decline is only an average, and stodes of some species may already be as depleted as those of the North Atlantic cod. The cod have not recovered, partly because limitedfishing was resumed in 1999 under pressure ftm local Canadian fishers, says Jeff Hutchings of Dalhouise University in Halifax. That bodes ill fbr West Africa, where a total ban on fishing depleted stodts would be even less likely. Even if the EU boats go home, the local people fish to survive. There are no government subsidies available and it will be almost impossible fbr them to give up subsistencefishing. The big worry now, is that if the West African fisheriergo the way of the Grand Banks, they may never come back. Debora MacKenzie
Earliest ancestor unearthed
THE discovery of our earliest human-like ancestor has shaken up the roots of humanity. The stunning hominid skull, uncovered in the Diurab desert in Chad, is 6 tO 7 million years old and is expected to transform our understanding of humanorigins. The skull is around 2 million years older than any accepted hominid fossil skull so far and combines a unique set of both ape and human-like features. The features suggest that hominids did not, as supposed, evolve key traits only the one time en route to becoming modern-day humans. News of the discovery was leaked to the press late last year, but this is the first time details of the fossil skull have been made public and published in a scientific journal (Nature, vOl 418, P 145). Named Sahelanthropus, the skull has characteristics which show it was close to the common ancestor of humans and chimpanzees. Although Sahelan thropus's brain was the size of a modern chimp's, its face was quite different, with large brow ridges and much smaller canine teeth. From the back, the skull "looks like a chimpanzee", says Bernard Wood of the George Washington University in Nature (vOl 418, P 133). Whereas from the front it could pass for a 1.75-million- year-old australopithecine, a much later group of hominids which include the famous Lucy. As well as the striking ancestry of Sahelanthropus, it's that unique blend of features which is causing a commotion among experts. "It's a great example of how the fossil record keeps showing how wrong our inferences are," says Susan Anton at the University of Florida in Gainesville. Another newly discovered skull, a relative baby just 1.75 million years old, has been found in Asia which has a different mosaic of features (see p 21). Wood says that Sahelanthropus lends weight to the idea that hominids diversifled into many forms as they evolved, each containing a range of different characteristics. "Features were mixed and matched in ways that we are only beginning to comprehend," she says. Human and apes supposedly diverged some 5 tO 7 million years ago, but the fossil record of this split is sparse. Last year, scientists in Kenya announced they had found the leg bones of an early human-ne animal, Orrorin tugenensis, which they dubbed Millennium Ancestor. They believed the creature walked upright around 6 million years ago. But experts have questioned whether Orrorin is a true hominid. Sahelan th ropus is thought to be related to another recently discovered hominid, Ardipithecus, which lived 5.8 tO 4.4 minion years ago, says Michel Brunet of the University of Potters in France, who led the international team which discovered the skull. Jeff Hecht
Fewer genes, better health
THE human genome was unveiled last year to much fanfare, self-congratulation and just a little disappointment. For despite our apparent sophistication, we find we have fewer genes than plants such as the humble rice plant. Now a London-based biologist thinks he has the answer to this apparent paradox. The number of genes we have may be a concession to our complex immune system, says immunologist Andrew George of Imperial College. If we had any more, our bodies would be crippled by autoimmune diseases because our immune cells wouldn't be able to leam to recognise and ignore the huge numbers of proteins the genes wouldchumout. Rather than the loo,ooo plus genes we thought we had, the "book of life" revealed that we make do with a mere 30,000 tO 45,000. That's startlingly few, considering that a simple sea urchin has only a few thousand fewer, and squid are though to have the same number (see Graphic). And rice plants may have uP tO 55,000. George thinks our immune system has placed an upper limit on the number of genes we can cope with. At the sharp end of the immune system are T cells, which circulate around the body and check the identity of other cells by examining the short sections of proteins presented on their surfaces. These protein fragments are taken from a random selection of those within the cell, so a cell infected with a virus presents viral proteins as well as its own. The T cell recognises the viral fragment and recruits other immune cells to destroy the infected cell. Crucially though, T cells must ignore all the "friendly" proteins coded for by our genes or else they will attack healthy cells. To prevent this, newly formed T cells that get it wrong are weeded out in the thymus gland in the neck. This only works as long as there aren't too many friendly proteins to ignore. Assuming that each gene codes for a distinct protein, George estimates that the immune system of an organism containing 30,000 genes would have to destroy a quarter of all new T cells just to eliminate the rogues that could turn on the body. But with loo,ooo genes, almost two-thirds of all new T cells would have to be eliminated, he says.
Maintaining an immune system that won't turn on the body simply becomes too wasteful, time consuming and expensive. VVhat's more, it raises the chances of a foreign protein looking like a normal one and slipping through the net. "It's a really exciting idea," says Laurence Hurst, an expert in genome evolution at Bath University. "It implies that simply adding new genes comes at a cost." However, George takes his theory a step further. He says that our relatively small genome may hinder our ability to adapt to environmental change. Since it can't add new genes, our genome has to respond by coming up with other ways of performing new functions, using the same protein in several different roles, for example. But that has its limits, says George. "There must come a stage when you've got less room to manoeuvre." in short, our immune system may be frustrating our ability to evolve (TRENDS in Im m unology, VOI 23, P 351). The same would apply to birds, reptiles and other mammals, which have similar immune systems. Dmitri Petrov, an evolutionary geneticist at Stanford University, is cautious. "Tbe idea should be kept on the table, but I don't think there's any evidence that it's true yet ' " He questions the general assumption that humans must have more genes than other life forms.
One company is trying to enforce a monopoly on testing for breast cancer genes. With other genes being bought up at analarm i ng rate, how long before all healthcare is in the hands of a few big companies and their lawyers? Sylvia Pagin Westphal investigates a worrying trend
On the outskirts of Salt Lake City, Utah, stands a modern building of glass and brick, typical of countless other offices built in the 1990s. What goes on inside, however, is anything but commonplace. The building is home to Myriad Genetics, a pioneer in genetic testing, and best known for developing the DNA test based on the BRCAl and BRCA2 genes to assess a woman's risk of breast and ovarian cancer. You'd think this company would be riding a wave of popularity, that its image would thrive on the gratitude of doctors and the thousands of women worldwide whose lives have been saved by the test. But you couldn't be more wrong. For many scientists, Myriad has become one of the most despised biotechnology companies in the world. It's being boycotted by Canadian health authorities and laboratories in the Netherlands, Belgium and Germany, challenged by the French government in a heated patent dispute, and has provoked deep animosity in Britain as the company negotiates with the National Health Service over testing policy. Myriad's patents give it broad rights over pretty much any diagnostic or therapeutic use of BRCAl and BRCA2 and the proteins they code for. What's upsetting people is that Myriad is trying to stop anyone else carrying out comprehensive tests for breast and ovarian cancer. Myriad's critics argue that by setting up a monopoly on testing, the company is attempting to profit at patients'expense. It's the quintessential David and Goliath story. Here's a big biotechnology company with its two key genes, going round the world telling small diagnostic labs they can't test people any more because the genes are private property. Critics contend that the monopoly Myriad is creating lets it set an unreasonable price for its tests. And academics are furious that companies hoarding the rights to genes may stifle valuable research by raising the price of genetic testing and restricting access to tests. But the detractors had better brace themselves for more. Other companies are following in Myriad's footsteps, including Athena Diagnostics, a Massachusetts subsidiary of Ireland's Elan Pharmaceuticals. Athena has bought exclusive patent rights to several diagnostic tests for neurological diseases, such as late onset Alzheimer's disease. The tests used to be routinely performed by some university labs, says bioethicist Jon Merz from the University of Pennsylvania in Philadelphia, who has looked closely at Athena's practices. He and others told New Scientist that the company has asked many labs to stop offering some of those tests, because they want to be the exclusive provider.
Disturbing implications Athena declined to comment on its strategy, but New Scientist has obtained a letter sent by Athena to a university laboratory in which the company states: "It is only by using Athena's facilities that other laboratories can offer this patented diagnostic test without infringing the patent." Because of letters like that, "a lot of small good laboratories are backing off from companies like Athena", says the director of one of the biggest university laboratories in the US, who preferred not to be named. "They just bully around small labs." But perhaps the most disturbing implication of all is that Myriad and Athena's modus operandi could be repeated by the pharmaceuticals companies a few years from now. Drugs companies are applying for patents on genes and their functions with unprecedented speed. And some of these patents are so far-reaching that, if granted, they could prevent anyone else from touching those genes to create drugs that act on them or even to test the genes for mutations in a patient. There are now numerous patent applications for key cell receptors that claim their associated genetic sequences and mechanisms of action. Being able to use these receptors could be vital for discovering whole classes of drugs, says Gordon Wright, a partner at patent law firm Elkington and Fife in Sevenoaks, Kent. "If it's inevitable that others must pass through that gateway to find a drug, it may be that [the patent owners] are in a position to control access," Wright says. "if they get too greedy on this, it's a danger." In the future, instead of several companies competing to create blockbuster drugs that act in a speciflc way - think of the statins that reduce cholesterol and stave off heart disease, or the new class of anti-inflammatories for arthritis called COX-2 inhibitors - a single drugs company could monopolise the information needed to create the next miracle cure. it would be goodbye to competition and hello to monopoly pricing and a slower pace of medical progress. The herald of this bleak scenario is Myriad. The company has been granted more than 25 patents in the US, Europe and elsewhere, giving it rights over the sequence, diagnostic and therapeutic uses of BRCAL and BRCA2. Soon after being granted the US patents in the mid-iggos, Myriad successfully halted most testing being done by labs in the US. These labs were offering different kinds of tests: some scanned the genes for mutations, others were simply testing for faulty versions of the gene's protein. All these labs were infringing the patents, so Myriad warned them to stop offering the tests. The company allows other labs to carry out limited tests on the genes, for a fee. But for full sequencing, Myriad insists that all samples are sent to its headquarters in Salt Lake City, no matter if the patients are thousands of miles away around the globe. Myriad's takeover was fairly smooth in the US. There was little fuss - at least in public. But the company has not had such an easy ride outside the US. Labs in several European countries are refusing to recognise the company's patents. For example, the Curie Institute in Paris with support from the French government has filed challenges to the BRCAI patents with the European Patent Office (EPO), arguing that Myriad's unwillingness to let anyone else do full testing would establish a monopoly, damaging scientific research and the welfare of patients. Human genetics societies in Germany, the Netherlands, Belgium and Denmark have also field a challenge with the EPO, says Dominique Stoppa-Lyonnet, head of oncological genetics at the Curie Institute. Laboratories in those countries have decided not to honour Myriad's patents, arguing that they have tests that are just as effective and several times cheaper. "We are still doing our own genetic testing, but we are aware that Myriad could put pressure for infringement of the patents," says Stoppa-Lyonnet. in part, this hostility has arisen because diagnostic labs at universities and hospitals had been used to operating in a very unrestricted manner.
"A single drugs company could monopolise the information needed to create the next miracle cure. lt would be goodbye to competition and hello to monopoly pricing"
For years, whenever a gene for a disease was published in a scientific joumal, researchers running university laboratories felt free to devise their own diagnostic test for it. Since many of the first gene discoveries that led to diagnostic tests were not patented, labs could offer their home- made test without fear of infringing anyone's intellectual property rights. Then, in the ig8os, the US passed the Bayh- Dole Act to encourage universities to patent their research results. Labs increasingly found that their in-house tests were for genes or proteins that had been patented by someone else, meaning they had to pay royalty fees. For example, whenever a lab carries out a genetic test for cystic fibrosis, it has to pay about $2 to the University of Michigan. But while the days of pay- per-use diagnostics had begun, at least labs could still perform the tests themselves. Then along came Myriad, intent on using its patents not just to charge other labs royalty fees, but to stop them doing the tests at all. Labs may have their own reasons for disliking Myriad's strategy, but there are wider fears about how the company's policy will affect healthcare and medical research. First, there's the cost of the BRCAl and BRCA2 test, which in the US is approximately $2700 a throw. In some countries, the cost is between double and triple the rate that labs used to charge. "The cost is prohibitive, so the local population is not opting to do it," says Doug Horsman, director of the Hereditary Cancer Program in British Columbia, where in-house testing for the two breast cancer genes was stopped in JUIY 2ool after the lab received a cease- and-desist letter from Myriad. In British Columbia, the number of families wanting the test has gone from roughly ioo families per year to about six, Horsman says. "It's a direct reflection of the price. if they'd come in with a reasonable price, they might have gotten hundreds of patients from us," he says. William Hockett, director of communications at Myriad, says that the pricing issue "is never portrayed accurately". He claims the only reason other lab tests were cheaper was because they weren't as comprehensive or sophisticated, and would often miss mutations. That's true in some cases, but not all. Stoppa-Lyonnet, for example, says studies have shown that the method used in France, which is not based on sequencing, is just as accurate as Myriad's, yet it's several times cheaper. But fears go beyond the cost of tests. There's also concem that Myriad's tactics wffl harm research. Generally speaking, it's widely acknowledged that once someone patents a gene, researchers interested in finding diagnostic tests or therapies based on that gene will shy away from it for fear of infringing the patent. A survey published this year by Merz demonstrated that simply knowing there are patents on the gene for hereditary haemochromatosis - a disorder in which the body retains too much iron - played a major role in deterring uP tO 30 per cent of more than ioo diagnostic labs from developing a test for the disease. Another widely voiced worry is that Myriad's restrictions could harm clinical studies by controlling the lifeblood of scientific research: data. If Myriad is the only one that can do the tests, that puts it in charge of the quantity and quality of data produced. But Hockett says that contrary to what some critics say, Myriad does not keep a database of all test results. And if it finds new mutations when sequencing somebody's DNA, they are sent straight to BIC, the public breast cancer information database.
No stifling of research
"We have sponsored long-term registries to follow women with mutations, such as that run by Dr Fred Li at Dana Farber Cancer Institute,' says Hockett. "We have provided no-cost testing and low-cost testing for dozens of research studies. Over 70o research papers have been published with these genes. Compare that to any other predisposition gene and you you can see that they are extremely weu researched - no stifling has taken place. Myriad has also cut a deal with the US National Cancer Institute to do tests funded by the institute at about half the regular price, which is close to what it would cost any lab to carry out the test. Still, however, Merz says many scientists are unhappy about sending all samples to Myriad because they'd prefer to do the test themselves and have control over the methods and validity of the results. In fact, there is one well-publicised case of a researcher so upset with Myriad's policy that he stopped cooperating with a breast cancer clinical trial rather than send his samples to the company. But whether this case, and similar examples, can be used as evidence that the company is unfairly "halting" research is not clear. One argument the company usft in reply to its critics is that in many clinical studies, academic institutions should not be immune from the rules applied to commercial users of its patents (see "Blurring the lines", page 33). There seems to be-no concrete evidence that Myriad's patents, or any other gene patents, have prevented scientists from studying fundamental questions about genes - such as learning about their molecular interactions inside cells. "It's really hard to get evidence," says Mildred Cho of Stanford University, who studies the effects of patenting on research. "There really isn't a whole lot out there, nothing systematic." But even in the absence of hard evidence, the perceived stifling of research by patents and monopolies such as Myriad's has created enough unease, and lawmakers have begun to act. In the US, for example, a bill to modify patent policy has just been introduced in Congress. According to Representative Lynn Rivers, a Democrat from Michigan who is sponsoring the bill, any scientist doing non-commercial research that involves patented genes should be exempt from a patent. "My greatest concern is that if research is foreclosed, the science stops cold," she says. Rivers proposes that if a researcher makes a commercially valuable finding, they should then be able to enter into negotiations with the patent holder to pay royalty fees. Likewise, medical researchers would be free to create their own tests for a patented gene without having to pay royalties on that gene. "I'm trying to avoid the possibility of a patent on a gene foreclosing any use of the gene," she says. Any attempts to change patent laws are always met with the same objections by industry: the whole purpose of a patent is to protect the inventor's right to exploit a discovery commercially, and without it a company could not justify investing in research in the first place.
"Any attempts to change patent laws are met with the same objections by industry: the whole purpose of a patent is to protectthe inventor's right to exploit a discovery"
And limiting a company's rights to stop anyone else profiting from their invention would ultimately choke innovation. These arguments are not unique to healthcare, however. According to Geoffrey Duyk, an ex-Harvard academic who co-founded Millennium Pharmaceuticals and is now Chief Scientific Officer at genomics firm Exelixis, the story of Myriad is the story of agribusiness versus the family farm, and amazon.com versus the corner bookstore. So the question becomes, should the rules for companies in healthcare be any different from those in other markets? If the balance between monopolies and licensing is one part of the problem, another issue is lurking beneath the surface: the breadth of patents. Some critics argue that Myriad's BRCAI and BRCA2 patents should never have been granted in the first place because their scope is too broad. But in fact, that may be a misconception. Myriad's patents are, in fact, no more comprehensive in their claims than thousands of others filed by companies and countless academic labs. The issue of hoW broad patents should be is almost unmanageably complex, and a topic of worldwide debate. There are those who feel that no genes should be patented, because they already exist in nature. But according to R. Stephen Crespi, a prominent patent attomey and consultant to the London-based law firm Williams, Powell and Associates, that objection has not been used much in the courts. "Even if it were well-founded, the objection is not so much a legal question as a philosophical one and therefore it cannot be fitted easily into the grounds available for invalidating patents," Crespi states in a recent essay. A more reasonable question is how far- reaching a patent should be relative to how much new knowledge has been uncovered. in January 2001, the US Patent and Trademark Office (USPTO) raised the bar for those trying to patent genes, stating that applicants must prove that they have a unique, non-obvious use for a claimed gene, such as a diagnostic tool for a specific disease. "You have to be able to show that you've characterised the gene and you would know what to use it for," says lila Feisee, former USPTO officer and now director of government relations and intellectual property at the Biotechnology Industry Organization in Washington DC. The move was prompted in part by the patenting frenzy in the iggos when companies, including Incyte Pharmaceuticals and Human Genome Sciences, flled thousands of patent applications for genetic sequences, even though they frequently had no idea what the genes did. But even if these guidelines had been in force when Myriad applied for the BRCAI and BRCA2 patents, they wouldn't have helped anyone challenge the breadth of the claims, since nobody disputes that the company sequenced the genes and researched their role in breast and ovarian cancer. That doesn't mean that companies don't try to get away with patent claims that go far beyond the knowledge uncovered by the research done on a gene. It's common nowadays for companies to aim to patent not only a specific gene and its protein but also - based on the molecule's function - to claim any inhibitors or activators, on any cell type and for any assay or therapeutic application. "People do try to claim everything," says Duyk. Industry insiders even have a name for these claims. They're called "Viagra claims". The term refers to Pfizer's attempts to claim rights not only to the active compound in the anti-impotence drug, but to any other compound that blocked the PDE-5 receptor on which Viagra works its magic.
"Too often patent claims go far beyond the l(nowledge uncovered bythe research done on a gene. Insiders even have a name forthem. They're called Viagra claims"
Most of the patents with extensive claims are still in the application process, Duyk says. He doubts that the majority will be granted. Even so, it's not unheard of for patent offices to approve seemingly overreaching claims. A famous example is a set of patents granted between 1988 and 1999 to Harvard University and DuPont for the "OncoMouse", a mouse genetically engineered to get cancer.
Lucrative royalty deals Researcher Phillip Leder at Harvard Medical School showed that inserting a gene called c-myc into mice caused them to develop tumours, and based on that knowledge the inventors were granted patent rights over research with any cancer-prone mice, not just ones created with Leder's methods. Though not for a specific gene, they illustrate how much ground can be gained with a powerful set of patents. And controversy has recently ignited over the patents, with prominent researchers publicly criticising the claims as overly broad and arguing that they are stifling cancer research. It's hard to see that a combination of broad patents and an unwillingness to license other researchers is in the public interest. Indeed, the impact could be worse if the trend took off in the pharmaceuticals industry. Traditionally, drugs companies have used patents as a way of getting lucrative royalty deals with one another, but that could change. To be fair, there's no sign yet that drugs following Myriad's lead. That could be because the bulk of molecules described in the latest generation of patent applications are compounds that are still under development. But there is another reason why the kind of market domination that's emerging in diagnostics may never appear in pharmaceuticals, even if the patents are there. In pharma, there are too many companies with deep pockets willing to fight overzealous patents in court. Ironically, Viagra is a good example. The EPO recently rejected Pfizer's claim to any molecules interacting with the PDE-5 receptor. Britain's patent office also threw out the claim. Thirteen companies, including the drugs makers Eli Lilly and ICOS, successfully argued that Pfizer's idea of using the PDE-5 receptor to correct erectile dysfunction was obvious to everyone before the company applied for its patent. The challenging companies put a good gloss on their success. "Patients benefit when they have more than one choice," says Lacy Fitzpatrick of ICOS. Yet they were clearly out to deny Pfizer control over the whole market for PDE-5 inhibitors: ICOS and Lilly are about to launch a very similar drug to Viagra. So, a greedy pharmaceuticals company may have a much harder time at establishing a monopoly than Myriad has had in its attempt to dominate the breast cancer testing market. And already some experts are saying that not even Myriad's monopoly will prevail, because market forces have begun to dictate that the monopoly route may not be the most efficient. "If Myriad were making lots of money that's one thing, but they aren't," says lain Cockburn, an economist and patent expert at BostonUniversity. But arguments that monopolies will not thrive seem to forget the huge prize on offer to a company that controls the diagnosis and treatment of a common disease. With a new generation of patents making that prize more easily attainable, the rewards for pharmaceuticals companies may be too tempting - and afl the more disastrous for society. It would raise the spectre of, say, a company not just "owning" one drug for treating Alzheimer's disease but also governing any progress in that field for the 20-year lifetime of its patent. What would governments do then?
"A well-developed sense of fair play helps non-human animals
live longer, more successful lives. In other words, virtue is
its own reward - fairer is fitter"
IF YOU think that we are the only creatures on Earth with a moral sense, then you're in good company. Most experts in behaviour believe that morality is a uniquely human trait, without which our complex social life would never have emerged. I disagree. Accuse me of anthropomorphising if you like, but I'm convinced that many animals can distinguish right from wrong. Decades spent watching wild and captive animals have persuaded me that species living in groups often have a sense of fair play built on moral codes of conduct that help cement their social relationships. Nature isn't always ruthlessly and selfishly competitive. That's not all. I suspect that herein lies the origin of our own virtue. Biologists have had real problems trying to explain why humans are frequently inexplicably nice to each other. It just doesn't make sense in evolutionary terms, unless there are ulterior motives behind our seemingly altruistic actions. Perhaps we expect a payback somewhere down the line, or maybe our good deeds are directed only towards kin, with whom we share genes and hence a biological heritage. Nobody has really considered the possibility that being considerate to your neighbours might sometimes be the best way to survive. But I'm starting to find evidence that a well-developed sense of fair play helps non-human animals live longer, more successful lives. In other words, virtue is it's own reward - fairer is fitter. It's an understatement to say that looking for the roots of morality in animals is very difficult, but at least we can start to break the problem down. The first question to answer is, are animals capable of the empathy and feelings that underlie morality? We know that in humans the neural basis for these feelings lie in the brain's amygdalae and hypothalamus, and they are mediated by neurotransmitters such as dopamine, serotonin and oxytocin. We also know that many animals, especially mammals, possess the same neurological structures and brain chemicals as we do. of course, this doesn't necessarily mean they share our feelings, but careful observation of animals in action suggests that at least some of them do. Recent overviews of research by Stephanie Preston and Frans de Waal from the Yerkes Primate Center in Atlanta and Stanley Kuczai's group at the University of Southem Mississippi in Hattiesburg show that empathy is more widespread among animals than science has so far been willing to recognise. They point to research that suggests non-human primates, dolphins, whales, elephants and hippopotamuses, and even some rodents, behave in ways that support the claim that empathy has deep evolutionary roots. In one classic study published in 19 64, Stanley Wechlin and his team at the Northwestern University Medical School in Illinois showed that a hungry rhesus monkey would not take food if doing so meant another monkey got an electric shock. In similar situations rats will also hold back when they know their actions would cause pain to another individual. Then there's the study published two decades ago by Hal Markowitz from San Francisco State University. He reported that after training Diana monkeys to insert a token into a slot to get food, he observed a male helping the oldest female who had failed to leam the task. On three occasions the male picked up the tokens she had dropped, put them into the machine, and allowed her to have the food. We'll probably never know whether these rats and monkeys were feeling empathy as we do. But what we can do is start comparing what's going on in animal brains with what happens in our own. Neuroimaging techniques such as PET scans and functional MRI are starting to shed new light on human emotions, and I hope that it won't be long before we start doing similar studies with non-human primates and other animals. In the meantime, watching animals in action has convinced many researchers, myself included, that they possess the emotions upon which a moral sense is built. Chimps and monkeys, for example, seem to feel embarrassment, whales and ravens show signs of falling in love, and even iguanas register pleasure (New ScientiSt, 29 April 2000, P 32). in my own research I have taken this one step further - looking for evidence of fair behaviour. I'm particularly interested in social play - the joyful rough and tumble common to many mammals, especially youngsters - because it has its own special rules of engagement, allowing participants to reinterpret acts that might otherwise seem aggressive or sexual. The fact that play rarely escalates into all-out fighting is a strong indication that animals do indeed abide by the rules and that they expect others to do likewise. My studies of infant dogs, wolves and coyotes based on careful observation and analysis of video playbacks reveal that they use a special signal to prevent misinterpretation of playful actions. They perform a "bow" -which entails crouching on the forelimbs while keeping the rear upright - when initiating play, or in association with aggressive actions such as biting, to modify their meaning. I've also found that players often use self-imposed handicaps to limit the force they use against a weaker playmate when body slamming orbiting. And role reversal is common, so that during play a dominant animal will often allow a subordinate to have the upper hand. Such behaviours reduce inequalities in size, strength and dominance between playmates, fostering the cooperation and reciprocity that are essential for play to occur. indeed, on the rare occasions when a canid says "let's play" and then beats up an unsuspecting animal, the cheat usually flnd itself ostracised by its erstwhile playmates. Similar cooperative behaviour has been found in many animals at play. For example, Sergio Pellis from the University of Lethbridge in Alberta found that rats will constantly monitor and fine-tune their behaviour to keep play going. But while there has been much talk about animal cooperation, no one has considered the role that social play may have had in the evolution of morality. Yet what could be a better atmosphere in which to learn the rights and wrongs of social interaction - the moral norms that can then be extended to other situations such as sharing food, defending resources, grooming and giving care?
My belief is that a sense of faimess is common to many animals, because there could be no social play without it, and without social play individual animals and entire groups would be at a disadvantage. if I'm right, morality evolved because it is adaptive. It helps many animals, including humans, to survive and flourish in their particular social environment. This may sound like a radical idea, particularly if you view morality as uniquely human and a sort of mystical quality that sets us apart from other animals. But if you accept my argument that play and fairness are inextricably linked, you're half way there. The challenge then is to show that individual animals benefit from these behaviours. it's hardly radical these days to suggest that play is essential food for the brain. Recent research shows that the more animals play, the bigger their brains grow (New Scientist, 9 June 2001, p 28). Social play seems to rewire the brain, increasing connections between neurones in the cortex. It hones an individual's cognitive skills, including logical reasoning, learning and behavioural flexibility. And it helps perfect survival skills such as hunting and mating, which will be essential in later life. Quantifying these benefits of play is extraordinarily difficult, but the more we learn about the way play affects the brain the more apparent it becomes that the activity is far from idle time-wasting. My own fleldwork has uncovered one of the penalties paid by animals that fail to engage fully in play. I've found that coyote pups who don't play much are less tightly bonded to other members of their group and are more likely to strike out on their own. And life outside the group is much more risky than within it. In my seven-year study of coyotes living in the Grand Teton National Park outside Moose, Wyoming, I found that about 6o per cent of the yearlings who drifted away from their social group died, whereas fewer than 20 per cent of their stay-at-home peers did. I'm sure that close scrutiny of other social animals will reveal more evidence that having a sense of fairness benefits individuals. More controversially, I also believe that a moral sense may benefit groups as a whole. That's because group members learn rules of engagement during social play that influence their decisions about what is acceptable behaviour when dealing with each other. Recent research by Kyoko Okamoto and Shuichi Matsumura at Kyoto University suggests that we are not the only primates to use punishment and apology to help reinforce the rules of social engagement. And sticking to the rules is essential if individuals are to work in harmony to create a successful group that can outcompete other groups. My observations of coyotes confirm that members of a pack who work together are more successful at driving off intruders than are single individuals, and I'm sure that if other researchers looked they would find similar evidence for the benefits of group living in other animals. I'm not arguing that there is a gene for fair or moral behaviour. As with any behavioural trait, the underlying genetics is bound to be complex, and environmental influences may be large. No matter. Provided there is variation in levels of morality among individuals, and provided virtue is rewarded by a greater number of offspring, then any genes associated with good behaviour are likely to accumulate in subsequent generations. And the observation that play is rarely unfair or uncooperative is surely an indication that natural selection acts to weed out those who don't play by the rules. What does all this tell us about human morality? First, we didn't invent virtue - its origins are much more ancient than our own. Secondly, we should stop seeing ourselves as morally superior to other animals. True, our big brains endow us with a highly sophisticated sense of what's right and wrong, but they also give us much greater scope for manipulating others - to cheat and deceive and try to benefit from immoral behaviour. In that sense, animal morality might be "purer" than our own. We should accept our moral responsibility towards other animals, and that means developing and enforcing more restrictive regulations goveming animal use. There is growing evidence that while animal minds vary from one species to another, they are not so different from our own, and only when we accept this can we be truly moral in our relations with other creatures and with nature as a whole. 0 Ma rc Bekoff teaches biology at the U n iversity of Colorado, Bou lder. He a nd Ja ne Gooda I I recently fou nded Etholo0as for the Eth ica I Treatment of An ima Is (www.ethologicalethics.oro. His latest book, Minding Animals(Oxford University Press), was published in Britain this month Further reading: "The evolution of punishment and apology" by Kyoko Okamoto and Shuichi Matsumura, fvoiutionoty fcology, vol 14, p 703 (2001) "Empathy: Its ultimate and proximate bases" by Stephanie Preston and Frans de Waal, Behavioral and Broin Sciences(in press)
26 0ctober 2OO2 New Scientist
Tree farms won't save us after all
FRED PEARCE, VALENCIA
THE Kyoto Protocol to halt climate change is based on a scientific fallacy. The protocol says that countries can help meet their targets for cutting emissions of greenhouse gases over the next decade by planting forests to soak up carbon dioxide. But the soil in these "Kyoto forests" will actually release more carbon than the growing trees absorb in the first ten years. "Countries will be able to claim carbon credits for the forests. But that won't reflect what is happening in the atmosphere," says Riccardo Valentine of the University of Tuscia in Vfterbo, Italy. Late last week in Valencia, Spain, he presented the first results of CarboEurope, a Europe-wide programme that has pioneered research into the carbon budget. The project's revelations could embarrass governments meeting in New Delhi this week to discuss implementation of the Kyoto Protocol. Earlier this month, Italy announced plans to achieve between lo and 40 per cent of its emission reductions target for 2012 through forest planting. But now its own scientists are warning that these sinks might not work. The problem is soils. Forest soils and the organic matter buried in them typically contain three to four times as much carbon as the vegetation above. CarboEurope's researchers have discovered that when ground is cleared for forest planting, rotting organic matter in the soil releases a surge of CO2 into the air. This release will exceed the C02 absorbed by growing trees for at least the first ten years, they say. Only later will the uptake of carbon by the trees begin to offset the losses from soils. in fact, says CarboEurope chairman Han Dolman of the Free University Amsterdam, some new forests planted on wet, peaty soils will never absorb as much carbon as they spit out. The world's densest network of C02 monitoring devices has revealed that Europe's forests are absorbing uP tO 400 million tonnes a year, or 30 per cent of the continent's emissions. Researchers once assumed that most of this came from young forests, since old forests were thought to be in equilibrium with the atmosphere - sucking up as much gas as they spew out. But, says Valentine, old forests actually accumulate more carbon than young plantations. This suggests that conservation of old forests is a better policy for tackling global warming than planting new ones. But the Kyoto Protocol takes none of this into account. "Besides ignoring soils, it has no measures to stop deforestation," says Valentine. Instead, it seems to give countries a perverse incentive to chop down existing natural forests and replace them with plantations. "They will be able to claim carbon credits for the new planting, while in reality releasing huge amounts of CO2 into the air," says Valentine. "There is nothing in the protocol to stop this." "if the politicians had known in 1997 what we know now, they would never have agreed to its rules on carbon sinks - at least, I hope they wouldn't," says Dolman.
First they called it the "missing link". Now some say it's just an ancient ape. Eitherway, this skull is forcing us to rewrite human evolution, says palaeoanthropologist Bernard Wood
THERE is a popular image of human evolution that you'll find all over the place, from the backs of cereal packets to advertisements for expensive scientific equipment. On the left of the picture there's an ape - stocky, jutting jaw, hunched in the knuckle-walking position. On the right, a man - graceful, high forehead, striding purposefully into the future. Between the two is a succession of figures that become ever more like humans, as the shoulders start to pull back, the torso slims down, the arms retract,the legs extend, the cranium expands and the chin recedes. Our progress from ape to human looks so smooth, so tidy. it's such a beguiling image that even the experts are loath to let it go. But it is an fllusion. Cut to another picture of human evolution. This July, a cracked and twisted face appeared on the front pages of most of the world's major newspapers. The skull, unearthed in the Djurab Desert in Chad, central Africa, is dated at between 6 and 7 million years old. At the time it was hailed as our oldest ancestor. In recent weeks, that claim has been bitterly disputed. Academic reputations may be at stake, but behind all the ballyhoo, the true significance of this find is emerging. It is forcing-us to rethink the idea of human evolution as a smooth progression without blind alleys or dead ends. It can't possibly be so tidy, as within this framework the Chad fossil makes no sense: this truly ancient specimen has the brain case of a chimp together with a face that looks uncannily like our ancestors living less than a million years ago. My own research on fossils from East Africa convinced me long ago that our evolutionary history is much more complex than we'd like to think. Other palaeoanthropologists see a single line of descent that you can follow like the trunk of a tree from its apex back down to the roots, but I have long argued that our ancestry is more like a bush with multiple tangled stems. Try following our own lineage back to its origins and you soon get lost in the thicket. The Chad fossil is most likely among the tangled stems at the base of the bush. But is it our oldest known ancestor - the "missing link" between humans and chimps? Indeed, is it one of us at all? If the new find has taught us anything it is that, paradoxically, the more we discover about our origins, the less we know. One of the many things molecular biology has done is confirm that humans are merely a rather peculiar African ape. Geneticists estimate that our common ancestor lived between 4 and lo million years ago, based on the rate at which genetic mutations occur and the measurement that we differ from chimps by 1 tO 2 per cent of our DNA. With the new finds from Chad - and other 6-miUion-year-old remains discovered at a Kenyan Rift Valley site called Lukeino (see New Scientist, i6 December 2000, P 5) - it looks increasingly likely that the split happened earlier rather than later. So some time between saY 7 and lo million years ago genetic variation within the population of our common ancestor polarised into two lineages, or "clades": one that includes us, and the other containing chimps and bonobos. Of course, we cannot look at the genes of our earliest ancestors. Instead, we use fossil anatomy as a pr,oxy fpE the genome, and treat morphological similarities as if they were geneticones. A competent anatomist will be able to tell the difference between most components of the modem human and chimp skeleton, but we palaeoanthropologists face a much tougher and more subtle task. We must trace these skeletal differences back in time, and work out what they looked like when the chimp and human lineages diverged. This is made more difficult because we have little idea of when the structures and behaviours peculiar to chimps arose. Although chimps have had their own independent evolutionary history going back as far as ours, we have absolutely no fossil record of that evolution. Nevertheless, the tidy interpretation of the human fossil record suggests that the "gap" between modern humans and our common ancestor with chimps has been filled. In this model you can trace the origins of our own genus, Homo, back in time through Homo erectus to Homo habilis and then to Australopithecus afarensis. The gap to the common ancestor is bridged by Australopithecus anamensis and finally Ardipithecus ramidus- Just one blip spoils the conventional ladder-like succession: the "robust" australopfths, or Paranthropus, who are generally interpreted as an extinct side branch of human evolution. And the place of one other fossil species, Australopithecus ajWcanus from southern Africa, is uncertain. The tidy model also purports to give clues about the detailed differences between the ancestral humans (hominins) and ancestral dhimps (panins) close to the time when they split. For example, studies of teeth from Ar. ramulus suggest that one of the earliest changes was in the size, shape and wear of the canines. Another assumption is that early paning were adapted for life in the trees, holding their torsos horizontally as they walked on all fours, whereas the original hominin was probably a "facultative" biped, who retained some tree-climbing abilities but was partially adapted for walking on two legs. A. afarensis is a facultative biped, A. anamensis is likely to be one also, but we don't yet know enough about the skeleton OfAr ramulus to tell how it moved. The creatures down near the base of the human tree might also have had a slightly larger brain than ancestral chimps. Not long ago most researchers were quite sure that these so-called "golden characters" would help us sort out the hominins from panins. But the fuller the human fossil record becomes, the shakier is the assumption that human characteristics such as manual dexterity, bipedalism and large brains are so special that they evolved only once. If this was the case, then the branching pattem, or cladogram, showing the relationship between fossil specimens should be clear and unambiguous. What's more, any piece of anatomy, or "character", we use to reconstruct a cladogram should show the same branching pattem as any other. But the reality is very different: character cladograms conflict. Clearly, species with shared morphology do not always inherit it from a common ancestor. The technical term for this is homoplasy. These days, most palaeoanthropologists agree that homoplasy occurs in the later stages of hominin evolution - and also in the evolution of extinct apes - so why not at the begffiwng of human evolution? In addition, there is no reason why rudimentary upright walking and the ability to make crude tools could not have evolved In a creature that was genetically closer to a chimp than to a modem human. This scenario becomes even more complicated if we entertain the possibility that around 6 or 7 million years ago there may have been apes that were neither ancestral chimps nor ancestral humans. Personally, I think that this was most likely the case. if so, the haystack gets larger, and the odds of finding and correctly identifying the ancestral human needle become even longer. This is the context in which the Chad discoveries should be set. The fossil remains of Sahelanthropus tchadensis - the ape's correct scientiflc name - which were unearthed by Michel Brunet from the University of Poitiers and his colleagues, include a lower jaw and teeth as well as the cranium containing the face. The jaw is thicker than a chimp's, and the canines show the flrst signs of moving away from an ape-like design - evidence consistent with its being an ape at, or near, the base of the human clade. However, what most deftwtely clashes with its 6 or 7-million-year-old date is the beetle-browed upper face. We are used to seeing brow ridges on the fossils of much later Homo species, none of which is older than 2 million years. And prominent brow ridges like the Chad ape's tend to come much later. If we use anatomy as a proxy for genetic relatedness, then the Chad face connects it with hominins dated at less than a million years old. That clearly can't be right. Although the Chad fossils were not dated by isotope methods - there are no nearby volcanoes to provide the necessary ash for carbon dating - fossil animals found at the site match others from East Africa that date to between 6 and 7 million years old. There is no way this ape is anywhere near as recent as the Homo specimens it resembles. More ridiculous still, under the terms of the tidy model where everything evolves just once, the Chad specimen's ancient date and modern-looking brow ridge means that any later fossil hominins with more primitive faces can't possibly be our ancestors. That includes the famous "Lucy" skeleton and even species we include in our own genus. As a supporter of the untidy model of human evolution, I interpret the Chad face if we evolved at a time when many new species of ape were emerging, identifying the fragmentary remains of one of them as the hominin ancestor is a tall order"
Neat tree suggests a simple evolutionary relationship
The actual evidence is tangled and more complex to conclude from.
The face of a skull is one of the skeleton parts most likely to be affected by homoplasy. Despite their physical similarities, the faces of the Chad ape and those of later hominins were not necessarily inherited from a common ancestor. Instead, they may simply have been shaped by similar social or dietary demands. If so, then the Chad remains don't fit neatly into a smooth progression of human evolution. But my interpretation is surely less radical than throwing Out 4 tO 5 million years' worth of the hominin fossil record. So, here is evidence for homoplasy right down at the base of the human evolutionary tree. The Chad find strengthens my conviction that our evolutionary history is far more complicated that many experts are willing to admit. Accepting this is liberating. It allows us to look afresh at the human fossil record and reclassify some of the oddball specimens that most experts have previously attempted to shoehorn into the tidy family tree. The resulting bush may not appeal to our innate wish to impose order on the world, but it is a more faithful representation of the evidence. And the implications of the Chad finds stretch even further. I believe these fossils also suggest that the earliest direct ancestors of modern humans and chimps were just two components of a diverse great ape fauna. This evolutionary bonanza, known as an "adaptive radiation", was most probably a response to the global cooling that was causing the contraction of Afhcan tropical forests and the expansion of woodland environments around 8 million years ago. Here, the location of the Chad fossil remains is significant. Today, the site at Toros-Menana in the Djurab Desert is little more than sand as far as the eye can see, but 6 or 7 million years ago it was forested, game was abundant and fish were plentiful in nearby lakes. This also reminds us that when the first human ancestors were beginning to appear, apes and ape-friendly environments were almost certainly much more widespread than they are today. More tellingly still, the Djurab Desert is over 15oo kilometres west of the East African Rift Valley, long touted as the home of the original hominins. Some experts have already questioned the conventional wisdom that hominin evolution was somehow triggered by the appearance of savannah grasslands in and around the Rift Valley. The new finds confirm that this scenario must be thrown out. So where does the Chad ape fit into this bigger, more complex picture? It may well be a creature very close to the base of the human bush, but it is impossible to tell whether it is a direct ancestor of modem humans. Indeed, if we accept that we evolved at a time when many new species of ape were emerging under the pressures of environmental change, then identifying the fragmentary remains of one of these apes as the hominin ancestor is likely to be a tall order. Facultative bipedalism, increased dexterity, and even a bigger brain, might have occurred in more than one member of an adaptive radiation. In fact, we should expect to see novel mixtures of familiar adaptations, and even novel adaptations, in a 7 tO lo-million-year-old radiation of African apes. We may never get a clear picture of the thicket of stems at the base of our evolutionary bush. Certainly, the search for the "missing link" is doomed to failure. But we can increase our understanding of human evolution by recovering new evidence from known sites, and from new sites in hitherto unexplored regions in central and West Africa. We must also search for the remains of extinct panin, which will provide a unique perspective on our own evolution.
Bemard Wood is Henry B. Luce professor of human origins at George Washington University in Washington DC