Hot off the presses! Jul 09 Nature

The Jul 09 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Japan's tipping point
  - Nature 460(7252):151 (2009)
  With changing demographics, a tight economy and increasing competition, Japan could slide from the top ranks of research nations. Drastic action is needed.
• How to stop blogging
  - Nature 460(7252):152 (2009)
  Organizers have only two options for their meetings: open or closed.
• Adieu to nuclear recycling
  - Nature 460(7252):152 (2009)
  President Barack Obama should be applauded for his decision to scrap commercial reprocessing.
• Perception: Picture imperfect?
  - Nature 460(7252):154 (2009)
  
• Ecology: A dusting of snow
  - Nature 460(7252):154 (2009)
  
• Evolution: Mary had a littler lamb
  - Nature 460(7252):154 (2009)
  
• Cancer biology: At rest in the bones
  - Nature 460(7252):154 (2009)
  
• Astronomy: A star is born
  - Nature 460(7252):154 (2009)
  
• Genomics: Closing in on cholesterol
  - Nature 460(7252):154-155 (2009)
  
• Microbiology: Supershedding mice
  - Nature 460(7252):155 (2009)
  
• Geology: Earth-shattering research
  - Nature 460(7252):155 (2009)
  
• Computational biology: Unstuck by design
  - Nature 460(7252):155 (2009)
  
• Neurology: Feeling out autism
  - Nature 460(7252):155 (2009)
  
• Journal club
  - Nature 460(7252):155 (2009)
  
• US stem-cell research expands
  - Nature 460(7252):156-157 (2009)
  Biomedical agency announces new funding policy for cell lines. Nearly 11 years after Wisconsin-led researchers reported the first isolation of human embryonic stem cells, the field became eligible this week for broad research funding by the US government. In final guidelines that went into effect on 7 July, the National Institutes of Health (NIH) established a process that will allow scientists who hold stem-cell lines derived before this date to apply for their inclusion in an agency-established registry of fundable cell lines. In doing so the agency, based in Bethesda, Maryland, acknowledged that the strict ethical conditions it laid out in draft guidelines published in April (see Nature 458, 950–951; 2009) may have excluded many existing cell lines from federal funding. After receiving more than 49,000 comments on the draft guidelines, "it became clear that there were lines that responsible people would all agree were responsibly derived … but might not meet the exact guidelines that we have put forth," said Raynard Kington, acting NIH director, on 6 July. A working group will be established to judge on a case-by-case basis whether pre-existing lines "meet the principles underlying the guidelines", he said. Those principles remain unchanged from the April draft: fundable lines must be derived from embryos that were created solely for reproductive purposes and are no longer needed. Parents must voluntarily donate the embryos without inducements or researcher influence, and written informed consent must be obtained. The final guidelines, like the draft ones, exclude funding for stem cells derived from embryos created for research, whether by in vitro fertilization, somatic cell nuclear transfer or parthenogenesis, when an unfertilized egg is developed into an embryo. Although lines created in the United States from 7 July onwards will have to follow the guidelines to the letter, scientists who create lines abroad in future may apply to the working group to demonstrate that a line was made under procedural standards that are "at least equivalent" to those provided in the final guidelines. The NIH director will give the final approval to all decisions made by the group. Kington said he expected the group to comprise nine to ten people, including ethicists, scientists and fertility doctors, and to be up and running "within the next couple of months", along with the new registry. "The NIH has done what is best for the field by having their own registry — one list that everyone can work from." Many scientists were delighted with the final guidelines. "It's a huge step forward," says George Daley, a researcher at Children's Hospital Boston and the Harvard Stem Cell Institute in Cambridge, Massachusetts. "It's flexible and science friendly." Sean Morrison, a stem-cell biologist at the University of Michigan in Ann Arbor, adds: "The NIH has done what is best for the field by having their own registry — one list that everyone can work from." Some scientists, including Daley, said that they were disappointed with the exclusion of embryos derived for research purposes, but pointed out that the agency intends to revisit the guidelines as the science evolves. The NIH guidelines depart in one significant way from existing National Academy of Sciences standards; they do not require consent from gamete donors — only from the couple seeking in vitro fertilization services. The guidelines respond to an executive order issued in March by President Barack Obama (see Nature 458, 130–131; 2009), who lifted restrictions imposed by President George W. Bush on 9 August 2001. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Flu jabs urged for developing countries
  - Nature 460(7252):156-157 (2009)
  Move should spur demand for vaccines and keep production facilities running. Boosting demand could help vaccine manufacturers keep their facilities open.Novartis AG Influenza experts are recommending an extensive vaccination programme against seasonal flu in developing countries, in part to boost demand for vaccines so that firms can ramp up production to cope with pandemics. The message came from scientists and policy-makers who met on 2–3 July in Siena, Italy, to assess the gaps in their knowledge about the current H1N1 pandemic virus. The governments of many developing countries remain to be convinced that flu is a major danger for their citizens relative to other health problems, says Abdullah Brooks of the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh. Yet Brooks presented research showing that around one-third of pneumonia deaths in children younger than 2 years old in his region can be attributed to the influenza virus. According to the United Nations agency UNICEF, pneumonia kills more than 2 million children under the age of five each year — more than any other disease. At the meeting, experts recommended that pilot studies be conducted in developing countries to measure the prevalence of flu virus in sick children, and to assess how much a flu-vaccination programme would reduce the burden of disease in the countries. UNICEF, health charities and the governments of rich nations would probably be approached for financial support. As well as providing a major public-health benefit, the effort could create a larger, more stable market for seasonal flu vaccines in the future. "A few months ago we were discussing whether we would need to close some of our manufacturing plants because we were losing so much money on flu vaccines," says Rino Rappuoli, head of vaccine research at Novartis in Siena, adding that the current H1N1 pandemic has helped to avert any closures as governments race to stock up on vaccines. For example, the firm was awarded US$289 million by the US Department of Health and Human Services (HHS) in Bethesda, Maryland, in May to produce H1N1 vaccine antigen as well as an adjuvant to amplify the immune response to the vaccine, thus reducing the amount of antigen needed in each shot and stretching manufacturing-plant capacity. Other vaccine companies, including GlaxoSmithKline, Sanofi Pasteur, CSL Biotherapies and MedImmune, will also benefit from $643 million in HHS orders. The US Food and Drug Administration (FDA) has yet to approve any flu vaccines that contain an adjuvant, a cautious response to the possibility that adjuvants could trigger autoimmune disease on very rare occasions. Yet in 2000, the European Medicines Agency approved Novartis's seasonal flu vaccine Fluad, which contains MF59 — an adjuvant based on squalene, a complex hydrocarbon that is the biochemical precursor to steroids. Novartis says that it has sold 45 million vaccination shots containing MF59, and that no side effects have been reported other than occasional inflammation at the injection site. "It isn't really clear what additional safety data the FDA could be waiting for," says Peter Palese, a virologist at Mount Sinai School of Medicine in New York. And a study published earlier this year has shown that MF59 can broaden the effectiveness of an H5N1 vaccine to tackle several similar viral strains — an effect that could potentially be applied in H1N1 vaccines as we! ll (G. Galli et al. Proc. Natl Acad. Sci. USA 106, 7962–7967; 2009). The consensus of the meeting was that H1N1 vaccines, which could be given to billions of people this year, should contain an adjuvant. These vaccination programmes will provide a unique opportunity to identify any extremely rare side effects, says virologist Albert Osterhaus of the University of Rotterdam, the Netherlands, as long as they have "mechanisms to monitor all cases of autoimmune disease to see if the vaccine is really to blame." Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Czech researchers angry over government changes
  - Nature 460(7252):157 (2009)
  Scientists in the Czech Republic are up in arms over drastic changes in the national science-funding system that they say will damage basic research in the long term. Starting next year, core funding for Czech universities and research institutes will be allocated according to rigorous metrics.
• Developing nations tackle climate
  - Nature 460(7252):158-159 (2009)
  Following up on a non-binding pledge to halve its emissions by mid-century, the Mexican government is finalizing regulations that would curb the country's projected emissions by more than 6% over the next three years. The goal of the regulatory programme, driven by President Felipe Calderón, is to demonstrate actual emissions reductions — totalling 50 million tonnes — before his government leaves office in 2012.
• Iran presidential candidate speaks out
  - Nature 460(7252):160 (2009)
  2005 contender Mostafa Moin talks about how the international science community can help Iran. N. TAVAKOLIAN/POLARIS/EYEVINE Biomedical researcher Mostafa Moin was a reformist candidate in Iran's 2005 presidential elections, following which Mahmoud Ahmadinejad became president. In a 2006 interview with Nature, Moin, a former minister for higher education and for science, argued that building a stronger civil and democratic society in Iran was key to the country's scientific development and it becoming a knowledge-based society. In an exclusive new interview, he discusses where the current situation leaves those ambitions. Scientific activity has stagnated. Students and young scientists have been discouraged. Pressure has been exerted on scientific forums and centres, and academic freedom restricted. The brain drain of elites has worsened. Administrations have been massively populated with people from the military and the security forces. We have an economic recession; destruction of ethical norms and public culture; and the scientific, political and cultural isolation of Iran in the international community. These are among the achievements of Ahmadinejad. Iranian scientists abroad have made, and will continue to make, a constructive contribution by throwing light on the false, suppressive and anti-development policies of Ahmadinejad and his government. The huge scientific capacity of Iranians abroad could also serve well in any serious effort to develop Iran, should a foresighted and compassionate government be established. Prominent universities and scientists worldwide can help through legitimate criticism of the Iranian government's treatment of students, academics, scientists and the people of Iran; its violations of citizens' constitutional rights and academic freedom. I would like to say to my scientific colleagues wherever they are that while Iran, an ancient civilization, has its own cultural background and national interests, the nation and its academics wish to be productive and constructive members of the international community. They reject government adventurism and the creation of a climate of tension internationally. Yes. The recent growth in Iranian women's and young people's political and social awareness has set the stage for their current demands for greater civil liberties, and structural and democratic reforms. The outcome of the 2005 presidential election, combined with the subsequent mismanagement of the government, has catalysed this process — and explains the 85% voter turnout in last month's presidential election, and the demand for change. The youth, and in particular the supporters of the reformist candidate Mir Hossein Mousavi, played a major role in creating the extraordinary enthusiasm and motivation surrounding the elections. I remain optimistic as to the role, and the movement, of Iran's youth. Iran's nuclear issue has become both a political problem and an issue used for domestic political ends, resulting in an artificially tense atmosphere at the international level. But a government that derives its authority from a democratic election is better placed to also build trust at the international level — with a view to exploiting nuclear energy legally and peacefully, to both support the national interest and strengthen international cooperation. I formally protested the illegitimacy and distortion of the first round and called for a ballot recount, but unfortunately the Council of Guardians rejected this request. Distrust towards the outcome of the recent elections has, I think, its roots in doubts with respect to the earlier election. My main mottos in the 2005 election were for the construction of a modern Iran through democracy, scientific development of the country and peace in the world. Fulfilment of the same remains among my basic ideals. ADVERTISEMENT There can be no grounds for a national reconciliation in an atmosphere of public distrust. Trust and transparency must first be established by proper examination of the complaints of the presidential candidates. In any case, it seems inevitable that Iran must move towards a political system based on democracy, justice and moderation. Click here Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• When Earth greened over
  - Nature 460(7252):161 (2009)
  A thick, green carpet of photosynthetic life, on the scale of that seen today, exploded across Earth 850 million years ago — much earlier than thought — a new study suggests. The matting — a mixture of algae, mosses and fungi — would have fixed atmospheric carbon into the soil, which would then have washed into the seas for burial, according to the study ("L.
• US AIDS chief lays out priorities
  - Nature 460(7252):162 (2009)
  The new head of the US President's Emergency Plan for AIDS Relief (PEPFAR) takes the reins of the sometimes controversial programme just as the global economic slump has made the job more difficult than ever. The Senate confirmed physician Eric Goosby as US global AIDS coordinator on 19 June.
• Evolution wins out in Hong Kong curriculum dispute
  - Nature 460(7252):163 (2009)
  
• Japanese diplomat chosen to lead nuclear watchdog
  - Nature 460(7252):163 (2009)
  
• Governments fail to reduce global biodiversity decline
  - Nature 460(7252):163 (2009)
  
• US scientist jailed for sharing sensitive data
  - Nature 460(7252):163 (2009)
  
• US Air Force will continue to share meteor data
  - Nature 460(7252):163 (2009)
  
• Lunar Reconnaissance Orbiter snaps test pictures
  - Nature 460(7252):163 (2009)
  NASA/GSFC/ARIZONA STATE UNIV. All is going smoothly so far for NASA's Lunar Reconnaissance Orbiter, which launched on 18 June. On 2 July it captured its first high-resolution test images of the Moon (pictured right), kicking off a year-long mapping mission. Regular updates from the orbiter can be found on its Twitter feed (http://twitter.com/LRO_NASA). Meanwhile, Nature is twittering the Apollo 11 Moon mission as it happened in real time — 40 years on (http://twitter.com/ApolloPlus40). Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Human genetics: One gene, twenty years
  - Nature 460(7252):164-169 (2009)
  When the cystic fibrosis gene was found in 1989, therapy seemed around the corner. Two decades on, biologists still have a long way to go, finds Helen Pearson. Download a PDF of this story. During the day, Lap-Chee Tsui and Francis Collins were attending a gene-mapping workshop. At night they were scrutinizing the pages churning out of a fax machine they had set up in a dorm room. Their hunt for the cause of cystic fibrosis had reached a gene that looked from its sequence like it might have a role in transporting ions through cell membranes, a process that goes awry in those with the disease. The fax they received that night from Tsui's lab showed that many people who have cystic fibrosis lack three base pairs from both copies of this gene, whereas those without the disease always have at least one copy intact. With that fax, on a rainy night in May 1989, "I was convinced — that was the moment," Collins says. Four months later a four-year-old boy with cystic fibrosis, Danny Bessette, was shown sitting cross-legged on the cover of Science, framed by a rainbow of chromosomes. Inside the magazine, three papers1,2,3 laid out the details of the discovery of the gene responsible for Bessette's condition — the first gene for a human disease discovered without the help of an already-known protein sequence or any clue to its whereabouts. "In this issue … there is a story that does not begin at the beginning or end at the end, but has a very happy middle," wrote Science's editor Daniel Koshland4. "One in 2000 children born each year with a fatal defect now has a greater chance for a happy future." By that stage, news of the finding had already leaked to the media, been the subject of two hastily assembled press conferences and been trumpeted in newspapers worldwide. "It would be difficult to overstate the importance of the cloning of the cystic fibrosis gene," wrote geneticist Peter Go! odfellow in Nature that month5. "The implications of this research are profound: there will be large spin offs in basic biology, especially in cell physiology, but the largest impact will be medical." So far, Goodfellow's prediction has proved wrong, at least as far as medical impact is concerned. As Jack Riordan, who collaborated with Tsui and Collins on the original discovery, puts it: "The disease has contributed much more to science than science has contributed to the disease." This is not to deny that medical progress has been impressive. An American born with cystic fibrosis today has a life expectancy at least ten years longer than one born in 1989 did. Such advancements help explain why Bessette — now 24, and pictured opposite — has a future at all. But many researchers concede that relatively little of that improvement can be laid at the door of the cystic-fibrosis transmembrane regulator gene, or CFTR. Gene therapy — the source of so much of the hope in 1989 — has so far bought no one with this condition a single additional year of life; no therapies targeted at the CFTR protein have yet been approved. Researchers have not even fully agreed on a hypothesis to explain how mutations in the gene cause the condition. But the gene itself "found its way into all departments", says Riordan, leading to progress in fields as diverse as protein trafficking and membrane transport. And the gene-hunting techniques that Tsui, Collins, Riordan and t! heir colleagues pioneered have laid the foundation for a genetic understanding of all human disease. "The disease has contributed much more to science than science has contributed to the disease." Jack Riordan Twenty years, although a long time in the life of a young man such as Bessette, is not the whole story. Several hundred million dollars have been spent trying to find a therapy that directly tackles the molecular defects that underlie cystic fibrosis; Collins, for one, thinks that this means the hopes on which gene therapy never delivered are about to be fulfilled. Like many researchers, he is excited by clinical results coming through on a pair of small molecules that could get mutant versions of the CFTR protein to work properly. Should the molecules be approved, "it will be a pair of home runs, a milestone for all genetic disease", Collins says. And those home runs would never have been hit without the gene and the opportunity to study the protein that needs fixing. "You can paint a direct pathway from the gene discovery [to those drugs]," he says. To call the path direct might be overstating it. Researchers have taken many paths from CFTR, and their travels have shown that behind this gene and every one found since lie dauntingly complex biological stories. "I think one of the lessons of cystic fibrosis is the recognition of the enormous challenge that faces us in human biology," says Riordan, now at the University of North Carolina, Chapel Hill. "It's not like going to the Moon — it's going to Mars." The size of the challenge can sap enthusiasm. "Looking back, it was an important contribution," says Tsui, "but I'm disappointed because at this time, from my own research, I was not able to help very much." Riordan says that he now views "the latest hot gene" with a "jaundiced eye". But one thing that shines through when speaking to these three and other researchers is their continued optimism, their passion and their sense of urgency. "Perhaps," says Collins, "we've taken our blinkers off. Perhaps we couldn't deal wi! th it before, and now we have a lot more tools to dissect the complexity." "It's not that it hasn't worked," says Riordan."It's only been 20 years." Blind beginnings Geneticists have been interested in cystic fibrosis since the disease was first identified in the 1930s. The disease is common in Caucasian populations — about 1 in every 25 people carries a mutated copy — and its pattern of inheritance is straightforwardly Mendelian: those with one mutated gene are healthy carriers; those who inherit two will have the condition. Doctors knew that although the pancreas often fails and the gut is unable to absorb nutrients, the lung is the organ that is crippled with recurrent and persistent infections, "and that's unfortunately the one that kills them", says Richard Boucher, a pulmonary physician and cystic fibrosis researcher at the University of North Carolina. But for decades no one knew exactly what was wrong with the cells, so no one knew what type of gene to look for. Paul Quinton helped change that. As a kid, Quinton had always coughed a lot, and his sweat was so salty that his clothes corroded the wire hangers they dried on. When, in 1965, as a 19-year-old at the University of Austin, Texas, he met a girl and his thoughts turned to marriage, he decided to find out what was wrong with him. The description of cystic fibrosis he found in the medical library fit his symptoms perfectly and he diagnosed himself with a disease that should already have killed him, but that he would spend the rest of his life studying. Quinton collected fresh sweat glands from visitors, from colleagues (Riordan, who visited Quinton's ranch, says he still bears the scars of Quinton's biopsies with a cork borer) and from other people with cystic fibrosis to explore why his sweat, and that of others with the disease, was so salty. In 1982, while working at the University of California, Riverside, an experiment measuring the ability of sodium and chloride to pass through the glands led him to finger a channel that was unable to conduct chloride ions across the epithelium of the skin, and that might also underlie problems in the lungs and the other affected organs6. "I feel silly saying it but I literally jumped up and ran up and down the hall shouting 'Eureka'," says Quinton, who now also works at the University of California, San Diego. "I still get chills; it was one of those moments you get once in a lifetime." The disease is evident when he speaks: he still clears his throat and coughs a lot. Lap-Chee Tsui, Francis Collins and Jack Riordan (left to right) celebrate their 1989 discovery of the cystic fibrosis gene with a patient.CANADIAN CYSTIC FIBROSIS FOUNDATION Quinton's discovery and others like it told geneticists what they should be looking for: a gene that is involved in the movement of chloride, and perhaps other ions, across the epithelium. By now an intense and competitive hunt was under way. It was the 1980s, when the human genetic sequence was largely uncharted territory, and the human genome project was still a twinkle in various eyes, including Collins's. Finding the gene would be a technical and intellectual challenge as well as a medical breakthrough. Until that point, almost all of the genes that had been associated with human diseases had been identified by first isolating the protein responsible. A protein's amino-acid sequence reveals much of the gene's probable nucleotide sequence, and that made pinpointing the gene easier. The few exceptions, such as those found for Duchenne muscular dystrophy and retinoblastoma, were helped by a few patients with chromosomal abnormalities that pointed to the gene's position. For! cystic fibrosis, researchers were working blind: they had no protein and no location. This was to be a big test of new 'reverse genetics' techniques, in which a gene is found by searching for markers in the genome that are consistently inherited with the disease in affected families and using them as signposts to the gene itself. Tsui, then at the Hospital for Sick Children in Toronto, Canada, and now at the University of Hong Kong, was a key player in the hunt; so were Robert Williamson at St Mary's Hospital Medical School in London, and a handful of other researchers. By 1985, several groups7,8,9 had shown that the gene mapped to a region of chromosome seven, but it was still a vast genetic wilderness somewhere between one and two million base pairs wide. In 1987, Williamson announced that he had landed on the gene, but soon after had to admit he had got it wrong. Nevertheless, many groups assumed that Williamson was close and dropped out of the race at that point. Says Collins: "Lap-Chee and I were more stubborn". "Perhaps we couldn't deal with it before, and now we have a lot more tools to dissect the complexity." Francis Collins Collins, then at the University of Michigan in Ann Arbor and until last year the head of the National Human Genome Research Institute in Bethesda, Maryland, met Tsui at that year's meeeting of the American Society of Human Genetics. A few years previously, Collins had described the technique of 'chromosome jumping', a way of leaping across the vast genetic distances from one marker sequence in a region to another that was much faster than the conventional way of chromosome 'walking'10,11. They agreed to collaborate: Collins's lab would bound to new positions, and Tsui's would walk forwards and backwards from the landing points looking for the gene. Two years later, on that rainy night in the dorm room, their fax machine told them they had found it. The Science papers showed that the gene looked like others encoding membrane proteins that transport ions. The three base pairs missing in the vast majority of people with cystic fibrosis eliminated an amino acid at position 508 of the protein's amino-acid sequence, a mutation called ∆F508. "It was exciting times," says Robert Beall, then executive vice-president for medical affairs at the Cystic Fibrosis Foundation in Bethesda, Maryland, and now its director. "We had been at a bottleneck. We didn't know why chloride wasn't getting out of cells, and that gene solved it." The scramble of competition continued as researchers rushed to work with the gene. John Hanrahan at McGill University in Montreal, Quebec, recalls the time he was collaborating with Riordan on a paper for Cell12. Riordan called him to ask him to fax through a figure for the manuscript as he was worried about a scoop from a competing paper at Science. "I raced to the airport in a snowstorm to send the originals by same-day courier, but it was the faxed version that went to press," Hanrahan says. "When people look at the traces they must wonder, 'Why are they so pixelated?'" But Hanrahan, like most researchers, says that the competition was a healthy one, even if it deprived them of a little sleep. "I think a lot of data were published and some mistakes were made, but there was tremendous excitement and the field moved ahead rapidly." From the beginning, the goal was gene therapy. Get a good gene into the patients and they would make the proper protein; with the proper protein they'd be cured. But the path from gene to therapy wasn't smooth. It took more than a year just to get bacteria to produce the protein from the cloned gene, because of 'cryptic' sequences within the gene that prevented the bacteria from expressing it. But by 1993 the first clinical trials were under way. "The expectation was that all you needed to do was get a little bit of stuff to act in the lungs and 'hey presto' you'd have a Nobel prize," says Steven Hyde, who works on cystic fibrosis gene therapy at the University of Oxford, UK. Among other things, the lung, researchers now realize, is just about the worst possible target for such an approach. Its sophisticated defences against infection have evolved precisely to prevent the sort of uptake and expression of foreign material the gene therapists were after. Mike Welsh at the University of Iowa and his colleagues, who in one of the first trials pushed the gene into cells in the nasal passage as a surrogate for those in the lung, later realized that the cells that had taken up the gene were probably damaged during the procedure. "A whole slew of people did similar trials and everyone got a little disillusioned." Hyde says. Disillusionment isn't enough to kill off an idea — but death is. In 1999, a severe immunological reaction killed Jesse Gelsinger in a gene-therapy trial for an inherited liver disease, casting a pall over the entire field. In the United States, the field has never fully recovered. In other countries — the United Kingdom and France, for example — researchers have been much more active in pursuing the technique. Around the same time, Beall decided to turn the gene into a way to find a therapy, rather than being the therapy itself. He wanted to take advantage of new tools coming online for high-throughput drug screening. Researchers inserted the gene into cells, expressed the mutated protein, then screened for drugs that could correct the way the protein is made or the way it works. "People thought we were crazy," Beall says. What started as US$2-million grant in 1999 has turned into an $76-million programme, and Beall proudly points to a chart showing the drugs working their way through the pipeline as a result. By far the most common mutation is ∆F508. It causes the protein to fold up poorly, and a drug known as a corrector is needed to help it fold correctly and get to the membrane it needs to sit in. Other mutations — there are now more than 1,500 known in the gene — require different approaches. Versions of the gene in which protein translation stops short need drugs to override the stop signal. Then there are proteins that get made, fold up and reach the membrane but just don't work properly. They need what are called potentiators. In March 2008, investigators presented results from a phase II trial of the potentiator VX-770 to a room of several hundred researchers at a meeting of the Cystic Fibrosis Foundation. Just two weeks of treatment in 20 people with a rare mutation called G551D had dramatically lowered some people's sweat chloride and produced some improvement in lung function — something that clinicians found particularly remarkable given the battered state of their airways. "When they showed those data and I saw the emotions from those physicians, it was unbelievable," Beall says. "It was the most emotional time since the discovery of that gene. It's telling you we can change the course of this disease." Collins agrees. "It was wildly better than even the most optimistic perspective for a small-molecule trial," he says. Phase III trials of VX-770, developed by Vertex Pharmaceuticals of Cambridge, Massachusetts, are now recruiting patients. Beall and others say that the drug might find a muc! h wider market if it is also used in people with other mutations, including ∆F508, in conjunction with a corrector. That corrector could be another Vertex drug called VX-809, which is just starting phase II trials. A special case Must it take 20 years to get from gene to drug? No. Various things have made cystic fibrosis peculiarly difficult. One has been a lack of a complete understanding of how the CFTR protein leads to the disease. Many think that the defective channel causes the lungs to absorb too much water; others have argued that the primary problem is an incorrect ion composition that disables the lungs' normal defences against infection. This debate became so fierce it was described as the 'salt wars'. At least part of the problem seems to lie in another ion channel that CFTR interacts with. "If you ask 20 people you'll get 20 different hypotheses," says Welsh. "Everybody's got their favourite — I think we don't know." "If you ask 20 people you'll get 20 different hypotheses. Everybody's got their favourite." Mike Welsh Then there are some purely technical problems. Mice with mutated versions of CFTR have few obvious lung problems and thus make poor models of the disease. (The models have, however, revealed something about why the mutated gene is so common — see 'A killer advantage'.) The CFTR protein is huge and is embedded in a membrane, making its structure difficult to determine with X-ray crystallography; plus the fact that airway cells tend to contain only a hundred or so copies of the protein, so there is very little of the stuff to play with. Together, these mean that no one has been able to resolve a complete high-resolution structure for the protein, which has hampered understanding of how it works and the design of drugs. Other genes have had it easier. Collins points to the gene for Hutchinson–Gilford Progeria Syndrome (HGPS), an extremely rare single-gene disease that causes young children to shows signs of old age. The gene was discovered by Collins's team at the National Human Genome Research Institute in 2003 (ref. 13) and by another group in France14, and a treatment based on it went into a phase II clinical trial in 2007 — a notably fast pace of translation. Collins puts much of the speed down to serendipity. The mutated protein was an extremely well-studied one called lamin A, and a cancer drug that had already reached late-stage clinical trials was found to work against the mutated protein, saving some laborious drug screening and safety testing. What's more, the task required of the drug is simpler. Drugs for cystic fibrosis have to compensate for or restore the function of a mutated protein, whereas those for HGPS simply have to block the action of one that has turned toxic. More than 1,500 mutations of various types have been found in the CFTR gene.CYSTIC FIBROSIS MUTATION DATABASE The discovery of CFTR deserves at least some credit in the HGPS story, though, as it does for accelerating the pace of translation after almost every gene discovery since 1989. That's because hard work and mistakes made in this field have saved effort in every other. "If you found a new gene tomorrow you could compress those 20 years hugely because of what's been done with cystic fibrosis," says Hyde. And gene therapy may yet prove possible for cystic fibrosis. In 2001, the Cystic Fibrosis Trust in Bromley, UK, asked Hyde's group and two others in Britain that were still working in the field to stop competing and start working together. They complied and have spent several years and around £30 million (US$49 million) working methodically through some of the problems — such as devising better ways to measure changes in lung function. Earlier this year, researchers at Imperial College London treated the first of 27 people with cystic fibrosis in what is expected to become the largest gene-therapy trial ever undertaken for the disease. The aim is to test whether the gene can be delivered safely, in a fatty particle called a liposome. If it is, the researchers will scale up to a 100-person randomized controlled trial to see whether it is effective. "I think we have now tempered the optimism of the early 90s with a heavy dose of realism," says Eric Alton, who directs the tr! ial. Clinical changes Throughout this time there have been dramatic changes in the way that cystic fibrosis is treated in the clinic. In 1994, Genentech introduced Pulmozyme (dornase alfa), an enzyme that breaks up some of the lung-clogging mucus that encourages infections. A few years later, aerosolized antibiotics were introduced to fight these infections more aggressively. Earlier this decade doctors in Australia started noticing that their patients who surfed felt better during the surf season — leading researchers to test the idea that the daily inhalation of super-salty water, called hypertonic saline, could help lubricate the lungs. It did15,16, and this is now standard therapy for many patients. Not all of them benefit from this approach, though: Bessette stopped taking hypertonic saline after a few years because it made him cough blood from a burst vessel in his lung. Pulmozyme does feature in his 40–50 pill-per-day regime, and he anticipates more advances that might improve his lung! function. "Yes, we all hope for a cure, but if they can just help us stay healthy that in itself is quite an accomplishment," Bessette says. "We have now tempered the optimism of the early '90s with a heavy dose of realism." Eric Alton Quinton, too, follows a rigorous regimen, inhaling hypertonic saline every day and taking intravenous antibiotics every few months. He rides his bike to work, but he can't run far or play basketball. Both upper lobes of his lung have been removed because of chronic inflammation. For someone born when he was, though, things could have been much worse — and thanks to research into the CFTR gene, Quinton knows why they're not. Although he has one copy of ∆F508, the mutation in his other gene, R17H, has relatively mild effects. He found this out when, several years after the gene was found, Garry Cutting at Johns Hopkins University School of Medicine in Baltimore, Maryland, analysed his genes as part of work on genetic testing for the disease. These tests are "probably the most common form of genetic testing in the world today", says Cutting, who now drafts clinical-testing guidelines for cystic fibrosis. In the United States and some European countries many pregnant women and their partners are offered testing for mutations in CFTR, forcing clinical geneticists to confront issues about genetic counselling and genetic risk that are likely to escalate as more and more genes become as well studied. Working with a gene that has so many mutations, most of which are still little understood, underlines the futility of testing for something with no known clinical severity and therefore no rational basis on which to make decisions about ending a pregnancy. "The agony I've seen for some couples where one is a carrier and one has a mutation of unknown significance," Cutting says, "it is just immense." Newborn screening, which is also commonplace in some countries and typically involves a biochemical test followed by a genet! ic one, throws up similar issues for clinicians who may be unable to advise parents how severely their child is likely to be affected. New studies are making the molecular landscape look even more complicated. Two years ago, the Cystic Fibrosis Foundation helped to launch a North American consortium to search for 'modifier genes' at work in the disease that might explain why some people with two copies of the ∆F508 mutation die at 16 whereas others have pretty healthy lungs into their 20s. The consortium members recently screened more than 4,500 people to look for genetic variations that are strongly linked with severity of the disease, says consortium member Michael Knowles from the University of North Carolina. One of the strongest variants to have emerged from previous studies of modifier genes, called TCF7L2, is also thought to strongly predispose carriers to type 2 diabetes17. The link may lie in the failure of the pancreas and consequent diabetes that cystic fibrosis frequently causes. Results such as these suggest that once the CFTR gene and its protein are viewed in context, cystic fibrosis will spiral into a new realm of dizzying complexity. If studies of one gene have expanded to fill 20 years, how many years can be filled once the tens or even hundreds of modifier genes are factored in, let alone whatever other influences there may be outside the genetic code? For Knowles, though, the results present an exciting opportunity rather than a daunting complexity. He sees cystic fibrosis as "leading the way" for researchers investigating more genetically complex diseases. If he and others can get to grips with the numerous mutations in CFTR and its modifiers, they say that cystic fibrosis could serve as a case study for personalized medicine. Newborns identified with the disease could have their CFTR gene and other major modifier genes analysed to choose the most appropriate therapies — assuming, that is, that such a range exists by that point. Although he has discovered molecular truths about himself that he might never have expected, "it would be hard for me to say I have benefited from the work I've done", Quinton says. Nonetheless, he, Riordan and others whose careers in this field stretch back farther than 1989 are still hopeful. Like most researchers and clinicians, they are focused on what they can achieve in the next 2–5 years, not what they should have achieved already. "I'd say don't give up," Quinton says. "This really is the only solution. As we succeed on one platform, it will make it much easier to succeed on another." ADVERTISEMENT "It's a helluva lot more complicated than we realized," he says. "We went to the Moon in '69 and the conceit was we could do anything — we corrected polio, we wiped out smallpox. But when you start taking the system apart we've been really naive." "But that's biology — it's not fair." * References * Rommens, J. M. et al. Science 245, 1059-1065 (1989). * Riordan, J. R. et al. Science 245, 1066-1073 (1985). * Kerem, B. et al. Science 245, 1073-1080 (1985). * Koshland, D. E. Science 245, 1029 (1989). * Goodfellow P. N. Nature 341, 102-103 (1989). * Quinton, P. M. Nature 301, 421-422 (1983). * Tsui, L.-C. , et al. Science 230, 1054-1057 (1985). * Knowlton, R. G. et al. Nature 318, 380-382 (1985). * Wainwright, B. J. et al. Nature 318, 384-385 (1985). * Collins, F. S. & Weissman, S. M. Proc. Natl Acad. Sci. USA 81, 6812-6816 (1984). * Collins, F. S. et al. Science 235, 1046-1049 (1987). * Kartner, N. et al. Cell 64, 681-691 (1991). * Eriksson, M. et al. Nature 423, 293-298 (2003). * De Sandre-Giovannoli, A. et al. Science 300, 2055 (2003). * Elkins, M. R. et al. N. Engl. J. Med. 354, 229-240 (2006). * Donaldson, S. H. N. Engl. J. Med. 354, 241-250 (2006). * Blackman, S. M. et al. Diabetologia (in the press). * Jorde, L. B. & Lathrop, G. M. Am. J. Hum. Genet. 42, 808-815 (1988). * Pier, G. B. et al. Nature 393, 79-82 (1998). 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• Science education: Reading, writing and nanofabrication
  - Nature 460(7252):171-172 (2009)
  The timetable for 15-year-old students at Yokohama Science Frontier High School (YSFH) can be busy. Before break, they might grow single-layer carbon nanotubes in argon gas and evaluate them with micro-Raman spectroscopy.
• Interrogation: has abuse been reduced by psychologists?
  - Nature 460(7252):173 (2009)
  Your Editorial 'Responsible interrogation' (Nature 459, 300; 2009), on involvement by psychologists in interrogation at detention centres, was misleading in several respects. You defend psychologists' participation as a protection for detainees, provided that the professional "adheres to, and is held accountable to, the most fundamental medical ethic of all: do no harm".
• Birds and people both depend on China's wetlands
  - Nature 460(7252):173 (2009)
  Following your News story 'Putting China's wetlands on the map' (Nature 458, 134; 2009) and the related Correspondence 'Time for China to restore its natural wetlands' (Nature 459, 321; 2009), we also wish to stress the need to manage and protect China's existing wetlands, and to remind delegates to the International Congress for Conservation Biology, starting in Beijing on 11 July, of these globally important issues.
• Route for political interests to weaken conservation
  - Nature 460(7252):173 (2009)
  The public often question the validity and economic implications of scientific assessments of biological diversity. Various interest groups, in particular, complain because they weren't consulted.
• Too small to overlook
  - Nature 460(7252):174 (2009)
  Voluntary reporting of nanomaterials by industry has failed. Mandatory measures are a step in the right direction, but the field needs more data sharing and oversight, say Andrew Maynard and David Rejeski.
• Darwin's last laugh
  - Nature 460(7252):175 (2009)
  We must look for mental commonalities between humans and other animals to understand the minds of either, says Frans B. M. de Waal, rebutting a recent claim to the contrary.
• Orderly anarchists
  - Nature 460(7252):176-177 (2009)
  The profit motive has led pirates to come up with surprisingly democratic and egalitarian social structures. It is a lesson in bottom-up economics, explains Michael Shermer.
• Solo journey to a fifth dimension
  - Nature 460(7252):177 (2009)
  An opera about string theory and five-dimensional space is hard to imagine. But one premiered recently in Paris.
• Where they lived
  - Nature 460(7252):178 (2009)
  When Einstein died in 1955, The Washington Post published a cartoon that has since become famous. It shows Earth floating among the other planets and heavenly bodies, with a sign tacked on to it bearing the words "ALBERT EINSTEIN LIVED HERE".
• Fresh formulae for portraiture
  - Nature 460(7252):179 (2009)
  New portraits of physicists David Brewster and Peter Higgs show that naturalistic images can find distinct ways to reflect scientists and their work, Martin Kemp explains.
• Evolutionary biology: Microbes exploit groundhog day
  - Nature 460(7252):181 (2009)
  Can microorganisms learn from history? When a sequence of environmental changes is repeated, natural selection might select for responses that enable the microbes to prepare for later challenges in the sequence.
• Vision: New light on allergy receptor
  - Nature 460(7252):182-183 (2009)
  A receptor usually found on immune cells implicated in allergy turns out to be a diagnostic marker and promising treatment target for a degenerative eye disease. Curiously, its role in the eye seems to be unrelated to inflammation.
• Organic chemistry: Forgotten hydrocarbons prepared
  - Nature 460(7252):183-184 (2009)
  Dendralene hydrocarbons have a reputation for being difficult — it seemed that these molecules couldn't easily be made. A practical synthesis of dendralenes opens them up for study, and reveals some surprises.
• Immunology: B cells break the rules
  - Nature 460(7252):184-186 (2009)
  A study of lymphocytes that lack a DNA-repair enzyme challenges long-standing dogma about the spatial separation of processes that rearrange antibody genes, and provides clues about the origins of B-cell cancers.
• Materials science: Nanotubes sorted using DNA
  - Nature 460(7252):186-187 (2009)
  A vast number of DNA sequences are possible, and so finding the few that bind to a particular non-DNA entity is a daunting task. A systematic search algorithm has found sequences that target specific carbon nanotubes.
• Quantum information: Circuits that process with magic
  - Nature 460(7252):187-188 (2009)
  Practical quantum computation will require a scalable, robust system to generate and process information with precise control. This is now possible using a superconducting circuit and a little quantum magic.
• Obituary: Herbert Frank York (1921–2009)
  - Nature 460(7252):189 (2009)
  A voice of calm in the era of nuclear weapons.
• The possibility of impossible cultures
  - Nature 460(7252):190-196 (2009)
  Insights from evolutionary developmental biology and the mind sciences could change our understanding of the human capacity to think and the ways in which the human mind constrains cultural expressions.
• Synthesis at the molecular frontier
  - Nature 460(7252):197-201 (2009)
  Driven by remarkable advances in the understanding of structure and reaction mechanisms, organic synthesis will be increasingly directed to producing bioinspired and newly designed molecules.
• Biomarkers in psychiatry
  - Nature 460(7252):202-207 (2009)
  The use of biomarkers to predict human behaviour and psychiatric disorders raises social and ethical issues, which must be resolved by collaborative efforts.
• Toxicology for the twenty-first century
  - Nature 460(7252):208-212 (2009)
  The testing of substances for adverse effects on humans and the environment needs a radical overhaul if we are to meet the challenges of ensuring health and safety.
• The role of black holes in galaxy formation and evolution
  - Nature 460(7252):213-219 (2009)
  Virtually all massive galaxies, including our own, host central black holes ranging in mass from millions to billions of solar masses. The growth of these black holes releases vast amounts of energy that powers quasars and other weaker active galactic nuclei. A tiny fraction of this energy, if absorbed by the host galaxy, could halt star formation by heating and ejecting ambient gas. A central question in galaxy evolution is the degree to which this process has caused the decline of star formation in large elliptical galaxies, which typically have little cold gas and few young stars, unlike spiral galaxies.
• Adaptive prediction of environmental changes by microorganisms
  - Nature 460(7252):220-224 (2009)
  Natural habitats of some microorganisms may fluctuate erratically, whereas others, which are more predictable, offer the opportunity to prepare in advance for the next environmental change. In analogy to classical Pavlovian conditioning, microorganisms may have evolved to anticipate environmental stimuli by adapting to their temporal order of appearance. Here we present evidence for environmental change anticipation in two model microorganisms, Escherichia coli and Saccharomyces cerevisiae. We show that anticipation is an adaptive trait, because pre-exposure to the stimulus that typically appears early in the ecology improves the organism's fitness when encountered with a second stimulus. Additionally, we observe loss of the conditioned response in E. coli strains that were repeatedly exposed in a laboratory evolution experiment only to the first stimulus. Focusing on the molecular level reveals that the natural temporal order of stimuli is embedded in the wiring of th! e regulatory network—early stimuli pre-induce genes that would be needed for later ones, yet later stimuli only induce genes needed to cope with them. Our work indicates that environmental anticipation is an adaptive trait that was repeatedly selected for during evolution and thus may be ubiquitous in biology.
• CCR3 is a target for age-related macular degeneration diagnosis and therapy
  - Nature 460(7252):225-230 (2009)
  Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization! , which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.
• Mechanisms promoting translocations in editing and switching peripheral B cells
  - Nature 460(7252):231-236 (2009)
  Variable, diversity and joining gene segment (V(D)J) recombination assembles immunoglobulin heavy or light chain (IgH or IgL) variable region exons in developing bone marrow B cells, whereas class switch recombination (CSR) exchanges IgH constant region exons in peripheral B cells. Both processes use directed DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ). Errors in either V(D)J recombination or CSR can initiate chromosomal translocations, including oncogenic IgH locus (Igh) to c-myc (also known as Myc) translocations of peripheral B cell lymphomas. Collaboration between these processes has also been proposed to initiate translocations. However, the occurrence of V(D)J recombination in peripheral B cells is controversial. Here we show that activated NHEJ-deficient splenic B cells accumulate V(D)J-recombination-associated breaks at the lambda IgL locus (Igl), as well as CSR-associated Igh breaks, often in the same cell. Moreover, Igl and I! gh breaks are frequently joined to form translocations, a phenomenon associated with specific Igh–Igl co-localization. Igh and c-myc also co-localize in these cells; correspondingly, the introduction of frequent c-myc DSBs robustly promotes Igh–c-myc translocations. Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours.
• Type IIn supernovae at redshift z 2 from archival data
  - Nature 460(7252):237-239 (2009)
  Supernovae have been confirmed to redshift z 1.7 (refs 1, 2) for type Ia (thermonuclear detonation of a white dwarf) and to z 0.7 (refs 1, 3–5) for type II (collapse of the core of the star). The subclass type IIn (ref. 6) supernovae are luminous7, 8, 9 core-collapse explosions of massive stars8, 9, 10, 11 and, unlike other types, are very bright in the ultraviolet12, 13, 14, 15, which should enable them to be found optically at redshifts z 2 and higher14, 16. In addition, the interaction of the ejecta with circumstellar material creates strong, long-lived emission lines that allow spectroscopic confirmation of many events of this type at z 2 for 3–5 years after explosion (ref. 14). Here we report three spectroscopically confirmed type IIn supernovae, at redshifts z = 0.808, 2.013 and 2.357, detected in archival data using a method14 designed to exploit these properties at z 2. Type IIn supernovae directly probe the formation of massive stars at high redshift.! The number found to date is consistent with the expectations of a locally measured17 stellar initial mass function, but not with an evolving initial mass function proposed18, 19, 20 to explain independent observations at low and high redshift.
• Demonstration of two-qubit algorithms with a superconducting quantum processor
  - Nature 460(7252):240-244 (2009)
  Quantum computers, which harness the superposition and entanglement of physical states, could outperform their classical counterparts in solving problems with technological impact—such as factoring large numbers and searching databases1, 2. A quantum processor executes algorithms by applying a programmable sequence of gates to an initialized register of qubits, which coherently evolves into a final state containing the result of the computation. Building a quantum processor is challenging because of the need to meet simultaneously requirements that are in conflict: state preparation, long coherence times, universal gate operations and qubit readout. Processors based on a few qubits have been demonstrated using nuclear magnetic resonance3, 4, 5, cold ion trap6, 7 and optical8 systems, but a solid-state realization has remained an outstanding challenge. Here we demonstrate a two-qubit superconducting processor and the implementation of the Grover search and Deutsch–J! ozsa quantum algorithms1, 2. We use a two-qubit interaction, tunable in strength by two orders of magnitude on nanosecond timescales, which is mediated by a cavity bus in a circuit quantum electrodynamics architecture9, 10. This interaction allows the generation of highly entangled states with concurrence up to 94 per cent. Although this processor constitutes an important step in quantum computing with integrated circuits, continuing efforts to increase qubit coherence times, gate performance and register size will be required to fulfil the promise of a scalable technology.
• Direct observation of correlations between individual photon emission events of a microcavity laser
  - Nature 460(7252):245-249 (2009)
  Lasers are recognized for coherent light emission, the onset of which is reflected in a change in the photon statistics1. For many years, attempts have been made to directly measure correlations in the individual photon emission events of semiconductor lasers2, 3. Previously, the temporal decay of these correlations below or at the lasing threshold was considerably faster than could be measured with the time resolution provided by the Hanbury Brown/Twiss measurement set-up4 used. Here we demonstrate a measurement technique using a streak camera that overcomes this limitation and provides a record of the arrival times of individual photons. This allows us to investigate the dynamical evolution of correlations between the individual photon emission events. We apply our studies to micropillar lasers5 with semiconductor quantum dots2, 3, 6, 7, 8 as the active material, operating in the regime of cavity quantum electrodynamics9. For laser resonators with a low cavity qualit! y factor, Q, a smooth transition from photon bunching to uncorrelated emission with increasing pumping is observed; for high-Q resonators, we see a non-monotonic dependence around the threshold where quantum light emission can occur. We identify regimes of dynamical anti-bunching of photons in agreement with the predictions of a microscopic theory that includes semiconductor-specific effects.
• DNA sequence motifs for structure-specific recognition and separation of carbon nanotubes
  - Nature 460(7252):250-253 (2009)
  Single-walled carbon nanotubes (SWNTs) are a family of molecules that have the same cylindrical shape but different chiralities1. Many fundamental studies and technological applications2 of SWNTs require a population of tubes with identical chirality that current syntheses cannot provide. The SWNT sorting problem—that is, separation of a synthetic mixture of tubes into individual single-chirality components—has attracted considerable attention in recent years. Intense efforts so far have focused largely on, and resulted in solutions for, a weaker version of the sorting problem: metal/semiconductor separation3, 4. A systematic and general method to purify each and every single-chirality species of the same electronic type from the synthetic mixture of SWNTs is highly desirable, but the task has proven to be insurmountable to date. Here we report such a method, which allows purification of all 12 major single-chirality semiconducting species from a synthetic mixture,! with sufficient yield for both fundamental studies and application development. We have designed an effective search of a DNA library of 1060 in size, and have identified more than 20 short DNA sequences, each of which recognizes and enables chromatographic purification of a particular nanotube species from the synthetic mixture. Recognition sequences exhibit a periodic purine–pyrimidines pattern, which can undergo hydrogen-bonding to form a two-dimensional sheet, and fold selectively on nanotubes into a well-ordered three-dimensional barrel. We propose that the ordered two-dimensional sheet and three-dimensional barrel provide the structural basis for the observed DNA recognition of SWNTs.
• Late Cretaceous seasonal ocean variability from the Arctic
  - Nature 460(7252):254-258 (2009)
  The modern Arctic Ocean is regarded as a barometer of global change and amplifier of global warming1 and therefore records of past Arctic change are critical for palaeoclimate reconstruction. Little is known of the state of the Arctic Ocean in the greenhouse period of the Late Cretaceous epoch (65–99 million years ago), yet records from such times may yield important clues to Arctic Ocean behaviour in near-future warmer climates. Here we present a seasonally resolved Cretaceous sedimentary record from the Alpha ridge of the Arctic Ocean. This palaeo-sediment trap provides new insight into the workings of the Cretaceous marine biological carbon pump. Seasonal primary production was dominated by diatom algae but was not related to upwelling as was previously hypothesized2. Rather, production occurred within a stratified water column, involving specially adapted species in blooms resembling those of the modern North Pacific subtropical gyre3, or those indicated for the ! Mediterranean sapropels4. With increased CO2 levels and warming currently driving increased stratification in the global ocean5, this style of production that is adapted to stratification may become more widespread. Our evidence for seasonal diatom production and flux testify to an ice-free summer, but thin accumulations of terrigenous sediment within the diatom ooze are consistent with the presence of intermittent sea ice in the winter, supporting a wide body of evidence for low temperatures in the Late Cretaceous Arctic Ocean6, 7, 8, rather than recent suggestions of a 15 °C mean annual temperature at this time9.
• Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment
  Naveiras O Nardi V Wenzel PL Hauschka PV Fahey F Daley GQ - Nature 460(7252):259-263 (2009)
  Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow1, 2, 3. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia4. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adi! pocytes5, and in mice treated with the peroxisome proliferator-activated receptor- inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis6, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.
• CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation
  - Nature 460(7252):264-268 (2009)
  Toll-like receptors (TLRs) are the best characterized pattern recognition receptors1. Individual TLRs recruit diverse combinations of adaptor proteins, triggering signal transduction pathways and leading to the activation of various transcription factors, including nuclear factor B, activation protein 1 and interferon regulatory factors2. Interleukin-2 is one of the molecules produced by mouse dendritic cells after stimulation by different pattern recognition receptor agonists3, 4, 5, 6. By analogy with the events after T-cell receptor engagement leading to interleukin-2 production, it is therefore plausible that the stimulation of TLRs on dendritic cells may lead to activation of the Ca2+/calcineurin and NFAT (nuclear factor of activated T cells) pathway. Here we show that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase C2 activation, influx of extracellular Ca2+ and calcineurin-dependent nuclear NFAT transloc! ation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiated dendritic cells, an event that is essential for maintaining self-tolerance and preventing autoimmunity7, 8. Consequently, blocking this pathway in vivo causes prolonged dendritic cell survival and an increase in T-cell priming capability. Our findings reveal novel aspects of molecular signalling triggered by LPS in dendritic cells, and identify a new role for CD14: the regulation of the dendritic cell life cycle through NFAT activation. Given the involvement of CD14 in disease, including sepsis and chronic heart failure9, 10, the discovery of signal transduction pathways activated exclusively via CD14 is an important step towards the development of potential treatments involving interference with CD14 functions.
• T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes
  - Nature 460(7252):269-273 (2009)
  Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process1. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4+ T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1 release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with select! ed ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4+ T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.
• Unlimited multistability in multisite phosphorylation systems
  - Nature 460(7252):274-277 (2009)
  Reversible phosphorylation on serine, threonine and tyrosine is the most widely studied posttranslational modification of proteins1, 2. The number of phosphorylated sites on a protein (n) shows a significant increase from prokaryotes, with n 7 sites, to eukaryotes, with examples having n 150 sites3. Multisite phosphorylation has many roles4, 5 and site conservation indicates that increasing numbers of sites cannot be due merely to promiscuous phosphorylation. A substrate with n sites has an exponential number (2n) of phospho-forms and individual phospho-forms may have distinct biological effects6, 7. The distribution of these phospho-forms and how this distribution is regulated have remained unknown. Here we show that, when kinase and phosphatase act in opposition on a multisite substrate, the system can exhibit distinct stable phospho-form distributions at steady state and that the maximum number of such distributions increases with n. Whereas some stable distributi! ons are focused on a single phospho-form, others are more diffuse, giving the phospho-proteome the potential to behave as a fluid regulatory network able to encode information and flexibly respond to varying demands. Such plasticity may underlie complex information processing in eukaryotic cells8 and suggests a functional advantage in having many sites. Our results follow from the unusual geometry of the steady-state phospho-form concentrations, which we show to constitute a rational algebraic curve, irrespective of n. We thereby reduce the complexity of calculating steady states from simulating 3 2n differential equations to solving two algebraic equations, while treating parameters symbolically. We anticipate that these methods can be extended to systems with multiple substrates and multiple enzymes catalysing different modifications, as found in posttranslational modification 'codes'9 such as the histone code10, 11. Whereas simulations struggle with exponentially increa! sing molecular complexity, mathematical methods of the kind de! veloped here can provide a new language in which to articulate the principles of cellular information processing12.
• A mechanism linking extra centrosomes to chromosomal instability
  Ganem NJ Godinho SA Pellman D - Nature 460(7252):278-282 (2009)
  Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes1, 2, 3, 4. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that e! xtra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient 'multipolar spindle intermediate' in which merotelic kinetochore–microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer.
• Uniparental expression of PolIV-dependent siRNAs in developing endosperm of Arabidopsis
  - Nature 460(7252):283-286 (2009)
  Most eukaryotes produce small RNA (sRNA) mediators of gene silencing that bind to Argonaute proteins and guide them, by base pairing, to an RNA target. MicroRNAs (miRNAs) that normally target messenger RNAs for degradation or translational arrest are the best-understood class of sRNAs. However, in Arabidopsis thaliana flowers, miRNAs account for only 5% of the sRNA mass and less than 0.1% of the sequence complexity. The remaining sRNAs form a complex population of more than 100,000 different small interfering RNAs (siRNAs) transcribed from thousands of loci1, 2, 3, 4, 5. The biogenesis of most of the siRNAs in Arabidopsis are dependent on RNA polymerase IV (PolIV), a homologue of DNA-dependent RNA polymerase II2, 3, 6. A subset of these PolIV-dependent (p4)-siRNAs are involved in stress responses, and others are associated with epigenetic modifications to DNA or chromatin; however, the biological role is not known for most of them. Here we show that the predominant pha! se of p4-siRNA accumulation is initiated in the maternal gametophyte and continues during seed development. Expression of p4-siRNAs in developing endosperm is specifically from maternal chromosomes. Our results provide the first evidence for a link between genomic imprinting and RNA silencing in plants.
• A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf–Hirschhorn syndrome
  - Nature 460(7252):287-291 (2009)
  Diverse histone modifications are catalysed and recognized by various specific proteins, establishing unique modification patterns that act as transcription signals1, 2. In particular, histone H3 trimethylation at lysine 36 (H3K36me3) is associated with actively transcribed regions and has been proposed to provide landmarks for continuing transcription3, 4; however, the control mechanisms and functions of H3K36me3 in higher eukaryotes are unknown. Here we show that the H3K36me3-specific histone methyltransferase (HMTase) Wolf–Hirschhorn syndrome candidate 1 (WHSC1, also known as NSD2 or MMSET) functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf–Hirschhorn syndrome (WHS)5, 6. We found that mouse Whsc1, one of five putative Set2 homologues2, 7, 8, governed H3K36me3 along euchromatin by associating with the cell-type-specific transcription factors Sall1, Sall4 and Nanog in embryoni! c stem cells, and Nkx2-5 in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. We propose that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.
• Ionic high-pressure form of elemental boron
  - Nature 460(7252):292 (2009)
  Nature 457, 863–867 (2009) This Letter presents the results of high-pressure experiments and ab initio evolutionary crystal structure predictions, and found a new boron phase that we named -B28. This phase is comprised of icosahedral B12 clusters and B2 pairs in a NaCl-type arrangement, stable between 19 and 89 GPa, and exhibits evidence for charge transfer (for which our best estimate is 0.48) between the constituent clusters to give (B2)+(B12)-. We have recently found that the same high-pressure boron phase may have given rise to the Bragg reflections reported by Wentorf in 1965 (ref. 1), although the chemical composition was not analysed and the data (subsequently deleted from the Powder Diffraction File database) seems to not have been used to propose a structure model. We also note that although we used the terms 'partially ionic' and 'ionic' to emphasize the polar nature of the high-pressure boron phase and the influence this polarity has on several physical properties of the elemental phase, t! he chemical bonding in -B28 is predominantly covalent. We acknowledge N. Dubrovinskaia, L. Dubrovinsky, E. Yu Zarechnaya, Y. Filinchuk, D. Chernyshov, V. Dmitriev, A. S. Mikhaylushkin, I. A. Abrikosov & S. I. Simak for drawing these issues to our attention.
• Slow earthquakes triggered by typhoons
  - Nature 460(7252):292 (2009)
  Nature 459, 833–836 (2009) In this Letter, address 1 was incorrectly listed. This oversight has now been rectified.
• Goliath
  - Nature 460(7252):298 (2009)
  It's all about timing.