NEWS FEATURE 164 Vol 460 9 July 2009 NATURE Vol 2009 Macmillan Publishers Limited All rights reserved NEWS FEATURE Vol 460 9 July NATURE Vol 460 9 2009July 2009 ONE GENE TWENTY YEARS 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 J LUIS MAGANA AP D uring 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 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 Goodfellow 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 The disease has contributed much more to science than science has contributed to the disease Jack Riordan trafficking and membrane transport And the gene hunting techniques that Tsui Collins Riordan and their colleagues pioneered have laid the foundation for a genetic understanding of all human disease 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 with 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 2009 Macmillan Publishers Limited All rights reserved 165 REF 2 AAAS NEWS FEATURE NATURE Vol Vol 460 9 July 2009 decades no one knew exactly what was wrong with the cells so no one knew