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The Promise of a Cure: 20 Years and Counting

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The Promise of a Cure: 20 Years and Counting NEWSFOCUS All grown up. Danny Bessette, a 24-year-old with CF, was 4 years old when he appeared on the cover of Science announcing the discovery of the CF gene. after signing up with Collins, in the spring of 1989. In collaboration with a large research group in Toronto, Canada, that had started an aggressive chase for the CF gene years earlier, the team cloned the CF gene— called the cystic fibrosis transmembrane conductance regulator (CFTR)—and nailed a crucial, disease-causing mutation (Science, 8 September 1989, pp. 1059, 1066, 1073). Everyone in the CF community recalls the electric moment when they heard the news. “I remember seeing it roll off the fax machine, gathering people in the lab, and thinking, ‘What did we need to know’ ” now? says Michael Welsh, a pulmonary physician at the University of Iowa, Iowa City. Most believed that the disease had grown vastly less complex overnight and would soon be eliminated, probably by gene therapy. The Promise of a Cure: on June 19, 2009 On the 20th anniversary of the identifica- tion of the CF gene, as new gene discoveries 20 Years and Counting pile up weekly and hype over the power of genes to transform medicine flows fast, CF The discovery of the cystic fibrosis gene brought big hopes for offers an object lesson in how difficult it is, and how long it takes, to convert genetic gene-based medicine; although a lot has been achieved over 2 decades, knowledge into treatments. Every CF expert the payoff remains just around the corner agrees that the gene discovery transformed their understanding of the disease’s pathol- www.sciencemag.org The gene hunt began quietly, with few the- which sticky mucus accumulates in the ogy. But even after so much hard work, not a atrics and much uncertainty. lungs and elsewhere, eventually killing the single therapy based on the CF gene has For Mitch Drumm, the starting gate patient. At the time, life expectancy hovered reached the market. Some promising treat- lifted in the fall of 1985. He and geneticist in the early 20s. ments, especially gene therapy, have proven Francis Collins met on opposite sides of a Coincidentally, CF had been on Drumm’s bitterly disappointing. volleyball net, during a faculty-student mind. Just months before, the infant son of “We were naïve,” says Johanna Rommens, SCIENCE mixer at the University of Michigan, Ann his family’s next-door neighbors, close who at the time was a postdoc in Lap-Chee Arbor. Drumm, shorter than the lanky friends in New Philadelphia, Ohio, had been Tsui’s lab at the Hospital for Sick Children Downloaded from Collins, was outmatched in volleyball. But diagnosed with the disease. Drumm still in Toronto, the counterpart to Collins’s Collins quickly recruited Drumm to join the recalls the phone call from his mother relay- group in Michigan. In her 20s and relatively lab he was setting up, as its first graduate ing the devastating news. Like many others new to science back then, Rommens couldn’t student. There, Drumm began experiment- studying CF, he became immersed in the imagine a problem that defied resolution. ing with a gene-hunting technique Collins field by a personal connection, which carried “I thought I could do anything,” she says. “I had developed. As a test case, they chose him through ups and downs in the decades sometimes feel discouraged that this was so cystic fibrosis (CF), an inherited disease in ahead. A big triumph came nearly 4 years hard.” Keen to experiment with other CYSTIC FIBROSIS KEY DATES 1989: 1938: 1990: CFTR, the cystic Physician Dorothy Scientists suggest fibrosis gene, is that protein folding Hansine Andersen 1983: found. Median is behind CF. provides the first Chloride life expectancy for clinical description those with CF is of cystic fibrosis. transport is identified as about 29. the major defect in CF. OF MEDICINE/WIKIPEDIA; (BOTTOM, LEFT TO RIGHT) LIBRARY CREDITS: (TOP) STEVE BARRETT; 1504 19 JUNE 2009 VOL 324 SCIENCE www.sciencemag.org Published by AAAS NEWSFOCUS genetic diseases, Rommens subsequently an excessive focus on gene therapy in the Even with these heartening advances in left the CF field. early years to have been a big mistake. Like an the early 1990s, there were hints that choppy Although gene therapy hasn’t paid off, investor who gambles much of his or her for- waters lay ahead. The CF protein was a bear prospects have improved for those with CF: tune on a single stock, “people kind of stopped to work with because it didn’t respond well Their median life expectancy has stretched doing the other things they were doing” and to classic analytical tools like Western blots almost 10 more years and now exceeds 37. turned instead to strategies for getting the and antibody assays, recalls Margarida This is thanks not to genetic knowledge, gene into lung cells, says Raymond Frizzell, a Amaral, now on sabbatical at the European however, but to more aggressive and earlier physiologist at the University of Pittsburgh Molecular Biology Laboratory in Heidel- treatment to keep the lungs clear. in Pennsylvania. berg, Germany, who worked on the protein at the University of Lisbon in Portugal. Soaring hopes “Nothing seemed to work.” In October 1989, a month after the CF gene In Wilson’s lab, meanwhile, postdoc John was published in Science, gene therapist Engelhardt, now at the University of Iowa, James Wilson strode to the speaker’s podium at was running into difficulties getting gene a Florida cystic fibrosis conference to discuss therapy to work. The gene’s expression var- prospects for gene therapy. Thousands of ied wildly depending on which parts of the people—physicians, scientists, families— lung researchers examined. One great appeal packed the meeting. “I get shivers talking of gene therapy for CF was that a vector car- about it right now,” says Wilson, who then rying a working CF gene could easily be worked down the hall from introduced into the lung with aerosols. But Collins at Michigan and is Engelhardt found that only about 1% of cells now at the University of lining the lung’s airway—the cells that come Pennsylvania. “The excite- into contact with aerosols—boasted high ment was palpable. I have levels of CFTR protein. on June 19, 2009 never felt energy like that Then and now. Geneticist Mitch Each advance provoked more questions. ever before.” Drumm (inset, right) worked with When Richard Boucher, an adult pulmo- There was broad consen- Francis Collins (inset, left) in the nologist at the University of North Carolina, sus that the time for CF gene 1980s and helped identify the Chapel Hill, won a three-way race to create therapy had arrived. Two CF gene. He remains in the CF the first mouse model of CF in 1992, he and advances buoyed hopes that field today (main picture). others were dismayed to find that the rodents this new technique, still in its didn’t mimic human disease. They shared infancy, would eliminate CF. First, scientists Early successes in basic CF research also the gut afflictions of CF patients, who must had managed to “cure” the disease in test convinced scientists that new treatments were take pancreatic enzymes for life to break www.sciencemag.org tubes. They introduced a normal version of right around the corner. In addition to correct- down thick secretions. But the lungs of CF CFTR into cells from CF patients, compen- ing the gene defect in cells, having CFTR in mice, unlike those of their human counter- sating for a defective gene that produced no hand revealed that the healthy CFTR protein parts, were healthy. protein, or none the cell could use. In addi- was an ion channel that helped transport chlo- Like Drumm, Boucher traces his passion tion another researcher, W. French Ander- ride and control the movement of water across for CF to a personal experience: His daughter son, then at the National Institutes of Health, cell membranes. Researchers determined that suffered several bouts of pneumonia as a baby began the first-ever clinical trial of gene ther- several mutations led to a protein-folding and was suspected of having CF. Panicked, he apy to treat an immune deficiency syndrome, defect—one of the first protein-folding dis- read up on the disease; this drew him to a Downloaded from demonstrating that gene transfer in people eases identified. Then in 1992, Welsh and his career teasing apart its mysteries. The CF was feasible. By then, in the fall of 1990, says colleagues published a paper in Nature mouse was a big one: Why were its lungs Wilson, “expectations for the success of gene explaining that the protein-folding problem clear? Boucher and others determined that the therapy for CF were as high as I’ve ever seen could be corrected by chilling the cells. animals had a second chloride channel that for any disease, under any circumstances, in Although this tactic wasn’t useable in patients, was unaffected by CF. This led to a new under- the 20 years I’ve been involved in this.” it allowed “people to say, ‘It’s misfolded but standing of how the airway surfaces stayed Looking back, many CF experts consider you can overcome that,’ ” Welsh says. healthy: As long as chloride could pass 1990: 1992: Patients with Scientists describe the first the same gene mouse model of CF, but the 1993: mutation don’t mice don’t have lung disease. The number of share the same mutations in severe disease, CFTR surpasses suggesting a role 1993: CF Mouse 200. Today, we for other genes or A 23-year-old man with know of over the environment.
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