Science seemed on the cusp of a revolution — hope was spreading that researchers might soon be able to identify genes that caused diseases that had bedeviled humanity for centuries and use that knowledge to devise medicines that were true cures.
That fall, biologist James Wilson stood before an audience of researchers, physicians, and cystic fibrosis patients and their families and described gene therapy, a way to replace the faulty gene with a good copy. Wilson had intended his talk to be technical and prophetic, but he was overwhelmed by the surging thrill in the room that science was about to save people's lives.
“It was one of the most amazing experiences that I’ve ever had,” Wilson said. “The excitement was palpable. People say that about things, about Taylor Swift, but it was even more electrifying than that. The expectations were through the roof.”
The importance of the cystic fibrosis gene discovery went far beyond a single illness. It helped build the case for the $3 billion project to sequence the entire human genome, which would alter understanding of human biology and shed light on rare and common diseases.
But the story of cystic fibrosis has been illustrative in a way that no one could have anticipated back then. In the early days of human genetics, the path seemed straightforward: Find the gene, fix the gene and repeat for other diseases. The cystic fibrosis journey, from an exuberant moment of insight to a major success, would take 30 years of persistent, methodical work: a feat of science, business, fundraising and patience that has become a model for other diseases.
“I specifically remember sitting with my doctor in the exam room, having the conversation that the gene was discovered,” said Josh Taylor, 48, of Virginia Beach, who has cystic fibrosis. “And him telling me the cure is just — he literally said, ‘In 5 to 10 years, we’re going to beat this.’”
It was not until late 2019 that another breakthrough fulfilled many of the hopes of 1989. Now, Taylor has what he has been waiting for all these decades — a new drug, Trikafta, that is effective for 90 percent of patients. Doctors marvel at what they think will be possible if it is given at an early age: a full life span.
Needle in a haystack
A “Kiss your baby” campaign swept across the country in the early 1980s. Ads on the backs of city buses urged parents to check their infants for salty sweat with a kiss, and official “Kiss your baby” weeks were declared in cities and states.
Like a fairy tale gone awry, a salty kiss foretold a tragic destiny: an early death from cystic fibrosis. Salty sweat was one of the first signs of a disease that would cause sticky mucus to clog children’s lungs and wreak havoc on their digestive systems.
The kiss test, borne out of midwife wisdom, was an effective public health tool and awareness campaign from the nonprofit Cystic Fibrosis Foundation, but it also reflected the relatively crude understanding of the disease.
Cystic fibrosis developed when a child had the bad luck to inherit two faulty genes, one from each parent. It was scary in part because the odds were invisible; parents with one copy of the gene had no symptoms. Today, genetic tests are so routine that they are used in medical clinics, and even for recreational reasons, such as tracking down ancestors. But back then, there was no test to detect whether a parent carried a defective gene because no one even knew what the gene was. It was buried somewhere in the 6 billion letters of DNA that were the blueprint for a human being. Those letters spelled out genes, and misspellings, or mutations, in those genes could have devastating results.
As scientists developed new tools to probe human genetics, cystic fibrosis quickly became one of the top targets. It is the most common inherited disease among Caucasians, afflicting 30,000 Americans, and its motivated patient group spurred the work forward with funding.
“All these human disease genes were floating around. We knew they were inherited, but we knew very little. We didn’t know what the genes were, or where they were located,” said Robert Nussbaum, a medical geneticist who was hunting genes for other diseases.
Finding a disease gene was a daunting task with few clues about where to look. Francis Collins, now director of the National Institutes of Health and then a scientist at the University of Michigan working on cystic fibrosis, was photographed for the university’s graduates’ magazine sitting in a haystack holding a needle, to convey the magnitude of the technical challenge.
The pressure was intense. A group in Europe had reported a possible success in 1987, generating headlines, although the discovery did not hold up. Meanwhile, families were desperate for advances.
“Almost everybody knew some family where it had happened, and it was heartbreaking to see what these kids go through,” Collins said.
Robert Beall, then an executive vice president at the Cystic Fibrosis Foundation, which was funding the work, was also “the most impatient human being I ever met — to his credit,” Collins said.
Collins partnered with biologist Lap-Chee Tsui, in Toronto — holding joint lab meetings at a midway point on the long drive, in London, Ontario.
After years of work, Tsui’s lab had narrowed the search to ever smaller stretches of DNA, pioneering new techniques in the search for the gene. Collins had invented a method to speed up the process called “chromosome jumping,” which allowed scientists to leap over sections of DNA — something he compares to leaping from one street corner to the next to initiate searches. Jack Riordan, another scientist in Toronto, discovered a bit of DNA that looked like it might be a part of the gene, providing an essential lead.
In May, a scientist in Tsui’s lab found a tantalizing clue — three missing letters of DNA in a patient with cystic fibrosis. The team would need to confirm that this genetic mutation was the cause of the disease. Collins and Tsui were at a scientific conference at New Haven, Conn., a month later when they got more evidence.
One rainy night after the day’s program was over, the pair raced to Tsui’s room, where he had installed a portable fax machine to receive updates from the lab. Among the papers that had spilled onto the floor was a table showing those three letters of DNA missing in multiple patients with cystic fibrosis, while they were present in healthy people.
“Lap-Chee was a little more skeptical, ‘I’ve got to see more data,’ ” Collins recalled. “I bought it, that was it. I wanted to scream and jump up and down.”
Tsui said a scientist who was staying in the adjacent room recalled hearing chuckles from their room. “We celebrated with a ‘slow jump,’ ” Tsui said.
Word of the discovery leaked out when a Reuters reporter called Collins’s laboratory and a graduate student picked up the phone and accidentally confirmed that the gene had been found.
Dual news conferences took place in Toronto and Washington, D.C. Tsui and Collins later presented their results to the scientific community at a major genetics meeting.
“I remember the audience got to its feet as if it were a single organism and applauded — everyone was giddy with the realization that the vision of gene mapping had come to fruition, we really could use disease gene mapping to find genes that had been such elusive and frustrating quarries for so many years,” Nussbaum wrote in a history of the meetings.
Collins would testify before Congress that it was necessary to fund the human genome project because the flat-out effort to find the cystic fibrosis gene simply would not be scalable in trying to understand thousands of other diseases.
Scientists were already beginning to look for ways to transform the knowledge of the gene into a treatment.
“Such an approach was absolutely impossible until the gene was in hand,” Collins told Congress. “But now it is.”
The rush to fix the gene
It was just a matter of time. Gene therapy, the thinking went, would soon cure cystic fibrosis, marking a turning point in the treatment of genetic diseases. The idea was relatively straightforward: Use a virus to ferry a good, functioning copy of the gene into patients’ lung cells.
Wilson teamed up with Collins and corrected cystic fibrosis in cells in a dish, a proof-of-concept experiment that became front-page news.
Excitement — among experts and the public — was soaring.
Wilson gave another presentation to the cystic fibrosis conference.
“The year before, I talk prophetically about gene therapy. And now I show up and say we cured cystic fibrosis in the test tube. And I’m talking about expectations . . . at that time, with a lay audience, if you cured in a test tube — ‘Wow, let’s go,’ ” Wilson recalled.
Several teams raced to test the therapy in people, appearing before a special federal committee that evaluated the safety, science and ethical issues of such clinical trials. This was so cutting-edge that science-fiction scenarios were debated, researchers said.
For example, the committee contemplated whether the virus carrying the good gene could go awry. There were fears of “an ‘Andromeda Strain’ virus that wiped out Bethesda,” recalled Ronald Crystal, a pulmonologist who led a trial at the National Institutes of Health, referencing the Michael Crichton techno-thriller about a killer microbe.
The first patients spent weeks inside two negative-air-pressure rooms built at NIH to ensure that didn’t happen.
The therapy didn’t pose a danger to the rest of the world, researchers learned. But human biology turned out to have all sorts of ways of resisting an easy fix, and it quickly became clear that gene therapy would not be simple in real lungs.
Then the entire gene therapy field screeched halted in 1999 with the death of Jesse Gelsinger, a teenager with a metabolic disorder who died after being treated for the disorder in one of Wilson’s gene therapy trials.
As the hope for a high-profile gene therapy success crashed, research continued on the basic, less glamorous work to untangle what went wrong with the cystic fibrosis gene. That understanding made it possible to develop ways to screen chemicals, to see if any showed promise as a drug.
Beall and Preston Campbell of the Cystic Fibrosis Foundation visited Aurora Biosciences, a San Diego biotech company that used robotics to massively speed up such testing.
“Bob and I were like kids in a candy shop,” Campbell recalled. After a small initial investment, the foundation stunned the nonprofit world in 2000 by awarding the company $40 million, a new kind of venture philanthropy arrangement in which if the company was successful, the nonprofit group would receive a share of the royalties.
A Massachusetts company, Vertex Pharmaceuticals, acquired Aurora in 2001, and although the cystic fibrosis work continued, it was considered a long shot, called the “fantasy project” internally, recalled Fred Van Goor, a scientist who joined the company around that time and became the biology lead for the cystic fibrosis program.
The scientific problem was huge: The most common gene mutation in cystic fibrosis created a protein that couldn’t do its essential job in the cell. The protein didn’t fold correctly, which interfered with its ability to reach the surface of the cell. And it didn’t function well once there, where it was supposed to work as a gate. That meant they’d need multiple drugs to help patients — one to get the protein to the right spot, the other one to open the gate.
Vertex’s first drug candidate was focused on just one of the problems — getting the gate to work better. Alone, it would help only about 4 percent of patients, whose disease was caused by a rare mutation. That drug, Kalydeco, was approved in 2012, but it remained unclear whether a drug could be made that would work for a larger group of patients.
Then, Vertex’s main product — a hepatitis C drug — was eclipsed by a better treatment from a competitor, and the future of the company and its cystic fibrosis research was cast in doubt.
“It obviously created an incredible crisis here at Vertex,” said Jeff Leiden, chief executive of the company. Vertex had to decide whether to stay in the hepatitis C fight and try to come up with a better medicine, sell the company, or — the option Leiden favored — go all-in on cystic fibrosis.
Vertex’s board decided to bet on cystic fibrosis, and in 2015, a two-drug combination called Orkambi, was approved for a larger group of cystic fibrosis patients. Excitement about the drugs began to yield to a societal debate about their high prices; Orkambi’s launch price was $259,000 a year.
Meanwhile, the company would need to develop a third drug to treat more patients.
Drug trials are “blinded” so that neither the patients nor the scientists know which people are receiving the drug and which are receiving a placebo. When Trikafta, the triple drug combination that would ultimately be approved, was unblinded from one trial in October 2018, researchers finally saw the slide showing how the drug affected lung function.
There was a stunned silence in the room for a full minute. The drug worked.
“There was the heart and the mind. . . . Our minds said, ‘Yup, just as expected,’ and our guts said, ‘Could this be true?’ ” said David Altshuler, Vertex’s chief medical officer.
Almost immediately, “we turned to all the things we’d have to do in the next five years to make this real for patients,” Altshuler said. “It’s like a symphony orchestra, because the research, the manufacturing, the clinical trials, the people who distribute, the lawyers, the packaging, all these have to work in incredible harmony.”
Patients and physicians rejoiced in early November 2019 at a scientific conference in Tennessee, where Collins took up his guitar and welcomed the audience to “CF Church,” singing a song that he first wrote not long after the gene was discovered — this time with updated lyrics: “To find that triple treatment has taken 30 years,” Collins sang. “There were times when nothing seemed to work and progress seemed too slow, but hope is in our genes, we dare to dream.”
But the next verse repeats the message spelled out on the wall at the Cystic Fibrosis Foundation in Bethesda: “Til it’s done.”
'We're on a roll here'
After such a long wait, 10 percent of cystic fibrosis patients, or about 3,000 people in the United States, are still waiting for a therapy that works for them.
Stacy Carmona, who was born just three years before the gene was discovered, is one of them.
“I’m so excited for the community. I’m so excited for the CF friends I have who so desperately need the drug. There are so many people hanging on by a thread, waiting for this,” Carmona said. “The flip side of that is you can’t help but wonder when is it going to be my turn?”
The foundation announced another $500 million in funding for the next wave of research this fall, to help find a cure for everyone.
The drugs approved so far compensate for the effects of a faulty gene, but they are not technically a cure or a gene therapy because they do not introduce a new version of the gene. Gene therapy is still a goal of this research, after 30 years — one of a variety of approaches the foundation is considering in the quest for a cure.
The cystic fibrosis success story, with a wait that will be too long for many desperate families and a success that will bring new questions to the fore — including how to pay for medicines with staggering price tags — is now playing out for other diseases.
Expensive therapies for a devastating muscle disease that kills young children have pitted families against insurance companies, and stunning progress against sickle cell disease is expected to raise new debates about access.
“What this does cause one to face up to is that the arc of discovery — from basic science to [Food and Drug Administration] approved therapy — is a long and complicated one,” Collins said. “It’s still going to be challenging for all the hopes and dreams we have for diseases that are still waiting. But we should be optimistic we’re on a roll here.”