Discovering the cystic fibrosis gene
In 1989, Dr. Lap-Chee Tsui and his collaborators located a single gene among three billion letters of human DNA, transforming outcomes in cystic fibrosis and ushering in the era of genomic research.
The Scientist
Dr. Lap-Chee Tsui, born in Shanghai in 1950, arrived at The Hospital for Sick Children (SickKids) in 1981 as a post-doctoral fellow in genetics, working with Dr. Manuel Buchwald. Two years later, he became scientist at the SickKids Research Institute and faculty member in Medical Genetics and Medical Biophysics at the University of Toronto.
Tsui's devoted much of his research lab's focus to one central objective: discover the genetic variant responsible for cystic fibrosis. In the era before the human genome was mapped, searching for a single disease-causing gene was, to most, an insurmountable challenge.
In pursuit of that mission Tsui led with humility and a quiet tenacity, uninterested in personal accolades but rather prioritizing collective achievement and collaborative science. His positive spirit, technical expertise and intuition influenced the research culture at SickKids and the careers of many emerging scientists that came through his lab.
The Target
When Tsui launched his lab, cystic fibrosis (CF) was among the most common fatal genetic conditions in children of European descent. In the decades previous, many didn't live past their mid-teens.
CF was known as an inherited disease capable of damaging many organs. It can trigger mucus buildup that causes infections, inflammation, respiratory failure and other complications in the lungs. In the pancreas, it can disrupt the digestive process and result in poor growth and malnutrition. By blocking the bile duct, it can cause liver disease.
For decades, clinicians could only treat its symptoms, because the cause of CF was unknown. There was no known faulty protein to work backward from — only a pattern of inheritance in families.
The Discovery
Tsui has said: "The right time, right place and right people."
His first breakthrough came in 1985. Using the innovative technique of genetic linkage analysis, Tsui and his lab members tracked DNA markers from families with multiple children with CF to narrow the search for CF's genetic foundation. They succeeded: the team found an associated gene on the long arm of chromosome 7, a result Tsui published in Science.
He knew the task of finding the exact gene would be akin to travelling along the DNA and, in the spirit of collaboration and efficiency, he sought help from colleagues with particular skillsets. Dr. Johanna Rommens (SickKids) performed "chromosome walking," a painstaking task to isolate overlapping DNA segments along chromosome 7. Dr. Francis Collins (University of Michigan) joined the hunt, using "chromosome jumping" to leap ahead and quicken the search.
Both techniques had never before succeeded in a major human disease.
Finding CFTR
By 1989, Tsui had found a DNA sequence he thought contained the CF gene. He recruited SickKids biochemist Dr. Jack Riordan to the mission and together they found a matching expressed gene in Riordan's sweat gland cDNA library. And in people with cystic fibrosis, a small piece of it — a specific three-letter deletion — was missing.
They called it the Cystic Fibrosis Transmembrane Conductance gene, or CFTR for short. It proved to be a chloride channel, a which that controls salt and water movement across cell surfaces — hence why CF thickens mucus in the lungs and blocks the pancreas.
Tsui published the findings in three consecutive papers in the September 8, 1989 issue of Science, with the team's discovery on the cover. It marked a turning point in medical genetics while reshaping how we understand CF at the molecular level and opening the door to therapies that have changed outcomes and quality of life for patients around the world.
The Impact
CFTR was the world's first major disease gene found through linkage mapping alone, proving it could be done without knowing the proteins involved. Tsui had established proof that the human genome could be searched for the cause of any inherited condition, helping to propel the global Human Genome Project.
The impact was widespread, including:
- Transformed outcomes in CF: Within a generation, CF turned from a paediatric disease to an adult one, as treatments born from the CFTR discovery reinvented patient management and raised the average life expectancy past 50-60 years.
- Ushered in precision therapies: Understanding that a defective chloride channel caused CF allowed the development of CFTR modulators: precision medicines that can bind to the defective CFTR protein and restore cellular function.
- Advanced open science: Tsui established a CF variant database at SickKids so labs anywhere could contribute to, and draw on, the latest genetic information about CF. Tsui freely shared and catalogued more than 2,000 CFTR variants, creating a global standard for open data in genomic medicine.
- Enabled universal newborn screening: This work made DNA-based diagnosis and carrier testing possible, leading to newborn screening programs across Canada and around the world.
- Launched world-leading genomic centre: In 1996 Tsui became SickKids Geneticist-in-Chief and, two years later, co-founded The Centre for Applied Genomics with Dr. Stephen Scherer, which has become one of the most essential vehicles for genomic discovery in the world.
A faxed letter from Dr. Bob Williamson, who extended his congratulations to Dr. Lap-Chee Tsui and his team for their ground-breaking discovery of the CFTR gene. Williamson's lab in London had been competing in the search for the CF gene, and the letter serves as a symbol of recognition and admiration for Dr. Tsui's accomplishment.