Life-Changing Cystic Fibrosis Treatment Wins $3-Million Breakthrough Prize
The triple-drug combination Trikafta has given a new lease of life to 90% of people with cystic fibrosis, an inherited disorder that affects the lungs and other organs. Now, the trio of researchers who spearheaded its development has won one of this year’s US$3-million Breakthrough prizes — the most lucrative awards in science.
Sabine Hadida, Paul Negulescu and Fredrick Van Goor at Vertex Pharmaceuticals in San Diego, California, developed the treatment by combining different drugs that help a faulty protein to function.
“The development of Trikafta has been one of the most phenomenal and outstanding achievements of biomedical research in the last 30 years,” says geneticist and physician Francis Collins at the US National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, who co-discovered the gene for cystic fibrosis in 1989.
The award was one of five Breakthrough prizes — awarded for achievements in life sciences, physics and mathematics — announced on 14 September.
Cystic fibrosis affects around 100,000 people worldwide, and for many years was considered a life-limiting condition. However, a study this year projected that treatment with drugs such as Trikafta (comprising elexacaftor, tezacaftor and ivacaftor) — approved by the US Food and Drug Administration in 2019 — can increase life expectancy from around 30 to more than 80 years. “I hear almost every day from people who were really in trouble, with cystic fibrosis severely beginning to affect their chance of survival,” says Collins. “Now, after going on Trikafta, they are back at work and thinking about what they might want to do for retirement.”
The disease is caused by mutations in the gene that makes the cystic fibrosis transmembrane conductance regulator protein (CFTR), which ordinarily spans the membrane of cells that line several organs and is involved in the production of mucus, sweat and other fluids. In people with cystic fibrosis, these proteins are misfolded and don’t function correctly. This causes a build-up of unusually thick secretions, including mucus in the lungs, leading to serious health issues.
Once the CFTR gene had been identified, most efforts focused on ways to modify the gene to treat the disease, with little success. The team led by Hadida, Negulescu and Van Goor instead searched for a drug combination to coax the misfolded proteins into functioning correctly. The three drugs in Trikafta work together: two help to deliver more CFTR to the cell surface and the third enables the protein to work better once it is there.
“There was a lot of scepticism that this could be done,” Hadida recalls. “But the patient community was cheering for us.” The drug-discovery process required a marathon effort, testing the effects of more than one million compounds on isolated human lung cells to identify candidate drugs for clinical trials.
Hadida says she feels “very excited, honoured and surprised” by the award, adding that credit should be shared by the company, people with cystic fibrosis and their families.
A second life-sciences prize was awarded for the independent discovery of two genes associated with the risk of developing Parkinson’s disease: GBA1, identified by geneticist Ellen Sidransky at the NHGRI, and LRRK2 by neurogeneticist Andrew Singleton at the US National Institute on Aging in Bethesda and neuroscientist Thomas Gasser at the University of Tübingen, Germany.
Sidransky describes being “blown away” after learning of her award, especially because she didn’t set out to study Parkinson’s disease. Originally a paediatrician, she moved to researching the rare hereditary disorder Gaucher disease, in which fatty substances build up in various organs because of a mutation in the GBA1 gene. When talking to people with the condition, she realized that many had relatives with Parkinson’s disease, allowing her to connect the dots. “I want to be a cheerleader for research into rare diseases,” Sidransky says. “This is a good example where a study can lead to insights for the wider population.”
Njideka Okubadejo, a neurologist at the University of Lagos in Nigeria, welcomes the award announcement. Okubadejo, Singleton — who leads the Global Parkinson’s Genetics Program — and others have identified a new genetic risk factor for Parkinson’s disease in the GBA1 gene in people with African ancestry that is rarely seen in those of European descent. “The next step is to find a biological mechanism by which the gene causes the disease,” Okubadejo says. “Then you can build upon that to reduce the likelihood of the disease occurring.”
A third life-sciences prize was awarded to immunologists Carl June at the University of Pennsylvania in Philadelphia, and Michel Sadelain at the Memorial Sloan Kettering Cancer Center in New York City for developing a CAR-T-cell immunotherapy treatment for leukaemia that stimulates patients’ own immune T cells to target and kill cancer cells. This therapy can lead to long-lasting remission of some cancers.
Theories of everything
Other Breakthrough winners include John Cardy at the University of Oxford, UK, and Alexander Zamolodchikov at Stony Brook University in New York, who share the physics prize for a body of work on ‘conformal field theories’ — a family of mathematical theories that applies to a huge range of physical phenomena, from boiling water to the surface of black holes. In most situations, the equations are extremely tough to solve exactly, but Zamolodchikov discovered a solution in 2D in the 1980s, and Cardy built on these results by proposing that the result could be generalized to 4D and by applying conformal field theories to better understand phase transitions in materials.
Cardy, who was “over the moon” to learn about the prize, recalls learning about Zamolodchikov’s work from two Russian scientists at a conference. “Hardly anybody in the West understood what they were talking about,” Cardy says. “But I came away convinced I had to start working on it.”
“Cardy and Zamolodchikov truly are giants of conformal field theories,” says David Tong, a physicist at the University of Cambridge, UK. “There are physicists around the world who are working on extraordinarily different problems, and yet they have a common language through the work of Cardy, Zamolodchikov and others.”
Simon Brendle at Columbia University in New York City has won the mathematics Breakthrough prize for his contributions to differential geometry — the study of curves, surfaces and spaces. Among other achievements, Brendle proved ‘Lawson’s conjecture’ concerning the minimal surface of a ‘3-sphere’, which is the surface of a hypothetical 4D sphere.
The Breakthrough prizes were founded in 2012 and are sponsored by Yuri Milner, a Russian-Israeli billionaire, and other Internet entrepreneurs, including Meta’s chief executive Mark Zuckerberg.
This article is reproduced with permission and was first published on September 14, 2023.