Five scientists whose discoveries have redefined the treatment of cystic fibrosis (CF) will be honored Oct. 4 at the annual Warren Alpert Symposium at Harvard Medical School.
The discoveries, which span the fields of genetics, physiology, pulmonology and pharmacology, have led to the development of life-altering precision-targeted treatments for the multi-organ genetic disease.
The Warren Alpert Foundation Prizewill be presented to:
- Francis Collins, Director, National Institutes of Health
- Paul Negulescu, Senior Vice President for Research, Vertex Pharmaceuticals
- Bonnie Ramsey, Vice Chair and Endowed Professor of Pediatrics, University of Washington School of Medicine; Director, Center for Clinical and Translational Research, Seattle Children’s Research Institute
- Lap-Chee Tsui, Founding President, The Academy of Sciences of Hong Kong; University Professor Emeritus, University of Toronto
- Michael Welsh, Professor of Internal Medicine—Pulmonary, Critical Care and Occupational Medicine, University of Iowa
The Warren Alpert Foundation, in association with Harvard Medical School, honors scientists whose work has improved the understanding, prevention, treatment or cure of human disease. Negulescu, Ramsey, Tsui and Welsh will share $500,000 in prize money. Collins, who will attend and present at the symposium, will decline the cash component of the award.
CF affects some 75,000 people in the United States, Canada, Europe and Australia. Life expectancy in CF has improved steadily over the past several decades. The median age of survival in the United States and other developed countries is now estimated to be in the early 40s, compared with a mere few months for children born with CF in the 1950s.
Thanks to the discoveries made by the five award recipients, this upward trend is likely to continue, with the advent of new therapies that repair the underlying disease-fueling protein malfunction and, in doing so, stave off organ damage and boost survival.
“Over the years, the Warren Alpert Foundation has honored some of the most elegant and transformative scientific achievements of our time, and the work of this year’s recipients is the very embodiment of the spirit of the award,” said George Q. Daley, dean of Harvard Medical School. “More importantly, the five scientists’ collective work powerfully illustrates the promise of basic discoveries made in the lab to profoundly alter the lives of patients through collaboration among fundamental researchers, biochemists and frontline clinicians.”
The elucidation of the genetic defect behind the disease, defining the molecular mechanisms that fuel CF development and the design of precision-targeted therapies represent the collective work of multiple scientists over several decades. The five award recipients made the key discoveries that propelled this quest forward.
“The work of the five scientists we are honoring is a triumph of modern medicine,” Joseph Martin, director and chair of the Warren Alpert Foundation’s board and former dean of Harvard Medical School. “We are humbled by the passion, dedication and acumen of a truly remarkable group of individuals whose achievements have touched the lives of patients and families across the world.”
The hallmark of CF is a genetic mutation that impairs cells’ ability to transport chloride, leading to the buildup of sticky mucus in the lungs and other organs and causing a constellation of symptoms, most notably recurrent lung infections and progressive scarring and loss of lung function, as well as a range of pancreatic, liver and other gastrointestinal problems.
Until 2012, treatment for CF remained purely symptomatic, focused on mitigating the effects of the disease.
In 2012, however, following decades of painstaking work in genetics, physiology and biochemistry, the FDA approved the first treatment that restores cells’ ability to transport chloride. That achievement was the cumulative result of work done by the five award recipients and their teams. Two dual-drug combination treatments followed, and triple-combination therapies are currently in development as a result of these initial discoveries.
The pivotal CF discoveries honored this year include:
- Identification of the gene responsible for CF and its cardinal sign—cells’ inability to ferry chloride in and out.
- Discovery of how mutations in the CFTRgene and its product—CFTR protein—precipitate disease development, its key symptoms and related downstream complications.
- Development of precision-targeted small-molecule treatments that correct the activity of the mutated protein.
- The design, oversight and execution of clinical trials that led to the FDA approval of the first two precision-targeted treatments for CF.
The foundational work was conducted by Lap-Chee Tsui and Francis Collins and their teams, whose research led to the discovery of the cystic fibrosis gene, elucidated its molecular structure and function and pinpointed its location. In doing so, they provided an entry point to understanding the basic defect that fuels a complex disease affecting multiple organs and organ systems.
Michael Welsh led the team that made key discoveries toward elucidating the role of the product of this gene, the CFTR protein, as the chemical transporter that allows chloride to move in and out of cells, showing how mutations in the gene and its product cause cells to malfunction and fuel disease development. These insights provided the rationale for the subsequent quest toward targeted therapies to repair the function of the aberrant protein.
Building on these key discoveries, a team of scientists at Vertex, led by Paul Negulescu, initiated research in 1998 to identify compounds that modulate the function of the CFTR protein. This work led to the discovery and development of the only CF medications available today that correct the underlying protein defect responsible for disease symptoms and restore cells’ ability to transport chloride. These medicines have ushered in a new era of CF treatment, which continues to advance with more compounds in development.
Pediatric pulmonologist Bonnie Ramsey was the architect of the clinical trial network and seminal studies that led to approval of the first, and subsequent, small-molecule treatments in current use and played a critical role in ensuring the translation of these therapies from lab to clinic.
Additionally, the Cystic Fibrosis Foundation, a research and advocacy group, provided catalytic support for the early-stage research that eventually led to the development of today’s small-molecule therapies. In doing so, the foundation played a transformative role and propelled forward the work being honored at this year’s symposium, according to members of the Warren Alpert committee.
The Warren Alpert Foundation Prize is given internationally. To date, the foundation has awarded more than $4 million to 64 scientists. Since the award’s inception in 1987, eight honorees have also received a Nobel Prize.
In addition to the five honorees and Dean Daley, the symposium will also feature invited speakers Pamela Davis, dean of the School of Medicine and Senior Vice President for Medical Affairs at Case Western Reserve University, and Jay Rajagopal, professor of medicine at Harvard Medical School and the Center for Regenerative Medicine at Massachusetts General Hospital.
