The Shaw Prize in Life Science and Medicine 2022 is awarded in equal shares to Paul A Negulescu, Senior Vice President and Site Head, San Diego Research, Vertex Pharmaceuticals Incorporated, USA and Michael J Welsh, Professor of Internal Medicine – Pulmonary, Critical Care and Occupational Medicine, Professor of Neurosurgery, Neurology, Molecular Physiology and Biophysics and Director of Pappajohn Biomedical Institute, University of Iowa, USA for landmark discoveries of the molecular, biochemical, and functional defects underlying cystic fibrosis and the identification and development of medicines that reverse those defects and can treat most people affected by this disorder. Together, these discoveries and medicines are alleviating human suffering and saving lives.
Cystic fibrosis (CF) is one of the most common, severe single-gene disorders, affecting more than 80,000 people globally. The single gene in which the disease-causing mutations fall is called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). The CFTR protein ensures the proper flow of chloride, a component of salt, that is present in secreted body fluids such as sweat, saliva and mucus. These fluids keep cells lubricated and are thus vital for the proper function of organs. In CF patients, these secretions become thick and sticky and, rather than acting as lubricants, clog passageways, especially in the lungs. The disease is fatal. There are many different mutations in CFTR that cause the disease, but a mutation called F508del is particularly important, and is present in about 90% of patients.
Michael Welsh from the University of Iowa discovered in 1990/1991 that the CFTR protein is a chloride channel and he revealed how its activity can be regulated. He corrected the CF defect in cultured cells by providing a normal CFTR gene, thereby showing that correcting the defect was a feasible therapeutic strategy. In extraordinary studies (1992–1993), Welsh then demonstrated how different CF disease-causing mutations affect the CFTR protein—some eliminated its production, some interfered with its trafficking to the cell membrane, and some prevented the opening or function of its chloride-transporting channel. Welsh categorized the different human CF mutations according to mechanism and laid out a scheme to correct each type of underlying defect. Importantly, Welsh showed that the CFTR protein with the common F508del mutation has multiple defects, the protein did not reach the cell membrane and was also defective for chloride transport. Very crucially, Welsh discovered an experimental condition that enabled the CFTR-F508del protein to make it to the membrane, and he showed that when the protein did reach the membrane, it functioned. That landmark discovery meant that if a therapeutic strategy could be developed to get CFTR-F508del to the cell membrane, it would be beneficial in combating the disease.
Paul Negulescu from Vertex Pharmaceuticals made the leap from mechanism to therapy. He and the Vertex team discovered small molecules to treat CF by embarking on an enormously risky strategy of screening for compounds that could “fix” a defective protein. Moreover, because there are many different CF-causing mutations, it was not clear that one medicine capable of treating the majority of CF patients could be developed. Negulescu first discovered a CFTR “potentiator” that stimulated CFTR channel function. This medicine, called Kalydeco, received breakthrough designation. However, Kalydeco was useful only for the subset of CF patients with certain rare mutations, not for the vast majority of CF patients with the CFTR-F508del mutation. In an even more bold effort, Negulescu then screened for molecules that could correct the trafficking defect of the CFTR-F508del protein. Remarkably, he discovered such a molecule, a “protein-corrector”. He combined the new molecule with Kalydeco, now named Orkambi. He improved on Orkambi twice more, combining two “protein correctors” with a “potentiator” to make Trikafta, approved in 2019. Trikafta helps patients with the CFTR-F508del mutation and patients with 177 rare CFTR mutations. Currently, 50% of all CF patients take Vertex CF medicines.
The combined contributions of Welsh and Negulescu represent the complete biomedical arc from basic discovery to application to the saving of lives. They are especially worthy of the Shaw Prize in Life Science and Medicine.
Life Science and Medicine Selection Committee
The Shaw Prize
24 May 2022 Hong Kong