Recent drug discovery success signals renaissance in biophysics

Abstract

With a scope that spans the hierarchy of biological organization from molecules and cells to organisms and populations, the discipline of biophysics has been proven to be particularly well suited for connecting the molecular embodiments of human diseases to the medical conditions experienced by patients. Recently, fundamental biophysical research on aberrant proteins involved in maintaining salt and water balance in our lungs, oxygen transport from our lungs to the rest of the body, and the pumping of blood by our hearts have been successfully translated to the creation of transformational new medicines that are radically changing the lives of patients. With these and other emerging discoveries, the field of applied biophysics is experiencing the beginnings of a veritable renaissance era.

First reported in western literature over 100 years ago, sickle cell anemia was dubbed a molecular disease in 1949 when it was revealed that a variant of normal human hemoglobin called sickle cell hemoglobin (HbS) created fibers upon deoxygenation that distorted red blood cells in patients, causing painful vaso-occlusive crises.¹ Decades of work on the thermodynamics, kinetics, and mechanism of sickling, including the development of crucial assays to measure oxygen binding and HbS fiber formation, finally led to the discovery of a small molecule that acts directly on hemoglobin (voxelotor) and was approved by the Food and Drug Administration (FDA) in 2019. There are several other promising curative therapies in clinical trials for sickle cell disease.²

Another inherited disease, cystic fibrosis (CF), was first described in detail by a pathologist in the 1930s. The gene for this monogenic disease was identified in the 1980s.⁴ Its protein product is the cystic fibrosis transmembrane regulator (CFTR). By constructing assays utilizing biophysical techniques to measure chloride transport by CFTR with human bronchial epithelial cells isolated from lungs of CF patients,³ a series of medicines were discovered over a period of two decades and approved by the FDA in the years spanning 2012–2020 that have vastly impacted the lives of patients.⁵

In people who have the condition known as hypertrophic cardiomyopathy (HCM), the heart muscle becomes less efficient at pumping blood. Complications of HCM include sudden cardiac death. It has been determined that some cases of HCM are caused by mutations in proteins, like myosin, that are integral to the heart's contractile unit, the sarcomere.⁶ Specialized biophysical assays that report on contractility were instrumental in identifying mavacamten, a novel small molecule inhibitor of myosin that was approved by the FDA in April 2022.⁷

At the core of the discoveries of these important medicines are essential biophysical assays that are the in vitro expressions of human biological phenomena reduced to precise measurements of a physical event: the phase change of a heme protein, the transport of chloride by an ion channel, and mechanical force generation facilitated by a motor protein. Without the right assay, the means to make these physical measurements, or the understanding of how protein function relates to cell and organ and patient function within genetically defined subpopulations, there would be no discoveries of these life-saving medicines.

Biophysics Reviews strongly supports the publication of research reports and reviews that capture the fundamental biophysical bases and practical applications of crucial assays that can be or have been employed in drug discovery and development work in biotechnology and pharmaceutical companies. More generally, the journal is dedicated to providing our readership with accounts of biophysics research conducted within diverse industrial enterprises—excellent scientific scholarship that is far too often never seen outside the companies where the work was performed. By showcasing the full range of biophysics work—from fundamental to applied, from academic and government institutes to private and public corporations, from molecular and cellular to organismal and population-based—Biophysics Reviews aims to further stimulate innovation in the field and to inspire a future generation of innovators.

The lungs that we use to inhale air from our environment, the blood that carries the oxygen we extract from this air, and the hearts we rely on to pump that blood to power our abilities to create and imagine, to climb, and to dream, are all objects in the hierarchy of biological matter that, when subjected to the lens of biophysical interrogation, allow us to ensure health and preserve life itself.