Enhancing ion channel research accessibility and productivity with automated electrophysiology

"Ion channels" are proteins present in the cell membrane of all cells. They permit and control the movement of ions such as sodium, potassium, calcium and chloride between the cell exterior and interior; such movement is key for maintenance of a healthy cell environment. Ion channels also underpin the generation of electrical activity in muscle, heart and nervous tissue. Ion channel dysfunction has been implicated in many pathologies, including cystic fibrosis, cardiac arrhythmias and nerve and muscle disorders. Ion channels are also targets of some clinically used drugs. They are both attractive targets for novel drug treatments and mediate unwanted "off-target" side effects of some treatments.

For decades, the gold-standard approach to the study of ion channels in health and disease has involved recording their electrical activity using a specialist method called "patch-clamp". The traditional 'manual' patch-clamp method involves an experimenter making a single recording at a time, using a finely tapered glass recording 'electrode' applied to the surface of a single cell. This method is highly skilled and laborious. Consequently, extensive efforts have been made to simplify and automate the patch-clamp process. Methods have been developed that are suitable for use in an industrial setting for the screening of new drugs. However, large scale automated patch-clamp systems trade off ease of use and ability to make multiple measurements against recording quality; it is difficult for most systems to match the quality of data from manual patch-clamp. However, recently, a device has become available called the QPatch Compact. This is a bench-mounted, self-contained automated device that combines the advantages of automated patch-clamp with the ability to tightly control experimental conditions and recording quality similar to manual patch-clamp.

The University of Bristol is a leading centre for research on ion channels from different body tissues. We seek a QPatch Compact automated patch-clamp system with two main objectives in mind. First, the system will accelerate ion channel research, facilitating the ability to interrogate ion channel (dys)function and drug effects (with 8-fold the throughput of manual recording). Second, because the device has been designed for use by those without specialist expertise, it will open ion channel research to a wider research constituency. Thus, the QPatch Compact will enable more extensive progress to be made in understanding normal and diseased ion channel function and the identification of novel therapeutic approaches that work through ion channel modulation.

In comparison to manual patch-clamp (PC) electrophysiology, automated PC (APC) electrophysiology greatly accelerates data acquisition and reduces the need for prolonged specialist training. The requested equipment, the Sophion Bioscience QPatch Compact system is unique in that it combines the lack of requirement for seal enhancers with high specification microfluidics and temperature control in a bench-top format. This instrument will provide key enabling technology for three groups of researchers: first, those already investigating ion channels and their dysfunction in human disease; second, those seeking to study ion channels, but without specialist skill and third those engaged in translation research on novel therapeutics. We propose to use the QPatch Compact to facilitate a broad range of medical research by multiple groups on ion channel function and dysfunction in the nervous system, heart, lungs, intestine, bladder and beyond. Specific applications include: i) Investigating the mechanisms of disease underlying cystic fibrosis (CF) through APC characterisation of the effects of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) channel on its transport of bicarbonate and their response to clinically-approved CFTR modulators in heterologous cells. ii) The APC based functional characterisation of variants of uncertain significance (VUS) reported in patients with suspected cardiac channelopathies and the functional impact of variants in the Piezo1 channel associated with osteoporosis. Finally (iii), the QPatch Compact will enable early identification of significant anti-'hERG' channel activity (central to UK drug safety regulatory guidelines) of promising novel compounds against any clinical target. In summary, the QPatch Compact will bring ion channel research within reach of those without specialist expertise and greatly accelerate throughput for researchers with prior expertise at the University of Bristol.