Scientists uncover new layer of complexity in how our bodies respond to drug treatments
Scientists from the University of Glasgow have played an important role in understanding why some patients respond better to drug treatments than others.
The study – published today in Nature and involving the University of Glasgow and a number of international partners – uncovers a new layer of complexity in how the body responds to medical treatments by using the power of data analysis on GPCRs.
GPCRs – or G protein-coupled receptors – are a family of proteins in the body and the molecular targets for many effective medicines (approximately 34% of approved drugs). However, there are individual responses to GPCR signalling in each of us, which could explain differences in receptor function and drug response.
These important drug target receptors exist in multiple structurally and functionally distinct versions distributed in a tissue-specific manner around our bodies.
By looking in detail at different isoform variants being produced from a single gene, the scientists in this study – led by Prof Madan Babu, St. Jude Children's Research Hospital, Tennessee – have illustrated how this knowledge may be developed for the benefit of patients.
Scientists based at the Medical Research Council-funded Laboratory of Molecular Biology in Cambridge defined the expression patterns of sequence variant isoforms of all GPCRs in different tissues, and even single cell types of the human body. This gave the team a detailed understanding, on a tissue-by-tissue basis, of natural receptor activation and drug effects.
Analysis of the functional responses of such GPCR isoforms to medicines, conducted at University of Glasgow, as well as at the Universities of Cambridge and Michigan, illustrated how to take advantage of the glut of data available to understand these questions.
For the study, the collaborators integrated and analysed genomics, transcriptomics, proteomics, structural, and pharmacological data for more than 300 receptors in 30 different tissues from individual donors. This investigation created a vast amount of data that was used to generate a new resource in the GPCR database maintained at the University of Copenhagen. This resource will allow experts interested in particular GPCRs to determine if their receptor of interest can exist in one or multiple isoforms and get detailed information of receptor isoform structural and functional data on a tissue-by-tissue basis.
Professor Andrew Tobin, from the University of Glasgow’s Institute of Molecular, Cell and Systems Biology, said: “This research shines a light on why some patients respond well to medicines and others do not. If we can understand key genetic differences that determine why some patients respond better to drug treatment than others then we will be able to tailor medicines to the specific needs of patients – this will be of benefit to patients and save time and money for the health service.”
Professor Graeme Milligan, of the College of Medical, Veterinary and Life Sciences at University of Glasgow said: “Multidisciplinary approaches than link experimental laboratory studies to the analysis of large data sets offer fantastic opportunities to develop novel medicines with reduced side effects. The studies we have been part of provide an excellent example of how data and experimental scientists can and must collaborate to improve human health.”
The work was funded by UKRI MRC, Wolfson College, FEBS, Marie Skłodowska-Curie actions, Swiss National Science Foundation, NIH, NIDA Core Center of Excellence in Omics, Systems Genetics, and the Addictome, NSF, UKRI BBSRC, AstraZeneca, Lundbeck Foundation, Novo Nordisk Foundation, Lister Institute, ERC, and ALSAC.
First published: 4 November 2020