Imperial academics have streamlined a signalling pathway in yeast to understand how cell sensing can be tuned by changing protein levels.

The research, published in Cell, could eventually help us understand drug side effects in humans, and has immediate implications for biotechnology research.

G-protein coupled receptors (GPCRs) are proteins which let cells detect chemical substances like hormones, poisons, and drugs in their environment. They allow cells to sense the levels of hormones like adrenaline, serotonin, histamine and dopamine, and can act as light, smell and flavour detectors with some located on the tongue to give us our sense of taste.

There are around 800 different GPCRs in our bodies and around one third of all medication acts using these receptors – including beta blockers, antihistamines and various kinds of psychiatric drugs. However, not enough is known about how GPCR signalling works – including how their genetic make-up can affect the way we respond to medicines.

Now, Imperial College London researchers along with colleagues at the University of Cambridge and AstraZeneca have used synthetic biology to demonstrate that these receptors’ responses can be predictably ‘fine-tuned’ in yeast cells specially engineered for the task.

In synthetic biology we want to turn yeast into programmable living sensors, and our study will help us further that goal. Dr William Shaw Department of Bioengineering

The research team, led by Imperial’s Dr Tom Ellis, used genetic engineering guided by mathematical approaches to synthetically alter yeast cells to better control not just what they sense, but how they react to it.

To study the signalling, the Cambridge team created mathematical models of a minimized GPCR signalling pathway with varying concentrations of different cell components and found the best levels for the most efficient signalling. This knowledge was then used by the Imperial team to genetically modify yeast cells to test the theory.

First author Dr William Shaw, of Imperial’s Department of Bioengineering and Centre for Synthetic Biology, said: “This study helped us understand exactly how we can genetically engineer a cell to sense the desired amount of something for us in a way that we have control of.

“In synthetic biology we want to turn yeast into programmable living sensors, and our study will help us further that goal. It also tells us that changes in the component levels in these cell systems have big effect on how sensitive the cells are.”

We learned important principles about why cells respond differently to the same molecules of the same concentrations. Dr Tom Ellis Department of Bioengineering

Genetic variation in GPCR genes causes many failures in drug-led treatments. For example, variation may cause rare side effects, or render drugs less effective at treating whichever disease they target.

As the researchers showed here, changes to the DNA regions surrounding the receptor and signalling genes alters their levels and this also leads to major changes in how cells respond. Thus, these findings could help guide future research into drug side effects in individuals with genetic variation and help guide the new age of personalised medicine.

Lead author Dr Ellis, also of Imperial’s Department of Bioengineering and centre for Synthetic Biology, said: “We learned important principles about why cells respond differently to the same molecules of the same concentrations. If there’s a variation in the DNA sequence that determines key component levels, then this can change everything.”

The researchers are now using their system to turn living yeast cells into biosensors that can be easily customised to detect desired amounts of hormones and chemicals of interest in samples. This will be used in biotechnology, synthetic biology and applied biomedicine.

Mark Wigglesworth at AstraZeneca, which co-funded the research, said: “GPCRs are fundamentally important to the function of healthy cell systems and they remain one of the most targeted proteins in human medicine. It is hoped that increasing our understanding of these proteins will lead to more innovative medicines in the future.”

The work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) in collaboration with AstraZeneca.

This article was adapted from a press release by St John’s College, University of Cambridge.

“Engineering a Model Cell for Rational Tuning of GPCR Signaling” by William M. Shaw et al, published 4 April 2019 in Cell.