The projects that earned Pioneer awards for four group leaders at the Babraham Institute
Four group leaders at the Babraham Institute are embarking on visionary projects to expand our understanding of human biology.
They are among 62 Pioneer award projects sharing £12million from the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, in support of early-stage frontier bioscience.
The projects, led by Dr Ian McGough, Dr Teresa Rayon, Dr Jon Houseley and Dr Maria Christophorou, will explore how toxic protein aggregates form, study how developmental time is set in different species, seek novel ways to tackle drug-resistant fungal pathogens and investigate the possibility that cells talk to each other using an as-yet-unknown signalling pathway.
Dr Simon Cook, the Babraham Institute’s director, said: “Congratulations to Ian, Teresa, Jon and Maria on these incredibly bold and visionary ideas and their success in securing Pioneer award funding to start investigating these concepts.”
The projects are:
Dr Ian McGough – understanding mRNA oxidation and its role in protein aggregation and ageing
As we age, our tissues suffer a decline in function and this is accelerated by the formation of protein clumps, or ‘aggregates’. They arise with the breakdown of protein quality control mechanisms and ultimately prevent normal cellular functions.
One theory is that oxidative stress drives this failure in protein quality control.
To date, efforts to prevent or counter the aggregation of proteins using drugs have focused on the proteins themselves. But we know that cellular damage caused by oxidative stress also affects a cell’s RNA molecules. This project will probe whether modified mRNAs (messenger RNAs) interfere with general protein quality control pathways and are themselves the origins of protein aggregates. If so, that could revolutionise our approach to preventing protein aggregation.
Dr McGouth will partner with institute group leader Dr Della David – a protein aggregation expert – on the project, which will use the intestine of the fruit fly (Drosophila melanogaster) as it shows age-related increases in oxidative stress and protein quality control issues.
The team will utilise the technology and knowledge in the institute’s mass spectrometry, genomics and bioinformatics facilities.
Dr Teresa Rayon – dissecting the species-specific rates of development
How is time measured at a cellular level? It remains a fundamental question that we cannot yet answer, even though we can witness its effects – such as equivalent structures being developed on different time trajectories in different species. Spinal cord motor neurons from humans, for example, develop about 2.5 times more slowly than neurons from mice.
Dr Rayon will build on her work studying how developmental timing is controlled to explore this question, using interspecies cell fusions. In particular, human and mouse neural progenitor cells from the equivalent developmental stage will be fused and the developmental dynamics of these hybrid cells analysed. This will involve gene expression profiling, measuring protein levels and studying protein degradation rates to identify key determinants of the developmental pace.
Cutting-edge proteomics will be brought to bear alongside classical experiments in developmental cell biology to reveal the fundamental molecular mechanisms involved.
Institute experts in proteostasis from the Samant lab and technical specialists from the institute’s imaging, mass spectrometry, flow cytometry and bioinformatics facilities will help with the project.
Dr Jon Houseley – exploring the acquisition of drug resistance in fungi
More than 1.5 million people a year are killed by fungal pathogens, which also destroy food crops that could otherwise feed 8.5 per cent of the global population.
There is widespread public awareness of drug-resistant ‘superbugs’, but not nearly as much appreciation of the threat of fungal pathogens to health and our food supply as they develop resistance to current treatments. The World Health Organization (WHO) published the first list of priority fungal pathogens in 2022.
Dr Houseley is an expert in how changes in the environment drive genetic change, ensuring survival in new conditions. He proposes that fungi use a rapid and reversible mechanism to confer drug resistance during exposure and that this is quickly lost once the challenge subsides. In his project, he will chart the formation and inheritance of extrachromosomal circular DNA (eccDNA) in the human pathogen Candida albicans – categorised by the WHO as a critical priority pathogen – and in the primary fungal pathogen of European wheat (Zymoseptoria tritici). This will enable him to explore whether eccDNA are used to drive up the copy number of resistance-conferring genes, passing protective status to their progeny in conditions of drug exposure.
The project team will use its developed assays for detecting eccDNA segregation to progeny cells, aided by expertise in the Institute’s flow cytometry, genomics and bioinformatics facilities, and working with experts on the target fungal pathogens.
Dr Maria Christophorou – are extracellular histones novel messengers in cell to cell signalling?
We understand that histone proteins play a key role in packaging DNA into tightly coiled, condensed units within the restricted space of the cell nucleus. But do they also have a signalling role, so far completely unappreciated, by which they influence cell fate and function?
Dr Christophorou believes they may indeed be communicating messages between cells, based on the observation that histone proteins are released from stem cells maintained in culture as they transition between pluripotency states.
This project could challenge current understanding of histone function, cell signalling and cell-cell communication.
The Christophorou lab will apply expertise in post-translational modification of histones to understand how histone proteins may be modified to act as signalling messengers that can influence cell state. Using state-of-the-art high-resolution microscopy and live imaging capability, along with mass spectrometry, the team will work with Dr Nick Ktistakis, who brings expertise in intracellular trafficking research to understand how histones are released from cells.
