Researcher in Spotlight – Chris Sibley

In our website feature “Researcher in Spotlight” this month we ask our researcher Chris Sibley to tell us a bit more about himself.

Could you give us a quick overview of your background and career so far?

I received my BA in Physiological Sciences, MSc in Neuroscience, and DPhil developing RNA-based therapies for neurological disease from Oxford University. I then moved to the lab of Professor Jernej Ule to carry out my post-doc focussed on RNA regulation. This was initially at the MRC LMB in Cambridge, then later at the UCL Institute of Neurology. It was during this post that I embraced functional genomics methods and, via a year-long collaborative visit to Professor Mike Inouye’s system biology group at Melbourne University (Australia), systems biology. I returned from Australia in 2015 to start my research group at Imperial College London with a Edmond J. Safra fellowship. I subsequently moved to Edinburgh in 2019 to continue my work with the support of the Simons Initiative of the Developing Brain and a Sir Henry Dale fellowship from the Wellcome Trust and Royal Society.

How did you become interested in your current field of research?

I developed a broad interest in neurological disorders during an undergraduate neuroscience module, then became fascinated with the regulation of RNA molecules in the nervous system during my post-doc in the particularly creative and innovative lab of Professor Jernej Ule. I still remain amazed by the many layers of RNA regulation that have been found in the nervous system and the numerous intricacies not apparent in other tissues. I was fortunate to play my small part by identifying one such novel method of regulation that is used by particularly long RNA molecules that are highly enriched in the brain. Starting my own lab has then allowed me to really integrate these interests in neurological disorders and basic mechanisms of RNA regulation together, and a major focus is to now understand how the observed changes in RNA metabolism in autism both manifest and impact neurodevelopment.

What are you currently working on and what importance does your work have for autism research?

Autism has a wide variety of potential genetic causes. Despite this genetic diversity, afflicted individuals share common changes in genetic ‘messages’ of RNA to suggest converging molecular mechanisms and disease drivers may be involved. To further our understanding of this we are using state-of-the-art approaches to evaluate the abundance of all RNA molecules in single cells as they are turned into neurons. Crucially, we are doing this after removing many individual genes linked to autism in a single experiment. Computational analysis of the thousands of single-cells from each experiment are being used to reveal the RNA signatures associated with each autism-relevant manipulation and identify the key RNA molecules that are disrupted by the different backgrounds as the cells differentiate. Further, systems biology methods we employ are being used to identify the master regulator genes that drive the RNA signatures associated with each perturbation, and identify those master regulators that act as hubs of mechanistic convergence across the different genetic backgrounds. We believe this strategy will provide penetrating insights into basic molecular mechanisms relevant to autism, whilst it has the potential to identify new drivers of the disorder for therapeutic targeting.

What do you enjoy most about scientific research?

I love the constant challenge it provides and the feeling that our experiments are moving knowledge forwards. Indeed, my lab are constantly exploring new avenues and embracing new developments in the field such that our research always feels progressive and never repetitive. There is then a huge motivational drive to make crucial discoveries that will one day be transformative to patients with neurological conditions. Finally, I will never tire of the frequent conversations I have with my colleagues about exciting new findings.

What do you like about the scientific community in Edinburgh?

Aside from being surrounded by many globally recognised leaders in their respective fields, like most others I love the collaborative environment that spans across the different university schools and departments. I collaborate with colleagues in both medicine, biology and chemistry, whilst everyone I meet is keen to discuss new ideas and look at ways of combining expertise.

What is your favourite high tech research tool?

Single-cell RNA profiling has been transformed in recent years by some fantastic technological developments that can allow over fifty thousand individual cells to be captured in their own tiny oil droplets in just fifteen minutes. These droplets then act as micro-reaction chambers for subsequent experimental steps to permit studies at single-cell resolution. The scalability this offers has led to some amazing findings in the field such as discovery of fundamentally new cell types and the characterisation of neurological disease associated cell states. We are fortunate to have one of these specialist microfluidic devices in our lab. It’s so simple, fun and powerful to use that we are presently expanding our applications. We hope it will help lead to our own major discoveries relevant to autism in the future.

What is your favourite low tech research tool?

We have a recycled and simple UV crosslinker (i.e. UV lights inside a metal box) in the lab which I’m fairly sure was purchased by the previous owner in the 1980’s. It still works a treat and is used almost weekly!

Where do you usually get the best ideas for your research?

Reading outside of my field has led to some of the more creative ideas. This has previously allowed me to re-apply technologies and software used in different applications for a new purpose in my field. Meanwhile, I’ve also been fortunate to work with some fantastic colleagues across all past posts who’ve helped discuss and evolve challenging concepts.

What is your hidden talent?

My not-so-secret hobby is kitesurfing – I will strike up a conversation about it with whomever I can! Edinburgh is fortunately blessed with wind and has plenty of amazing coastline nearby to explore.