Shining a light on the ‘dark genome’

26 Sep 2023

Image: Prof Wendy Bickmore

Prof Wendy Bickmore from the University of Edinburgh believes that uncovering the complex roles of gene enhancers is ‘a grand challenge for human genetics in the 21st century’.

During her undergraduate studies in biochemistry, Prof Wendy Bickmore realised she wanted to work on “discovering the rules of life”.

She undertook a PhD in molecular biology and followed that with postdoctoral research where, as she describes it, she “attempted and failed to clone a gene for a human genetic disease”.

A short spell at a cytogenetics lab “ignited a desire to understand not just individual genes, but to understand how genes are organised and controlled within the context of human chromosomes and in cells,” she says.

These days, Bickmore is director of the Human Genetics Unit in the Institute of Genetics and Cancer at the University of Edinburgh. Her research is funded by the UK Medical Research Council (MRC).

This summer it was announced that a project she is working on has received MRC funding of £46.3m. The aim of the project is to shine a light on the ‘dark genome’ – the underexplored 98pc of people’s DNA which may hold insights into complex genetic diseases.

“It’s exciting that we now have so much human genome sequence data, but we need to turn that data into knowledge about how our genome works in health and disease,” Bickmore said at the time.

Tell us about your current research.

My current research focuses on the genetic switches – termed enhancers – in our genome that control how, when and where our genes are expressed in different cells and tissues.

What is fascinating is that enhancers are often located a long way away – in DNA terms – from the genes that they regulate. So, how do enhancers communicate with their target genes over such distances?

We are investigating whether the 3D folding of the genome is important for bringing enhancers and genes physically close enough to each other so that enhancers can act on their target genes.

To do this, we combine genome engineering to manipulate the molecular machinery that folds the human genome, synthetic biology to control the activity of enhancers, molecular methods and super-resolution microscopy to examine the spatial relationship between enhancers and genes.

We are able to harness these approaches to address such a fundamental biological problem because of our strong multidisciplinary team.

In your opinion, why is your research important?

Humans are complex organisms not because of the number of genes in our genome – which is not much more than in the genome of a fruit fly – but because of the precise way our genes are controlled in the hundreds of different cell types in our bodies.

This control is encoded in the hundreds of thousands of enhancers embedded in the 98pc of our genome that does not contain genes, the so-called ‘dark genome’.

We have not identified all the enhancers in our genome, we do not know which genes they regulate and in which cell types, and we do not understand how enhancers work at locations in the genome distant from the genes they regulate. And, although we know that mutations in enhancers can cause disease, we do not understand how to interpret changes in enhancers found in people and in tumours.

Addressing this knowledge gap is, in my opinion, a grand challenge for human genetics in the 21st century and necessary for improving the diagnosis, management and treatment of human genetic disease and cancer.

What inspired you to become a researcher?

As an undergraduate, I had the opportunity to do a research project in a Medical Research Council (MRC) unit. It was spending time amongst researchers in that unit, who were so passionate about what they do and who were prepared to give up their time to train a young student, that made me realise that I wanted to become a researcher like them and to spend my working life discovering the rules of life. I can only hope that I have had the same positive influence on the next generation of researchers.

What are some of the biggest challenges or misconceptions you face as a researcher in your field?

There is an idea that just collecting loads of data (big data) will generate the answers we need.

We need to turn that data into knowledge, to do experiments to test hypotheses and to challenge dogma.

We have the whole genome sequences of millions of humans but we are barely scraping the surface in terms of understanding what that data means for health and disease.

Do you think public engagement with science has changed in recent years?

Public engagement with science has been transformed in recent years. It used to be very didactic – we expected the public to just turn up and listen politely while we taught them about our research. Now it is much more of a two-way conversation and as scientists we are now better at listening, especially to the patient voice.

As an institute, we foster this through our Shining a Light on series of public and patient events, each of which focuses on a different disease and involves both researchers and patients discussing their work and experiences.

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