Exonerating the exon: what happens when the genome loses its instructions?

At its simplest, the genome is the complete set of DNA; within this are genes, the functional segments of DNA, and each gene is made up of “coding” exons and “non-coding” introns. Essentially, if the gene is a sentence, the exons are the words, and the introns are the spaces that make these words legible.

But what happens when we start taking those important exons away? Will the sentence still make sense?

We sat down with Postdoctoral Fellow Dr Britt Hanson, who works in the Wellcome Sanger Institute’s Generative Genomics Programme, to talk about her day-to-day work in Dr Leo Parts’ lab and her project: Delete Everything. By stripping the genome piece-by-piece, Britt aims to uncover the specific genetic segments that are absolutely essential for cells to survive and thrive, and those that are dispensable.

Britt also shares her journey to the Sanger Institute, who inspired her scientific career and what it is like living in the UK compared to growing up in South Africa.

The best thing about my average day is that there is no such thing as an average day. My days are a dynamic mix of wet and dry lab tasks. On the wet lab side, I spend my time culturing haploid human cells, meaning they only have half the genetic material of “normal” human cells, and performing tests to see how specific genomic changes impact the ability of the cells to flourish. A typical experiment involves manipulating the genome in cells and then looking deeper into the functional effect using various exciting technologies such as next generation sequencing and single-cell RNA sequencing. On the dry lab side, I spend time on the computer designing and analysing these experiments. All in all, the amount of time I spend nurturing my cells or working at a screen is dependent on the stage of the project I’m on.

What I find exciting is that I’m never repeating the same experiment over and over. I get one experiment finished and then I move on to the next. Something might take an hour; something might take a day or two. This is why computational work can fit so easily around wet lab work and the variation suits me well because repetitive tasks tend to dampen my motivation.

I also like to take some short breaks walking around the Wellcome Genome Campus. I previously worked in central London so one of the drawcards of working at the Sanger Institute was to be enveloped in nature and a friendlier, more peaceful environment.

At the end of my day, I sometimes go to the gym on Campus where I can unwind and calm my mind.

My PhD was in gene therapy development for genetic neuromuscular disorders including Duchenne muscular dystrophy (DMD), caused by a mutation in the dystrophin gene, and spinal muscular atrophy (SMA), caused by a mutation in the SMN1 gene. Both are characterised by progressive muscle wasting. I was using genome engineering to try and work out how we can create therapeutics for those two disorders. If you cut out parts of the gene that are affected, can you then restore the function of the gene? While on a relatively small and targeted scale, it was my wide window into genome engineering research where I’m currently trying to do a very similar thing but on a very large scale, with more advanced technologies.

Although I am a wet lab trained scientist, I have always had a very strong desire to learn the computational side of molecular biology. There have been occasions throughout my career where I have been exposed to some bioinformatics and coding, and I really enjoyed it, but it was only a dip of the toe, not a deep enough dive.

That’s why I initially aspired to work at the Sanger Institute because I knew that it had a great balance between wet and dry lab work, plus it’s world-renowned for high impact computational biology. So, at the end of my first postdoc job in London, I thought I would be bold and apply to join the Institute where I could put my skills to good use but also have the potential to grow and learn a lot more.

I initiated discussions with various group leaders and senior scientists at the Sanger Institute about potential careers and then I saw it: a postdoctoral fellow job advertised in Leo Parts’ lab. I applied, interviewed for the role and Leo and I had an extensive back-and-forth about project directions, making sure that it would be the right fit for both of us. This was something I really valued about Leo’s approach to building a team. It was also really important as his team’s science is discovery-driven to generate new insights about fundamental genomics, while I have a more patient-focused, translational background, which I am determined to carry through in my career. Leo and I agree strongly on the idea that in order for meaningful science to happen, there should be a balance of uninhibited exploration with a clear intention towards positive societal impact, and so, here I am trying to do just that.

For the whole of high school, I was really interested in biology, science, and maths and so when I did a careers guidance course, they suggested I do medicine or work in the insurance industry by becoming an actuary. Those are clearly very different careers, and it seemed like they were my only options. This was rather short-sighted, of course.

I wasn’t sure exactly what I wanted to do but I knew I was much more interested in the theory behind medicine and disease mechanisms rather than being a doctor that sees and treats patients directly. By the time I figured that out, it was too late as I had already accepted my offer to study medicine at the University of Cape Town. Luckily, when I arrived at the department, they gladly offered me the opportunity to swap a medical degree for a Bachelor of Science (usually, students are trying to swap the other way around!).

I took courses in genetics, biochemistry, and microbiology – and genetics emerged as a front-runner for me by the end of my BSc degree. So, I continued on to do an honours and master’s degree both at the University of Witwatersrand in Johannesburg. Then, I moved to the UK in 2017 to start my four-year PhD programme at the University of Oxford.

The arm of my research in Leo’s lab is called, “Delete Everything”. Ultimately, the goal is to try to delete the entire genome in small manageable bites to find the genetic pieces that cells really need to thrive, and those that the cell can do without.

To give some context, each gene has sections of DNA called exons and introns that alternate throughout. The genes are spread across the entire genome with regions in between known as “intergenic” DNA. Exons are sections of DNA that code for proteins so, naturally, are really important. Introns and the intergenic DNA, though non-coding, do have important regulatory and functional roles, many of which are yet to be uncovered.

The work we do is focused on understanding the fundamentals of how the human genome works. This involves an iterative process that combines AI with classical wet-lab experiments to select the most interesting and possibly mysterious regions of the human genome. We then check what their function is and learn from this for future experiments. We look at a single cell level to strip away the complexities of systems biology, leaving just the genes in a context where the effects of our experimentation are far simpler to interpret.

The goal is to drive discovery and provide knowledge that can be used to better understand how genes work and why they sometimes do not. These findings can then be used to design novel therapies or diagnostic strategies to combat genetic conditions.

My current project starts at a more zoomed-in level to delete every exon, one by one, from a selection of genes. To apply my translational lens, I'm focusing on genes that are implicated in neurodevelopmental disorders. The outputs of this research could help inform many different avenues. For example, the results could contribute to the development of an approved gene therapy that “skips” exons because they carry disease-causing mutations during transcription – the stage where the RNA message is being written from the DNA code. This means those exons won’t be included in the final instructions to make the required protein, and normal (or relatively normal) function can be restored. So, if we can do a screen where we remove each exon and ask whether we can take it out without changing the original gene’s function or not, we can help inform the development of those types of gene therapies.

Similarly, in Sanger Institute Director and Senior Group Leader, Professor Matt Hurles’ group, they are working on what’s called saturation genome editing (SGE). This means they are taking every single nucleotide, the basic building blocks of DNA – known as A, T, C and G – and changing it to every other possible DNA letter to see if there are any functional effects. Ultimately, the team wants to help diagnose neurodevelopmental disorders that have incredibly rare variations in their DNA. However, to be able to do this for every exon of every gene, even with a smaller selection of key genes and the vast expertise and infrastructure available at Sanger, this could take decades. We hope that if we can delete entire exons one by one and see the effect of each deletion on cell fitness, we could possibly help their team to prioritise exon targets for SGE.

What's really exciting is the scale that the Generative Genomics programme operates at and the idea that nothing is beyond the realm of possibility – which is crazy! I have to completely reframe how I think about projects having previously worked in an NHS lab. Until now, I have been used to getting a long wish list and then narrowing it down, whereas in our group, we get the long list, and we make it even longer.

I find that I have been easily inspired throughout my career – by the range of really interesting people working in my field, and at the institutions I have been so fortunate to have been a part of.

If I have to choose one, the person who has inspired me most in my career, especially in my journey to Sanger, was my honours and master’s supervisor, Dr Marco Weinberg. Marco is a pioneering South African scientist who is based in North Carolina, USA and so I didn’t get to spend my day-to-day with him during my studies, and yet he still managed to have such a massive impact on my life and career as a whole.

My supervisor challenged me to think bigger, have more self-confidence and to go for what I wanted, not what I believed I deserved. Initially I had no plans to study beyond my MSc, but he and his team at the University of Witwatersrand inspired me to pursue a PhD, and when it came time for me to apply for programmes, he encouraged me to look abroad. I decided that the USA was too far from home in South Africa and that the time difference would be challenging to keep in touch with my family and friends, so he suggested applying to the University of Oxford.

The UK somehow seemed much closer to home and, although it was still a scary thing, I trusted him so much that I went for it, got it, and I don't regret doing it at all. I would never have thought to apply to Oxford if he didn't put that idea into my head and make me believe that I could do it. We still keep in touch. We email and have virtual calls every now and again and if I need any advice, I go straight to him. I’m lucky to have a lifetime mentor in him.

It's very different but also familiar in a lot of ways. There are a lot of South Africans in the UK, which is great, but I do really miss being around family and friends back home, and I miss access to the beautiful nature that South Africa has to offer. I do prefer the day-to-day lifestyle in the UK with the extensive public transport infrastructure that has given me a lot more independence. Of course everyone talks about the critical difference in weather, but I don't really mind that. I (quite) like the rain!

I would say go for it. If you are interested in finding out more about how the body works at the most fundamental level and why, and you want to create something from your own ideas, then a research career in genomics is definitely worth exploring.

Within science and research more broadly, there are so many different topics and all sorts of roles. There are people who come up with the research questions and design experiments, people who help to carry out the experiments and those who analyse the data, and everything in between. Some people like to always be on their toes by adapting and changing tasks every day, and some people like to do more routine work. Both are very important and there is something in this career path to suit everyone.

A research career comes with so many benefits, most importantly being able to do something that you find genuinely interesting, while having a good work-life balance. That's really conducive to being happy at work and in life. Also, nothing is set in stone, so it's definitely worth trying!

The culture and the collaboration. I am in awe of all the interesting people here, but also how curious everyone is to learn more about the field. Every time I go to a talk, there are always people asking fascinating questions and engaging in the talk even if it's not about their own topic.

I also like the feeling that there is a broad support network with entire teams dedicated to ensuring employees are looked after and have a good work-life balance.

When I am feeling nerdy I like to listen to the Cambridge Tech Podcast. It’s about innovation and technology happening in and around Cambridge, which I find really inspiring. In fact, I usually feel nerdy, but I often switch off when I listen to podcasts, so I find it really relaxing. I do sometimes like to listen to history podcasts, like A Short History Of…, but then my husband tries to quiz me on them, and I can't remember anything! I do enough reading for my day job, so I read books for leisure on a more sporadic basis. As it so happens, I am currently reading There are Rivers in the Sky by Elif Shafak (my favourite author).

Probably ‘Brown Eyed Girl’ by Van Morrison. My mum, my sister and I all have brown eyes, so my dad would always sing that with us. It makes me think of my wonderful family back in South Africa who I miss very much.