Categories: Sanger Life12 July 20226 min read

Searching for the roots of childhood cancer

Dr Thomas Oliver is a trainee pathologist at Addenbrooke’s Hospital in Cambridge, and is studying for a PhD at the Sanger Institute. He works on understanding the origins of childhood cancers with Dr Sam Behjati and Dr Raheleh Rahbari. We spoke about his work, and a newfound fascination with eels.

Tell us about your work

Childhood cancers are unlike those found in adults – they tend to arise from cells that never made it to a mature state. These cells get “stuck” along their developmental trajectory, and this has implications for which treatments they receive and how they respond to them. For example, one of the cancers I have studied, the malignant germ cell tumour, tends to require less intense chemotherapy regimen in children than in adults. How one defines child here is a bit tricky though – are the tumours of teenagers’ true childhood cancers or are they just adult tumours rearing their head early on? It is important to get the treatment decision right. You don’t want to under-treat and risk relapse whilst over-treating can result in profound, lifelong side effects for the child. It’s rather like a therapeutic “Goldilocks zone”.

Evidence has emerged over the last few years that the first step for many childhood cancers occurs whilst the patient is still a baby in their mother’s womb. If we can identify what this step is and what cell it is occurring in, then we can start to devise better tailored screening and treatment options. My work focuses on examining the DNA and RNA of cells, sometimes through microdissecting out tiny groups of them, to answer these questions. All cells naturally acquire genetic mutations over a lifetime, the vast majority of which are harmless. The specific collection of mutations a cell has in its DNA provides the story of that cell’s journey, right from the fertilised egg. If you do this for lots of different regions of a tissue or even a whole person, you can get a really high-resolution view of these earliest developmental steps. The RNA provides the second layer – it can tell us what fetal cell type a childhood tumour resembles, providing clues as to its origin and why it stopped maturing.

Detailed genetic and transcriptomic surveys are already having a profound impact on the way we classify and treat tumours although there is still a lot to do. Hopefully, our work will be an important contribution to the ongoing transformation of patient care!

Why did you become a scientist?

After I finished medical school, I did a couple of years of general clinical work before becoming a trainee pathologist. Then I decided that I wanted to combine academic work with clinical work. Pathology is a great specialty for that because the day-to-day work is often looking down a microscope, trying to answer questions: What is this? Why is it there? What features will impact the way it is treated? Asking these questions, studying tissue, very naturally lead into doing research.

Over the past few centuries, pathologists have successfully used the microscopic appearance of stained tissue sections to categorise diseases and predict their behaviour. It is really gratifying now that I can explore the molecular changes behind these observations. We are beginning to understand the underlying mechanisms behind what we see.

How is genomics influencing pathology in the clinic?

Pathology is moving from the traditional examination of stained slides alone to more molecular pathology, incorporating next-generation sequencing data into our assessment. You still need to have the review of cells under the microscope - which I love looking at, I think it's very beautiful - but then it can be supplemented with more information.

For example, the gold standard care for children in England with cancer is whole genome sequencing of their tumour, yielding incredibly rich data about what genetic changes and mutational processes a cancer has undergone. Not only do these guide therapy but, occasionally, they reveal the diagnosis too. Some “edge case” tumours are difficult to identify down the microscope but their repertoire of mutations may be characteristic for a particular type. It’s another piece of the puzzle.

I think it's incumbent on us as pathologists to embrace these technologies, understand how they work and how to interpret them to deliver the best, patient-tailored care.

Who are your science heroes?

My supervisor at Addenbrooke’s, Dr Liz Hook. She manages a busy clinical workload, runs parts of the medical course, and does a lot of public engagement / outreach work to get people interested in science. I don't know how she finds time to do all these things. She is a fount of knowledge for all things pathology too. She's been very good at offering me guidance at different points in my career, and she's always been a very strong advocate for me during my clinical training.

Beyond my colleagues, Siddhartha Mukherjee’s writing, particularly The Emperor of All Maladies has been very inspiring. He is a wonderful non-fiction writer (and oncologist) who tells the story of humanity’s relationship with cancer. It was from him that I learnt about the marvellous work of Sidney Farber, a paediatric pathologist who pioneered the first chemotherapy trials. Reading it set me on the path to study cancer and pursue paediatric pathology.

Is there a word or phrase that is overused in your team?

There are certainly some buzz words within the field that we use in our team. ‘Mutational landscape’ is a very common one, ‘clonal expansion’ would be another we love using. They are so useful though that it would be hard to get rid of them…

One word used quite a lot, often by seniors, is the adverb ‘just’. So you ‘just’ need to do this…. many requests that contain the word ‘just’ invariably end up needing much more work than was originally envisaged!

Can you describe the Sanger Institute in up to 10 words?

Packed with inspiring and collaborative colleagues.

I feel very privileged to do my PhD here. The work is so exciting and, whether it is a conversation in a corridor or presenting new data in a meeting, I get to see how the minds of some of the most brilliant people in the field work, and their creative solutions to longstanding problems. It’s an incredibly humbling experience.

What's the most surprising thing you've learned recently?

I’ve read an amazing book recently called The Book of the Eels, by Patrik Svensson. It’s part memoir of his relationship with his dad, and partly a history of humanity’s relationship with eels.

I now think eels are the most fascinating creature on the planet – the book is full of mind-boggling facts about these enigmatic creatures! For example, eels only develop gonads when they are ready to reproduce, dissolving their stomachs and sustaining themselves on their fat reserves alone as they make their final trip, thousands of kilometres to their birthplace and breeding ground in the Atlantic Ocean. That is pretty impressive, right?

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