24 Dec Q&A: In conversation with Lister Fellow John Knight
John Knight was awarded the Lister Prize in 2023. He is a Lecturer in Cancer Biology at the University of Manchester, where he leads a research programme identifying methods to improve colorectal cancer treatment and patient stratification.
We caught up with John to learn about his research interests, his scientific goals and his experience applying for the Lister Prize.
Q: You’re described as a discovery scientist. What does that mean?
A: Discovery scientists learn new things about fundamental biology while also contributing to helping people. We’re researchers with a medical remit. The way we are researching disease goes beyond innate biology and brings in a clinical setting too. Doing things this way can be beneficial to both basic science and clinical science.
Q: Your specialism is the relationship between protein synthesis and disease. How does disease change the way we make our proteins?
The way proteins are made is pretty consistent – a ribosome moves along the mRNA to make the protein. But how fast the ribosome moves and how often it starts making a protein depends on a lot of different signalling pathways. And those signalling pathways themselves can be regulated by disease.
In a normal cell, there’s a process of sampling the environment outside the cell and using that information to decide whether to signal for protein synthesis. In cancer cells, those ‘let’s go’ signals get turned on when they shouldn’t be. So the machinery that makes proteins, the ribosome, just keeps going. It will be selecting genetic information to transcribe into proteins more often, and it will be moving along the transcript sequence faster. More protein means cells and groups of cells can grow faster. The cells can divide more often and become a tumour.
Q: Does this work differently in different parts of the body?
A: If a tumour develops in a part of the body where there aren’t enough resources to build proteins quickly, as in the case of ovarian cancer, the growth needs to be slower so the cells can survive. In my area of research, colorectal cancer, the cells develop in an area that’s very rich in resources so protein synthesis can happen very fast. We’ve seen that if you inhibit the translation, the proliferation slows down dramatically.
There’s a kind of double-edged sword for the cancer, because moving faster means growing faster. But if you don’t have enough building material – amino acids – to make more proteins, or enough energy to do it, you end up with something called a metabolic catastrophe where the cancer cells just capitulate – give up and die. My Lister Prize application was based on this understanding that you can induce a metabolic catastrophe by speeding up RNA-to-protein translation.
I’m taking a pan-cancer approach, looking at different tumour types in the same lab and asking: What are the fundamental differences between them? Is it something that develops as they as they form? Is it a pressure that gets added later? To help answer these questions, we want to get hold of primary tissue from patients to look at the expression of these major regulatory pathways or elongation rates. Hopefully we’ll be able to use the amazing Christie Hospital biobank near our lab. There might be really obvious differences in regulation between different disease types, which is quite exciting.
Q: How do you measure changes in protein translation speed?
A: There are reliable methods, but they are very difficult and time consuming. They’re not amenable to high throughput drug identification, which is what I wanted to do. So to tune protein synthesis – make it either faster or slower – we came up with a method based on elongation (a stage in the translation process). An elongation reporter gives you a different colour depending on whether you’ve got fast elongation or slow elongation. Part of my Lister Prize application was on developing that, and we’ve got it working quite nicely. We are now using it to find new ways to alter the rates of translation.
Q: Has the Lister Prize allowed you to make more ambitious research plans?
A: The money has been absolutely brilliant and it’s supporting work in the lab already. It’s also given me confidence that the approach I want to take is a good one. There’s been lots of support from the community too, and I’ve enjoyed going to the Annual Meeting and talking to different people in different research areas.
Q: What led you to apply for the Lister Prize?
A: I was commuting to work and I got a daily news email from the faculty here at Manchester University. The Prize was mentioned as a funding opportunity. I started reading about the Prize and what they’re looking for, and thought “I’m ticking a lot of boxes here.”
Q: What would you say to someone who is considering applying?
A: I would say “go for it”. I think even if you’re not successful, it’s great to get that input on your thoughts and what you’re doing. If I hadn’t got the funding, I would still have had that positive outcome to take forward to the next application. After going through the interview I’d had such a lot of really good feedback. And if you’re lucky enough to get the funding then yes, I can’t speak highly enough of the Lister team and the community support.