In conversation with Johnathan Cooper-Knock

Professor Johnathan Cooper-Knock is a clinician-scientist at the Sheffield Institute for Translational Neuroscience (SITraN). He is the first MND Association Rob Burrow Professor in Translational Neurobiology, a role created in honour of the late Rob Burrow CBE to accelerate research that delivers treatments for people with motor neurone disease.

Q: How does it feel to be named the first Rob Burrow Professor – and what does the title empower you to do next?

A: I’m tremendously honoured. Meeting Rob Burrow’s parents as part of the appointment was an absolute highlight – being able to communicate my gratitude and to see what they’re doing to raise awareness and funds for a cause I really believe in. The next step is to honour their support by getting effective therapies to patients as fast as possible.

This Professorship also helps me think about how we can work together with  the new Rob Burrow Centre in Leeds. It is such a unique place that provides specialist clinical care, support, and research under one roof. I think that a number of the things my lab has been developing – like prediction tools for the MND patient journey – can be better moved toward the clinic faster if we test them in Sheffield and Leeds jointly.

Q: What first drew you into this field of research? And how did Sheffield shape your approach as a clinician-scientist?

A: During my medical studies I got interested in neuroscience. As a medical student in Oxford, I did a research project with Professor Kevin Talbot – one of the first times I’d met  patients suffering MND. It made a real impact on me: the tragedy of the disease, how aggressive it is, and how it often seemingly comes out of nowhere.

I moved to Sheffield in 2008 into a clinical academic post, and I’ve always intended to do both clinical work and research and they each inform the other. Professor Pamela Shaw has been my mentor ever since I came to Sheffield – she’s been tremendously inspirational. The Institute I sit in was built by Pam, and her model of joining cutting-edge molecular biology with the clinic and clinical trials is the model I’ve learned from.

Q: Where is your science breaking new ground right now?

A: A key insight in my lab is that you can reduce the search space for genetic discovery by using biology to tell you where to look. If you look across the whole genome there are too many changes to identify what’s driving disease. So, we focus on what we know about MND: it affects motor neurons. It turns out that if you look at the bits of the genome that are active and important in a motor neuron, you can ignore about 90% of the genome. In work we published a few of years ago, this approach helped us identify several hundred risk genes – orders of magnitude higher than ever before.

We’re now doing the same thing with other cell types involved in disease using single-cell and spatial transcriptomics technologies. This will help us build a more complete picture of where genetic risks act across the environment which contains motor neurons.

Q: So, is there a particular discovery you think may be a game-changer for patients?

A: We used a deep-learning approach to search for genetic influences on survival, and one non-coding variant on chromosome 7 stood out because it increased expression of a gene called CCDC146 and made motor neurons display features of MND when we tested it in the lab.

We noticed that people and mice with no CCDC146 are otherwise healthy, so we tried to reduce expression of this gene with an antisense oligonucleotide as a potential new treatment for MND. Lowering CCDC146 consistently improved survival of MND patient-derived neurons and dramatically extended survival in a mouse model of severe MND disease.

We also found that CCDC146 sits in the primary cilium of motor neurons, and reducing it helped restore both cilia structure and localisation of TDP-43, a vital protein that normally resides in the cell nucleus. It regulates RNA metabolism, splicing, and stability, but we already know that in MND it moves to the cytoplasm and can’t do its job properly. Together, these findings suggests that cilia-related signalling might be a broadly relevant way to slow MND progression. That could transform people’s lives.

Q: You’re building prediction tools clinicians can use – what can they do already, and how will you test them?

A: Using deep learning, we can now predict when a person will need an abdominal feeding tube, called a PEG, with an error of a couple of months. We can make the prediction at the point of MND diagnosis. This is incredibly useful for care planning, but also we hope it will give patients and their carers a better sense of what to expect.

The input data is pretty standard, things clinicians usually have at diagnosis: such as site of symptom onset, when symptoms first occurred, age, sex, and weight. But even if some of these data are missing, we are able to “impute” missing information and achieve good prediction accuracy. We’ve validated the model in two independent datasets and are now designing a multi-site ‘switch-on/switch-off’ trial – one period using current clinical practice, another using the tool – to see if we can improve outcomes.

Q: Your work focuses on the genetics if MND, but how do environment and lifestyle intersect with molecular mechanisms?

A: We’re looking at what moves someone from being genetically at risk to developing disease. We have a focus on exercise. I want to say this up front: I would not tell anybody to stop exercising – exercise is good for the vast, vast majority of people. But our data suggest that in a very small proportion of people doing extreme amounts of exercise, there is a link to risk of MND.

Our goal is to identify who is genuinely at risk so people can make informed decisions. We’re also dissecting the molecular mechanisms – at the neuromuscular junction in flies, for example, we can protect animals genetically predisposed to MND from exercise-induced motor neuron toxicity using a drug.

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Our goal is to identify who is genuinely at risk so people can make informed decisions._”

Q: You’ve already made some amazing discoveries and developed clinically applicable tools? What does winning the Lister Prize mean for you – scientifically and personally?

A: It’s been fantastic. The Prize has raised the profile of the lab. The funding is going into a long-term goal: bringing the latest technologies into my lab in Sheffield to guide the hunt for MND risk genes. And the network has already been brilliant – conversations at the annual meeting have already changed how I think about aspects of the C9orf72 genetics and structural variation, and the Lister community has connected me quickly to cilia experts.

As a geneticist you can suddenly ‘wander into’ a field you’re not yet expert in; those connections are absolutely critical. Just like being a clinician-scientist keeps you clinically focused, all these perspectives and connections help you keep yourself open to new ideas, methods and different views of the big picture, which is, of course, extending and improving the quality of life for people diagnosed with MND.