Q&A with Dr Jemeen Sreedharan

David Hague Early Career Investigator of the Year 2019, Alzheimer's Research UK
What do you think has been your biggest contribution so far to the field of dementia research?

My most highly cited work is the identification of TDP-43 mutations in patients with MND. However, I think this has been surpassed by our recent TDP-43 knock-in mouse, which revealed a multitude of mechanisms by which these mutations could actually cause dementia. We are the first group to demonstrate that TDP-43 mutations perturb TDP-43 autoregulation, and this is exciting because it immediately suggests therapeutic opportunities. Not only this, but by comparing mutant mice with different phenotypes in our study we think we’ve already identified disease-resistance factors. So, while identifying mutations in humans was important, understanding the mechanisms of these mutations in a physiological ‘knock-in’ system has been an enormous step forward.

What does winning the David Hague Early Career Investigator Award 2019 mean to you?

It is fantastic! The David Hague Award is so highly regarded in the field, and the generous amount of money I’ve been given will immediately have a major impact in the way my lab functions. The funds will give us the opportunity to initiate some exciting new research projects that we have had in mind for a while. The Award reflects the efforts that I have made over the past 10 years to first identify TDP-43 mutations, then find genuine TDP-43 modifiers using flies, and then move my studies into the mouse. The prestige of the award will no doubt be a major addition to my CV that I hope research fellowship panels will notice when considering my applications in the next year or so.

In 2018 you were successful in securing a number of project grants as a PI, what is your experience of the grant application process? What do you find most challenging about it?

Failures aside, I have found the grant application process to be quite enjoyable. Coming up with novel questions and novel experimental ideas time and time again when writing applications can be challenging, but when you do conceive of something genuinely new it is very satisfying. It is an essential part of our job as scientists to come up with ambitious ideas, and it is vital that we communicate these plans effectively to reviewers. This challenge of communicating thoughts to a broad panel of peers is perhaps the single most difficult part of the writing process. In the process of applying for a grant it’s infuriating when you fail, but it makes you better next time round.

What advice would you give to clinicians who are thinking about combining clinical duties with research?

You are needed!

We need more clinicians conducting neuroscience research. As a group, medics think about patients first, which is key to identifying biomarkers of disease and developing therapeutic agents. The flexibility that a clinical academic career affords and the wonderful opportunities to explore and make new knowledge are highly attractive aspects of the job. Neurologists as a group tend to be very inquisitive individuals who already have many of the qualities necessary for a career in science. The work is not easy and training to be both a doctor and a scientist takes time, but the rewards, at all levels, can be enormous.

What do you think are the biggest challenges facing dementia research in the next 10 years?

This is a tough question. As a community I think we’ve done a pretty good job finding genetic causes of dementias, and we have made progress in understanding the mechanisms by which some of these mutations could contribute to disease. We have also developed some excellent tools to administer therapeutic agents to the brain, and these will only get better. More work is still needed on all these fronts to ensure we do not lose momentum. I think one of the biggest challenges may be in getting to patients early enough. With all the knowledge and drugs in the world it would be a shame if we fail simply because disease has progressed too far by the time the patient gets to the clinic. A lot of current dogma about disease causation is based on models of disease that try to recapitulate the end stages of disease. Newer models of disease that are not reliant on overexpression of disease-linked proteins are important, and somehow, we need to translate observations from these models to find useful biomarkers that predict dementia in humans. There is still so much to do.

What’s next for the Sreedharan lab??

Thanks to our discoveries in the fly and our TDP-43 knock-in mouse we have a lot of credible leads that we are working on. We want to continue to develop the mouse model further as a translational tool and have already shared it widely with groups around the world. My group has been focussed on using brain MRI to study the mouse and we have already made some intriguing observations. We have also recently started using human iPSCs and CRISPR editing to better understand TDP-43 autoregulation in vitro. We think this will lead to therapeutic targets for MND and FTD. We also want to return to screening for modifiers of TDP-43 toxicity in vivo using the power of Drosophila genetics. I had great success doing this in the USA as a postdoc, finding three modifiers of neurodegeneration. I am sure that we can find many more modifiers. I’ll be putting these and a few other ideas together for Fellowship applications in the near future to build the lab in the longer term. It’s all designed to accelerate progress towards therapies for dementia and motor neuron disease.