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European Lead Factory testimonial: Sara Brown
Sara Brown is a clinical academic dermatologist at the University of Edinburgh whose research focuses on how genetic factors influence predisposition to the inflammatory skin disease atopic eczema and associated conditions. The Brown Lab uses human skin organoid models to investigate the role of molecular genetic factors in health and disease. The ultimate aim of her work is to identify targets for the development of new and better treatments for people affected by eczema, dry skin (ichthyoses) and related allergic conditions.
Sara is programme owner of one of the European Lead Factory (ELF) crowdsourced screening programmes. We interviewed Sara about her experiences with the ELF.
How did you first learn about the European Lead Factory?
I was working at the University of Dundee at the time. Dundee is home to the National Phenotypic Screening Centre, that runs the phenotypic screens for the ELF. It was through discussion with colleagues there that I first learned about the ELF and then I searched online to find out more. I also attended a couple of the ELF webinars which were very helpful; they provided me with a good insight into the opportunities offered and answered many of the questions I had.
What has been your experience with the application process for a screening programme with the ELF?
Applying for this type of in-kind support - as opposed to a more direct financial grant - was a new experience for me. The application did require quite a lot of upfront knowledge of assay development and drug screening and some of the questions were difficult to understand for me as a clinical academic dermatologist.
Luckily I had the advantage of being able to talk directly to the team in Dundee and everybody I have interacted within the process has been supportive and patient in explaining things to me! This helped greatly in determining what was feasible in our application and moving forward with that. I have learnt a lot and it has been a very positive experience.
We have made good progress in a relatively short amount of time which is amazing. There is no way that myself or my lab working with colleagues in Dundee could have taken the work so far without the European Lead Factory.
Something that I would highlight when asked about the ELF by other researchers are the milestone payments that are part of the terms and conditions for running a fully funded programme at the ELF. If the programme moves forward and continues to be successful, milestone payments need to be made to acknowledge the co-investments made by the ELF consortium. These milestone payments do seem large sums of money, but as I'm 100% sure that I would not have reached this stage without collaborating with the ELF, It does make very good sense to me.
What can you tell us about the actual screening programme and your journey to date?
Our screening programme is a phenotypic screen and it is the first of its kind run by the ELF, which we are very proud of. In our programme we use primary human skin cells. The assay that we developed was based on a hit from genome wide association studies (GWAS).
The primary cells that we use are keratinocytes, and the GWAS hit we chose to target is intergenic, but previous work in my lab has shown a functional effect in our skin organoid model.
Keratinocytes can be quite challenging cells to work with and the need to grow them to differentiation has held back the field of eczema drug discovery, so the main therapeutic targets are immune and inflammatory cells, rather than keratinocytes themselves.
It took us many months to optimise the cell-based assay, which was key to getting through the ELF application process. We optimised the assay in various rounds of work, testing it, trying it, improving it, and assaying it again. When we were confident that the assay was robust and reproducible to an extent, we carried out an annotated compound screen with the National Phenotypic Screen Centre team.
Results from this compound screen confirmed that the assay performed well, after which the 50,000 compound screen was executed by the ELF team, and all results have passed the quality control metrics. This was very exciting to me and my team. We now have a qualified hit list of the top 50 hits that we can take forward.
Translational research needs funders to support the early and obviously more risky steps in drug discovery. Without that support, we'll never get the exciting basic science through to the clinic.
Of those top 50, together with a medicinal chemist expert and others from the ELF, 15 top hits were selected and these are being resynthesized at the moment. This is the current stage of the programme, it is very promising and exciting, but I know we still have a long way to go!
What is the major added value of the ELF?
For me, the major added value of the ELF is the sharing of expertise at each stage. As a researcher with specialist clinical and biological knowledge, I have been able to direct the work, whilst benefiting from experts in the field of drug discovery and medicinal chemistry. I knew very little about assay development, for example the parameters that are required in terms of variance and reproducibility within a 384-well format. So making sense of the annotated compounds and full 50,000 compound screens would not have been possible for my lab group alone. Within the ELF programme we are partners so we can work together, benefiting from complimentary expertise for the best outcomes.
It is really not an over-statement to say it has been an amazing privilege to discuss our own project with experts in the field of drug discovery and medicinal chemistry, combined with the input that we received from industry. Within the ELF, we as researchers aren’t just handing over therapeutic candidates, we can work with the experts on the pathway of discovery, which will ultimately benefit patients, our most important goal.