DDW’s Megan Thomas spent March 1-2, 2022 at the fourth ‘CRISPR in Drug Discovery: From Targets to Therapeutics’, which took place at Babraham Research Campus in Cambridge, UK. Finding it insightful and eye-opening, she looks forward to the next event on ELRIG’s agenda, ‘Research & Innovation’ at The Kings Centre in Oxford on March 29-30.
After my experience at ELRIG’s Drug Discovery 2021 in Liverpool, UK, I felt reassured that ELRIG was doing everything it could to ensure a smooth transition to a ‘new normal’ and a return to community events. I think this was reflected in the turnout at CRISPR in Drug Discovery in the ever-impressive Babraham campus in Cambridge, where all tickets and exhibition booths had sold out by 18 February. The excited energy was palpable from the start of the two-day focus on the applications of the rapidly developing CRISPR technologies with an emphasis on drug discovery applications.
After Andrew Bassett from the Sanger Institute, Marcello Maresca from AstraZeneca and Kilo Maratou from GlaxoSmithKline had welcomed us, we heard from Greg Findlay, whose work linking variants to functional effects with Saturation Genome Editing at the Francis Crick Institute is paving the way for a better understanding of rare variants and how these genetic data inform disease. Findlay presented a case where CRISPR enables rapid, scalable and efficient genome editing, which I expect the clinical community will continue to embrace.
Findlay was followed by sponsorship presentations, which showcased how this exciting science and data can be used in the real-world. Thereafter, we heard from Pavel Tolar from University College London on what CRISPR screening reveals about B cell function and pathology. By contexualising the overall goal to establish a full complement of genes that control B cells by looking at mechanisms by which cells recognise foreign substances, modelling a T cell dependent B cell response, genome-wide screens for B cell activiation and differentiation (in Cas9-expressing mice), and outlining the possibilities CRISPR afford the science, Tolar painted a picture of the ‘heroic effort’ that has been made to date and his optimism for the future.
In the afternoon, Euan Stronach from GlaxoSmithKline presented, ‘High Throughput Functional Genomics approaches to understanding Niraparib PARPi biology’. When it comes to the functional genomics at GSK, Stronach says that their mission is to identify and validate new targets and indications. He was followed by Britt Adamson at Princeton University, who gave his captive audience more information about the work the Adamson lab is doing to map the mechanistic landscape of DNA repair and made a case to convince us that the strategy is effective moving forward, bolstered by their rich data set.
The plenary keynote presentation by Soumya Raychaudhuri from the Broad Institute was next on the agenda. Raychaudhuri, who is also a Professor of Medicine at Harvard University, covered the topic ‘Defining the regulatory effects of autoimmune disease alleles in specific T cell states’. After a final poster presentation, the day ended with Jay Shendure from the Institute of Protein Design and the University of Washington on leveraging CRISPR as a Molecular Recorder, or rather, recording lineage information via genome editing.
Day two kicked off with a keynote presentation from Richard Wade-Martins from the Oxford Parkinson’s Disease Centre at the University of Oxford. His topic was, ‘iPSC models of Parkinson’s: from disease mechanisms to target discovery’. He started by orientating us: if we want to better understand Parkinson’s disease, we need to better understand the mechanisms. The Oxford Parkinson’s Disease Centre is generating multidisciplinary models to do just this.
Emma Rawlins from the Gurdon Institute at the University of Cambridge then presented on applying CRISPR to human tissue-derived organoids, while offering comparisons between mouse and human lungs and what that means for their work. Thereafter, Sahba Seddighi from the National Institutes of Health presented, ‘Proteogenomic Identification of Mis-splicing Biomarkers in ALS/FTD’. These preliminary studies indicate that the iPSC neuron proteogenomic pipeline predicts disease-relevant markers of TDP-43 mis-splicing and provide a workflow for development of novel protein-based biomarkers of TDP-43 mislocalisation.
In the afternoon, Marius Wenig of Standford University School of Medicine presented on gene editing and the neuronal reporogramming to investigate synaptic biology. Him and his team have explored transcription factor-mediated reprogramming approaches which allow the induction of neuronal cell identity from various cell types as distantly related as skin fibroblasts and found that combined expression of key lineage determination factors allows the generation of pure excitatory, or inhibitory or dopamine neurons. The keynote presentation from Laura Sepp-Lorenzino at Intellia Therapeutics then took a deep dive into in vivo and ex vivo therapeutic gene editing, how this will transform medicine, and what it takes to build a full-spectrum genome editing company.
Following another insightful poster presentation, Gerard Schwank from ETH Zurich SUI took the microphone to present on translational genome editing for treating genetic liver diseases. He spoke interestingly about the notion of CRISPR as a drug, and the possibilities that has. Building on this feeling of potential that echoed through the presentations, Kiran Musunuru from Perelman School of Medicine spoke on how CRISPR base editing can be used to treat cardiovascular and metabolic diseases.
The conference presentations finished on a high with a conversation between Omar Abudayyeh and Jonathan Gootenberg from McGovern Institute for Brain Research at MIT. The diversity of cell types and states in humans can be scalably measured and defined by expressed RNA transcripts and other cell-specific features, yet tools to control cells are lacking. The two covered the new molecular technologies for genome editing and cell control by describing a set of molecular technologies their lab is developing to address cell engineering at multiple levels, including large cargo DNA insertion, specific RNA editing technologies, and RNA sensors for programmable protein expression.
Next on the agenda
There is nothing left to do now except look forward to the next conference from ELRIG in Oxford, which will discuss how cutting-edge science continues to be identified and explore how emerging technologies will enable this science to be translated into successful therapeutics. The four sessions will address different aspects of innovation across drug discovery and place an emphasis on both the digital age and novel modalities.
CRISPR in Drug Discovery 2023 www.elrig.org/portfolio/crispr-in-drug-discovery-2023/