Across the world, clinicians and scientists have volunteered to make their skills and resources available to the COVID-19 response. Here's what we've been doing to contribute to this global effort.
We have been preparing for a global pandemic for many years and worked with the WHO on influenza, MERS and Ebola. Since January 2020 we have focused all of our activities on coronavirus research.
The whole lab have got behind this effort with extraordinary enthusiasm, redeploying to do whatever was needed. We're all contributing where we can:
- Leading the GenOMICC study, which has discovered genetic associations with severe Covid-19 that may lead directly to new therapies.
- Leading the ISARIC 4C consortium (together with co-leads Calum Semple and Peter Openshaw), which has provided a comprehensive description of the new disease, defining the importance of obesity, diabetes, and age; produced a widely-used prognostic tool (the 4C score); and provided essential weekly updates to government (SAGE).
- Contributing to the steering committee, design and recruitment to the RECOVERY trial, which found the first effective treatment for Covid-19, dexamethasone and has convincingly excluded two others (hydroxycholoroquine and lopinavir/ritonavir)
- Helping to establish the RECOVERY Respiratory Support trial to test different modes of ventilatory support
- Leading global harmonisation in observational outbreak research (the ISARIC CCP)
- Contributing to WHO Panels (Clinical Management; Research Prioritisation)
- Providing advice on clinical management, trials and supportive care to UK Government (NERVTAG & MHRA)
- Caring for patients with Covid-19 in intensive care
Our existing research has mostly been paused, but some essential elements continue under the leadership of Sara Clohisey, who has essentially stepped into my role running the lab while I'm working flat-out on COVID-19. More information on our research programme in peacetime can be found below on this site.
Translational genomics in critical illness
We are trying to understand the mechanisms that make people desperately sick in sepsis, influenza and emerging infections, so that we can find ways to help them survive and recover. Since there is biological variation in the host response to injury, and some of this variation is genetic, we can use this genetic variation to find new treatments.
Combining signals by meta-analysis
We develop and use computational methods to combine data from different sources. The ultimate aim is to use these signals to lead us to biological processes that might be amenable to treatment. We influenza as a model for the broader host response to critical injury.
We develop and apply computational tools, and use in vitro and in vivo genome editing with CRISPR to generate and test hypotheses.
Read a summary of our approach in this perspective article:
Science (New York, N.Y.): 2014;344: 807-8. doi:10.1126/science.1255074
Combining CRISPR screen with diverse experimental sources: meta-analysis by information content (MAIC)
Using genome-wide CRISPR knockdown in human cells, we found 121 host genes that the flu virus needs to replicate itself. About half of them are new discoveries, and might make good therapeutic targets (https://www.nature.com/articles/s41467-019-13965-x). This is important because we've argued for a while that if we design drugs to target these host genes/proteins, it will be harder for the virus to evolve resistance to our treatments (http://dx.doi.org/10.1126/science.1255074).
We found a lot of new genes, but we also validated many findings from previous groups. So we've taken the concept of meta-analysis - well established in clinical research - into basic science.We developed an algorithm called meta-analysis by information content (MAIC) to integrate our new findings with many previous studies of host genes required by flu.
Code to run the MAIC algorithm can be downloaded from github.com/baillielab/maic.Li B et al. Nature Communications 11:164(2020)
Combining genetic signals with cellular transcriptomics: coexpression of GWAS hits
Our post-GWAS analysis method (network density analysis; NDA) reveals new biological features of numerous disease states and traits. It works by examining a coexpression network of transcription start sites (discovered in FANTOM5). We find that transcripts containing GWAS hits for a given trait tend to fall into more dense groupings in the coexpression network than randomly-selected transcripts.
NDA demonstrates that GWAS hits for a given disease tend to be near promoter/enhancer elements with similar expression profiles, which enables us to find more hits, fine map probable causative SNPs, and implicate cell types in pathogenesis. Surprisingly, for some diseases, the underlying variants fall into distinct functional groups, suggesting either dual mechanisms of disease, or distinct disease endotypes.Baillie JK et al. Shared Activity Patterns Arising at Genetic Susceptibility Loci Reveal Underlying Genomic and Cellular Architecture of Human Disease.PLOS Computational Biology 14, no. 3 (March 1, 2018): e1005934. PMC5849332.
Combining biological hypotheses with genetic signals: gene set hypothesis testing
The lack of specific hypotheses in traditional genome-wide association studies has a disadvantage - it greatly limits the statistical power, ensuring that only the strongest signals can be detected, even with very large numbers of subjects.
Gene set hypothesis testing (GSHT) enables investigators to take a biological hypothesis and test it using GWAS data. For example, in our paper, we tested the hypothesis that failure to downregulate inflammatory signals during macrophage maturation is a key mechanism in the pathogenesis of Crohn's disease. We defined search criteria to find inflammatory genes that are downregulated during macrophage differentiation, and then empirically tested the hypothesis that these genes are likely to be associated with Crohn's disease.Baillie, J. K. et al. PLOS Genetics 13, e1006641 (Mar. 6, 2017).
Testing guilt-by-association: FANTOM5
In the FANTOM5 consortium we showed that, with a sufficiently rich expression dataset, it is possible to infer functional relationships between genes (and other transcribed elements in the genome, such as enhancers and lncRNAs) by grouping them according to similarities in expression. We proved this using known pathways, but the real value of this finding is that it enables us to discover relationships between genomic regions about which almost nothing is already known.Forrest*, Kawaji*, Rehli*, Baillie*, et al. A promoter-level mammalian expression atlas. Nature: 2014;507: 462-70. PMC4529748
Throughout the history of medicine, progress has been made by recognizing patterns of disease, or syndromes. When new technologies are invented, they can reveal observable characteristics that have close relationships to disease trajectories, outcomes, and most importantly of all, response to therapy. Genomics and transcriptomics have these properties, but raise an additional challenge: the scale of the data is such that detecting relevant signals is a substantial computational and mathematical challenge.Scicluna BP , Baillie JK. The Search for Efficacious New Therapies in Sepsis Needs to Embrace Heterogeneity. American Journal of Respiratory and Critical Care Medicine: 2018;doi:10.1164/rccm.201811-2148ED
Russell, C. D. & Baillie, J. K. Treatable traits and therapeutic targets: Goals for systems biology in infectious disease. Current Opinion in Systems Biology 2, 139–145 (Apr. 2017).
Pairo-Castineira E , Clohisey S, Klaric L, Bretherick A, Rawlik K, Parkinson N, Pasko D, Walker S, Richmond A, Fourman MH, ..., Baillie JK. Genetic Mechanisms of Critical Illness in Covid-19 medRxiv: 2020; 2020.09.24.20200048. doi:10.1101/2020.09.24.20200048
Millar JE , Neyton L, Seth S, Dunning J, Merson L, Murthy S, Russell CD, Keating S, Swets M, Sudre CH, ..., Baillie JK. Robust, Reproducible Clinical Patterns in Hospitalised Patients with COVID-19 medRxiv: 2020; 2020.08.14.20168088. doi:10.1101/2020.08.14.20168088
Horby P , Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, ..., Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. The New England Journal of Medicine: 2020; doi:10.1056/NEJMoa2021436
Bretherick AD , Canela-Xandri O, Joshi PK, Clark DW, Rawlik K, Boutin TS, Zeng Y, Amador C, Navarro P, Rudan I, ..., Baillie JK, Haley C. Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits. PLoS Genetics: 2020; 16: e1008785. doi:10.1371/journal.pgen.1008785
Neyton LPA , Zheng X, Skouras C, Doeschl-Wilson A, Gutmann MU, Uings I, Rao FV, Nicolas A, Marshall C, Wilson L, Baillie JK, Mole DJ. Molecular Patterns in Acute Pancreatitis Reflect Generalizable Endotypes of the Host Response to Systemic Injury in Humans. Annals of Surgery: 2020; doi:10.1097/SLA.0000000000003974
Docherty AB , Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, ..., Baillie JK, Semple MG. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ (Clinical Research Ed.): 2020; 369: m1985. doi:10.1136/bmj.m1985
Clohisey S , Parkinson N, Wang B, Bertin N, Wise H, Tomoiu A, Summers KM, Hendry RW, Carninci P, Forrest ARR, ..., Baillie JK. Comprehensive characterisation of transcriptional activity during influenza A virus infection reveals biases in cap-snatching of host RNA sequences. Journal of Virology: 2020; doi:10.1128/JVI.01720-19
Li B , Clohisey SM, Chia BS, Wang B, Cui A, Eisenhaure T, Schweitzer LD, Hoover P, Parkinson NJ, Nachshon A, ..., Baillie JK, Hacohen N. Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection. Nature Communications: 2020; 11: 164. doi:10.1038/s41467-019-13965-x
Clohisey S , Baillie JK. Host susceptibility to severe influenza A virus infection. Critical Care (London, England): 2019; 23: 303. doi:10.1186/s13054-019-2566-7
Baillie JK , Bretherick A, Haley CS, Clohisey S, Gray A, Neyton LPA, Barrett J, Stahl EA, Tenesa A, Andersson R, Brown JB, ..., Hume DA. Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease. PLoS Computational Biology: 2018; 14: e1005934. PMC5849332
Roach RC , Hackett PH, Oelz O, Bärtsch P, Luks AM, MacInnis MJ, Baillie JK. The 2018 Lake Louise Acute Mountain Sickness Score. High Altitude Medicine and Biology: 2018; 19: 4-6. PMC6191821
Baillie JK , Arner E, Daub C, De Hoon M, Itoh M, Kawaji H, Lassmann T, Carninci P, Forrest ARR, Hayashizaki Y, Faulkner GJ, ..., Hume DA. Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease. PLoS Genetics: 2017; 13: e1006641. PMC5358891
Arabi YM , Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, Al-Omari A, Hajeer AH, Senga M, Denison MR, Nguyen-Van-Tam JS, ..., Fowler RA. Middle East Respiratory Syndrome. The New England Journal of Medicine: 2017; 376: 584-594. PMC5362064
Hall DP , MacCormick IJC, Phythian-Adams AT, Rzechorzek NM, Hope-Jones D, Cosens S, Jackson S, Bates MGD, Collier DJ, Hume DA, ..., Baillie JK. Network analysis reveals distinct clinical syndromes underlying acute mountain sickness. PloS One: 2014; 9: e81229. PMC3898916
Forrest ARR*, Kawaji H*, Rehli M*, Baillie JK* , de Hoon MJL, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, ..., Hayashizaki Y. A promoter-level mammalian expression atlas. Nature: 2014; 507: 462-70. PMC4529748
Dunning JW , Merson L, Rohde GGU, Gao Z, Semple MG, Tran D, Gordon A, Olliaro PL, Khoo SH, Bruzzone R, ..., Baillie JK. Open source clinical science for emerging infections. The Lancet. Infectious Diseases: 2014; 14: 8-9. doi:10.1016/S1473-3099(13)70327-X
Baillie JK . Translational genomics. Targeting the host immune response to fight infection. Science (New York, N.Y.): 2014; 344: 807-8. doi:10.1126/science.1255074
Baillie JK , Digard P. Influenza–time to target the host? The New England Journal of Medicine: 2013; 369: 191-3. doi:10.1056/NEJMcibr1304414
Everitt AR , Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, ..., Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature: 2012; 484: 519-23. PMC3648786
Baillie JK , Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F, Brennan PM, Rizzu P, Smith S, Fell M, Talbot RT, ..., Faulkner GJ. Somatic retrotransposition alters the genetic landscape of the human brain. Nature: 2011; 479: 534-7. PMC3224101
We are very grateful to recieve funding from the following sources: Wellcome Trust, BBSRC, Sepsis Research (FEAT), Intensive Care Society, MRC.