Director, Microbiome Discovery
Senior Scientist, Bioinformatics
Associate Director, Microbiome Discovery
The occurrence of, and treatment responses to, a diverse spectrum of human diseases, including respiratory, metabolic, cancer and inflammatory bowel disease, has been linked to changes in the bacterial communities that colonise our mucosal surfaces, including the skin, lung and intestinal tract.
These communities, collectively referred to as the microbiome, interact with their human host via the production of metabolites and activation of microbe-sensing signalling pathways both locally and at distant sites. The advent of novel sequencing technologies has meant that the microbiome can be easily characterised, and therefore readily targeted.
It has been hypothesised that replacement of a disease-linked, or a dysbiotic, microbiome with a healthy microbiome could influence disease phenotypes, and that baseline ‘signatures’ could help predict which patients are likely to respond to treatment or conversely, experience disease progression.
In Microbial Sciences at AstraZeneca, our goal is to use a range of computational, experimental and translational modelling to harness the microbiome and identify key links with disease. From this, we want to identify drugs targets and candidates that could play an important role at the intersection of the microbiome and host.
Support for Microbiome Modification as a Therapy
Our immune system has evolved to respond to and defend against pathogens. It is becoming increasingly apparent that the immune system also takes cues from the microbiome,1 which directs maturation of immune cells, regulates host metabolism and modulates inflammatory responses across the body.
Early clinical trials to determine if replenishing all or some of a diseased microbiome with a healthy one can influence diseases, have yielded promising initial results.2 It is hoped that these therapies could either be used as a stand-alone or as an adjunct to improve the efficacy of the existing standard of care.
In the context of intestinal infection with the bacterium Clostridioides difficile, numerous groups are demonstrating successful treatment with microbiome modulation such as with faecal microbiota transplant, even when antibiotics are unable to influence disease.3 Similar trials are underway to test the ability of microbial modulators to treat colitis, metabolic disease and certain types of cancer. There is also growing evidence that the efficacy of immunotherapies in cancer can be enhanced by microbiome modulation. Taken together, these data present an additional avenue for development of combination therapeutics involving microbiome modulation therapy in combination with immune targeting therapies.
Mining the Microbiome/Host Interface
While the link between the microbiome and human cellular function is acknowledged, the mechanisms or signals through which the bacterial communities “talk to” our cells have yet to be fully described. This presents a unique opportunity for exploration of novel drug targets and candidates at the interface of human physiology and an untapped organ, the microbiome.
Understanding the interface of the microbiome and human physiology requires a coordinated effort across multi-disciplinary expert teams, including data scientists, microbiologists and biologists. The environment at AstraZeneca enables formation of these cross functional teams. As such, we have developed an end-to-end workstream built to identify novel microbiome targets from large, multiomic datasets, validate these targets using translational studies and ultimately deliver promising therapeutics to patients in need.
The microbiome represents a new, untapped frontier for biomarker identification and drug discovery. Utilising technological advances which enable analysis of large datasets and the disease area expertise present across our organisation, we are unlocking the potential of the microbiome to identify actionable biomarkers and bring novel therapies to patients.
1. Gopalakrishnan, V et al. “Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.” Science (New York, N.Y.) vol. 359,6371 (2018): 97-103. doi:10.1126/science.aan4236
2. Baruch, Erez N et al. “Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.” Science (New York, N.Y.) vol. 371,6529 (2021): 602-609. doi:10.1126/science.abb5920
3. McCune, V L et al. “Results from the first English stool bank using faecal microbiota transplant as a medicinal product for the treatment of Clostridioides difficile infection.” EClinicalMedicine vol. 20 100301. 16 Mar. 2020, doi:10.1016/j.eclinm.2020.100301