Scientists are currently hampered in the discovery of optimal drug targets by a failure to understand biological processes at a systems level.
CCAIM’s first aim in the biomedical arena is to leverage structural, metabolic and genetic metadata to develop multiscale generative models – at the level of molecules, cells, organs and whole organisms – to uncover novel targets for antibiotics and host-directed therapies, and define new approaches to modulate inflammation and immunity.
We will also develop new, interpretable deep learning methods to better predict the functional impacts of the protein mutations seen in antimicrobial resistance and cancer using structural modelling, and develop in silico screening methods that better ascertain feature weights and interactions. Crucially, these methods will explicitly state the confidence of machine-learning (ML) predictions.
Finally, we will create new ML/AI methods in cheminformatics to define the boundary conditions for the drug-like chemical space, initially focusing on predicting adequate bacterial permeability to support structure-guided antibiotic development.
Sometimes, however, the scientific agenda is set by world events, and CCAIM was swift to tailor its biomedical discovery approaches to help tackle the COVID-19 pandemic.
A team led by CCAIM Co-Director, Andres Floto, a Professor of Respiratory Biology at the University of Cambridge, is exploring a combination of structural and dynamic modelling approaches to predict new drug targets against SARS-CoV-2, the virus that causes COVID-19. This methodology involves the analysis of a metabolic model that integrates the cell metabolism of various cells of humans infected with coronavirus. The model is providing an in silico comparison of the biochemical demands of the virus versus the infected host cells, and expanding the model to predict the effect of various treatment regimens for COVID-19, looking for- the best drug-optimisation strategies against the virus.
The more we can learn about the fundamental biology and interactions of SARS-CoV-2, the more powerful this sort of drug discovery work becomes. This brings us to CCAIM team member Dr Sarah Teichmann, and her colleagues at the Wellcome Sanger Institute and Human Cell Atlas (HCA) Lung Biological Network.
To explore which of the body’s cells could be involved in the transmission of COVID-19, these researchers analysed multiple datasets of single-cell RNA sequencing, from a variety of tissues from healthy people, including cells from the lung, nasal cavity, eye, gut, heart, liver and kidney. This research, published in Nature on 23 April 2020, looked for individual cells that expressed both of two key proteins that the virus attaches to when infecting our cells – ACE2 and TMPRSS2. They discovered that two types of cells in the nose have particularly high levels of these, making them likely points of entry for COVID-19. This sort of science is foundational to developing medical responses to the pandemic.