Multiscale modelling and control of soft biological matter: Linking biomolecular interactions to macroscopic function

Biological functions emerge from the molecules that make up cells, tissues and organisms. At high concentration, interacting biomolecules often form intermediate or mesoscopic structures that determine biological function, but the properties of these structures cannot be identified through measurements of the biochemical properties of the molecules in isolation.

Mesoscopic structures formed by biomolecules with perturbed interactions, and by the actions of viruses and bacteria, have been implicated in a range of pathologies that affect millions of people worldwide, including neurodegenerative diseases, cancer, diseases of the blood, infectious diseases such as influenza, and bacterial infections. Soft matter physics, in which the aim is to provide a consistent physical description of how properties and processes at mesoscopic and macroscopic length scales emerge from molecular constituents, is a promising approach to address this biological challenge.

However, this requires physical models grounded in accurate biomolecular interactions, and tools that can simulate biophysical processes across length scales.

In this project, I will build a theoretical framework to predict how macroscopic biological functions emerge from the properties of mesoscopic structures formed by interacting microscopic biomolecules. I will build, validate and apply the framework in the contexts of three experimentally tractable and clinically relevant biological systems with strong underlying physical links - I have identified an international network of collaborators to perform the experiments for validation. I will achieve the following objectives:

1) To connect the molecular interactions of proteins to the mesoscopic properties of biomolecular condensates and their effects on macroscopic functions in cells.

A recent paradigm shift in biology has revealed that many human proteins and RNA can condense or aggregate to form liquid-, gel- or solid-like structures under cellular conditions. Biomolecular condensates, a physiological example of this process, have been implicated in diseases including neurodegenerative diseases, infectious diseases and cancer. However, it is largely unknown how physiological and pathological molecular interactions contribute to condensate functions in health and disease.

2) To connect the molecular interactions of phages to the mesoscopic properties of phage droplets and their effects on macroscopic functions in bacterial biofilms.

Bacterial biofilms are a leading cause of antimicrobial resistance, which is thought to cause 700,000 deaths each year globally, with a cumulative cost of $100 trillion by 2050 if no action is taken. Recent evidence suggests that viral phages expressed by various bacteria may have important effects on antibiotic resistance, but to contribute to improved treatments for the many diseases associated with such bacterial infections, we need to understand the mechanisms that confer phage-expressing bacteria with these benefits.

3) To connect the molecular interactions of hemoglobin fibrils to the mesoscopic properties of fibril aggregates and their effects on macroscopic functions in sickle cell blood.

Pathological biophysical dynamics of red blood cells are a hallmark of diseases of the blood that affect millions of people worldwide, including sickle cell disease (SCD). In SCD, blood increases in viscosity and may clog in deoxygenated conditions, causing death if left untreated. There is an ongoing clinical effort to develop genetic and pharmacological treatments for SCD, but we lack tools to prioritise specific treatment strategies or to clinically monitor patients and identify complications before they manifest physiologically.

The specific outcomes in each biological system will have relevance to molecular diseases and bacterial infections that affect millions of people worldwide, and the general framework will be applicable to further biological systems and a vast array of diseases.