Molecular Engineering for Rapid Low-Cost Metabonomic Profiling and Metabolite Detection

Our bodies produce hundreds of different small molecules based on a core chemical framework, known as steroids. These families of steroids play crucial roles in cellular structure, signalling, digestive health and reproduction, and because of this role in signalling many steroids (testosterone, progesterone etc.) are also given as drugs. Subtle changes in the precise balance of steroids are often a marker of biological dysfunction or disease (e.g. metabolic disease), or of steroid drug use/abuse. And due to the ubiquity of steroids in biological processes, if organisms are over exposed to steroids during development, then huge damage can be done (e.g. fish and amphibians in sensitive aquatic ecosystems) .

Measuring the relative concentrations of different steroids (creating a steroid profile) in many different samples (blood, faeces, urine, wastewater) enables us to diagnose disease, monitor health or design better environmental remediation, but this is extremely challenging due to the chemical similarities between the steroid molecules. Currently steroid profiling is only possible with high performance chromatography coupled with mass spectrometry, a costly and labour-intensive measurement requiring a lot of expertise. Attempts to generate simpler specific antibody assays are unwieldy, requiring tens or hundreds of expensive antibodies and the use of radioactive tracers. Neither are suitable for 'point-of-need' use near a patient or in the field. In this fellowship I will develop a new array of sensors for profiling bile acids and other steroid molecules, using an innovative chemical toolbox and sensing methodology developed in my laboratory. My method uses fast and inexpensive luminescence spectroscopy and is suitable for translation into a point-of-need steroid profiling tool.

I hope to make steroid profiling a routine clinical or research measurement and will demonstrate the merits of the technique to measure the profile of a family of steroids called bile acids, in blood, that have been shown to be strongly diagnostic of both early- and late-stage liver disease (the 3rd highest cause of death in the UK and increasing), informing on underlying cause, severity and possible treatment pathways. Whilst 'total serum bile acid' quantification is routine, it is often uninformative, and the crucial profile detail of different concentrations of various bile acids that we can measure will enable a 'precision medicine' approach, particularly in the case of detecting alcoholic hepatitis. Alongside detecting liver disease, there is a growing body of evidence highlighting the potential of steroid profiling in detecting early-stage gastric cancers (7th highest cause of death), cardiac disease (leading cause of death), and metabolic disorders including diabetes in an increasingly overweight population, as well as many other conditions.

Steroid profiling can also be used in laboratory experiments to quickly find new ways of degrading steroids in wastewater treatment. I will translate my technology to work with collaborators in water engineering to rapidly discover degrading solutions for estrogens and androgens and work towards preventing environmental damage from human and veterinary medications entering the water systems. Our work will ultimately lead to better detection and management of disease, better understand metabolic health and the effects of diet, and better systems to protect the environment - a One Health approach.