Membrane proteins—the molecular gateways that let nutrients in, pump waste out, and allow cells to talk to one another—are notoriously difficult to produce in the lab, and that bottleneck is slowing down drug development. These proteins make up 20–30% of all human proteins and are the targets of the world’s ten best-selling medicines, representing US$180 billion in annual drug sales. They are also essential for vaccines against COVID-19, Hepatitis B, and pertussis. Yet producing them in functional form is a trial-and-error process that often requires screening hundreds of experimental conditions, because the proteins stress the cells that make them and need specific lipid environments to work properly. This project aims to remove that roadblock. The researchers will systematically map the cellular stresses that limit membrane protein production, then build a computer-aided design tool that predicts how to optimise both yield and cell growth. They will also engineer cells with autonomous feedback control—so the cells self-regulate protein production in response to stress—and develop systems that tune the cell’s own lipid composition to match what each membrane protein needs. If successful, the work could transform drug screening and vaccine manufacturing, making it faster and cheaper to identify new medicines and produce biologics at industrial scale.
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SOCIETAL IMPORTANCE. Membrane proteins are essential for life, medicine and industrial biotechnology and yet remain understudied due to their (1) low abundance and (2) physical properties which makes isolation difficult. However, 20-30% of all proteins are membrane proteins with biological functions underpinning signal transduction, nutrient import/export, and cell-to-cell communication. Membrane proteins are potent drug and vaccine targets. Currently, the top ten selling medicines worldwide, and in total US$ 180 billion worth of drug sales, target membrane proteins. Multiple vaccines, including those for COVID-19, Hepatitis B and pertussis, target virus surface or bacterial membrane proteins. Non-pharmaceutical markets include biopesticides (worth US$ 3 billion) and antifungals (worth US$ 19 billion). Artificial expression of membrane proteins is frequently used in pharmacology to identify drug molecules, which may inhibit or enhance protein function. However, engineering high levels of functional membrane protein production remains challenging, limiting the efficiency of drug screening, reducing identification of new drugs and limiting transformative potential. Production of membrane proteins enables progress in promoting human health and provides bio-inspired solutions to pressing societal challenges caused by climate change; however, obtaining high yields of functional protein constitutes a fundamental roadblock to progress which this proposal addresses. SCIENTIFIC CHALLENGE. Despite the importance of membrane proteins in these key industries, their production remains challenging with production of each protein requiring trial and error methods - in some cases requiring screening of 100s of different combinations of experimental factors. This is in part due to the complex process of membrane protein production which results in multiple stresses on cellular production platforms (significantly reducing cell growth and bioprocess productivity). The cell membrane's lipid composition significantly impacts protein function - potentially rendering any proteins produced non-functional due to lack of lipid factors. Therefore, scientists must test multiple different cell types in an expensive and laborious process. This bespoke platform development limits production capacity of functional membrane proteins and, in doing so limits drug screening and development. PROJECT OUTLINE. We address these challenges by first carrying out a detailed systematic characterization of the cellular processes which limit membrane protein production. This will be used to develop a predictive computer aided design tool to enable designs which facilitate both production and cell growth. We will use these tools to design and implement autonomous feedback control strategies that enable living cells to self-regulate protein production in response to stress and therefore maximise production and yield. These systems have the potential to enable increased yields in a 'hands off manner'. We will engineer new cellular regulatory systems capable of tuning the cell's lipid production rate so that the cell membranes' composition and physical properties can be tuned to meet those needed for optimal membrane protein function. We will develop computer aided design tools which enable the prediction of optimal membrane composition. We will demonstrate the function of our new cellular systems to produce high value biomedical membrane proteins and demonstrate their production performance at scale in industrially relevant conditions.
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