Professor Neil Bulleid

Manipulating mammalian cells to create efficient protein factories

One of the major challenges facing the biopharmaceutical industry is to produce sufficient therapeutic proteins in a cost effective way to meet market demand. Over the past twenty years great progress have been made in both upstream and downstream processing which has enabled some products to reach the market place. However, these are just a few examples of the many more potential therapeutic proteins that currently cannot be produced in sufficient quantities. The level of protein production in mammalian cells is now not limited by the level of protein expression, rather it is limited by the cell’s capacity to fold and assemble the translated polypeptide chain. This limitation is particularly true for proteins entering the secretory pathway which not only need to fold correctly but also must be post-translationally modified to form the correct disulphide bonds and to be N-link glycosylated. Correct folding relies upon both the capacity of the folding machinery to cope with the protein load and the environment of the ER to allow correct disulphide formation. Incorrectly folded proteins are prevented from being transported from the ER and are degraded. Hence to increase recombinant protein yield we need to increase the cellular capacity to process the translated polypeptide chain into a correctly folded functional molecule. We are currently collaborating with UCB-Pharma, one of the largest producers of therapeutic antibodies. Our goal is use a synthetic biology approach to engineer mammalian cells and maximise the production of novel biopharmaceuticals.