My research over the past decade has focused on optimising protein production using the yeast Pichia pastoris, which has been used for over 30 years to make recombinant proteins. This yeast is different from the type that you put into bread or beer (Saccharomyces cerevisiae) because it doesn’t ferment and produce alcohol (ethanol). The great thing about this is it means that it grows to high cell densities. So, if you’re trying to make lots of protein, and you think of each cell of yeast a mini factory, the more factories you have, the more protein you get out of it in the end. In 2008 I started a PhD, which was funded by a pharmaceutical company, Fujifilm Disoynth Biotechnologies, with the aim to find ways to make more protein faster and cheaper. Ultimately if you are working to make drugs or vaccines, if you can make the individual components more efficiently, the cost overall goes down. This set the groundwork for the rest of my career to date and although I did publish a lot of papers from my PhD, it’s really the skills that I developed that benefited me the most.
I completed my PhD in 2013, after which I started a role as a Research Associate where I continued to work on Pichia pastoris. I work within the field of Synthetic Biology, the premise of which is summarised by Richard Feynman’s quote “What I cannot create, I do not understand”. I’ve worked on a lot of projects during my Postdoc, unlike a lot of scientists I’ve been fortunate to have a long contract within the same lab. Part of the reason for that is that my field is very small, there are not many scientists in the UK who investigate Pichia pastoris at a molecular level, so finding a lab that does the type of research that I want to do is difficult. The main part though, is that my boss is an incredible mentor and champion. It’s one of the key pieces of advice I’ve learned in my career; find people who will support you and lift you up and believe in you far more than you ever can believe in yourself.
I started my Postdoc investigating the link between the structural organisation of the Golgi apparatus and glycans, the sugars that are added to proteins, using Pichia pastoris. This is quite an abstract idea and the project was what we consider blue sky science, understanding the relationships may lead to better technologies down the line even if there is not an industrial goal. Glycans are often considered a critical quality attribute (CQA) when producing proteins in recombinant systems. If you have the wrong sugar component, the protein can become unstable or not work as effectively. For instance, if you’re trying to produce a human antibody in yeast, the wrong sugars can have a negative impact. Our paper recently got published after 7 ½ years of work, where we found out that altering the structure of the Golgi apparatus had no effect on the sugar patterns of proteins.
I then moved on to working on pioneering a novel cell-free protein synthesis (CFPS) platform for Pichia pastoris. The idea behind this is to take the yeast cells and break them open but doing it in such a way that components are still active. CFPS was originally used in the 1960s and was the technique they used to break the genetic code, establishing what codons correlated to what amino acids. But the technology has grown immensely from there, and now we can use it to make proteins that can be used for personalised medicine, or toxic proteins that are otherwise difficult to make. I was the first person to generate a CFPS platform in Pichia pastoris, and several companies are interested in commercialising this work. This platform has the potential to be huge, the great thing about CFPS is that you can freeze-dry the samples, meaning that you can ship them around the world with no cold chain, and when they arrive at the destination, all you need to do is add water to make them active again. We’ve been using this platform to make virus-like particles (VLPs) that can be used for vaccine research.
The work that I have been proudest of is my latest project, which I have worked on for the past four years as a researcher on the Future Vaccine Manufacturing Research Hub. The aim of this work is to increase the tools and technologies available to low-to-middle income counties, so that they can generate their own vaccines without worrying about patents or licensing. I work with a company in Bangladesh and have hosted some of their research scientists where I taught them the skills and knowledge they’d need to create their own vaccine. Currently, five targets that we’ve been working on together are undergoing animal studies to find out if they’re suitable to be used clinically, including human papilloma virus (HPV) vaccines. Because of my field of study, it meant I was primed to work on a Covid-19 vaccine in Feb 2020. Our aim was not to be first out of the block but to work on second generation vaccines that could be made cheaply and in countries that may not have the infrastructure required to make the new vaccines such as the adenovirus vaccines or the mRNA vaccines. Older technologies still exist for a reason, and if we can have more countries producing vaccines then we will have less limitations on supply.
Not all research has an industrial or applied aspect to it, when I was choosing a field to go into I was particularly drawn to that kind of research. Having something tangible is rewarding, but it’s the contribution to knowledge and exploring rabbit holes that you didn’t even know existed that has brought me my greatest joys in science.