Nicola Burgess-Brown: Unravelling proteins
Recombinant protein expression in host cells such as bacterial or insect cells facilitates the production of large amounts of proteins, which can be used for crystallisation to obtain the protein structure, or in cellular assays to look at their function. Collaborations with partners such as academics, industry and patient groups aim to find compounds that can be developed into potential drugs.
Q: Why is it important to understand the structure and the function of proteins?
Nicola Burgess-Brown: Proteins are found in every cell in the body. They are involved in virtually all processes within cells and they are the targets that drugs bind to. In order to understand how a protein works, we have to alter its function such as stop it working or make it work better. We do this by adding tool compounds, which are potential drugs, to the proteins in cells and follow their activity; this is the first step in developing medicine. We can also look at the blueprint, the atoms that make up the protein, by viewing its three dimensional structure. I can show you this on a model: this is the protein and we can view how the compound binds within the structure to stop it working or make it work better. This enables us to design more effective compounds.
Q: How does your own research help in understanding proteins?
NBB: My research is the very first step in making proteins, which involves taking the information from the human genome, the DNA, and making copies of each gene which codes for a particular protein. We use a method called recombinant protein expression in host cells such as bacterial or insect cells, essentially asking them to make large amounts of the protein. This protein can then be used in other experiments such as crystallisation to obtain the protein structure, or in cellular assays to look at protein function. My group specifically identifies those proteins which are produced to the highest level to enable all of these experiments to be undertaken.
Q: Who are your research partners and how does it all fit together?
NBB: Our research partners are academics, charities, governments, industry and patient groups. All of whom need large amounts of pure specific proteins to carry out new research. All of these groups want to collaborate with the SGC and together we are interested in the areas of oncology, metabolic diseases and neuroscience, with particular focus on Alzheimer's disease. We are funded by Alzheimer's Research UK to study the genes, the proteins involved in Alzheimer's. This is a very important area of research for the future, particularly with people living longer and the disease becoming more prevalent. In the UK there are approximately 850,000 people suffering from Alzheimer's and this is expected to rise to 2 million by 2051. We also work with the European Lead Factory, which is a large consortium of pharmaceutical companies and academic groups who together try to find lead compounds which could be potential drugs. The role of my group in this project is to produce the proteins which are used in cellular assays to identify which compounds affect protein function.
Q: What are the most important lines of research that have emerged over the last 5-10 years?
NBB: In the past scientists had to extract proteins from cells or tissues, which is a very inefficient process, until recombinant protein production, in other words using a host to express the protein, became available. Recombinant protein production has improved significantly over the past few years with advances in new expression systems, high throughput technologies, miniaturisation and removing bottle necks in processes. But difficult proteins still remain challenging; they require special skills and technologies. We aim to develop or improve expression methods to enable the production of challenging proteins such as integral membrane proteins, or IMP's as they are known. These are particularly challenging because in order to produce them in the lab they require many litres of cells and they must be prepared in the presence of detergents. Detergents create problems in that they often prevent the proteins from crystallising, so structural biology of membrane proteins is very challenging. However the SGC in Oxford over the past 5 years have managed to solve the structures of five human membrane proteins and this amounts to 10% of those solved worldwide, so we are making a large contribution to this area of research.
Q: Why does this line of work matter and why should we fund it?
NBB: There are thousands of proteins involved in cellular processes in our bodies, many of which play important roles biologically. When something goes wrong with a protein, for example too much is produced or it becomes mutated and no longer functions properly, this very often results in disease such as cancer. Although we are now able to make many proteins in host cells, such as bacterial or mammalian cells, there are still lots of proteins that we cannot produce in this way with current technologies. So it is very important that we continue to develop new tools and expression systems to enable production of the most challenging proteins, many of which are also important drug targets.
Q: How does your work fit into translational medicine within the department?
NBB: My research is the very first step to enable translational medicine. The SGC in Oxford have extensive experience in making proteins, solving their structures and seeing how compounds bind within the structure. We can also design cellular assays to test the function of the protein and determine the most effective concentration to use the compound at. NDM can help us take this a step further, to test these compounds in cells from patients and possibly all the way to a clinical candidate.