THE ART OF SCIENCE
is keeping an open mind
"Imagination is more important than knowledge" - Albert Einstein
The projects in the lab are constantly evolving, but you can find a overview of the questions that drive our research in the about section.
Details of the systems and processes we study and why are below:
Understanding signal integration at the kinetochore
The kinetochore is a beautiful system to understand signal integration because so many different signal converge onto one localised complex to control chromosome segregation. Multiple kinases and phosphatases must work together to ensure this process occurs accurately at each round of cell division, and this fidelity is lost in cancer cells to drive chromosome instability and tumour evolution. We are investigating how this occurs by using biochemistry, cell biology, synthetic biology and mathematical modelling; specifically, to study how these enzymes must co-operate at kinetochores. You can get a glimpse of this signalling complexity in the image on the right which is from this kinetochore signalling review. You can also find out more about kinase-phosphatase co-operativity in these reviews here and here, and also how it can protect against cancer here.
We aim to uncover fundemental signalling concepts
The beauty of studying the kinetochore is that it is a fascinating signalling complex that is relevant for disease. However, this system can also uncover fundamental concepts that are relevant for many other signalling pathways. See the about section to read more about these ideas, but this recent paper also provides a good example.
In this study we demonstrated that two phosphatases - PP1 and PP2A-B56 - function differently at kinetochores by coupling in opposite ways to phosphorylation inputs. In this case, these inverse phospho-dependencies appear to be more important that any intrinsic catalytic preferences: a concept that we illustrated with mathematical modelling. Our genome-wide analysis suggested that these phosphatase families have evolved to respond positively (PP2A) or negatively (PP1) to phosphorylation inputs, which probably explains why these are two of the best conserved and most important phosphatase families in eukaryotic cells.
Fundemental science can underpin major clinical breakthroughs
We believe strongly that investment in fundemental science is critical to make major breakthroughs in treating disease. You are never sure where the next CRISPR will comr from, which is why curiosity-driven science is so important. However, we also believe that clinical breakthroughs are often not capitalised on enough because of a lack of basic understanding. One area that we are studying is this respect concerns the mechanism of action of anti-cancer drugs.
Mechanism of drug action - Paclitaxel
We are studying why paclitaxel - one of the first broad-spectrum anti-cancer drugs to be discovered - is so effective in the clinic. It is important to understand this because many other "better" drugs have been developed, that target mitosis more specifically, but these do not have the same clinical efficacy. If we could understand what makes paclitaxel unique in this respect, then we could use this information to make better drugs or perhaps use paclitaxel more effectively. Our hypothesis, which we have mathematical modelling data to support (see image), is that drug efficacy relates to the ability of paclitaxel to become concentrated and "trapped" inside 3D tumour environments. A bit more about that project here.
Mechanism of drug action - CDK4/6 inhibitors
We are studying how CDK4/6 inhibitors induce tumour-selective killing, whilst causing relatively little off-target toxicity. This unique property distinguishes this class of drugs from most other cell cycle therapeutics which cause severe dose-limiting toxicities. Our research in this area implies that CDK4/6 inhibitors cause genotoxic stress by downregulating replisome components during a G1 arrest. This is important because these drugs are already known to arrest tumour cells more efficiently in G1 than healthy cells. Therefore, if they arrest the right cell types but then cause genotoxic damage as a result of that arrest, this could produce the same overall effect as most non-targeted anti-cancer drugs (DNA damage), but it a manner that is targeted to tumour cell types. Find out more about this project here and read the preprint here.
Public engagement to explain basic concepts about cancer progression and prevention
Cancer is a progressive disease that results from mutations that accrue in different tissues throughout life. These mutations are for cancer what narrowing arteries are for heart disease: both underlie their respective diseases and both progress throughout life at different rates depending on risk factors. The problem is that most people see cancer as an all or nothing disease, which makes them less likely to take lifestyle choice in early life to help prevent it. Also, it is easy to visualise what a bacon roll may do for a narrowing artery, but not many people understand what smoking actually does to our cells.
We are currently developing an computer game - in collaboration with Robin Sloan (Abertay University) - to inform teenagers about the genesis, evolution and progression of cancer. The player tries to control the spread of mutant cells in a strategic game, and in doing so, experiences exactly why the mutational burden from risk factors is so bad.