Cardiovascular disease is the leading cause of death worldwide. Heart attacks occur when a blood clot blocks the coronary artery, restricting blood flow to the heart muscle. Atherosclerotic plaques in the coronary artery walls cause heart attacks when they rupture and expose their pro-coagulant contents to the blood supply, forming a clot.
Research in the field currently focusses on detecting plaques which are prone to rupture (i.e. “vulnerable plaques”) in the hope that removing them from patients with coronary artery disease will lower their risk of heart attack. OCT (optical coherence tomography) is a relatively new medical imaging technique enabling precise visualisation of “vulnerable plaque” morphology (such as a thin fibrous cap, a lipid core, calcifications) in a similar way to ultrasound, using light instead of sound to create an image of the tissue. However, one key feature yet to be made visible with OCT is macrophage infiltration into the cap of the plaque.
Preliminary studies have shown that macrophage visualisation within plaques may be possible with OCT and my thesis project aims to enhance this visualisation. Along the course of my project I will be working on in vitro models (a model “phantom” artery and ex-vivo human arteries), in vivo animal models as well as a human clinical trial. If we can enhance the detectability of macrophages within atherosclerotic plaques with OCT we could potentially distinguish vulnerable plaques from non-vulnerable ones and thus vulnerable patients from non-vulnerable ones!
I came across OPTIMA completely by chance when I had not yet started my search for PhDs and I was hooked when I heard about their aims and ideals. Most importantly for me, all the projects having an optical medial imaging component are very clinically relevant and many boast a "bench to bedside" philosophy. The added interdisciplinary component is what makes this PhD program unique, perhaps more challenging but certainly fun! And finally the taught entrepreneurship component of the OPTIMA program teaches us the importance of knowing how to commercialise science, a invaluable skill for our future careers, whatever they may be...
My project is centred around the creation of a diagnostic tool for cervical cancer which is automated, inexpensive and based on the ‘molecular pathology’ of the samples used. This is to try and improve the timing and accuracy of diagnosis for patients, and also to reduce the burden of manual diagnosis for clinicians. The project will involve looking at two different methods of using the optical scattering technique Raman spectroscopy to analyse the biochemical makeup of cells from the cervix.
The first method is the global approach, where all the biochemical differences between normal and cancerous samples are considered. This will be done using wavelength-modulated Raman spectroscopy (WMRS) to probe the vibrational energy levels of molecules in the sample, and does not require any major sample preparation. The second method is the targeted approach, where a specific marker for the cancer in question (such as an increase in the production of a particular protein) is measured in each sample. This will be carried out using surface–enhanced Raman spectroscopy (SERS). The Raman signal enhancement is provided by metal nanoparticles which have been tagged with an antibody to the protein being studied. The intensity of the Raman peaks for these ‘functionalised nanotags’ correspond to the levels of the target in the sample. The project will also look at how the Raman spectra can be automatically collected from thousands of cells in the same sample. Hopefully the final tool will improve cervical cancer diagnosis for patients and healthcare services alike.
Granzyme B is the signature enzyme of choice for CD8+ T Cells in our immune systems response against foreign bodies. CD8+ T Cells form a major part of the adaptive immune system and without their effector activity we would succumb to many infections and diseases. The activity of these cells is kept under control by T regulatory cells (Tregs) which are able to suppress function of CD8+s when required, in order to prevent autoimmune diseases.
Patients suffering from cancer have the ability to draw large numbers of CD8+ cells with specificities to tumour antigens to the TM. Therefore, in theory, these T cells should be able to mediate clearance of malignant cells in much the same manner as invading microbes/bacteria. However, in cancer patients these T cells are unable to eradicate the tumour because of an increasing number of CD4+ CD25+ Foxp3+ Tregs found in the TM. As previously described, Tregs have the capability to suppress the immune system, however, in the presence of malignant cells they should not suppress the immune response to such an extent that tumours can thrive. As such, the increasing ratio of Tregs:CD8+ T cells results in a worse prognosis and leads to development of tumour tolerance rather than tumour clearance. However, crucial questions remain unanswered: 1) what are the specific signals / molecules that give rise to an elevated number of Tregs in the TM, and 2) how Tregs suppress CD8+ T cell cytotoxicity in vivo.
In order to answer these questions my research combines both organic chemistry and immunology through the development of a fluorescent probe specific for CD8+ T Cells by labelling Granzyme B. Through fluorescence imaging of CD8+ T Cells in the TM we hope to address some of the previously unanswered questions.
In 2015, lung cancer killed more than 1.5 million people worldwide. Lung cancer is the second most common form of cancer, leaving only 15% of patients alive five years after diagnosis. One of the reasons for this harrowing statistic is that many people are not diagnosed until advanced stages of the disease, during which treatments for lung cancer become less effective. Therefore, new techniques for early stage diagnosis are needed to help increase the number of earlier diagnoses and improve patient outcome.
I am developing new diagnostic tools which will allow for earlier detection of lung cancer, using bio-orthogonal reactions (reactions that can take place inside cells without interrupting normal biological processes). These reactions can be targeted so that they only occur inside cancer cells. I am using fluorescent probes that will be activated, or "switched on", by these bio-orthogonal reactions to image lung cancer cells. The benefit of using fluorescent probes is that the optical light emitted can be quantified in real time to visualise tumours. These new diagnostic tools are non-invasive, faster and more cost effective than current methods.
The primary benefit of working in the OPTIMA CDT is that I am part of a collaborative network of people who are constantly exchanging ideas. In addition, exposure to courses within the Business School helps improve my understanding of how to translate ideas to products for the general public.