Meet Ruairidh the scientist.
My name is Ruairidh Harrigan and I am currently in the final months of my PhD.
My journey at Ulster University began in 2015 when I started my undergraduate degree in Stratified Medicine (now called Personalised Medicine).
At the time Stratified or Personalised Medicine was very new, and the degree at Ulster University, which began in 2014, is the only dedicated undergraduate degree of its kind in the UK (as of Aug 2022).
My journey at Ulster
While studying for my A-levels I wanted to study Radiography at Ulster University Jordanstown campus, but I fell short of the required grades.
When I found the Stratified Medicine degree through UCAS Clearing, I had never heard of it and thought it looked interesting. Fortunately, my grades were good enough to secure a place and I enrolled.
The degree is based at the Magee campus with teaching at C-TRIC, Altnagelvin Hospital. During my bachelor’s degree I learned a wide range of skills and knowledge from wet-laboratory techniques to advanced bioinformatic data analysis.
For me, the most valuable part of the degree was the opportunity to take a year placement between years two and three.
During my placement I worked at the Northern Ireland Centre for Stratified Medicine at C-TRIC, Altnagelvin Hospital as a Research Assistant under Professor Dennis Alexander, on a study investigating protein expression in patients Multiple Myeloma (MM); a rare type of blood cancer that mainly affects older adults.
For 12 months, I volunteered my time from 9am to 5pm to work on the Multiple Myeloma project and worked in a shop part-time at the evenings and weekends.
I immediately fell in love with cancer research. I received training in lots of areas which elevated my skills and knowledge to a new level.
I became proficient in flow cytometry, blood and bone marrow sample processing, advanced multicolour flow cytometry, tissue culture, DNA/RNA extraction, protein extraction, PCR, and proteomic analysis of large datasets, often working entirely independently.
After placement I went back to the degree with a new energy and purpose. I wanted to graduate with a First Class Honours degree and secure a place in a PhD programme in cancer research.
A specific interest in acute myeloid leukaemia
During my final year of Stratified Medicine, a new lecturer called Dr Kyle Matchett joined Ulster University and set up his lab at C-TRIC. Dr Matchett’s lab studies acute myeloid leukaemia (AML) which is an aggressive type of blood cancer that affects children and adults of all ages.
I met with Dr Matchett and I expressed my interest in applying for his PhD project.
I heard from PhD students at C-TRIC that the most important things to consider when applying for a PhD project were whether the project interests you and whether you can see yourself working with the supervisor.
The project seemed to be perfect. I had all the required skills and experience, and met most of the desirable criteria. Dr Matchett had never had a PhD student before, but he came across as professional, caring, compassionate, and motivated, and I had no doubt this project was for me.
I applied for the position, got my First Class Honours degree, and in September 2019 I began my PhD project.
My PhD project
The project is titled “Developing novel synergistic drug combinations with venetoclax in acute myeloid leukaemia”. The project aims to find new therapies for children and adults with acute myeloid leukaemia.
AML is one of the most difficult to treat leukaemias. Until recently treatment options have been limited to intensive chemotherapy regimens with highly toxic effects.
Older patients are generally considered unfit for intensive chemotherapy and historically have had particularly poor outcomes. In recent years, the AML treatment landscape has shifted dramatically with the advent of DNA sequencing technologies and the development of targeted therapies.
Venetoclax is one of the most important developments of the last decade for the treatment of AML. Venetoclax when used by itself performs poorly and patient responses are relatively low. However, when venetoclax is combined with routinely used, low intensity chemotherapy drugs, survival rates improve significantly.
Venetoclax in combination with either hypomethylating agents or low dose chemotherapy is the current gold standard treatment for patients with newly diagnosed AML who are unfit for intensive chemotherapy. Indeed, clinical trials are currently underway to establish whether venetoclax based therapies are more effective than intensive chemotherapy.
Some patients do not respond to venetoclax based therapy. Patients who respond and achieve remission often relapse and become progressively more difficult to treat. The goal of my project is to use a high-throughput screening approach to find new drug combinations with venetoclax to increase its effect.
To achieve this goal, I first set out to demonstrate how effective venetoclax is by itself when added to AML cells lines. AML cell lines are cells which have been taken from a patient with AML and are grown in a flask in the laboratory as a simple model of the disease.
This first set of experiments included dose response experiments where venetoclax was added at various concentrations to 8 different cell lines over a period of 3 days.
Interestingly, each cell line responded differently to venetoclax with cell lines being either very sensitive, moderately sensitive, or resistant even at high concentrations.
This diversity in responses to venetoclax observed in the cell line models is reflected by the differential responses seen in patients who are treated with venetoclax based therapies.
Venetoclax targets the BCL-2 protein which allows cancer cells to evade normal cell death when highly expressed.
I performed qPCR gene expression analysis on the BCL2 gene and Western blot analysis on the BCL-2 protein and found that BCL-2 is expressed in all cell lines and expression does not correlate with sensitivity to venetoclax in the 8 AML cell lines.
These findings indicate there are factors which influence venetoclax sensitivity and resistance other than expression of the target protein.
Evie and I have recently been developing a high-throughput drug screen experiment to test more than 2,000 FDA approved drugs in AML cell lines using an automated liquid handling robot.
This experiment has taken a huge effort and a few late nights to design and optimize but we have finally performed two large drug screens and we are currently analysing results.
The results from these experiments will inform the next stage of my project. I will identify candidate compounds to be paired with venetoclax and investigate how well they work together in combination.
Finally, I will investigate the most synergistic venetoclax-based combinations in all 8 cell lines and cell samples from patients to further characterize the effects of the new combinations compared to venetoclax alone.
This research may potentially lead to the discovery of more effective venetoclax based therapies for AML which could improve response rates and reduce risk of relapse.
One of the best aspects of PhD life is the opportunities to travel and present at conferences. I had planned to travel to The United States and Europe this year to present my work at international conferences but due to travel restrictions and event cancellations it wasn’t possible.
I did however, recently presented my work as a poster at the Annual Irish Association for Cancer Research (IACR) Conference in Cork, Ireland which was a great experience and is one of the highlights of my PhD.
I also presented at the Ulster University PhD festival of Research 2022 at the Magee campus which was my first presentation in front of an audience. I recommend taking part in the Festival of Research to anyone who can.
It’s a great way to meet other PhD students, hear about their research and practice your own presenting and networking skills.
Giving back, and moving forward
The UU Doctoral College has been a tremendous help throughout my PhD from the induction sessions to weekly online research development program (RDP) courses.
I’m grateful to Ulster University for the education and opportunities they have given me. One way in which I have tried to give back to the University is by volunteering as a UU Giving Day Ambassador.
UU Giving Day 2022 was celebrated on 2nd and 3rd March, and my goal was to spread the word and encourage friends, family and people in my network to give what they could to support our campaigns.
This includes childhood cancer research, pancreatic cancer research, Mind your Mood student wellbeing initiatives, student scholarships and UU School of Medicine scholarships. Giving Day was a massive success and we helped raise £105,589.
During my time at Ulster I have met so many great people, I’ve had excellent lecturers and project supervisors and I couldn’t have asked for a better start to my career. Doing a PhD has been incredibly difficult, but it is the most rewarding thing I’ve ever done.
I aim to complete my remaining lab work by October and submit my PhD thesis in December 2022. I’m excited to be completing my PhD after 3 years of hard work.
In the new year I hope to defend my thesis, secure a postdoctoral research position, and continue to develop my career in the fascinating field of cancer research.
