Last week was another superb week for circadian research in the Molecular and Cellular Therapeutics Department. The Curtis Laboratory published our first big paper on the immune body clock in Nature Communications. This study originated back in 2013. I was still a postdoc in Prof. Luke O’Neills laboratory at Trinity College and was intrigued by some of the studies that showed that multiple sclerosis (MS) was affected by the circadian disruption. A key study showed that teenagers who work shift work before the age of 18 are more susceptible to multiple sclerosis in later life. I wondered if we would see any differences in multiple sclerosis if we disturbed the immune body clock. I approached Prof. Kingston Mills also at Trinity College, who is one of the world leaders of multiple sclerosis and has a key mouse model that recapitulates certain features of MS, called experimental autoimmune encephalomyelitis (EAE). The first experiment we conducted was to see if a mouse which does not have the molecular clock in macrophages was more susceptible to disease, and low and behold it was! This project was driven by one of the most talented researchers that I have ever had the pleasure of working with, Dr. Caroline Sutton, who is a senior postdoctoral fellow in Prof. Mills lab. This project is a great example of collaboration between multiple labs, Mills, O’Neill and my own new group here at RCSI.
And if that wasn’t enough! We also hosted the circadian expert Prof. Qing-jun Meng for our second institutional seminar series on Thursday. Prof. Meng is a world expert on clocks in the musculoskeletal system at University of Manchester. I met Qing-jun in 2013, and have followed his research intensely. He has made seminal discoveries on the impact of the clock on cartilage and invertebral disk function and how this leads to diseases of ageing, such as osteoarthritis and lower back pain. He had the audience enthralled for an hour with his rhythmic images of cells glowing with 24-hour rhythms, and his use of Google searches. It was an absolute pleasure to have Qing-jun with us for the day, and I hope that we can have him back again in the near future.
Some news features on the article can be found here:
Dr Justyna Surowka, Medical University of Lublin, Lublin, Poland
(Current Erasmus Post-doc with the O’Connor group) presented “Assessment of chosen immune cell populations in patients with ovarian cancer”
Despite the decades of studies on developing new therapeutic strategies, ovarian cancer remains one of the malignancies with the highest mortality rate. Therefore, new therapies, among them immunotherapy, are in demand. Recently, Kurman and Shih proposed a new classification of ovarian cancer. It is based on molecular and histopathological differences between tumors and divides them into two subtypes: type I and type II ovarian cancer. However, there are no studies exploring functions of an immune system in those types of ovarian cancer. We demonstrated that each type of ovarian cancer can induce a unique phenotype of dendritic cells and differentiation of Tregs, both associated with immunosuppressive function, which may be an obstacle while developing effective anticancer dendritic cell vaccination.
Dr Sudipto Das presented “Dissecting the epigenome of metastatic colorectal cancer”
The talk highlighted the experimental and analytical pipelines that have been established in the lab in order to develop single-base pair resolution DNA methylation maps derived from difficult-to-handle FFPE (Formalin Fixed Paraffin Embedded) tissue. We next applied these optimized approaches to primary tumour samples derived from 58 metastatic colorectal cancer (mCRC) patients and 10 matched normal samples, with an aim to unravel the methylation alterations across both conventional gene regulatory regions such as promoters as well as alternative regulatory elements such as enhancers of protein-coding and non-coding genes. Intriguingly, we have now identified a DNA methylation specific signature consisting of 377 differentially methylated loci that differentiates tumour and normal and in parallel provides us with three distinctive clinical clusters, which show a significant overlap with prognostically relevant consensus molecular sub-types of CRC. However, further work is warranted to ascertain the precise function of the signature as well as their role in predicting patient response to treatment.
The second part of the talk detailed about the ongoing genomics focused on “n-of-1” genomic studies which essentially involves atypical cancer presentation in patients, with the idea of understanding the biology of such unusual clinical phenotypes and moreover to identify any potential therapeutic targets.
On November 14th, we welcomed almost 50 secondary school students at our Department for Lab Safari. The event was designed to encourage young people to consider a career in Science, Technology, Engineering, Maths and Medicine through hands-on experience and demonstrations prepared by our researchers. We developed 6 different workstations focused on Cancer biology and biomarkers, Drug Discovery, Multiple Sclerosis, Human Genetics and Immunology/Body clock
The event was opened by Prof. Tracy Robson, Head of MCT, sharing her career path in research and lessons that she learnt. Dr Avril Hutch, Head of RSCI Equality and Diversity Unit, also spoke about stereotypes in STEMM careers and having an awareness of unconscious bias.
Our workstation was led by Caragh Stapleton, Katherine Benson and Edmund Gilbert, centered around human genetics. Our activity set out to teach participants about inherited traits and demonstrate how variation in our DNA influences our physical attributes. We investigated a number of traits including PTC taster (using PTC taste strips), colour blindness, widows peak, tongue rolling, attached earlobes, bent little finger, eye colour and red hair. Each participant noted whether or not they had the given trait and we then discussed the hypotheses of the genetic variants influencing the different traits.
Our workstation was led by Olga Piskareva and John Nolan. We explained the concept of biomarkers and the importance of discovering novel biomarkers for neuroblastoma, a childhood malignancy. Various chromosomal aberrations can be biomarkers of neuroblastoma aggressiveness. One of the strongest predictors of rapid neuroblastoma progression is MYCN status. We selected several neuroblastoma cell lines with known MYCN status providing a good illustration of biomarker’s quantity. Using immunodetection, we visualised the differences in the MYCN presence.
Our workstation was led by Annie Curtis, Mariana Patricia Cervantes Silva, George Timmons and Cathy Wyse. The theme of our activity was on the body clock and immune function. We discussed with the students why they get jet lag and what that has to do with their body clock. Students then moved to the first station where they got a chance to add colouring to macrophages, so we had red, yellow, blue and green macrophages and were able to look at their coloured macrophages under a microscope. Then they moved to the next station where they got to see the master clock which resides in the hypothalamus of the brain under a microscope. Finally, we displayed some images of activated macrophages and explained their function.
Cancer Cell Biology
Our workstation lead by Sudipto Das, Gillian Moore and Stephanie Annett, focused on showcasing the various laboratory-based approaches applied regularly to identify and investigate novel gene or protein-based biomarkers of cancer progression. Within our workstation, we highlighted three key areas including how samples following biopsy from a cancer patient are used to construct tissue microarrays which are used for assessing the importance of a certain protein in cancer. This was followed by demonstrating a particular tissue culture-based method used to study anti-cancer properties of drugs and finally displaying an array of microscopic images of blood vessels developing in a given tumour.
Our workstation was led by Claire McCoy, Remsha Afzal and Conor Duffy. The research focus at our lab safari station was Multiple Sclerosis (MS). We explained how the causes of MS are unknown, but that it is characterised by an influx of immune cells into the brain and spinal cord. Our research aims to investigate one type of immune cell called the macrophage. We aim to understand the damage macrophages cause in MS and if we can reverse this to provide an alternative tool for MS therapeutics. We really enjoyed explaining our research at the Lab Safari, where we showed students how MS impacts on brain function and showed them examples of activated macrophages under the microscope.
Our workstation was led by Dermot Cox and Padraig Norton. Students were given a brief history of drug discovery. Then they were introduced to the basic concepts of how a drug binds to its target and the different ways in which a drug can bind. Students were then shown a demonstration of molecular docking on a computer whereby a small molecule, or drug candidate, was virtually docked into a target binding site using the software.
The event was led by Dr Maria Morgan, Anne Grady, Prof. Tracy Robson, Dr Olga Piskareva and John O’Brien. Guides on the evening included Olwen Foley, Camille Hurley, Mary Ledwith, Seamus McDonald and Shane O’Grady.
Prof Luke O’Neill delivered the inaugural lecture at the RCSI Research Seminar Series yesterday. Luke O’Neill is the professor of Biochemistry and Immunology at Trinity College Dublin. Luke is a world-renowned scientist known for his contributions to the field of Immunology, more specifically Toll-like receptors, innate immune signaling, cytokines and most recently Immunometabolism. He is one of Ireland’s most influential scientists having published >300 publications and is in the top 1% of the world’s most cited scientists in Immunology. He is the recipient of many prestigious awards including the Boyle Medal for Scientific Excellence and last year was elected a Fellow of the Royal Society.
Luke told us many exciting stories. The first highlighted how the inflammasome sensor NLRP3 is critical for the production of the pro-inflammatory cytokine IL-1. A cytokine essential for our fight against infection, but is elevated and extremely damaging in many diseases including Rheumatoid arthritis, colitis, Parkinson’s, Alzheimer’s, diabetes and hypertension. Luke’s team discovered a small molecule inhibitor against NLRP3 that has shown efficacy in 32 models of disease, as astounding effect never observed before. The inhibitor is now entering clinical trials and could excitingly pave the way as a radical treatment for many diseases.
The second story introduced the concept of Immunometabolism, a phenomenon where immune cells utilize metabolic pathways to generate inflammatory mediators. In response to infection, immune cells such as macrophages increase the production of glycolysis whilst at the same time cause a block in Kreb’s cycle. This block leads to the accumulation of intermediates such as succinate. Importantly, Luke has shown that succinate is critical for the production of IL-1 via the transcription factor HIF-1alpha. Inhibition of succinate ablates IL-1 production in response to infection, as well as in a number of disease models tested. Luke highlights that the manipulation of energy pathways could very likely provide an alternative mechanism for therapy in inflammatory disorders.
It was a real pleasure to hear Luke speak at RCSI. To learn more about the above stories, check out the following publications:
I have recently arrived as a Postdoctoral Researcher in Dr Claire McCoys Lab in the Molecular and Cellular Therapeutics Department (MCT) at RSCI. I specialise in immune signalling pathways and inflammatory complexes underlying infectious and inflammatory diseases, including multiple sclerosis (MS), sepsis and highly virulent strains of influenza.
After obtaining my BSc in Biotechnology in 2005 from Dublin City University I was awarded a postgraduate scholarship from the Irish Research Council and went on to complete my PhD in Immunology in 2009 (DCU). I conducted my postdoctoral training in innate immune signalling with Prof Luke O’Neill in Trinity College Dublin with a strong focus on understanding the mechanisms regulating a key inflammatory complex in immune cells known as the inflammasome.
I am excited to be joining MCT and the McCoy Lab. Like Claire, I have a passionate interest in medical research and chose to work in inflammation because it has a central role in the progression of a broad range of diseases. I am also passionate about community engagement, science communication and educating the next generation about the importance of medical research and the role of inflammation in disease.
Dr Rebecca Coll is a Research-Industry Fellow at the University of Queensland, studying innate immunity and novel anti-inflammatory drugs. Rebecca received her PhD in Immunology in 2013 under the supervision of Professor Luke O’Neill at Trinity College Dublin and moved to Associate Professor Kate Schroder’s group at the Institute for Molecular Bioscience in UQ in 2014. Over the last five years, her research has focused on inflammasomes – protein complexes at the heart of inflammation and disease – and how these complexes can be targeted therapeutically to prevent damaging inflammation.
Rebecca led the biological characterisation of MCC950, a small molecule inhibitor of the NLRP3 inflammasome and an exciting prospect as a new therapy for treating patients with NLRP3-mediated diseases. In 2016, Rebecca received the Research Australia Discovery Award for her work on MCC950.
I have recently arrived as a Lecturer in Biochemistry/Immunology within the Molecular and Cellular Therapeutics Department at RSCI. I am a dedicated and passionate Biochemist/Immunologist who obtained a BA (Mod) in Biochemistry from Trinity College Dublin in 2001.
In 2006, I completed my PhD at the University of Dundee, Scotland after which I conducted my postdoctoral training in innate immunology with Prof Luke O’Neill. In 2010, I received a Marie Curie Mobility Fellowship where I gained scientific independence and re-located to the Hudson Institute of Medical Research in Melbourne, Australia. In 2014, I was awarded an Australian NHMRC project grant enabling me to lead an independent research team, conducting my research specifically on the regulation of microRNAs in innate immune cells, with a particular focus on inflammatory diseases such as Multiple Sclerosis.
My lab aims to understand how microRNAs regulate inflammation in disease. Our particular focus is how the pro-inflammatory microRNA, miR-155, plays a fundamental role in one immune cell subset called the macrophage. Macrophages are the sentinel cells of our immune system and quickly respond to infection to clear invading microbes. However, in chronic inflammatory diseases and autoimmunity, the presence of macrophages largely contributes to the damage, tissue destruction and symptoms associated with these diseases. Our research has shown that miR-155 is a key driver of this response. My lab aims to identify the molecular and functional mechanisms that underpin inflammatory macrophages, with the aim that miR-155 inhibition will lead to real therapeutic potential.
Multiple Sclerosis (MS) is a progressive degenerative disease where the prevalence in Ireland far exceeds the global average. Disease onset occurs between 20-40 years, an age critically affecting working and family life. To this day, there is no known cause and no cure for MS. Although, the early disease can be managed by current drug therapies, there is no treatment at the later progressive stages of disease, and no known treatments to repair the damage caused to the central nervous system. My research aims to uncover the role of macrophages in MS, and the contribution of miR-155 in this effect.
Claire McCoy is the recipient of a prestigious Marie Curie International fellowship and an Investigator Project Grant from the National Health and Medical Research Council (NHMRC), Australia. Altogether my research has attracted €800K in both national and international funding. I have published >21 highly cited and seminal publications in Nature Reviews Immunology, Nucleic Acids Research, Journal of Leukocyte Biology and Journal of Biological Chemistry. I am book editor for Springer Science, USA, as well as peer reviewer for international journals and funding agencies.
I will be talking about my research at 12pm TR4, Monday 13th Feb. The title of my talk will be ‘miR-155, a master regulator of the immune response’.
Dr. Claire McCoy
Lecturer in Biochemistry/Immunology,
Royal College of Surgeons in Ireland,
123 St Stephens Green,