Five MCT researchers were selected to give oral presentations at RCSI Research Day 2018 – Wednesday 7th March
Category: Early Career Investigators (Post-doctoral Fellows):
Mariana Patricia Cervantes Silva: Those mitochondria have got rhythms! Mitochondrial activity and antigen processing in dendritic cells is dependent on the molecular clock protein BMAL1
Stephanie Annett: The role of FKBPL in LPS induced endothelial barrier dysfunction.
Category: All Postgraduates (Thesis in 3)
Rebecca L Watkin: S. aureus induced miR330-3p expression triggers abnormal permeability in an ex-vivo 2D model of sepsis.
Orla Fox: Uncoupling Activated Protein C Functions by Inhibition of PostTranslational Beta-Hydroxylation.
Edmund Gilbert: The Irish DNA Atlas: Revealing Fine-Scale Population Structure and History within Ireland
Many MCTers presented their research at the 54th Irish Association for Cancer Research Meeting on February 22-23, 2018. The annual IACR meetings bring together the Irish cancer research community and distinguished international speakers. 260 attendees registered for the meeting with 150 abstracts accepted for oral and poster presentations. Notably, the IACR meeting committee creatively shapes the way this conference run. This year, the most dynamic session – Oral Poster Presentations (Prof. John Fitzpatrick Medal, 5 min talk+1 min Q&A) was set for the lay audience with the judging panel consisting of patients, patient advocates and researchers. Very interesting experience, have to say. Two MCT research studies were selected for this session: Olga Piskareva presented the collaborative project between her team and Prof Fergal O’Brien (TERG) “3D Tissue-Engineered Cell Model Of Neuroblastoma For Evaluating Cytotoxic and miRNA-Targeted Therapeutics” and O’Connor’s collaborative project on “RNA Sequencing Identifies BRD3 As A Novel Therapeutic Target In Invasive Lobular Carcinoma Breast Cancer” was presented by Kathryn Haley. Darran O’Connor himself was an invited plenary speaker. He talked about “The Power Of 1: What Can We Learn From Molecular Case Studies?” at the plenary session Emerging Techniques In Biomarker Discovery, Drug Development And Patient Stratification. MCT had a spot at the Proffered Paper Session with John Nolan presented the first data of the NCRC funded project “Modulation of Drug Resistance in High-Risk Neuroblastoma Through Exosomal miRNA”. Many other MCTers had Posters. For Shane O’Grady and Lisa Dwane, it was the last conference in the PhD status and for Olga Piskareva – in her role of Honorary Treasurer f0r the IACR!
Well done to all!
The 55th Irish Association for Cancer Research Meeting will be taking place in Belfast.
Reported by Olga Piskareva
On 25th January 2018 – President of Ireland, Michael D. Higgins, honoured Dr Claire McCoy with the SFI President of Ireland Future Research Leaders Award at a special ceremony in Áras an Uachtaráin in Dublin. Claire was among one of five recipients for this prestigious award and receives a total of €1.5m, which will support a team of 4 researchers; Dr Jennifer Dowling (Senior Post-Doctoral Researcher and hon. Lecturer), Dr Elizabeth John (Research Assistant), Ms Remsha Afzal (PhD student) and Mr Conor Duffy (PhD student).
Congratulating the awardees at the event in Áras an Uachtaráin President Michael D. Higgins said, “I am delighted to receive the wonderful scientists who have been granted SFI Future Research Leaders Awards. This award celebrates their scientific achievements and significant dedication. Their work is evidence of the ongoing world-class research being carried out in Ireland, positioning us as a global leader for scientific excellence.”
Congratulating the awardees, Prof Mark Ferguson, Director General of Science Foundation Ireland and Chief Scientific Adviser to the Government of Ireland, said “The President of Ireland Future Research Leaders Award is designed to attract to Ireland outstanding new and emerging research talent. In supporting these talented and innovative individuals, we are delighted to recognise early career researchers who have already displayed exceptional leadership potential at the frontiers of knowledge. The development of leadership skills in these researchers early in their careers is vital to ensure research and innovation in Ireland continues to progress. Our investment highlights the importance that Science Foundation Ireland places on supporting all stages of academic careers, and on the attraction and retention of star researchers.”
The research of Dr Claire McCoy is based in the Molecular and Cellular Therapeutics Department at the Royal College of Surgeons Ireland. Her research is focused on significantly advancing current therapeutic strategies for the treatment of multiple sclerosis (MS), where Ireland has the highest global incidence. Speaking of her award, she said “Obtaining this SFI Future Research Leaders award is the highlight of my career to-date. Not only does it enable me to lead a growing research team, it will also significantly contribute to the cutting-edge research being conducted at RCSI. Most importantly, it helps to place Ireland at the forefront of multiple sclerosis research worldwide.”
Reported by SFI communications and Dr Claire McCoy
The Irish DNA Atlas, a study of Irish genetic history and diversity led by researchers at the Royal College of Surgeons in Ireland (RCSI) and the Genealogical Society of Ireland (GSI), has recently published in findings into the genetics of Ireland in the Nature Publishing journal Scientific Reports (The Irish DNA Atlas: Revealing Fine-Scale Population Structure and History within Ireland). The Irish DNA Atlas is a cohort of individuals with four generations of ancestry from specific regions in Ireland, recruitment is organised and managed by Seamus O’Reilly at the GSI. Mr O’Reilly helps potential recruits finish, or double-check, family history and pedigree charts for the recruitment process, and mails out sample kits and paperwork for their return to RCSI.
The researchers, led by Professor Gianpiero Cavalleri at RCSI, have found; i) different groups of Irish individuals, clustered by genetic similarity alone; ii) the genetic differences between these groups are incredibly small, iii) members of each of these groups share ancestries from similar regions in Ireland (see image below); iv) a migration event(s) is observed in the north of the island of Ireland that dates somewhere in the 17th and 18th centuries and is from Britain; v) a number of genetic barriers within in Ireland, notably; in the north, and between Leinster and Munster; and finally vi) a significant level of Norwegian-like genetic ancestry throughout Ireland is observed for the first time and this is associated with a genetic migration into Ireland around the turn of the first millennium.
Using the Irish DNA Atlas in conjunction with a dataset of British individuals with regional ancestry (the People of the British Isles Study) the project was able to clusters 2,103 individuals from Ireland and Britain based on genetic similarity as 30 distinct genetic groups (see image 1 for clusters within Ireland). People within the same group are more genetically similar to each other than they are to individuals in other groups. When each Irish individual is colour coded by the group and is placed on a map based on where their great-grandparents were born, we generate a map shown below. Shown to the left are the geographic spread of the identified clusters and on the right a map of Irish kingdoms that represent proto-Provinces circa 800AD.
Analysing the Atlas, the broadest groups within Ireland are either; nearly 100% made up of Irish/Northern Irish individuals (i.e. from the island of Ireland), or are a mix between Irish and mainland British individuals. In the case of the latter, this suggests that those (Irish and mainland British) individuals have shared Irish and British genetic ancestry. The Irish individuals within these mixed groups are mainly from the north of Ireland (predominantly those who are blue crosses in the image above), and the British members are predominantly from the north of England and the south-west of Scotland.
These groups/clusters of near 100% Irish membership are interpreted as mainly ‘Gaelic’ Irish, and the genetic differences between these groups are incredibly small. The groups/clusters are grouped geographically and most are remarkably faithful to the boundaries of the Provinces in Ireland (shown on the left map). We compare these clusters and kingdoms from around 800AD in the above image for illustrative purposes. The reflection between the genetic and historical groups suggests that these Provinces and the kingdoms they represent have subtly impacted the genetic landscape of Ireland. Of particular note is within Co. Clare, which has historically been both parts of Munster and Connacht. Individuals with ancestry from Co. Clare reflect this by showing a mix of genetic groups found within both Munster and Connacht.
In addition to identifying different genetic groups within Ireland, the research sought to investigate whether previous migrations into Ireland had a detectable genetic impact on the genetics within Ireland. Having already identified groups of Irish individuals mainly in the north of Ireland who appeared to a mixture of Irish and British genetics, the researchers tested whether this could be due to a specific event creating these mixed groups. They estimated that these mixed groups are from a number of admixture events in the past, dating around the 17th and 18th centuries.
As well as migrations from Britain, the researchers asked whether evidence of migrations from wider afield, i.e. from continental Europe, could be found. A surprisingly larger amount of Scandinavian – specifically Norwegian – looking ancestry in all our Irish clusters was detected (see below image). This image shows along the horizontal axis each of the 30 genetic groups identified in Ireland and Britain. Along the vertical axis is the average proportion of the genome that’s the closest similarity is found in each of the 10 reference European populations. Ireland and Wales share a lot of French-like ancestry, but Ireland shows a lot of Norwegian-like ancestry compared to England or Wales. In fact, in this Norwegian respect, Ireland shows a similarity to Orkney.
This similar pattern of elevated Norwegian-like in Ireland and Orkney is interesting as Orkney is a region with strong evidence of Norwegian Viking genetic migration and mixture. Therefore the researchers investigated whether this Norwegian ancestry in Ireland was due to a mixture event dating from the time of the Viking activities in Ireland. They dated the ancestry to sometime around 1000 AD, which agrees with a ‘Viking Hypothesis’. This result was perhaps the most surprising using the Irish DNA Atlas, as previous work with Y-chromosomes found no evidence of Norse genetics within Ireland. However now, with whole-genome data, the extent of Norwegian mixture within Ireland is able to be shown.
This research has been funded through a Career Development Award from Science Foundation Ireland. RCSI is ranked among the top 250 (top 2%) of universities worldwide in the Times Higher Education World University Rankings (2018) and its research is ranked first in Ireland for citations. It is an international not-for-profit health sciences institution, with its headquarters in Dublin, focused on education and research to drive improvements in human health worldwide. RCSI is a signatory of the Athena SWAN Charter.
Reported by Edmund Gilbert
MCT Research Talks
Cystic Fibrosis (CF) is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. CF is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene which encodes a chloride channel responsible for helping conduct chloride and other ions across epithelial membranes. Loss of functional CFTR channel disrupts ionic homeostasis resulting in mucus production that clogs the lungs and results in a vicious cycle of chronic infection/inflammation. There are almost 2,000 different variants in the CFTR gene and 70 % of CF patients contain a mutation at position 508, which results in the loss of Phe508 and disruption of the folding pathway of CFTR. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane and function correctly as a chloride channel. The Coppinger research lab is focused on understanding the basic mechanisms of CF disease with a focus on the ΔF508 mutation and translating these findings into diagnostics/therapies. We are particularly interested in two areas of research 1. Using basic science technologies to identify novel signalling pathways in CF to discover new CFTR corrector therapies in ΔF508 CF models. We have recently discovered the PI3K/Akt/mTOR signalling pathway to be dysregulated in CF models and a possible therapeutic avenue worth further exploration in CF. Additionally, we are interested in 2. Investigating how diminished ΔF508 CFTR activity leads to heightened inflammatory cell recruitment and CF airway pathogenesis. Exosomes are nanovesicles (40–100 nm) actively secreted by cells and are crucial mediators of intercellular communications. We hypothesised that exosomes may be released from ΔF508 CF patient bronchial cells/fluids and play a role in regulating immune cell function. Preliminary data has confirmed this hypothesis and also indicated exosomal signatures may possibly serve as markers of disease progression in CF. These studies are in collaboration between several groups at the National Children’s Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital University College Dublin, Cystic Fibrosis Unit, St Vincent’s Hospital.
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:
Written by Annie Curtis
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.
Registration is closed and all places on the MCT Lab Safari have now been filled.
We can’t wait to meet our potential future scientists tomorrow at 5pm! The lab coats are ready and the MCT labs have never looked so clean. We have prepared some great experiments and demonstrations to showcase our ongoing research. Everyone will have an opportunity to explore our labs and perform some hands-on science activities.
MCT Lab Safari Programme:
4.50pm: Arrival and registration – Front Hall SSG
5pm: Welcome and brief introductions
5.05pm: Meet a leading scientist and hear her career journey
5.15pm: Visit our research laboratories in small groups safari style
6.30pm: Q&A with refreshments
TUESDAY, 14th NOVEMBER, 2017 5PM – 6.30PM
RCSI, ST STEPHENS GREEN, DUBLIN 2