Omics in Disease Diagnosis and Therapy

Our new ‘thematic’ MCT Research Seminar Series was launched on November 8th with the opening talks on ‘Omics in Disease Diagnosis and Therapy’. The aim of the new format, with presentations spanning several research groups and diseases to facilitate knowledge exchange and foster cross-collaboration.

Dr Sudipto Das – Genomic and epigenomic approaches as a vital discovery platform

The talk broadly focused on various genomic and epigenomic platforms that have been established in the lab enabling us to interrogate the various alterations that underpin disease-associated features. Using specific clinical case examples, the talk demonstrated how the whole genome, exome and shallow sequencing have allowed us to further our understanding about atypical clinical presentation of known cancer types. Furthermore, the application of targeted methylation sequencing on FFPE tissue and it’s further utilization to stratify metastatic colorectal and heart failure patients using deep learning approaches was also explained.

Dr Katie Benson – Integrating Genomics into the Clinical Care Pathway

Next-generation sequencing is quickly replacing single gene tests in clinical practice. The integration of these genomic tests has been slow as a result of barriers including data processing and interpretation, handling of incidental findings, storage of data and access to genetics services and clinical geneticists. The Epilepsy Lighthouse project, building on the success of the epilepsy electronic patient record (EPR), has used eHealth technologies to facilitate the integration of genomics results into the epilepsy clinic. This has facilitated multidisciplinary team discussions of patients and their genomics results. As part of this project, we have sequenced 97 adult and paediatric Irish epilepsy patients and successfully provided a genetic diagnosis in 24% of cases.

Dr Chiara DeSanti – MicroRNA function in health and disease

Since the sequencing of the human genome back in 2001, non-coding RNAs have been shown to play a critical role in regulating gene expression at a transcriptional, post-transcriptional and translational level. Among the several classes of non-coding RNAs, our group is interested in microRNAs (miRNAs), small non-coding RNA molecules (18-25 nt in length) firstly discovered in C.elegans as negative regulator of gene expression through binding to the 3’untranslated region (UTR) of a target mRNA and inhibiting its translation and/or leading to mRNA degradation. MiRNAs expression was found altered in all human diseases so far, where they have been proposed as diagnostic/prognostic biomarkers and as key players in the pathogenic process itself due to their pleiotropic ability to bind hundreds of mRNAs simultaneously. Therefore, it’s hugely important to define true miRNAs::mRNAs interactions to understand their biological role and the pathways that they affect, in the overall aim of designing therapeutic strategies to enhance or block miRNAs. In order to do so, online target predictions is usually the first step, but experimental validation is needed to verify the in silico-predicted interaction. Several methods have been developed to address this issue, and they can be indirect (i.e. transcriptomic and proteomic changes are measured after over-expression/depletion of a miRNA), or direct (i.e. miRNA::mRNA complexes are captured and physical interactions are assessed, including the RCSI-developed method called miR-CATCH). Gold standard for the validation of high-throughput screening is the luciferase assay, again routinely used in several laboratories across the College. In our group, we are focussing on the role of miR-155 in macrophage polarisation in the context of multiple sclerosis (MS), a neurodegenerative disease where proinflammatory macrophages infiltrate the central nervous system and promote chronic inflammation and damage to myelin sheath. Our hypothesis, supported by preliminary data by our PI Dr MCoy and other researchers, is that miR-155 is promoting the proinflammatory state in macrophages and therefore blocking it would reduce inflammation and alleviate disease progression. Although proof of concepts for antimiR-155 therapy have been attempted in a mouse model of MS (EAE model), we are hoping to boost its efficacy by improving the delivery to macrophages of more stable versions of antimiR-155 or target-site blockers that minimise off-targets effects.

 

 

 

Harnessing FKBPL to target cancer and vascular disease

Pathological blood vessel formation (angiogenesis), or the inability of endothelial cells to perform their physiological function (endothelial dysfunction), are defining features of disease. The endothelium actively controls vessel integrity, vascular growth and remodelling, tissue growth and metabolism, immune responses, cell adhesion, angiogenesis, haemostasis and vascular permeability.  It is, therefore, a vital and largely unexploited target for novel therapies.

Prof Tracy Robson’s team have identified and characterised a novel anti-angiogenic protein, FK506 binding protein like – FKBPL, significantly advancing our understanding of the anti-angiogenic process, in particular, how tumours recruit blood vessels to support their growth. This led to a collaborative study with Almac Discovery to develop therapeutic peptides based on FKBPL’s active domain to explore their potential in cancer by targeting the ability of tumours to recruit blood vessels to grow, invade and metastasise beyond the site of the primary tumour.  The team are also testing the ability of these peptides to sensitise tumours to current therapies and to target cancer stem cells that lead to the onset of resistance and/or recurrent disease.   Importantly, these studies led to a ‘first in man’ phase I clinical in cancer patients where the clinical candidate drug, ALM201, was very well tolerated over a wide range of doses.  Prof Robson’s team (Dr Stephanie Annett and Dr Gillian Moore) will discuss this data together with new data suggesting a strong role for FKBPL in vascular endothelial dysfunction and possible implications therefore in other diseases associated with vascular disease.

Graham Cotton, Tim Harrison, Tracy Robson, Gillian Moore, Seamus Browne and Stephanie Annett (left to right)

Multiple Sclerosis Research Network – 30th May 2018

In honour of World MS Day on the 30 May 2018; the Molecular and Cellular Department in the Royal College of Surgeons Ireland along with Trinity College Dublin, MS Society Ireland and Novartis have joined together to create an MS Research Network event.

The event will comprise of three parts; the first is a World MS Day Fundraiser located in the main foyer of RCSI between 8.30 – 10 am, please come and support the #bringinguscloser campaign. The second is a Researcher Forum for scientists working on MS in Ireland, with the aim to establish an official researcher network to enhance collaboration, visibility, and congeniality. The third is a Public Event to launch the most recent MS Society report and inform the public of the importance and relevance of MS research that is conducted in Ireland.

All are welcome to these events (see below details). To register for the day event, email Harriet Doig at harrietd@ms-society.ie, to register for the evening event, email Emma Kinnane at emma.kinnane@novartis.com.

Written and organised by Claire McCoy

World MS Day Fundraiser – Royal College of Surgeons, Main Foyer. 8.30 – 10am

Researcher Forum – Royal College of Surgeons in Ireland, Tutorial Room 2/3
12.00 Meet and Greet (lunch is provided)
12.30 Harriet Doig (MS Society Ireland). ‘The value of a research network in Ireland’
12.40 Claire McCoy (RCSI). ‘The importance of microRNA-155 in Multiple Sclerosis and my contribution to an MS research network’
13.10 Eric Downer (Trinity College Dublin). ‘Exploring Exercise & Cannabinoids as Therapeutic Targets in MS’
13.40 Una Fitzgerald (NUIG). ‘My research and how I can contribute to an MS research network’

14.15 Tea Break

14.45 Jill Moffat (Queen’s University Belfast). ‘The Northern Ireland MS network – challenges and opportunities’
15.00 Denise Fitzgerald (Queen’s University Belfast) ‘My Research and how the Northern Ireland MS network benefits it’
15.30 Mary Fitzsimons (Beaumont Hospital). ‘How to build an MS electronic patient record, lessons from the epilepsy lighthouse project’
15.45 Alexis Donnelly (Patient advocate). ‘How patients can help build MS research’

Public Event – Trinity Biomedical Sciences Institute, Trinity College Dublin
18.00 MS Society Report Launch
18.20 Clinician – Orla Hardiman (Beaumont Hospital and Trinity College Dublin)
18.40 Researcher – Claire McCoy (RCSI)
19.00 Patient Advocate – Joan Jordan (Patient Advocate)

Development of Novel Treatments for Sepsis

MCT Research Talks

Sepsis is a major challenge in the intensive care unit, where it is one of the leading causes of death. It arises unpredictability and can progress rapidly. Globally there are an estimated 30 million cases of sepsis each year which results in more than 8 million deaths in adults and 5 million deaths in children. Of those who do survive a further one third will die in the following 12 months, those who survive often face life-long consequences, such as new physical, mental and cognitive problems. Although this number is gathered from several sources, all content to the fact that it is likely an underestimate and therefore may very well be the leading cause of mortality worldwide. Currently, there are no approved drugs on the market to control the underlying pathophysiology that triggers the dysregulated host response to sepsis and therefore the management plan focuses on reducing the infection through the use of aggressive intravenous antibiotic therapy and source control. Therefore the cardiovascular infection research group is investigating a therapeutic option that acts early to prevent bacteria binding to the host vascular endothelial cell in the first place would be commercially advantageous as it will prevent the infection from progressing to septic shock and a life-threatening situation as a result of multi-organ failure.

Prof. Steve Kerrigan’s research team

Funded by: Science Foundation Ireland, Enterprise Ireland, Irish Research Council, British Heart Foundation, Health Research Board, Wellcome Trust

MCT at RCSI Research Day 2018

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

Well done!!!

MCT Research Talks November 27th 2017

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.

MCT Lab Safari Activities

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

Tracy Robson

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.

Caragh Stapleton

Human Genetics
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.

Olga Piskareva and John Nolan

Cancer Biomarkers
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.

Mariana Patricia Cervantes Silva

Immunology/Body Clock
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.

Stephanie Annett

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.

Conor Duffy

Multiple Sclerosis
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.

Padraig Norton

Drug Discovery
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.

Tracy Robson and Anne Grady

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.

HEAD OF DEPARTMENT’S WELCOME

 

Prof. Tracy Robson Head of Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland
Prof. Tracy Robson Head of Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland

It gives me great pleasure to welcome you to MCT’s blog page. Our department is based within the Royal College of Surgeon’s in Ireland (RCSI) situated on Dublin’s beautiful St Stephen’s Green.  This was one of the initial attractions for my move to Dublin from Queen’s University Belfast in Aug 2016, in addition to the vibrant and innovative environment that RCSI provides, through its achievements in education and research.

Our research focuses on understanding the molecular basis of disease in order to develop and apply our findings to the identification of biomarkers and new drug targets. Our aim is to improve the diagnosis, treatment and, ultimately, prevention of disease; enabling MCT to be at the forefront of personalized medicine. With newly renovated state-of-the-art facilities, strong links with Beaumont Hospital, our clinician-scientist teams are leading therapeutic and biomarker discovery in the areas of autoimmune and inflammatory disease, cancer, cardiovascular disease, infection, platelet biology and neurological and psychiatric disease. This is facilitated by strong collaboration with industry allowing us to translate our findings appropriately, revolutionizing healthcare through discoveries and innovations that improve people’s lives.

I hope that you enjoy reading our blog page which seeks to capture the dynamic nature of the teaching and research environment within MCT and pays testimony to the significant accomplishments of our all of our staff and students.  I hope that we can inspire you ………

Tracy Robson