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.

Prof Luke O’Neill delivered the inaugural lecture at the RCSI Research Seminar Series

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:

Introducing Ingmar Schoen

Hi everyone in MCT! Thanks for the warm welcome!
 As some of you know, I have joined RCSI as a StAR research lecturer in June. My plan is to establish a lab on ‘MechanoVascular Biology and Microscopy’. What do I mean by this?
 The first part ‘MechanoVascular Biology’ sets the scope. I am interested in how cells in the cardiovascular system use mechanical forces to achieve their tasks. As mechanical and chemical cell functions are tightly related, both play important roles in health and disease. Most research has focused on one or the other aspect, but not both. The novel research field of ‘mechanobiology’ takes an integrative approach to better understand how physical forces co-regulate chemical processes on the molecular level. In my previous work at ETH Zurich, I have studied how fibroblasts sense matrix stiffness and respond to it. Here at RCSI, I want to study platelets in the context of thrombosis and, over the years, investigate their interplay with endothelial cells.
The second part ‘Microscopy’ highlights one of the major working horses in my lab. Following the credo ‘seeing is believing’, watching cells can tell you a lot about how they do things. I use microscopy to test hypothesis but also to discover unexpected behaviour. Over the years, I have developed several new microscopy techniques to look at sub-second dynamic processes, directly measure cellular tractions, or determine the nanoscale architecture of multi-protein structures. These are great tools to better understand how the processes starting from platelet activation and ending with the consolidation of the thrombus are regulated in space and time. For this we will use in vitro models, but I am keen to move in the future towards in vivo imaging.
By now, you may have noticed from my scientific viewpoint and my enthusiasm for technology that my background is in physics. I studied physics with a specialization on biophysics at the Technical University Munich. My PhD work at the Max Planck Institute of Biochemistry focused on electrical stimulation of neurons with extracellular electrodes. After a short postdoc at the Ludwig Maximilians University Munich where I studied bi-molecular binding kinetics in living cells, I moved to ETH Zurich in Switzerland. That’s where I have started with mechanobiology and super-resolution fluorescence microscopy, which I know bring over to RCSI.
 A long way is lying ahead of me to cross the bridge towards clinical research. I look forward to having many inspiring discussions with you, already thank you for the ones we had so far, and hope that I can make a valuable contribution to the research here at RCSI!
Looking forward to seeing you at MCT Research Talks on 16th October 2017 at 12.00 TR4!
Kind wishes,
Ingmar
 

Timely Announcement for Nobel Prize

 

Last Monday while in Amsterdam with my Mam and two sisters, a friend of mine sent a text to let me know that the 2017 Nobel Laureates in Physiology and Medicine were Hall, Rosbash and Young.  They were awarded the Nobel for their work in identifying the key genes that create circadian or body clock rhythms in the fruit fly. My feet literally were stuck to the ground, it was thrilling to know that these gentlemen would get the recognition that they so deserve, but also what this will mean for the field of science that I am so passionate about. The body clock is the molecular timekeeping system that exists in practically every organism on the earth and in every cell in our body. Simply put, it allows the cell to tell what time of day it is. Why is that important? We live on a spinning planet and because of the earth’s rotation to the sun, all life on earth has been subjected to daily periods of light and heat, dark and cold. The body clock allows us to anticipate and respond to these 24-hour predictable environmental changes and synchronises our physiology to it. For example, the body clock increases cortisol levels in the body ahead of awakening, this helps us to become active once we wake. The body clock also increases expression of digestive enzymes in the intestinal tract during daylight hours (this is why curry chips at 3am is never a great idea!).

Back in the 80’s Hall, Rosbash and Young independently isolated a gene called Period, they showed how the gene encodes a protein PER that builds up in cells at night and degrades during the day. This daily rise and fall of PER essentially allow the cell to track time of day. How thrilling it must have been for them to observe this daily change in the mRNA levels of Period gene (Figure 1- black line), all that is changing along the x-axis is the time of day.

So what does this mean three decades later? We have made great strides in understanding how the molecular clock works. We now know that the clock keeps time by a series of transcriptional-translational feedback loops. We also know that the clock controls 40% of all coding genes within the body. The body clock controls all aspects of our physiology from metabolism to immunity.

Many diseases, such as osteoarthritis and cardiovascular disease, are highly time of day dependent. Moreover, it appears that disruption of our body clocks, caused by our non-stop 24/7 lifestyle and exposure to artificial light at all times of day, is partly responsible for the increase in chronic inflammatory diseases. Unfortunately, most cell culture systems are not synchronized with the time of day, and this, in my opinion, is one of the main reasons that many researchers unknowingly neglect this field. Finally, we are making great strides in attempting to time specific treatments to the right time of day, an area called chronotherapy. Therefore, it is my hope that this increased awareness of the body clock will bring more researchers into this fascinating field. If we don’t fully understand how our body clock controls physiology and disease we will certainly be left in the dark.

Annie Curtis is a Research Lecturer and runs the Immune Clock laboratory at MCT and is fascinated by all things body clock related.

 

A possible therapeutic avenue in Cystic Fibrosis

Cystic fibrosis (CF) is an inherited chronic disease that primarily affects the lungs and digestive system. CF is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, a chloride channel responsible for helping conduct chloride and other ions across epithelial membranes. The loss of a functional CFTR channel disrupts ionic homeostasis resulting in mucus production that clogs the lungs and pancreas and results in a vicious cycle of chronic infection and inflammation as the disease progresses.

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. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Clinically, progress has been made in recent years identifying therapeutics that target CFTR dysfunction in patients with specific mutations. However, small molecules that directly target the most common misfolded CFTR mutant, ΔF508, and improve its intracellular trafficking in vitro, have shown modest effects We performed a study aimed to identify new therapeutic targets that will help address the unmet clinical need for CF patients homozygous for  the ΔF508 mutation.We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR.  Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.

Judith Coppinger and her team: Mark Ward and Zivile Useckaite

We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR.  Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well-described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.

This study was a collaboration between several groups at University College Dublin, Cystic Fibrosis Unit, St Vincent’s Hospital, Royal College of Surgeons in Ireland, Beaumont Hospital and the University of Mainz, Germany. Ongoing work in this area is taking place at the National Children’s Research Centre. Further details can be found here in a recent publication on this work.

The 13th World Congress of Biological Psychiatry

In keeping with the strategic objective of further increasing our international profile in the research domain, Professor John Waddington (Emeritus, MCT) has recently returned from the World Congress of Biological Psychiatry, Copenhagen, where he was invited to organise, Chair and speak in a symposium on ‘Psychosis is disrespectful to diagnostic boundaries: Nosological and pathobiological implications of psychoses beyond the schizophrenia spectrum’. He was also invited to Co-Chair and speak in a second symposium on ‘Beyond unitary models of psychosis: Confronting complex aetiology and dimensionality’. This reinforces the high standing in which our investigators are held in the international scientific community. 

Inflammasomes – key molecules in inflammation and novel targets for the treatment of inflammatory diseases

MCT Research Talks – 19th June 2017

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.

Dr. Rebecca Coll

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.

 

Claire McCoy

 

Extending international collaboration: ‘the future is East’

 

While RCSI is an institution with a long-standing international perspective on education in the health sciences, it has as a strategic goal the further extension of its international activities, particularly in relation to research collaborations. RCSI is doing so through several mechanisms, which include Science Foundation Ireland International Strategic Collaboration Awards (ISCAs), namely ISCA-Brazil, ISCA-China and ISCA-Japan, awards from the Japan Society for the Promotion of Science (JSPS), the EU Erasmus+ programme, and via joint programmes with individual institutions. Over the past several years, I’ve been pleased to contribute to these developments and continue to do so in my new role as Professor Emeritus.

In October-November 2016, I spent three weeks in Japan under a JSPS Invitation Fellowship. From a base at Hoshi Pharmaceutical University, Tokyo, I also visited and gave seminars at Nihon University at its Tokyo and Matsudo campuses, Nagoya University, and Takeda Pharmaceutical Company, Fujisawa. Even after many previous visits to Japan, it’s difficult to describe the enduring professional and personal pleasures of interacting and fostering collaborations with Japanese academics/scientists and enjoying their beautiful country and so hospitable a culture and society. In addition to ongoing research collaborations with Prof. Hiroko Ikeda and her colleagues, this summer will see the second exchange of RCSI and Hoshi University students to participate in the International Research Summer School, directed in RCSI by Dr. Sarah O’Neill (MCT), whereby up to four students from each Institution travel to the other to undertake a 2-month research project. Additionally, later this year Dr. Sudipto Das (MCT) will travel to Hoshi University under a JSPS Postdoctoral Fellowship to further extend collaborative research studies. We hope that such interactions will grow over the years to come.

In February-March 2017, I spent three weeks in China under a joint appointment as a Professor of Pharmacology in the College of Pharmaceutical Sciences at Soochow University, approximately 100 km west of Shanghai. China is a country that is now pursuing a ‘twin-track’ approach of “… internal restructuring of its economy combined with exposure to global trade winds and investment”. While this presents some similarities but many fascinating contrasts with academe in both Japan and Ireland, interacting and fostering collaborations with Chinese academics/scientists also brings many professional and personal pleasures. While there, I gave three undergraduate lectures on mental health, met with postgraduate students and postdoctoral researchers, and facilitated the visits of Prof. Tracy Robson & Dr. Darran O’Connor (MCT), Prof. Jochen Prehn (Physiology & Medical Physics) and Prof. Brian Kirby (School of Pharmacy) to Soochow University and the subsequent reciprocal visits of Profs. Xinliang Mao and Xinchen Teng to RCSI. In addition to ongoing research collaborations with Prof. Xuechu Zhen, this summer will see the third exchange of RCSI and Soochow University students to participate in the International Research Summer School, whereby, as with Hoshi University, up to four students from each Institution travel to the other to undertake a 2-month research project. Dr. Darren Griffith (Pharmaceutical & Medicinal Chemistry) will be the next RCSI colleague to visit Soochow University and we hope that such interactions, like those with Hoshi University, will grow over the years to come.

At the Monument to the laboratory mouse, a sculpture in front of the Institute of Cytology and Genetics of the Russian Academy of Sciences, to commemorate the use of mice in genetic research to understand mechanisms of disease and develop new drugs

It is difficult to think of a greater contrast than my recent visit, April 2017 under Erasmus+ funding, to Novosibirsk State University and the Institute of Physiology and Fundamental Medicine. Novosibirsk is Russia’s third-largest city and is located in Siberia, approximately 2,800 km east of Moscow. The University and Research Institutes are located in Akademgorodok [Akadem = academic, gorod = town, ok = small, hence Akademgorodok = small academic town], the purpose-built educational and scientific centre of Siberia constructed in the late 1950s approximately 30 km south of the city of Novosibirsk. In April, there was still some snow on the ground and the nearby Ob river was still frozen and will remain so until the end of May. During my stay there, the weather ranged from one blizzard and one (in their terms) ‘regular’ fall of snow through to warm, sunny periods with a temperature of 20C; Prof. Marc Devocelle (Pharmaceutical & Medicinal Chemistry) and I were reluctant to travel to Novosibirsk until April, to avoid the harsh Siberian winter, a meteorological objective that was only partially successful. This academic centre has both original and new buildings, with good teaching and research facilities. Under the kind offices of Profs. Vladimir Pustylnyaki and Michele Debrenne, Novosibirsk State University, I gave three undergraduate lectures on the neuroscience of mental health, and under the auspices of Dr. Tatiana Lipina, Institute of Physiology and Fundamental Medicine gave a postgraduate seminar.

During a research seminar at the Institute of Physiology and Fundamental Medicine

Meetings with them and several other colleagues explored the potential for future research collaborations. After what we regarded as a good meeting, one colleague reached into a cupboard for a bottle of vodka and poured us each a generous measure; he hoped this would induce ’emotional warmth’ commensurate with what he regarded as the positivity of the meeting. After this had been imbibed, he then poured a second generous measure of vodka, to reinforce these positive sentiments. Clearly, RCSI needs to reconsider its policies in this regard with a view to appropriately realigning its practices to these new international standards. As I write this in the second week of May, Prof. Konstantin Volcho, Dr. Ekaterina Semenova and Dr. Artyom Rogachev are currently making reciprocal visits to RCSI under Erasmus+ funding and we hope that such interactions, like those with Hoshi and Soochow Universities, will grow over the years to come.

To paraphrase: ‘The future is bright, the future is East’.

John Waddington   

Dr Annie Curtis wins L’Oréal-UNESCO Fellowship For Women in Science

Our congratulations to Dr Annie Curtis with L’Oréal-UNESCO Fellowship For Women in Science Award! Well done!

She was awarded a prestigious L’Oréal-UNESCO For Women in Science 2017 Fellowship at a ceremony held at the Royal Society in London on May 5th.

She was one of five winners of these fellowships and the only Irish winner this year. The fellowship will support her research into understanding the precise mechanisms by which the body clock restrains inflammation from a key immune cell called the macrophage.

Professor Tracy Robson said: “This is a fantastic achievement and I am proud to congratulate Dr Annie Curtis on this highly competitive award for which there were nearly 300 applicants. It is a great testament to her research within the recently established Immuno-Clock Lab. Annie will be an excellent ambassador for Women in Science and this award reflects the world-class research ongoing at RCSI. Indeed the only Irish winners of these For Women in Science fellowships now reside within this institution.”

Recipients of L’Oréal-UNESCO For Women in Science 2017 Fellowship. Courtesy of RCSI Communications Department

The recipients of L’Oréal-UNESCO For Women in Science 2017 Fellowship:

  • Dr Annie Curtis, Royal College of Surgeons in Ireland, the human body clock and inflammation
  • Dr Radha Boya, University of Manchester, Nanoscience
  • Dr Manju Kurian, UCL Great Ormond Street, Neurology
  • Dr Bethan Psaila, University of Oxford, Haematology
  • Dr Priya Subramanian, University of Leeds, Mathematics

RCSI Communications Department