Genetics Microbiology Newsletter 2016 17

newsletter

2016/17 SCHOOL OF

Genetics and Microbiology

WELCOME Thanks to the high quality education and training and a strong track record in research, Trinity genetics and microbiology continue to perform strongly. We hope that this foundation enables you, our graduates, to pursue a variety of careers in Ireland and internationally and to be proud of Trinity whatever you choose to do. As you know, School of Genetics and Microbiology encompasses the rich fabric of the Smurfit Institute of Genetics and Moyne Institute of Preventive Medicine with a diverse group of faculty, researchers and students from over thirty countries. The research and teaching in genetics include molecular, cellular, developmental, behavioural, medical, population and quantitative genetics and evolution while microbiology focuses on the genetics, cellular and molecular biology of microbes (bacteria, yeasts, fungi and virsuses) of medical, industrial and technological importance, including interactions between microbial pathogens and their hosts aimed at advancing knowledge that is likely to influence positively the development of vaccines, diagnostic tools and novel preventive and therapeutic treatments to combat and control infectious and communicable diseases affecting mankind and domestic animals worldwide. Below we present a few examples of the recent developments which illustrate the level of the very impressive work that is being done. We thank you for your continued involvement with the school and its two departments and look forward to seeing you in Trinity and hearing from you.

Professor Charles Dorman Head of School

Professor Charles Dorman

Newsletter 2016 – 2017

Cancers Trick the Immune System into Helping Rather Than Harming The research, led by Smurfit Professor of Medical Genetics Seamus Martin, and conducted by Research Fellow, Dr Conor Henry, discovered how certain cancers hijack the immune system for their benefit – tricking it into helping rather than harming them.

Professor of Medical Genetics Seamus Martin.

While most of us are aware that our immune system protects us from infection, we may be less aware of the key role that cells of the immune system also play in coordinating the repair of damaged tissue. This ‘wound-healing’ aspect of the immune response stimulates growth of new cells within damaged tissue and brings extra nutrients and oxygen into the injured tissue.

However, cancers frequently exploit the woundhealing side of the immune system for their own ends. Indeed, cancers have been described as ‘wounds that do not heal’ due to their ability to masquerade as damaged tissue in order to receive help from the immune system. But just how cancers switch on this wound-healing response is not well understood.

Cervical cancer cell releasing wound healing signal (green). Photo credit: SJ Martin.

The team found that a molecule called TRAIL — which is frequently found in high concentrations on many cancers — can become ‘re-wired’ in certain tumours to send an inflammatory ‘wound-healing’ signal. Ironically, TRAIL normally delivers a signal for cells to die, but the Trinity scientists found that this molecule can also send a wound-healing message from tumour cells. The research was recently published in the prestigious journal Molecular Cell.

Quiescent Yeast Cells Not So Quiet It has been estimated that many cells spend the majority of their lifetime in a non-dividing, or quiescent state. During quiescence (or G0), these cells are often considered as ‘resting’, whereby metabolic activity and gene expression are reduced. Another key characteristic of quiescence is that this state is reversible, and cells can re-enter the cell cycle to resume growth when specific conditions occur.

Numerous cells in the human body persist in this non-dividing state, including neurons and muscle cells. Stem cells also form quiescent populations which, for example, can re-enter the cell cycle in response to tissue damage to aid repair. Furthermore it is now known that cancer cells can become quiescent, during which time they are more resistant to drug treatments.

However, research into this so-called ‘inactive’ cellular state has often been over-looked, and the mechanisms that regulate quiescence are poorly understood.

A collaboration between Dr Alastair Fleming of the Department of Microbiology, Dr Karsten

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Hokamp of the Department of Genetics and Professor Mary Ann Osley at the University of New Mexico, USA, used the humble brewer’s yeast, Saccharomyces Cerevisiae, as a model organism in which to study cellular quiescence.

The study revealed that the genomes of the ‘inactive’ quiescent cells retained many of the chromosomal signatures that are normally associated with actively growing cells, despite their shut-down in cellular activity. Furthermore the transcription machinery, although inactive, remained associated with most genes across the quiescent cell genome. Together, the study revealed that quiescent yeast cells are not inert, but are highly poised to resume growth and proliferation when the environment becomes favourable.

Dr Conor Young, a lead author of the study said, “The most interesting aspect of the study was that yeast showed a burst of transcription activity just before their exiting the cell cycle, during which many of the chromosomal marks required for active growth were deposited along

the cell genome. It is like the yeast cells make a ‘last-gasp’ attempt to arm themselves with the chromosomal attributes required to best ensure their survival and re-entry into the cell cycle.”

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Genetics and Microbiology

The ‘Goldilocks’ Genes Hold Clues to a Plethora of Diseases Geneticists, led by Professor in Genetics Aoife McLysaght, used our evolutionary history to shine light on a plethora of neurodevelopmental disorders and diseases. Their findings isolate a relatively short list of genes as candidates for many diverse conditions including autism spectrum disorders, schizophrenia, ADHD, intellectual disability, developmental delay, and epilepsy.

There are over 20,000 genes in the human genome that contain the all-important codes used to produce specific proteins in the body.

In their study, the Trinity geneticists focused on regions of the genome that are duplicated or deleted in some individuals. These regions, termed ‘copy number variants’ (CNVs), are abundant in humans.

Not all CNVs result in noticeable differences between individuals – sometimes the genes within them function similarly regardless of the number of copies present. However, variations in other CNVs are implicated in a variety of debilitating disorders and diseases. These disease CNVs are large, and a major challenge

is to identify which genes within the regions are causing the problems.

Professor in Genetics at Trinity, Aoife McLysaght, said, “Our idea was that there must be some genes within these regions with ‘Goldilocks’ properties: too much or too little duplication, and things don’t work properly. The number of copies must be just right.”

The Trinity team looked back over our evolutionary history to discover which genes don’t tolerate increases or decreases over evolutionary time. This segment of their work suggested that the key is in the presence of these Goldilocks genes within the diseasecausing CNVs. Genes that are key in human development (those that kick into action at an early embryonic stage) seem to be particularly important.

The team also found that CNVs associated with developmental disorders tended to vary far less in terms of the number of gene copies present than was the case for CNVs whose variations are not associated with disorders. This pattern

Professor Aoife McLysaght.

held true across different mammal species (from sheep to dogs, and from rabbits to gorillas).

The implication here is that wider variations in the number of gene copies may evolve and persist in benign CNVs, but not in disease-linked CNVs – the effects would be too physiologically serious to be passed on by an individual to his/ her children.

Forces Holding Bacteria Together in Staphylococcal Biofilm

Leanne Hays, PhD student, Professor Tim Foster and Assistant Professor Joan Geoghegan.

A collaboration between Assistant Professor Joan Geoghegan, Professor Emeritus Tim Foster, both of the Department of Microbiology, and Professor Yves Dufrêne at the Université Catholique de Louvain, Belgium, resulted in

the publication of several papers including one most recently in the Proceedings of the National Academy of Sciences of the USA. The ability of staphylococci (including MRSA) to colonise implanted medical devices such as catheters, artificial joints and heart valves is a major factor contributing to infection. Surgery is often required to remove and replace colonised devices. The bacteria adhere to the biomaterial and grow in multicellular communities called biofilm which are impervious to antibiotics and are resistant to host immune defences. Until recently the glue that held the biofilm cells together was considered exclusively to be a sugary polymer.

The Staphylococcal Pathogenesis Laboratory discovered that many strains, including some MRSA, are held together by interactions between proteins attached to their surfaces.

prevent biofilm promoted by one particular staphylococcal protein called SdrC from forming. Leanne Hays, PhD student in the Department of Microbiology, found that it was possible to stop bacteria from attaching to surfaces and to each other using a small blocking peptide. The peptide prevented the SdrC protein from recognising other bacteria and stopped the staphylococci from growing as a biofilm. This collaborative work carried out with Professor Yves Dufrêne and his team has given us a clearer understanding of the nature of bacterial cell cohesion and the forces that hold staphylococci together in a biofilm.

The new findings offer opportunities for the development of novel compounds to prevent or disrupt biofilm formation.

The current paper uses Atomic Force Microscopy to unravel the molecular forces that hold together bacteria in a biofilm. It shows that it is possible to 3

Newsletter 2016 – 2017

Visualising How Salmonella Genes are Regulated Scientists based at the University of Liverpool and Trinity have determined the roles of the important regulatory systems that allow the human pathogen Salmonella Typhimurium to cause disease. The Department of Microbiology team led by Professor Jay Hinton, including Dr Aoife Colgan, the lead author of the study, and Assistant Professor Carsten Kröger, used the latest RNA-seq technology to study mutant bacteria that are unable to regulate key virulence processes, and defined the regulatory proteins that control expression of Salmonella coding genes and small RNAs during infection.

The lead author of the study, Dr Aoife Colgan said, “By using mutants of a single Salmonella strain that lack 18 different regulatory systems,

we have generated a unique set of data. I am excited that the results are now available to all researchers at SalComRegulon, that my work can now be used to gain new insight into the process of Salmonella infection, and perhaps inspire new therapies.”

Professor Hinton said that he hoped that the data would contribute to our understanding of Salmonella-induced gastroenteritis, and to the lab’s current research on a lethal disease in Africa called invasive non-typhoidal Salmonellosis.

The study is published in the open-access PLoS Genetics journal, and the data are freely available online at tinyurl.com/SalComRegulon.

Geneticists Pinpoint Three New Genes with Important Roles in MND across subjects. The team compared between MND patients and healthy individuals to help to understand what genetic variation may cause the disease.

Dr Russell McLaughlin.

Through Project MinE, researchers in Trinity have helped to isolate three new genes that shed light on the underlying causes of motor neurone disease (MND).

A team led by Trinity collaborators in the Netherlands and London conducted the largestever MND genetic analysis, which brought together the efforts of over 180 scientists from 17 different countries. Using DNA samples donated by over 12,000 patients with MND and over 23,000 by healthy individuals, the team profiled millions of common genetic variations

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There are around 110 new cases of MND each year in Ireland, with those affected typically between 50 and 70 years old. Individuals diagnosed with MND suffer progressive paralysis, which ultimately leads to death, typically within 3-5 years of the first symptoms. Both genetic and environmental factors play a role in the development of MND, but pinpointing and understanding the genetic causes will help to hasten the development of effective treatments for what is currently an incurable disease.

The new study, published in leading journal Nature Genetics, pointed the scientists towards three previously unknown genes, and also provided the best indication yet of exactly how scientists should continue their search for the causes of MND. Dr Russell McLaughlin, a geneticist from the Trinity MND Research Group and one of the lead authors of the study said, “Some diseases,

like schizophrenia, appear to be caused by the added effects of thousands of genes commonly seen in the population, each of which could not cause the disease on its own. With MND, it seems that a similar mechanism may be at play, but the genes that add up to cause the disease are much more rare.”

This apparent rarity of genes that cause MND means that scientists are now tasked with conducting even larger and more fine-grained studies to uncover the remainder of what causes the disease. This will be combined with very detailed family oriented studies led by Professor Orla Hardiman at the Academic Unit of Neurology in Trinity, which will enable research that is already underway at Trinity and at institutions in several other countries to expand the search beyond common genetic variation to include genes only seen in a small number of people. The Nature Genetics paper can be viewed at dx.doi.org/10.1038/ng.3622.

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Genetics and Microbiology

Plant Kingdom Provides Two New Antibiotic Candidates Scientists have isolated peptides (strings of amino acids) with antibiotic effects on bacteria that spoil food and cause food poisoning, after turning to the plant kingdom for help in boosting our arsenal in the ongoing war against antibiotic resistance.

The scientists found two small peptides from widely cultivated crop species (one from broad beans and one from cowpea) that were especially effective.

Further work then confirmed that when these peptides were used together, and with a human peptide that is also an antimicrobial, their protective effects were beefed-up in a one-two antimicrobial punch.

Associate Professor and Head of Microbiology at Trinity, Ursula Bond, led the team that published its research in the journal Applied and

Environmental Microbiology.

Professor Bond said, “There are two major advantages to these small peptides in that no resistance mechanisms have emerged yet, and in that they can be inexpensively synthesised in the lab. Initially, our aim was to identify peptides that provide protection against food-spoiling bacteria, but these peptides may also be useful as antibiotics against bacteria that cause serious human diseases.”

The research team behind the discovery had previously isolated a human peptide that is a potent antimicrobial agent against many of the bacteria that spoil beer during industrial fermentation. Instead of screening for other human peptides with similar desired effects, the scientists scanned plant peptides databases

and focused on the peptides whose structural blueprints were similar to the human one with the desired characteristics.

Many of the most effective antibiotics are derived from proteins produced by plants, but there is a growing need to discover new therapeutic candidates as resistance is increasing in bacterial species that have major health and economic implications for society.

Professor Bond added, “We reasoned that natural peptides found in many plants and plant seeds might be useful new antibiotics, because plants have evolved these systems to protect themselves against the billions of bacteria and fungi they interact with in the soil every day.”

Taxidermy Analysis Reveals Genetic Diversity of British and Irish Goats Trinity researchers, alongside colleagues in University College Cork, Dublin City University and the Irish Goat Society, discovered that intensive selective breeding over the last 200 years and high extinction rates among wild goats have reduced the genetic diversity of domestic goats.

Trinity geneticists explored and compared the genetic links between modern-day domestic goats and the museum specimens of older goats.

The landmark study saw mitochondrial DNA of nine modern samples analysed alongside 15 taxidermy samples. The analysis of the latter samples revealed that these goats had created two distinct genetic groups, separating them from other European breeds. None of the modern Irish breeds sampled had any genetic links to the two groups, however, showing a decline in genetic diversity of the Irish goat population. The current research is the first time that taxidermy samples have been used in the research of livestock genetics.

Lara Cassidy, a researcher in Trinity’s School of Genetics and Microbiology, said, “Studying these specimens and comparing them with moderday animals” also helps to pinpoint existing populations that have retained some of the past genetic diversity, much of which has been lost to

Male billy goat from a feral herd in Mulranny, Co Mayo, Ireland. Photo credit: John Joyce.

industrialised breeding. Retaining this diversity as an option for future breeding is very important.”

Some of these populations, she warned, are being pushed to extinction. This study has highlighted an endangered feral herd that reside in Mulranny, Co Mayo, where a genetic similarity has been discovered between these goats and the extinct ‘Old Goat’ populations that date back to the 1800s and lived on the Isle of Skye. These Mayo goats, then, can be considered the last

remaining ‘Old Irish’ goats. These populations were once common sights across Britain and Ireland, but have today been largely replaced by Swiss breeds, with ‘Old Goats’ now only found in small, feral herds – their existence is currently under threat from the loss of their habitat, as well as culling and extensive inter-breeding with Swissbred flocks.

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Newsletter 2016 – 2017

New Genes from Scratch named in honour of John Burdon Sanderson (JBS) Haldane, who was a British scientist known for his contributions to the fields of physiology, mathematics, evolution and genetics. He is credited with laying the foundations for modern evolutionary synthesis, having created models of population genetics, which essentially unified the theories of Mendelian genetics and Darwinian evolution via natural selection in the early 20th century.

Professor in Genetics at Trinity, Aoife McLysaght, had the honour of delivering the 2016 JBS Haldane Lecture at the Royal Institution of Great Britain in London. The lecture is organised by the Genetics Society UK. Taking place once each year, it recognises an individual for his/ her outstanding ability to communicate topical subjects in genetics research. The lecture is

The DNA in every living cell, including all of those in our bodies, has been passed down from our ancestors, going right back to the origins of life.

In recent years, geneticists have used new technologies to compare the all-important DNA sequences in different species and individuals that explain why life’s myriad variations exist.

Having direct access to the blueprints that have sprung from billions of years of evolution has provided these geneticists with incredible information about how – and why – evolutionary novelties arise.

Professor McLysaght, who was the first to discover a set of new genes that only occur in humans, explored these ideas in her lecture.

She placed a particular emphasis on our rapidly growing understanding of how new genes evolve, and on the link between new genes and disease, including cancer.

New genes may appear in genomes in a variety of ways, but much of Professor McLysaght’s work focuses on the origins of de novo genes, which are those that arise from sections of the DNA code which previously did not code for proteins.

Interview with Alumna The mapping of the (p)ppGpp signalling network will provide a greater understanding of how S. aureus can persist in the human host.

1. What was your childhood ambition?

Rebecca Corrigan BA, PhD (2004)

On getting her PhD in 2008 from Trinity, Rebecca spent six years as Post-Doctoral Research Associate at Imperial College London.

Since 2015 Rebecca is Sir Henry Dale Research Fellow at the Department of Molecular Biology & Biotechnology at University of Sheffield. The overarching aim of her research involves an indepth characterisation of nucleotide signalling systems in the Gram-positive pathogen Staphylococcus aureus. Her previous research has led to the development of a genomewide approach to analyse nucleotide-protein interactions. Rebecca’s current work focuses on utilising this methodology, in conjunction with biochemical assays, to identify binding targets for (p)ppGpp, nucleotides that are involved in promoting persistent and recurrent infections.

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When I was in primary school I always wanted to be a teacher, most likely because both of my parents were primary school teachers.

This changed though during secondary school when I realised I had a real interest in science and biology in particular. The idea that microbes that are invisible to the naked eye can cause so many debilitating human disease fascinated me and I found myself quite enjoying (ie not hating) studying biology for the leaving cert.

2. What made you decide to study microbiology in Trinity?

When choosing a university I knew I wanted to stay in my home town of Dublin, partly as most of my friends were staying and partly for financial reasons as this let me live at home while studying. I also knew that I had a keen interest in microbiology and considered Trinity, UCD and DIT as potential places for further study. Having done a lot of research into the type of degrees offered, I chose Trinity mainly because of the type of molecular microbiology course that was on offer there. The Department

of Microbiology offers a course that gave me a solid background in bacterial genetics, as well as offering a full-time laboratory project in the fourth year which provided me with the handson lab skills that were essential to furthering my career. I was also drawn by the fact that we would be lectured by active researchers who were well-regarded in their field.

3. What appeals to you most about your current role?

I would say that I am quite enjoying the mentorship process. Having students in the lab and seeing their skills develop over time is quite rewarding. I’m also quite lucky in that my fellowship gives me the freedom from a heavy teaching load and so I still get to spend time doing what I love best which is experimental research.

4. What are your strongest memories of Trinity?

All of my favourite memories would stem from the two years I spent in the Moyne Institute. Once you get into third year you are mostly based in the Moyne and the sense of camaraderie and inclusion of students in the affairs of the department really helped to make you feel part of a community. I would say that the fourth year of my degree, far from being

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the most stressful, was the most enjoyable. We spent one term being incorporated into the research labs and were made to feel part of an active research environment. The department also hosted numerous wine receptions not only to welcome us, but also to celebrate our results and achievements, which were always great fun.

5. Have you any advice for students or fellow alumni?

For any science students in their third year I would advise to seek summer placements in labs around the world. I was very fortunate as one of my lecturers, Professor Tim Foster, helped me to find a summer internship in the lab of Professor Richard Novick, a prestigious

Genetics and Microbiology

staphylococcal researcher at New York University. This three-month stint improved my lab skills and benefitted me enormously going into my fourth year lab project. I was also incredibly lucky to have Professor Novick include my name on two scientific publications, which inspired me to go on and do a PhD with Professor Foster at the end of my degree.

Interview with Alumna

Maria Delaney (née Daly) BA (2008)

Maria Delaney (@mhdelaney) is an awardwinning science and health journalist. Her writing has appeared in The Sunday Times, The Irish Times, Guardian.co.uk, Ars Technica, Creative Nonfiction, and more. She has radio experience with national stations including RTÉ Radio 1 and Newstalk, and was part of the team producing Inside Culture on RTÉ Radio 1 during its first season on air. She won the Association of British Science Writers’ (ABSW) Newcomer Award, Britain & Ireland, 2015.

Maria completed a BA in Genetics in Trinity, and a MA in Journalism in DCU, for which she received the John Thompson Marketing & Media Scholarship. For more of her work, visit: mhdelaney.com.

1. What was your childhood ambition?

I was pretty curious about a lot of different areas. I remember thinking I’d love to try out every possible career for a day to see what they were like… working as an electrician, in an abattoir (yes, this was on my list as there was one in Carlow on the river walk), on a farm etc.

Science seemed a good fit with my curiosity and endless questioning so that was my first choice on my CAO when the time came.

2. What made you decide to study genetics in Trinity?

As a young teenager I had an aviary and kept

a detailed account of the bird’s family trees and feather colour, beginning my interest in inheritance and genetics! Fascination wasn’t the only driver behind my path to genetics.

Having two Mendelian conditions in my family showed me the consequences when an error in our DNA occurs.

how closely related they were… leading me to stare at snakes for hours. I loved that experiment! As well as memories of my course, many of my strongest memories are playing basketball for Trinity, making lots of cups of tea for friends… one of the perks of living on campus, and the fun nights out.

Though there is a course in human genetics in Trinity, I opted for the Science route as it gave me more choice and meant I didn’t have to commit to genetics straight away as I was also, and still am, interested in environmental science. Trinity’s course seemed the best choice for me. Having my brother who was studying psychology on campus helped keep my worrying mother happy too!

5. Have you any advice for students or fellow alumni?

3. What appeals to you most about your current role?

The flexibility in both projects and work-life balance make working as a journalist and radio producer interesting and ever evolving.

My career has changed many times since my graduation having moved from working in pharmaceuticals to science blogging, then science and health journalism, with a recent stopover at radio production in the culture sphere. The nature of my job means I research different topics, often in-depth, and am constantly learning. I’ve almost achieved my childhood goal of trying out every possible career, albeit by meeting and talking to lots of people through my work.

4. What are your strongest memories of Trinity?

An experiment I’ll never forget is creating a very inaccurate phylogenetic tree of badly faded snakes in jars of formaldehyde in the Natural History Museum. We were set loose as freshers in the museum and asked to look at similar animals, and try to figure out from appearance

Join a club or society! Science is a very big course and at the start I found it hard to make friends as you’d sit beside new people every day. Playing basketball for Trinity was absolutely brilliant not only from a sport/ fitness aspect, but it gave me a wonderful set of friends. Different opportunities are also available in clubs. For instance, I was captain of the Basketball Club in third year and that leadership experience helped me during interviews and future jobs.

Another piece of advice is to get some work experience during the summer in the area you see yourself working in. It’s a very competitive world out there and many students you’ll be competing against in interviews will have this type of experience. There are a number of summer scholarships available to students.

These helped me work in a lab in the US, as well as a lab in Trinity during my undergrad.

For alumni, my biggest tip is to meet people for a chat if you’re looking to change career or struggling with your current job. When I was working in pharmaceuticals, I really missed science as it wasn’t part of my daily job so I was looking for other options. A meeting with one of my genetics lecturers changed the course of my career as they suggested starting a science blog. These type of chats can offer new perspectives and even identify skills you didn’t realise you had, such as writing in my case.

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Remember. The power of a legacy to Trinity There’s an old saying that the true meaning of life is to plant trees under whose shade one does not expect to sit. When you leave a legacy to Trinity however big or small, you’re planting a tree which will grow to provide shelter to many.

You’re empowering ground-breaking research which will benefit people in Ireland and all over the world. You’re supporting students from all backgrounds to access a Trinity education.

You’re helping preserve our unique campus and heritage for new generations.

When you remember Trinity in your will, you join a tradition of giving that stretches back over 400 years – and reaches far into the future.

For more information about leaving a Legacy to Trinity, please contact Eileen Punch.

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