UCD Conway Focus Winter 2013

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Issue 20,23 3 Winter 2013

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research " Celebrating 10 years of excellence On September 12th 1 ! 2013, UCD Conway % the 10th Institute celebrated anniversary

5 6

of its official opening with the launch of Igniting Discovery, a publication (67 -! and !

highlighting the research innovation achievements ! 8 ! of Conway researchers in 5 the past decade.

$ ' !

7 Over 700 PhD graduates and 350 1

9 postdoctoral researchers have been 4

: (9 4 :- educated and trained to exacting % ! 5 international standards in the past ten 6

$

years. These highly-skilled individuals have

taken up employment in the

medical device and pharmaceutical, ICT ! " industries as well as in public agencies and

# academia, in Ireland and abroad.

$ " % & The Institute’s research " portfolio includes research publications

3,275 $ peer reviewed " % with the top 1% published in the most

prestigious scientific such as ' (" ) " journals Nature, Science and Cell. In addition *+ ,UCD Conway researchers currently have

- successful collaborations, leading to .

" $ publications, with scientists from

" " "

% . over 1,500

in " organisations 70 countries. % Earlier this year, Conway Fellow, Professor Des Higgins broke the barrier of 100,000

/" # total citations for his work on DNA " -+ + % " +% "

"

" sequence comparisons; making him the

" most highly cited Irish scientist in the past decade and one of the

most highly cited " scientists worldwide. %

The Clustal programme to " align protein . " " sequences from research group the of Professor Higgins is just one of a number of "

exciting has emerged

% . innovations that from the Institute. Since 2003, Conway *01.,

researchers have disclosed 108 inventions, % ' " filed 139 patents, concluded 21 licence

agreements and incorporated spin-out compa " 7 UCD nies from the outputs of Institute research " " programmes. " 01.% Professor Walter Kolch, Director said,

- 23 “When the Institute was established, its " " model of multidisciplinary and collabora tive research was considered a radical "

" vision of how scientific should carried $% 4 research be

" out. Today, it is the standard.� gold " " Professor Des Fitzgerald, UCD Vice-Presi " "

dent for Research Conway In

added,

“UCD %

$ "

changing economic and research horizon maintaining excellence.�

% while research ' (" " " " " / 5 " ' ' " " " % & 6.

Director (" with

" Prof Walter Kolch, pictured PhD students " " ! " , Paul (l-r), Anna Sanders, Natalia Volinsky Lavin and Mattia Bramini " 5 " %7

" " 8 + % + & 9 : 0 : : . . 1 1 + + : . : : ' (" ;% + ' % 23 3 / 22< ==*>,?@A >@

stitute has been a highly effective driver of

0 productivity " and excellence since research

" " " " its establishment. Through its intellectual $ " and infrastructural capabilities, it has risen to the challenge of providing solutions

to societal needs in the face of a rapidly " " "

Prof Des Fitzgerald, UCD Vice-President for Research presents the first copy of ‘Igniting Discovery’ to Ms Beatrice Conway, daughter of the Institute namesake, Prof Edward J. Conway FRS

) / Director’s Message

Welcome! 1

8 8

;

In the last 3 months, we marked a milestone in the life of the Institute with " our 10th anniversary celebrations. This " coincided with the 2013 UCD Conway $ Festival of Research & Innovation and by " (" a visit our distinguished scientific " $ advisory board.

% . " B the in ' As we enter next phase the life of the we intend continuing to =3 Institute, ' build research excellence and sustain ; 23 ; " the A " %

4 " C vibrant environment that ignites discovery, " drives innovation and

impacts positively on < society for generations. / " I extend congratulations to Professor " " " " William Gallagher, Director the first

of

Irish Cancer Society funded Collaborative

"

" Cancer %Research Centre, BREAST-PREDICT.

This funding award is a milestone for

cancer research Ireland 4 in that will give new hope to patients and their families.

-+ It also highlights our commitment and mission $ to carry out research into the " fundamental " "

" /

molecular of disease. 0 basis

23 3%

Following 0 their " recent successful applications, I am delighted to welcome " " a number of new Conway Fellows and " their teams whose research programmes strengthen " + will undoubtedly the research strategy of the Institute into the future. "

Walter " Kolch Professor "

% Director B 4 : -+ + 0 "

<2:4 <7' ' ' 1 '0 / D;+-D E '0 /; 0+ D ; ; +&

+ 0 . 0

2013 Conway Festival medal for cilia research 5 5

5 ! 7 9

5 Doctoral candidate, Nils Lambacher

4 Conway was awarded the 2013 UCD ' Festival of Research & : Innovation gold medal, sponsored by Cruinn Diagnostics : $ ' 7A ! for his research on the regulation of

5 ! cilium structure in the worm model,

! Caenorhabditis elegans. ' 1 ! 9

7 1

Nils, who is carrying out5 5 his studies under theB00"$ supervision of Conway Fellow, Dr

Oliver Blacque, impressed the judging

. 0 . his concise panel with overview of this and its innovative B research project % potential. . "

D; N allB N Cilia are present on nearly of our cells " They and act like cellular antennae. play fundamental roles in many motility and " " sensory functions, including signalling "

pathways critical to development.

%

Ciliopathies is the collective name for a . of B diseases . and

range human syndromes

mutations disrupt that arise when genetic "

function. One the cilium structure and such example is nephronophthisis, the *0' ,

most common cause of kidney failure in children affecting 50,000 live births .

" 1 in in Canada. (" ! " " D; O B %

The research abstract by Nils Lambacher

+

shortlisted B . was one of 30 for moderated 64 + " " % "

" 23 3 " Recent publications Conway from "

" " "

" presentation from 130 submissions. The winners "

Crispin %7 other category were Alexander (Ferguson group); Elena +

. Karolina

Woods (Gautier group); Weiner+ " (McCann 6. group);

. Gorzel Karen Hanrahan group)

and (Watson Fiona McGillicuddy " " (substituted for Orla Finucane).

% .

heard Delegates at the conference plenary

" lectures from Dr Frank Walsh, CEO,

Wellcome Ossianix; Dr

Julian Parkhill, Trust Sanger and Professors % . Institute

" Cormac Taylor " and Des 10 Higgins, UCD. Professor Sir Stephen O’Rahilly, "

University of Cambridge awarded was %7 the Ulysses medal, UCD’s highest . ) of his B accolade in recognition outstanding

to "

" contribution research concerning the mechanisms to molecular

" " leading diabetes, related metabolic obesity and

# " and disorders. endocrine 5 B G

In the innovation session, Dr David

" O’Connell and Professors Stephen # % Pennington, William Watson, Fionnuala / A 333 0 the McAuliffe and Gil Lee described journeys undertaken been to translate innovative research into 0' % findings +" "

applications to

positively impact society.

They faced discussed challenges " in commercialising research with the " % .

"

" chaired Brendan % 0 expert panel, by Mr 0' Director of & Cremen, UCD Enterprise

" including " " "

Commercialisation, Mr Damian % . CEO Nutritics; -+ + " O’Kelly, & Founder Dr Elizabeth 0' Roper, Partner, Rock " $ Spring Ventures; Dr Ruth McMahon, Commercialisation Specialist, Enterprise Ireland Suzi Jarvis, Co-Director, and Prof %

TCD-UCD Innovation Academy.

64 " " 0' " sponsors The primary of the

2013 UCD Festival of Research $ % . Conway & Innovation " were Cruinn Diagnostics Ltd, Bio-Sciences, Ltd and Roche Diagnostics Servier.

7 $ B . % 6 " $ B " 7% 0 " " 00 " B D; N " $ $ * / 5, " " % 2013 Conway Festival medal winner, Nils Lambacher (left) and Prof Des Fitzgerald, UCD Vice-President for Research

Revealing chinks in the armour of hepatitis B virus Fellow, Dr Neil Ferguson provide new insights into the structure and thermodynamics of human hepatitis B virus (HBV) replication and show chinks in the armour of HBV that provide new avenues for therapeutic intervention.

00 " " (" " " "

" %

Their published in the - findings, Proceedings of the National Academy of Sciences, show how subtle thermodynamic tuning of HBc structure, using point mutations or small molecules, can prevent capsid assembly and halt viral replication.

References JĂźrgens MC et al (2013). The hepatitis B virus preS1 domain hijacks host trafficking proteins by motif mimicry. Nature Chemical Biology 9,540-547 Alexander CG et al (2013). Thermodynamic origins of protein folding, allostery and capsid formation in the human hepatitis B virus core protein. PNAS USA 110,E2782-2791 (doi:10.1073/pnas.1308846110)

' &0F "

Each year, 600,000 people die following infection with this blood-borne virus while 350 million people chronic HBV A have infections. 1 ! 9 7

Despite HBV having only four genes, 5 % identifying targets and @ > , ‘druggable’ developing therapies have 5 5 improved been hampered by how challenging HBV 5 $ proteins are to study in vitro. &0F

Ferguson the Dr is " deconstructing HBV lifecycle at molecular level 0 % to figure out how component fit together + Cparts

" and facilitate HBV infected replication 0 within liver cells. 3 %

" " Crucial to HBV replication are a series highly coordinated, *D.GB, of molecular self 0 % . One assembly processes. key stage is the assembly of a protective protein shell (virus that envelopes the viral capsid) " $ genome. Ferguson’s team have been able % to disrupt the sequence of molecular " that events make the viral core protein capsids. " (HBc) form " "

“Capsid formation may be an Achilles’ heel for HBV. If you prevent the protein " " the virus to from assembling, is unable mature and become infectious�, says Dr Ferguson. % & " forms, After the capsid it is wrapped of in another shell made viral proteins " " cells.

that help it escape from infected

. preS1, The team " % showed that a part of

" the virion envelope,B" is another potential therapeutic By mimicking target. " its human counterpart, preS1 tricks the $ host protein export machinery " into participating viral replication in but % without unduly stressing this machinery $ to the point of cell death. D.GB

(" first

HBV biomolecular % This work, the interactions mapped at atomic 4 (" resolution, the " structural and provides " thermodynamic roadmap needed to "

design antivirals. work aims novel " Future to therapeutically preS1 functions $ target % without impacting normal hepatocyte . " " functions. " "

&0F % B " " % 6 " ("

#" "

" " " 7 % . " "

Connection between folding, allostery & 1 " 0 protein - + capsid formation.[A]During protein folding, denatured " % HBc chains[D] associate to form an Îą-helical, dimeric intermediate[I2]. This intermediate is a structural stepping stone between alternative native dimers: N2ASS (can assemble into capsids) & N2INC (cannot form capsids). Point mutations & small molecules ? can preferentially stabilise N2INC & ablate capsid / &0F formation.[B]Crystal structures of HBc hexamer % that corresponds to the 3-fold axis found on capsids B" / (" +% % (blue/green in [A]) shows HBc has significant structural " F 23 3 >CC >A variation (black arrows) when crystallised under different conditions (blue & magenta).[C]Close up of HBc dimer structure from [B]showing structural variations are propagated throughout the HBc structure, in accord with the structural plasticity found by the Ferguson gp.

Hitting inflammation in the guts Researchers in UCD Conway Institute and Systems Biology Ireland have identified a way that a new class of antiinflammatory drugs may be used to treat inflammatory bowel disease (IBD).

"

;- 1BK

IBD describes a group of commonly occurring and severe diseases including disease $ ' Crohn’s and ulcerative colitis. A A 9 A Treatment options for the hallmark symptom of chronically inflamed intestinal ₏"E+!+00 tissues are limited, often ultimately 5 7 requiring surgical< removal of inflamed F tissue. ' (7 F 5 19.

The team led by Conway Fellow, Professor 5 $ Cormac Taylor have previously shown that a class drugs called hydroxylase inhibitors of* % : % ", may provide a new approach to the " " " treatment of IBD. This study now outlines how this occurs at the molecular level.

Hypoxia is a key microenvironmental feature of inflamed tissues that strongly impacts on the inflammatory processes. A family of oxygen-sensing enzymes called HIF-hydroxylases are responsible for controlling the cellular adaptive response to hypoxia. This new*+: , study, led by Prof Cormac Taylor, " " and Dr +: Scholz Dr Eoin Cummins Carsten and published in the Proceedings of the % . " National Academy Sciences, show of " 2Athat hydroxylase inhibitors work by blocking a * > " @ " , pro-inflammatory pathway termed the IL-1 A " # " " pathway; a key driver of inflammation. %

These results give significant new . -+ + "

information as +

to a new level of % crosstalk % G between hypoxia and inflammation / " " " and provide a mechanism to explain how this new approach to the control of

inflammation may work. “This research stems from studies in our laboratory over the last decade into how cells respond to decreased oxygen levels. We found that cells can adapt to low oxygen levels much like mountain climbers adapt to low oxygen levels at altitude. If we use drugs to mimic this adaptive response in inflammation, it suppresses the +: inflammatory response� says Taylor.

% . "

This collaborative project is supported by Science Foundation Ireland. " " "

Reference Regulation of IL-1β–induced NF-ÎşB by hydroxylases

links key hypoxic and inflammatory +: % ;signaling pathways. Carsten C. Scholz, Miguel A. S. Cavadas, Murtaza M. % I" % Alex von B Tambuwala, Emily Hams, Javier RodrĂ­guez, " % Kriegsheim, Philip Cotter, Ulrike Bruning, Padraic G. Fallon, Alex Cheong, Eoin P. Cummins, and Cormac T. Taylor. PNAS 2013 ; published ahead of print October 21, 2013, doi:10.1073/pnas.1309718110

5 ;$ " Addressing critical gaps in breast cancer research G will claim 55 8 Breast cancer more than

= ! *185,000 lives by 2030 if 10 critical = ! gaps that exist in

$ breast cancer

8 !addressed. research are not urgently

5 ! published This landmark research, 5 5 = recently in the international open 5 $ access journal, Breast Cancer Research

is a unique collaboration of over 100

G scientists, internationally recognised / professionals G 0 " clinicians+ and healthcare '

from the UK and Ireland.E . *G0' ., + 1 B B " "

During 2012, the leading UK research ("

charity, Breast Cancer $ Campaign, a series &BD+ facilitated of workshops, each " " % covering a specialty area of breast

cancer. Nine expert groups focused on

5

thematic identifying key gaps in their " " area and detailing how these gaps could % / be addressed.

"

% 4 identified

Ten priority gaps cover areas

of genetics, prevention, diagnosis, and support.

treatment Five key strategic solutions were also proposed " " to address these gaps and help treat and "

support breast cancer patients. These include funding, research infrastructure, multidisciplinary collaborations as well as improved methods of studying the disease and designing clinical trials.

Q

" " % Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT, + " &BD+ Professor William led "

Gallagher who $ the working group on Novel Targeted (" % 0 Therapies, Preclinical Research and " " Biomarkers commented, “Overcoming

# G0' . these gap areas by prioritising this will research reduce over-treatment of cancer 4 patients

breast by identifying those chemotherapy " $ who will benefit from radiotherapy, " and patient " (" or improve % . " " outcomes by tailoring treatment to each " individual.�

;- + ' " "

*Projected breast cancer prevalence in the UK in 2030. " " Møller ;1 Maddams J, Utley M, H. > Projections of cancer B in the % B "

prevalence United Kingdom, 2010-2040. British Journal of Cancer 2012; 5 ;$ 107: 1195-1202.

?!! % % ?=3=3! 5 ;$

Critical gaps and translational priorities for the

! research B % successful prevention and treatment of breast cancer. Breast Cancer Research 2013, 15: R92 doi:10.1186/ 5 ;$ ? bcr3493

" " &BD+ 5 G F% / B% + B " /% " " B 23 3 @ *C, 23 KP23C

%

The UK charity aim to raise ÂŁ100 million . G0' . over the next decade to tackle the critical 5 ;$ ;- + ' gaps identified. In Ireland, the Irish

Cancer Society have similarly committed " " &BD+ in the proceeds of fundraising, part due the Cancer $ Month to Breast Awareness % . $ to campaign ‘Get the Girls’, research with

" the launch of a Collaborative Cancer Research Centre, BREAST-PREDICT " in August 2013.

This brings together Ireland’s leading . " breast cancer researchers with the ultimate goal of achieving tailored treatments for individual patients based on the characteristics of their particular tumour. This personalised medicine approach will improve outcomes for breast cancer patients both in Ireland and worldwide.

Pictured (l-r) at the launch of the Irish Cancer Society G0' . / + G Collaborative Cancer Research Centre BREAST 5 ;$ PREDICT: Mr John McCormack, CEO Irish Cancer Society, Professor John Fitzpatrick, Head of Research, Irish Cancer Society; Sharon Burrell, breast cancer survivor and Professor William Gallagher, Director of the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT

Conway Fellow and Director of the Irish < 1 H F

8 5 5

C

5 $ Conway researchers are among

"

" %

Irish Laboratory Award Finalists the finalists in the inaugural Irish G 2%A Laboratory Awards. The initiative was "

%and . celebrate launched to promote

the leading people and companies in science. Irish

" people " in " Over 50,000 are employed % research and development, production

and processing. This industry is now - " worth 50 billion euro to the economy.

"

" "

: " "

The competitive application process is % 0 judged by a panel of experts drawn from disciplines. across a range " of scientific

" " gala Winners will be announced at the in the DoubleTree " by % dinner Hilton Hotel

Dublin on December 3rd 2013. . " 8

Category finalists: Prof Cormac (medical Taylor

laboratory & research laboratory of the year), Dr Alfonso " % 0 $

Blanco (education laboratory & laboratory staff member David Croucher " leader of of the year), Dr (young the " $ year).

%

+ : 6' " " "

" "

" 7% . " " 1 " 0 & ' % ? B "

% 9 8 + G 4 % )+ ' : % / E / *23 3,

Developing treatments for irreversible blindness

+ ;$ that includes researchers from the or reverse these ocular diseases. For the

A new European research consortium of industry and academic partners will focus efforts for drug discovery : development 5 of novel = ! and eye therapeutics halt or reverse 5 to 7 ocular > ? diseases blindness. leading @ 5 to 8 5 A

The & Development B/ ‘Drug B. Discovery B0,0$ 75 of Novel Eye Therapeutics’ (3D-NET) project 9 ! 9 5 8 5 will be funded through a â‚Ź1.8 million Marie Curie Industry-Academia Pathways 5 : 55 and Partnerships (IAPP) grant award from the EU Framework 7 Programme. 5 ( :- 7 > ? $

Conway Fellow, Dr Breandan Kennedy will lead and coordinate the consortium

University of Valladolid (Spain), KalVista Pharmaceuticals (UK), RenaSci Ltd (UK) and Grupo FarmacĂŠutico . Gadea B " (Spain).

Millions of people worldwide from

"

suffer

ocular that deteriorate their diseases

"

" quality of life. Conditions such as age " related degeneration (AMD) or %macular 0 " + diabetic (DR)1 85 are leading 1 retinopathy B causes of irreversible blindness, and are " F a growing problem as the worldwide " population ages. " "

% There is a significant unmet clinical need for more effective treatments to halt

first time, the consortium exchanges industry and academic expertise in the development drugs with " potential to of / / treat and enhances " ocular disease G"

/ % : the capabilities and infrastructure required to + G"

test drugs relevant pre-clinical ' these E - in $ models.

$ " F ) " The Kennedy laboratory will contribute " screening to the consortium by efficiently on ocular compounds for effects and

" % angiogenesis visual function in the

zebrafish model and validate ‘hit/lead’ drugs in pre-clinical mouse models of ocular disease.

Welcoming Conway Fellows 1 new " " # " Professor Guenther Eissner served as Senior Vice President and Head of Biolgical : 5 5 Research of the Italian pharmaceutical 8 company Gentium (2004-2007) before being appointed to the Chair for :5 B0,0 C

! Interdisciplinary Stem Cell Research at the 5 : ( :-D University of Munich. His major research 9 9 $ focus is on endothelial pathology in transplant mesenchymal B medicine and on

" stem cells in transplant and regenerative " " medicine. Prof Eissner is establishing % . " Fellows collaborative projects with Conway % . on lung-specific endothelial cell biology; cells $

mesenchymal stem and hypoxia/

angiogenesis; endothelium in inflammation " and oncology; " fibrotide and platelet

% function. + 1 + &

Professor Koelle graduated Sabine " " in Veterinary at the University of J. K Medicine " L5C:MJ. K Munich, Germany, where she also studied medicine and dentistry. She joins UCD from the University of Vienna where she was Head of the Dept of Anatomy, Histology and Embryology. Her research is focused on reproductive medicine, especially on improving the results of assisted reproduction. Prof Koelle hopes " imaging +

" to combine modern techniques " with molecular analyses in proteomics / 23 3% . and genomics to create new diagnostic therapeutic tools " and " and in subfertility " infertility.

School and Sheffield Teaching Hospitals NHS Foundation Trust. Prof Wilson will " " be investigating the pathogenesis of " " inflammatory musculoskeletal diseases. % His research interests include the genetic and influences rheumatoid . epigenetic " J. K in arthritis; ageing and epigenetics; and " pharmacogenetics therapies. " of biological

Prof Sabine Koelle, Professor of Anatomy & Developmental Biology, UCD School of Medicine and Medical Science

+

Professor Kenneth Wolfe joins % & UCD from the Smurfit Institute of Genetics,

Trinity %College Dublin where he was Head of Genetics (2011-13). His research area

evolution in " " is genome eukaryotes with

" aJ. K focus on yeasts as a primary system " " to work on. Current research projects

Wolfe % . underway in the laboratory are " " investigating gene gain* and loss; orphan , gene evolution; " evolution genes; order of yeast "

"

% the MAT locus system. Dr Darran O’Connor has successfully built an independent research group within UCD Conway Institute focused on the discovery, validation and mechanistic anchoring of novel cancer biomarkers. Dr O’Connor has a number of funded collaborations with Conway Fellows through the SFI strategic Molecular " Therapeutics research cluster, " $ for Cancer Ireland and EU FP7 health programme, AngioPredict.

Prof Gerry Wilson, Arthritis Ireland/UCD Chair of Rheumatology, UCD School of Medicine and Medical Science

+ 23 3 ' ' *'' ,< B E B %

D " + E " "

H + "

Professor Gerry Wilson joins UCD from the University of Sheffield. A graduate of Medicine from Queen’s University Belfast, he was Professor in Rheumatology and Honorary Consultant Rheumatologist at the University of Sheffield Medical

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1

B % 1 " B " / . 8

Prof Guenther Eissner, Professor of Translational Systems Biology, Systems Biology Ireland

Prof Kenneth Wolfe, Professor of Genomic Evolution, UCD School of Medicine and Medical Science

* % 8 I" % , 5 8 * % 8I" % , + * % I" % , "

" " % Dr Darran O’Connor, UCD School of Biomolecular & Biomedical Science

! " # $% & $ '# ()*+* ,- .,/ /.0/ 1# ()*+* ,- .,/ /.0, 2# $ $ 3

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