ECRs at ICaMB: For he’s a jolly good (RS) Fellow

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As you saw from our post a couple of weeks ago, ICaMB has recruited several new PIs. To make sure we all know more about them and their research, we decided to have a series specially dedicated to them: Early Career Researchers (ERCs) at ICaMB. First in the series is Dr Kevin Waldron.

by Dr Kevin Waldron

As some of you will already know, I was awarded a Sir Henry Dale fellowship in 2012. This is a new funding scheme for early career researchers, which is co-funded by the Wellcome Trust and the Royal Society. The scheme provides exceptional research support for fellows, including funding a postdoctoral research assistant for the duration of the project (5 years initially, with potential extension for a further 3) as well as all direct research costs, with the aim of supporting the researcher while they forge an independent research career and carve out their research niche. As a result they are highly coveted and extremely competitive – the interview at the Wellcome Trust in July 2012 was probably the most intimidating experience of my career. My award was one of the very first round, in which 10 awards were given from a pool of about 100 applications.

Enjoying the sights of Ha Long Bay (Vietnam)… and doing some deep thinking about my science, of course…

Though the grant was awarded in Summer 2012, I only activated the grant in May 2013 (primarily so that I could swan off on an extended holiday travelling round South East Asia – but that’s another story). Since May there have been two new additions to my lab team; Emma Tarrant, a postdoctoral research associate funded by the fellowship grant, and Anna Barwinska-Sendra, a new PhD student. This combination of good funding and great new people will allow us to really get our teeth into our research question over the coming years, free of the hassle of grant writing and worrying about where the next funds are coming from.

 

I have been studying bacterial metal homeostasis since I started my PhD with Prof. Nigel Robinson (now in Durham), way back in 2003. During that period I studied cyanobacteria, but my current research is focused on the Gram positive mammalian pathogen Staphylococcus aureus. S. aureus has become a major medical problem in recent decades due to the rise of strains that are resistant to multiple conventional antibiotics, with the term “superbug” and the acronym “MRSA” entering the popular consciousness – see for example here, here and here. The organism is particularly problematic in hospitals, where it causes significant morbidity and mortality (see for example these UK and US studies). Though infection control measures introduced in hospitals are proving successful in reducing the number of S. aureus-related deaths, both the prevention and treatment of hospital-acquired infections remain major burdens on patients and on the NHS budget. S. aureus is also problematic in farm animals, being a major cause of bovine mastitis and of lameness among broiler chickens.

My favourite metal

One intriguing new approach to prevention of infection in such settings is the use of solid copper or copper-containing alloys. Copper surfaces show wide-spectrum antimicrobial activity and are certified by the US EPA as antibacterial and ‘self-sanitising’. Multiple trials have shown that these materials can reduce bacterial copper load on touch surfaces in hospitals (see here for example), and the effects on disease transmission are currently being tested. In fact, this is not a new approach at all: as this YouTube clip explains, copper has been used since ancient times to sterilise drinking water and to treat minor ailments, even being mentioned by Hippocrates in ~400 BC. Copper is the active ingredient in numerous agricultural fungicides including Bordeaux mixture, in use since 1885.

The mechanisms by which copper, either as metal salts or as solid metal surfaces, kills bacteria are unknown. Dissolved copper ions are thought to play an important role in the killing mechanism even from solid copper surfaces. In fact, the toxicity of excess concentrations of essential metal ions (as opposed to non-essential metals such as lead and mercury) has been historically under-studied and has merely been seen as a confounding factor of studies of normal metal homeostasis. Copper is redox-active, a potent Fenton catalyst, and therefore may catalyse the production of reactive oxygen species in vivo. It is also at the top of the Irving-Williams series, meaning it will bind extremely tightly to proteins, potentially having deleterious effects on their function when present in excess.

Our goal is to identify and understand these toxicity mechanisms, both to shed light on new aspects of metal homeostasis and to find better ways of exploiting this toxicity for medical and commercial applications. To do this we’re going to use a combination of multiple experimental approaches in collaboration with a number of world experts in diverse fields. We will use proteomic methods to identify S. aureus proteins that become aberrantly associated with copper under high-copper growth conditions, and then characterise the functional effects of those aberrant associations using traditional biochemistry and molecular genetics. We will combine this with metabolomics studies of the effects of copper toxicity on bacterial metabolism. Finally, we will use genetic screens to identify mutant strains that display increased copper resistance. Together, this should give us a comprehensive view of the effects of copper toxicity on the cell, with the aim of elucidating the multiple mechanisms by which excess copper interferes with normal function.

The Waldron lab group: Jack Stevenson, Emma Tarrant, Anna Barwinska-Sendra, Stuart York and Kevin Waldron (left to right)

 

So we’re just starting off on a long-term quest, with lots of experiments to keep us busy for the next few years. It’s an exciting time in the Waldron lab.

 

 

 

 

Links

Sir Henry Dale Fellowships   http://www.wellcome.ac.uk/Funding/Biomedical-science/Funding-schemes/Fellowships/Basic-biomedical-fellowships/WTDV031823.htm
Wellcome Trust www.wellcome.ac.uk/index.htm
Royal Society www.royalsociety.org
US EPA www.epa.gov/pesticides/factsheets/copper-alloy-products.htm

Thermolastics wins ACTION 2013

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Kate Clark is a PhD student in ICaMB who recently won first prize as part of the Thermolastics team at ACTION 2013.  Here she tells us what it was all about and how she found the experience

By Kate Clark

I’m a PhD student in David Lydall’s lab, and I was part of the ThermoLastics team that recently won ACTION 2013.

ACTION is an annual, EPSRC-funded, 6 month programme open to both postgraduate students and research staff (http://research.ncl.ac.uk/action2013/).  The aim of ACTION is to generate ideas from the Newcastle University research community to tackle societal challenges in the North East. This year, there were three societal challenge themes: sustainability, social renewal and changing age.  Participants were asked to create a social enterprise that addressed one or more of the challenge themes.  The programme started with a two-day residential, where teams were formed and business ideas were generated.  This was followed by a series of 1-day training labs, which introduced teams to key aspects of developing a business.

I formed a team with three engineering PhD students – Thomas Bohl, Eesha Raut and Amy Green.  Eesha and Amy are chemical engineers, partly working for companies during their PhDs, and Thomas works on developing sustainable fuels.  My research background is yeast genetics, which is quite different to that of my team members!  However, one of the best aspects about ACTION is that inter-disciplinary collaboration is encouraged and we soon found that we had a number of similar business ideas.

The initial two-day residential meeting for ACTION2013 was held during a cold snap in March, so we started looking at a socio-economic measure called fuel poverty, which is where households spend 10% or more of their income on heating their homes adequately. We did a little more research and found that nearly 25% of households in the North East are in fuel poverty – the second highest rate in England.  We decided to build a social enterprise around reducing fuel poverty, and believed that the best way to do this would be to offer cheap home insulation that was suitable for any home.  The North East has very old housing stock, most of which does not have cavity walls, so we wanted to develop internal insulation for solid walls.  Also, we wanted our product to be sustainable so we experimented with using finely shredded household plastic as the insulation material – currently only around 50% of household plastic waste is recycled.  At this point we decided on our name, ThermoLastics – Thermo for warmth, and Lastics for making plastics last for longer!

Our first prototype product was a plasterboard panel filled with finely shredded plastic from household plastic waste.  The panel is fitted to the internal wall of the home.  Our second prototype used a 3D-printed plastic matrix that can be filled with shredded plastic insulation.  Currently, we are investigating ways to maximize the insulation potential of plastic waste, such as using finely milled plastic to form fibres.  To find out more, visit http://www.thermolastics.co.uk/

Overall, we hoped that our business would address all three of the societal challenges: sustainability (through using recycled plastic), social renewal (by reducing expenditure on fuel bills, which might help families to lead more active, social lives) and changing age (because 50% of those in fuel poverty are over 60).

The Thermolastics team, Amy Green, Thomas Bohl, Eesha Raut and Kate Clark being presented with their award by Dr Bryn Jones, the Newcastle University Dean of Postgraduate Studies

ACTION 2013 culminated in a one-day showcase event at the Great North Museum, which was part of the British Science Festival 2013.  Teams first pitched their ideas to a panel of judges, who were business experts from the North East.  Then, teams opened their trade stands, displaying their business ideas, to judges and the public. We were delighted to be declared the ACTION 2013 winners, as decided by the expert judges, and were thrilled to be awarded the People’s Choice Award too – decided by votes from members of the public.  The prize awarded by the judges is £2,000 per team member to put towards developing the business further, or developing ourselves as entrepreneurs.

Prior to ACTION 2013, I had no business experience but by the end of the programme, I had helped design and develop a product, produce a business plan, pitch the business and run a trade stand – so I have learned a great deal.  The ThermoLastics team has decided to stay together and explore ways in which we can fund research and development for our product.  Perhaps we will even bring it to market in the future – watch this space!

 

Links

Action 2013: http://research.ncl.ac.uk/action2013/
Thermolastics: http://www.thermolastics.co.uk/
The Lydall Lab: http://research.ncl.ac.uk/lydallab/Welcome.html
Newcastle University Societal Challenges: http://www.ncl.ac.uk/about/values/societal/
British Science Festival 2013: http://www.britishscienceassociation.org/british-science-festival

The new ICaMB recruits

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As many ICaMB members will have been aware, we have been very busy this year recruiting a new generation of Principal Investigators (PIs).  New faces bring new ideas and fresh perspectives and we are very excited to have successfully identified and then persuaded a number of talented scientists to join us in Newcastle.  In addition, we congratulate Yulia Yuzenkova, one of our current postdocs, for winning a prestigious Royal Society University Fellowship.

Independent Researcher Establishment Scheme (IRES)

For our new IRES fellowships we sought to identify three new PIs in any area of research that fitted within the broad interests encompassed by ICaMB.  These awards are for a 5-year period and, after review, are intended to lead to a permanent academic position in our Institute.   The new IRES fellows will be expected to establish an independent research programme and obtain the funding to build a research group. We received many high-quality applications for these positions and the competition was very intense. We are very happy, therefore, to welcome our three IRES fellows and look forward to them being our colleagues for many years to come.

 

Dr Owen Davies

Research Interests: The synaptonemal complex is a giant molecular ‘zipper’ that binds together homologous chromosome pairs along their entire length during meiosis.  It is essential for meiotic recombination, crossover formation and fertility. Despite its discovery almost 60 years ago, we still lack any information regarding its molecular structure and function. My research is directed towards overcoming this knowledge gap and defining the full three-dimensional structure of the human synaptonemal complex together with the molecular basis of its function in meiosis.

Background: After my PhD, I secured a post-doctoral fellowship from the Royal Commission for the Exhibition of 1851, which I took to the Institute for Stem Cell Research, University of Edinburgh. There I worked with Dr. Sally Lowell studying the molecular triggers of early lineage commitment in embryonic stem cells. It was during this time that I formulated the ideas for my long term research plans for studying the molecular structure and function of the synaptonemal complex in meiosis. Over the last three years, I have initiated this research at the Department of Biochemistry, University of Cambridge, working with Dr. Luca Pellegrini.

Owen has already relocated to Newcastle and has started work in ICaMB

 

Dr Josana Rodriguez

Research interest: By breaking symmetry, cells are able to generate diversity, migrate, and organise themselves into more complex structures such as tissues and organs. Misregulation of such cell polarity is implicated in a number of human diseases, most notably cancer. Tumour progression is correlated with disruption of epithelial polarity and randomized orientation of the cell division plane caused by misplacement of the mitotic spindle. These observations show the importance of cell polarity for the correct development of an organism and the tight regulation required between cell polarity mechanisms and the cytoskeleton.

My aim is to identify new interactions between cell polarity and the cytoskeleton, and to understand them in a whole organism context during morphogenetic movements and tissue organisation. I would like to extend these studies to analyse the possible implication of these interactions in diseases such as cancer and neurodegenerative disorders.

 

Background: I am currently a postdoctoral research fellow at The Gurdon Institute (Wellcome Trust/Cancer Research, UK) working in the laboratory of Dr. Julie Ahringer (2006 to date). My postdoctoral research identified genes involved in the polarisation of cells through high-throughput genetic screens in C. elegans. I have been a Wolfson College Fellow since 2009 (University of Cambridge).

Josana plans to relocate to Newcastle in July 2014 after completing some ongoing studies in Cambridge

 

Dr Niall Kenneth

Research Interests:  My work focuses on the signalling properties of a family of intracellular proteins called the IAPs (inhibitor of apoptosis). These proteins were originally characterised as modulators of cell death but have since emerged as key signalling intermediates that regulate a variety of cellular functions. X-linked IAP (XIAP) has been the subject of much recent interest as a possible therapeutic target in cancer due to its greatly elevated expression in tumour cells and its well-documented ability to inhibit cell death. Additional work has identified germline mutations in the XIAP gene that cause a severe primary immunodeficiency known as X-linked lymphoproliferative disorder (XLPD).  My work aims to understand the role played by XIAP in essential cellular processes and to reconcile this with its role in pathogenesis.

Background:  After my PhD, I joined the group of Dr Sonia Rocha at the Centre of Gene Regulation and Expression at the University of Dundee, where I focused on the control of gene transcription following DNA damage and hypoxic stress, regulated by the NF-kB and HIF transcription factors. In 2010, I relocated to the USA to join the laboratory of Professor Colin Duckett, at the University of Michigan, where I have continued to work on transcriptional regulation and developed my interests in the IAP proteins and how they are altered in disease.

Niall will relocate to Newcastle in April 2014

 

Royal Society University Research Fellowship

The Royal Society URF is one of the most prestigious fellowships awarded to young scientists seeking an independent research career.  We are therefore extremely happy that based on her outstanding postdoctoral work in ICaMB, Yulia Yuzenkova has recently received this award.  

Dr Yulia Yuzenkova

Research Interests: My research is focussed on mechanisms of gene expression in cyanobacteria, one of the most ancient and ecologically important, but under-studied group of organisms on Earth. Approximately 2.3 billion years ago cyanobacteria invented photosynthesis, which transformed all subsequent biological history of Earth. Nowadays they live everywhere where sunlight is available and produce 30% of atmospheric oxygen; furthermore, they can convert inert atmospheric nitrogen to the forms digestible by other organisms. I will be working on transcription in cyanobacteria and its coordination with other major processes in the cell, such as DNA replication and translation.

Active centre of the T. thermophilus RNAP elongation complex with unfolded (inactive) and folded (active) Trigger Loop domain conformation.

Background: I did my PhD in the Institute of Molecular Genetics in Moscow and then my first PostDoc in the Waksman Institute in Rutgers, the State University of New Jersey, USA where I performed structure-functional studies of bacterial RNA polymerase.  After moving to Newcastle University, I have been working on a variety of projects investigating the mechanisms of transcriptional regulation by bacterial RNA Polymerase.

 

New ICaMB Professor

In addition to our new young PIs, we have also recruited a new young(ish) Professor, Jonathan Higgins from the Brigham and Women’s Hospital at Harvard Medical School 

Prof Jonathan Higgins

Research Interests: Cell division is a short but dramatic part of the cell cycle. To ensure precise inheritance of the genetic material, chromosomes must be disentangled, condensed, and then “bi-oriented” on microtubules so that they can be sorted properly into the daughter cells. My lab aims to understand fundamental processes that control these events: specifically, the post-translational modifications of histone proteins that dictate recruitment and displacement of regulatory proteins to and from chromatin during cell division. In particular, my lab has revealed the role of histone kinases such as Haspin in localizing key “error-correcting” proteins to centromeres in mitosis.

Haspin phosphorylates Histone H3 to create a binding site for the Chromosomal Passenger Complex (CPC) at the centromeres of chromosomes in mitosis. The CPC, which contains the kinase Aurora B, acts to prevent incorrect attachments of microtubules (grey lines) to kinetochores (grey ovals), to ensure the appropriate segregation of chromosomes during cell division.

Background: I was born in Stockton-on-Tees and grew up in North Yorkshire. During my postdoc with Michael Brenner at the Brigham and Women’s Hospital (BWH), Harvard Medical School (HMS), I discovered a novel gene, which turned out to be Haspin, within an intron of the integrin gene I was studying. I started working on Haspin as a side project, and then more seriously when I joined the faculty at BWH/HMS to set up my own research group.

Jonathan will relocate permanently to Newcastle in July 2014

The next generation of ICaMB PIs and Research Fellows

Owen, Josana, Niall, Yulia and Jonathan join a growing group of new PIs in ICaMB, which include 2 further Royal Society URF award winners together with recipients of Wellcome Trust/Royal Society Henry Dale and Career Re-entry Fellowships. We are confident that their talent drive, and enthusiasm will ensure a bright future for research in Cell and Molecular Biosciences in Newcastle.

Dr Suzanne Madgwick: Suzanne is a Wellcome Trust Career Re-entry Fellow researching mechanisms of meiosis

Dr Heath Murray: Heath is a Royal Society University Research Fellow researching the Regulation of Bacterial DNA Replication Initiation

Dr Paula Salgado: Paula is a Lecturer in Macromolecular Crystallography studying the mechanisms of host-pathogen interactions

Dr Claudia Schneider: is a Royal Society University Research Fellow investigating nonsense mediated mRNA decay pathways

Dr Kevin Waldron: is a Wellcome Trust/Royal Society Henry Dale Fellow investigating the role of essential metal ions in pathogenic bacteria

 

ICaMB success in the Summer Sun

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Your ICaMBlog team would like to wish our readers, followers and colleagues a joyful and restful August. We have decided to take a well earned break over the next month to muse on new ideas for when we all get back into the swing of the new academic year in September.

Before we look forward we have some hot off the press news to pass on to the ICaMB community and those further afield.

We are sure everyone will agree that our current cohort of MRes students deserve a big pat on their backs for finishing their project assessments this week with some very professional project presentations and a brilliant Poster evening on Tuesday (30th July).

 

We are also very happy to inform you that Anna Stanton (Main supervisor: Dr Judith Hall) won the MRes Poster prize. Anna’s project explored the detection of bacteria in vaginal epithelial cells and how hormones influence this response. Anna, we assume, will be taking a short break to enjoy this wonderful summer before getting back into the lab to continue her project during her PhD studies.

But that’s not all, we have more success to report! As part of the prize giving the MRes team of the Graduate School also picked 10 runners up. In no particular order we must also therefore congratulate Pippa Harvey (Dr Jeremy Brown), Anthony Moore (Prof John Hesketh) and Sophia Valaris (Dr Jun-yong Huang) for their prizes.

Where next then? The coming months offer some interesting activities for ICaMB members. This year the British Science Festival is being held in Newcastle from September 7th – 12th and a number of us have projects being showcased. A particular highlight of the festival is on Sunday Sept 8th, called “University Family Challenge”.  Paula Salgado is leading a structural biology drop in activity looking at 3D puzzles of infections,while Phil Aldridge and Jeremy Lakey are inviting families to “Epifection: Build the Bug“, which involves lego! Moreover, our collaboration with Leading Edge is being highlighted through the perspective of the Year 9 participants.

Epifection is a digital interactive project developed by Phil and a number of other Academics across the University that will run through the entire festival. It explores the decisions we need to make in the face of a infection outbreak. It also exploits Phil’s addiction to his smartphone!

After the festival the next big event in the ICaMB calendar will be the Away Day on 14th October. The program of activities is looking rather exciting and will provide a great opportunity for ICaMB members to network and discuss the research we are all doing (and maybe go out for a beer or light refreshment afterwards!).

The Away Day compliments our summer social event, the famous “Boat Trip.” Floating down the Tyne enjoying the sun allowed many of us to relax, meet sometimes familiar characters as well as new faces.

 

 

Regarding new faces, over the next few months a number of new researchers will be moving to ICaMB. More on this when we return in September.

So on that note we wish everyone a superb break over August. For those staying, work hard but enjoy yourselves too: remember Science is Fun, even if it looks like 300 tubes or 10 96-well plates to process.

We hope the first few months of us running this blog have shown you both the fun and serious side of research in ICaMB. There will be more to come in the Autumn.

We leave you with this picture of St Mary’s Lighthouse at sunset….enjoy

Links

 

A ‘tail’ to tell – Lakey lab discovery could lead to a new class of antibiotics

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Dr Chris Johnson

“Most of us know that we should wash our hands after being around animals but do most of us know the reasons why? As a researcher who spends most of his time in the lab killing E. coli, using E. coli specific antibiotics I should be well aware of the dangers of this often underestimated Gram-negative bacteria. However when my youngest daughter contracted E. coli O157 after visiting an agricultural show in Scotland in 2011 (even though we had followed the hand washing procedure), I realised that I did not appreciate how nasty this bacteria can be. Thankfully after 6 weeks in hospital including a lengthy stretch on dialysis my daughter made a full recovery but not everyone is so lucky.”

Professor Jeremy Lakey

The urgent need to develop new drugs to target pathogenic bacteria has been a theme of the ICaMB blog since its inception in early 2013.  However, these words from Dr Chris Johnson, a postdoc in Jeremy Lakey’s laboratory, bring home the seriousness of the problem.  Fortunately, Chris is in a position to do something about this.

Many of you will have realised that last week saw another potential breakthrough in ICaMB’s ongoing ‘War on bacteria’ (and here, here and here).   This time the PI making the news, with data demonstrating the possibility of a whole new class of antibiotics, was Professor Jeremy Lakey.  And when we say making the news, we mean that literally. The ITV interview of Jeremy and his team can be viewed here

This story has made news around the world and has been featured in newspapers in Australia and India (and here), as well as closer to home.  Here is the official university press release.

So what’s going on?  If you want to read the primary paper it is here

The unstructured domain of colicin N kills Escherichia coli. Mol Micro 89:84-95

Chris Johnson, who was the lead author on this manuscript explains:

“E. coli produces protein antibiotics called colicins which are used to kill E. coli and closely  related bacteria in the eternal bacterial arms race. In order to further understand how one of these, colicin N (ColN), works, we dissected the protein into its individual domains to see how each part behaved in isolation. Quite by chance we found that part of the protein, THE TAIL, was actually toxic to them. Although far less efficient than the entire ColN molecule, it remains specific for E. coli and furthermore, the specificity is housed within an intrinsically unfolded domain (a domain which has no defined 3D structure). Although this is a very basic discovery in its early stages, it allows us to appreciate novel mechanisms to kill E. coli.” (see the full version of this at the bottom of the page)

Some more about Jeremy

Any of you who were bioscience undergraduates in Newcastle will know Jeremy Lakey from his famous recreations of protein structure using party balloons.  Others may know him for co-founding Orla Protein technologies.  Some of us know him as a man who will always buy his round in the pub.  All of us know him as a great scientist and colleague.  Furthermore, Jeremy is a leading supporter of Leading Edge and recently a group of 6 Year 9 school pupils from St Cuthberts RC School looked at how ColN acts against E.coli when you start changing the amount of salt they are grown in. As many ICaMB scientists may know Jeremy also runs a workshop with Ponteland Community High School to explore bacterial shape and their surfaces using LEGO.

But did any of us think that one day Jeremy Lakey may SAVE THE WORLD from antibiotic resistant bacteria? Possibly.

The detailed science

Most Gram- negative bacteria produce protein antibiotics which are used as weapons in the battle between competing populations of bacteria.  E. coli produces protein antibiotics called colicins which are use to kill E. coli and closely related bacteria.  Once colicins are released into the extracellular milleu they dock onto their targets via specific outer-membrane receptors and then seek out an internal, periplasmic, binding partner (the Tol or Ton proteins) which helps them translocate into the cell.  We study colicin N (ColN) which comprises of an intrinsically unfolded N-terminal translocation (T) domain, involved in TolA and OmpF binding.  Its central receptor binding (R) domain binds lipopolysaccharide whilst its C-terminal 200 amino acids define the cytotoxic pore-forming (P) domain. This latter feature is common to all pore-forming colicins and forms a channel in the inner-membrane causing K+ release and cell death.  Other colicins have C-terminal domains which display cytotoxic activities that include DNAase or RNase activity.  Irrespective of the particular cytotoxic activity, all colicins are comprised of three domains (T-R-P) and it was assumed that the sole role of the T and R domains was to deliver the cytotoxic C-terminal domain across the outer-membrane.

In order to investigate the mechanism of ColN activity we dissected the protein into its individual domains.  We were attempting to block the toxic activity of full length ColN by pre- incubating E. coli cells with the intrinsically unfolded T-domain.  The rationale behind the experiment was that we could block all the available receptor sites on the E. coli target cells by saturating with T-domain, such that when the full length ColN was added to cells it would be non-toxic, as all the essential receptor binding sites would be already sequestered.  However rather than protecting the cells, T-domain was found to be toxic and like full length ColN provoked K+ efflux.   Although less efficient than full length ColN, T-domain is strictly dependent upon the same receptor proteins, OmpF and TolA for killing.  Since these receptors are only found in E. coli-like bacteria, T-domain displays the unusual combination of a generic killing mechanism coupled with extreme specificity housed within an intrinsically unfolded domain.

Links

Jeremy Lakey’s University home page: http://www.ncl.ac.uk/camb/staff/profile/jeremy.lakey

Follow Jeremy Lakey on Twitter: https://twitter.com/JeremyLakey

ICaMB: http://www.ncl.ac.uk/camb/

The Centre for Bacterial cell Biology: http://www.ncl.ac.uk/cbcb/

The official Newcastle University press release: http://www.ncl.ac.uk/press.office/press.release/item/chance-finding-could-lead-to-new-antibiotics

Link to ITV story:

http://www.itv.com/news/tyne-tees/story/2013-07-05/breakthrough-in-combatting-bacterial-infection/

The ‘Australian’ story: http://www.theaustralian.com.au/news/breaking-news/tail-could-be-used-for-new-drugs/story-fn3dxix6-1226674131684

The ‘Times of India’ Story: http://articles.timesofindia.indiatimes.com/2013-07-06/science/40406695_1_escherichia-coli-e-coli-protein

The Northern Echo story: http://www.thenorthernecho.co.uk/news/10524003.Scientists__chance_find_may_develop_new_generation_of_antibiotics/

Jeremy’s company, Orla Proteins: http://www.orlaproteins.com/about-orla/the-board.aspx

 

Leading the Way… in Protein Structure

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By Kevin Waldron

This week, ICaMB welcomed the Leading the Way winners into our labs for an exciting day of science. As you may remember from our previous post a couple of weeks ago, Leading the Way was ICaMB and Leading Edge’s collaborative pilot scheme to take some of ICaMB’s great science (and early career scientists) into a local school, George Stephenson High School in Killingworth. That week was a great success, inspiring all of its participants: students, teachers and ICaMB members alike.

The overall winners during the week in GSHS were the AU team, made up of Lucy Hainsworth, Libby Macpherson, Rebecca Brown, Lauren Rhodes, Abbey Wrightson, Kimberley Stoker, Sophie Anson, Connor Little, Nathan Clapperton. AU designed an outstanding poster to illustrate how the prion protein represents a biomarker of mad cow disease (or, more scientifically, variant Creutzfeld-Jakob disease, vCJD), how the structure of this protein changes from the ‘normal’ form to the ‘abnormal’, disease-causing form, and how knowing the structure of the prion protein can enable us to design a diagnostic test.

AU’s prize was to spend a day in an ICaMB laboratory, learning about how we determine the structure of a protein, with the members of the judging panel, Dave Bolam, Paula Salgado and myself.

After a brief welcome and introduction, we kitted our guests out in fetching lab coats, supplied them with ‘Leading the Way’ lab books and got started.

Showing the kids how to plate cells on a petri dish

 

First, the kids tried their hands at microbiology with the Waldron lab, streaking E. coli cells onto agar plates and then picking colonies to inoculate cultures for recombinant protein production.

 

 

Practising to become a PhD student, staring at a pouring column…

Next, Dave Bolam and his team demonstrated how a His-tagged protein can be purified using affinity chromatography, and then the kids loaded each of their protein samples on SDS-PAGE gels. Remarkably, all of the students successfully purified their target protein, though it’s worth noting that this was not actually the prion protein, PrPC (Imagine the risk assessment!).

 

“Here, let me help you” says Dave.

 

“It was great fun spending time with enthusiastic kids and giving them a flavour of what we do. It reminds you why you do science in the first place“, says Dave after taking part in this type of activity for the first time.

“We’re doing science now, Miss!” – shouted one of the students

 

 

The day finished with a demonstration of protein crystallisation with Paula Salgado and Will Stanley of the Structural Biology Laboratory. The students attempted to crystallise lysozyme (with mixed success), and then observed protein crystals under the microscope.

“It’s always great to share our love for science with young minds and see them get really excited about carrying out the experiments we do routinely. It’s a breath of fresh air in the lab. Hopefully we’ve given them an experience to remember, as well as a better understanding of research in a biomedical institute.” commented Paula at the end of the day.

 

Although this was a high-paced tutorial in protein production and structure determination – a process that usually takes at least several weeks, and in some extreme cases an entire career – the students received a hands-on demonstration of some real-life research techniques. We all hope that this experience, even at such an early age, might just implant the idea of a future in science for some of these young people.

But from my own perspective, I can say that their enthusiasm has been infectious (no pun intended), and is a timely reminder of why I got into science in the first place – because at school I always found science classes more interesting than any others. I would have loved such an opportunity when I was that age.

Thanks go to Phil Aldridge, ICaMB’s Leading the Way coordinator, all of the members of the Waldron, Salgado and Bolam labs who helped out during the visit, the staff of George Stephenson High, and most of all to the members of the AU team, for making the day a success.

 

George Stephenson High School http://www.gshs.org.uk/home

 

Breaking news: Mitochondria replacement therapy given green light

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Breaking news –  by Prof Bob Lightowlers

Professor Dame Sally Davies, the Governments Chief Medical Officer, has today given support to a change in the law that will allow the form of mitochondrial replacement therapy that is being pioneered here in Newcastle, has we mentioned before.

Its great news for any prospective mother with mitochondrial DNA disease who is concerned about transmitting the disease to their children.

Most media is covering this – BBC, Guardian, Telegraph – but if you are still confused, we thought it would be good to recap the essential points:

Electron micrograph of a cell (coloured blue) revealing part of the mitochondrial structure (orange) within. The entire length of the mitochondrion is about 5 micrometres.

– Mitochondria are crucial structures found in all cells in our body and they take our common foodstuffs such as fats and sugars and turn them into energy. They have their own genetic element, mitochondrial (mt) DNA. Much smaller than our chromosomes, mtDNA is essential for energy production.

– In 1988, scientists in the UK and US recognised that certain diseases were caused by mutations in mtDNA with the main disorders related to your muscle tissue and the brain.

– It is estimated that at least 1:10,000 people suffer from disorders associated with defects in mtDNA – that’s more than 6,000 people in the UK.

– Mitochondrial DNA is only transmitted to babies by their mothers. Unfortunately, as you inherit your mothers mitochondria, diseases caused by mtDNA mutations are inadvertently transmitted from the mother.

– Doug Turnbull, Director of the Wellcome Trust Centre for Mitochondrial Research (WTCMR) and I have wondered since the 1990s whether it would be possible to prevent the transmission of the faulty mtDNA from the mothers to their children by transferring the nucleous from an egg of the mother carrying these mtDNA mutations into a healthy egg whose nucleous had been removed, and then fertilise it

– Professor Mary Herbert, Doug and a group of us from the Mitochondrial Research Group were able to show that such a swap could be performed without any or very low levels of the defective mtDNA being transferred. Importantly, there was also no defect detectable in the reconstituted cells.

– In August 2012, the government asked the Human Fertility and Embryological Authority (HFEA) to find out what the general public thought of the procedure.  The results were collated  and the Human Fertility and Embryological Authority made a recommendation to Government. There was an overall support for the new technology with only 10% being fairly or strongly against the concept of mitochondrial gene replacement

To understand all the details and find out the whole story, see my post a while ago here.

The Wellcome Trust also has a very nice video explaining the science behind the news story:

 

 

Links

Wellcome Trust Centre for Mitochondrial Research http://www.newcastle-mitochondria.com/
Human Fertility and Embryological Authority (HFEA) http://www.hfea.gov.uk/index.html
HFEA mitochondria puclib consultation 2012 http://www.hfea.gov.uk/6896.html

 

Science Minister visits Centre for Bacterial Cell Biology

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by Dr Heath Murray 

On June 27 the RH David Willetts MP, Minister for Universities and Science, visited the Centre for Bacterial Cell Biology (CBCB) to hear about how research on bacteria can lead to: development of novel antibiotics, design of synthetic biological systems, and even understanding the origins of life on earth. Dr Heath Murray (CBCB & ICaMB) tells us more about this visit.

Mr. Willetts was given a guided tour of the new Baddiley-Clark building by the director of the CBCB, Prof Jeff Errington.

Jeff (left) outlines CBCB research to David Willetts (right), with Heath (middle back) paying close attention

Jeff discussed why he left Oxford University after 25 years to start the CBCB at Newcastle, the first Centre of its kind in the UK to provide a world-class facility in which to carry out fundamental research on bacterial cells. During the tour Jeff highlighted how the localised network of international researchers at the CBCB, working on biological problems in model bacterial organisms provides an unparalleled setting in which to exchange ideas and to benefit from related advances in microbial cell biology. While walking around Jeff noted how the open plan of the Baddiley-Clark building promoted interactions amongst the various research groups, thereby creating a uniquely stimulating environment for the scientists that work there.

This was a very fruitful visit with interesting discussions, as highlighted by Jeff: “I was impressed at how quickly the Minister picked up the key biological points we wanted to make, such as about how our work impacts on thinking about the origins of life!”

An image similar to those seen by David Willetts showing severe DNA segregation defect in a mutant Bacillus subtilis strain, observed using epifluorescent microscopy. (DNA: blue; origin of replication: green, cell membrane: red)

 

I then demonstrated the bespoke microscopes available within the CBCB to the Minister, highlighting how the small size of bacterial cells (only a few micrometers) makes microscopic analysis technically challenging and how the CBCB is utilizing state-of-the-art super-resolution microscopes to overcome this difficulty. I also explained how researchers use genetic engineering to fuse their “proteins of interest” to the Green Fluorescent Protein (GFP) from the jellyfish Aequorea victoria, thus creating tools to visualize the localization of proteins or nucleic acids within living bacterial cells using fluorescence microscopy.

 

Heath explains the potential applications of the research to the Science Minister

 

The Minister was keen to see the live demonstration of our fluorescent microscope and seemed amazed by how clearly the organization of the bacterial chromosomes was immediately apparent. He quickly appreciated that interfering with this process might have application in the development of new antibiotics.

 

 

We were all left with the clear feeling that Mr. Willetts enjoyed hearing about the science taking place within the CBCB and how this fundamental research provides insights crucial for the discovery and development of new antibiotics, as well as providing solutions to a wide range of industrial and environmental problems. “It was an interesting meeting – very reassuring to hear that the Minister is keen to make sure that Government continues to invest in Blue-Skies Research”, Jeff concluded.

 

ICaMB Research Update: Zenkin lab Science paper

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Congratulations to ICaMB and CBCB researchers Soren Nielsen, Yulia Yezenkova and Nikolay Zenkin and  who have a paper published in the prestigious journal Science today.

Nikolay Zenkin: RNA Polymerase researcher

There are three RNA Polymerases in Eukaryotic cells and although much attention focuses on the role of RNA Polymerase II, since it transcribes mRNAs from protein encoding genes, it is easy to forget that the majority of transcription in the cell is accomplished by RNA Polymerase III.  RNA Polymerase III (or Pol III as it is commonly known) is responsible for the synthesis of ribosomal 5S rRNA, tRNA and other small RNAs.

 

Soren’s paper, entitled “Mechanism of Eukaryotic RNA polymerase III Transcription” termination solves a long-standing mystery in the field of how transcriptional termination by RNA polymerase III takes place. Their study reveals an elegant scenario, in which co-transcriptional folding of highly-structured RNA polymerase III transcripts causes termination at the end of their genes. This mechanism ensures proper folding of the structural/catalytic RNAs synthesized by RNA polymerase III prior to RNA release. Analogies with bacterial termination suggest that this fundamental mechanism may have emerged before divergence of bacteria and eukaryotes.

Here is the Science Editor’s summary of the paper

It is as important to terminate any biological process as it is to start it. Transcription, copying information encoded in genes into RNA, requires accurate and timely termination. Nielsen et al. (p. 1577) present a mechanism for transcription termination by RNA polymerase III, the enzyme that synthesizes the majority of RNA molecules in eukaryotes. In this scenario, the folding of the RNA as it is transcribed by polymerase into a highly structured transcript causes termination at the end of its synthesis. This mechanism may serve as a control of proper folding of structural or catalytic RNAs synthesized by RNA polymerase III. Comparison with other organisms suggests that this mechanism emerged before divergence of bacteria and eukaryotes.

And here is the abstract of their paper

Gene expression in organisms involves many factors and is tightly controlled. Although much is known about the initial phase of transcription by RNA polymerase III (Pol III), the enzyme that synthesizes the majority of RNA molecules in eukaryotic cells, termination is poorly understood. Here, we show that the extensive structure of Pol III–synthesized transcripts dictates the release of elongation complexes at the end of genes. The poly-T termination signal, which does not cause termination in itself, causes catalytic inactivation and backtracking of Pol III, thus committing the enzyme to termination and transporting it to the nearest RNA secondary structure, which facilitates Pol III release. Similarity between termination mechanisms of Pol III and bacterial RNA polymerase suggests that hairpin-dependent termination may date back to the common ancestor of multisubunit RNA polymerases.

Links

Link to the Science paper: http://www.sciencemag.org/content/340/6140/1577.abstract

Nikolay Zenkin laboratory home page: http://www.ncl.ac.uk/camb/staff/profile/nikolay.zenkin#tab_research

Centre for Bacterial Cell Biology: http://www.ncl.ac.uk/cbcb/

Science magazine: http://www.sciencemag.org/

Link to the Science cover: http://www.sciencemag.org/content/340/6140.cover-expansion