Author Archives: Neil

IPA Update: The Mysterious World of Biotech

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By the IPA committee

On Thursday 30th January for the 4th Science Lives Seminar the ICaMB Postdoc Association (IPA) decided to delve into what it is really like to work in the Biotech industry, by hosting Dr Keith Foster from Syntaxin Ltd (Oxford, UK). For many of us Postdocs, the Biotech Industry is an unexplored entity…so how and why did Keith Foster make the transition from Postdoc to a Biotech company co-founder? And, what advice would he give Postdocs thinking of making the same leap?

Dr Keith Foster giving his presentation

Dr Foster’s talk started by illustrating his personal experience; he obtained a PhD in biological sciences in London then set his sights on a getting a post-doc position. He explained that he had first thought he would head to the bright lights of the USA for this but as his wife’s dentistry qualifications were not recognised over there, the couple moved to Nottingham to pursue their respective careers.  At this point Keith really wanted to pursue a long and successful academic career and said he couldn’t imagine leaving academia.

However, he soon realised that you can never have a career plan set-in-stone as within the first couple of years of his post-doc, Keith and his wife found out they were expecting their first child. He recalled this period as a wake-up call, like an alarm telling him he should get what he considered a “real job”, meaning he wanted a stable, and hopefully permanent job to support his growing family. He said he quickly realised that in a field as dynamic as science you not only have to evolve and make career moves for personal circumstances, but also, because the world of science is ever changing, we never know what to expect around the next corner!

So, from Nottingham, Keith made his big move to industry as a Senior Scientist, the company being SmithKline (before it became GSK). Much to his surprise in his new job, he found that he could still put to use his “passion for science” at the bench and really got a thrill from the drug development and translational aspects of the projects that were new to him. Early on Keith started working on the protein, Botulinum neurotoxin, which he says he  “fell in love” with and this protein remains his passion to this day with Keith recently having opened his own company based on it 20 years or so later, Syntaxin Ltd.

Like many of our PIs, being the big boss at Syntaxin Ltd means that Keith does not himself spend time at the bench, but he does insist that any Postdoc going into a company as a Senior Scientist would have to do lots of bench work, making what an academic postdoc and an industrial senior scientist do on a daily basis “very similar”. We should however expect a pay rise! Nice!

Keith Foster’s company was recently bought by a French company (IPSEN). This is where one of his biggest pieces of advice came from… always leave on good terms, and try not to make any enemies! It turns out that IPSEN actually made Keith redundant earlier on in his industrial career. However, Keith moved on, working at a handful of other companies on his way, but couldn’t believe it when he managed to shake hands with IPSEN over a multi-million dollar deal for his company all those years later! A real lesson in the importance of networking and maintaining those contacts!

Another point that Keith highlighted was that Biotech or the pharmaceutical industry may not be the holy grail that many PhD students or post-docs think it is…. he posed the question is there really more job stability there these days? In academia we have fixed two or three year contracts, but industry is also highly competitive and money is hard to come by, with some firms choosing to move away from the UK and making redundancies.

To wrap this seminar up, like all our Science Lives Seminar speakers, we asked him to mention how he managed to handle a personal life and successful research career in parallel. Being a father of 4, and now a grandfather of 5, he obviously didn’t spend all of his time working. He did say however “my wife laughed when she read this question”. They obviously would not have both given the same answer!

After the seminar there was the usual informal session for post-docs to ask questions over a glass of wine or a beer, and after the IPA committee enjoyed a friendly and filling meal with Keith at the Broad Chare.

The IPA is in the process of organising our next social event, updates will follow by email and on the website. Look out!  If you would like to become involved with the IPA and help organise future events, please get in touch!

IPA Committee

IPA is run by Postdocs, for Postdocs. Get involved!

IPA page on the ICAMB website: http://www.ncl.ac.uk/camb/research/postdoc/association/

IPA Facebook page: https://www.facebook.com/groups/462376430446559

Institute for Cellular and Molecular Biosciences: http://www.ncl.ac.uk/camb/

Pruning the Tree of Life

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Dr Tom WIlliams

Anyone who has studied biology has seen an image of the tree of life in the text books.  Most of us think of this as being set in stone, one of the rock solid foundations on which evolutionary biology is built.  However, all is not quite as settled as it seems.  Recently, a Nature article from the laboratory of ICaMB’s Professor Martin Embley challenges the traditional three domain structure of the root of life.  Here, first author on the paper, Dr Tom Williams, tells us the story.

By Dr Tom Williams

Our modern understanding of the tree of life began in 1977 when Carl Woese and his colleagues discovered the Archaea, a group of prokaryotes originally isolated from extremely hot or salty environments. Although Archaea looked indistinguishable from Bacteria under the microscope, their gene sequences were at least as different to those of Bacteria as from the eukaryotes – the group of organisms, including fungi, animals and plants, whose cells contain a mitochondrion and a nucleus. According to these analyses, living cells should be classified into three main groups: Bacteria, Archaea and eukaryotes – rather than the two (prokaryotes and eukaryotes) that had previously been established based on cell structure. In 1990, Woese and his colleagues published another seminal paper in which they argued for this “three domains” classification. This three-domains tree has become an iconic image in biology, and is often found in the popular science literature, as well as many textbooks – you’ve probably seen it before. Here it is from a 1997 review by Norman Pace:

The traditional 3 domain Tree of Life. From: A molecular view of diversity and the biosphere. Pace NR Science (1997) 276: 734-740

 

Professor Martin Embley

This was certainly the tree of life that I was familiar with, first as an undergrad and later as a Ph.D. student at Trinity College Dublin. So I was surprised and very intrigued when a certain Martin Embley came to talk at an Irish bioinformatics meeting, claiming that support for the three-domains tree was not as strong as you might expect. New work from his lab instead favoured the “eocyte tree”, in which the eukaryotes (or, at least, some of their genes) actually evolved from within the Archaea. If true, this tree would imply that there were originally only two types of cells – Bacteria and Archaea – and that the eukaryotes (i.e., us!) originated later in a partnership between the two primary domains.

The new model of the Tree of Life proposed by the Embley lab

Fast-forward a couple of years, and I was thinking about where I wanted to do my postdoc. I remembered Martin not only from that talk, but also from some interesting work (2nd link) he had done on a group of parasitic fungi called Microsporidia. I joined his group and began working on microsporidians, but I was still very interested in the tree of life and the origin of eukaryotes. In the meantime, DNA sequencing technology had been improving, and microbial ecologists were beginning to publish genomes from new groups of Archaea that could not be grown in the lab, and so had never been studied before. One of the really exciting findings from these studies was that some Archaea contained genes that looked very similar to fundamental components of our own cells, such as actin and tubulin – two proteins that help to define the microscopic “skeleton” of eukaryotic cells. When we added these new genomes to our analyses, we found even stronger support for the eocyte tree; those findings were reported last year in Proceedings B. At about the same time, a number of other researchers were reporting something similar: as our view of archaeal biodiversity increased, support for the three-domains tree was on the wane. Given the prominent position of the three-domains tree in the literature, and the importance of this question for understanding early life on Earth, we decided to write a review summarizing these recent developments in the field – it came out in Nature this week, and it’s the reason for this blog post!

As we delved back into the 30 years of literature on the molecular tree of life, one of the most interesting discoveries for me was a seam of eocyte literature that I hadn’t been aware of previously. Although many analyses over the past three decades have recovered the three-domains tree, and it appears in all the textbooks, the literature has actually never been unanimous in its support. Nonetheless, it is only in the last five years or so that support for the eocyte hypothesis has reached critical mass, perhaps due to improvements in our statistical methods and, more recently, sampling of archaeal biodiversity.

The Embley lab: Back row, left-to-right: Kacper Sendra, Martin Embley, Tom Williams, Robert Hirt. Front row: Shaojun Long, Ekaterina Kozhevnikova, Andrew Watson, Paul Dean, Maxine Geggie,Alina Goldberg-Cavalleri, Sirintra Nakjang.

Of course, our latest work is almost certainly not going to be the last word on the relationship between eukaryotes and other cells. Our methods are getting better – in part thanks to the statisticians we are collaborating with here in Newcastle – but there is much room for improvement, and so much about the microbial world that we still have to discover. Still, if the eocyte tree is correct – and it appears to be the best-supported tree on the current evidence – then that has important implications for how we understand early life on Earth and the origin of our own cells. For one thing, it rules out the eukaryotes as a primordial cellular lineage, as old as the Bacteria and Archaea. Instead, it suggests that the Bacteria and Archaea were established and diversifying on Earth before the origin of eukaryotes, resurrecting the concept of an “Age of Prokaryotes” on the early Earth. Of course, when you think about the phenomenal number of Bacteria and Archaea that live in your own body, never mind the wider environment, you might well argue that it never ended…

This work was supported by a Marie Curie postdoctoral fellowship to Tom Williams. Martin Embley acknowledges support from the European Research Council Advanced Investigator Programme and the Wellcome Trust.

Links

The Nature Article: http://www.nature.com/nature/journal/v504/n7479/full/nature12779.html?WT.ec_id=NATURE-20131212

The Proceedings B paper: http://rspb.royalsocietypublishing.org/content/279/1749/4870

The Embley lab website: http://research.ncl.ac.uk/microbial_eukaryotes/

Microsporidia papers: http://www.nature.com/nature/journal/v452/n7187/full/nature06606.html

http://www.nature.com/nature/journal/v453/n7194/full/nature06903.html

ICaMB PhD studentship opportunities

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PhD student recruitment season is upon us.  If you or maybe someone you know is interested in a doing PhD in Cell and Molecular Biosciences in a leading UK Research Institute (that happens to be based in one of the most exciting yet affordable cities in the UK), then read on.  This year we are giving you an early preview of the opportunities available in ICaMB and telling you a bit about who we are and what doing your PhD here with us has to offer.

ICaMB PhD students benefit from being in a dynamic and well funded research environment with access to state of the art technology.  Our research interests cover the cutting edge of bacterial cell biology all the way through to eukaryotic cell signalling and cancer research.  ICaMB investigators have been awarded £39.32M since 2008, which includes major funding from the Wellcome Trust, the ERC, BBSRC, The Royal Society, Cancer Research UK, Leukemia and Lymphoma Research and the Association of International Cancer Research.

 

PhD students do not exist on experiments alone and the ICaMB PhD student association PAN!C helps to facilitate social as well as scientific interactions.  You can read more about PAN!C in a previous ICaMB blogpost.

 

The recent 2nd year PhD student presentations

Below we have listed the MRes/PhD Studentships scheduled to begin in ICaMB in September 2014.  These are also listed on the ICaMB website, where they will shortly be formally advertised. Further details of the projects and guidelines on how to apply, will be posted in the next few weeks.  However, if you would like further details about the projects NOW you can contact the named supervisor directly or the ICaMB Postgraduate Tutor Dr Tim Cheek (email tim.cheek@ncl.ac.uk).  In exceptional circumstances, especially if the prospective applicant already has interviews arranged at other institutions, we can expedite and fast track the interview process (please contact Tim Cheek for more details if this applies to you). 

Eukaryotic Cell Biology

The last year has seen a lot of recruitment activity in ICaMB, one result of which was the appointment of three new PIs as part of our Independent Researcher Establishment Scheme (IRES). We introduced Dr Owen Davies, Dr Niall Kenneth and Dr Josana Rodriguez recently.  Doing PhD research with a new PI offers the chance to work at the bench directly with a young and enthusiastic scientist at the top of their game.  Many ‘first’ PhD students go on to achieve great things. There was great competition for our IRES positions and a PhD position with any of these new PIs promises to be a rewarding experience.

Title of Studentship: Uncovering the molecular basis of homologous chromosome synapsis by the synaptonemal complex during mammalian meiosis
Funding Source: BBSRC DTP
Supervisor: Dr Owen Davies (email owen.davies@ncl.ac.uk)

Title of Studentship: What are the protective roles of XIAP in the response to oxidative stress?
Funding Source: BBSRC DTP
Supervisor: Dr Niall Kenneth (email niallk@med.umich.edu)

Title of Studentship: Understanding microtubule dependent signalling in the generation of cellular asymmetries
Funding Source: BBSRC DTP
Supervisor: Dr Josana Rodriguez (email josanarsl@googlemail.com)

We also have PhD studentships available with Prof Brian Morgan and Dr Elizabeth Veal. Both PIs are investigating the important area of oxidative stress signalling (relevant to many diseases, including cancer) using the model organisms Saccharomyces cerevisiae and Caenorhabditis elegans and publish routinely in high impact journals, such as  Molecular Cell. A PhD in either lab provides an opportunity to work at the cutting edge of research into eukaryotic cell signalling.

Title of Studentship: How does the regulation of ubiquitin/ubiquitin-like pathways determine cellular responses to reactive oxygen species?
Funding Source:BBSRC DTP
Supervisor: Prof Brian Morgan (email brian.morgan@ncl.ac.uk)

Title of Studentship: Understanding how hydrogen peroxide signals control cell growth, survival and ageing
Funding Source: BBSRC DTP
Supervisor: Dr Elizabeth Veal (email elizabeth.veal@ncl.ac.uk)

Host-Microbe Interactions

The next two positions complement each other, with one exploring the host’s reaction to microbes while the second focusses on the microbe’s response to the host. Dr Judith Hall and Dr David Bolam are both key members of ICaMB and have a strong track record as PhD supervisors. So if you have an inclination towards exploring innate immunity or diving into the growing community of microbiologists interested in the microflora that interacts with us on a daily basis, maybe one of these two posts is for you.

Title of Studentship: Dissecting the role of the Dectin-1 Receptor in the Innate Defences of the Uro-genital Tract
Funding Source: Dr William Edmund Harker Foundation
Supervisor: Dr Judith Hall (email judith.hall@ncl.ac.uk)

Title of Studentship: Understanding how the mucosal layer is a microbial niche within the gut microbiota
Funding Source: BBSRC DTP
Supervisor: Dr David Bolam (email david.bolam@ncl.ac.uk)

Bacterial Cell Biology 

The final two positions are both located in the Centre for Bacterial Cell Biology, affiliated to ICaMB. You can read up on our work on bacterial cell biology in previous posts including our investigations with bulging bacterial cells to explain division, how we explode bacteria for science, or highlighting a recent paper from Nikolay published in the prestigious journal Science. In addition, Yulia Yuzenkova was recently awarded a prestigious Royal Society University Research Fellowship and her research was featured on the ICaMB blog.

Title of Studentship: Cyanobacterial transcription machinery
Funding Source: BBSRC DTP
Supervisor: Dr Yulia Yuzenkova (email yulia.yuzenkova@ncl.ac.uk)

Title of Studentship: Bacterial immunity and multi-drug resistance
Funding Source: BBSRC DTP
Supervisor: Prof Nikolay Zenkin (email nikolay.zenkin@ncl.ac.uk)

Please note that there are eligibility requirements for BBSRC DTP studentships (link to download pdf).

Typical ICaMB laboratory space

Links

ECRs at ICaMB: My Meiotic Journey

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In the latest of our series focussing on the new Early Career Researchers (ECR) in ICaMB, we feature Dr Suzanne Madgwick.  Suzanne recently returned to the lab after a career break by successfully applying for a Wellcome Trust Career Re-entry fellowship.  She tells us more about her science, her life and why coming back into science was always something she wanted to do.

 By Dr Suzanne Madgwick

After 6 years officially away from science I am thrilled to be back, almost 10 months in to my first fellowship position and about to supervise my first PhD student ….. though more than a little frightened by how fast the time is going! ICaMB has been a very positive and supportive place to come back to and the future looks bright for our growing meiosis team.

Not many PhD students get to ride horses as part of their project

I started out my meiotic journey not as a cell biologist, but as a Physiology and Nutrition student at the University of Leeds where I quickly found that the area of biology I am most fascinated by is the complexity, control, and number of systems a body has dedicated to reproducing itself. From my degree I went straight into a PhD here at Newcastle, in SAgE, with Dr Andrew Beard studying endocrine control of the developing reproductive system in cows. Whilst adolescent bulls are not the easiest experimental model to deal with, like most people I have very fond memories of my PhD. A definite highlight was a year of practical work carried out at a veterinary university in Canada, being able to round up my animals on horseback and drive oversized farm vehicles!

Brightfield image of an in-vitro matured metaphase II stage mouse oocyte showing polar body 1 (containing the waste chromosomes) from the first meiotic division. Approx diameter of the oocyte = 80um

Although I am proud of my PhD work, during this time my interests made a definite shift from whole animal reproductive systems to the molecular control of the reproductive cells themselves. Luckily, Professor Keith Jones (formerly of ICaMB) offered me a Post Doc position in his lab researching an arrest point in the life of a mammalian oocyte that maximises the window of opportunity for fertilisation. This was a successful time and we were able to publish a number of papers detailing the control of this arrest and how spermatozoa are then able to awaken an oocyte. I was left in no doubt that I had found not only the area, but also a method of research that I thoroughly enjoy being a part of.

Nearing the end of my post doc and armed with a pretty solid CV, I turned my interest to my own meiosis and made the decision to leave science on a high and spend a few years concentrating on bringing up a family. I always knew I would attempt a comeback, researching and bookmarking the Wellcome Trust Career Re-entry pages at the same time as I planned my exit.

Suzanne's research no longer requires access to a combine harvester

After 5 years of baby and toddler groups, and 2 confused little boys wondering why their mother suddenly started needing to go back to school (I was asked at one point if it was because I didn’t try very hard when I was at proper school the first time) I began regular visits to the lab and a period as full time mother / nocturnal grant writer. I can’t say any of this was very easy, but I also can’t imagine having the same enthusiasm for any other career. The support and advice I have had from both the Institute and the Wellcome Trust regarding career re-entry has been excellent. Taking a break from science was certainly the right decision for me. For anybody else considering this there are a number of ways for both men and women to re-enter a career in science, (in addition to the Wellcome Trust there is our own Faculty/Barbour Fellowship scheme, as well as the Dorothy Hodgkin and Daphne Jackson fellowships ).

The end stage of the application process was an interview at Wellcome Trust headquarters in London and whilst I tried to appreciate the privilege of being there in the first place, I have to agree with Kevin Waldron and say that it was also the most intimidating experience of my career. My second visit to the interview room for a Fellows conference in the summer was a far more relaxed and really a very inspirational meeting of both current and past Career Re-entry Fellows, including Newcastle’s Professor Helen Arthur who took a 10 year break.

Balancing a career and a young family is a certainly a tricky juggling act which I’m sure most parents have experienced. Attempting to work part-time in research is also pretty difficult (largely I admit a self-inflicted problem caused by the drive to try out the next experiment). I’m still working on this balance. Thankfully the Fellowship Scheme has the flexibility to be able to make changes to working hours and my children are already very interested in quizzing me about cells. I confess a great deal of pride when I recently overheard my 4 year old give a very basic yet accurate description of aneuploidy to his nursery teacher.

My current interest is in the events surrounding aneuploidy in female meiosis. Human oocytes have an extremely high failure rate, frequently resulting in an error in chromosome segregation, which is considered to be the leading genetic cause of birth defects and miscarriages.

Suzanne getting ready to inject oocytes using a mouth pipette*

In particular I plan to concentrate my research on unknown aspects of cell cycle control in mammalian oocytes through the first and most error prone of the meiotic divisions. Theories formed towards the end of my post doc along with more recent preliminary data have led to the hypothesis that an entirely novel mechanism of metaphase exit may exist in female meiosis; one which has not previously been noted through studies in mitosis. Our experimental approach is to use fluorescently-tagged gene constructs in real time live cell assays. mRNA encoding these constructs is microinjected into oocytes, resulting

in a fluorescent signal as a result of protein expression. Fluorescent expression and mRNA knock down experiments characterise the behaviour of resulting proteins. Of particular interest is, the targeting of the maturation promoting factor (MPF) component cyclin B1, which is crucially destroyed to allow chromosomes to segregate. A full understanding of how oocytes progress through cell division will help to explain why female meiotic cells do not have the same capacity to check and repair themselves as healthy mitotic cells do.

Intriguingly, like female meiosis, a failure to correctly regulate chromosome division is a major phenotype of virtually all cancers. Hopefully by investigating features of a cell cycle that appears to allow cells to proliferate despite division errors, my research will be of interest beyond meiosis and to the wider field of cell biology.

*mouth pipetting is considered to be a quick and accurate way of stripping cumulus cells and transferring delicate oocytes in minimal volumes of media. Glass Pasteur’s are drawn over a Bunsen burner and broken to give a pipette diameter of just a few microns above that of the oocyte.

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

 

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

 

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

IPA Update: What’s it like to work for Nature?

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By the IPA committee

Thursday 23rd May saw the IPA’s second Science Lives Seminar. Following on from our first talk about the realities of establishing an independent research group in academia, the IPA wanted to explore what else a post-doc can do. What are our alternative careers?

To start answering this question, we invited Dr Andrew Jermy, a senior editor at Nature, to give us a talk on his career in journal editing.


Postdocs waiting to hear either (a) how to publish their papers in Nature or (b) how to work for Nature

Dr Jermy’s talk started by illustrating his personal experience. Like all of us, he completed a PhD in the biological sciences field and then did two short post-docs before he decided to leave academia to start a career in editing, first at Nature Cell Biology, followed by  Nature Reviews Microbiology and now more recently at Nature. To achieve this, he used his networking skills as he had met someone currently working for Nature at conference. Hint, keep building up your contacts! It was very interesting for us all to understand the motivations that brought him to try a new and alternative career. “Getting bored of waiting for westerns to come out of the developer”, he repeated several times.  Maybe he is not the only one?

Dr Jermy also described the several different job entry levels possible at Nature, something that applies generally to many of the larger scientific journals.  We now have a much better idea of what working for a scientific journal actually entails and where we could slot in. He pointed out that in this kind of career you need a keen interest in all science, as well as being constantly on top of the cutting edge research in your specific editing field. The ability assimilate information quickly and handle up to 40-50 papers per month, while travelling to conferences and universities is also a must. On the other hand, Dr Jermy underlined that his job is not a simple 9-5 job.  However, he can work from home and with the advantage of a permanent position as well as opportunities for career progression, this can make his career more family-friendly than what we post-docs are used to. Ultimately, this career seems ideal for those post-docs who no longer enjoy working at the bench, but still enjoy the other aspects of scientific life, such as reading, writing and networking at conferences.

Andrew demonstrates the Nature ‘secret handshake’

There was however much more to Dr Jermy’s talk than the career side… he gave practical tips to post-docs who want (or maybe its better to say wish) to submit a paper to Nature; from the title to the covering letter, from the abstract to the “style” of writing. Dr Jermy made a clear point that the philosophy of the journal is not to bin 90% of the papers they receive, but to focus on helping the top 10% of the articles emerge and get published. Finally, did you know you can send a pre-submission enquiry to Nature, asking if your scientific results are of interest before going through the long and painful online submission? Helpful for everyone!

After the seminar there was an informal chat-session, useful for post-docs to ask questions in a relaxed environment, helped of course by a beer in our hands!

The IPA wishes everyone a nice Summer and we will see you all for our next social event: a barbecue in September, a perfect occasion to give a warm welcome to new post-docs joining ICAMB as well as for all the current post-docs and final year PhD students to get together for the beginning of a new academic year.

Updates will follow on the website.

IPA Committee

IPA is run by Postdocs, for Postdocs. Get involved!

Links

IPA Facebook page: https://www.facebook.com/groups/462376430446559
Institute for Cellular and Molecular Biosciences: http://www.ncl.ac.uk/camb/
Newcastle University: http://www.ncl.ac.uk/
Nature Journal: http://www.nature.com/nature/index.html
Andrew Jermy’s twitter page: https://twitter.com/jermynation

Spills and pills: thrills for a structural biologist

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One of the newest recruits to ICaMB is Professor Bert van den Berg, who arrived here in December 2012.  Bert is already off to a great start having been awarded a Royal Society Wolfson Research Merit Award in April.  Here we have asked him to tell us why he decided to join ICaMB and the research that lead up to this prestigious award.

By Bert van den Berg


Bert, looking thrilled

I joined ICaMB in January, coming from the University of Massachusetts Medical School in Worcester, where I was a tenured faculty member in the Program in Molecular Medicine. While I had a great and productive time in this department, after eight years I felt increasingly isolated academically and started to look for another position. ICaMB seemed a great fit for my research interests, with a large number of scientists interested in bacterial biochemistry and cell biology. Since ICaMB was also looking to strengthen its efforts in structural biology, the decision to cross the pond and join ICaMB wasn’t a very hard one. I am happy to be here, and I hope and expect that my expertise in membrane protein structural biology will also be a benefit for the faculty within ICaMB and will lead to successful collaborations.

My lab has been studying protein channels (see below) for about nine years. Determining structures is really the only way to obtain deep insights into protein function. In addition, seeing a new protein structure for the first time is often an “aha!” moment and, at least for me, the closest thing to a true discovery in modern science. In any case, the importance of structural biology for science is clear from the large number of Nobel prizes awarded to the field over the years.

What do the cleanup of oil spills and the treatment of many bacterial infections have in common? The answer is that both processes depend on the efficient passage of bacterial membranes by small molecules.

Oil spills and antibiotics have more in common than you may realise

Gram-negative bacteria are surrounded by two lipid membranes, which are termed plasma membrane and outer membrane. The outer membrane borders the cell and is a very efficient and sturdy barrier that protects the cell from noxious substances in the external environment, such as bile acids in the case of E. coli bacteria living in the gut. However, since bacteria also require nutrients for growth and function, protein channels are present in the outer membrane to allow the uptake of such small molecules. In our work we use X-ray crystallography to determine the atomic 3D structures of the channels, most of which are shaped like hollow barrels. Based on the structures we propose transport models, which we then test by characterisation of mutant proteins.

Many Gram-negative bacteria are able to use industrial pollutants such as oil as food sources, a process called biodegradation. The enzymes that catalyse these remarkable processes are located inside the cell but not much is known about how the pollutants enter the cell in the first place, something that is clearly required before they can be degraded. We study the highly specialised channels that mediate the uptake of these water-insoluble (“hydrophobic”) molecules. In addition, we are interested in discovering cellular adaptations that allow biodegrading bacteria to grow on these toxic compounds. We think that this research may lead to insights that will aid the design of bacterial strains that are optimised not only for bioremediation but also for important other processes such as production of biofuels.

The other main focus of research in my lab is to understand how antibiotics “hijack” outer membrane channels to enter bacteria. Being water-soluble, antibiotics are dependent on protein channels for membrane passage. Bacteria that are under antibiotic pressure will often change or remove the channels through which antibiotics pass, resulting in resistance.

Movie showing ampicillin movement through E coli OmpF protein channel. The view is from the outside of the cell. Movie made by Matteo Ceccarelli (University of Cagliari).

In concert with other mechanisms such as enzymatic degradation and increased efflux by pumps, this acquired antibiotic resistance has the potential to become a huge and global problem in public health. New drugs are therefore urgently needed. The problem is that not nearly enough new drugs are currently in pharmaceutical pipelines, due to the costly and risky nature of antibiotic development. However, pharmaceutical companies are starting to realise that the fundamentals of drug design need to change, and that they have to collaborate with academic labs that are studying the basic biology of small molecule membrane transport.

My lab is participating in an exciting, EU-funded joint venture between big pharma, small biotech firms and academic labs aiming to understand the influx/efflux of drugs in a number of pathogenic Gram-negative bacteria. Beyond the potential benefits for drug design, it is hoped that this project will change the way in which industry and academia work together to benefit public health.

 

Links

Royal Society Wolfson Merit Awards: http://royalsociety.org/news/2013/new-wolfson-research-merit-awards/

Bert’s ICaMB homepage: http://www.ncl.ac.uk/camb/staff/profile/bert.van-den-berg

Newcastle Structural Biology website: http://sbl.ncl.ac.uk/people/bert_research.shtml

Structural Biologist Nobel Prize Winners: http://www.ebi.ac.uk/pdbe/docs/nobel/nobels.html

IMI TRANSLOCATION project: http://www.imi.europa.eu/content/translocation