University policy: evidence and evaluation

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The ICaMBlog this week features an article from Professor Bernard Connolly. Bernard is retiring today (March 31st 2016) and so we asked him if he could write a post on ‘anything he wanted’. Here Bernard discusses his frustrations with the frequent lack of evidence based policy making in universities.

Prof ConnollyI began my academic career as an undergraduate student at Sheffield University in 1973, I finish as the Professor of Biochemistry at Newcastle in 2016. Possibly the biggest change to have occurred over this forty or so years is the degree of surveillance and monitoring to which everybody at the University is subject. During my undergraduate studies attendance at lectures was voluntary and it was up to me to decide if, and when, I should consult my tutor. While a PhD student and postgraduate there was no concept of mandated and recorded meetings with my supervisors and the only reports I was expected to prepare were first drafts of eventual publications. When starting as a lecturer at Southampton University, I had about five minutes with the Head of Department, was shown an office and left to get on with it. I had no formal meetings with my “line manager” (indeed this concept did not exist) and I was prepared for undergraduate teaching with a single three hour session. Today undergraduate attendance at lectures is recorded as are compulsory meetings with tutors; sanctions are applied for non-compliance. PhD students have multiple supervisors/mentors and are required to record compulsory meetings with them. A number of intermediate reports must be produced and assessed along the road to graduation with a doctoral degree. Staff have a PDR once a year and are required to complete forms detailing the work they perform and how they occupy every hour at, and away from, work. Although I personally prefer the old system, this article is not aimed at discussing which is better. Rather, it is to enquire how the University implements policy changes, often introduced at the cost of great disruption, to ensure they are based on best current practice. Further, how are the outcomes of these changes determined and any benefits measured?

Conquest quote

A few years ago all undergraduate teachers were informed that they would be required to use the “buddy system”. Here, two academics are paired and required to attend, and write a report, on one of their buddie’s lectures. Although not onerous, I enquired about evidence that such a scheme was beneficial. After much badgering I was eventually sent a link to two publications. The first, admittedly in a peer reviewed journal, consisted of about ten subjects beingcartoon asked if they found the scheme helpful. This paper could be used as an example of how not to do science and I can only assume that the author, a young medical doctor, felt that any publication, no matter how poor, would benefit his future career. The second was not even peer reviewed, rather a trenchant statement of a scheme supporter bereft of any evidence. The purpose of the buddying is assuredly to improve undergraduate teaching and, as we survey our students almost to destruction, I enquired if an improvement in quality had been observed. I received no reply and concluded that this scheme was started on the whim of the dean involved, based on little evidence and with no mechanism in place to observe its consequences. This example is trivial but similar considerations apply to the much more consequential issues addressed in the first paragraph. I have yet to be presented with evidence that constant monitoring and assessing of students and staff is based on rigorous studies that clearly demonstrate positive effects. We survey our undergraduates continually and for postgraduates and postdoctoral workers have data on their accomplishments (do PhDs graduate on time, how many publications result from Bernard phototheir work, what are their future job successes). But this data is never correlated with policy changes to measure their efficacy. Similarly for staff, following the introduction of PDR, has teaching improved, has grant funding increased, have more and better publications resulted? Overall is the University a better place in which to work, perhaps monitored by absenteeism rates, which correlate well with staff happiness. As academics we must insist that anybody introducing new policies should present the evidence underpinning the change. A system for monitoring outcomes, which places minimal burden on students and staff, should be demonstrably in place. While benefits at the individual level may be small they should surely be apparent over the entire University body. Finally anybody introducing procedures based on little evidence or not leading to favourable outcomes should rapidly be removed from any position of authority.

 

 

The ICaMB PhD student symposium: what does it mean to the supervisors?

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A strong and vibrant PhD programme is essential for any successful academic department. PhD students bring energy and enthusiasm to their projects (well that’s the idea anyway) that frequently reminds many jaded professors contemplating the hell that is ResearchFish why they went into this business in the first place. Typically a PhD student progresses from hesitant first steps in the laboratory to becoming a confident scientist with ownership of their project. Although in the moments before a PhD viva some of that confidence has been known to slip away. The ICaMB Postgraduate Research Symposium is an important showcase that allows our final year PhD students to demonstrate not just the exciting science they have been doing but also just how far they have come over the last 3/4 years. But there is also a serious side to this for ICaMB. In the last REF (where we <cough> did quite well), our PhD students made a major contribution to our returned papers. Brian Morgan has crunched the numbers and discovered that PhD students were first authors on 30% of our 3*/4* submissions (see Figure), including papers in Cell (x2), Nature, Science, Molecular Cell, Nature Chemical Biology (x2) and PNAS (x3). Moreover, in our UO5 return, 3 out of 4 of our Impact cases were underpinned by PhD student research.

Graph

This year, the first day of the symposium was on March 14th with a second to be held on April 29th. We’ve covered the ICaMB PhD symposium before but this year we thought we’d do something different and ask some of the PhD supervisors what this meant to them. All of us are proud of the PhD students that come through our labs, even if, occasionally, there are some grey hair inducing moments on the way. Seeing a final year student confidently discuss their project and answer questions is an important moment for a PhD supervisor. Below we have a varied group of supervisors, from a definitely not jaded professor discussing their final PhD students, to a newer PI discussing their first.

Harry Gilbert: Ana Luis and Jon Briggs

The two final year students from my laboratory who are contributing to the 2016 Postgraduate Research Symposium are Ana Luis and Jon Briggs. These are my last PhD students and it is great to finish with such excellent scientists. Neither student is on the traditional BBSRC/MRC DTP. Jon is supported by the Faculty to work on my Wellcome Trust Senior Investigator Award and Ana is funded mainly from my overheads and more recently by my ERC grant. Jon did a summer placement with Waldemar and his undergrad project in my lab. I was very impressed with Jon and was delighted he was willing to do a PhD with me. I said to Jon his project could be funded by BBSRC, requiring that he did a PIP (Professional Internships for PhD Students) or the Faculty in which case the three month break was not required. Jon said “I want to do science during my PhD and not be distracted by other activities”. Ana wanted to do a PhD with a glycan lab and came highly recommended by one of my previous PhD students, Carlos Fontes from the University of Lisbon, Portugal. So Ana is doing a three year PhD with no MRes, PIPs etc. Some of us, of a certain age, may remember these type of PhDs.

Harry, Jon and AnaThe two students have worked on glycan degradation by the human gut microbial community, or microbiota. Jon is focussed on the biochemistry of selected enzyme systems and the extent to which there is cross feeding of oligosaccharide products generated during the degradative process. Ana, like Jon, has used molecular genetics and biochemistry to explore the enzymology of these glycan degrading processes, while also using X-ray crystallography to study the structure and function of key enzymes.

Both students are remarkable in that they work on their own project within a largish collaboration. This is fine but on a regular basis, well almost weekly, they are given “the opportunity” by their supervisor to alter the objectives of their project almost on a weekly basis. They adapt to these unusual demands brilliantly. We all have tremendous respect for both students; they work extremely hard, are technically excellent, flexible and, most importantly, think carefully about their science, designing and carrying out a series of decisive experiments to resolve critical components of the glycan degrading process. Maybe the best testimony I can provide is that it is not possible to distinguish Ana and Jon from the postdocs in the lab, they are an inspiration to all of us.

 

Paula Salgado: Adam Crawshaw

Paula and Adam

Being your supervisor’s first PhD student can be a mixed bag. You will get a lot of their attention, so help will always be available. But at the same time, as they find their way as independent researchers, any issues will be closer to your own progress than for many of your colleagues. As I saw Adam present his work at the ICaMB Postgraduate Research Symposium, I was reminded of my own journey as a “first student”, several years ago. As I shared my supervisor’s progress, so has Adam shared mine. It has been fantastic seeing him develop, visibly learn and acquire so many skills. Even when his project didn’t go according to plan and experiments were proving hard, he didn’t lose the drive, the enthusiasm. It was with pride that I saw him give a confident talk, answer questions and be humble enough to challenge his own work. He has learned many techniques, from crystallography to circular dichronism, from molecular biology to NMR – he took it all in willingly and enthusiastically. His contribution to understanding several aspects of Clostridium difficile pathogenicity will be in the scientific papers produced, as well as in the future of my “Structural Microbiology” lab. It was great to hear him present all the work he did over the last 3.5 years to our colleagues. Well done!

 

Dianne Ford: Joy Hardyman

 Joy Hardyman’s presentation at the ICaMB Postgraduate Student Research Symposium was on the topic of zinc, which we have studied in our lab for many years. Joy’s PhD research is funded by an MRC studentship, which not only gave Joy the opportunity for research training but also really allowed us to add value to data we collected as part of a BBSRC grant, and generated an additional publication (Hardyman JEJ et al (2016) Metallomics (in press)).

Dianne and Joy

Global zincThe lab’s focus is the basic cell biology of zinc, which is essential to understanding zinc nutrition. Zinc nutrition is a global health challenge, with an estimated 17.3% of the global population at risk of inadequate zinc intake. Also older people, including here in the UK, are particularly at risk of sub-optimal zinc intake or low plasma zinc concentrations.

Zinc rich foodsAt the end of our BBSRC grant we had some intriguing microarray data that we had set aside because we struggled initially to make sense of it. We had depleted cells of a transcription factor known to have a role in zinc homeostasis (MTF1) then challenged them with zinc, with the aim of identifying the gene targets of this transcription factor. However, rather than see gene responses to zinc being attenuated we saw ‘sensitisation’ of the transcriptome response to zinc. We now know that this is because the usual response of the intracellular protein metallothionein, which effectively ‘mops up’ intracellular zinc, was attenuated because this response is under the control of MTF1.

We all need zincInterestingly, we now think this model, where MTF1 is depleted, may allow us to study what happens to zinc homeostasis in cells as they age, because cells from older individuals have higher levels of metallothionein. Thus, cells with MTF1 depleted may represent a ‘younger’ phenotype. We will now explore the suitability of this as a model of zinc balance in the ageing cell with a view to using it in further research to gain a better understanding of zinc dys-homeostasis in older age.

 

Kevin Waldron: Anna Barwinska-Sendra

Anna’s project began as something of a ‘sideline’ of research in my lab, something that I’d originally initiated when I first started my own independent research back in 2010 but then put on the back burner due to limited resources when my ‘lab group’ consisted solely of me. I re-initiated the project when Anna approached me for a short period of work experience in my lab in 2012. It is a tribute to Anna’s drive and enthusiasm that, within just a few days of her being in my lab, I was keen to keep her on in some form, and I was delighted when she later accepted my offer of a PhD studentship to continue this project in my lab. It’s one of the best decisions I’ve made in my short time as a PI.

Kevin's lab

I set Anna the task of determining the metal specificity of the two superoxide dismutase (SOD) enzymes that are encoded within the genome of Staphylococcus aureus. SODs are essential for the bacterial defence against the reactive oxygen species (ROS) superoxide anion, and both of these enzymes were predicted to be manganese-dependent. However it was emerging that, during infection, pathogens such as S. aureus experience host-imposed manganese starvation, a process termed nutritional immunity, which raised the possibility that one or both of these enzymes might be able to use an alternative cofactor for catalysis, most likely iron. Anna has confirmed that one of these enzymes is cambialistic in vitro, which means it is catalytically active with either metal cofactor, something that’s exquisitely rare amongst metalloenzymes. We hypothesise that this cambialistic property of this SOD is a mechanism by which S. aureus is able to circumvent nutritional immunity and resist the onslaught of oxidative attack during manganese starvation.

Anna has been an exceptionally productive student during her time in my lab, and I’ll be sorry to lose her when she completes her studies later this year. She has a bright future in research. Her project also highlights the importance of PhD student projects to a ‘basic research’ lab like mine, as they enable more exploratory, high-risk, high-reward projects such as this, and allow us to take our research in whole new directions that would not be possible within the constraints of traditionally-funded, Research Council grant-based projects.

 

Jeremy Lakey: Alysia Davies

Alysia poster prize

Alysia’s studentship is rather unusual as it is funded by the BBSRC, Bioprocessing Research Industry Club (BRIC) and has a partner company, Pall, who make a huge range of products used in the production and purification of biomolecules. BRIC is a very proactive organisation that meets twice a year for students and post docs to present their work. It also arranges training and skills schools to enhance the employability of the graduates especially those wishing to enter the fast growing bioprocessing industry. This industry is responsible for delivering the next generation of treatments based upon large protein and DNA molecules rather than small molecules such as penicillin. The magic bullets in all this are immunotherapies based upon large proteins called monoclonal antibodies. These are used in the treatment of many conditions such as cancer (Avastin) or rheumatoid arthritis & Crohn’s Disease (Humira). One difference with such large molecules is that they can provoke an immune response which prevents further treatment. Such responses are more common if the proteins stick to each other; a process known as aggregation. Alysia’s project is to develop rapid tests for aggregation so that problem batches can be detected early in the factory and removed. We hope these tests will make the medicines both safer and cheaper.

 

David Lydall: Joana Rodrigues and Marta Markiewicz

Joana Rodrigues, from Portugal, and Marta Markiewicz, from Poland, will complete their EU (Marie Curie) International Training Network funded PhDs very soon.   On this basis I will vote to stay in Europe.

Lydall lab

As a supervisor I have been delighted to have Joana and Marta in my lab.  It is really rewarding to have bright, enthusiastic, international members of the lab.  Very often the most rewarding aspect of my job is observing PhD students gain confidence, experience and strength during their comparatively short time in the lab.  I think this has certainly been the case for Joana and Marta and they both gave excellent talks at the symposium.

As is usual, at least in my lab, the projects Marta and Joana have pursued have drifted substantially from where they started.  It is one of the most fun aspects of supervising PhD students that there are few, if any, “milestones” to be met during a PhD.  Despite this chaos, philosophy usually occurs, doctorates are earned and knowledge improves.

Joana and Marta have each worked in budding yeast on proteins that are conserved in human cells and that affect cancer.  Joana has made substantial inroads to our understanding of how the PAF1 complex interacts with and affects telomere function.  Marta has shown how Dna2 protein, known to be important for DNA replication, may play its most important functions at telomeres.  We are just in the process of submitting papers from both Marta and Joana.  They have also each agreed to stay in the lab for a further year to capitalize on all their hard work.

Joana and Marta were recruited to the Codeage International Training Network, which is centred in Cologne (http://itn-codeage.uni-koeln.de).  For all three of us this was our first involvement in such a network.   It has been a lot of fun and we have networked our way from Cologne, to Crete and Milan.  We are looking forward to the final meeting in Crete in September.

Jeremy Brown: Shiney George and Man Balola

I have 3 PhD students in the final year of their studies. 2 of them, Shiney George and Man Balola gave excellent presentations on their work on translational control of viral gene expression in the Symposium earlier this week. My lab has been dependent on PhD students for the last few years, and I can only thank them for the positive contribution that they have all made to the lab’s research output: without them there would have been little, if any, progress. Nearly all the lab publications in the last few years have had PhD students as first authors, and the current group have generated excellent data for the next papers that we will publish.

Jeremy's lab

My students over the past few years have had very different sources of support, from self-funded through sponsored to Research Council support. This has led me to reflect on the disparities between funding arrangements, and also how this and the structure of PhDs has changed over the years. I was very lucky when I did my PhD – I was the recipient of a Welcome Trust Prize Studentship. These were quite a novelty at that time, a relatively new scheme, with more generous stipend than other studentships, but the same length – 3 years – as most other studentships. At that time pretty much all PhDs were: go to the lab; do the work; learn the trade; write the thesis.

In the years since my time as a PhD student there has certainly been a shift in how PhDs are organised with alterations to funding for students, various add-ons in terms of knowledge and skill training being tried and in some cases discarded, and a move towards longer, 4 year, training. Some of this could be argued to have diluted the important ‘learn the trade’ part of a PhD, though there are clear pros to enhanced training too. Perhaps more worrying though, there is considerable disparity in the provision for students funded from different sources. One obvious issue is the budget for laboratory costs, which is woefully inadequate for many studentships, but much more adequately costed from others. This has to impact at some level the ambition and scope of PhD projects. Another issue is that while the formal length of PhD (i.e. the time from starting to when the book has to be submitted) is pretty much standard at 4 years, there are differences in the length of funding of PhDs. As we know, as staff in ICaMB we can apply for 4 year BBSRC studentships, 3½ year MRC, and faculty studentships (including this year the Research Excellence Academy) that provide 3 years.

There are few level playing fields in life, but as a PhD is an academic qualification one might naively expect that the duration, resources and other support should, where possible, be similar, at least within a country. Why are there such disparities, how confusing must this be for anyone hoping to employ someone with a PhD? Bioscience needs bodies and PhD students are the backbone and key work-force of a good number of laboratories (mine included). There is then strong competition between academics for studentships each year – evidenced particularly by the very large number (>150) of applications for faculty studentships this year – and disappointment for those who are unsuccessful. Conversely there are many aspiring to a career in bioscience for whom a PhD is a key step. So, there are strong reasons to spread the available resource as broadly as possible, and it is easy to rationalise the way in which resources are being used. I would make the comment (my personal view) that at a time when significant efforts being made to even out opportunities at a number of career stages, we should when possible make sure that we do not undermine this at the early stages, by having some PhD students advantaged over others. And this is before the vagaries of supervision, luck and other factors kick in.

Athena SWAN is open for discussion

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Posted by Suzanne Madgwick

Following on from the success of our Athena SWAN Bronze Award we began an open discussion on social media by posting an article about its principles and practice, the good and the bad! It’s been pretty clear that not everyone is entirely happy, some with the charter in principle and others with actions in ICaMB related to the charter. The issue is polarised both nationally and within the department. We certainly don’t want to shy away from this and so we asked you for your anonymous views.

The one consistent thread that emerged again from this feedback is that we all agree on the importance of gender equality in the workplace, this has never been in doubt. HOWEVER opinions on other aspects vary wildly, you’ll see from the following matrix that we don’t even all hold the same views on the AS team.

This has been a very productive exercise with which we can develop our future direction. Thank you for taking the time to post your comments. We’ve put together a team summary statement  and a full comments matrix to highlight our future approach and the types of conversations we are having. We have also organised the comments into a few main topics which are available by clicking on the pages below for a quick view.

We hope we can continue to openly discuss. So have a look at our statement for a more general view, the summaries focusing on the topics that interest you most and please do let us know what you think.

Positive discriminationPositive Discrimination

                                                         A Box ticking exerciseBox ticking 

 

Butterfly programmeThe Butterfly Program

 

                                                        BullyingAS4

 


AS5Having children harms your career

                                                        A historical problem?Historical problem?

 

Don’t forget to take the time to look through the full matrix. This is a working document that will continue to improve through open discussions and with your valuable feedback and help, so please leave your comments!

Thanks again

The AS team.

Spending Review 2015 – what does it mean for science?

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by Paula Salgado

After many months of speculation and concern, the details of the Spending Review 2015 when it comes to science feels, at first, as a massive relief. After all, the Chancellor announced that science funding would be protected in real terms this time, “raised to £4.7bn by 2020 and capital spending to remain at 6.9£bn over this period”. We should be celebrating, surely! However, a detailed analysis shows that this really means that public investment in science will be frozen for the next 5 years. In fact, according to a detailed analysis (source: Scienceogram.org):

  • The Science Budget is and will remain lower in real terms than it was in 2010.
  • The Science Budget is falling per person living in the UK, and as a fraction of GDP. By 2020, the Science Budget will be nearly 20% lower as a fraction of GDP than it was in 2010.

And we also need to look at the details, not just the main headlines. The science resource budget (those £4.7bn) will now include a newly announced Global Challenges Fund “to ensure UK science takes the lead in addressing the problems faced by developing countries whilst developing our ability to deliver cutting-edge research.” Depending on how this fund will be managed and organised, there is a concern that this could mean that some of the funds which are currently part of the Science Budget will be diverted to sustain the Governments commitment to spend 0.7% of GDP on international development.

It is also still not clear how the implementation of the Nurse Review in to how Science is funded in the UK will undoubtedly affect the funding landscape. Setting up an overarching structure will have its costs and we need to see how that will translate into funding allocation.

But most importantly, this flat cash real-terms freeze is yet another failed opportunity to increase investment in research and development that is required to maintain the UK’s leading role and sustain economic growth. Five years of flat cash has already had a detrimental effect on R&D, not only in terms of the decline in available funds but also in reputation and work of labs across the country. With the positive economic signs announced by the Chancellor, the Government had a chance to reverse the current managed decline of R&D in the UK but decided to continue on a similar path. The long term effects of these decisions will only be clear over the next few decades – but that is why many, including the Wellcome Trust and RCUK, reacted with caution at the real-term freeze announcement.

The lead up to the Spending Review

Lettter in FT calling on the Chancellor not to cut science funding (Sept 7, 2015)

Lettter in FT calling on the Chancellor not to cut science funding (Sept 7, 2015)

With rumours of 20 to 40% cuts being “leaked” throughout the summer and even a rushed review from a private consulting company looking on how to make cost savings across the Department for Business, Innovation & Skills (BIS), the scientific community had reasons to be concerned. Many voices spoke publicly against the axe falling on public science funding: a letter from many charities and learned societies, together with several companies was published in the Financial Times, UK top scientists sharing their views on Buzzfeed and several opinion pieces in the media from leading scientists and journalists urged the Government to not impose any cuts and seriously consider increasing current investment in order to support future growth. Behind the scenes, influential learned societies and campaign groups lobbied the Chancellor, the new Minister for Universities and Science, Jo Johnson, and the new Secretary for BIS, Sajid Javid to stress the same points. And the House of Commons Science & Technology Committee made detailed recommendations that the science budget should be increased, just a few weeks before the Spending Review announcement.

Science is Vital chair, Dr Jenny Rohhn, and vice-chair, Prof Stephen Curry, at the rally in London, 26th October 2015

Science is Vital chair, Dr Jenny Rohhn, and vice-chair, Prof Stephen Curry, at the rally in London, 26th October 2015

But it wasn’t just prominent voices. As in 2010, Science is Vital organised a grass roots campaign to get the voice of scientific community and all supporters of science be heard. There was a big science event in London with scientists, patient groups, journalists and entertainers all rallying to support sustained public investment in science. Across the UK, local events raised the same issues within local communities, getting people to joint watch the event in London but also discuss how science is important to them. And nearly 2000 people wrote a postcard to George Osborne, telling him why they thought Science is Vital.

Science Minister commenting on Science Budget announcement in Spending Review 2015 on Tweeter

Science Minister commenting on Science Budget announcement in Spending Review 2015 on Tweeter

The fact that the Science Minister has now used the phrase “Science is Vital” publicly in at least two occasions, including in his reaction to the SR2015 on social media, means that this important message is getting across our politicians and key decision makers. As more  details of the Spending Review are announced in the coming days and weeks, we will surely have opportunities to continue to let them know why Science is Vital.

What do you think? You can leave your comments below.
Science is Vital is also asking for your reactions.

 

 

 

 

Climbing the Tree of Life

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MartinIn this week’s blog, Professor Martin Embley reflects on the  the journey that led to him, his collaborators and his laboratory to fundamentally change our views on evolution and the Tree of Life.

The Early Years

My early career was a bit of a random walk while I tried to figure out what I really wanted to do. After my PhD in Newcastle on bacterial diseases of trout and salmon, I got a job teaching industrial microbiology at North East London Polytechnic in 1984. It was an odd but interesting place, a number of staff appeared to have strong religious beliefs of various sorts and wanted to talk about them, and one colleague thought he could change traffic lights from red to green so he never had to slow down. I was keen to keep doing some research and I was interested in evolution, but like a lot of newly independent researchers I struggled to get any funding. My big break came when I got a “cultural exchange” grant from Newham Council to go to Poland to learn some molecular biology and I met Professor Erko Stackebrandt who was passing through. Erko had worked with Carl Woese in pioneering the use of ribosomal RNA sequences to investigate evolutionary relationships among prokaryotes. I persuaded him to let me visit his lab in Germany to learn the new techniques and in 1991 these skills got me a job at the Natural History Museum in London.

The Museum wanted to set up a lab using molecular sequences to investigate evolutionary relationships. The film Jurassic park was just about to appear and there was tremendous excitement about the potential of ancient DNA. The Museum gave me free rein regarding my own research as long as it had evolution at its core. So I decidedTree of life to work on the early evolution of eukaryotic cells. At the time two ideas were central to views of early eukaryotic evolution. One was that the “three domains tree of life” was an accurate description of the relationships between eukaryotes and prokaryotes (you can see the tree here). The other was that some eukaryotes, including obligate intracellular microsporidian pathogens, had never had mitochondria because they split from other eukaryotes before the mitochondrial endosymbiosis. I’ve been trying to test these two ideas for the past 25 years and while it’s often been difficult and frustrating, it has also been a lot of fun.

A Team Effort

Like most PI’s I’ve relied on attracting talented young scientists to do the work that we have published. Robert Hirt walked into my lab off the street and asked me if he could do a project involving eukaryotic evolution and ecology. He already had a first author paper in Cell and now he wanted to do something different. We didn’t do much ecologMitochondriay together but Robert and I co-supervised PhD student Bryony Williams who showed that microsporidians actually contained a tiny, hitherto overlooked mitochondrion, now often called a mitosome.

Unlike our own mitochondria, the microsporidian mitosome doesn’t make ATP, because it has lost all of the pathways used by classical mitochondria to make energy. Alina Goldberg in our lab – now at Newcastle – and Sabine Molik in the lab of Roland Lill in Germany spent Mitochondria 2the next seven years showing that the mitosome functions in the biosynthesis of essential cytosolic and nuclear Iron/Sulphur (Fe/S) proteins. The discovery of a tiny mitochondrion in microsporidia (Figures 1 and 2) was an important piece of evidence that led to current ideas that the mitochondrial endosymbiosis occurred at the origin of eukaryotes. Thus, it is now thought that all eukaryotes contain an organelle related to mitochondria, and its most conserved function is in Fe/S protein biogenesis, not ATP production.

Figure 1Figure 2Competing Hypotheses

In the three domains tree of life, eukaryotes are a separate domain that is most closely related to the domain Archaea and the host for the mitochondrial endosymbiont is already a eukaryote. Although this hypothesis appears in most textbooks, there have actually been a number of alternative hypotheses published over the years (Figure 3 shows one of them), but these have largely been ignored. Cymon Cox spent three years analysing molecular sequence data to identify which of the competing published hypotheses was best supported and reached the surprising conclusion that it was not the three domains tree but an alternative hypothesis called the eocyte tree (you can read a discussion about the differences between the two trees including a picture of the eocyte tree here). In the eocyte tree, eukaryotes originate from within the Archaea, suggesting that eukaryotes are not a primary domain of life like Archaea and Bacteria, but are instead a product of genetic and cellular contributions from both prokaryote domains. Very excited by these results, we sent Cymon’s paper to Nature where it was reviewed and quickly rejected. We appealed, it was revised, it was reviewed again, and it was rejected again, all in all pretty dispiriting, but a common experience for most scientists. However, after hearing me talk about Cymon’s work at a meeting, we were invited to submit Cymon’s paper to PNAS where it was finally published in 2008.

Figure 3A Mixed Response

Although Cymon’s paper has been highly cited it is true to say that the initial response from the community was very mixed. We received emails suggesting that we had manipulated our results to get the answer we wanted and one of the reviewers told us that it was impossible to infer such ancient events using molecular sequences. In responding we agreed that it was difficult to be confident about anything that happened billions of years ago based upon small amounts of data and even the best methods of analysis, but that people in the field seemed happy to use the same data and worse methods to support the three domains tree. Cymon eventually moved on, scarred but not defeated, and Tom Williams took over the project when he came to Newcastle on a Marie Curie Fellowship in late 2010. Over the next few years, more data was published as new Archaea were discovered and new methods of analysis were developed, and every analysis that Tom, or others, did on these data produced a version of the eocyte tree, so that it is now the best supported hypothesis – at least in our opinion.

More evidence emerges

Hypotheses are only useful when they make predictions that can be tested by further research, and evolutionary hypotheses are no different. The eocyte tree predicts that new species that share more features in common with eukaryotes will be discovered among the Archaea, and this prediction now appears to have been spectacularly fulfilled by recent discoveries from Thijs Ettema’s lab in Sweden. The new paper describes the discovery, so far only from metagenome data, of an archaeal lineage called Lokiarchaeota that contains many genes for proteins that were previously thought to be eukaryotic specific, including homologues of proteins used in the eukaryotic cytoskeleton, in membrane remodeling and in phagocytosis.  This is incredibly exciting and the challenge is now to isolate Lokiarchaeota and other new lineages into culture so that their biology and physiology can be studied in the laboratory.

An Interesting Journey

Scientific work is often written up as if it were a linear progression towards improved understanding, a type of “Whig history” which does not accurately reflect how science is really done. In reality, science is a collaborative endeavour with lots of dead ends, confusion and false trails, and we could easily be walking down some of those still. Nevertheless, the currently prevailing paradigm for eukaryotic evolution is now very different to the popular views held in the 1990s when I started my research career. All eukaryotes are now thought to contain a mitochondrial homologue that generally functions in Fe/S protein biogenesis, and the host for the mitochondrial endosymbiont is thought to have originated from within the Archaea. Eukaryotes are thus viewed as the product of an interaction between (at least) those two prokaryotic partners and are not a primary domain of life but one derived from prokaryotic antecedents. The complex features that we take to define eukaryotic cells including our own, such as the nucleus, large genomes and diversity of RNAs, are thus secondary features that have evolved since those primordial interactions. I’m not sure what my religious former colleagues would have made of the work I’ve done since leaving NELP, but it’s been an enjoyable and interesting journey for me.

Links

The Tree of Life: http://www.pnas.org/content/87/12/4576.full.pdf

Bryony Williams’ paper: http://www.nature.com/nature/journal/v418/n6900/full/nature00949.html

Alina Goldberg and Saline Molik paper: http://www.nature.com/nature/journal/v452/n7187/full/nature06606.html

Mitochondria and Fe/S proteins: http://www.nature.com/nature/journal/v440/n7084/abs/nature04546.html

The eocyte tree: http://phenomena.nationalgeographic.com/2012/12/20/redrawing-the-tree-of-life/

Cymon Cox paper: http://www.pnas.org/content/105/51/20356.full

Tom WIlliams paper: http://www.nature.com/nature/journal/v504/n7479/full/nature12779.html

Thijs Ettema lab paper: http://www.nature.com/nature/journal/v521/n7551/abs/nature14447.html

A novel copper storage protein discovered by ICaMB scientists

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In a recent issue of Nature the discovery of a new family of proteins that store copper ions inside bacterial cells was reported. This work was carried out by Prof. Chris Dennison’s lab (ICaMB) in collaboration with Dr. Kevin Waldron (ICaMB), Dr. Arnaud Baslé (ICaMB), Dr. Neil Paterson (Diamond Light Source) and Prof. Colin Murrell (UEA). Here, Kevin tells us about this discovery and what its implications could be for the biotechnological exploitation of methane.

Methane, the main component of natural gas, is produced by both geological and anthropogenic processes on Earth, and can be released into the atmosphere. The biosphere’s primary mechanism for limiting the amount of methane (a powerful ‘greenhouse gas’) that escapes into the atmosphere is through its consumption by methane-oxidising bacteria, or methanotrophs (literally ‘methane-eating’), who utilise methane as both a carbon and energy source.

Transmission electron micrograph of a M. trichosporium OB3b cell showing the intracytoplasmic membranes that house the copper-dependent enzyme pMMO.

Transmission electron micrograph of a M. trichosporium OB3b cell showing the intracytoplasmic membranes that house the copper-dependent enzyme pMMO.

The key enzyme that methanotrophs use to oxidise methane to produce methanol is called methane monooxygenase (MMO). Almost all methanotrophs possess a membrane-bound form of MMO that requires copper (Cu) for activity, called pMMO (some strains also possess an iron-requiring alternative soluble enzyme, called sMMO). Therefore, these bacteria have an unusually high demand for copper, a metal that is essential for most organisms but is used rather sparingly, mainly because it can also be extremely toxic.

Previous studies of methanotrophs have revealed that they utilise unusual mechanisms for acquiring the copper they need for pMMO. For example, they produce and secrete a small, modified peptide called methanobactin that is involved in high affinity copper uptake, analogous to the more familiar siderophore iron uptake systems.

The model methanotroph, Methylosinus trichosporium OB3b, was analysed in the hope of uncovering novel copper proteins. Soluble extracts were resolved by two-dimensional liquid chromatography, with the copper content of resulting fractions monitored. The most abundant copper pool was found to contain a small, cysteine-rich protein that had not been studied previously and Chris Dennison (PI) and I (Co-I) obtained a BBSRC grant to investigate this and related proteins.

The presence of 13 cysteine residues in a mature protein (after cleavage of its signal peptide) with only 122 amino acids was immediately significant, as its thiol sidechain is often found in copper-binding sites. The recombinant protein was extensively studied using a suite of biochemical and biophysical methods to determine its in vitro properties This novel tetrameric protein is capable of binding up to 52 Cu(I) ions with high affinity, consistent with a potential role in the storage of this essential metal and was therefore named Csp1 (copper storage protein 1). A mutant strain of M. trichosporium OB3b that lacks this Csp1 protein (as well as a closely-related protein, Csp2) shows a phenotype consistent with a copper storage role of these proteins in vivo.

The crystal structure shows that the apo-monomer adopts a well-characterised four-helix bundle motif with all 13 cysteine sidechains pointing into the core of the bundle. The protein structure is essentially unchanged in the presence of copper, except that the core of each monomer has filled with 13 Cu(I) ions, bound by the cysteine sidechains. This is an unprecedented structure for metal storage.

The structure of the Cu(I)-Csp1 tetramer, with the 13 Cu(I) ions bound within the core of each four-helix bundle shown as orange spheres.

The structure of the Cu(I)-Csp1 tetramer, with the 13 Cu(I) ions bound within the core of each four-helix bundle shown as orange spheres.

The implications of this discovery could be of wide impact. There is a great deal of interest in using methanotrophs and MMOs in industrial biotechnology. Available methane is on the increase due to ‘fracking’, but importantly methane can also be produced from sustainable sources such as through the degradation of biomatter (biogas). Methanotrophs and the MMOs could in future be exploited using synthetic biology approaches for gas-to-liquid conversion, for the production of liquid fuels as well as bulk and fine chemicals from renewable methane.

Any such biotechnological applications require an understanding of how the production of pMMO is regulated and how this complex enzyme is assembled, including the cellular delivery and insertion of the essential copper cofactor. The work published in Nature shows that Csps are an important piece in that assembly jigsaw.

Furthermore, bioinformatics has shown that cytosolic members of the Csp family are also encoded in other bacterial genomes. Most bacteria are thought not to require copper in their cytoplasm, so the presence of cytosolic Csp homologues in their genomes could re-write our basic understanding of their use and homeostasis of copper.

Links:

Nature article: http://www.nature.com/nature/journal/v525/n7567/full/nature14854.html

News & Views: http://www.nature.com/nchembio/journal/v11/n10/full/nchembio.1918.html

BBSRC website: http://www.bbsrc.ac.uk/news/fundamental-bioscience/2015/150827-pr-bacteria-that-could-protect-our-environment/

ACS Chemical & Engineering news: http://cen.acs.org/articles/93/web/2015/08/Protein-Stores-Copper-Methane-Digesting.html

Press release: http://www.ncl.ac.uk/press.office/press.release/item/could-bacteria-help-protect-our-environment

Another Cell-ebration

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Heath MurrayKevin WaldronLast year we brought you details of the inaugural CBCB Symposium. In July the second CBCB symposium was held, and today we hear from the organisers, Kevin Waldron and Heath Murray, about this latest successful event.

The idea for an annual Centre for Bacterial Cell Biology (CBCB) symposium was originally conceived in 2013, and aimed to showcase both the high quality and the immense breadth of research activity that goes on in this unique Centre. It would also be an excellent opportunity to bring together the CBCB research community based in both the Medical School and in the Baddiley-Clark building to discuss their work and build future collaborations.

It wasn’t long after our 2014 Symposium was over when the organising team (Bernie Shaw, Heath Murray, Kevin Waldron and Jeff Errington) began planning for this year’s second event. Obviously we were delighted with the success of that first meeting, but of course it also applied a little pressure on us as organisers; this year’s event had to achieve a similar level of success. Fortunately, the feedback we had received from the 2014 event included a number of constructive suggestions from the CBCB community about how we might be able to improve the Symposium, and we tried to incorporate as many of these ideas as possible.

One of our postdoctoral researcher speakers, Yoshi Kawai, addresses the Symposium audience on the subject of L-forms

One of our postdoctoral researcher speakers, Yoshi Kawai, addresses the Symposium audience on the subject of L-forms

One suggestion was to include a number of more junior speakers in the Symposium Programme as well as PIs, and we are grateful to those postdocs who volunteered to present their work to the CBCB audience. Alexander Egan told us about his research in the Vollmer lab on the proteins that coordinate biosynthesis of the cell envelope during growth and division. Yoshi Kawai of the Errington lab explained  how L-forms, bacteria that lack their cell wall, can be produced in the lab and how they propagate in a manner independent from the known bacterial cell division machinery, as well as speculating on their implications for early life forms on Earth. Marcin Dembek of the Salgado lab contrasted the mechanisms that govern sporulation in Clostridium difficile, a pathogen that primarily causes infections via spores, and the model organism Bacillus subtilis. Finally Didier Ndeh described his research in the Gilbert lab on how gut bacteria degrade the most structurally complex dietary polysaccharide known, rhamnogalacturonan II. PI speakers covered further topics relating to antibiotic discovery and their mechanisms of action and synthetic biology.

In addition to our CBCB researchers, we also again invited two high-profile external speakers. The day started with Mark Leake (University of York) who told us about his research using state-of-the-art microscopy for in vivo imaging of single molecules within the bacterial cell. And the Symposium was concluded by John Helmann (Cornell University) on the subject of transcriptional stress responses in one of CBCB researchers’ favourite model organisms, Bacillus subtilis.

Poster prize winner Lauren Drage

Poster prize winner Lauren Drage

Another of the suggestions that we incorporated into the Symposium schedule this year was a poster session, which was accompanied by light refreshments (of course!) immediately after the day’s talks. We had a great turnout, with more than 20 posters on display, and the session generated a lot of lively scientific discussion. Again the Symposium organisers are very grateful to all those members of CBCB who participated in the poster session. We awarded three poster prizes, with congratulations to winner Lauren Drage for her excellent poster describing her research in the Aldridge lab looking for biomarkers for diagnosis of urinary tract infections, and to our two runners-up, Martin Sim (Wipat lab) and Clare Wilson (Errington lab); and of course thanks to our poster judges, Lucy Eland and Yulia Yuzenkova.

Finally, we all got to enjoy an informal barbecue dinner and drinks, where the science discussions could continue into the evening.

Jeff Errington and John Helmann in post-symposium discussions

Jeff Errington and John Helmann in post-symposium discussions

Planning has already begun for next year’s Symposium, which will be held on the 8th July 2016, and will feature two more external keynote speakers, Christine Jacobs-Wagner (Microbial Sciences Institute, Yale University) and Prof. Tracy Palmer (Molecular Microbiology, University of Dundee). We welcome your feedback too, so if you attended this year’s Symposium and you have any suggestions about how we might improve next year, please let us know.