Sanger Science

Sanger Institute discussed the value of EU funding with local MEP Vicky Ford

Vicky Ford, Member of European Parliament for the East of England, visited the Sanger Institute to discuss the benefits and challenges of EU funding for research. Credit: Genome Research Limited

19 July 2012

Written by Mark Thomson

The EU doesn’t just fund fishing and farming, it also helps to drive new research. On Monday 16 July 2012, Sanger Institute staff met with Vicky Ford, Member of the European Parliament for the East of England, to discuss the benefits and challenges of European Union research funding. Vicky is a UK representative on the European Research Council (ERC) and is heavily involved in improving the EU Funding Programme for Research and Innovation 2014-2020.

As a research administrator involved in BASIS (Breast Cancer Somatic Genetics Study), Sancha Martin, was able to share first-hand experience of opportunities and the hurdles you come across with EU funding. “Funding from the EU allows our findings on the genetics of the most common form of breast cancer to be rapidly released with minimal restrictions. This provides the foundation for other researchers to develop their studies into diagnostic tools and treatments,” Sancha explains.

“We really value EU funding to help us to carry out and coordinate our research, but working across countries and nationalities can be a challenge. For example, the EU uses terminology to describe projects that can be quite alien to our researchers and the differences in languages mean administrative terms could easily become ‘lost in translation’. So we have to work hard to regularly and clearly communicate between all the collaborating institutions, to make sure that everyone clearly understands their role in the project and their delivery outputs.”

From his perspective as a member of faculty and research collaborator on EVIMalaR (European Virtual Institute of Malaria Research), Matt Berriman guided Vicky through the benefits of collaborating with a large number of Institutes throughout Europe. The programme is funded by the EU as an FP7 Network of Excellence and he is grateful for the exciting and empowering work he and his fellow researchers are able to carry out. But, he also notes that the reporting needed requires strong administration and communication skills for success.

“EVIMalaR is a great success story of European research integration, enabling us to share knowledge and resources extensively across institutes and continents,” Matt says. “However we did find the EU’s language of ‘clusters of activities’ and ‘work packages’ rather contrived because it sometimes created the impression that activities were isolated or stand-alone, when they were actually deeply embedded within one another. We also found that the simple move of hiring an administrator with good communication skills alleviated our reporting burden almost overnight and freed us to carry on our research.”

The meeting was a very useful opportunity for Vicky to understand the needs of researchers and administrators, while our staff found it was a great chance to help influence the future of EU funding. By working with the ERC and colleagues at other European research institutes and universities, our researchers and administrators are hoping to create organisational frameworks for sustained European collaboration in a wide range of research areas.

Mark Thomson is a member of the Media, Public Relations and Communications team at the Sanger Institute… more

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Colin Barker and his Colinator Colony Picking Robot
Sanger Life

Colin’s Colony Collecting “Colinator” minimises mindless monotony

Colin Barker and his Colinator Colony Picking Robot

Colin Barker with ‘The Colinator’ colony picking robot. Credit: Genome Research Limited

18 July 2012

Written by Colin Barker

I’m an engineer at the Sanger Institute and I’m often asked to work with scientists to find new ways to make research techniques faster, more efficient and, sometimes, a whole lot less boring.

About two years ago, Bill Skarnes (who leads the stem cell team) asked me to build a robot to help with the colony picking process. It is a dull and monotonous task that is also labour intensive and highly repetitive – an ideal process to be given to a robot. The team works with colonies of stem cells that are grown for a few days and then need to be identified, isolated and separated in the space of just 24-48 hours. This need to separate out the colonies is a major bottleneck in the research process.

So that I could create a robot that will mimic the way the researchers work in the most appropriate fashion, I sat in the laboratory clean rooms observing the researchers in action. I rapidly realised that this was a highly skilled and delicate operation and that a robot would never be able to fully replace the researchers’ expertise. Knowing which colonies to pick, and which to leave, is a skill that is best left to the scientists.

However, I knew that if I could automate the rest of the process I could help bring benefit in several ways. My robot would relieve RSI caused by repeated pipetting to aspirate and separate colonies, remove the eye strain of peering down a microscope, and save valuable time by freeing researchers to do other, more creative, tasks. The challenge was set.

I worked closely with Wendy Bushell from the ES Cell Mutagenesis team to design ‘The Colinator’ – a robot that accurately picks 96 colonies in under 14 minutes, to an accuracy of less than the width of a human hair. It uses an image detection system to highlight colonies on screen for the researcher to choose. Once the best colonies have been chosen, the Colinator gently slices, slides and lifts each colony away from the plate using a syringe needle with an accuracy and reliability of close to 100 per cent. The picked colony is then dispensed into a well, and the needle is washed clean before returning to pick another one. Not only does the robot enable researchers to continue with other tasks, but the gentle picking process keeps the colonies intact and increases the cells’ ability to grow and thrive.

The Colinator will soon be working full time in the Sanger Institute laboratories, but the story doesn’t end there. We are now working with a commercial partner to turn the Colinator into a line of machines that can be used in labs around the world to free researchers from monotonous colony picking tasks. Watch this space, as they say.

Colin Barker is an engineer at the Wellcome Trust Sanger Institute… more

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Sanger Life

Sanger Institute Scientist receives the Eppendorf Award for Young European Investigators

26 June 2012

Written by Aileen Sheehy

Dr Elizabeth Murchison has made quite an impact since she first joined the Wellcome Trust Sanger Institute in 2009. Since her arrival on a NHMRC Australian Overseas Fellowship, she has been awarded the L’Oréal-UNESCO UK and Ireland For Women In Science Fellowship, a science heirloom from the Medical Research Council to honour female role models in science and has spoken about her research at the TED [Technology, Entertainment, Design] conference, a non-profit event dedicated to bringing together the world’s most fascinating thinkers and doers.

To add to Elizabeth’s already impressive list of accomplishments, she has now been awarded with the 2012 Eppendorf Award for Young European Investigators for her ongoing research into the deadly transmissible facial cancer that is spreading among the endemic population of Tasmanian devils in Tasmania and threatening the survival of the species.

In 2010, Elizabeth was the lead researcher to create a draft genome sequence for the endangered Tasmanian devil (announced at the AMATA 2010 Conference in Hobart, Tasmania). Elizabeth’s research continued with a catalogue of the mutations present in the transmissible facial cancer endemic in the Tasmanian Devil population published in Cell (PUBMED: 22341448; PMC: 3281993; DOI: 10.1016/j.cell.2011.11.065). This study has led to clues about where the cancer came from and how it became contagious

Since starting her research at the Sanger Institute, Elizabeth has extended her research, by looking at another transmissible cancer called Canine Transmissible Venereal Tumour – a sexually transmitted cancer found in dogs. Although recovery rates are far higher in the canine cancer than in the Tasmanian devil cancer, the principles of transmission through cell transplantation are the same.

Looking at these cancers is providing Elizabeth with unique insights into what happens when a cancer can survive beyond its host. In evolutionary terms this affords Elizabeth a fascinating glimpse of the risk factors for the potential outbreak of similar diseases in other species, including humans.

With the Eppendorf Young Investigator Award which was established in 1995, Eppendorf AG honors outstanding work in biomedical research and supports young European scientists up to the age of 35. The Eppendorf Award is presented in partnership with the scientific journal Nature. The official presentation of the Award took place at the EMBL Advanced Training Centre in Heidelberg, Germany, May 9, 2012.

Aileen Sheehy is a member of the Media, Public Relations and Communications team at the Sanger Institute.

Sanger Science

Exploring Salmonella’s deadly sub-Saharan adaptation

Salmonella Typhimurium [Credit: Genome Research Limited]

21 June 2012

Written by Rob Kingsley

I contributed to a literature review article that was published in The Lancet in May 2012 that we hope will produce a wider appreciation of the severity and distinct causes of a disease that is an important cause of death in African adults and children.

Invasive non-typhoidal Salmonella (iNTS) is a blood-borne infection that kills approximately one in four of people in sub-Saharan Africa who catch it. Yet, in the rest of the word, NTS is simply an unpleasant disease: it is a leading cause of acute inflammatory diarrhoea that is self-limiting and tends to be fatal in less than 1 per cent of people.

This difference in the severity of the disease in sub-Saharan Africa when compared with the rest of the world is due, in large part, to synergy with other factors including young age of the person, malnutrition, or coinfection with malaria or HIV. However, our collaborative research with laboratories in Kenya, Malawi and Liverpool using whole-genome sequence analysis has also uncovered an additional complicating factor; the bacterium responsible for the severe disease is distinct from that found in the rest of the world.

In 2009, we announced that a distinct genotype of Salmonella Typhimurium, designated ST313, had emerged as a new pathogenic group in sub-Saharan Africa, and might have adapted to the susceptible population in these regions. While Salmonella Typhimurium genotypes associated with inflammatory diarrhoea have spread globally, the ST313 genotype is specifically associated with susceptible populations in sub-Saharan Africa. The genetic make-up of the pathogen may therefore contribute to the severity and/or epidemiology of this disease. The molecular basis of this association is now the subject of intense interest in laboratories across the world.

I work as part of research consortium that includes the Wellcome Trust Sanger Institute, laboratories in the UK and US, and – most importantly – collaborators from several sub-Sahara African countries, which has contributed significantly to understanding this disease. The collaboration combines local field studies in Malawi, Kenya, Uganda, Democratic Republic of Congo, Mali and Nigeria with molecular and genome sequencing efforts in laboratories around the world.

Despite the significant steps we have taken in understanding this disease in recent years, advocacy for further field studies and the development of effective intervention strategies is lacking. By developing a complete understanding of the epidemiology of this neglected disease, we hope that new avenues will open for development and implementation of vaccine and public health strategies to prevent infections and interrupt transmission.

Rob Kingsley is deputy head of Bacterial genetics within the Microbial Pathogenesis team at the Wellcome Trust Sanger Institute … more

Review article: Feasey et al. Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet 2012 (Epub ahead of print). doi: http://dx.doi.org/10.1016/S0140-6736(11)61752-2

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Sanger Science

Four Institute researchers have made it to Reuters most influential list


21 June 2012

Written by Aileen Sheehy

Four of the Wellcome Trust Sanger Institute researchers have made it to the Thomson Reuters top 15 most influential scientific researchers of 2011. Professor Mike Stratton, Dr Andy Futreal, Dr Peter Campbell and Dr Panos Deloukas, according to citations tracked during 2011, recorded some of the highest numbers of “Hot Papers” published over the preceding two years.

On 12 April 2012, the Intellectual Property & Science business of Thomson Reuters announced The Hottest Research of 2011, a ranking of the most influential scientific researchers and research papers of the year by Science Watch®, its open Web resource for science metrics and analysis. This year’s group of 15 Hottest Researchers each contributed to at least 10 Hot Papers, covering key areas such as genetics, cardiology, epidemiology and cancer research.

Professor Mike Stratton, Director of the Sanger Institute and joint head of the Cancer Genome project is the highest ranked of the Sanger Institute researchers at an impressive joint second position with 13 influential papers published over the past two years. Dr Andy Futreal, former head of Cancer Genomics at the Sanger Institute and current researcher at the MD Anderson Cancer Centre, is placed at third position with 12 influential papers. Dr Peter Campbell, current head of Cancer Genomics at the Sanger Institute, is positioned joint fourth in the rankings with 11 influential papers.

Dr Futreal, Dr Campbell and Professor Stratton, as part of the Cancer Genomics team at the Sanger Institute in from 2009 to 2011, used the human genome sequence and high-throughput mutation detection techniques to identify cancer causing mutations and hence identify genes critical to the development of human cancers. Some of the team’s most significant findings since 2009 were the identification of a gene mutation associated with blood cancers and the discovery of chromosomal crisis where the genome can be shattered into hundreds of fragments in a single cellular catastrophe.

Dr Panos Deloukas, whose research interest lies in coronary artery disease and myocardial infarction and leads the Genetics of Complex Traits in Humans Group, is ranked at joint fifth after contributing to 10 of the influential papers.

Dr Deloukas heads the Sanger Institute’s contribution to the Wellcome Trust Case Control Consortium, a consortium that aims to understand patterns of human genome sequence variation. The Consortium has undertaken three experiments so far: genome wide association studies of seven complex human diseases of major public health importance such as bipolar disorder (BD), coronary artery disease (CAD) and Crohn’s disease (CD), a genome wide study for tuberculosis, and an association study for breast cancer, multiple sclerosis, ankylosing spondylitis, and autoimmune thyroid disease.

The year’s Hottest Researchers were identified using citations that occurred during calendar year 2011 for papers published between 2009 and 2011.

Aileen Sheehy is a science communicator in the Media, PR and Communications Team at the Sanger Institute.

Sanger Science

Gene responsible for diarrhoeal disease transmission identified

Clostridium difficile [Credit: CDC/Dr. Gilda Jones]

21 June 2012

Written by Laura Deakin

As a Ph.D student at the Wellcome Trust Sanger Institute, I have been investigating how Clostridium difficile bacteria are able to infect people for nearly four years. This bacterium, which is found in hospitals and is rife in the developing world, has been a hot topic of discussion in both the scientific literature and mainstream media in recent years.

C. difficile is the leading cause of antibiotic-associated diarrhoea in developed countries and has been responsible for a number of deaths in hospital patients. The bacterium releases spores that are highly infectious and cannot be killed by standard hospital cleaning routines. As a result C. difficile bacteria are now widespread in many hospitals and they are capable of causing major epidemics that are becoming increasingly frequent and severe.

To understand how the bacteria are able to infect people and transmit from one person to the next, I have been investigating the role of a gene called spo0A. Working with the C. difficile team at the Institute, I infected mice with C. difficile, to allow us to recreate and study many aspects of the disease; including its persistence and transmission in humans.

Using these mice as a model, we are able to mimic the transmission of C. difficile within hospitals and the effects of different techniques employed to minimise its spread. For example, we are able to explore the impact on transmission of patient-to-patient contact and shared rooms, and to study the effectiveness of patient isolation in lowering infection rates.

The study we published online in the journal Infection and Immunity looked at the role the spo0A gene plays in allowing C. difficile to transfer from person to person. We found that the bacterium had to have a normal version of the gene for it to be transmitted. The gene is essential for disease transmission.

Further study revealed that spo0A is also responsible for the persistent nature of C. difficile. This persistence is seen in patients who have been given vancomycin (a powerful antibiotic) to treat the disease. The treated patients recover and return home to an environment that contains C. difficile. The bacteria are then able to reinfect them, resulting in a second wave of disease. Some people can experience multiple episodes of infection over many years. Successful reduction of transmission would greatly reduce the threat of C. difficile as a cause of disease in hospitals.

Our findings suggest that the spo0A gene is a potential target for the development of therapies to disrupt or stop C. difficile transmission. The discovery of this genes role also has clinical implications relating to the management of patients in hospital to minimise transmission: for example by isolating infected patients and by using ‘barrier nursing’ (that is, the wearing gloves, gowns when treating the patients and employing heightened disinfection regimes).

This discovery is just the beginning: now that we’ve identified the importance of spo0A in transmission and persistence, we are now expanding our search to find other, related, genes that may also play a role. Finding these genes will allow us to identify points of intervention that might ultimately be used to contain the bacteria’s spore-mediated transmission and limit the spread of C. difficile.

Laura Deakin is a Ph.D student in the Microbial Pathogenesis team at the Wellcome Trust Sanger Institute… more

Paper: Deakin L et al. Clostridium difficile spo0A gene is a persistence and transmission factor. Infect Immun 2012. doi: 10.1128/IAI.00147-12

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Credit: Luc Viatour / www.Lucnix.be
Sanger Science

Creating a gold-standard, not a rotten, tomato genome

Credit: Luc Viatour / www.Lucnix.be

Credit: Luc Viatour / www.Lucnix.be

Recently the full reference genome of the tomato (Solanum lycopersicum) was published in Nature (31 May 2012). Here, at the Wellcome Trust Sanger Institute, some of our sequencing people took part in the international collaboration of 10 countries that developed the DNA sequence. Each research group was tasked with working on a different chromosome, and we sequenced Chromosome 4. By being part of the project we were able to share our experiences and knowledge from producing animal reference genomes to enable the plant genome research teams to work together to deliver high-quality, standardised data.

When the tomato genome sequencing project began the teams estimated that the genome was 950 million base (Mb) pairs in size, split across 12 chromosomes. This was no small undertaking: it is one-third the size of the human genome (a project that had taken a worldwide collaboration 10 years to deliver). In addition, the project had limited funding resources, meaning that the work needed to be as tightly focused and efficient as possible.

Fortunately only 25 per cent of the tomato genome contains gene-rich areas, so the project teams agreed that capturing and sequencing these areas only would provide the most valuable information in the most effective way. To achieve this, we used mapping techniques to identify the gene-rich areas and used clone-by-clone sequencing to fully sequence them using the shortest number of sequencing runs.

Clone-by-Clone sequencing

We took clones taken from existing libraries and digested them with restriction enzymes, producing a fingerprint signature for each. We processed these fingerprint signatures in a database known as FPC (Fingerprint Contigs). Sections of signature in common indicate an overlap between clones and these overlaps can often be verified if known markers can be placed in them. By knowing where each clone belonged on the chromosome, we were able to select only a minimal set of clones to cover the area of interest. We made the FPC database for all the chromosomes publically available for the research community.

Fig 1. Screenshot showing the Fingerprint Contigs database. Clones highlighted in red and grey show the minimal tiling path selected for the sequencing project.

Using this approach, we mapped, sequenced and finished the gene-rich clones of Chromosome 4, which was estimated to be roughly 19Mb long. The UK team was led by Principal Investigators Gerard Bishop from Imperial College London, Graham Seymour from Nottingham University, Glenn Bryan from Scottish Crop Research Institute, and Jane Rogers from the Sanger Institute.

Finishing the genome

However, mapping and sequencing are not the whole story when producing a high-quality reference genome: the sequences need to be pieced together and inconsistencies resolved. In other words, the sequences need to be finished. This can be a long and time-consuming process, especially if a project consists of differing standards and approaches. Fortunately, we have long experience in finishing DNA sequencing data from our work on the human, mouse and zebrafish genome projects. So, to enable the other international teams draw on our experience and to develop the common standards needed for efficient finishing, we organised two International Finishing Workshops.

In these, representatives of the different research groups from across the world met and discussed the various challenges of working with the sequencing data. It was a chance to pool experience and look at efficient ways to progress each data set for each of the chromosomes. Our discussions centered around techniques for improving the data for the clones as well as ensuring that the metrics all the teams used to assess the quality of each clone was comparable.

Through meeting together and talking through the issues, the teams ensured that the resulting genomic sequence from all the laboratories involved showed parity. This data was then annotated and made publically available for the wider Solonaceae research community.

Another area that we were able to make a useful contribution to was to guide the project teams through the challenges of adopting and incorporating new technology sequencing data; which the project went on to adopt.

Funding bodies: BBSRC, EU-SOL, DEFRA and the Wellcome Trust

Sanger Life

Fourth Institute bioinformatician wins open access award

A fourth Wellcome Trust Sanger Institute alumnus – Heng Li – has won the eleventh Benjamin Franklin Award for Open Access in the Life Sciences. Remarkably the Institute has trained and developed more than one third of the winners of this award, reinforcing the data-sharing and open-access ethos of the Institute. Even more remarkably, all four winners have been trained in Richard Durbin’s research group: Heng Li (2012), Alex Bateman (2010), Sean Eddy (2007) and Ewan Birney (2005).

Heng Li was chosen from a shortlist of seven open-acess practitioners by voting members of the Bioinformatics.org community.

The Sanger Institute is founded on, and dedicated to, the open-access and sharing of data to power bioinformatic research around the world. However, data sharing without the tools to interpret and interrogate the data is useless. So the Institute is also committed to research that powers the development of, and delivery and sharing of, software to allow genomic data to be compared, mined and studied.

It’s therefore really fitting that Heng Li has been awarded the Benjamin Franklin Award for Open Access in the Life Sciences. His input has created essential tools to enable next-generation sequencing data to be analysed, interpreted and shared. For example, he has helped to produce a range of sequence alignment tools and algorithms including SAMtools, BWA, MAQ and TreeSoft. Using these programs, researchers have been able to read the whole genomes of organisms to find genetic differences between individuals in the same species. For example, research into structural changes in the genome and the genetic basis of human disease based on the 1000 Genomes Project use this software.

In addition, he has developed tools to analyse gene family evolution and build phylogenetic trees, including the TreeBeST program, TreeFam and EnsemblGeneTrees databases. Research using these resources is revealing insights into the evolution of species and the changes happening within them.

Yet such tools are of little value unless researchers are given help and advice in using the software and databases and mining their full potential. Heng has not only contributed to the creation and sharing of a wide range of vital software tools that form an essential resource for bioinformaticians around the world, he is also dedicated to the ideal of sharing knowledge by helping bioinformaticians to understand and use his tools by regularly contributing to bioinformatics forums and guiding new users.

Info on previous winners from Richard Durbin’s group (taken from the Benjamin Franklin Award page on Bioinformatics.org website):

2010 – Alex Bateman
Alex won the 2010 Benjamin Franklin Award for leading the freely available PfamRfam and MEROPS databases. He was also the Executive Editor for the open-access Database issue of the journal Nucleic Acids Research for many years. Furthermore, Bateman helped initiate the RNA Families track at the journal RNA Biology, where a Wikipedia article is required for each published RNA family.

2007 – Sean Eddy
Sean received 2007 Benjamin Franklin Award for the development and free distribution of HMMER, which has revolutionized the use of profile Hidden Markov Models in protein sequence analysis, and for the co-creation of the Pfam database of protein domains and families, which has been an essential counterpart as the basis of genome annotations, family classification systems such as GO, and much of our common language of protein annotation.

2005 – Ewan Birney
Ewan Birney was honoured with the 2005 Benjamin Franklin Award for his promotion of Open Access in bioinformatics and science. He has been a key developer in the Ensembl and BioPerl projects and a strong advocate for making genome information freely available.