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ISMB News


This page contains recent ISMB News items. Previous ISMB news items are available in the archive.

Latest ISMB Newsletter

The latest ISMB newsletter can be read here.

 

Research by the Waksman Lab into Bacterial Secretion Sheds Light on Antibiotic Resistance
March 2014

A team of scientists led by Professor Gabriel Waksman has uncovered the system that allows the sharing of genetic material between bacteria, and therefore the spread of antibiotic resistance. The research, published in Nature and funded by the Wellcome Trust, reveal the mechanism of bacterial type IV secretion, which bacteria use to move substances across their cell wall.

As type IV secretion can distribute genetic material between bacteria, notably antibiotic resistance genes, the mechanism is directly responsible for the spread of antibiotic resistance in hospital settings. It also plays a crucial role in secreting toxins in infections - causing ulcers, whooping cough, or severe forms of pneumonia such as Legionnaires’ disease. Using electron microscopy the team were able to reconstruct the system as observed in the bacteria E. coli. They saw that the mechanism consists of two separate complexes, one in the outer membrane of the cell, and the other in the inner membrane, which are connected by a stalk-like structure that crosses the periplasm – the space between the two membranes. The complexes at both the inner and outer membranes form pores in the membrane, via which substances can be secreted.

Professor Waksman said: ‘This work is a veritable tour de force. The entire complex is absolutely huge and its structure is unprecedented. It is the type of work which is ground-breaking and will provide an entirely new direction to the field. Next, we need to understand how bacteria use this structure to get a movie of how antibiotics resistance genes are moved around.’ ‘Understanding bacteria’s secretion system could help design new compounds able to stop the secretion process, thereby stopping the spread of antibiotics resistance genes. Given that antibiotics resistance has become so widespread and represents a grave threat to human health, the work could have a considerable impact for future research in the field of antimicrobials.’

Asymmetric Composite Structure of the T4SS3–10 Complex

Asymmetric Composite Structure of the T4SS3-10 Complex

a, Front view. The map is a composite generated by merging independently processed core complex and IMC reconstructions. b, Cut-away front view. Electron density is colour-coded, ranging from red to blue, indicating regions of strong to weak density, respectively. The IMC has pseudo-two-fold symmetry around the particle long axis. c, Side view. U-, M- and L-tier substitute for upper, middle and lower tier, respectively.

  • Click here to read the full article, published in Nature (doi:10.1038/nature13081)
 

ISMB Commentary
January 2014

Beyond tumour suppression: p53 is a key regulator of vertebrate regeneration

Salamanders are the champions of regeneration. Unlike mammals, these organisms are able to regenerate an impressive repertoire of body structures, including spinal cord, heart, brain and entire limbs. Understanding how salamanders regenerate complex structures is of great biological interest because it can provide insights into fundamental cellular processes as well as eventually teaching us how to stimulate regeneration in humans. Recent research from ISMB researchers Max Yun, Phillip Gates and Jeremy Brockes has uncovered a new molecular mechanism for controlling the process of salamander regeneration, dependent on the tumour suppressor p53.

The authors sought to understand the molecular mechanisms that control regeneration using the salamander limb as their system. Limb regeneration depends on the reprogramming of differentiated cells within the mature tissues. Upon amputation, these cells dedifferentiate and re-enter the cell cycle to proliferate, forming a mound of progenitor cells called a blastema. These cells can then undergo a redifferentiation process that leads to the restoration of the limb. What are the molecular mechanisms underlying the regulation of such critical dedifferentiation-differentiation processes?

Their research, published in the journal PNAS, shows that regulation of p53 is central to the answer. They found that, as regeneration begins, the salamander temporarily downregulates p53 activity enabling the reprogramming of differentiated cells and their re-entry into the cell cycle. Later on, the organism upregulates p53 to trigger redifferentiation as the new limb is formed. The authors were able to show not only that these changes in p53 activity happen but that they are functionally critical for regeneration.

How is this strict temporal regulation achieved? The authors suggest a key role for a p53 dominant negative isoform, Np73, which they found to exhibit an inverse pattern of expression through salamander regeneration compared to p53. When its expression was artificially prolonged the redifferentiation phase of regeneration was delayed. Based on these findings, the authors propose that in salamanders the absence of tumour suppressors that stabilise p53 allows p53 activity to fluctuate (albeit under strict temporal control) in a manner which would not be possible in other species. The control of this fluctuation by regulators such as Np73 enables salamanders to execute the precise dedifferentiation and redifferentiation of adult tissue required for limb regeneration.

This research uncovers a key molecular mechanism controlling differentiation and its reversal in vertebrates. Additionally, it provides a new perspective on the functions of the key tumour suppressor p53. It reveals how subtle regulation of p53 is critical to a process which must orchestrate dedifferentiation, proliferation and redifferentiation whilst maintaining strict genomic integrity. Hence, the interplay between p53’s functions in tumour suppression, cell plasticity and development don’t have to be trade-offs. Strict p53 temporal regulation, revealed here in one remarkable species, is permissive for regeneration but retains its acute tumour resistance, a well-established characteristic of this process.

Full article: Maximina H Yun, Phillip B Gates & Jeremy P Brockes. “Regulation of p53 is critical for vertebrate limb regeneration”. PNAS (2013) October 22, 110 (43): 17392-7.

Regen-Limb

Above: Regenerated salamander limb. The red line indicates the regeneration plane. (Image: Maximina Yun, Phillip Gates & Jeremy Brockes)

[Posted: January 2014]

 

Prof Ivan Gout receives BBSRC Responsive Research Grant
December 2013

Congratulations to Prof Ivan Gout, who has received an award of £474, 000 from BBSRC for the project 'Role of DNA Binding in the Regulation and Function of Ribosomal S6 Kinase 2'.
£386k will be used by Prof Ivan Gout and £88k by his co-investigator Prof John Hartley in the Research Department of Oncology, UCL Cancer Institute.

[Posted: January 2014]

 

Professor Helen Saibil is part of academic team behind new biology imaging centre at Diamond
December 2013

Professor Helen Saibil, Bernal Professor of Structural Biology at Birkbeck, is one of the academic leads for a new imaging centre for biology which will be built at the Diamond Light Source in Oxford. The centre will be funded by a £15.6 million grant from the Wellcome Trust, The Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). The new centre will provide scientists with state-of-the-art experimental equipment and expertise. The powerful cryo-electron microscopes will reveal more of cell structure to help further understand molecular make-up and will provide new tools to visualise single bio-molecules. The facility will offer two high end Cryo-Electron microscopes, a sample preparation laboratory with a super-resolution fluorescence microscope, and equipment for vitreous sectioning with an ion-milling beam.

Read the full press release here.

[Posted: December 2013]

 

Dr Vitor Pinheiro receives ERC 4-year grant
November 2013

Congratulations to Dr Vitor Pinheiro, who has been awarded a ERC grant of just under 1.2M euros.
The grant will begin in February 2014 and will fund two post-docs - one in a 4-year post and one 3-year post with a delayed start.

The funded work focuses on pushing synthetic nucleic acids one step closer to the cell. Dr Pinheiro's previous work has seen him develop enzymes that could interconvert XNA and DNA information. This project will go a step further developing XNA->XNA replication and a viable genetic element in XNA.

[Posted: November 2013]

 

Dr Saul Purton receives BBSRC funding for Network in Algal Biotechnology
November 2013

Congratulations to Dr Saul Purton, whose application for funding for a network in Algal Biotechnology has been accepted by the BBSRC to receive a 5 year award of £1.4M.
The network is one of ten nationally to be awarded on the BBSRC's programme of industrial biotechnology and bioenergy funding announced earlier this year.

[Posted: November 2013]

 

ISMB members awarded Wellcome Trust Sir Henry Dale Fellowships
November 2013

Congratulations to Drs Filipe Cabreiro and Alan Cheung, who have each been awarded a prestigious Wellcome Trust Sir Henry Dale Fellowship.

[Posted: November 2013]

 

Dr Saul Purton awarded four BBSRC 4-year PhD Studentships
October 2013

Congratulations to Dr Saul Purton, who has received 4 BBSRC funded studentships for 2014/15 in response to his Strategic Longer and Larger (sLoLa) grant proposal.

[Posted: October 2013]

 

New book on 'Protein-Ligand Interactions' by ISMB Biophysicists
October 2013

Drs Tina Daviter and Mark Williams at the ISMB Biophysics Centre have edited a new book on Protein-Ligand Interactions, published by Springer.
Experts from around the world have written easy-to-follow protocols for the discovery and characterization of protein-ligand binding. With lots of background information, both theoretical and practical, the book is designed to provide a coherent introduction to biophysics; understandable for beginners and enlightening for experts. These protocols will serve as great resources for current and future users of the ISMB's wide range of biophysics instrumentation.

[Posted: October 2013]

 

ISMB Core Member promotions
October 2013

Congratulations to the following ISMB Core Members on their recent promotions:

  • Prof John Christodoulou (Research Department of Structural and Molecular Biology, UCL) promoted to Professor of Biological NMR Spectroscopy
  • Dr Maya Topf (Department of Biological Sciences, Birkbeck), promoted to Reader in Computational Biology

[Posted: October 2013]

 

Dr Carolyn Moores receives BBSRC Research Grant
October 2013

Congratulations to Dr Carolyn Moores, who has received a Biotechnology & Biological Sciences Research Council (BBSRC) grant of £351,254 over 2 years, starting from January 2014.

[Posted: October 2013]

 

Prof Gabriel Waksman elected to German Academy of Sciences
August 2013

Professor Gabriel Waksman, Head of the ISMB, has been elected to the German National Academy of Sciences or Leopoldina. His election is in recognition of his research into the structural and molecular biology of secretion systems in bacteria. These systems determine bacteria survival, adaptation and evolution, making them ideal targets for developing new antibiotics.

Election to the Leopoldina, the oldest continuously existing academy of medicine and the natural sciences in the world, is the highest academic honour awarded by a German institution. Its membership of 1,400 distinguished scholars is drawn from 30 countries and past members have included such eminent scientists as Marie Curie, Charles Darwin, Albert Einstein and Max Planck.

Professor Waksman commented on his election: "I am delighted to have been elected to this prestigious academy. It not only recognises the quality of the work we've done over the years, but also, cements a strong relationship between my laboratory and laboratories in Germany."

Read more about the work of the Waksman Lab.

[Posted: August 2013]

 

Prof Steve Perkins receives Alexion Pharmaceuticals grant
August 2013

Congratulations to Prof Steve Perkins, who has been awarded a grant of $98,733 for 6 months initially, from Alexion Pharmaceuticals, Inc. The grant will fund one Post Doctoral Researcher.

[Posted: August 2013]

 

Dr Matilda Katan (Principal Investigator) and Dr Christine Orengo (Co-Investigator) awarded CRUK Programme Grant
August 2013

Congratulations to Matilda Katan and Christine Orengo, who have been awarded a CRUK Programme grant worth £975,251 running for at least 4 years from October 2013. The grant will include funding for 4 PDRAs.

[Posted: August 2013]

 

Prof Helen Saibil awarded BBSRC Grant
August 2013

Congratulations to Prof Helen Saibil, who has been awarded a BBSRC grant of £387,500, starting in August 2013 to run over 3 years. The grant will part-fund the purchase of an electron detector.

[Posted: August 2013]

 

Dr Christine Orengo awarded BBSRC Bioinformatics and Biological Resources (BBR) Research Grant
July 2013

Congratulations to Dr Christine Orengo, who has been awarded a BBSRC BBR research grant of £612,409 for four years from January 2014. The grant includes funding for 1 PDRA.

[Posted: July 2013]

 

Dr Lisa Cabrita awarded Alpha-1 Foundation Project Grant
July 2013

Congratulations to Dr Lisa Cabrita, a senior post-doc in Dr John Christodoulou's group, who has been awarded an Alpha-1 Foundation project grant worth $195,935. The grant will run for 2 years from January 2014, and includes funding for 1 PDRA.

[Posted: July 2013]

 

Dr Vitor Pinheiro receives BBSRC grant
June 2013

Congratulations to Dr Vitor Pinheiro, who has been awarded a BBSRC grant worth £459,002. The grant will fund 1 PDRA.

[Posted: June 2013]

 

ISMB Graduate Symposium, 11-12 June 2013
June 2013

This annual event is designed to give PhD students at the ISMB the opportunity to present their work and is typically attended by over 100 PhD students and supervisors.

The 2013 ISMB Graduate Symposium will take place on Tuesday 11 and Wednesday 12 June in the JZ Young Lecture Theatre, Anatomy Building, UCL.

Professor Liz Shephard, Research Department of Structural and Molecluar Biology, will be the guest speaker.

Full programme details will be circulated among members of the ISMB soon.

[Posted: May 2013]

 

UCL student wins Eisenthal Prize to work with Professor Steve Perkins
May 2013

Congratulations to Anna Miles, a second year Biochemistry student at UCL, who was this year's winner of the Biochemical Society Eisenthal Prize to carry out a summer studentship project with Prof Steve Perkins at UCL.

[Posted: May 2013]

 

Featured Publication
April 2013

Structural and Energetic Basis of Folded-Protein Transport by the FimD Usher


Geibel S., Procko E., Hultgren S.J., Baker D., Waksman G. Nature 496, 243–246, doi:10.1038/nature12007

Published this month in Nature, Prof Gabriel Waksman, his group member Dr Sebastian Geibel and their collaborators have revealed the structural and energetic process by which bacteria transport pili across their outer membrane. Pili are a key target for a new generation of antibiotics, as without them bacteria are unable to group together and to stick to human cells causing infection.

In the cystitis bacteria, pili enable bacteria to group together and then to attach to the wall of the bladder. The bladder cells then engulf the bacteria and this makes antibiotic treatment very difficult. Once inside the bladder cells the bacteria can lie dormant, making recurrent infections common. It is believed that a new generation of antibiotics could be developed to disrupt the process of pili biogenesis, making the condition easier to treat.

Previous research by the ISMB members uncovered how pili biogenesis is initiated by the protein FimD – an usher in the outer cell wall. FimD is responsible for recruiting subunits, assembling them into a pilus, and secreting the pilus as it is being formed. From this work, the team was able to develop a model for the way the usher carry out all these tasks. The latest research, funded by the Medical Research Council, provides experimental proofs for the model proposed before and shows how, once the subunits have been assembled, the new pilus is secreted from inside the FimD protein to the exterior, via a pore, across the outer bacterial membrane.

The team has now revealed that as the pilus is assembled, the first subunit (FimH) engages with the usher and undergoes structural changes. This creates the necessary energy for this subunit, which forms the tip of the pilus, to displace the plug which is normally found inside the pore, and to pass through the pore itself. As subsequent subunits of the pilus pass into the pore, other structural changes in FimH prevent the pilus retreating back through the pore.
The team has also revealed that within the usher’s pore there are specific binding sites for the tip and the subsequent subunits of the pilus. These binding sites are 180 degrees apart within the barrel of the pore (facing each other); so that the pilus is held in a central position as it emerges from the pore, facilitating its exit.  Furthermore, it has n that as the pilus passes through the pore it follows a rotational and translational path, enabling subsequent subunits to continue being added within the usher as the tip emerges, while the pilus is still held in a central position.

"For the first time we have been able to see the structural and energy pathways via which the FimD usher protein facilitates the transport of the newly assembled pilus across the outer membrane of the bacteria. This process is a key target for the development of new antibiotics, as if biogenesis of new pili can be disrupted the bacteria will be unable to attach themselves to human cells and infection will be much less likely. “We have been working for a number of years to try and understand the process of pili biogenesis and an understanding of this process takes us a step closer to the development of new antibiotics which will successfully treat cystitis – a common and extremely painful condition, as well as other bacterial infections.”

[Posted: April 2013]

 

ISMB's 5th Bi-Annual Retreat - registration now open
April 2013

Registration is open for the 2013 ISMB retreat. The retreat will take place at Robinson College, Cambridge on 3rd and 4th July. For more information and to register, visit the ISMB Retreat webpages.

[Posted: April 2013]

 

Dr Adeline Goulet paper selected as Article of the Month by the French Society of Biochemistry and Molecular Biology

April 2013

A study by Dr Adeline Goulet in the Moores group, “The structural basis of force generation by the mitotic motor kinesin-5”, has recently been published in The Journal of Biological Chemistry (Dec 28 (2012); 287(53): 44654-66.)

Kinesin-5 motors are important in eukaryotes for the formation and maintenance of the microtubule-based, bipolar mitotic spindle. Kinesin-5s have also been of great interest as novel targets for anti-cancer therapies: kinesin-5-specific drugs block mitosis and are in phase II clinical trials. By using cryo-electron microscopy and sub-nanometre resolution structure determination, Goulet et al have visualised ATP-dependent conformational changes in the kinesin-5 motor domain while bound to its microtubule tracks. These structures provide insight into the mechanism of force generation by kinesin-5s. They also present evidence for auto-regulation of motor activity by a kinesin-5-specific loop that acts as a competitive inhibitor to ATP binding. Future work will be directed at understanding the significance of this finding in the context of the mitotic spindle.

The paper has been selected as Article of the month (April) of the Société Française de Biochimie et de Biologie Moléculaire (http://www.sfbbm.fr/index.php?option=com_content&view=category&layout=blog&id=98&Itemid=62). This work is an inter-disciplinary collaboration with Professor Steve Rosenfeld at the Cleveland Clinic, and was funded by the BBSRC.

[Posted: April 2013]

 

Professor Steve Perkins receives MRC, EPSRC-NSF and Alexion grants
April 2013

Congratulations to Prof Steve Perkins, who has been awarded the following grants:

  • MRC grant worth £630,000 over 3 years, funding one PDRA
  • An EPSRC-NSF grant worth £1.4 million over 4 years, funding up to four PDRAs
  • An Alexion grant worth £133,000 over 1 year, funding one PDRA

[Posted: April 2013]

 

Professor Gabriel Waksman receives MRC grant
April 2013

Congratulations to Prof Gabriel Waksman, who has been awarded a MRC grant worth £2,000,000. The grant will fund 3 PDRAs over 5 years.

[Posted: April 2013]

 

ISMB Students in Research Poster Competition
March 2013

On 25th and 26th February, UCL ran a Research Poster Competition which offered graduate students an opportunity to meet, advertise and discuss the innovative research they are undertaking.

Overall 247 students registered for this year's Research Poster Competition (Arts & Humanities, Laws, Social & Historical Sciences – 13; Built Environment, Engineering Sciences, Mathematical & Physical Sciences – 66; Brain Sciences & Life Sciences – 101, and Medical Sciences & Population Health Sciences – 67).

In the Brain Sciences & Life Sciences Group two ISMB students won runner up prizes (£100 each):

Anna Adams, (Kaila Srai Group)
"Exploring New Routes to Labelled Hepcidin"

Susan Andrew, (Richard Hayward Group)
"You are what you eat: host ion scavenging by intracellular Chlamydia trachoma tis"

[Posted: March 2013]

 

Drs Hazel Smith, Andrea Townsend-Nicholson and Suzanne Ruddy receive SLMS Innovation grants

March 2013

Congratulations to Drs Hazel Smith, Andrea Townsend-Nicholson and Suzanne Ruddy on being awarded SLMS Innovation grants. The grants will be used to implement an exciting Chemistry module for Biological Science students; develop interactive online tutorials for Bioscience students and strengthen links with Yale and to produce films that showcase research laboratories to our undergraduate students.

[Posted: March 2013]

 

Welcome to Prof David Lomas

New Dean of Medical Sciences and ISMB Core Member

The ISMB is delighted to welcome as an ISMB member Prof. David Lomas PhD, ScD, FRCP, FMedSci.
David is the new Dean of the Faculty of Medical Sciences at UCL. His research interests are in understanding the mechanisms of diseases caused by protein misfolding, in particular the serpinopathies, in order to develop novel therapies.

David chairs the MRC Population and Systems Medicine Board, the Respiratory Therapy Area Board at GlaxoSmithKline, and is Chair of the Research Committee and Trustee of the British Lung Foundation. More recently he has chaired the strategic priorities working group for the NHS 100,000 genome project. David has strong experience in applying structural, molecular, cell and computational biology techniques to address unmet clinical needs. Such interface work is increasingly important but it can be challenging for clinicians and scientists, who often work in isolation from each other, to bridge successfully. He is very keen to facilitate such cross-talk between researchers in the ISMB and UCL-affiliated clinicians. Examples of this might include arranging access to relevant ex vivo clinical samples to further test hypotheses supported by in vitro data, or discussing relevant clinical applications of a novel technology. David is happy to be contacted with ideas for such interactions (d.lomas@ucl.ac.uk). They fit within his broader strategy whereby UCL’s internationally prestigious hospitals will actively partner with new (and existing) world-class scientific institutes to optimise biomedical research at all levels.

Links

[Posted: March 2013]

 

Professor Gabriel Waksman receives ERC Advanced Grant
February 2013

Congratulations to Professor Gabriel Waksman, who has been awarded a ERC Advanced Grant of just over £2 million for the project, 'Structural biology of Legionella’s Effectors and Secretion System'. The grant will fund 3 PDRAs over 5 years.

[Posted: March 2013]

 

 

 

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