The 2017 ISMB Retreat

The Institute of Structural and Molecular Biology (ISMB) at Birkbeck and UCL holds a conference each summer where all members of the Institute's constituent departments come together to discuss their research. In even years, this takes the form of the ISMB Symposium: two intense days of research talks from ISMB core members and invited research leaders. In odd years, the focus turns to the younger members of the Institute with the ISMB Retreat. This, usually held in Cambridge University's Robinson College, is a two-day residential event featuring plenaries from outside speakers, shorter talks by students and postdocs from the ISMB, an activity designed to get young researchers thinking about science-based careers outside an academic lab, and a poster session. The 2017 retreat, held on June 29 and 30, was the seventh in the series.

There is a full report of this retreat (written by me) with photos on the ISMB website. Do check it out! Here are just a few highlights that are relevant to students of structural biology.

The three keynote speakers were Lori Passmore (MRC Laboratory of Molecular Biology (LMB), Cambridge; Bill Rutherford (Imperial College, London); and Bart Vanhaesebroeck (UCL Cancer Institute). Structural biology was a feature of all three talks, although most prominently in Passmore's. She was recently appointed as a group leader at the LMB, where her group uses high resolution electron microscopy to study the process of poly-adenylation (link to PPS section 8): the addition of the 'poly-A tail' to newly synthesised messenger RNA molecules during the maturation process. Much of the work she discussed has still to be published, apart from a section on techniques development: a physicist in her group, Chris Russo, has worked with her to devise a novel, gold-based substrate for mounting specimens in the electron microscope that eliminates most specimen movement and thus increases resolution.

Bill Rutherford gave an engaging talk, unusually featuring hand-written slides, on the mechanism of action of photosystem II, one of the complex proteins involved in photosynthesis. The evolution of photosynthesis was responsible for the increase in oxygen in the Earth's atmosphere that made multicellular life possible, and Rutherford explained how the increase in oxygen had led to further changes in the structure and mechanism of the photosystem that had the overall effect of decreasing its efficiency. Bart Vanhaesebroeck's lecture, which ended the retreat, described the mechanism of the phosphoinositide-3-kinase family of proteins and their role in cancer. Inhibitors of these kinases (link to PPS section 5) might prove useful anti-cancer drugs, almost certainly as part of combination therapy.

The programme also included nine short talks by students and young postdocs. The excellent quality of these was highlighted by the judges of the best talk, who were unable to come to a consensus judgement. In the end, two equal prizes were given, to Jennifer Booker, who studies the structure of sodium channels (see e.g. this post from September 2016) in Bonnie Wallace's group at Birkbeck, and to Sapir Ofer, for a talk on her PhD studies of the structural and molecular biology of archaeal histones. Proteins in this family are responsible for packing DNA into the chromosomes of eukaryotic cells; bacteria pack DNA using an entirely different mechanism, but the mode of packing in archaea - single-celled organisms that have no nucleus and are defined as prokaryotes but are more closely related to eukaryotes than to bacteria - was unknown until recently.

The retreat always includes an activity to challenge ISMB students and postdocs to think about career opportunities beyond academic research, and this year's proved particularly popular. It was a Dragons' Den style competition in which the younger delegates were split into teams, assigned mentors and given an hour to create a fictitious life science company, develop a bid for funding and present this to a panel of 'dragons'. Three finalists were chosen to battle it out in front of the rest of the delegates. The competitors worked hard and all 'companies' produced ideas that held water to at least some extent, but there could be only one winner. That was a company named TerraNova, which presented an antibody-drug conjugate for primary progressive multiple sclerosis.

Under the Microscope: Kinesin Motors and Cancer.

This post was written first for the Birkbeck College events blog and is re-posted here with permission.

There are many different types of cancer but each is caused by the failure of a cell to control its normal healthy cell division.  Uncontrolled proliferation produces a cluster of cancerous cells, a tumour, often the first indicator of many cancer types.  Several prevalent cancer drugs target microtubules, which are used by the cell to orchestrate the intricate ballet of cell division, but disabling this machinery provokes various unpleasant associated side effects.  In this lecture, which was part of Science Week, Dr Carolyn Moores, of the Department of Biological Sciences at Birkbeck shared some exciting recent developments in her work which pave the way for new cancer drugs which are less toxic to the rest of the body.

To understand the size of the machinery under discussion, if a human body were amplified to fill the whole of Buckingham Palace, each cell would be approximately the size of a single grain of sand.  These cells need to replicate, both to grow and to repair normal wear and tear and this replication is a delicate and highly regulated process.  Dr Moores showed a video of a dividing cell, taken from a remarkable online library of cellular images.  This process starts with the separation of the chromosomes, the familiar four legged bearers of our DNA, of which there are 23 pairs in humans.  The chromosomes arrange themselves in the centre of a spindle-like framework, which then retracts in opposite directions, separating each chromosome into halves and grouping them into two new nuclei centres, ready for the division of the rest of the cell. 

An image of mitosis showing the microtubules (in green) in spindle formation and chromosomes (in blue) about to be divided

The dynamic spindle framework at the heart of this incredibly accurate mechanism is primarily composed of microtubules along with associated proteins including members of the kinesin family of molecular motors, which organise them.  Microtubules are made up of pairs of tubulin molecules, or dimers, each of which has a polar structure.  The dimers bind to each other both longitudinally, with opposites attracting so that the overall polarity is maintained, and laterally so that long thin stable cylinders are formed.  These cylinders can grow and shrink with great flexibility and at all lengths the cylindrical structure provides a frame which can withstand the tension required in pulling chromosomes apart.  Drugs that block the dynamics of microtubules can therefore block the ability of cells to proliferate, which is why they are used in chemotherapy.  Unfortunately, microtubules are also critical in healthy cell repair, as well as providing frameworks essential for cellular structure, organelle positioning and vital transport networks within the cell.

Kinesins are highly attractive as potential targets since each appears to operate primarily in support of one of the major microtubule functions, in which case an inhibitor could be designed to attack the cell’s ability to divide without affecting its other vital processes.

Kinesin proteins comprise several domains, one of which is the motor domain, responsible for the protein’s movement.   This motor binds to a microtubule and uses it as a track with a directionality given by its polarity.  It also binds ATP, the universal cellular fuel, which provides the energy required to move along the track.  This has been particularly well studied in kinesin 1, whose function is to transport cargo along the microtubules.  In a mechanism that Dr Moores compared to a child walking on his hands, each unit of cargo is transported by a linked pair of kinesin 1 molecules.  The molecules alternate so that one will bind to the microtubule and the energy source, ATP, and then its partner will displace it so that the motor effectively steps hand over hand along the microtubule track.  Structural studies of kinesin 1 bound to a microtubule show that a small linker region of each kinesin reacts with the polarity of the track to point and presumably inform the direction of travel.

Dr Moores’ group are studying kinesin 5, which combines into oligomers of four molecules and forms crosslinks between microtubules.  This has been shown to be essential to cell division in humans.  The structural studies have involved cryo electron microscopy which has given a 3D model of the motor domain of kinesin 5 bound to a microtubule, both binding ATP and without ATP present.  Electron microscopy is a technique much like ordinary microscopy except that an electron beam is used instead of visual light and this gives images at a molecular level.  This technique is covered in detail in the TSMB course, one of the options following PPS for students working towards an MSc.   I have included the link although current PPS students will not have access to the course material.  The fact that a fast freezing method is employed is extremely useful since biological samples are effectively viewed in solution, as they are in their natural state.  By fitting x-ray crystallography models, which give atomic level detail of smaller molecular configurations, into the 3D cryo electron microscopy models, an enormous level of detail is obtained.

Drugs that target kinesin 5 are currently in clinical trials and appear to be successful so far.  It would appear that the drugs interact with an on/off switch elucidated by Dr Moores’ team but at the moment the precise function of the on/off switch is not known.  PDB 1Q0B shows an example of an inhibitor bound to kinesin 5 at the loop which functions as a switch.  Work continues in this rewarding area of study with the aim of understanding the purpose of the on/off switch and consequently being able to design future cancer drugs which have even higher specificity and consequently better outcomes.

Dr Moores has written a section of the TSMB course covering structural investigation of kinesin 5.  Again, unfortunately, current PPS students will not yet have access to this link.  The piece is taken from the last section of TSMB, which showcases the application of the many different structural techniques covered in the course to the study of a wide variety of proteins.

More details of Dr Carolyn Moores’ work are available at http://www.bbk.ac.uk/biology/our-staff/academic/carolyn-moores/