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.

Epigenetics for Beginners

Before I start, I’d like to briefly introduce myself and say hello.  My name is Jill Faircloth and I studied the PPS course in 2009-10 and then went on to take the TSMB course the year after.  I posted a proper introduction of myself in my first blog in March this year.  I also gave some tips from previous years on managing the revision and project work during the summer and thoughts on the two follow on courses.  

Since that time I have started writing for The Brain Tumour Charity.  The challenge there is to write explanations of the highly technical research being sponsored in language that can be understood by a non-scientist.  This PPS blog is a fantastic opportunity for me to continue to explore protein structure research, which I enjoyed very much during my MSc, and hopefully to bring interesting and relevant pieces of work to your attention.  Since you have only just begun to look at protein structure, however, I thought I’d begin with a beginners guide to a hot topic: epigenetics.

The nature versus nurture argument has long been a fertile source of entertaining and/or heated debate.  As team nature pinned their colours to the mast of the all powerful genome, the nurture camp would gleefully point out that identical twins often exhibit different personalities, proof that the genome is not the ultimate dictator.  A compromise was generally agreed upon whereby an individual’s personal traits were thought to be formed by a nurture overlay on a nature foundation.

Epigenetics is the emergent science which is poised to provide a more sophisticated answer both to the origins of individuality and to the question of how dividing cells in a developing foetus have the ability and apparent programming to become brain cells or liver cells or any of the other very many different types of cells in a mature organism.

  

To understand the epigenome, we must first look at the storage of DNA in the nucleus.  The familiar double helix of DNA is tightly wound around histone proteins, packaged in groups of eight.  Each histone package is wound twice round by the helix to form a nucleosome so that the DNA appears as a string sporting nucleosome beads along its length.  This thread of nucleosomes is woven into a rope called chromatin which, in turn, is woven into a chromosome.

  

Each of the diverse cells of the body carries the same DNA which encodes the entire genome, that is, the code for every protein required throughout the organism.  The epigenome is the system of molecules which acts upon the packaged DNA to determine which of the genes encoded is activated in any particular cell.

There are two key methods employed by the epigenome, both of which can act to “turn off” particular genes:

• ·         the histone proteins can be post-translationally modified so that they bind the DNA more tightly, thereby shielding some genes from transcription, and

• ·         small chemical groups, predominantly the methyl group, bind to the DNA at CG pairs.  A gene with several methyl caps will be blocked from transcription but removal of the caps will allow re-activation of the gene.

Illustration of epigenetic mechanisms adapted from Wikipedia

Using this mechanism, cells with exactly the same genome can behave differently since they can have different combinations of histone modifications and methyl groups, i.e. different epigenomes, controlling which genes are expressed and which are dormant.  The processes which govern how cells acquire these different epigenomes are not well understood although it is known that the basic patterns are encoded on the genome and are then altered by environmental factors.  These include signals from neighbouring cells so that a cell’s location is a key factor in determining its unique epigenome.

Cell location is not the only factor, however, as demonstrated in a study by Frago et al, (2005),  which showed that although identical twins begin life with the same epigenome, wide differences accumulate over time in the acetylation of their histones and the methylation of different genes.  This is thought to account for the clear differences seen in the personalities and disease susceptibilities of monozygotic twins.

Another illustration of an environmental factor is provided by some intriguing research into the epigenome of honey bees.  This study, (Lyko, F. et al, (2010)), found that all of the honey bees in a swarm have the same genome but as larvae they are given a different diet, with future queens receiving royal jelly, and this creates a difference in the methylation of more than 550 genes, including those for histones.

Another study not only demonstrates that diet has a strong epigenetic effect but also shows that this can have transgenerational ramifications.  Kaati et al, (2002) surveyed the long term health of the residents of a sparsely populated region of Sweden called Ӧverkalix, which has been prone to cycles of high harvest yields followed by years of famine.  The results showed that the paternal (but not maternal) grandsons of men who experienced famine in preadolescence were less likely to die of cardiovascular disease whilst paternal grandsons of men who enjoyed plentiful food were more likely to die of diabetes. Interestingly, the opposite effect was found with women.  Women whose paternal (but not maternal) grandmothers were exposed to famine whilst in the womb, i.e. when their eggs were forming, were found on average to have a shorter lifespan.

Epigenetic changes are usually considered to apply to the genome within the lifetime of the organism but the Ӧverkalix study demonstrated that changes occurring in a sperm or egg which is then fertilized can have a transgenerational effect.  In other words, environmental effects on the epigenome are potential evolutionary drivers.

Epigenetics also excites a great deal of interest from a clinical point of view.  A great many cancers are found to be associated with both aberrant DNA methylation patterns and a histone deviant called H2AZ.  These abnormalities cause disactivation of certain genes which could provide vital clues to the mechanisms of malignancies and their possible treatment.

  

The National Institute of Health in the USA allocated $190m to epigenetics research between 2008 and 2013, recognizing its potential to explain the molecular processes behind human development and many important human diseases.    This investment is bearing fruit with a recent announcement that variations associated with several common diseases have been found in non-coding regions of DNA.  88% of these regions are responsible for regulating genes during foetal development and are known to be susceptible to environmental exposures.   In other words, environmental factors experienced in utero produce epigenetic changes which can manifest decades later as adult onset diseases (Maurano, M.T. et al, (2012)).

There is still much to discover in this advancing field but between the potential for a whole new regime of therapies and the possibility of an explanation of the interaction between nature and nurture there is also much to be excited about.