The. Magazine of the Biochemical Society. Vol. 40 No. 5 October The Brain

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1 The Biochemist Magazine of the Biochemical Society Vol. 40 No. 5 October 2018 The Brain

2 YOUR SCIENCE YOUR PUBLISHER A home for every paper in the molecular biosciences and broader life sciences Biochemical Journal Exploring molecular mechanisms that underpin biological processes Clinical Science Linking basic science to disease mechanisms Bioscience Reports A home for sound scientific research in all areas of cell biology and molecular life sciences Essays in Biochemistry Reviews from experts in the field highlighting recent hot topics in biochemistry PUBLISH YOUR PAPER IN ONE OF OUR JOURNALS Biochemical Society Transactions The reviews journal of the Biochemical Society Neuronal Signaling Covering all aspects of signaling within and between neurons Emerging Topics in Life Sciences Interdisciplinary themed issues, a review article journal, guest edited by experts in the field PortlandPressPublishing = Fully Open Access 08/18

3 The Biochemist Vol. 40 No.5 Contents The Brain MEK Editorial 3 Regulars ERK Nucleus CREB CRE Control RNA Trained RNA + RG h 24 h 24 h Protein sy Unsensitized (Reflex not prolonged) Unsensitized Features The (mis)remembrance of things past: 4 mechanisms of memory storage, updating and why we misremember An exploration of how are memories stored in the brain, and how it can be that what we remember is not necessarily what actually happened. Amy Milton Exploring neurodegeneration at the 9 atomic level How does the mis-folding of the microtubule-associated Tau proteins contribute to neurodegeneration? Adam Tozer Regulation of memory storage through 12 epigenetic alterations: a new role for RNA A look at the newly discovered role of small non-coding RNAs (ncrnas) as potential master regulators of learning-induced epigenesis, neuronal plasticity and, ultimately, memory. Alexis Bédécarrats and David L. Glanzman Santiago Ramón y Cajal, the ultimate 16 scientist? Winner of the Nobel Prize for Physiology or Medicine in 1906, Santiago Ramón y Cajal s work help to lay the foundations for modern neuroscience. This article looks back at his life and legacy. Salvador Macip Careers A day in the life of a science technician 18 Sebastian Punter Lifelong Learning Evidencing your lifelong learning with e-portfolio 22 David Smith Science Communication Competition A life without microbes: How germ-free research 26 is revealing the necessity of bacteria for our brains Jenna Herbert Policy Matters Shining a spotlight on immigration 30 Emma Sykes News Events and Meeting Reports 32 Introducing the Chair of the Basic Bioscience Theme Panel 34 CEO Viewpoint 37 Book reviews 38 Cartoon 39 Prize Crossword Coming up in Science and Space October 2018 Biochemical Society 1

4 ADVERT SPACE A BIOCHEMICAL SOCIETY SCIENTIFIC MEETING Redox Signalling in Physiology, Ageing and Disease 1 3 July 2019 Newcastle, UK Find out more at bit.ly/redox-signalling

5 Editorial For advertising and inserts contact: Marketing Department Biochemical Society Charles Darwin House 12 Roger Street London WC1N 2JU tel.: +44 (0) ; fax: +44 (0) Production by Portland Press Limited Editorial team: Anastasia Stefanidou, Emma Pettengale and Clare Curtis Design by Peter Jones Printed by Cambrian Printers Ltd, Aberystwyth Published by Portland Press Limited six times a year (February, April, June, October, October and December). The Biochemist 2018 Biochemical Society ISSN X (Print); ISSN (Online) Charles Darwin House 12 Roger Street London WC1N 2JU tel.: website: Registered charity no Subscriptions Science Editor: Chris Willmott (University of Leicester, UK) Editorial Board: David Pye, Shane Hegarty, Harriet Groom, Matthew Lloyd, Patrick Walter and Heather Doran. The Editors are pleased to consider items submitted by Society members for publication. Opinions expressed in signed articles are not necessarily those of the Society. US agent: Air Business Ltd, c/o Worldnet Shipping Inc., , 146th Avenue, 2nd Floor, Jamaica, NY 11431, USA Periodicals postage paid at Jamaica, NY11431,USA. Postmaster: address corrections to The Biochemist, Air Business Ltd, c/o Worldnet Shipping Inc., , 146th Avenue, 2nd Floor, Jamaica, NY 11431, USA For all features: 2018 The Author(s) This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND). Find us on Facebook at Biochemical Society Follow us on The field of neuroethics by Chris Willmott, Science Editor For many readers of The Biochemist, it will have been curiosity about the inner workings of the body, and what goes wrong in states of disease, that triggered their journey into studying molecular biology. No organ of the body is more important than the epicentre of that very curiosity, the brain. Through a variety of approaches, we are building understanding of the functioning of both the healthy and the diseased brain. These discoveries raise a plethora of ethical questions, and represent one dimension in the burgeoning field of Neuroethics. As far back as 2002, philosopher Adina Roskies noted that Neuroethics encompassed both the ethics of neuroscience and the neuroscience of ethics. Even sticking, in the present context, to ethical issues associated with biochemistry, there are plenty of examples where dilemmas are raised. If someone s aggression is linked to possessing the wrong Monoamine A oxidase gene and, in consequence, they are less efficient at breaking down neurotransmitters, can they be held less culpable for criminal behaviour than someone with the more restrained allele? As we start to understand more about the molecular changes (e.g. epigenetics) underlying the influence of environmental factors on behaviour, can it be acceptable to artificially mimic those changes in order to achieve the same (or a different) outcome? Is there an ethical difference between providing Ritalin to a boy with attention deficit, in order to move their concentration more into the normal range, and offering the same drug to a university student hoping to avoid distraction in the run-up to an exam? Is it morally acceptable to conduct brain-based research on model organisms, when the relevance of that research become more applicable to human health as the animal studied get closer in mental capacity to humans? If, as an alternative, we use human brain tissue organoids in research, is there a point in their development when they are too human to use in this way? And would transplanting human brain organoids into rodent models be an acceptable alternative to research on primates? Features in the present issue touch on some of these dilemmas. Does understanding of the malleability of memory offer the potential to treat post-traumatic stress disorder, or to overcome phobias? Does emerging knowledge of the role of small non-coding RNAs in mediation of long-term memory allow for similar exploitation? Does structural information about Tau proteins offer promise in tackling dementia of various forms? And, in a slightly different way, what role did ethics play in the rivalry between Santiago Ramón y Cajal and Camillo Golgi? There are also fascinating ethical implications in the work of Adrian Owen, described in the review of his memoir Into The Grey Zone. October 2018 Biochemical Society 3

6 The Brain The (mis)remembrance of things past: mechanisms of memory storage, updating and why we misremember Amy Milton (University of Cambridge, UK) Memory is a critical function of the brain; we treasure many of our memories, and it is widely believed that our past experiences make us who we are. However, decades of psychological research has revealed that we are prone to having misinformation introduced into our memories, and a recent study has suggested that many people s first memories are not actually real, but reconstructions based upon family stories and old photographs. So, how are memories stored in the brain, and how can it be that what we remember is not necessarily what actually happened? Memory is a fascinating function of the brain, and one that has united psychologists, neuroscientists, physiologists and biochemists in trying to understand its underlying mechanisms. Memory can be studied at many levels, with the unifying view that memories are stored as traces or engrams within the brain following activation of specific networks of brain cells (neurons) during an experience. There are various types of memories, from memories of events that we can pass on in words, to learned emotional responses (e.g. fear) that we have to particular environmental cues (e.g. spiders). These memories upon different brain structures, and all depend upon the formation of engrams. Over the past 50 years, our understanding of the mechanisms underlying memory has advanced markedly. It is recognized that biochemical changes occur at the level of individual neurons, increasing their signalling efficacy with other neurons within the memory trace. This view has traditionally emphasized the stability of memory. However, more recent work has revealed how we can balance stability and flexibility, allowing memories to be updated with new information. Memories, it seems, can be modified, allowing updating, but also inaccuracies to be introduced (while also providing an opportunity for developing new memory-based treatments for mental health disorders). Memories are made of this: the synaptic plasticity and memory hypothesis The search for the engram began in the 1900s with physiologists such as Richard Semon and Karl Lashley attempting to find memory traces in the brain. The notion of the engram entered mainstream memory research in 1949, when Donald Hebb proposed his theoretical mechanism of how learning could occur in the brain in his book, The Organization of Behavior. Now known as Hebb s rule, this encapsulates memory under the slogan neurons that fire together, wire together. However, it was another 20 years before any evidence emerged to support Hebb s hypothesis. Tim Bliss and Terje Lømo, working in the lab of Per Andersen at the University of Oslo, were investigating the effects of electrical stimulation of a specific brain structure, the hippocampus, in anaesthetized rabbits. What they discovered, and published in their seminal 1973 paper, was a process that they termed long-term potentiation (LTP). This physiological process produced a long-lasting change in the efficiency of signalling between neurons in a network following a strong electrical stimulation. Further research revealed that LTP had properties that were consistent with associative learning: it required a level of stimulation beyond what is required for normal synaptic transmission (i.e. plasticity was cooperative ). LTP only worked when the two neurons involved were active 4 October The Authors

7 The Brain (Release of Mg 2+ block) Neuronal membrane GPCRs NMDAR AMPAR AC Ca 2+ /CaM camp PKC Ras/Raf-1 CaMKII CaMKIV PKA MEK Rap1 B-Raf ERK Nucleus CREB Protein synthesis CRE Figure 1. Simplified schematic of the post-synaptic molecular mechanisms underlying long-term potentiation and memory consolidation. The NMDA subtype of glutamate receptor is constitutively blocked by a magnesium ion, which is released when the post-synaptic neuron is sufficiently depolarized (e.g. by activation of the AMPA subtype of glutamate receptor, which is permeable to Na + ). Thus, the NMDA receptor is double-gated, requiring both post-synaptic depolarization and glutamate binding to allow Ca 2+ into the cell. This calcium influx initiates a signalling cascade that ultimately results in the synthesis of new proteins to stabilize structural changes that support the functional changes in signalling efficiency. Abbreviations: AC, adenylyl cyclase; CaM, calmodulin; CaMK, calcium-calmodulin-dependent protein kinase; camp, cyclic adenosine monophosphate; CRE, camp response element; CREB, camp response element binding protein; ERK, extracellular signal-regulated kinase; GPCRs, G-protein coupled receptors; MEK, mitogen-activated protein kinase kinase; PKA, protein kinase A. within a brief time window (i.e. it was both associative, and input specific). These properties mapped well with the properties of associative learning, and led Bliss and Lømo to tentatively speculate that they may have found the mechanism by which Hebb s rule worked in the brain. From 1973, the numbers of papers on LTP, particularly attempting to relate LTP to the process of memory consolidation, increased markedly. Decades of work by scientists prominent in the field James McGaugh, Eric Kandel, Richard Morris, Graham Collingridge, to name but a few has shown that both LTP and memory consolidation depend on a set of shared synaptic plasticity mechanisms (Figure 1). These involve the NMDA subtype of postsynaptic ionotropic glutamate receptor, the entry of calcium into the postsynaptic neuron, activation of protein October The Authors 5

8 The Brain kinases and ultimately the activation of gene transcription and protein synthesis to stabilize the structural changes that underlie the functional change in synaptic signalling efficacy. The synaptic plasticity and memory (SPM) hypothesis gained huge momentum in neuroscience, and focused on addressing whether changes in synaptic plasticity could be observed when an animal had undergone a learning experience (they can) and whether manipulating synaptic plasticity blocking or overwriting it could interfere with memory consolidation (it does). This was originally addressed through pharmacological studies, but more recent work from the labs of Susumu Tonegawa, Sheena Josselyn and Paul Frankland have begun to directly visualize and selectively manipulate the neurons that make up the memory trace. However, it is only recently that the strongest test of the SPM hypothesis has begun to be addressed experimentally. If our understanding of the molecular mechanisms of memory is correct, then it should be possible, according to the SPM view, to implant a memory by directly manipulating synaptic plasticity in the brain. Tim Bliss refers to this memory mimicry as his Marilyn Monroe criterion, in light of the fact that he would like to have an implanted memory of having had dinner with the actress. Experimentally, we are not quite there yet, but the recent advances in optogenetic technology have made this criterion more addressable. In mice, it is possible to implant a false memory of an aversive event occurring in a particular context. In 2013, the Tonegawa lab selectively labelled neurons involved in encoding the memory of one context (A) with a fluorescent marker and the lightsensitive channel Channelrhodopsin 2 (ChR2). They later exposed the mice to the aversive event of receiving a mild electric footshock in a distinct context (B), while simultaneously stimulating the labelled neurons with blue light. They found that when the mice were later tested, they showed fear to context A, even though they had never experienced an aversive event in that context essentially, they had artificially linked the memory of context A with the shock, and the mice behaved as if they really had experienced an aversive event in that environment. Therefore, even the strongest test of the SPM hypothesis is experimentally supported. Memory appears to be based on long-term changes in synaptic plasticity occurring between networks of neurons that form the engram. Keeping it real(?): the reconsolidation hypothesis The emphasis of memory research in neuroscience, however, presents a problem; if memories are based on long-term, stable changes in synaptic plasticity, then how can we account for the psychological findings suggesting that memories are often inaccurate, and prone to the introduction of misinformation? Psychologists have traditionally placed emphasis on the dynamic nature of memory, rather than the stability of the engram emphasized by neuroscientists. How to resolve these two different points of view? Even as far back as the 1960s, there had been indications from the neuroscience literature that the view emphasizing memory stability may not be completely accurate. In 1968, two articles published in Science suggested that even old, well-established memories become malleable under certain conditions of retrieval. However, the failure of prominent memory researchers to replicate these findings, and the lack of a molecular mechanism to account for the behavioural findings, made cue-dependent amnesia relatively easy to dismiss. For 30 years, the field instead focused, with great productivity and success, on characterizing the molecular mechanisms of LTP and memory consolidation. However, in 2000, evidence emerged that made the cue-dependent amnesia findings harder to ignore. Karim Nader, working in the lab of Joseph LeDoux, showed that a fully consolidated fear memory could, under the right conditions of retrieval, return to a state where it was sensitive to manipulation with an amnestic agent. Nader s account was clearer than the original papers. He tested the memory of pavlovian fear conditioning, which was well-characterized psychologically and in terms of the underlying brain circuitry. Nader targeted a brain structure, the amygdala, known to be critical for the storage of the pavlovian fear memory trace, and induced amnesia using a protein synthesis inhibitor, which had a recognized mechanism of action and could be related to synaptic plasticity changes. The cue-dependent amnesia research was therefore rediscovered, reinvigorated, and renamed as memory reconsolidation. The reconsolidation view has similarities to the original consolidation view of memory, but with some important differences (Figure 2) that allow memory to be seen as much more dynamic and flexible than the traditional view. The key difference is that, rather than considering a memory as existing in a short-term or longterm store, it should be considered in terms of its activity state. Memories in the active state are transient and highly malleable much like the traditional view of shortterm memory, whereas memories in the inactive state are more stable and persistent, similar to the traditional view of long-term memory. The critical difference in the reconsolidation view is that memories do not simply move from a short-term to long-term memory store, but instead can cycle between active and inactive states throughout their lifespans. Under certain conditions of retrieval and it is not necessarily the case that every retrieval event converts an inactive memory to the malleable active state memories are destabilized and returned to a state 6 October The Authors

9 The Brain Reconsolidation / restabilisation Memory in active state Reactivation / destabilisation Memory in inactive state Figure 2. Schematic of the reconsolidation hypothesis. Rather than defining memories as being in short-term or long-term memory stores, it is more accurate to characterize them as being in a malleable, unstable active state, or a more stable and persistent inactive state. According to the reconsolidation hypothesis, memories can move from the inactive to the active state under certain conditions of retrieval (likely involving a violation of expectations) and consequently reconsolidate (or, more mechanistically, restabilize) back to the inactive state in the updated form in which they can become updated. This capacity for updating also makes the memory vulnerable; similar to when you are drafting an and the computer crashes before it is sent. The ability to edit and redraft is highly adaptive, but under specific (unfortunate) conditions it would be possible to lose what was written. Reconsolidation: not just a rerun of consolidation Although initially met with some scepticism, over the past two decades the reconsolidation hypothesis has become increasingly accepted by the field. Reconsolidation has been observed by multiple labs, investigating different types of memory, in species ranging from crabs to humans. The research has tended to focus in two different, though related, directions: one basic line of research has been attempting to characterize the molecular mechanisms of reconsolidation, and comparing them to consolidation, while the other, more applied, line of research has been attempting to determine whether reconsolidation could be exploited to treat mental health disorders such as posttraumatic stress disorder and drug addiction. The processes by which a memory reconsolidates (or, more mechanistically, restabilizes) are similar to those that underlie initial memory consolidation (Figure 1). Reconsolidation depends upon activity at NMDA receptors, the activation of protein kinases, and the recruitment of transcription factors to initiate protein synthesis in the same way as consolidation, although there do appear to be differences in the pathways underlying the two processes. (For example, while the consolidation but not reconsolidation of a contextual fear memory depends upon the protein BDNF, reconsolidation but not consolidation of the same memory depends upon the protein Zif268.) The processes differ more with respect to the mechanisms underlying the conversion of the memory from the inactive to the active state; destabilization, which is specific to reconsolidation (Figure 2). This appears to require protein degradation through the proteasome system, possibly depending upon similar mechanisms to processes underlying synaptic weakening. At the cellsurface level, destabilization appears to be activated by particular receptors, many of which modulate intracellular signalling either through specific patterns of calcium activation (L-type voltage-gated calcium channels and NMDA receptors containing the GluN2B subunit) or by activating intracellular second messengers. One question of intense interest has been the requirement for the neurotransmitter dopamine; release of this neurotransmitter has previously been shown to correlate with situations in which there is a violation of expectations, or prediction error. Intuitively, it would October The Authors 7

10 The Brain make sense that memories would enter a state in which they could be updated in situations where an individual experiences surprise; using the memory produces a prediction that is incorrect. This would indicate that the memory was not fully accurate, and needs to be updated. This view has been supported with behavioural evidence from crabs, rats and humans memories update when there is new information to be incorporated and research is ongoing to determine how dopaminergic signalling relates to this. Exploiting reconsolidation to treat mental health disorders As noted above, a major implication of the reconsolidation view is that even old, fully consolidated memories can return to an unstable and malleable state under the right conditions. This has a potential impact in the development of new therapies for mental health disorders such as post-traumatic stress disorder (PTSD), phobia, and even drug addiction. In these disorders, emotional memories associating environmental cues (e.g. spiders, syringes) with motivationally relevant outcomes (e.g. fear, a drug high) become maladaptive and come to dominate behaviour. For example, a patient with a severe spider phobia may refuse to leave the house in case they encounter a spider. These memories are usually old and well-established before a patient presents in the clinic looking for treatment, so the possibility of inducing the maladaptive memory into an unstable state in which it can be disrupted pharmacologically (as has been done by the lab of Merel Kindt) or interfered with by the use of specific cognitive tasks (such as the computer game Tetris, in the lab of Emily Holmes) is very promising for new treatment development. The more the understanding of the basic mechanisms develops, the more refined these treatments will become. recent and relevant information. As Daniel Schacter noted when considering his 7 sins of memory, it is important to appreciate that the function of memory is not to look back, but forward; in evolutionary terms, our memories need only to be accurate enough to know how we should behave the next time we are in a similar situation, not to recall with perfect accuracy what happened in the past. Further reading Akhtar, S., Justice, L.V., Morrison, C.M. and Conway, M.A. (2018) Fictional first memories. Psychological Sci (in press), doi: / Fenno, L., Yizhar, O. and Deisseroth, K. (2011) The development and application of optogenetics. Ann Rev Neurosci 34, Josselyn, S.A., Köhler, S. and Frankland, P.W. (2015) Finding the engram. Nat Rev Neurosci 16, Loftus, E.F. (2017) Eavesdropping on memory. Ann Rev Psychol 68, 1 18 Martin, S.J. and Morris, R.G.M. (2002) New life in an old idea: the synaptic plasticity and memory hypothesis revisited. Hippocampus 12, Milton, A.L. and Everitt, B.J. (2010) The psychological and neurochemical mechanisms of drug memory reconsolidation: implications for the treatment of addiction. Eur J Neurosci 31, Nicoll, R.A. (2017) A brief history of long-term potentiation. Neuron 93, Ramirez, S., Liu, X., Suh, J., Pignatelli, M., Redondo, R.L., Ryan, T.J. and Tonegawa, S. (2013) Creating a false memory in the hippocampus. Science 341, Schacter, D.L. (1999) The seven sins of memory: insights from psychology and cognitive neuroscience. Am Psychol 54, Tronson, N.C. and Taylor, J.R. (2007) Molecular mechanisms of memory reconsolidation. Nat Rev Neurosci 8, Visser, R.M., Lau-Zhu, A., Henson, R.N. and Holmes, E.A. (2018) Multiple memory systems, multiple time points: how science can inform treatment to control the expression of unwanted emotional memories. Phil Trans R Soc B 373, Final thoughts on memory: looking forward, not back Although the capacity to update gives us a dynamic and flexible memory system, the downside is that this allows for misinformation to be introduced into memories. Studies in psychology, including the seminal work of Elizabeth Loftus, has made it clear that memories are not 100% accurate, and that information presented after an event for example, through the use of misleading questions can affect the way in which an event is remembered. This may seem like a major evolutionary disadvantage, but in reality it is a relatively small price to pay for a memory system that can update with more Amy Milton is a Lecturer in Experimental Psychology at the University of Cambridge, and the Ferreras-Willetts Fellow in Neuroscience at Downing College, Cambridge. Her research interests focus on the neurochemical and molecular mechanisms of memory reconsolidation, and the application of reconsolidation-based interventions to mental health disorders including post-traumatic stress disorder, drug addiction and obsessive-compulsive disorder. 8 October The Authors

11 The Brain Exploring neurodegeneration at the atomic level Adam Tozer (Content and Communications Manager, MCI-Neuroscience, UK) Tau proteins are microtubule-associated proteins essential for the correct functioning of neurons. This small family of proteins, amino acids in length, are abundant in the brain and exist to stabilize microtubules in neurons and glia (non-neuronal cells of the central nervous system) to ensure correct trafficking of cellular cargo and cell maintenance. However, they have a dark side. When Tau isoforms become hyperphosphorylated they misfold and aggregate, forming fibrillary tangles that build up within cells, rupturing membranes and killing the host cells, before being taken up by surrounding cells to induce further Tau misfolding. Prion-like spread The self-repeating amplification of misfolded Tau seeding further misfolding in other Tau proteins leads to propagation of disease across the brain. Similarities to the spread of prion diseases, such as Creutzfeldt- Jakob Disease (CJD), means Tau is considered to be prion-like. The implication of misfolded Tau in the pathology of several diseases, including Alzheimer s disease, has led to the grouping of these diseases into a family of Tauopathies (Box 1). The pathologies of these Tauopathies is distinct for each disease and characteristic of the isoform of Tau that has gone rogue and misfolded. Box 1. The Tauopathies The Tauopathies Alzheimer s disease Tangle-only dementia Chronic traumatic encephalopathy Argyrophilic grain disease Progressive supranuclear palsy Corticobasal degeneration Globular glial tauopathy Pick s disease There are six isoforms of the Tau protein, generated by alternative splicing of mrna transcripts from the MAPT gene, and distinguished by the number of repeats of the microtubule binding domain motif within their structure. Some have three repeats (3R Tau) comprising R1, R3 and R4, and others four repeats (4R Tau) comprising R1, R2, R3 and R4. Academic scientists and Pharma companies have spent years trying to destabilize Tau aggregates in in vitro assays and disease models, in an attempt to develop treatments or better diagnostic tools for these Tauopathies. To date, these efforts have been unsuccessful, hampered by a lack of structural information about the Tau filaments. That is not to say they haven t had blueprints to work with; in the late 1980s and early 1990s seminal papers were published describing the structure of the misfolded Tau that underlies Alzheimer s disease. A negative staining approach was used, but unfortunately the resolution needed to model the protein in threedimensions, at a resolution below 20 Angstroms was not achievable at that time (for structural biology, the lower the number of Angstroms, the better). Seeing Tau at the atomic level In 2017, a collaboration between scientists at the MRC s Laboratory of Molecular Biology (LMB) in Cambridge UK, spearheaded by group leaders Dr Michel Goedert and Dr Sjors Scheres solved the three-dimensional atomic structure of the human Tau filaments that causes Alzheimer s disease at the atomic level, using cryo-electron microscopy (Cryo-EM). October The Authors 9

12 The Brain Cryo-EM involves suspending thin layers of purified Tau protein on a carbon grid, which is rapidly frozen in liquid ethene. The rapid freezing prevents the formation of ice crystals. The frozen grid is then imaged on a transmission electron microscope. Electrons shoot through the layer of purified Tau protein molecules in their suspended animation, onto the sensors behind. The resulting image is similar to that of an untuned television screen, as information about the immobilized Tau molecules is captured by the electron microscope. This snowy data set of thousands of molecules in their random positions in space is then analyzed and reconstructed into a three-dimensional configuration using a statistical program, such as RELION. Reconstruction of the Alzheimer s disease-causing Tau filaments at the atomic level (3.4 Angstroms) revealed the filaments were made of an almost 50/50 mixture of 3R and 4R Tau isoforms, contributing to a C -like folded conformation. Different Tau, different disease In a more recent paper, the group tested their hypothesis that different Tau isoforms induce different filamentous structures. They isolated and visualized Tau proteins from a human patient who had died from a different Tauopathy, Pick s disease. Pick s disease or frontotemporal dementia (FTD) is a relatively rare form of dementia, diagnosed in less than one in twenty cases. The neuronal degeneration takes place almost exclusively in the frontal and temporal lobes of the brain, robbing the sufferer of their personality and language ability. Using the same Cryo-EM approach as in the previous study, the group reconstructed the Pick s disease Tau at almost 3.2 Angstroms resolution, and were astonished to see the difference in the conformation compared with the misfolded Tau in Alzheimer s disease. Where the Alzheimer s disease filaments had comprised 3R and 4R Tau isoforms and had a C shape fold, the Pick s disease Tau was made up exclusively of 3R Tau and the filaments had a long J shape fold (Figure 1). They also discovered there are two types of filaments, narrow and wide, and they are helical in nature. Narrow filaments were more abundant than their wide counterparts and so they were able to delve deeper into their structure. They identified the 3R Tau structure contained nine ß-strand regions compared with the 8 ß-strand regions in 4R Alzheimer s disease Tau. These biophysical differences, coupled with other changes, contributed to its unique conformation. The question of what causes Tau isoforms to obtain their toxic gain-of-function remains unresolved. However, these recent findings provide the most detailed pictures to date of the structure of the Tau isoforms underlying two important Tauopathies. It is hoped this new structural insight will enable better understanding of the processes involved. Seeding disease Since the Pick s disease Tau structure was determined using protein isolated from a single patient, the group wanted to investigate the generality of the Pick s disease Figure 1. In Pick s disease (left), Tau molecules adopt a long J-shaped fold, while in Alzheimer s disease (right) they form a C that contains fewer domains. Reproduced with permission from Falcon, B. et al. (2018) Nature 561, October The Authors

13 The Brain fold. Obtaining Tau extracted from the brains of eight additional patients, they performed Western blot analysis using repeat specific antibodies. They reasoned that if the Pick s disease Tau filaments were exclusively comprised of 3R Tau, the proteins from these patients ought to be immune-negative to an antibody specific for R2, the domain excluded from the 3R isoform (but present in 4R Tau), whilst maintaining positive immunoreactivity for the other binding motifs. They found this to hold true for the Tau proteins obtained from the eight other patients. The road to better diagnosis It is too early to assume that knowledge of the structures of these disease-causing Tau proteins at the atomic level will allow drug companies to produce cures for the diseases in the near future. However, better tools for diagnosis may be a realistic proposition. By understanding the conformation of these Tau filaments, it may be possible to design Positron Emission Tomography (PET) ligands that can bind to either of the conformations and show up in a PET scan, enabling a confirmatory diagnosis. In the meantime, the LMB team will continue to apply their approach to illuminate the structural differences of misfolded Tau in the remaining Tauopathies. Further reading Goedert, M., Eisenberg, D.S., & Crowther, R.A. (2017) Propagation of Tau aggregates and neurodegeneration. Ann Rev Neurosci 40, Crowther, R.A. (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci 88, Fitzpatrick, A.W., Falcon, B., He, S., Murzin, A.G., Murshudov, G., Garringer, H.J. et al. (2017) Cryo-EM structures of Tau filaments from Alzheimer s disease. Nature 547, 185 Scheres, S.H. (2012) RELION: implementation of a Bayesian approach to cryo-em structure determination. J Struct Biol 180, Falcon, B., Zhang, W., Murzin, A.G., Murshudov, G., Garringer, H.J., Vidal, R. et al. (2018) Structures of filaments from Pick s disease reveal a novel Tau protein fold. Nature 561, Adam gained his PhD in Neuroscience from the University of Leicester in 2012 before working as a postdoctoral neuroscientist at the University of Cambridge, the MRC s Laboratory of Molecular Biology and the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, UCL. In 2017 he transitioned into science writing and communication. You can find him on Instagram and October The Authors 11

14 The Brain Regulation of memory storage through epigenetic alterations: a new role for RNA Alexis Bédécarrats and David L. Glanzman (University of California Los Angeles, USA) A fundamental assumption in modern psychology and neuroscience is that memory is stored as physical changes in the brain. More than a century ago, the famous neuroanatomist Ramón Y Cajal (see the article entitled Santiago Ramón y Cajal, the ultimate scientist? in this issue of The Biochemist) postulated that changes in the strength of synaptic connections between neurons were the physical substrate for memory. Extensive experimental evidence has since established the dominance of this connectionist view, referred to as the synaptic plasticity model. However, although the synaptic plasticity model broadly accords with the results of neurobiological studies of learning and memory, it does not fully account for the extraordinary resilience of memory despite the significant loss of synapses during such phenomena as development, trauma and ageing. Here, we will focus on the newly discovered role of small non-coding RNAs (ncrnas) as potential master regulators of learning-induced epigenesis, neuronal plasticity and, ultimately, memory. In support of this idea, recent data from our lab indicate that RNA can promote the transfer of long-term memory from a trained to an untrained (naïve) animal. The memory transfer experiments The idea that RNA can mediate the biophysical neuronal changes associated with memory is not new. In the early 1960s, Swedish biologist Holger Hydén was perhaps the first to theorize that RNA is involved in learning and memory. Hydén s visionary hypothesis found support from one of the most controversial observations made in the history of experimental psychology. In a set of experiments that would later become infamous, James McConnell and colleagues reported that they were able to induce a form of associative learning, known as Pavlovian or classical conditioning, in planarians, a type of flatworm. In this type of learning, the animal receives training in which delivery of an initially neutral stimulus, referred to as the conditioned stimulus or CS, is paired with a stimulus that produces an innate response in an animal; the latter stimulus is known as the unconditioned stimulus or US. After successful training, the CS alone will evoke a response in the animal that resembles that originally induced by the US; this post-training CS-induced response is referred to as the conditioned response or CR. As described by McConnell in a paper published in 1962, worms received training in which a flash of light, the CS, was paired with an electric shock, the US. After several bouts of training, the worms exhibited a CR either turning or contraction when exposed just to the light. (Control groups of worms received stimulation with either the light or the shock alone; according to McConnell, these worms did not exhibit the CR.) Then, taking advantage of planarians extraordinary capacity for regeneration, McConnell and his team addressed the issue of whether memory could exist outside of the brain. When individual worms that had been classically conditioned were cut into two halves the tail and head both halves were able to regenerate the missing part. Impressively, the two types of regenerated worms, both those from head fragments and those from tail fragments, exhibited a conditioned behavioural response when exposed to the light alone. An even more remarkable experimental result followed. In a subsequent set of experiments, the researchers cut trained worms into small 12 October The Authors

15 The Brain pieces and fed the pieces to naïve worms (planarians are cannibalistic.) The naïve worms that had been fed trained worms subsequently expressed greater numbers of the conditioned responses to the light CS than did naïve worms that had consumed pieces of untrained worms. These results indicated that memory could be transferred from trained to naïve worms through cannibalism. Training of donors and RNA extraction Tail shocks 24 h Sensitized (Reflex prolonged) Siphon touch Trained RNA McConnell s research attracted a great deal of public attention, as well as significant funding from governmental agencies. Numerous laboratories attempted to replicate the phenomenon of memory transfer, not only in planarians, but also in fish and rats. In line with Hyden s hypothesis, RNA was believed to be the agent of memory transfer; indeed, several research teams reported successful memory transfer via injection of RNA extracted from trained animals. Unfortunately for McConnell and other proponents of memory transfer, and perhaps, in retrospect, for the field of learning and memory in general, the results of these experiments could not be consistently reproduced. Because of the controversial nature of McConnell s claim, as well as the absence of a concrete molecular basis for memory transfer, research into this phenomenon sank into oblivion. RNA transfer to naive recipients Trained RNA Control RNA 24 h 24 h Sensitized Unsensitized (Reflex not prolonged) Molecular bases of long-term memory Trained RNA + RG h Unsensitized It is now widely accepted that long-term memory memory lasting more than 24 h requires gene expression and the synthesis of new proteins; the gene products serve to maintain persistent alterations in synaptic strength and neuronal excitability. DNA, the molecular template for the synthesis of proteins, is present in every cell type. In neurons, transcription factors which control the conversion of DNA into RNA such as CREB1 and CREB2, trigger or repress the expression of genes required for long-term memory. Eric Kandel, who played a major role in establishing the memory-related functions of these transcription factors in studies of the mollusc Aplysia, a large sea slug, won the Nobel Prize in Physiology or Medicine in In more recent years, a handful of laboratories have investigated the role of epigenetic processes, which alter the three-dimensional structure of the DNA, in learning and memory. In particular, DNA methylation the stable addition of a CH3 group to a cytosine base has attracted significant attention. When DNA is methylated in promoter regions, the transcription and production of proteins is disrupted. If this process prevents the production of proteins that act as transcriptional repressors, such as CREB2, then the transcription and translation of memory-promoting proteins, such as the transcription factor CREB1, which would otherwise be inhibited by CREB2, is favoured; this is believed Figure 1. RNA extracted from sensitized Aplysia induces sensitization-like behavioral enhancement in untrained animals. Whole RNA was extracted from the central nervous system (CNS) of donor animals 24 h after training with electrical shocks delivered to the tail. The training induced long-term sensitization of the siphon withdrawal reflex, as indicated by the prolongation of the reflex in response to a weak touch of the siphon. RNA was also extracted from the CNS of control (untrained) donor animals (not shown). RNA extracted from trained donors (trained RNA) or from untrained donors (untrained RNA) was injected into naïve recipient animals. The trained RNA produced prolongation of the reflex in recipients 24 h later, whereas the untrained RNA did not. Untrained recipients that received simultaneous injections of trained RNA and a DNA methyl transferase inhibitor, RG-108, did not exhibit sensitization when tested 24 h later. to facilitate the formation of a stable memory. DNA methyl transferase, the enzyme responsible for DNA methylation, is partly regulated by the presence of small ncrnas. The relationship between DNA methylation and small ncrnas is imperfectly understood. It appears, however, that a subclass of small ncrnas, known as piwi-interacting RNAs or pirnas, directly interacts with the DNA methyl transferase responsible for the addition of a methyl group to the CREB2 promotor. October The Authors 13

16 The Brain Figure 2. Model for RNA-induced memory in Aplysia. (A) Learning induces serotonin release within the nervous system; serotonin triggers an intracellular molecular cascade involving RNA and protein synthesis that regulates the methylation status of DNA (arrows indicate bi-directional regulations). (B) Among the RNAs synthetized during learning are non-coding RNAs that indirectly regulate the methylation of DNA through the enzyme DNA methyl transferase (DNMT). This methylation silences the transcription of memory repressors (for example, CREB2) thereby promoting the production of a second wave of proteins essential for neuronal plasticity and longterm memory formation. RNA regulates long-term memory through DNA methylation Can a memory truly be transferred via RNA? That is the question we addressed in experiments reported in a recent article published in eneuro. To attempt a modern demonstration of RNA-induced memory transfer we used Aplysia for the following reasons. (1) Aplysia exhibits a robust and easily quantifiable defensive response to possibly threatening stimuli withdrawal of the gill and siphon. When lightly touched, these external organs, which are critical for respiration, retract; the gill retracts beneath the mantle, a flap-like extension of the body wall, and the siphon retracts into the body cavity that contains the mantle and gill. (2) The duration and intensity of this behaviour can be decreased or increased for long periods of time ( 24 h) as a consequence of different forms of learning. (3) The neural circuit responsible for this reflex is largely known, both with respect to the individual neurons within the circuit and to the synaptic connections among them. (4) The molecular pathways involved in learning and memory in Aplysia are to a great extent analogous to those involved in learning and memory in vertebrates. To induce the expression of the RNA(s) critical for memory, we first trained a group of animals using a procedure that induces long-term sensitization of the defensive withdrawal response. Here, mild electrical shocks were repeatedly delivered to the tail of the animals in a spaced training regimen. The training resulted in enhancement of siphon withdrawal 24 h later, as measured by the increased duration of the siphon s contraction in response to a light touch. Total RNA was extracted from the central nervous system of the trained donor snails, purified, and then injected directly into the hemolymph of a second group of naïve recipient animals whose siphon withdrawal was unsensitized. Twenty-four hours later the recipients exhibited an enhanced retraction of the siphon, as if they themselves had been subjected to long-term sensitization training. Animals in a second group of naïve recipients received an injection of RNA extracted from an untrained donor group of snails. The animals in this second group of recipients did not exhibit an enhanced reflex when tested 24 h after the injection, which supports the idea that the enhancement of withdrawal observed in the animals that received the RNA from the trained donors was not due to a non-specific effect of the injection. Critically, the RNA-induced long-term sensitization depends on DNA methylation, as shown by the lack of behavioural enhancement when an inhibitor of 14 October The Authors

17 The Brain the DNA methyl transferase, RG-108, was injected into the recipient snails simultaneously with the RNA from trained donor snails. This result lends further credence to the notion that sensitization memory had indeed been transferred by the injected RNA, because, as we had previously showed, tail-shock-induced long-term sensitization is also blocked by RG-108. The RNA from trained animals also produces some of the biophysical changes associated with long-term memory in Aplysia. We observed that, when treated with RNA from trained animals, sensory neurons that mediate the withdrawal reflex showed an increase in intrinsic excitability, similar to the increase observed in animals following training with tail shocks; by contrast, RNA from untrained animals did not induce increased excitability in sensory neurons. RNA alone therefore appears sufficient to induce critical molecular and cellular changes that represent the physical substrate of memory. Further reading Bédécarrats, A., Chen, S., Pearce, K., Cai, D. and Glanzman, D.L. (2018) RNA from trained Aplysia can induce an epigenetic engram for long-term sensitization in untrained Aplysia. eneuro 5, Blackiston, D.J., Shomrat, T. and Levin, M. (2015) The stability of memories during brain remodeling: a perspective. Commun Integr Biol 8, e Landry, C.D., Kandel, E.R. and Rajasethupathy, P. (2013) New mechanisms in memory storage: pirnas and epigenetics. Trends Neurosci. 36, Parrish, N.F. and Tomonaga, K. (2018) A viral (Arc)hive for metazoan memory. Cell 172, 8 10 Pearce, K., Cai, D., Roberts, A.C. and Glanzman, D.L. (2017) Role of protein synthesis and DNA methylation in the consolidation and maintenance of long-term memory in Aplysia. elife 6, e18299 Zovkic, I.B., Guzman-Karlsson, M.C. and Sweatt, J.D. (2013) Epigenetic regulation of memory formation and maintenance. Learn Mem 20, Which RNAs and how? The next step will be to identify which RNAs are responsible for producing these memory-related changes. RNA sequencing analyses performed by Eric Kandel and colleagues have identified hundreds of small ncrnas that regulate the function of the nervous system in Aplysia. Particularly interesting in the context of our results is a 28-nucleotide-sized class of pirnas. The expression of a subset of these pirnas was found by Kandel and his fellow researchers to be upregulated by serotonin, the neuromodulatory transmitter required for long-term sensitization in Aplysia. Furthermore, the pirnas were shown to facilitate the methylation of DNA in the promoter region of CREB2, thereby enhancing the induction of long-term memory. Alexis Bédécarrats obtained a PhD in Neuroscience from the University of Bordeaux under the direction of Romuald Nargeot at the Institut de Neuroscience Cognitives et intégratives d Aquitaine (INCIA). From 2016 to 2018 he investigated the epigenetic basis of learning and memory as a postdoctoral fellow in Glanzman s laboratory. Bédécarrats is currently a postdoc in the laboratory of Istvan Mody at UCLA, where he is carrying out neurophysiological investigations of abnormal, epileptiform neural activity in the mammalian brain. Besides identifying the exact species of RNA that are critical for the memory transfer effect we observed, it will be necessary to determine how the critical RNAs become integrated into the cellular machinery that drives the epigenetic and downstream biophysical changes responsible for long-term memory. The discovery that application of RNA to the nervous system induces long-term cellular changes that mediate memory in Aplysia suggests the potential involvement of an extracellular, RNA-mediated, signalling pathway in memory formation. Finally, the ability of RNA to directly activate molecular pathways that underlie memory opens a promising avenue for future treatments for learning-related disorders, such as dementia and post-traumatic stress disorder. David L. Glanzman obtained his PhD in Psychology from Stanford University. Afterwards, he did postdoctoral research with Franklin B. Krasne in the Department of Psychology at UCLA and, subsequently, with Eric R. Kandel at the Howard Hughes Medical Institute at Columbia University. He is currently a Professor in the Departments of Integrative Biology & Physiology, and Neurobiology, as well as a member of the Brain Research Institute, at UCLA. Photo credit: Josh Fogel. October The Authors 15

18 The Brain Santiago Ramón y Cajal, the ultimate scientist? Salvador Macip (University of Leicester, UK) The Nobel Prize in Physiology or Medicine for 1906 was shared by two scientists that set the basis for understanding how the brain works: Camillo Golgi and Santiago Ramón y Cajal were awarded the honour in recognition of their work on the structure of the nervous system. Yet, contrary to what usually happens in these situations, one of them was wrong and tried to sabotage the theories of the other one, refusing to admit his mistakes even when he gave his acceptance speech. How did Santiago Ramón y Cajal, a humble Spanish doctor, manage to upstage the legendary Italian pathologist and change forever the way we see the brain? Santiago Ramón y Cajal ( ) was a family man, a ground-breaking photographer, an artist, an accomplished writer, a hypnotist, an avid chess player and many other things but, above all, he was a scientist. Science was his job, his passion, his obsession and his refuge. When his daughter Enriqueta caught a serious fever, probably a meningeal tuberculosis, and the limited medical resources of the time were not enough to offer a cure, his wife Silveria stood guard by her bed all night, while Santiago escaped to his study, unable to cope with the situation, where he could isolate himself of the troubles that plagued the real world. There, in his private domain, he would normally spend every free minute he had using his microscope to explore new horizons and solve the questions that intrigued him the most. It was his stubbornness, patience and immense powers of observation that led him to become one of the most accomplished scientists of his and perhaps all time. The son of a self-taught rural medic in the impoverished region of Aragon in mid-19 th Century Spain, Santiago was a troublesome child that everyone thought would amount to no good. He constantly got into fights and was a practical joker. Once, he even managed to assemble a makeshift cannon that he and his friends used to blow down a fence. The rigid school system of the time did not work for him, and he would rather spend his time reading adventure books or looking at things and then drawing them. However, his father, a strict man, had other plans. Although Santiago really wanted to be an artist, he was forced to study medicine. In keeping with his character, Santiago rebelled, but after years of bargaining and pleading, including a stint working as a shoemaker s apprentice, he finally relented and attended the medical school in Zaragoza. There, he discovered that things at the university were not as bad as he thought. There were plenty of opportunities to quench his never-ending curiosity. His new awareness of the puzzle-solving dimension of medicine really excited him. He also came to realize that his passion for art was actually an asset when studying anatomy. He eventually joined the department, where his father also worked. Thus, his career as a scientist began by dissecting cadavers and drawing what he saw, as well as teaching the basics to the new students. Very early on he realized that it was understanding how the human body works that truly interested him, not being the one that deals with it when the patient gets sick. Having assisted his father, under duress, on many occasions when he was a child, Santiago knew that he was going to be happier working in a laboratory than at the hospital or visiting sick people from town to town. And this is exactly what he did for the rest of his life. Already a married man and with a growing family, Santiago moved to Valencia, where his name quickly became linked to the study of infectious diseases, the topic he had to teach at the university there. He gained notoriety (and a few lifelong enemies) when he used scientific reasoning to discredit a vaccine that was being given to quell the cholera epidemic that was ravaging the city in But microorganisms were not what really interested him and he soon turned his attention to the most mysterious of the organs in the human body: the brain. It was in Barcelona, where he moved to in 1888, that Santiago made his most famous discoveries. He arrived with the idea of perfecting his burgeoning studies on nervous tissues, excited because Barcelona was then a thriving city where some of the best doctors and scientists 16 October The Authors

19 The Brain of the country were working has been considered his annus mirabilis, the year that all the pieces of the puzzle started fitting together. Santiago was 35 years old when he realized that the mess of fibres that one could see when looking at a stained cut of the brain was actually a forest of neurons. His intricate drawings, still useful and amazing to look at 130 years later, describe what he was seeing in as much detail and accuracy as a photograph would do today. They are a testament to his ability to observe nature, as well of his artistic prowess, being put to use in ways that his father would never have dreamed of when he was trying to dissuade Santiago from becoming a professional painter. The turning point of Santiago s career came when he took advantage of knowledge gained from photography, one of his enduring hobbies, and applied it to his science. He used understanding of the chemistry of photograph developing to improve a famous technique devised by Camillo Golgi. The Italian biologist was already legendary when Santiago started studying samples under his cheap microscope. It was thanks to Golgi s special silver staining that Santiago could begin his work. But the young Spaniard was clever enough to tweak the method to achieve a clarity and resolution that no one had seen before. It was this, plus the many hours that he spent on the microscope, that allow him to see the nervous system in a different way. Santiago was the first to propose that neurons were individual cells that communicated with the others through long arms that looked like branches in a forest full of trees, instead of a single continuous network like Golgi and everyone else believed at the time. The contributions of Golgi to histology and the study of the brain are numerous and essential, making him a deserving recipient of any prize. However, he failed to recognize how Santiago s theory worked much better than his when describing how neurons are organized. Despite his opposition, the rest of the world caught on to the new discoveries pretty fast, and soon Santiago became a celebrity. It happened first in scientific circles, but his fame quickly expanded everywhere else, especially after the Nobel Prize, the first for a Spanish scientist, pushed him into the spotlight that he disliked so much. In 1892, Santiago left Barcelona for Madrid, where he lived the rest of his life trying to shun the sudden recognition that he had acquired. Even for a country that, historically, had never been too interested in science, it was difficult to ignore the revolution that Santiago s discoveries had brought to medicine and thus to society. He continued his research until the very last day, at the same time training a new generation of Spanish histologists and scientists that took his legacy even further. Part of this legacy also includes a cluster of highly entertaining books for all audiences. Still read regularly in Spain, the books offer a mix of autobiographical writings with thoughts on the most diverse topics, culled from his experiences of years of being an avid observer. They are often related to science but also include politics, history and all the other topics that concerned him. Despite his wide array of interests, Santiago will be remembered above all as a man devoted to science. The evening his daughter Enriqueta was fighting for her life, Silveria was unable to draw Santiago s attention, even when she realized the girl was getting worse. Locked in his study, glued to the microscope, like many other nights, Santiago was oblivious of what was happening outside his kingdom. When he eventually came out of the room, many hours later, he found his wife nursing the dead body of Enriqueta. She had not wanted to disturb him, so she just remained alone in her room, crying in silence. This is one of the many examples which show that, for Santiago Ramón y Cajal, science always came first. Thanks to his unconditional devotion, he managed to change the world. Salvador Macip is a scientist and writer. He attended medical school at the University of Barcelona, where he also obtained a PhD in Molecular Genetics. He is an Associate Professor at the Department of Molecular and Cell Biology of the University of Leicester, where he heads the Mechanisms of Cancer and Ageing Laboratory. He has published over 30 books in Spain, many of which have been translated. These include popular science books such as Where Science and Ethics Meet (with Chris Willmott, winner of the XIX European Price for the Popularization of Science) and a biography of Santiago Ramón y Cajal. October The Authors 17

20 Careers A day in the life of a science technician Sebastian Punter received a BSc with honours in Biochemistry from the University of Huddersfield in June In January 2018, he joined Cape Cornwall School, West Cornwall as a Science Technician Specialist, where he has spent the last 8 months supporting the school science department. He is an associate member of the Royal Society of Biology (AMRSB), as well as an early career member of the Biochemical Society. Peter Wotherspoon (Training & Careers Intern, Biochemical Society) spoke to him about his work. How did you get into science? I ve always been interested in science, ever since being at secondary school. During my time there, I grew a fascination for the intricate chemical detail found within the human body. I realized I wanted to further my knowledge, so I took both biology and chemistry at A-Level. During this time, I became more interested in the functions and processes at a chemical level, solidifying my belief that I wanted to study biochemistry at university. Can you describe a typical day? My day starts with a 6:00 am alarm, followed by an hour s drive to work, arriving at school around 8:10 am, earlier if there are more complicated practicals to set up. Each working day is different, dependent on which practicals I m preparing; I consult Lab Logger to check my agenda and start from there. Mornings are spent preparing equipment and chemicals for practicals, I work 2 days in advance to prevent last minute problems. In addition to this, I also clear material used in previous practicals and set up others as the day progresses. After lunch, I might update chemical stocks, answer s, maintain or order equipment. I then update Lab Logger with general notes regarding the day s practicals from information received from the teachers. My working day ends around 4.00 pm and I then head for home. What inspires you about your job? What inspires me about my job is with each practical I prepare and set up inside the classroom, there may be a chance a student will be become fascinated with science, just as I did. I gain satisfaction in knowing the work I do makes the department run smoothly and the students are involved, and interested, when carrying out experiments. I have made the department more efficient by introducing Lab Logger, to help the teachers organize their requirements for lessons and, in turn, this enables me to provide a consistently good service. I have also suggested ideas to make lessons run more smoothly and the department more CAREERS IN MOLECULAR BIOSCIENCE POLICY FOOD INDUSTRY THE COSMETIC INDUSTRY PHARMACEUTICAL LABORATORIES PUBLISHING SALES AND MARKETING 18 October 2018 Biochemical Society

21 Careers organized, and these have been accepted by the staff and introduced. On a personal note, I feel I have successfully made the transition from university to my first job. I have grown in confidence and am more inspired as to where my future will lead me. Job profile Science technicians can work across all levels of educational institutions including secondary schools, colleges and universities. They support the work of educators by providing practical demonstrations, managing departmental equipment and engaging with students. What do most people not realize about your job? Most people don t realize how much effort and dedication goes into keeping a school science department running. There is so much preparation, thought and organization which needs to take place before a lesson is given. In addition to this, there is huge responsibility for the vast array of chemicals which have to be stored, and disposed of, according to the code set by the advisory service, CLEAPPS. I am responsible for the day-to-day budgeting of the department, and for the purchasing of equipment, chemicals, stationery, supermarket shopping for food used in practicals, and more random items such as finding a local butcher who is willing to supply pig eyeballs. I am also a Fire Marshall for the whole school and a departmental First Aider. For career information from the Biochemical Society, visit Careers.aspx Qualifications and key skills Generally, a strong interest in science, organizational skills and the ability to communicate scientific concepts to different audiences are required. While some science technician posts do not require a degree, only asking for A-level or equivalent qualifications in science subjects, more specialist positions may require a degree in a relevant subject and further progression towards teaching may require a postgraduate certificate in learning and teaching. Responsibilities Responsibilities include preparing materials for science teachers, supporting staff and students through demonstrations, managing equipment and chemical stocks and ensuring health and safety guidelines are adhered to. More senior positions may require contribution to the development of their departments, advising educational staff and undertaking teaching responsibilities. Salary and career development Starting salaries for technicians depend on the qualifications held at entry, commencing from 15,000. At a more senior level with responsibilities in teaching and demonstrating, technicians can earn up to 30,000. Continued professional development (CPD) is often provided by the employer and events are run by organizations such as the Association for Science Education. Science technicians can also apply for professional registration (RSciTech). RESEARCH LAW FIRMS HOSPITALS UNIVERSITY LABS TEACHING October 2018 Biochemical Society 19

22 NOMINATIONS OPEN FOR THE BIOCHEMICAL SOCIETY AWARDS 2020 This is your chance to nominate someone who deserves recognition ADVERT for their SPACE work. The awards recognize established and early career researchers, scientists, educators and industry partners for their contribution to the molecular biosciences. We encourage nominations that reflect the diversity of the bioscience community. Nominations can be submitted by both members and nonmembers of the Biochemical Society. DEADLINE 31 JANUARY 2019

23 NOMINATIONS OPEN FOR The Biochemical Society Awards 2020 THE 2020 AWARDS ADVERT SPACE CENTENARY AWARD COLWORTH MEDAL EARLY CAREER RESEARCH AWARDS GLAXOSMITHKLINE AWARD HEATLEY MEDAL AND PRIZE INDUSTRY AND ACADEMIC COLLABORATION AWARD INTERNATIONAL AWARD KEILIN MEMORIAL LECTURE MORTON LECTURE TEACHING EXCELLENCE AWARD THUDICHUM MEDAL LECTURE

24 Lifelong Learning Evidencing your lifelong learning with e-portfolio David Smith (Sheffield Hallam University, UK) Electronic or e-portfolios act to bring the products or objects of learning and experience together in a digital format. They make visible the accumulation of learning, competencies and experience. The outputs can be shared with employers, accreditors and tutors alike. Used to their full potential they act as an area for focused reflection and future goal setting. In this article we will explore what an e-portfolio can be, what it can contain and how to create one. e-portfolios are a rich digital tool e-portfolios fall between the public realm of social media sharing and the professional persona found within LinkedIn. Many universities have access to bespoke e-portfolio platforms which are integrated into the virtual learning environment (VLE) for staff and student use. However, bespoke packages are not always needed as tools, such as the freely available Google apps, that allow the sharing of outputs can be just as effective. The digital nature of an e-portfolio allows rich, interactive content over and above what can be achieved on paper. YouTube videos, SlideShare presentations, audio recordings of conversations, links to publications almost anything you can interact with or embed can be included. How can they be used? In their simplest form, an e-portfolio is a collection of artefacts that have been uploaded in an organized manner. A deeper use of e-portfolios is as a focal point for reflection over time, organized in a chronological order with evidence of development. Below are a number of ideas of how e-portfolios could be used. Long-term assessment e-portfolios can make learning and achievements visible to employers, funding and accrediting bodies, giving a qualitative window into longterm achievements, the impact of the work and the capabilities of the student. Development of scientific writing, practical laboratory skills and evidence of effective group work over the course of a year can all be evidenced. Once they are created, academics can offer feedback to students on the contents and give guidance on further personal development. Showcase of practice A bespoke collection of standout artefacts provides a powerful and comprehensive digital résumé of an individual. Items such as graphics, pictures, multimedia, stories, journals, certificates of training or laboratory outputs can all be displayed. Rather than stating that a talk or poster has been given, an embedded recording or copy of the work could be shown alongside the data that generated it. Bespoke e-portfolios for employers can be created, showcasing key skills requested in the job specification and included as a link in the cover letter. Thinking back to evidence employability Students can keep a record of experiences gained through their course as a means of demonstrating competency. This may be how problems were solved during a laboratory project or reflections on group work tasks. Such reflections can provide answers to the interview questions asking for examples of when and how you have demonstrated leadership or dealt with a difficult situation. The e-portfolio acts to highlight to both the student and the employer that the student has these core qualities. Thinking forward for personal development A longitudinal view of outputs gives a comprehensive picture of growth and progress that can be used during reflection. By reflecting on the artefacts in the e-portfolio and asking questions such as what went well? and how can I improve? the learner can gain insights into their personal strengths and areas for development and create an action plan to achieve them. 22 October 2018 Biochemical Society

25 Lifelong Learning Impact e-portfolios are not just for students. Demonstration of the impact of your teaching and research are critical for both promotion and funding. You may, for example, want to collate meeting abstract text alongside PDFs of posters or slides, direct links to publications and photos or videos of outreach activities on a given project or theme. These can then be drawn on during grant writing as evidence of impact or pulled together during promotion rounds to demonstrate leadership in a given area. Getting to the nuts and bolts of e-portfolio creation What to write? Having some level of structure of an e-portfolio can greatly help in their creation. Initially, you may want to create areas for students on scientific writing, presentation skills, employability or group work. In each section, prompts can be given as to the type of artefacts that could be uploaded or reflected on. For example, in a scientific writing section, students can be prompted to upload the feedback from a recent assessment: Talk about your feedback (and your own feedforward) for the gene editing essay and any other scientific writing you have engaged in during your first year on the course. A small amount of guidance gets over the dreaded blank page and gives a clear point to start from. How to write it? The initial mechanics of creating the e-portfolio can sometimes be a challenge for both academics and students alike. Here, structured tutorials can be a great help. An effective and simple icebreaker exercise is to get the students to upload a photo and write a short paragraph about themselves. Prompts such as tell us where you have come from and why you have chosen this course can be a good start. The students learn how to use the basics of the e-portfolio package and the academics can put a name to a face, finding out a little about their students at the very beginning of the course. The more advanced features, like embedding videos or slides, can then be supported through screencasts and drop-in sessions. The tricky art of reflection Reflective practice is the act of self-observation and self-evaluation. Students can be made to feel comfortable with this process, in the private space of the e-portfolio with the knowledge that what they write will only be seen by the tutor. However, reflection is not always easy. Often, when asked to reflect, knowing what to say or write is challenging as much of the earlier thinking has been subconscious or nonverbal. Here, prompt questions and structure can really help in the process. What happened? So what? Now what? What occurred during the task? How might what I have learned affect my future decisions? How will I develop this skill? The Learning Cycle developed by David Kolb is one way of structuring this reflection; other methods, such as the Gibbs reflective cycle, are also useful. These cycles are based on the idea that deep learning (learning for real comprehension) comes from a round of experience, reflection, development and active testing. Experience evidencing or describing something that has happened Reflection thinking about and reviewing the experience Development learning from the experience, developing a new idea or setting a goal Active testing trying out what you have learned to gain a new experience Standing back, thinking about what has happened, identifying difficulties and focusing on areas for improvement, then going out and doing it, is the reflective cycle in action. The end product So what might it all look like when it s finally produced? From the student perspective, a section of the e-portfolio may look something like this: (Experience) A formative 10-minute presentation was given in class and received low marks for delivery. A YouTube video of the presentation was embedded in the e-portfolio as evidence. (Reflection) The written description alongside the presentation identified issues with going over time and forgetting what was going to be said. The student also talked about feeling nervous and scared. (Development) Presentation techniques were discussed with the personal tutor and the suggestion to practice beforehand to an empty room was given. (Testing) Notes were used so as not to forget content and the talk was practised to keep to time. Reflection on the second talk noted that because they were better prepared they were less nervous. The recording of the new presentation was then used as evidence to an employer of effective presentation skills. October 2018 Biochemical Society 23

26 Lifelong Learning From a personal point of view, I have been keeping an e-portfolio for the last five years. Initially, I created it so I could better understand the process, and support my students in a core skills module. I began by gathering a body of evidence around my research and teaching practice. I noted that although I was creating innovative teaching materials, as evidenced by quotes from my students, they were not founded in theory and shared only with my own department. I set a goal to share more widely by presenting at external conferences. To embed a culture of evidenceinformed teaching I enrolled in a mentoring program to develop the pedagogy of what I was doing. The wider dissemination of my practice was then used during my National Teaching Fellowship application. Further reading JISC (2008) Effective Practice with e-portfolios: Supporting 21st Century learning JISC (2012) Crossing the Threshold. Moving e-portfolios into the mainstream Peyrefitte M and Nurse A (2016) e-portfolios: evaluating and auditing student employability and engagement. York, Higher Education Academy. sites.google.com/site/reflection4learning/home learn.solent.ac.uk/mod/book/view.php?id=2732 Thanks to Southampton Solent University 2012 for the inspiration on the student example. An e-portfolio makes lifelong learning real. Whether it s your own professional development or your students experiences, by collecting products or objects of learning from real-life tasks and reflecting on these, personal meanings are developed. The reflective process tells stories about these experiences and the e-portfolio is the book in which they are recorded. David is a National Teaching Fellow, teaching Molecular Bioscience and Biochemistry. He is a Senior Fellow of the Higher Education Academy and has received the Sheffield Hallam Vice Chancellors Award for Inspirational Teaching. David has been research active in the field of biosciences for over 20 years focusing on the molecular basis of neurodegeneration in diseases such as Alzheimer s and Parkinson s. His teaching involved the innovative use of digital technology to enhance student learning October 2018 Biochemical Society

27 ADVERT SPACE A BIOCHEMICAL SOCIETY SCIENTIFIC MEETING BMP Signalling in Cancer II 1 3 April 2019 St Anne s College, Oxford, UK Find out more at bit.ly/bmp-signalling

28 Science Communication Competition A life without microbes: How germ-free research is revealing the necessity of bacteria for our brains Jenna Herbert (University of Oxford) The Science Communication Competition is now in its eighth year. As in previous years, it aims to find young talented science writers and give them the opportunity to have their work published in The Biochemist. In 2015, a new branch of the competition was launched to include video entries. Overall this year s competition attracted 74 entries and these were reviewed by our external panel of expert judges. The second prize in the written category was awarded to Jenna Herbert from the University of Oxford, whose article is presented here; the second prize in the video category was Ellie Staniforth from the University of Glasgow. Ellie s video can be viewed at bit.ly/scicomm David Vetter was a normal boy, mostly. He grew up in Texas, and he liked Star Wars. He was also born with a genetic defect that left his immune system completely non-functional. As a result, he was forced to live in a sterile isolator for his 12 short years of life, earning him the nickname Bubble Boy. David, along with films like The Boy in the Plastic Bubble (1976) and Bubble Boy (2001), has inspired us to think about a life completely isolated from germs. Would we be healthier? Would our bodies, or our brains, function differently? Scientists have begun to answer these questions by studying rodents that spend their entire lives in sterile bubbles: germ-free mice. Our microbial passengers You carry with you trillions of bacteria, most of which reside in the digestive tract. In exchange for a warm environment with plenty of sustenance from the fibres we eat, your gut bacteria (collectively known as the gut microbiome) are important for nutrient synthesis, digestion, and the development and maintenance of our immune systems. But for the remainder of this article, put yourself in the paws of a germ-free mouse. Your life isn t ostensibly all that different than that of other rodents. You spend your days running around and sniffing your cage mates. But you live in an incubator resembling the isolator the bubble boy inhabited. Without a full complement of bacteria, perhaps it s not surprising that you need additional nutrients in your diet and have a higher risk of infection because of an immature immune system. What may be more unexpected, however, is the abnormal way your brain has developed, leaving you stressed, defenseless and socially inept. Stressed out Imagine that you re about to go through a stressful experience. When you were human, this might have been a speech or a job interview. But as a lab mouse, this more likely involves a researcher dropping you into a tepid pool of water without warning to perform the forced swim test. You don t like water, and when you are dipped in the tank, you panic and frantically swim to and fro to find an escape. Your brain secretes chemicals that signal the adrenal glands (located above the kidneys) to produce stress hormones called glucocorticoids, the most common of which in humans is cortisol. Glucocorticoids are then released into the blood and have a wide range of effects in the body and brain to prepare you for fight or flight. 3 Stress hormone levels that are too high or longlasting, however, can be damaging, so evolution has developed a clever way to prevent this: glucocorticoids 26 October 2018 Biochemical Society

29 Science Communication Competition inhibit their own production, creating a negative feedback loop so that under normal circumstances, hormone levels don t get too elevated and return to baseline quickly. 3 After five minutes in the tank, the researcher removes you from water and takes a blood sample. When the results come back, she finds that your stress hormone levels have sky-rocketed above those of a normal stressed mouse. This means you have a hyperactive stress response, and the heightened exposure to glucocorticoids is harmful for your body and immune system and, ultimately, your brain. 4 We don t understand why yet, but the presence of a microbiome seems to be critical for the correct development of your brain s stress circuitry. A defenseless brain You re not loving life as germ-free lab mouse. Not only are scientists putting you in tanks of water against your will, but your stress hormones are out of control. Now, the researchers want to test your brain s immune response by administering a mild pathogen. In a normal brain, spider-like cells called microglia are constantly on patrol. Microglia wear many hats, serving as the brain s janitors, architects, and soldiers. They work around the clock, clearing away dead or damaged cells. While the brain is growing and developing early in life, they also help to mold it, eliminating unnecessary wiring to construct an efficient machine. 5 At the first sign of infection or damage, microglia spring into action. They retract their spidery legs (called dendrites), multiply, and call for help, releasing chemical signals to recruit other immune cells to the site of the attack. 5 The researcher injects the pathogen. You actually have more microglia than a normal mouse, but they are sluggish to respond to the invasion, and they don t release signals to other cells to help mount an attack. 6 What s more, the selectively-permeable barrier that normally isolates your brain from your blood has been compromised without the aid of the microbiome. 7 Toxins are seeping into your brain, and you lack the Further reading Haberman, C. (2015) The Boy in the Bubble Moved a World He Couldn t Touch. New York Times Luczynski, P., Neufeld, K.A.M.V., Oriach, C.S., Clarke, G., Dinan, T.G. and Cryan, J.F. (2016) Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int. J. Neuropsychopharmacol. 19, 1 17 Spencer, R.L. and Deak, T. (2017) A user s guide to HPA axis research. Physiology and Behavior 178, Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X.-N.X. et al. (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 558, Nayak, D., Roth, T.L. and McGavern, D.B. (2014) Microglia development and function. Ann. Rev. Immunol. 32, Erny, D., Hrabě de Angelis, A.L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E. et al. (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Tóth, M. et al. (2014) The gut microbiota influences bloodbrain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158 Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T.G., and Cryan, J.F. (2014) Microbiota is essential for social development in the mouse. Mol. Psychiatry 19, Heijtz, R.D., Wang, S., Anuar, F., Qian, Y., Bjorkholm, B., Samuelsson, A. et al. (2011) Normal gut microbiota modulates brain development and behavior. Proc. Natl. Acad. Sci. 108, Tazume, S., Umehara, K., Matsuzawa, H., Aikawa, H., Hashimoto, K. and Sasaki, S. (1991) Effects of germfree status and food restriction on longevity and growth of mice. Jikken Dobutsu 40, Rabot, S., Membrez, M., Bruneau, A., Gerard, P., Harach, T., Moser, M. et al. (2010) Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, Harach, T., Marungruang, N., Duthilleul, N., Cheatham, V., Mc Coy, K. D., Frisoni, G. et al. (2017) Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci. Rep. 7, Sampson, T. R., Debelius, J. W., Thron, T., Wittung-stafshede, P., Knight, R., Mazmanian, S. K. et al. (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson s disease. Cell 167, Arentsen, T., Raith, H., Qian, Y., Forssberg, H. and Heijtz, R. D. (2015) Host microbiota modulates development of social preference in mice. Microbial Ecology in Health & Disease 26, 1 8 The Microbiome in Health and Disease (2017) Edited by Julian Marchesi, Emerging Topics in Life Sciences 1, (4) October 2018 Biochemical Society 27

30 Science Communication Competition proper protection of the microglia. This was just one exposure to a pathogen, but in the real world, you would be exposed to bacteria and viruses constantly without defenses, leaving your body and brain vulnerable. Not a social butterfly For one final test in the lab, you are placed in between two chambers. One is empty, and one contains another mouse. Mice are social animals, and they typically prefer a new four-legged friend over the empty compartment. You, however, are more timid than the usual mouse. You would much rather escape to the vacant chamber than sniff and explore another animal. 8 In a second test, you are put in the same chamber, but now you have the choice between the mouse you met earlier and a new mouse. In this task, there s no private section to escape to. The best option, you decide, is to choose what is familiar and spend more time with the old acquaintance. Perhaps you want to avoid the awkwardness of an entirely new social interaction. You don t realize that normal mice usually choose to meet new rodents with new smells. They are curious creatures that explore new things, but you favor familiarity. Perhaps the most surprising trait under the influence of the microbiome is social behaviour. It may seem like a stretch (and perhaps a bit like science fiction) that our behaviour could be affected by bacteria. But our microbes can alter the levels of a number of chemicals in the brain, including some you may have heard of, such as serotonin and dopamine. Ultimately, it s these chemicals that determine how we think and act. Our microbes: small but mighty A life without microbes is still something we can only imagine. But based on studies in germ-free mice, it doesn t sound ideal. It s clear that the microbiome is extremely important to our brain health. We don t know how exactly the microbiome communicates with the brain, but the middlemen are likely the vagus nerve (which allows the gut and the brain to communicate with each other), byproducts of bacterial digestion of fibre that can alter brain function, and interactions with immune cells. It s important to note that although many characteristics of the germ-free brain are abnormal, being abnormal isn t always clearly a bad thing. Mice without microbes are not as anxious as normal rodents. They live longer and are more resistant to weight gain. Also, mice that have been genetically modified to have Alzheimer sor Parkinson s-like syndromes do not show symptoms if they grow up without a microbiome. And finally, as is often the case in science, studies sometimes contradict each other. One study, for example, found that germ-free mice are actually more sociable than normal animals, the exact opposite of the findings discussed in this article. So there isn t a nice story here about gut bacteria as the perfect symbiotic pals. What the brain and behaviour of germ-free mice can show us, however, is which aspects of our neurobiology may be influenced by our microbes. The next step will be understanding how to target our microbiomes, using dietary modifications or even foecal microbiota transplants (the transfer of good bacteria from a healthy donor to a patient), to optimize our brain health and combat disease. 28 October 2018 Biochemical Society

31 Summer Vacation Studentships Vacation laboratory placements for undergraduate students. Summer 2019 ADVERT SPACE Grants are available for stipends of 200 per week for 6 8 weeks, and up to 1,600 in total, to support an undergraduate student to carry out a summer lab placement. This scheme not only benefits the student as they get valuable research experience, but the supervisor also gains an extra pair of hands in the lab. THE DEADLINE FOR APPLICATIONS IS 22 FEBRUARY 2019 For full details on the criteria and more information on how to apply, please visit bit.ly/summervacationstudentship or contact 09/2018

32 Policy Matters Shining a spotlight on immigration Emma Sykes (Science Policy Officer, Biochemical Society) The Biochemical Society s Policy Network looks into immigration policies to support science and innovation. Since the UK s decision to leave the European Union in June 2016, Brexit has dominated the political landscape. While Brexit will result in numerous implications for the UK, one of the prominent areas of concern for the scientific community is the movement of people and wider immigration policies that may affect the status of international scientists living in the UK, and UK scientists living abroad. With March 2019 looming ever closer, immigration policies have experienced a great deal of scrutiny from organizations, parliamentary committees and the Government alike. The movement of people was a key item on the agenda at the Brexit Summit held by the House of Commons Science and Technology Committee in February The same Committee later published a call for evidence on the scientific community s needs from immigration policies (June 2018). Following the publication of data revealing that thousands of STEM professionals were being refused visas on the basis of arbitrary caps, the Campaign for Science and Engineering (CaSE) led a successful campaign resulting in medical professionals becoming exempt from the caps for Tier 2 Visas. As doctors and nurses make up the greatest proportion of applicants to Tier 2 visas it is hoped that their removal from the cap will result in more visas becoming available for scientists, technicians and other STEM professionals. Given the high level of scrutiny into immigration policy, the Biochemical Society decided to feature the topic in our latest Policy Spotlight. The Policy Spotlight is a new initiative for members of the Society s Policy Network, where members have the opportunity to share their opinions on a specific focus topic. The Immigration Spotlight was particularly well timed as the outcomes helped to shape the Society s input into the House of Commons Science and Technology Committee s inquiry An immigration system that works for science and innovation ; an inquiry which the Biochemical Society responded to through the Royal Society of Biology. The Immigration Spotlight highlighted the views and concerns of Network members. Respondents were keen to emphasize the benefits of free movement of people for the scientific community. Most agreed that such free movement is important both to advance scientific research and also to advance the careers of people allowed to move freely between countries. Further benefits of free movement, as recorded by the Immigration Spotlight included: The ability to attract and retain skilled scientists and technicians to support UK research; Providing opportunities to work alongside and collaborate with scientists and technicians based internationally; The ability to travel to and access research facilities based internationally. With recent CaSE figures suggesting that 72% of UK-based scientists spent time at non-uk institutions from 1996 to 2015, it is unsurprising that the Spotlight revealed that the molecular biosciences follow this trend, with a number of respondents having worked or studied outside of the UK. Numbers aside, testimonials from the Spotlight begin to show that benefits of the free movement of people go beyond access to international labs and retaining skilled people in scientific teams. It became clear that benefits are felt not just through the quality of the scientific work, but that the movement of people enriches the social and cultural lives of those working in the science sector, with Network members writing: 30 October 2018 Biochemical Society

33 Policy Matters I learn a lot from international colleagues, not just scientifically, but also culturally, which is such a nice experience. It opens doors for future international collaborations as well. People bring in a wide variety of skills, and different approaches to projects. The contact network of the group is very extensive, due to the international makeup of the team. This is essential for high-impact research. The Spotlight also highlighted concerns regarding current immigration policies, and Network members expressed a desire for the Government to provide clear guidance on immigration policies following Brexit. In particular, to clarify the status and rights of EU scientists working in the UK and support for skilled scientists and their families who wish to come to work and live in the UK. Immigration policies are important. They can have a profound effect on research and innovation in science, both in the UK and globally. The movement of skilled and experienced scientists and technicians affects the UK s knowledge base, economic productivity and the societal gains we receive from the life-sciences sector. The reason for this is simple. Scientists are people, and policies that affect the scientist will undoubtedly affect the science. Further Reading: CaSE policy review on immigration: sciencecampaign.org.uk/resource/immigration2018. html The Royal Society of Biology response to the Science and Technology Committee of the Common s inquiry on an immigration system that works for science and innovation (June 2018) Policy/RSB_response_to_HoC_STC_An_Immigration_ system_that_works_for_science_and_innovation_ inquiry_for_submission.pdf House of Commons Science and Technology Committee Report: An immigration system that works for science and innovation (July 2018) publications.parliament.uk/pa/cm201719/cmselect/ cmsctech/1061/ htm Tier 2 refusals: Full FOI data by occupation House of Commons Science and Technology Committee Report: Brexit, Science and Innovation March 2018 publications.parliament.uk/pa/cm201719/ cmselect/cmsctech/705/70502.htm The next Policy Spotlight will be on the topic of regulations relating to the molecular biosciences. If you wish to get involved in the Policy Spotlight or join the Policy Network, please October 2018 Biochemical Society 31

34 News Upcoming Events The Changing Landscape of Research on Ageing: Models, Mechanisms and Therapies 7 November 2018, Glasgow, UK Meeting Reports The Dynamic Cell III March 2018, Manchester, UK Synthetic Biology UK November 2018, Bristol, UK YLS Genome integrity: a lifetime s challenge November 2018, Montpellier, France Life Sciences 2019: Post-translational Modifications and Cell Signalling March 2019, EMCC, Nottingham, UK BMP Signalling in Cancer II 1-3 April 2019, St Anne s College, Oxford, UK Deubiquitylases: From Mechanism to Physiology June 2019, UK Redox Signalling in Physiology, Ageing and Disease 1 3 July 2019, Newcastle, UK Protein Engineering II: from New Molecules to New Processes July 2019, University of York, UK 9th European Conference on Tetraspanins 4 6 September 2019, Schloß Waldhausen, Budenheim, Germany Nanodomains in Cyclic Nucleotide Signalling September 2019, London, UK Synthetic Biology UK November 2019, Warwick, UK F Scientific Meeting Public Event Medal Lecture Training Events and Courses Free to attend For more information: 32 October 2018 Biochemical Society This Biochemical Society and British Society for Cell Biology joint meeting attracted 233 attendees and over 125 posters exploring various aspects of cytoskeletal biology. The meeting started with a fabulous plenary lecture from Tony Hyman (MPI-CBG, Germany) who discussed the cell biology of phase separation likening the behaviour of the aqueous and lipophilic solutions in his experimental set up to a very expensive vinaigrette. The first session on Cell Migration and the Extracellular Matrix spanned in vivo biology to computational modelling and cell biology and cancer to biophysics and it was great seeing the interdisciplinary science on show. Day 2 opened with a session on new technologies that have been developed to image and probe cell function and the next session on cytoskeletal dynamics showcased a variety of projects that exemplify how motile and active these elements are. In the fourth session on cell division, we looked to explore how the cytoskeleton was rearranged to facilitate the division process and the meeting concluded with a session on cell cell interactions. This session really got everyone thinking about how tissues behave and how the cell division mechanisms that were largely elucidated in single cells operate in the context of whole tissues. Jeremy Carlton (Kings College London, UK) Anne Straube (University of Warwick, UK) New Horizons in ESCRT Biology April 2018, Surrey, UK This meeting covered regulation of degradative sorting and ESCRT-dependent multivesicular body biogenesis, exploitation of ESCRTs to effect viral release, roles for ESCRT proteins during cell division, mechanisms of ESCRT-III assembly and emerging roles for ESCRT proteins. The meeting began with one of the most recently described ESCRT functions, that at the nuclear envelope, with great talks trying to understand how ESCRT-III activity is coordinated at this organelle. There was exciting data regarding how the ESCRT machinery assembles during cytokinesis, how it could be regulated by the oxidation state of F-actin and how this machinery functions in the context of whole animal cytokinesis. One of the highlights of the meeting was the progress in biophysical analysis of these proteins with lively debate over advances in understanding how ESCRTs form filaments and catalyse membrane fission. The field is really coming together to finally get a biophysical handle on how membrane remodelling is accomplished by this machinery and the new assays combined with amazing structural data look set to provide new understanding of how reverse-topology membrane fission is performed. The meeting stayed up-to-date with new findings regarding how ESCRTs were recruited to damaged endolysosomes to repair them and keep them functional. This exciting story was a completely new and unexpected role for ESCRT proteins in the cell, showed how ESCRTs have important functions in maintaining organelle integrity, and was great to showcase at this meeting. Additional functions of the ESCRT machinery in membrane repair and regulation of cell migration were also revealed in this meeting, thus highlighting exciting emerging areas in this field. Jeremy Carlton and Juan Martin-Serrano (Kings College London, UK)

35 Local Ambassador Jacqueline Nairn News Dr Jacqueline Nairn is Deputy Director of Teaching in the School of Biology at the University of St Andrews where she is the degree controller for the Biochemistry degree and the Integrated Masters in Biochemistry degree. Jacqueline has published biochemistry research articles on central metabolism and innate immunity, and in 2014 she moved to a more teaching focussed role at the University of St Andrews. What motivated you to become a scientist? I was motivated by a number of high school teachers, including my chemistry teacher, who used real-world examples to bring chemistry to life. I was late to the world of biology, taking biology in my final year at high school as a crash higher. I found my biology teacher s enthusiasm for the wonders of biology infectious. I can still recall the explanation of the simplicity and the beauty of DNA replication. My Latin teacher was also a key figure with many of the translations of Latin words helping to explain the new vocabulary encountered in chemistry and biology. What inspires you about molecular bioscience? The relationship between form and function never disappoints. As an undergraduate student, I particularly enjoyed protein science and enzymology. In the mid-1980s, the number of available protein structures was limited, and molecular graphics was in its early stages of development. Despite this, Professor Nick Price and Dr Lewis Stevens conveyed the wonders of protein structures and their amazing roles in a range of contexts. Now that I am in a teaching role, with the availability of a vast array of bimolecular information, I find it incredibly rewarding to see our current students similarly inspired by the structure and function of biomolecules. What are you reading at the moment? In the office, I am reading a range of papers to help shape a new suite of tutorials for our undergraduate students. Out of the office, my reading appetite has grown exponentially in recent years. My bedside book is Sebastian Barry s The Secret Scripture. After reading his wonderfully uplifting Days Without End, I was keen to read more of his work. The audio book on my commute is Jackie Kay s superb memoir Red Dust Road. What s on your lab bench/desk right now? I am developing teaching materials for our Integrated Masters programmes, Honours projects and tutorial programme. I am also working with an undergraduate student to develop some research methods. What s been the greatest challenge in your career so far? My greatest challenge was making the decision to move from my previous institution and associated role. However, the move to the School of Biology at the University of St Andrews, and a teaching focussed role, turned out to be the most rewarding part of my career to date. Mentorship was incredibly helpful at this time, and I would recommend that every bioscientist should have a good mentor at every stage of their career you can always learn something from conversations with others who have trodden a similar path. What is your advice for someone who would like to pursue a career in molecular bioscience? The advent of bioinformatics, molecular interaction explorations and macromolecular imaging marks an incredibly exciting time to embark on a career in molecular bioscience. Molecular bioscience is primed to answer interesting questions in biology, and to address some important global issues such as the development of novel biofuels, more efficient food production and tackling disease. I would advise early-career molecular bioscientists to secure an internship to gain experience, to build networks within/across institutions and through membership of learned societies, and to remain curious about all aspects of Biology. What do you do in your spare time? Running with a good friend ticks both physical and mental wellbeing boxes. We are incredibly lucky to live in such a beautiful country with some great running routes. In addition to being a Biochemical Society Ambassador, I am actively involved with the Royal Society of Biology in Scotland in which I enjoy working with fellow committee members on biology-related issues in Scotland. Ambassadors are a key group of members that help us to raise awareness of the Biochemical Society, promote its activities, recruit new members and act as the Society s point of contact at their institution. If you would like to get involved as an Ambassador, please contact: The 8th International Conference on Notch Targeting in Cancer June 2018, Grecian Park Hotel, Konnos Bay, Cyprus This small conference of participants comprising established and new PIs and postdocs/phd students operated like a workshop and combined lectures with open air discussion sessions, with plenty of time for informal discussion on site at coffee, lunch and dinner. The conference brought together established clinicians treating patients with cancers where Notch signalling is known to be oncogenic, and basic scientists discussing the latest mechanistic insight into the canonical and noncanonical Notch signalling pathways. Sessions were divided into stem/progenitor cells, development and differentiation aspects, biomarkers of Notch activation, and mechanistic insights. This enabled discussion of new and emerging possibilities for therapeutic intervention (specific examples of novel therapeutics discussed included small molecule inhibitors and monoclonal antibodies). Sponsorship of this meeting by the Biochemical Society allowed us to invite a newly established PI from the US, Dr Vincent Luca, whose previous work used in vitro evolution to develop Notch ligands with higher affinity for the Notch receptor and led to identification of crystal structures of Notch ligand complexes. Vince talked eloquently about using structure-guided protein engineering to selectively target Notch activity in different cells. Additionally, PhD students were given the opportunity to present posters and short talks. Overall, it was a highly informative conference, which promoted close collaboration and discussion, held in a wonderful location on the Cypriot coastline. Penny Handford (University of Oxford, UK) October 2018 Biochemical Society 33

36 News Introducing the Chair of the Basic Bioscience Theme Panel Michelle West (Subject Chair of Biochemistry and Biomedicine and Professor of Tumour Virology, University of Sussex, UK) I would like to introduce myself as Chair of the Basic Bioscience Theme Panel (BBTP). This panel and role was newly created in March 2017 as part of restructuring that took place within the Biochemical Society to improve the scientific meeting application and review process. The BBTP is the largest of the three new Theme Panels that were created and sits above six existing Research Area committees. The Research Areas are Genes, Molecular Structure and Function, Energy and Metabolism, Cells, Signalling and Biological Systems. The Research Areas provide broad representation across the Molecular Biosciences, the area of science championed by the Biochemical Society (it s not just Biochemistry!). The Chairs of the six Research Areas are members of the BBTP which meets four times a year. As Chair of the BBTP I am also a trustee of the Biochemical Society so take part in key discussions relating to the strategy and operations of the Biochemical Society at its Council Meetings that take place four times a year. I am passionate about promoting the visibility and achievements of women in science (and increasing diversity in general) and have championed this cause within our meetings programme. As a result, all applications for Biochemical Society scientific events (meetings and training events) now require that at least 40% of invited speakers are women and that wherever possible, attempts are made to achieve 50% representation. We also ask that programme coordinators select speakers from a range of career stages and try to include representation from Industry. Increasing diversity is an ongoing process that is embedded in Biochemical Society strategy and we continue to review and expand our guidelines and policies to reflect the diversity of the bioscience. I was very supportive of the introduction this year of hybrid scientific meetings, where presentations and questions are hosted on an online platform in real time. This enables those who cannot attend in person to register as online attendees and take part virtually. This is another great step towards encouraging inclusivity for those who may struggle with work or family commitments to travel to meetings. What happens at a BBTP meeting? We discuss recently submitted proposals for scientific meetings and make decisions on which proposals should be supported (these decisions are then ratified by the Conferences Committee). Sometimes we recommend approval subject to some changes to the proposal. If these are minor, a decision on the proposal may subsequently be made by . If these are major, the proposal will need to be submitted to the next round for re-review, but support is not guaranteed. We also discuss ideas for future meetings and proposed changes to processes and strategy that relate to the meetings programme. The BBTP also reviews the success and feedback of previous meetings and monitors registration levels for upcoming meetings. What types of scientific meeting does the Biochemical Society support? The Biochemical Society supports three kinds of meetings: sponsored events, scientific meetings and Harden conferences. They can take place in any part of the UK or overseas and can be run jointly with another society or organization. Sponsored events: These are independently run meetings of any length that the Biochemical Society sponsors by providing 500. This would normally be expected to cover a specific speaker s travel, accommodation and registration expenses. In return the meeting would publicize this Biochemical Society sponsorship in the meeting promotional material and at the meeting. The meetings supported must meet Biochemical Society guidelines on the strength of scientific content, programme organization and gender balance. These meetings are not run by Biochemical Society staff. Scientific meetings: These are normally 1 3 days in length and are run by Biochemical Society staff. This 34 October 2018 Biochemical Society

37 News means that, once approved, abstract submission, venue contract negotiation, online registration and meeting organization will be handled by the Biochemical Society. Biochemical Society staff will also handle the day-to-day running of the meeting. The programme coordinators, however, play a critical role in handling all scientific aspects of the meeting, including the abstract selection process, the programme organization and publicizing the meeting in the relevant field. It is important to point out that the secretariat support provided by the Biochemical Society is provided free of charge and that the registration fees for the meeting are calculated based on the direct costs of the meeting only (e.g. venue fees, food, invited speaker travel costs) with the aim of breaking even. The Biochemical Society and programme coordinators actively seek sponsorship to offset these direct costs and keep registration fees as low as possible. Harden Conferences: Named after Sir Arthur Harden, a founding member of the Biochemical Society, these conferences are the Biochemical Society equivalent of a Gordon Research Conference. They are usually 3 5 days in length and are fully residential, often at a semi-remote venue to encourage interaction between participants. They cover a specialist topic within the molecular biosciences but ideally one that would have broad interest across sub-disciplines. The support and running of Harden Conferences is as for scientific meetings, but the meeting is run as a closed meeting to encourage presentation of unpublished findings. If you are interested in organizing a scientific meeting and need more help and advice, please contact We look forward to hearing from you! Life Sciences 2019: A key meeting about post-translational modifications (PTMs) in biological processes The Physiological Society, the British Pharmacological Society and Biochemical Society are joining forces to bring you the latest research and discuss important challenges. Life Sciences 2019: Post-Translational Modifications and Cell Signalling March 2019 East Midlands Conference Centre, Nottingham, UK Submit your abstract by 21 January 2019: bit.ly/ls19abstract October 2018 Biochemical Society 35

38 ADVERT SPACE A BIOCHEMICAL SOCIETY SCIENTIFIC MEETING Protein Engineering II: from New Molecules to New Processes July 2019 University of York, UK Find out more at bit.ly/events_protein_engineeringii

39 News CEO Viewpoint Kate Baillie (Chief Executive, Biochemical Society and Managing Director, Portland Press) In 2009, the Biochemical Society, together with the Society for Experimental Biology and the British Ecological Society, co-located to a new, jointly-owned premises at 12 Roger Street with the vision of creating a bio-sciences hub: Charles Darwin House. The then Society of Biology had just been formed as a result of a merger between the Institute of Biology and the Biosciences Federation, and the plans for the hub were developed in the context of a life sciences sector looking towards opportunities for greater integration with both the new Society of Biology and other sister Societies. It was also hoped that by occupying the same premises, the co-owner societies of CDH would be able to work in closer collaboration, while also benefitting from any cost efficiencies generated by shared services. The ground floor conference centre was envisaged as an incomegenerating operation which would offer meetings space to both the co-owners and external clients. At the outset, the Biochemical Society provided a number of services to CDH Ltd (the company created to manage the buildings), including premises management, IT support and accountancy, at below market rates, thereby effectively subsidizing the business. This was at the time part of the Society s strategic commitment (as stated in the 2013 strategic plan), both to the bioscience hub, and to the goal of exploring federation, integration or merger with the Royal Society of Biology by Since its foundation, the hub has been joined by three more co-owners the Society for General Microbiology (now the Microbiology Society); the now Royal Society of Biology; and, most recently, the Society for Applied Microbiology. The partnership also acquired a second building, Charles Darwin House 2 (107 Gray s Inn Road) which has been used primarily as an investment property, with office space rented to other scientific organizations. Over recent years it has become evident that the potential benefits of shared services have not been realized. In addition, substantial increases in business rates meant that generating income from external clients of the conference centre was no longer viable and this income stream disappeared. The cost base of CDH Ltd has increased significantly as a result, and now requires additional financial support from the Society and other co-owners. The Chief Executive s and Trustee representatives of the co-owners held a summit meeting on 23 April to discuss these concerns and to try and find a route forward to solve the prevailing financial issues, as well as trying to find a more effective way to manage the buildings. Many possible avenues were explored both at the Society s Council and similar meetings of other co-owning Societies, however at a subsequent meeting, in July, it was unilaterally agreed that the biosciences hub experiment had not worked. As a result, it has been agreed that both buildings will be sold, the CDH partnership will be dissolved and that the Biochemical Society will seek a new home. While this is the end of an era, the move also represents an exciting new chapter for the Society. Throughout these considerations, we have emphasized the importance of continuing to seek opportunities for collaboration, which is an important part of how we work. We do not anticipate that our collaborative partnerships and projects will be adversely affected by this move indeed, many of the Society s successful collaborations to date have taken place with societies beyond CDH such as the Nutrition Society, British Pharmacological Society and The Physiological Society and we will continue to seek out opportunities to partner with other organizations and leverage opportunities for strategic partnership wherever possible. Undoubtedly, readers will be asking what is next for the Society? For now, concrete details are yet to emerge and a variety of options are being explored, but I will keep readers abreast in this column as details of the move to new premises materialize. Whilst physical co-location has not worked well as a catalyst for change and integration and this must be acknowledged in terms of the best use of our charitable resources, the Biochemical Society is proud to have played a major role in spearheading the idea of a more collaborative sector. Finding new and innovative ways to expand our influence across the sector as a whole remains an objective central to our purpose which is recognized in our current and future strategy. October 2018 Biochemical Society 37

40 Book Reviews Into The Grey Zone by Adrian Owen Over the past decade, amazing strides have been made in the ability to diagnose consciousness in some patients in a Persistent Vegetative State and other grey zone conditions. At the forefront of this work has been neuroscientist Adrian Owen. He has now published a first-hand account that maps out the parallel evolution of both the technology to probe within the cranium and the ingenious tests they have developed to demonstrate that the subject is awake and aware. It is a remarkable and moving read: I cannot think of any other book that has simultaneously thrilled me with the clear and logical presentation of scientific experiments and moved me to tears with their implications for patients and their families. If you want to avoid spoilers, now is the time to stop reading the review and order a copy of the book. In successive chapters, each illustrated by stories or real patients, Owen walks us through the move from Positron Emission Tomography to functional Magnetic Resonance Imaging (fmri). The latter has the advantages of both being quicker and not involving a radioactive burden for the participants. At the end of the book there are also steps towards use of electroencephalography (EEG), which lacks the finesse of fmri but is considerably cheaper and more mobile, significantly improving access to awareness testing. This touches on an important nuance, the distinction between demonstrating consciousness and interacting with that consciousness. Various assessments, for example monitoring brain activity whilst the patient watches a suitable film, can reveal awareness, if the observed results match those of healthy volunteers when they watched the same movie. Probably the most dramatic intervention, however, is the use of fmri to communicate with grey zone patients via a series of yes/no questions. Responses to the invitation to imagine you are playing tennis and imagine you are walking through your house elicit consistent and distinguishable patterns of brain activation. By using these thought processes as proxy yes and no answers, communication has been established with approximately 20% of patients who seemed otherwise unresponsive. The capacity to interrogate patients in this way has implications for our understanding of brain function, but more importantly for the care of unfortunate souls trapped in this limbo state. This is translational research at its finest. Chris Willmott (University of Leicester, UK) Brainstorm: Detective Stories from the World of Neurology by Suzanne O Sullivan The human brain is a fascinating product of evolution, the intricacies of which we still do not fully understand. Suzanne O Sullivan s Brainstorm delves into the real-world consequences of when things go wrong and follows her methodology in determining the underlying causes. In this thought-provoking book, O Sullivan recalls some of her most memorable experiences as one of the UKs leading neurologists. Each investigation focuses on a specific case, a patient who presents with wild and wacky symptoms: a man who sees cartoon dwarves running across the room, another whose personality completely changes, and a girl who falls down a Wonderlandesque rabbit hole. What conditions could possibly cause these symptoms? The title is somewhat misleading, as this is fundamentally a book about epilepsy. Each chapter is written as a detective story; the initial meeting between doctor and patient; the holistic investigative approach taken by the author, utilizing the patient s backstory as well as diagnostic tools to determine the root cause of the problem; and the various treatments and medications available. All wonderfully interwoven with historical and current knowledge of the brain s inner workings. The result is a series of fascinating tales that highlight the complexity of epilepsy, a disease that can cause a mindboggling, and sometimes frightening, array of symptoms, from inappropriate cursing to full-on loss of muscle control. This book is more than just a narrative of doctor-patient meetings; it acts to highlight the disparity between our understanding of neurological disorders and diseases of other organs. O Sullivan puts epilepsy front and centre as a disease in which a deeper understanding and improved treatment options are desperately needed. This is best exemplified by the sections recanting treatment options (either drugs or surgery) in which low success rates are compounded by potentially serious side effects. Brainstorm provides an interesting personal insight from the view of a physician and is a must-read for anyone affected by epilepsy or with an interest in neurology and medicine. Matthew Lewis (The Biochemical Society/Portland Press) 38 October 2018 Biochemical Society

41 Book Reviews Inventing Ourselves: The Secret Life of the Teenage Brain by Sarah-Jayne Blakemore Adolescence is a time of turmoil, often mistakenly believed to be a modern invention when in fact teenage angst has been well documented for thousands of years. I have previously seen Professor Blakemore talk about her work on the development of the adolescent brain at a neuroscience conference. She is as engaging in print as she was in person, bringing her passion and advocating for this often misrepresented group. Using accessible but still technical language style to convey neurological and psychological information to the reader, she engages you with stories from her own adolescence. Each chapter builds on the preceding ones, gradually leading the reader from point to point, describing the evidence, from clinical trials to university studies everything is presented clearly and in a nonbiased way conflicting reports are mentioned along with possible reasons for discrepancies. Personal experiences and examples from the author put the discussion into a real-world context, and the underlying message is on the duality of adolescence as a time of great vulnerability but also enormous creativity. The discussion is interesting and engaging, and this was very enjoyable to read. It gives a new perspective on the teenage behaviour we all remember, either from ourselves or our peers, and what we see today. Definitely recommended for anyone with an interest in neuroscience, psychology or anyone dealing with teenagers! Emma Pettengale (The Biochemical Society/Portland Press) Postgraduate Handbook: A comprehensive guide for PhD and master s students and their supervisors by Aceme Nyika Many postgraduates still remain uncertain and doubtful about the core characteristics of being graduated even after good grades, which is learning the abilities of critical and independent thinking. Self-driven active learning and clear motivation for undertaking postgraduate studies are the key factors, and it is therefore necessary to learn these while performing postgraduate studies at university. In this book, Aceme Nyika chooses to explore, in-depth, various factors which should be considered before going to university to pursue higher studies. Critical and independent thinking should be developed from early postgraduate studies which can help you to become more independent in research later in your career, which is a necessary factor to survive as explained. This book not only gives an idea of why you should pursue postgraduate studies, but also an overview of various types of postgraduate programmes. Thereafter, focus on learning abilities, data analytical skills and writing skills must be learned while doing postgraduate studies, to perform quality research. Although thousands of books are available on research methodology with more specific subject-based explanations, this book is quite handy and easy to adopt for some basics of research methodology to keep the contents on track. The relationship between early-career researchers (for masters and doctoral students) and their mentors are still underestimated, but it is one determining factor which must be considered a high priority. It is difficult for texts to explain situations that exist between students and mentors during the period of study (because of realtime scenarios), some principles have been described to understand this relationship. A good part of the book is, as the author explains with case studies, is where some PhD students share their experiences with their supervisors the chapter is entitled Guy! Let me tell you about my PhD supervisor. This helps to understand various situations in terms of practicalities and approaches, while growing professionally during postgraduate studies. Raj Rajeshwar Malinda (National Institute for Basic Biology, Japan) Brain surgery By Benoît Leblanc ( October 2018 Biochemical Society 39

42 Back reactions Prize Crossword N.A. Davies Across 3. Major brain region that coordinates movement (10) 5. Mantle anatomy of the cerebral cortex (7) 7. The potential for something to happen in a nerve (6) 8. Uneasy or apprehensive (7) 10. Centre relating to smell (9) 14. Region where impulses are transmitted (7) 16. The study of the nervous system (9) 18. Functional unit of the brain (6) 19. Oblongata; stalk-like structure of the brain (7) 20. Colour of pure snow (5) Down 1. Ascending axis of a plant (4) 2. Centre of thought (5) 4. That which occupies space (6) 6. Ability to recall (6) 7. Threadlike extensions of 18 across (5) 9. A cavity within the brain (9) 11. Anatomical division of an organ (4) 12. Star shaped cell (9) 13. Grey matter structure for sensory transmission at the rear of the forebrain (8) 15. Connecting fibres within the brain (4) 17. That between white and black (4) 19. That which influences movement (5) Solutions to the crossword featured in the August 2018 issue are: Across: 5.Microbial, 9.Crop, 10.Alginate, 11.Tolerance, 12.Protein, 13.Agronomy, 16.Insect, 19.Allergen, 20.Yeast, 21.Iron Down: 1.Entomophagy, 2.Resistance, 3.Rice, 4.Banana, 6.Nutrients, 7.Texture, 8.Disease, 14.Natural, 15.Vitamin A, 17.Starch, 18.Soy Crossword Competition Win This month s crossword prize is a Hippocampus brain tissue 16OZ travel mug. Simply the missing word, made up from letters in the highlighted boxes to by Monday 5 November. Please include the words October crossword competition in the subject line. Congratulations to the winner of the August competition: Peter Hambleton The missing word from last issue s competition was potato. Peter Hambleton received a Science4you Sweet Factory Kit. Terms and conditions: only one entry per person, entrant must be a current Biochemical Society member; closing date Monday 5 November The winner will be drawn independently at random from the correct entries received. The winner will receive a Hippocampus brain tissue 16OZ travel mug. No cash alternative available. No employee, agent, affiliate, officer or director of Portland Press Limited or the Biochemical Society is eligible to enter. The winner will be notified by within 7 days of the draw. The name of the winner will be announced in the next issue of The Biochemist. The promoter accepts no responsibility for lost or delayed entries. Promoter: Biochemical Society, Charles Darwin House, 12 Roger Street, London WC1N 2JU; do not send entries to this address. 40 October 2018 Biochemical Society

43 Biochemical Society membership Discover the benefits including: Access to a range of grants and bursaries to support your research and travel Savings of up to 375 on Open Access article publishing fees in Portland Press journals * Up to 100 discount on registration fees at Biochemical Society events Opportunities to submit proposals for Biochemical Society events Up to 1500 to run a seminar series in your institution Personal online access to Biochemical Journal and Biochemical Society Transactions Automatic membership of the Federation of European Biochemical Societies (FEBS) and access to FEBS Fellowships Join now at biochemistry.org/join * Portland Press Limited (Company Number ) is the wholly owned trading subsidiary of the Biochemical Society (registered charity No ) Vat No. GB /2018

44 NEURONAL SIGNALING Covering all aspects of signaling within and between neurons THE NEXT HOME FOR YOUR PAPER SUBMIT YOUR BEST RESEARCH AT neuronalsignal.msubmit.net = Fully Open Access PortlandPressPublishing 10/18