Monthly Archives: February 2016

History and Historical Revisionism – Is What We Read Of The Past Ever A True Reflection Of How It Really Happened

This week I was alerted to a wonderful quote about books and reading – ‘the miracle of literature is that it can get you to understand, even a tiny bit, what it is like to be another human being’. My all-time favourite quote on reading before finding this one, goes ‘I read to realize I am not alone’. I have always been a ‘bookworm’ throughout just about all of my life. My mother often used to laugh in my pre-teen years, as whenever she called me, I would never hear her, as my head was always ensconced in a new book, and my mind always enthralled by tales created by great writers of the past to a level that the fiction of what I was reading often claimed more of my attention than that of the reality around me. As I grew older and became an academic, my taste for reading changed completely away from fiction to non-fiction, and I am sure whatever intelligence, viewpoints, perceptions and way of reasoning I have developed is mostly down to what I have read and absorbed from reading (obviously social interactions, particularly with significant role models, either negative or positive, played their part in my development too). A significant discussion with a highly respected old family friend, Simon Pearce, in my early thirties, when he said to me I should read history to best understand life, had a profound impact on me, and while always being interested in history, perhaps because of this advice from someone whose intellect I greatly admire, the last decade I have read a lot of history, and have indeed benefitted I think from doing so in many ways. But history, and the description of it, can be a ‘treacherous’ teacher, given that it is by nature reflective, dependent on the world-view and background of the historian who writes it, and a product of the contemporary zeitgeist of the current period of time in which it was or is written, and one therefore has to be very careful of how much one ‘believes’ of what one reads of history as being truly representative of the events as they happened in the times they describe.

History is defined as the study of past events, especially of human affairs. The word history is thought to have come from the Ancient Greek word ‘historia’, meaning ‘inquiry’ or ‘judge’. Historians are folk who write about history, and it is still controversial if a historian should be merely a chronicler or compiler of past events, or a critical analyst of them. Generally it is perceived that written documentation or transcripts of past events are necessary for historical accounts to be both assimilated and described, and events occurring prior to the presence of written records are described as ‘pre-historic’, and fall in to the realm of archaeological based academic work. We therefore have a relatively short period of historical ‘knowledge’, given that the first texts written have only survived from a few thousand years in the past, and the great period of human life and ‘history’ prior to these is virtually unknown, save what can be gleaned from archaeological digs and speculation from what is found in them. History is divided up into a number of fields of study, from a generic perspective which includes comparative history (historical assessment of social and culture entities that are not confined to national boundaries) and counterfactual history (the study of history as it might have happened had different circumstances arisen), and from a specific perspective includes the history of particular epochs of time or the history of specific human activities (such as military or economic history).

Academic researchers studying the field of history occupy themselves with identifying and solving the philosophical conundrums related to studying history such as what the correct ‘unit’ of study of the past is (for example is it the individual human condition, or the prevalent culture of the time, or the activities of the nation or state and how it impacted on the individual and other nations or states around them), and whether from history patterns or cycles of behaviour at either the individual or nation level can be determined. As described above, a ‘problem’ of history is that it is always written at a certain contemporary time, which will have a dominant social thinking and view of the past, and it is surely difficult for a historian not to be affected by this when writing their own account of whatever component of history they are involved with writing about. An even more post-modern view which has been suggested is that history as a concept is irrelevant from a generic perspective, as the study of history is always reliant on a personal interpretation of sources, and thus ‘history’ as a general concept is a redundant one. History writing itself often moves in ‘patterns’ of its own, with some epochs focussing more on ‘glorifying’ the successes of nations or ‘great’ individuals in history (and clearly many nations create ‘official’ historical publications as a way of glorifying their past, or justifying / ‘cleansing’ the more sordid components of their past) with subsequent epochs of history writing challenging these ‘glorious’ interpretations of history in a more dispassionate and reasoned way.

A good example of all of the interest of history as a subject, how it can be revised and manipulated for national or individual ‘gain’, and how with reflection a more balanced interpretation of the true nature of history is derived became evident to me after ‘studying’ from a reading of history perspective the role of Winston Churchill in World War Two. Churchill was, and perhaps still is, surely one of the most well-known figures in history in the Western world, and if you polled folk for their knowledge and opinion of him, they would say he was the person who saved Britain during the war, and / or led the country to ultimate triumph during the war in a heroic and masterful way (though even the knowledge of Churchill is becoming ‘dimmed’ with the passing of time as it does with all people). My own interest in him, and the World War Two period, stemmed from growing up in the 60’s and 70’s with a father who had an interest in military history and was for a short period of time in the civilian force military, and with the knowledge that a grandfather had fought in World War Two and was interned for a long period of it. On our bookshelf in the home of my youth were all Churchill’s volumes he himself wrote on the history of World War Two in the decade after it ended, and I remember with fondness many discussions with my Dad, or between him and his friends that I listened to way back then, describing or arguing about Churchill’s leadership during the war, and the merits of his place in the pantheon of successful military and political war leaders in general historical terms.

I had a mostly positive viewpoint regarding Winston Churchill and his part in ‘winning the war’ because of these early experiences of ‘history according to Dad’ for most of my life, until I started reading more carefully other accounts of the events during the war and Churchill’s part of them. The most startling of these accounts which very much changed my perspective on Churchill were the war diaries of General (later Field Marshal) Alan Brooke, who was the Chief of the Imperial General Staff (CIGS) and military leader of all Britain’s ground forces, and worked in tandem with Churchill who was the political leader. Diaries are fascinating, given that as long as they are not altered at a later point in time, they tell things ‘how they are’ on a daily basis, albeit with the particular viewpoint of the person writing them, and I have read and re-read Brooke’s diaries between 10 and 20 times to date (and they are about 1000 pages in length, so each doing so was surely a ‘labour of love’) given how astonishing the information described in them is. For what became clear to me when reading them, is that Churchill, in writing his own version of the ‘history of World War Two’ after it was complete, essentially wrote an autobiography giving his own interpretation of his own role during the war, and as such (like so many autobiographies) glorified his own role, attenuated or ignored his own responsibilities for the more sordid or disastrous events Britain suffered or was part of during the war, and perhaps most shamefully, was not generous in acknowledging the role of people around him in ‘winning the war’ (and I am talking person wise, rather than country wise – surely Russia can take almost 90 percent of the credit for ‘winning’ that war). Some of the most disastrous campaigns of the war – Norway and Greece for example – were shaped and driven by Churchill himself, yet from reading his books one would assume that the British and Allied Force Generals were almost solely to blame for these disasters, and that he was almost completely uninvolved in the strategic or tactical decisions that led to them. Throughout the war he constantly tried to push forward strategically appalling choices for campaigns – one example being his constant ‘push’ for an expedition against the ‘northern tip’ of Sumatra – which his military staff had to work daily to resist him initiating, and which would have dispersed the forces available in a disastrous ‘minor campaign’, similar to the Gallipoli and Antwerp campaigns in World War One, of which Churchill was similarly the architect. It is astonishing to read Brooke’s diary (and the diaries or personal war accounts of a number of other military and political staff of that time, most of which validate Brooke’s diary account of the war) to see how many times his advisors and folk like Brooke had to spend most of their day ‘heading off’ or convincing Churchill not to continue with his wild schemes, rather than what appeared to be the case when reading Churchill’s own written accounts of World War Two, when it appeared as if Churchill was the architect of all successes, and his military staff merely carried out his great ideas. And this is to say nothing about Churchill’s role in the area bombing of Germany, or his astonishing ‘imperial’ (a nice word for racially biased) views on India, or his personal habits, or injudicious views on most subjects freely imparted to all and sundry on an almost continuous basis. If he was a politician in modern times, with the current daily media scrutiny they face, he would surely not have lasted more than a few days before having to resign in disgrace and shame as a result of his utterances and behaviour as a Prime Minister as he did in those times back then.

All of the fascinating and enjoyable time I have spent reading about this topic, apart from being a relaxation ‘tool’ in itself, did indeed, as our great old family friend Simon Pearce said it would, teach me a whole lot of lessons about not just history, but life itself. Firstly, it taught me that the character of any ‘great’ person, or indeed any person, is surely complex, and while someone like Winston Churchill surely had a number of attractive and positive traits, he also had a lot of negative and extremely selfish traits that unless carefully ‘looked for’ would not ‘reach the light of day’ when reading most historical accounts either of his life or that of World War Two. Secondly, it taught me that one needs to be cautious in believing only one account of anything, least of all the person who is the one telling the story / giving the account of how things happen. Thirdly, it taught me that history if often created by those involved in it who write about it afterwards in a way that will benefit that person themselves in an unduly positive way (as they say, history is mostly written by the ‘winners’ of any event being written about). Fourthly, it taught me not to put anyone on a pedestal from reading about past events that they were involved in – as my great current work mentor, Professor Nicky Morgan, often reminds me, even the greatest leaders have ‘feet of clay’. Fifthly, it taught me never to have a fixed paradigm about anything from the past – my own interpretation of and ‘feeling for’ this period of history was very different in the time of hearing about the events then as told by my father, or reading Winston Churchill’s own books about World War two as a teenager, compared to the more complex, less positive perspective I have of Winston Churchill and the events occurring during World War Two today, thanks to a reasonably extensive reading of different sources of information of events occurring at that time in the last few years. Finally, it made me think about the importance of diaries – a long lost ‘art’ that perhaps needs to be revived – there is much to be gained from keeping a daily diary about events. If Alan Brooke had not spent a few minutes before bed each night writing up a description of his daily life working in close proximity to Winston Churchill in his diary, we would be the poorer for not having it, and our understanding of events way back then would remain simplistic and perhaps unbalanced.

There are surely, therefore, a lot of lessons one can learn not just about history and historical revisionism (as Churchill’s own post-war writings of events surely were), but also in understanding contemporary life and how in describing it some folk who want to personally gain from the telling of it, may be able to do so by how they subjectively describe events of which they were part. There is surely a positive gain from keeping a daily or weekly diary, so that one can be to a greater degree sure of one’s own history, or at least of the events happening during a particular period of time from one’s past if one wishes to review it, than if one did not have a recorded history of it. Equally, one surely needs to be aware when reading the ‘official’ history of any person, organization, community or nation state, that it may be written with potentially (some would say surely) an either subconscious or conscious / overt or covert bias (as much as it should also be remembered that each time one personally reflects on or writes about an experience one has been part of, it will surely also have one’s own particular bias and perspective), and should therefore always be read with caution. Reading, and for me particularly reading about history, is both one of the most enjoyable activities that I can ever do, and the activity that I learn most from, but I know that a lot of what I read, particularly biographies, and certainly autobiographies, need to be read with a large ‘pinch of salt’. So when I am done with writing this, I will surely look forward to later today taking up again the current historical tome I am enjoying reading. But, surely, I will read it with our salt-shaker very close to me!

Cell Function And Metabolic Flux Control – The Puzzle of Regulation of Massive Numbers Of Continually Occurring Processes In A Spatially Challenged Environment

In the early years of my medical training, many years ago, it was hugely exciting to learn the basic science of how the body functioned, before we learnt about the pathological processes affecting body function, and how to treat these. Two visual memories have always stuck in my mind from the lectures I attended back then. These were both of some brilliant diagrams drawn on the blackboard during these basic physiology and anatomy lectures by two charismatic teachers. The first was of the neural pathways flowing to and from the brain, and these complex but organized information directing structures were drawn with such clarity that they entranced me, to the extent that they perhaps in part led to me becoming an integrative neuroscience and system regulation researcher for much of my career. The second blackboard drawing I remember was of the metabolic pathways of a cell, which made me feel a sense of awe regarding the complexity and sheer volume of processes and structures present in a cell when I saw them for the first time as line drawings on the blackboard way back then. Being throughout my life more of a systems and processes, rather than a specifics and detail, type of thinker and person, these cell pathway pictures made me feel a touch ‘queasy’, no matter how beautiful they were drawn, and this ‘queasiness’ I felt then perhaps moved me ‘away’ from molecular or cellular biology as a career choice, because intuitively I knew even then I would never have the capacity, or interest, to learn each different enzyme or DNA or protein structure in the cell, and how each of these ‘worked’ to provide the basic energy needed to sustain life as we know it. A couple of days ago, Professor Craig Sale, one of the UK’s foremost Physiology and Exercise Science researchers, and surely one of the nicest persons on the planet, posted a fascinating review article on Twitter examining basic cellular metabolism changes related to exercise to rest transitions, and reading about the associated changes in ATP, NADH, and CrP, amongst other cellular substrates and enzymes described in this review article, reminded me of those flow diagrams of my medical training days, and got me thinking about the basic function of the cell, and how the flux of all these basic cellular substrates is managed in the microscopic cellular environment.

The cell is the basic structural and functional unit of any organism, including us humans. One’s entire body is made up of cells, and it is thought that each person consists of around 10 trillion cells (a number so vast I can’t get my head around it). While the cells making up different structures in the body like skin, muscle, bone have some differences in their structure and function, the basic ‘makeup’ of all cells is almost identical, and fascinatingly from an evolutionary perspective works similarly across all species and indeed most living structures. Each cell is surrounded by a cell membrane, and has a number of organelles in it that are important for its survival and optimal function, including a nucleus (where the cell’s DNA is stored which is important for replication), mitochondria (the energy creating ‘powerhouses’ of the cell), and several storage and structure creating entities known as the Golgi apparatus and endoplasmic reticulum, amongst others. The cell membrane is important not just for structural integrity, but also for controlling the movement of substrates, fuels, metabolites and signalling molecules into the cell, using enzyme related receptor mechanisms. The cell’s interior consists of a fluid substance known as cytoplasm, in which enzymes and cofactors either break down carbohydrates, fats and proteins into basic energy products (the basic energy molecule in the cell is adenosine triphosphate – ATP) in a process known as catabolism (this process also occurs at a rapid, energetically efficient process in the mitochondria), or builds up structural components required to repair damage in the cell, or to create a second cell when the cell replicates, in a process known as anabolism.

In either the cytoplasm of the cell, or the mitochondria, are the numerous metabolic ‘pathways’ which were so elegantly drawn for us in our student days, and as a ‘cascade’ through numerous sequential intermediary products in a process managed by sequential enzymes and co-enzymes, fuels such as carbohydrates and fats are catabolised into basic energy products such as ATP. For example in the cytoplasm of the cell, the ‘glycolytic’ pathway occurs, while in the mitochondria the ‘Krebs cycle’ and ‘citric acid cycle’ are different catabolic pathways. Oxygen is a necessary requirement of the mitochondrial basic energy producing processes which are therefore defined as ‘aerobic’ pathways, while the cytoplasmic glycolytic processes do not require oxygen, and are defined as ‘anaerobic’ pathways. The anaerobic glycolytic pathways are not as efficient in producing basic energy as the aerobic pathways, and produce metabolic by-products which need to be removed from the system, such as lactic acid. Because lactic acid builds up during high intensity exercise like sprints or other ballistic / maximal activity, it is thought that during high intensity exercise the cells become oxygen deprived or ‘anaerobic’, and the glycolytic pathways are use preferentially and as a final energy ‘reserve’, though whether cells are ever completely oxygen deprived and therefore rely on ‘anaerobic’ mechanisms to produce fuel during activities of daily living or during exercise is still controversial. There are an enormous amount of different pathways in a cell, and seemingly each month, a new enzyme, co-factor, intermediate product, or metabolic by-product is discovered, which creates an even more complicated ‘picture’ of the working environment in each cell.

The regulation of these complex cellular activities and structures has focussed principally on metabolic flux and enzyme kinetic processes. Metabolic flux is defined as the rate of turnover of molecules through a specific metabolic pathway, and describes the ‘movement’ of substrates or intermediary products ‘through’ a specific pathway. Metabolic flux is related to the ‘need’ of both the general body and specific cell environment for energy, and is increased when there is greater need (for example when one exercises), or when there is greater substrate present (for example after a meal). One of the most amazing things in science is how each of the different ‘steps’ of each pathway increases sequentially and in a temporally co-ordinated way when increased need or increased substrate availability occurs, to ensure that the pathways work correctly and are not ‘overwhelmed’ whenever there is the need for increased activity in all its component parts. This coordinated increase in activity in an entire metabolic pathway is thought to be controlled by increased and optimized enzyme function at each step of the specific pathways processes. Enzymes are protein molecules that can ‘manipulate’ and therefore control other molecules and substrates, and enzyme kinetics is defined as the study of the chemical reactions that are regulated by enzymes. When there is increased energy requirements, the function of the pathway’s enzymes is up-regulated, in order to ‘deal with’ the increased demand. The function of an enzyme can be plotted (for those technically minded folk an example of this is the Michaelis-Menten function equation) as substrate concentration increases, and generally at the start of a period of increased ‘need’, enzyme activity at each different step of a metabolic pathway is rapidly increased to compensate for the increased requirement. Subsequent to this initial rapid increase in enzyme activity, enzyme activity ‘levels out’ as the absolutely maximal activity capacity of the enzyme is reached. The enzyme kinetic / cell regulation researcher folk suggest that the rate limiting capacity of any pathway (and therefore the energy creating ‘controller’) is that of the enzyme with the ‘lowest’ functional capacity – in other words, the enzyme in a pathway that can least up-regulate its function in a time of increased energy demand or increased energy fuel supply, is the factor that controls the metabolic properties and activity of that particular cell. In this paradigm, therefore, the human body’s physical functional capacity is related to these cellular-level rate limiting enzymes, together with the quantity of energy fuels available that can be used by the enzymes.

All this knowledge of basic cell structure and function, that is still increasing incrementally (perhaps even exponentially) as yet another cellular regulatory molecule, enzyme or membrane signalling / transduction regulatory protein is discovered, still fills me with as much awe today as it did nigh on thirty years ago when I first learnt about it as a first year medical student. But, I do believe that a lot more research is needed in the field of cellular metabolic regulation for us to have a clearer understanding of its regulatory processes. Indeed, the wonderful ‘pictures’ drawn of the metabolic pathways may, in a paradoxical way given that they are so complex, be describing cellular regulatory mechanism in a too simplistic manner, and we perhaps have a long way to go still to fully understand regulatory control mechanisms at the cellular level. For example, hundreds, if not thousands of different metabolic pathways are actively catabolizing substrate fuels, or synthesizing new structural molecules, at any one point in time. Likewise, thousands, if not millions of different individual molecules are being acted upon, or are acting upon other molecules, in any one cell at any single point in time. How the integrity and fidelity of each metabolic pathway is maintained in the face of all this co-existing ‘other’ metabolic activity has still not been determined. How each molecule ‘knows’ where it ‘has to go’, and where in the cell it will be acted upon, at a single point in time, let alone in the required temporally appropriate manner, is still pretty much unknown. Equally, how the function of individual cells is harmoniously regulated as a component of the gestalt millions and billions of cells in a specific organ, which all must be similarly up-regulated in time of need or increased substrate concentration, and then down-regulated at time of work-rest transition, is not understood at all. Whether different specific cells have different efficiencies and metabolic milieus compared to that of their neighbours, has also not been determined, and for us to have knowledge of this conundrum will need spectacular new laboratory techniques to be developed. How the afferent ‘messages’ from each cell become a gestalt ‘message’ to the brain which ‘suggest’ a requirement for an initiation of behavioural change, when for example fuel supplies are depleting, is also completely unknown, as is how each different cell receives similar efferent information to either increase anabolic or catabolic need as it is required. Furthermore, the relationship between the ‘physical’ control processes such as enzyme kinetic control process or metabolic flux determinants, and electrical / electromagnetic energy, is not clear. All active metabolic control mechanisms are underpinned by electrical activity changes, or at least electrical activity can be detected in cells whenever physical chemical changes occur in the cell. One of the most interesting research papers I have ever read described a study of NADPH activity in macrophage cells. When interleukin-6, a humoral (blood / fluid related) signalling / regulatory molecule was added to the cells, the concentrations of NADPH increased. When an electrical current was supplied to the cells along with interleukin-6, the concentration of NADPH increased even more than when just the interleukin-6 was added. How this ‘piezo-electric’ electrical / chemical interaction works at the cellular level is still not clear, as is whether electrical, or electromagnetic activity, are subsidiary or integral components of cells and their metabolic regulation.

A beautiful picture or line drawing of a particular metabolic pathway of a cell gives us therefore a ‘snapshot’ of the processes involved in that particular pathway, but does not give us the full picture of what must be ‘dizzying’ real life / real time activity occurring as a hugely complex, interactive, always changing, process and environment in any one cell, let alone in an aggregation of cells. How control processes occurs in not just one cell but similarly in many cells is another problem of an order of magnitude greater than we can perhaps currently understand with our available research techniques and conceptual frameworks we use to understand such function, which usually involve breaking down such dynamic processes into its composite parts to allow easier explanation. By reducing the complexity such in order to do so, we perhaps lose our capacity to understand the ‘gestalt’ control processes and mechanisms in the cell. A good scientist will always be humbled by the awareness of how much activity, and how much regulatory control, is required for even a single, ‘simple’ cell, which is the basic building block of all physical life processes and structures we know of and are made of. An integrative systems scientist like myself will always admire and respect the work done by the scientist folk who work at solving the ‘detail’ that exists in each cell and its individual component. But the big questions of cellular function and metabolic regulation are still surely ahead of us to be answered, and beautiful flow diagrams of cellular metabolic regulatory pathways, as those which will always be engraved in my mind from those seminal days of my academic youth were, will never be sufficient to allow understanding of the ‘place’ of the regulatory processes in the cell in the bigger picture of the regulation of life as we know it.

Perhaps using a three dimensional high-tech video clip of real time cellular activity, some charismatic lecturer, way in the future, will be able to explain to some young medical students how it really does all work, when I have long been resting in my pine box, and my cells are of the earth and being used as energy for another generation of cells in another future scientists body. Time will tell. But, for now, I will have to be satisfied with the memory of those beautiful drawn cellular pathways, and keep trying to remember the names of each substrate, enzyme and intermediate metabolite associated with them. And if I could go back in time, I would tell those two great lecturers that their drawing skills and passion for their subject matter were still remembered thirty years down the line, and inspired a career choice for me!

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