Tag Archives: Negative feedback

Homeostasis And The Constancy Principle – We Are All Creatures Of Comfort Even When We Go Out Of Our Comfort Zone

It is autumn in our part of the world, and the first chills are in the air in the late evening and early morning, and the family discussed last night the need to get out our warm clothes from storage in readiness for the approaching winter, in order to be well prepared for its arrival. After sharing in the fun of Easter Sunday yesterday and eating some chocolate eggs with the children, a persistent voice in my head this morning instructed me to eat less than normal today to ‘make up’ for this out of the normal chocolate eating yesterday. It is a beautiful sunny day outside as I write this, and I feel a strong ‘urge’ to stop writing and go out on a long cycle ride because of it, and have to ‘will’ these thoughts away and continue writing, which is my routine activity at this time of morning. After a recent health scare I have been checking on my own physical parameters with more care than normal, and found it interesting when checking what ‘normal’ values for healthy folk are, that most healthy folk have fairly similar values for things like blood glucose, blood pressure, cholesterol concentrations and other such parameters, and that there are fairly tight ranges of values of each of these which are considered normal and a sign of ‘health’, and if one’s values are outside of these, it is a sign of something wrong in the working of your body that needs to be treated and brought back into the normal range either by lifestyle changes, medication, or surgical procedures. All of these got me thinking about the regulatory processes that ensure that the body maintains its working ‘parts’ in a similar range in all folk, and the concept of homeostasis, which as a regulatory principle explains and underpins the maintenance of this ‘safe zone’ for our body’s multiple activities, including the sensing of any external or internal changes which could be associated with the potential for one of the variables to go out of the ‘safe zone’, and initiates changes either behaviourally or physiologically which attempt to bring the variable at risk back into the ‘safe zone’ either pre-emptively or reactively.

Homeostasis is defined scientifically as the tendency towards a relatively stable equilibrium between inter-dependent elements. The word was generated from the Greek concepts of ‘homiois’ (similar) and ‘stasis’ (standing still), creating the concept of ‘staying the same’. Put simply, homeostasis is the property of a system whereby it attempts to maintain itself in a stable, constant condition, and resists any changes or actions on the system which may change or destabilize the stable state. It’s origins as a concept were from the ancient Greeks, with Empedocles in around 400 BC suggesting that all matter consisted of elements which were in ‘dynamic opposition’ or ‘alliance’ with each other, and that balance or ‘harmony’ of all these elements was necessary for the survival of the individual or organism. Around the same time, Hippocrates suggested that health was a result of the ‘harmonious’ balance of the body’s elements, and illness due to ‘disharmony’ of the elements which it was made up of. Modern development of this concept was initiated by Claude Bernard in the 1870’s, who suggested that the stability of the body’s internal environment was ‘necessary for a free and independent life’ and that ‘external variations are at every instant compensated for and brought into balance’, and Walter Cannon in the 1920’s first formally called this concept of ‘staying the same’ homeostasis. Claude Bernard actually initially used the word ‘constancy’ rather than homeostasis to describe the concept, and interestingly, a lot of Sigmund Freud’s basic work on human psychology was based on the need for ‘constancy’ (though he did not cross-reference this more physiological / physical work and concepts), and that everyone’s basic needs were for psychological constancy or ‘peace’, and when one had an ‘itch to scratch’ one would do anything possible to remove the ‘itch’ (whether it be a new partner, a better house, an improved social status, or greater social dominance, amongst other potentially unrequited desires), and further that one’s ‘muscles are the conduit through which the ego imposes its will upon the world’. He and other psychologists of his era suggested that if an ‘itch’, urge or desire was not assuaged (and what causes these urges, whether a feeling of inadequacy, or previous trauma, or a desire for ‘wholeness’, is still controversial and still not clearly elicited even today), the individual would remain out of their required ‘zone of constancy’, and would feel negative emotions such as anxiety, irritation or anger until the urge or desire was relieved. If it was not relieved for a prolonged period this unrequited ‘itch’ could lead to the development of a complex, projection or psychological breakdown (such as depression, mania, anxiety, personality disorder or frank psychosis). Therefore, as much as there are physical homeostasis related requirements, there are potentially also similarly psychological homeostasis related requirements which are being reacted to by the brain and body on a continuous basis.

Any system operating using homeostatic principles (and all our body systems do so) has setpoint levels for whatever substance or process is being regulated in the system, and boundary conditions for the substance or process which are rigidly maintained and cannot be exceeded without a response occurring which would attempt to bring the activity or changes to the substance or process back to the predetermined setpoint levels or within the boundary conditions for them. The reasons for having these set boundary conditions are protective, in that if they were exceeded, the expectation would be the system would be damaged if the substance or process being regulated (for example, oxygen, glucose, sodium, temperature, cholesterol, or blood pressure, amongst a whole host of others) was used up too quickly or worked too hard, or was allowed to build up to toxic / extremely high levels or not used enough to produce life-supporting substrates or useable fuels, which would endanger the life and potential for continued activity of the system being monitored. For example, oxygen shortage results in death fairly quickly, as would glucose shortage, while glucose excess (known as diabetes) can also result in cellular and organ damage, and ultimately death if it is not controlled properly. In order for any system to maintain the substance or process within homeostasis-related acceptable limits, three regulatory factors (which are all components of what is known as a negative feedback loop) are required to be components of the system. The first is the presence of a sensory apparatus that can detect either changes in whatever substance or process is being monitored, or changes in the internal or external environment or other systems which interact with or impact on the substance or process being monitored. The second is a control structure or process which would be sent the information from the sensory apparatus, and would be able to make a decision regarding whether to respond to the information or to ignore it as not relevant. The third is an ‘effector’ mechanism or process which would receive commands from the control structure after it had made a decision to initiate a response in response to the sensed perturbation potentially affecting the system it controls, and make the changes to the system decided upon by the control structure in order to maintain or return the perturbed system to its setpoint value range.

The example of temperature regulation demonstrates both the complexity and beauty of homeostasis in regulating activity and protecting us on a continuous basis from harm. Physiological systems in most species of animals are particularly sensitive to changes in temperature and operate best in a relatively narrow ranges of temperature, although in some species a wider range of temperatures is tolerated. There are two broad mechanisms used by different organisms to control their internal temperature, namely ectothermic and endothermic regulation. Ectothermic temperature regulators (also known as ‘cold-blooded’ species), such as the frog, snake, and lizard, do not use many internal body processes to maintain temperature in the range which is acceptable for their survival, but rather use external, environmental heat sources to regulate their body temperature. If the temperature is colder, they will use the sun to heat themselves up, and if warm, they will look for shadier conditions. Ectotherms therefore have energy efficient mechanisms of maintaining temperature homeostasis, but are more susceptible to vagaries in environmental conditions compared to endotherms. In contrast, endotherms (also known as ‘warm-blooded’ species), into which classification humans fall, use internal body activity and functions to either generate heat in cold environments or reduce heat in warm conditions. In endotherms, if the external environment is too cold, and if the cold environment impacts on body temperature, temperature receptors measuring either surface skin temperature or core body temperature will send signals to the brain, which subsequently initiates a shiver response in the muscles, which increases metabolic rate and provides greater body warmth as a by-product of fuel / energy breakdown and use. If environmental temperature is too warm, of if skin or core temperature is too high, receptors will send signals to brain areas which initiates a chain of events involving different nerve and blood-related control processes which result in increased blood flow to the skin by vasodilatation, thereby increasing blood cooling capacity and sweat rate from the skin, thus producing cooling by water evaporation. All these endotherm associated heating and cooling processes utilize a large amount of energy, so from an energy perspective are not as efficient as that of ectotherms, but they do allow a greater independence from environmental fluctuations in temperature. It must be noted that endotherms also use similar behavioural techniques to ectotherms, such as moving into shady or cool environments if excessively hot, but as described above, can tolerate a greater range of environmental temperatures and conditions. Furthermore, humans are capable of ‘high level’ behavioural changes such as putting on or taking off clothes, in either a reactive or anticipatory way. It is evident therefore that for each variable being homeostatically monitored and managed (on a continuous basis) there are a complex array of responsive (and ‘higher-level’ pre-emptive) options available with which to counteract the potential or actual ‘movement’ of the variable beyond its ‘allowed’ metabolic setpoints and ranges.

There are a number of questions still to be answered regarding how homeostasis ‘works’ and how ‘decisions’ related to homeostasis occur. It is not clear how the regulatory mechanisms know which variable they ‘choose’ to defend as a priority. Brain oxygen would surely be the most important variable to ‘defend’, as would perhaps blood glucose levels, but how decisions are made and responses initiated for these variables preferentially, which may impact negatively on other systems with their own homeostatic requirements, is not clear. Furthermore, there is the capacity for ‘conflict’ between physical and psychological homeostatic mechanisms when homeostatic-related decisions are required to be made. For example, one’s ego may require one to run a marathon to fulfill a need to ‘show’ one’s peers that one is ‘tough’ by completing such a challenging goal, but doing so (running the marathon) creates major physical stress for and on the physical body. Indeed, some folk push themselves so hard during marathons that they collapse, even if they ‘feel’ warning signs of impending collapse, or of an impending heart attack, and choose to keep running despite these symptoms. To these folk, the psychological need to complete the event must be greater than the physical need to protect themselves from harm, and their regulatory decision-making processes clearly valences psychological homeostasis to be of greater importance than physiological homeostasis when deciding to continue exercising in the presence of such warning symptoms. However, running a marathon, while increasing physical risk of catastrophic physical events during the running of it, if done on a repetitive basis has positive physical benefits, such as weight loss and increased metabolic efficiency of the heart, lungs, muscles and other organ structures, along with enhanced psychological well-being which would be derived from achieving the set athletic performance-related goals. Therefore, ‘decision-making’ on an issue such as running a marathon is complex from a homeostasis perspective, with both short and long term potential benefits and harmful consequences. How these contradictory requirements and factors are ‘decided upon’ by the brain when attempting to maintain both psychological and physical homeostasis is still not clear.

A further challenge to homeostatic regulation is evident in the examples of when one has a fever, where a high temperature may paradoxically be beneficial, and after a heart attack, where an altered heart rate and blood pressure setpoint may be part of compensatory mechanisms to ensure the optimal function of a failing heart. While these altered values are potentially ‘outside’ of the ‘healthy’ setpoint level range, they may have utilitarian value and would be metabolically appropriate in relation to either a fever or failing heart. How the regulatory homeostatic control mechanisms ‘know’ that these altered metabolic setpoints are beneficial rather than harmful, and ‘accepts’ them as temporary or permanent new setpoints, or whether these altered values are associated with routine homeostatic corrective responses which are part of the body’s ongoing attempt to induce healing in the presence of fever or heart failure (amongst other homeostatically paradoxical examples), is still not clear. Whether homeostasis as a principle extends beyond merely controlling our body’s activity and behaviour, to more general societal or environmental control, is also still controversial. For example, James Lovelock, with his Gaia hypothesis, has suggested that the world in its entirety is regulated by homeostatic principles, and global temperature increases result in compensatory changes on the earth and in the atmosphere that lead to eventual cooling of the earth, and this warming and cooling continues in a cyclical manner – and most folk who believe in global warming as a contemporary unique catastrophic event don’t like this theory, even if it is difficult to support or refute without measuring temperature changes accurately over millennia.

Homeostatic control mechanisms can fail, and indeed our deaths are sometimes suggested to be the result of a failure of homeostasis. For example, cancer cells overwhelm cellular homeostatic protective mechanisms, or develop rapidly due to uncontrolled cellular proliferation of abnormal cells which are not inhibited by the regular cellular homeostatic negative feedback control mechanisms, which lead to physical damage to the body and ultimately our death, for these or other reasons that we are still not aware of. In contrast, Sigmund Freud, in his always contrary view of life, suggested as part of his Thanatos theory that death in the ultimate form of ‘rest’ and is our ‘baseline’ constancy-related resting state which we ‘go back to’ when dying (with suicide being a direct ‘mechanism’ of reaching this state in those whose psyche are operating too far away from their psychological setpoints, whatever these are), although again this is a difficult theory to either prove or disprove. Finally, what is challenging to a lot of folk about homeostasis from a control / regulatory perspective is that it is a conceptual ‘entity’ rather than a physical process that one can ‘show’ to be ‘real’, much like Plato’s Universals (to Plato the physical cow itself was less relevant than the ‘concept’ of a cow, and he suggested that one can only have ‘mere opinions’ of the former, while one has absolute knowledge of the latter, given the physical cow changes as it grows, ages, and dies, while the ‘concept’ of a cow is immutable and eternal). It is always difficult scientifically to provide categorical evidence which either refutes or support concepts such as universals and non-physical general control theories, even if they are concepts which appear to underpin all life as we know it, and without which function we could not exist in our current physical form and living environment.

As I look out the window at the falling autumn leaves and wonder whether we will have a very cold winter this year and whether we have prepared adequately for it clothes-wise (pre-emptive long-term homeostatic planning at its best, even if perhaps a bit ‘over-the-top’), while taking off my jersey as I write this given that the temperature has increased as the day has changed from morning to afternoon (surely a reactive homeostatic response), and as I ponder my health-related parameters, and work out how I am going to get those that need improvement as close to ‘normal’ as possible (surely as part of behavioural homeostatic / health-optimization planning), I look forward to that bike ride now I have managed to delay gratification of doing so until I have completed writing this (and feel a sense of well-being both from doing so and by realizing I am now ‘free’ to go on the ride and by doing so can remove the psychological ‘itch’ that makes me want to do it and therefore return to a state of psychological ‘constancy’ / homeostasis). Contemplating all of these, it is astonishing to think that all of what I, and pretty much all folk, do is underpinned by a desire to be, and maintain life, in a ‘comfort zone’ which feels right for me, and which is best for my bodily functions and psychological state. Given that all folk in the world have similar physical parameters when we measure them clinically, it is likely that our ‘comfort zones’ both physically and psychologically are not that different in the end. Perhaps the relative weighting which each of us assigns to our psychological or physical ‘needs’ create minor differences between us (and occasionally major differences such as in folk with psychopathology or with those who have significant lifestyle related physical disorders), though at the ‘heart of it all’, both psychologically and physically, is surely the over-arching principle of homeostasis. While on the bike this afternoon, I’ll ponder on the big questions related to homeostasis which still need to be answered, such as how homeostasis-related decisions are made, how the same principle can regulate not just our body, but also our behaviour, and perhaps that of societal and even planetary function, and how ‘universals’ originated and which came first, the physical entity or the universal. Sadly I think it will need a very long ride to solve these unanswered questions, and remove the ‘itch that needs scratching’ which arises from thinking of these concepts as a scientist who wants to solve them – and I don’t like to spend too long out of my comfort zone, which is multi-factorial and not purely bike-focused, but rather is part bike, part desk, part comfy chair, the latter of which will surely become more attractive after a few hours of cycling, and will ‘call me home’ to my next ‘comfort zone’, probably long before I can solve any of these complex issues while out on the ride watching the autumn leaves fall under a beautiful warm blue sky, with my winter cycling jacket unused but packed in my bike’s carrier bag in case of a change in the weather.


The Negative Feedback Loop – The Absolute Fundamental Principle Governing All Life Processes

I was asked this week in my current work role to give a welcoming address to the Society for Endocrinology, Metabolism and Diabetes of South Africa later this year as the University of the Free State is hosting their annual conference this year. This got me thinking of diabetes as a disorder, which occurs as a result of the failure of regulation of blood sugar concentrations due to a number of different reasons and causes. Understanding generic regulatory processes and system control mechanisms and activity has been the major focus and interest of my research career to date, and I have spent a lot of my life trying to understand and make sense of what are life’s underlying governing principles. Perhaps the most basic control mechanism (and an astonishingly simple one), without which life could not exist in any shape or form, is the negative feedback loop, which can be described as either a governing principle or regulatory process.

Negative feedback is defined as occurring when some function or product which is the output of a system, process, or mechanism, is fed back into the same system in a manner that tends to reduce the output being generated by the system in response to an external input to the system or a perturbation of the system by an external agent. Negative feedback can be thought of as planned corrective behaviour of any system which brings it back to baseline whenever it moves away from the baseline. It is also important in purposive behaviour, as negative feedback mechanisms allow corrective behaviour to occur if activity is performed which is not in the direction of the intended goal of the purposive behaviour. A nice example describing how negative works feedback was put forward by my long time polymath collaborator and friend at the University of Cape Town, Professor Vicky Lambert. When one plans to leave a house, one forecasts what clothes one will wear by looking outside and seeing if it looks cold or warm from visual cues one picks up looking through the window at the external environment which one shortly plans to enter, or from checking the local weather forecasts. Whether one has put on too many or too few clothes will only be apparent when one actually goes outside and one’s skin temperature receptors are exposed to the outside air, and this initiates feedback regulation – either taking off clothing, or putting more on, or going back inside if it the temperature is different to what one predicted it would be and is either too cold or hot when outside. These different corrective responses to the stimulus would result in the correct body temperature occurring to allow survival, no matter what the elements outside, and this temperature regulation by addition or removal of clothing is a nice example of how a negative feedback loop control mechanism occurs in our daily life.

As per this example, a negative feedback control system therefore requires three components to work. The first component is the presence of a sensory apparatus that can detect either changes in whatever substance or process is being monitored, or changes in the internal environment or other systems which interacts with or impacts on the substance or process being monitored. The second component would be a control structure or process which would be sent the information from the sensory apparatus, would have stored information about the baseline / routine levels of the system which need to be maintained to allow continued successful function of the system, and would make a decision based on comparing the changes detected to what these baseline ‘setpoint’ values are, and ‘decide’ whether to make changes as a result of the information received, or to maintain the current level of activity of the system if deciding that the changes detected do not have the capacity to harm the system. The third component would be an effector mechanism or process which would enact or make the changes to the system decided upon by the decision making control structures. These basic negative feedback loop components are found in all life processes and structures, and are fundamental to life, as if they were not present activity that is potentially harmful would continue or accelerate until the system is overwhelmed to the point of being damaged and eventually destroyed. An example is in cancer cells, where for some unknown reason the normal inhibitory feedback mechanisms regulating cell division become dysfunctional, and normal body structures are overwhelmed by aggressively proliferating cells that cannot be ‘turned off’ by negative feedback processes.

Negative feedback loops are not just found and control the human body, but occur in and regulate all structures and systems that we use in daily life, such engines, airplanes, airconditioners, speaker amplifiers, for example. All activities we do, such as turning a boat’s rudder when seeing an iceberg, or moving a baby away from a hot kettle, or to changing our behaviour or environment after a non-optimal social interaction, are examples of negative feedback control loop mechanisms ‘at work’ in our daily lives. Indeed, philosophers often suggest that the capacity for negative feedback is the essential factor necessary for determining whether a system, process or structure is ‘alive’ – though these debates are often surely didactic rather than pragmatic, such as in philosophical discussions of whether thermostats can be considered to be ‘alive’ as they respond automatically to stimuli, something which sounds easy to answer, but in essence when one thinks about it becomes difficult to take a firm opinion about from a defining ‘life’ perspective, even if one is aware that such a debate is fundamentally absurd.

Diabetes and the regulation of blood sugar levels is a classic example of the negative feedback loop and how important to us for our survival. In healthy folk, after one has a meal, one’s blood sugar concentrations start to increase as the meal is ingested, and this would be picked up by sugar level sensors in different parts of the body. These sensors quickly send signals to regulatory control centres in the brain and body, which then directs the pancreas to release insulin, which quickly converts the blood sugar into other forms of stored energy in the different cells of the body (such as fat), and by doing so the blood sugar levels are maintained between fairly tightly ‘allowed’ boundaries. In diabetes, after food is ingested, for a variety of reasons, when ‘instructed’ to do so, the pancreas does not respond appropriately, or cannot do so, and insulin is not secreted in some types of diabetes, while in others, no matter how much insulin is secreted, the cells do not respond to it. So the negative feedback loop mechanism starts failing, and this causes the blood sugar levels to drift either above or below the normally ‘acceptable’ boundaries allowed by the body, and the elevated blood sugar can cause direct damage to tissues and cells in the body if it stays high for too long a period of time. Interestingly, when the fast-acting blood sugar controlling feedback loop starts failing, as it does in diabetes, a number of longer / more complex negative feedback loops are initiated, some involving other hormones being secreted that are not normally utilized to the extent they are in diabetes, in an attempt by the body’s regulatory control centre to return the blood sugar levels to tolerable levels, and others being behavioural in response to the symptoms induced by too high blood sugar (such as increased tiredness, weight loss, and increased passing of urine), such as decreasing ingestion of food with high sugar content, exercising more, or seeing the doctor and being given pills and medications to counter the effect of the non-functioning insulin pathways. All these changes would be in themselves examples of longer time-duration negative feedback control loop mechanisms, which are brought into action when the basic negative feedback loop fails, in an attempt to restore the blood sugar levels to the most optimal level possible, in order to ensure life continues as optimally as possible, for as long as possible, even in the impaired state from a system regulation perspective which the diabetes condition creates for those suffering from it.

So from my own research interest perspective, I am looking forward to hopefully hearing a lot about the latest developments in diabetes management and how metabolic regulation is better understood when the conference comes to town in a few months time. I am pretty sure though that whatever new information has been found and will be described at the conference, the principle of negative feedback control will remain sacrosanct as the accepted mechanism by which all metabolic activity is controlled in the body. Beyond diabetes though, it creates quite a paradigm shift in how one views life when one understands that just about all activity one does throughout one’s daily life (actually, all activity, period) is associated with some particular negative feedback loop cycle – whether it is getting food to maintain our fuel supplies, doing exercise to maintain one’s health, visiting friends to maintain one’s wellbeing, going to work each day to ensure one has enough funds to allow basic shelter and survival requirements to be ensured, everything we do is related to some negative feedback loop being active and occurring to ensure our ongoing survival and future wellbeing. How such a relatively simple principle came to underpin all of our activity and be so fundamental to life and existence, and how such a ‘principle’ came to be the one that controls and regulates all life at some point in our past, is of course another story, and provides ‘grist for the mill’ for many years more future study, research and thought!

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