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!