Join us as we explore the book “On Rheostasis: The Hierarchical Organization of Physiological Stability” with author Tyler Stevenson. In this interview, we will discover the inspiration behind Professor Stevenson’s work and the key concepts that make his book a must-read for anyone interested in this exciting field.
Interview conducted by Dr Konstantina Linardopoulou.
K [Konstantina]: Can you provide some background on the concept of rheostasis?
T [Tyler]: Rheostasis was a concept that gained popularity in the 1990s. Prior to that, homeostasis was the dominating idea in medical sciences. Homeostasis was characterised by Cannon, who was influenced by mechanical engineering principles. The idea of homeostasis was that a controlled system maintained any type of change at a set point. Set points were critical for the maintenance of physiological stability. However, as physiologists studied physiological systems, they realized that set points varied, and the variation around a set point or regulated change was a challenge to the idea of homeostasis. This did not mean homeostasis didn’t exist, but rather, there was something more. Nicholas Mrosovsky, in the late 1980s, brought together all these examples of how set points and physiological systems changed, and they changed with a predictable cycle. He referred to that as rheostasis, which could be separated from homeostasis.
The problem really is that since the 1990s, we’ve been able to genetically modify mice and Drosophila, and they became the staples of the vast majority of physiological research. The focus shifted towards genetics, and most individuals who understood physiological systems became geneticists and for the past 30 years, the focus has been on homeostasis. But for the most part, the principles that underlie rheostasis have been given significantly less attention. So, one of the purposes of the book is to remind everyone that homeostasis has a defined scope in which it could be applied to set points and physiological balance, and rheostasis is another system. And a lot of what people are studying right now, which is claimed as homeostasis, is actually rheostatic processes.
K: What inspired you to write the book on the hierarchical organisation of physiological stability?
T: There were two reasons why I wrote the book. The first reason is professional frustration with the field that neglects the fundamental difference between homeostasis and rheostasis. Although everyone uses homeostasis in their titles, they don’t fully understand the homeostatic systems. Therefore, I wrote this book to bring attention to rheostasis and how it can be distinguished from homeostatic systems at multiple levels of genetic, cellular, neuronal pathways, and behavior. The second reason is personal. I had long-term funding, a thriving lab, and was teaching several courses. I felt that I was starting to coast in my career and needed a new challenge. Writing the book was a new challenge that I wanted to take on.
K: In the book, you mention that rheostasis is the regulated change in physiology. Could you elaborate on this concept and how it differs from homeostasis?
T: Great point! In my book, I discuss four or five different examples of how homeostasis and rheostasis can be separated at multiple levels. One example is body temperature regulation. Our body temperature is typically around 37.5°, and this core temperature is stable, regardless of external factors like drinking hot coffee (said as was lifting my coffee mug to have a sip). If there’s even a slight change in our core body temperature, several physiological systems are implemented to maintain stability, such as shivering or sweating. However, we also have a rheostatic system that regulates daily changes in our set point. During the day, our body temperature is slightly lower, at around 37 to 37.5°, whereas later in the night, it drops by about a degree or two. This change is beyond what homeostasis can account for, and it is predictable and regulated. This regulated change is governed by different genes and neurons than the homeostatic change, and it is a completely different system. Overall, the amount of variability around our body temperature during the afternoon vs. midnight remains the same, indicating that homeostatic systems are maintained. It’s fascinating to see how different systems work together to ensure our bodies function properly!
K: Can you share some examples from the book that illustrate the concept of rheostasis (such as daily/seasonal changes in hormones, sleep-wake cycles, or female reproductive cycles)?
T: We discussed the impact of body temperature on physiological systems, including how body temperature in females changes across the menstrual cycle and how oestrus cycles in hamsters are also tied to body temperature. Another physiological system that we could discuss is energy balance, which is referred to as homeostasis. Homeostatic systems typically involve short-term changes in energy balance, such as getting hungry and eating food. However, there are also long-term changes in body weight that are not necessarily tied to food intake. For example, the daily change in body weight is regulated, and people often weigh more at the end of the day than they do in the morning. This change is partly tied to the amount of calories consumed the day before, but there is a confound between regulated daily change and homeostatic systems. The menstrual cycle and female body weight are two examples of longer-term regulated changes that are not tied to food intake. Female body weight changes significantly across the oestrous and menstrual cycles, which can impact a woman’s fitness and ability to get pregnant. Dieting is a different homeostatic system that can be characterized as an allostatic system.
K: Does hibernation fit in here too?
T: Absolutely. The program we are referring to is a rheostatic one, as it involves cycles that will occur year after year. This is because the species we’re studying have long lifespans, such as polar bears and hamsters (although hamsters have a shorter lifespan of three to five years in the wild, this isn’t confirmed). The Siberian hamster, in particular, has homeostatic systems that change throughout the day, as well as rheostatic systems which result in daily changes. However, they also have a seasonal program. Our lab conducts research on this, where we keep them in a summer-like state. If we place them in short days, they lose body weight due to the short-day response, which helps them survive the winter. However, they spontaneously revert back to the long-day state after about six months, which isn’t an adaptive response. This reversion allows them to anticipate spring and summer conditions. This timer is only about six months, and it is a regulated change, which we characterize as a homeostatic program response. Despite the differences between the long-day and short-day photoperiod, the homeostatic systems remain intact. Therefore, if we restrict a hamster’s food during long or short days, the variability and the response to that food restriction is exactly the same. The long-term changes in body mass remain intact.
Recently, Callum Stewart, a PhD student driving this research, identified different cell groups in the brain which control the short-term homeostatic energy balance and those that control the long-term changes in energy balance. Thus, there is a homeostatic system and a rheostatic system that are completely independent and drive different changes. Both of these systems need to work together to ensure the survival of the hamster through the winter.
K: How do newly identified genes, advances in cellular understanding, and brain neuron communication relate to the concept of rheostasis as presented in your book?
T: That’s a tricky question and I think it can be understood by giving an example of the cellular and genetic basis of daily time. Homeostatic systems act on short-term changes to maintain balance, usually over seconds to minutes to an hour. However, the daily change in regulated set points occurs over 24 hours and is controlled by a distinct set of genes that regulate homeostatic systems of physiological systems. In the past 20 years, advances have been made in understanding the cellular clockwork that gives each cell (except red blood cells, which have a different mechanism) a 24-hour rhythm. This means that any type of tissue – when taken out of the body and put into a dish – will maintain 24-hour time for up to about 3 days. However, the period or rhythm of that clock starts to wane because it needs input from other cells, such as those in the brain.
In the brain, there is a region called the suprachiasmatic nucleus (SCN) that gives 24-hour time to the brain and all peripheral tissues. In the SCN, cells have the ability to maintain 24-hour time independently of other cells. This clock is essential for the programmed daily change in any physiological system, and applies to all physiological systems, but can also be differentiated from the homeostatic systems in each one of those physiological systems. The daily clock and the circadian clock could be the best way of characterising the difference between homeostasis and rheostat. This is because of the genetic 24-hour clock, which is absolutely programmed. That cell is going to go through a particular rhythm, a 24-hour rhythm, that sets the daily change in any set point, independent of the control of a physiological system.
For example, maintaining testosterone and estrogen levels in males and females is largely stable, aside from the female reproductive cycle. The amount of estrogen and testosterone in a typical male is stable, and any change in that induces a homeostatic response to make more or less of those hormones. The SCN aids input into the neurons that control the balance of sex steroids. Gonadotropin releasing hormone is in the brain, and projects down to the pituitary to control gonadotropin release. This goes down to the gonads, controlling testosterone and estrogen levels. These hormones then provide feedback into the brain to shut off gonadotropin release, generating a classic negative feedback loop that maintains the stability of testosterone and estrogen. The suprachiasmatic nucleus is an entirely different system in the brain that feeds into the control of gonadal cells and provides the daily change in set point. If testosterone or estrogen levels are measured at the same time each day, there will be a daily rhythm in those sex steroids that is independent of the homeostatic system.
K: The hypothalamus acts as a homeostatic regulatory centre – is there a different centre for rheostasis in the brain?
T: Homeostasis can be controlled at different levels depending on the physiological system that you are referring to. Some systems have simple feedback mechanisms that don’t require the involvement of the hypothalamus and instead rely on spinal reflexes. However, when it comes to the hypothalamic control of homeostatic systems like body temperature or reproductive physiology, different brain regions are involved in maintaining the balance. For example, the gonadotropin-releasing hormone (GnRH) is involved in reproductive physiology, and the suprachiasmatic nucleus interacts with different structures within the hypothalamus to maintain both homeostatic and rheostatic balance. In humans and hamsters, seasonal changes in energy balance are governed by neurons in the arcuate nucleus. Short-term changes in energy balance are regulated by neuropeptides such as neuropeptide Y and agouti-related protein. These neuropeptides change in response to starvation or overeating to maintain homeostatic balance. On the other hand, long-term changes in homeostatic balance are regulated by somatostatin and proopiomelanocortin. For instance, in hamsters, the arcuate nucleus provides a long-term signal for being obese or lean.
K: The book proposes that homeostasis and rheostasis act independently. What are the practical implications of this for healthcare and medical treatments?
T: I think the biggest issue right now is to educate healthcare providers about the concept of maintaining balance. Currently, the primary approach to treating chronic illnesses is to maintain homeostasis, which assumes that there is only one system responsible for maintaining balance. However, there are multiple ways to maintain balance, and it’s important to consider this when treating patients. By understanding whether an issue is related to homeostasis or another system, the appropriate treatment can be provided. The majority of clinical issues are related to rheostatic systems, which are not necessarily life-threatening. However, if the homeostatic system is compromised, the consequences can be fatal. For example, if someone cannot regulate their body temperature, they may become hypothermic or hyperthermic, which can lead to death. On the other hand, if a rheostatic system is damaged, it can cause severe problems, but it is not immediately life-threatening.
K: “Hierarchical organization of physiological stability”. Can you explain this concept in more detail and its implications for health and disease treatment?
T: Yes, I need to introduce another physiological system called allostasis. Allostasis is a process that explains how experience and individual differences can regulate physiological stability. The stress response is the physiological system that has been best characterized as allostasis, but there’s a wide range of individual variation in how individuals respond to stress. There are different pathologies in stress responses, and individuals with PTSD are an example of this. Their stress response is very different based on their experience. However, there’s nothing wrong with homeostatic systems or rheostatic systems. They still show these programmed changes. The difference is how they deal and react with a particular stressor. This is because the brain systems that are in place to govern that regulated change are entering regions such as the amygdala, hippocampus, prefrontal cortex, that work together within an individual to represent the particular stressor that they’re being challenged with. Sometimes these stressors are just made-up things that individuals have in their minds, like psychological constructs, which are entirely different from allostatic and rheostatic systems. These can be perceived or unperceived, not real stressors, that are causing a physiological response. The pathways that give rise to that physiological response are very different, and so you can have a hierarchy.
In this case, the stress response has three different levels. The first level is the homeostatic system, which is driven by the hypothalamus to pituitary adrenal axis. When stimulated by corticotropin-releasing hormone (CRH), it projects down to the pituitary to release adrenocorticotropin stimulating hormone that goes down to the adrenal glands to stimulate the production of glucocorticoids. Glucocorticoids feed back into the hypothalamus pituitary to maintain the homeostatic balance. You want to maintain a good level of glucocorticoid hormone production, which is healthy and necessary. Too much becomes pathological.
The second level is the rheostatic system, which is also providing input to this system. The suprachiasmatic nucleus feeds into the CRH neurons in the hypothalamus because your glucocorticoid levels change across the day cycle. This is another neural system, and we’re not going to get into it now.
The third level is the allostatic system, which is composed of higher brain regions such as the hippocampus and frontal cortex that also feed into the CRH neurons in the paraventricular nucleus. That particular cell group in the hypothalamus is governing homeostasis through the pituitary adrenal axis, receiving rheostatic input from the suprachiasmatic nucleus, and receiving allostatic input from these higher brain regions. This gives rise to a three-tiered system. You have a level that is innate, where homeostatic systems and rheostatic systems are in place. There’s nothing you can do to change them significantly. You also have experience-dependent mechanisms, like the amygdala, hippocampus, and prefrontal cortex, that can provide what is referred to as ‘top-down’ input into the physiological system. The stress response is an excellent way of highlighting these three different mechanisms.
K: So, psychology can change homeostasis and rheostasis?
T: Psychology can’t change homeostasis. Psychology can’t change rheostasis. Psychology can change how these systems are working over long periods of time.
K: Can you tell us about your research journey and the discoveries that inspired the content of your book? Whose idea was it? Was it hard to find a publisher?
T: When I read Nicholas Mrosovsky’s book, I already knew about his research from when he was a PhD student. He was a prolific and well-known physiologist. The challenge for him was that he didn’t get into the genetic revolution until towards the end of his career. When I started my lab in Aberdeen, I spent more time reading old literature for fun. When I revisited Nicholas’ ideas, I realized that it was time to show how the genetic revolution of the past 20-30 years could inform the mechanisms of rheostasis and how they differ from homeostasis. We have these two systems, and I wanted to outline what rheostasis was at a genetic level. I felt that the best way to convey these ideas was through a popular science book, which would reach more people than a review paper or a talk. The driving force behind writing the book was entirely independent.
The origin of this project was quite exciting. The initial idea was to write 300 words every night, so that by the end of a year, half a book would be completed. However, this proved to be easier said than done. The first three chapters were enjoyable to write, filled with excitement. Yet, as I progressed to chapters four and five, motivation and enthusiasm began to dwindle. It became more challenging.
There came a point where some of my ideas were challenged as I couldn’t find a commonality across different physiological systems. This led me to conduct more research. After a couple of months, chapters one through seven started to come together, focusing on the distinction between homeostasis and rheostasis. At that point, I felt I had something substantial to present to a publisher.
Once I had rough drafts of chapters one to seven, I reached out to experienced individuals who had published before for insights. Advisors like Russell Foster from Oxford, with multiple publications, and Jacques Balthazar, who had written books, provided valuable guidance. When approaching the publisher I wanted to work with, I could mention these advisors, adding credibility to my proposal.
I found it important to note that Nicholas Mrosovsky had previously published with Oxford University Press, and I considered it relevant to approach them for my updated research over the past 30 years. Fortunately, Oxford University Press was eager to publish the book, eliminating the need to shop around. The challenge I faced was writing the last three chapters. Although I initially thought it would be difficult, the excitement returned once the foundational chapters were complete and a publisher was secured. Chapters eight through ten were enjoyable to write. Chapter eight integrated various physiological systems, presenting a model of hierarchical organization. Chapter nine, not originally intended for the book, delved into mathematical modeling of physiological systems, providing evidence of their distinctiveness at a mathematical level. The last chapter explored the implications of current knowledge on homeostatic systems and long-term studies, considering the future of human populations, potential space travel, and the impact of environmental changes on our physiological systems. This final chapter emphasized the challenges ahead and acknowledged the uncertainty of solutions, highlighting the importance of observing how these challenges would affect different levels of homeostasis.
K: How did you go about writing and structuring the book, particularly the chapters on long-term physiological stability and modelling physiological dynamics? Were other people involved, and if yes, how many? How long did it take, start-to-finish (i.e. when did this whole journey get started)?
T: Good question, and a difficult one to pinpoint. The individuals who assisted me were immensely helpful. The collaborative process involved writing a chapter, receiving input from various experts, and refining the content accordingly. Neil Evans was particularly helpful; he meticulously read through every chapter, offering insights that enabled me to present my ideas in a more accessible manner. My forte isn’t writing for the general public, so reaching a broader audience posed a challenge, and Neil played a crucial role in overcoming that hurdle. I’m also grateful for the contributions of other colleagues who provided critical evaluations for each individual chapter. Fran Ebling and my former undergraduate advisor, Scott MacDougall Shackleton, were among those who dedicated their time to reading and reviewing substantial portions of the book. Their input ensured that the concepts I aimed to convey would be easily understandable.
The process of writing the book extended beyond the initial plan—I didn’t write 300 words every single night (laughing). I started the project in the autumn of 2019 and then COVID-19 pandemic happened in 2020. However, the silver lining was that the flexibility gained from eliminating daily commutes allowed me to dedicate more time to writing. Despite this, the book wasn’t completed until December 2022, making it a three-year endeavour to craft 10 chapters.
Each chapter underwent multiple revisions, and the overall timeline involved roughly a month to write the first draft of each chapter. Subsequently, the following two years were dedicated to extensive revisions and refining the content.
K: What do you believe is the most significant contribution your book makes to the field of physiology and life sciences? Were there any other textbooks previously covering this topic, or is this the first?
T: There was one book previously published on rheostasis in 1990, and now we have this one coming out in 2023, so it is a substantial update on the original one. The original book discussed that physiological systems can change and were different from homeostasis, but it did not explain how. At the time, most physiologists were measuring circulating hormones, and they did not know anything about different brain regions or genes. Over the past 30 years, advances in research have helped to clarify the differences between the three systems (rheostasis, homeostasis, and allostasis). My hope with the book is that it challenges the common myth across scientists that homeostasis is just a single system, and we move on from single systems to tiered systems. And when we study anything, just because you measure a hormone (i.e., testosterone), doesn’t mean that you’re studying homeostasis. If you look at food intake and the amount of insulin, you’re not studying homeostasis; that is only one part of a tiered system. So as soon as we can start thinking beyond a single system to a tiered system, I think we’ll make better insights, interpretations of the data and advances in our understanding of how physiological systems actually work.
K: How might your book’s concepts and findings influence future research and medical practices?
T: No idea. I hope the people in my immediate circle actually read the book. If they do, that would be a win.
K: You have an impressive academic background and have received several awards for your research. Can you share some insights into your academic journey and your motivations for pursuing a career in this field?
T: Education has always been a challenge for me. I came from a large family and was the middle child. By elementary training, I was not a star pupil at all. I had some serious learning challenges and the right way of phrasing it is I just was delayed reaching my potential. So it wasn’t until secondary school that my academic abilities started to come out, and it was mostly in the realm of philosophy.
My sister was fantastic in encouraging me to read certain types of books. Although my reading skills were good, my comprehension was not up to the mark. She suggested me to read books like ‘Animal Farm’, which I think triggered something in me, a motivation and an interest. And my drive to read philosophy exploded. I was also heavily influenced by religious teaching at the time as well, so when I went to university, it was to try to understand this period in Christianity between the death of Jesus in 33 AD and the writing of the Nicene Creed 300 – 380 (Nicene Creed is the Congress of individuals that came together to say which books would be in the New Testament or not). But I just wanted to understand what happened at that time. So when I went to university, I was going to study religious studies with a minor in philosophy because that’s the only thing that I felt as if I was strong in, and I wanted to go to Princeton. I had the idea of going to Graduate School because Eileen Pagels was working there at the time and some of her books were really amazing. So, that was my pathway.
When I got to university, I thought it’d be important to take a course in psychology because I wanted to understand how people thought and represented the world. But I also thought it would be important to take biology because I understood there’s something called evolution. Well, after my first year, I became really interested in biology and psychology and how animals functioned. That sparked my interest in physiology as well as psychology. So, my undergrad was neuroscience before neuroscience was really a discipline, which was physiology and psychology. And then from there, I wanted to understand how animals or physiological systems changed because if you could change a physiological system, you could really change an individual’s state, not just humans, but any animal because there was so much happening in the periphery that would ultimately impact the brain.
And then, for my PhD, I really started to realise that these systems are interacting, and they all have their own independent timers that, when they coincide, give a very species-specific fitness. And since then, I’ve just been trying to develop or use other tools and techniques to answer the exact same questions that people have been asking for decades. I am not asking any new questions I am just finding new ways of answering questions.
K: Could you tell us more about your role at the University of Glasgow and the Laboratory of Seasonal Biology?
T: It has grown to become its own entity now, and I am just one spoke in a bigger wheel. The bigger wheel is the students, postdocs, and collaborators who are all working together to use new tools to answer the same questions and my role now within this complex web is to keep it going—keep the inertia going. And I see my role in that is to continue to find ways to give the people who are doing the work that I’m living vicariously through the opportunities to keep doing that and to maintain the group that they’ve essentially created.
K: As a scientist, you’ve likely spent a lot of time observing and studying animals. Have you ever come across an animal behaviour or adaptation that was so unusual or funny that it made you laugh out loud?
T: The funniest one I think I’ve ever seen—and I do hope that Ellie remembers this—torpor and hamsters, it’s absolutely amazing. There was one time going in and seeing hamsters engaging in torpor, which is nothing new, but we were able to capture a video of a hamster engaging in torpor in Ellie’s hand, and it still makes me laugh. So, if I give a presentation, you will probably see this video—and it still makes me laugh!
Tyler Stevenson’s book “On Rheostasis” was published on 26 February 2024 by Oxford University Press. The book explores the balance of life and how living systems adapt. The book is written for all readers, including those who are not scientists. It explains complex topics in a way that is easy to understand. It is available for purchase online here.
