The Myth of Homeostasis: Implications for Neurodegeneration

Myths of physiology

This is my first attempt at a blog for the Skeptics Circle. I won't go after the obviously wrong alternate medicine cranks, quackery, woo and the delusional thinking that other skeptics handle so easily (which I see as the equivalent of fishing with dynamite in a bucket). When you are successful, the results are not entirely satisfactory because you don't end up with anything useful (just fish guts splattered everywhere). I will go after myths that are more damaging because some scientists actually believe them and waste time pursuing dead ends based on wrong ideas and clutter the literature with sloppy thinking which delays development of real treatments for real patients. I plan to write on a number of myths over time. Some may object to their favorite myths being debunked. Feel free to object and (try to) defend your myths, but be prepared to back it up with facts and logic, just as I am prepared to back up everything I say with facts and logic.

One of the most pernicious and pervasive myths, one which seriously interferes with progress in understanding and treatment of dysfunctional physiological states is the myth of homeostasis. The term was coined by Walter Bradford Cannon in 1932 from the Greek homoios (same, like, resembling) and stasis (to stand, posture). He also coined the term "fight or flight", which is actually a useful concept and is ironically completely inconsistent with the concept of homeostasis. How can physiology change to engage in fight or flight by remaining static? It can't. There has been some attempt to fix the flawed homeostasis concept with things such as "dynamic homeostasis" which I see as a simple oxymoron, and akin to the epicycles of the geocentric solar system model. Another approach is to limit the physiological parameters that homeostasis applies to, a "homeostasis of the gaps" idea. Ad hoc complications to try and rescue a failed hypothesis.

The idea of homeostasis (not a hypothesis because it is demonstrably wrong) is that in order to maintain physiologically appropriate conditions internally and maintain itself as a living organism, organisms maintain a state of homeostasis. That is many physiological parameters are maintained in a static state, and deviations from that static state are dysfunctional and are actively countered via compensatory pathways. A disease state occurs when homeostatic mechanisms are overwhelmed and homeostasis cannot be maintained. Ok, not a bad default assumption in 1932 when you are not able to really measure anything inside an organism, let alone inside an organ, or a cell or an organelle. Before there was any real idea of how cells functioned, a simplistic assumption there was something (not quite) magical called "homeostasis" that kept everything constant helped researchers to ignore the obvious complexity they couldn't begin to measure and focus on the very simple things they could measure, temperature, pH, water consumption, urine output (which usually were controlled by physiology better than the accuracy of the measurement techniques of the time). It is a step up from vitalism (which posits an imaginary life force that does the same thing), but only a small step. When all you can measure are simple things, with low precision and only on a very long time scale, everything does look constant. If you could only measure heart rate averaged over 10,000 beats (about 3 hours), you could detect a change if someone ran a marathon, you couldn't if they only ran a mile. 5 minutes with a 3x heart rate would be lost in 3 hours of 1x. Now we know that heart rate is actually chaotic, with inter-interval spacing varying in a power-law manner. Chaotic behavior is characteristic of systems of multiple coupled non-linear parameters. Many physiological systems are known to be chaotic; it is likely that virtually all of them are (all known physiological systems comprise systems of multiple coupled non-linear parameters). What about a chaotic system is or can be "static"?

On some level for an organism to maintain itself in a living state all parameters have to be kept within a certain range. But that range is not necessarily the value at rest or a constant. Organisms do remain alive with those parameters at values different than at rest. The value that physiology calls for at any moment may be different than the value at rest if a different value achieves some physiological goal different than remaining alive at rest. Are there any parameters that are kept static? Not so far as I have been able to find any evidence for in the literature. Virtually all parameters are regulated via feedback control, but that precludes stasis. Many parameters are regulated via feed-forward control. That is, parameters are adjusted in anticipation of a future need, not in response to a past need. This is a subtle point, but feed-forward is absolutely essential. When the heart pumps blood, the blood going through the heart is needed at a future time, when that blood reaches the target organ. The heart has to pump blood in anticipation of the need of the organ for that blood. When the liver puts glucose into blood, it is for a future need, when the glucose reaches the organ that uses it. Feed forward control is necessarily less precise than feedback control, but a sacrifice of efficiency for speed is a good evolutionary trade-off.

As skeptics, our default position has to be that we don't know something, rather than to assume that something has a particular property or value. Do we know that any parameters of physiology are static? No, we don't unless we actually measure them sufficiently precisely over the time and length scales in the physiological state of concern. We do know that those parameters are highly regulated, and regulated by control system(s) that are extremely complicated, extremely robust, which have evolved over billions of years, the details of which remain mostly unknown. We do know that these control systems evolved only to preserve the life and reproductive capacity of organisms that have them. There is no evolutionary pressure to maintain any physiological parameter constant; there is only evolutionary pressure to sustain the life and reproduction of the organism. If preserving the life or reproductive capacity of an organism would be better achieved by changing a control setpoint, presumably physiology would have evolved to do so (yes, I know, duh).

Some might argue that even though nothing is actually static, that homeostasis is a useful concept because it makes "intuitive sense". That is a wrong idea. The most dangerous and pernicious bad ideas are those that are wrong but which do make "intuitive sense". Most people's intuition is poorly suited to sorting out bad ideas. All woo and quackery is accepted by some because to them it makes "intuitive sense". As skeptics we must have zero tolerance for demonstrably false ideas, especially when they make intuitive sense. The problem is with our intuition. If our intuition is wrong, we must compensate for that wrong intuition and reject compelling ideas whenever they are wrong.

Researchers may not be comfortable without a backdrop of something "constant". A century ago, physics had the concept of absolute time and space. Relativity showed that concept to be wrong and reality could be better understood without it. Some physicists had great difficulty abandoning absolute time and space and adopting relativity.

Good control of any physiological parameter requires a setpoint and regulatory mechanisms to restore deviations from that setpoint. Physiological control is fabulously good. Far better than most actually appreciate. Bad control can either be good regulation around a bad setpoint, or bad regulation around a good setpoint (or some of both). Homeostasis posits that the "setpoint" is constant and fixed, and that any dysfunction is due to bad regulation about that fixed "homeostatic setpoint". A skeptical position is that any setpoint might not be fixed, it may well be a control parameter, and a deviation from the at rest setpoint might actually be a compensatory response to correct a dysfunctional state. Since we don't know every single physiological role of each and every single physiological parameter, we don't know if physiology is best served by maintaining that parameter constant or not. If that particular parameter is used as a signal (and it must be if anything is controlled by it including the parameter itself), then a deviation of that parameter may be the absolutely necessary trigger to activate a downstream pathway necessary for compensation. With a homeostatic perspective, any deviations of physiology from the "at rest" state are considered pathological or dysfunctional. But this ignores what is cause and what is effect. If physiological parameters are coupled (as we know they are), different parameters cannot be regulated independently. If multiple parameter(s) change, what is or should be the treatment goal? Which parameter(s) should be kept fixed so as to maintain homeostasis? The vast majority of physiological parameters cannot be measured and are regulated in each cell somewhat independently of all other cells. How do we choose which one(s) are important and are the "homeostatic" ones? Only through actual measurement.

I will focus on ATP concentration in cells which relates to my NO research. Don't worry, this is the only paragraph that I discuss NO in. NO regulates the ATP setpoint via sGC, and is the diffusible signal that communicates ischemic preconditioning (discussed below). Superoxide generation triggers ischemic preconditioning, consumption of NO by that superoxide turns cells generating superoxide into NO sinks, and the fall in NO propagates the ischemic preconditioning signal (as spreading long term depression in the brain) between cells. I mention it here so I can avoid mentioning NO later and confine NO physiology to this one paragraph. Some of the specifics relate to my previous blog on how fevers affect energy status in the brain and how low ATP shows up as white matter hyperintensities. I focus a lot on ATP in nerves because it is somewhat simpler there and relates to my work in autism, Alzheimer's and Amyotrophic Lateral Sclerosis (ALS). In many ways these neurodegenerative disorders are all "the same", in that they are characterized by low NO and low ATP (which I think is the ultimate cause). Just the details are different. But of course there are always a lot of details, and it is easy to get lost in those details and get caught up in the differences (which are mostly unimportant regarding treatment possibilities) and ignore the similarities (where treatment possibilities lie). The forest for the trees problem.

I will try to get into glucose regulation in a later blog. Regulation of glucose level is important under different conditions, and standard practices may be (actually are) detrimental, for example what glucose level is best to artificially impose in the ICU. Those who seek to engage in Evidence Based Medicine may want to consider the actual evidence for the optimum blood sugar under conditions such as sepsis. For example, why would we expect it to be the same as in non-sepsis when the immune system mostly functions by glycolysis and in experimental animals LPS always causes an increase in blood glucose? Maybe the hyperglycemia of sepsis is functional. I appreciate that a default of an "at rest" glucose level might be reasonable in the absence of any studies showing higher levels to be superior. But we don't know if higher levels would be superior unless we actually test them.

In the case of glucose, what glucose parameter is important? Carbohydrate consumption? Carbohydrate assimilation? Glucose level in bulk blood? Glucose level in CSF? Glucose level in extravascular fluid adjacent to the cells actually taking it up? Glucose levels inside cells? A recent (1999) "review points out that there is no compartment of glucose in the body at which all glucose is at the same concentration, and that models of glucose metabolism, including effects of insulin on glucose metabolism based on assumptions of concentration homogeneity, cannot be entirely correct." I would be more blunt; such models are wrong. (But I am not writing this for a journal requiring approval by an editor or peer reviewers who may believe in homeostasis).

In obesity, what is "homeostasis" trying to keep constant? Is it total organism energy status or energy status of the brain (the most important part of energy status)? If the part of the brain that controls appetite doesn't have enough ATP, presumably it would call for more substrate irrespective of the amount of depot fat the organism has (which the brain cannot use unless the organism is in ketosis). If there are insufficient mitochondria in the liver to support gluconeogenesis and the Cori cycle to recycle lactate into glucose, the only way to maintain glucose supply to the brain may be via consumption of carbohydrates or cachexia which may result in anorexia or obesity. Anorexia and obesity may be more similar than people think because they are both characterized by reduced energy status in the brain. You can actually have both obesity and cachexia simultaneously. During sepsis, muscle is catabolized to make glucose and body fat levels actually increase (I think to dispose of lactate but that is for a future blog).

Body temperature is pretty well controlled in humans and is often used as an example of one of the "homeostatic" parameters. Temperatures too far above or below "normal" can be fatal, but acute illness often produces a fever, and in experimental animals, blocking a temperature increase interferes with the recovery from infection. Under the homeostasis idea, preventing fever would augment homeostatic temperature control and would restore improved function more quickly. It doesn't. Raising body temperature as a response to infection is found in all vertebrates including endothermic animals such as fish. It is also found in insects.

Elevated temperatures affect how immune cells react. Presumably the body is using fever as a signaling mechanism. Driving mitochondrial respiration very high increases metabolic heat and would produce local heating, precisely the proper signal to attract macrophages and to activate them. Blocking fever may make one feel better, but it is likely to prolong the illness.

ATP Regulation

As a charged molecule, cell membranes are impermeable to ATP. Each cell necessarily regulates ATP via mechanisms which are independent of (but obviously related to) surrounding cells. Even now, there is no technique to measure ATP non-destructively in single cells on the time scale it is controlled at (sub second). Typically ATP is measured by freeze clamping a bit of tissue with liquid N2 cooled copper tongs (to stop production and consumption) and then assay it after dehydration or other denaturing of making and using enzymes. Typical minimum sample sizes are a few hundred to a few thousand cells. Measuring the averages of a few hundred cells doesn't tell very much about what ATP is doing in individual cells (or in sub-cellular compartments). ATP can be measured non-destructively by fMRI, but only in large volumes (very large compared to single cells and the length scale where ATP is actually controlled at).

ATP is exquisitely well regulated. Is there any evidence that it is kept "static"? No, there isn't. There are 3 potential ATP parameters, ATP production rate, ATP consumption rate and ATP concentration. Over the course of a day, oxidation of 2000 calories of glucose (0.56 kg) and efficient conversion to ATP produces some 55 kg of ATP. Pretty obviously the ADP and P are recycled many times and over a day's time the production and consumption is essentially exactly balanced. Since ATP isn't stored, production and consumption is balanced in essentially real time.

How many different pathways consume ATP? Conservatively it must be at least 10^5 in each cell, probably 10^6 or more. There is the synthesis of ~10^4 proteins in each cell. If we assume 10 additional pathways including post translational processing, phosphorylation, de-phosphorylation, ubiquitination, proteolysis, folding, transport by motors, and more, we can easily get to 10^5. The precise number is not necessary, simply that there are very many. Each of those pathways consumes ATP and is (to some extent) necessarily regulated separately from all others. How are all of those pathways controlled? The answer is very well.

We know that ATP consumption (and hence production) can vary by an order of magnitude (in heart muscle). We know that sufficiently severe ATP depletion causes necrotic death. We know that transient periods of acute ischemia induce what is called ischemic preconditioning (IP). Ischemic precondition is a lower ATP state, but more importantly is a lower ATP consumption state. This IP state induces a temporary state where the organism, organ, or cell can better tolerate ATP depletion and survive undamaged. The details of IP are mostly unknown, but because the effect is extremely common and robust, it no doubt represents an early evolved and fundamental stress response of cells.

Each of those 10^5 pathways can only be controlled locally. That is, the consumption of ATP is local to the molecules directly interacting with that ATP, the control of that consumption must be local too. There are many mechanisms, including phosphorylation, conformation changes, binding of peptides to block ATP consumption, many more and combinations of all of these. So what signal is used to communicate the cell's ATP status to each of those pathways and so regulate each of those pathways independently? It has to be a small molecule to be able to get every where. There are not 10^5 different small molecules, virtually all of these pathways must use the same signaling molecule for regulation appropriate to ATP status. That molecule must also couple to ATP. My conclusion is that many (if not most) pathways must use ATP itself as the signaling molecule to adjust activity to cellular ATP status. This is an extremely important conclusion. If so, it would mean that ATP cannot be regulated to be constant as the homeostasis idea requires. In addition to being the energy source, ATP must also be the signal that regulates consumption of that source. ATP would be an ideal control signal to use because it exactly tracks ATP status. No intermediate signal inducing delay or error is necessary. Regulation would be completely stable. Presumably ATP was the first signal that cells used to measure ATP status and regulate pathways accordingly. As cells evolved that signal has become more complicated, but it won't be replaced so long as it works. We know there are many proteins that bind to other proteins depending on ATP status (the heat shock proteins for example).

We know that some pathways can consume ATP until the cell dies, for example muscle contraction. A useful survival feature. The heart continues to pump until the heart kills itself from ATP depletion. One can continue to run from a bear until one drops dead from exhaustion. This demonstrates that muscle contraction has a low ATP threshold for being turned off. Other pathways such as axonal transport have higher thresholds for being turned off (see discussion below), that is they are turned off earlier as ATP levels fall.

Ischemia occurs when there is disruption of the supply of substrates (O2 and glucose) to cells. With insufficient substrate, cells cannot make ATP via their normal pathways. As ATP falls (due to insufficient substrate), cells must either make more ATP or use less (or both). Disruptions to ATP supply are leading causes of cell death. In one sense, the ability to generate sufficient ATP to maintain cellular integrity is virtually the definition of what it means to be alive. If the ability to make ATP is blocked by insufficient supply of substrates, the only way to preserve ATP concentration is to use less. With no storage, ATP not consumed is as good as new ATP generated. Following invocation of IP, cells do use less ATP, and this persists for the length of the IP period.

If IP reduces ATP consumption, can cells stay in an IP state indefinitely? It is quite clear they cannot. IP can only be a transient state, because if it was possible for cells to maintain long term a state of reduced ATP consumption, they would have evolved to do so, so that more resources could be devoted to reproduction. The IP state would become the new default metabolic state. This has not happened. We can conclude that a long term IP state is incompatible with life and/or reproduction. Since IP happens in cells that don't divide (nerves in the CNS), long term IP is incompatible with life.

Since IP reduces ATP consumption and is protective over some period of time, there must be ATP consuming pathways that are not essential during that time period and can be shut off to preserve ATP, however those pathways are essential for longer time periods (or they would not be conserved).

In my blog on acute psychosis I use the acute stressor of "running from a bear" as the archetypical stress where to be caught is virtually certain death. To escape from a bear virtually any injury short of death is an excellent trade-off. The trade-offs in IP are similar. Any injury short of death is also an excellent trade-off if it prevents death from ATP depletion. All instances of ATP depletion are either transient or the cell dies. Normally, the ATP crisis will only last until the compensatory pathways have increased ATP production to compensate. The transient nature of all ATP crises can indicate which ATP consuming pathways can be shut down. If a pathway is not crucial for life (over the length of the crisis) and is not involved in increasing ATP production (over the length of the ATP crisis) it can increase ATP availability by being shut down. This is the essence of the difference between the "fight or flight" state and the "rest and relaxation" state, the ATP status, as measured by the ATP level. This is discussed in my blog on placebos.

Let us consider nerves. Nerves only obtain ATP from oxidative phosphorylation and then only by oxidizing carbohydrates, ketone bodies and other small organic acids. They cannot obtain ATP from glycolysis or from the oxidation of lipid. Nerves are also large cells. The cell body contains the nucleus where the DNA is stored, and so is where virtually all protein synthesis occurs. The vast majority of the metabolic activity of nerves occurs in the axons, where most of the cytoplasm is. Axons are small diameter extensions of the cell that may extend for inches, or in the case of motor neurons as much as a meter from the cell body. It is down these axons that the action potential is transmitted. What is also transmitted down these axons are all the proteins and organelles synthesized in the cell body that are used at the tippy end of the axon including mitochondria. These are transported out via ATP powered motors with variable velocities, and then transported back when they get "tired". There are two modes, a slow mode (~1 micron/second), and a fast mode several times that. Usually the fast mode is for transport of endocytosed receptors on the tippy end back to the cell body. In either case, the transport time is very long compared to the duration of an ATP crisis (minutes), and this slow transport can't contribute to ATP production, so it is something that could be shut down. ATP consumption by actin is a major energy consuming pathway in neurons.

Is axonal transport shut down when there is insufficient ATP? One of the most reliable symptoms of all of the neurodegenerative diseases is what is called white matter hyperintensities (WMH). On MRI, the white matter (primarily axons so named because myelin is white, cell bodies are gray) exhibits decreased water diffusion. The precise mechanism of WMH remains unknown. I discuss some of the physiology of this in my blog on fevers and autism. Acute ischemia (from blocking a cerebral artery) causes WMH to occur very rapidly I suspect it is a controlled shut-down of axonal transport to conserve ATP. The reduced water diffusion results from reduced convective transport of water entrained by moving cargo in the axons (my hypothesis). WMH is observed to spread (spreading depression), and that spreading occurs slowly, not via action potentials.

But this blog is about homeostasis specializing in ATP homeostasis, not WMH. All of the neurodegenerative diseases characterized by WMH also are characterized by reduced metabolism, by SPECT, by fMRI, by cerebral blood flow, by MRS, by just about every measure that can be made.

What does the idea of homeostasis say about it? Not much. Homeostatic mechanisms have failed. What does a skeptic of homeostasis say about it? If a substantial fraction of ATP consumption is reduced, how many pathways are involved? 1, 10, 100's or more? For a substantial fraction to be disrupted, presumably a substantial number of the 10^5 or more pathways are disrupted. Either the regulation of hundreds of pathways has "gone bad" simultaneously and in characteristic ways for each of the diverse neurodegenerative diseases, or the regulation remains good, but around a bad setpoint. Since multiple cells are involved, and each of these pathways is regulated local to the individual cell, bad regulation of hundreds of pathways via independent mechanisms simultaneously seems extremely unlikely. That leaves good regulation around a bad setpoint. Since spreading depression can propagate and signal a cell to reduce its metabolic activity, presumably that is a normal regulatory process.

Many neurodegenerative diseases are also characterized by accumulation of damaged proteins, amyloid in Alzheimer's, Lewy bodies, tau inclusions in taupathies, alpha-synuclein in Parkinson's, polyglutamine inclusions in Huntington's, SOD1 inclusions in G93A ALS mice, and lipofuscin in all of them. Amyloid also accumulates in non-neuronal tissue in diabetes, obesity, dilative cardiomyopathy, end stage kidney failure and other degenerative diseases characterized by amyloidosis. The association of these protein inclusions is virtually universal but whether they are a cause, an effect, or merely associated with the degenerative disease is unknown. In most cases these inclusions are poly-ubiquitinated, that is they have been tagged for disposal but that disposal hasn't happened. It has been suggested that sometimes aggregation of some of these proteins may be protective. During hibernation, some animals polyphosphorylate tau, a process that is thought to precede the pathological association into aggregates observed in the taupathies. How does homeostasis explain hibernation? what is being kept static?

Cells have 3 main mechanisms for disposal of proteins that are not longer needed or that have been damaged, the proteasome and autophagy. The proteasome is used to dispose of protein molecules one at a time. They get linked to ubiquitin and then the ubiquitin-protein complex gets transported to the proteasome where first ATP powered unfoldases unfold the protein into a single length, then that piece is fed into the proteasome where ATP powered proteases break it up into little bits. The little bits are then recycled separately. The proteasome is used for control purposes also, some proteins are synthesized and then degraded and when their degradation is impeded, then they reach a level that activates something. For example Hypoxia Inducible Factor 1-alpha (HIF-1α) is rapidly synthesized and rapidly degraded under normoxia, but when the O2 tension drops, the degradation stops and HIF-1α accumulates and activates transcription.

The other two protein degradation systems are related to each other. There is Chaperone Mediated Autophagy (CMA) and autophagy. CMA can also process single proteins, autophagy is more of a bulk process where macroscopic quantities of cytoplasm are engulfed for degradation and recycle. The only way that whole organelles such as mitochondria can be recycled is via autophagy. The material to be degraded is engulfed, protease precursors are ported in, the pH is lowered via V1ATPase which pumps in protons. The low pH activates the proteases and they degrade the contents. Conditions are made reducing via porting in cysteine which reduces disulfide bonds which are exported as cystine to the cytoplasm where cysteine is regenerated. This takes ATP to produce the pH gradient. The V1ATPase is inhibited by oxidative stress, which makes sense to save ATP during IP triggered by ROS.

So what if there isn't enough ATP? Proteins that are damaged and ready to be disposed of are not doing anything constructive, they are just taking up space. All they are good for is as substrates, but they need to be taken apart and the bits remade into proteins or oxidized to make ATP. That takes time and ATP to do so. Their recycle can be put off for a little while if ATP is needed for something more important (such as running from a bear). If you have something better to do, you can always put off getting rid of the garbage. Garbage takes up less space if it is aggregated together (a trick I have found to work in living space too ;).

In conclusion (finally!), the idea of homeostasis posits that important physiological parameters are kept constant. We know that isn't the case, but many persist in clinging to that belief and invoke "homeostasis" as a principle of physiology even though there is no data to support it. It is long past time that the idea was abandoned.