Sunday, August 5, 2007

Low nitric oxide, acute psychosis, postpartum psychosis, infanticide and the murder of Katie McCarron by her mother

Necessity knows no law.
Publilius Syrus

Whoever fights monsters should see to it that in the process he does not become a monster. And if you gaze long enough into an abyss, the abyss will gaze back into you.
Friedrich Nietzsche

Know your enemy well, for in the end that is who you become.
Old Chinese Proverb

Nothing in life is to be feared. It is only to be understood.
Marie Curie

An ounce of prevention is worth a pound of cure.
Ancient wisdom

There have been a number of blogs in the Autism Hub regarding the tragic murder a year ago of Katie McCarron by her mother Dr. Karen McCarron. Kevin's blog is a good place to start. A number have imputed monstrous evil on the part of any mother that could suffocate her child. In this blog I will discuss another explanation. Similarly, PZ Myers has blogged about a child injured in a microwave. There has just been a horrific case where a mother hanged her 3 children and herself. Her 8 month old apparently survived.

I didn't know of the Katie McCarron case until I read about it recently. What I write here is not to justify or to provide excuses for what Karen McCarron did. There is, and can be no legal or moral justification for murdering a child. Unfortunately, humans are not legal or moral creatures, we are evolved creatures, and unfortunately there are evolved reasons for a mother to murder her child. Evolved reasons that predate humans, primates, and perhaps even placental mammals. I don't know anyone who has committed infanticide, I don’t know of any infanticide connection with anyone that I do know. I do know that many women experience postpartum depression. My mother did. I think her postpartum depression following the birth of my 3 year younger brother was a factor that facilitated the abuse that my older brothers perpetrated on me. My interest here is purely to try and prevent such things from happening in the future. It relates to NO physiology, and I am quite sure that raising NO via my technique would be effective at preventing the metabolic stress that I hypothesize leads to postpartum psychosis and infanticide. The best (and perhaps only) time to start would be before conception.

This blog will discuss logical and physiological reasons why females would evolve the ability and motivation to commit infanticide, present examples in other mammals, and suggest that these physiological effects may be important in cases of maternal infanticide such as Andrea Yates, and Karen McCarron. My discussion will go to the core of what we consider valuable, what we hold dear, and what one is willing to sacrifice one's life for, or things that are even more precious than one's life. If you find this topic upsetting, do not read further. My goal is not to excuse what happened, but rather to understand it, so that such occurrences can be prevented in the future. The most important behaviors are those that evolve to survive the most difficult times. Easy times are easy to survive. It is when times are the hardest that most evolution occurs, and when our physiology forces us to do things we would never imagine we were capable of.

This blog is not about any individuals, other than those named. There is tremendous stigma, societal and self-induced, antipathy and even hatred against women who are not "good mothers". My intent is not to add to that. My own belief is that every woman wants to be and tries to be a "good mother" to her infant and child. Unfortunately, what constitutes a "good mother" by societal standards is not the same as the "successful mother" paradigm that is hard wired by our genes. The "successful mother" paradigm trumps the "good mother" desire every mother has.

Humans are only descended from "successful mothers". There are no "unsuccessful mothers". "Unsuccessful mothers" are women who die childless and so are not mothers. What is a "good mother" is defined much by our family of origin, and our own experience as a child of being mothered. The "successful mother" paradigm is much more fundamental, and I think is to a large extent "hard wired". That is, how the "successful mother" acts and reacts isn't so much due to her cognition and reason, but rather to her physiology and autonomic responses. Her reason and cognition may provide rationales for what her physiology compels her to do, and those rationales may become incorporated into an idiosyncratic "good mother" paradigm by her and her children. An example would be "spare the rod and spoil the child". Anti-vaccine beliefs are another. There is no rational reason to believe that vaccines are inherently bad, but a mother who is scared, and feels angry and betrayed may latch onto vaccines as the reason. Feelings the mother has may generate "explanations" which have no basis in fact, only in belief. Many superstitions (aka "old wives tales") likely derive from correlations that were erroneously attributed causation. The more stress someone is under, the more likely they are to latch onto delusional beliefs.

Pregnancy, birth, and the postpartum period are extremely stressful for women. In evolutionary times, many women died in childbirth or shortly thereafter. No doubt there are many compensatory physiological adaptations, behaviors and strategies that have evolved to survive many of the different stressors that caused these deaths. I want to emphasize that evolution selects for traits that minimize the sum of non-reproduction from all causes simultaneously. If a trait causes X deaths, but saves 2X, then it is a fabulously successful trait. I think that infanticide is just such a trait. Under conditions of severe metabolic stress, a mother doesn't have the metabolic resources to keep herself and her child alive. If she dies, the child will too. If the child dies, the mother may live and reproduce another time (or maybe not). Brutally hard decisions to make, but your genes don't care.

It can be extremely difficult, if not impossible, to do something counter to the "successful mother" paradigm. It is an autonomic response, much like anaphylaxis. Anaphylaxis can easily kill you, but an extremely vigorous immune response at another time can be life-saving. The "successful mother" paradigm is the same. On some occasions it can preserve the reproductive capacity of the mother, at other times it doesn't. Evolution has configured the "successful mother" paradigm to maximize reproductive success under all conditions, especially when conditions are extremely harsh (the most difficult time to be a mother or child). The only way the body "knows" if conditions are extremely harsh is by the physiological parameters involved. If the physiological parameters that control the "successful mother" paradigm get into the "right" range, that paradigm will be invoked. That is the essence of how NO is involved. Low NO is one of the signals that the body uses to activate "stress" responses. When NO is low for any reason, all of those stress responses are activated easier, sooner, at a lower threshold and persist longer. I think that is what happened to Karen McCarron. A low NO state invoked the infanticide paradigm, she made a "Sophie's choice" as to which of her children was had better reproductive prospects and killed the other one. I see it as a tragic circumstance, not the act of an evil or bad person. I see it as the act of a desperate mother, a mother compelled by her physiology to do a very desperate thing. A thing she regretted in the very next moment (so much so that she tried to kill herself), and will regret to her dying day. But your genes don't "care" how you feel, all they "want" is to be successfully replicated.

Becoming pregnant, carrying a fetus to term, successfully birthing the infant, nursing that infant until weaning, and then raising that infant until they become self-sustaining in food gathering takes considerable and long term effort. It is best to not start the process unless there is a good chance it can be completed. If the process is started, and conditions deteriorate, there are a number of strategies that can be invoked to "start over". Some of these are outlined in Table 4. If environmental conditions deteriorate such that the process cannot be sustained, the only successful option is to start over. It is exactly like a chain. Food supply to the fetus, infant, and child must be continuous. If it is interrupted, the chain breaks, the child dies, and the process must be started over. The initial stages, ovulation and pregnancy require substantially less resources than the later steps. If the chain is going to break, better to break it earlier so an earlier start can be made on a new pregnancy, one that may lead to successfully raising the infant until he/she is self-sustaining.

I am emphasizing and belaboring these points because they are so objectionable that no one in their right mind would consider that any circumstances would make it acceptable to murder a child. That is exactly and precisely the point! No one in their right mind would consider it acceptable to murder a child, much less do it. That is why metabolic stress induces psychosis. A very deep and profound psychosis, sufficient to nullify the love and maternal instincts that a mother has when not under metabolic stress. It needs to be appreciated that psychosis and infanticide are just as much maternal instincts as are love and affection. Just as much instincts and just as important under the circumstances when they are needed, and instincts that are just as compelling to follow.

Considerable infertility is mediated by low NO. Oocytes require NO to maintain the ability to be fertilized. Low NO shortens the time period during which fertilization can occur. In discussing this with the author, at the last NO conference, we agreed that it was most likely a "feature" to reduce fertility under times of stress (which are low NO states). He thinks a low NO state from the loss of my bacteria would exacerbate infertility, and that my bacteria are a promising potential treatment for this type of infertility. These NO effects are most likely part of the reason for reduced fertility during diabetes. Polycystic ovarian syndrome, PCOS is characterized by elevated blood sugar, elevated androgenic steroids, and infertility. Many of the symptoms of PCOS are characteristic of the metabolic syndrome, including obesity, increased vascular stiffness, low grade chronic systemic inflammation, insulin resistance. There are physiological mechanisms by which low NO can induce all of these effects,

No doubt low NO affects male fertility as well. NO is essential for activation of sGC, production of cGMP and the physiology of erections. A major cause of reduced fertility in males is varicocele, which is characterized by varicose and tortuous veins in the testes. Varicose and tortuous veins are a common symptom of low NO. The only way that tortuous veins can develop is if the flow of blood affects the morphology of the vein. It is like the meandering of a river, the flow removes material from the bank where velocity is high and deposits it at the bank where velocity is low. The meandering of blood vessels is similarly mediated by the flow of red blood cells. These cells are the sink for nitric oxide, so the on the concave side, where inertial forces keep the RBCs (denser than plasma) up against the wall, the NO concentration is lower. One of the things that regulates angiogenesis (mentioned later) is NO. The low NO causes the vessel to regress in the direction that NO is lower. The vessel regresses on the concave side becoming tortuous just like the meandering of a river. This is the same mechanism that causes tortuous vessels in the retina and the brain.

I have been working on this for some time, and the longer I work on it, the larger and more complicated it becomes. That is typical of all things that I work on. As I get enmeshed in the details, there are a lot of details, all of which support the hypothesis to some degree. I haven't included references to everything from the literature, but everything is well supported. Either directly or by a very strong chain of facts and logic. Including all the references and explanation would make it several times longer, and I don't have time for that these days.

If you have questions, leave a comment and I will answer the question. I appreciate this is going to be hard to follow and that some may (will) find it controversial.

There are multiple lines of reasoning that all lead to the same conclusion; extreme metabolic states induce physiological and mental states which serve to preserve the survival and reproductive capacity/potential of the organism. In that light, infanticide is a predictable extreme consequence of extreme metabolic and/or other stress. There are a number of delusional states that some of us are familiar with, the runner's high for example. Acute psychosis from stimulant abuse, cocaine, amphetamine, PCP is also well described in the literature. Acute violent psychosis from hypoglycemia is also common. I think these are all "features" of low ATP in the brain. A "feature" to trigger protective mechanisms which are invoked when a human is under extreme metabolic stress. I think that postpartum depression, postpartum psychosis and infanticide are invoked by increasingly extreme metabolic stress in the postpartum period. The only way to prevent postpartum psychosis and infanticide is by preventing the metabolic stress that causes it. Deterring infanticide by subjecting mothers who kill their infants to harsh treatment will not work. Putting more stress on women in the postpartum period will increase psychosis and increase infanticide.

I have accelerated my publication schedule, so as to get this out there. The last section is quite incomplete, that is how I see to prevent this from happening. I will post more on that later.

Background, NO, energy physiology and ATP physiology
These relate to my research on nitric oxide physiology. NO is a pleiotropic signaling molecule involved in thousands of physiological pathways. NO is generated at a site, diffuses a distance, and activates an NO sensor. The onset time, duration and strength of every such signal must depend on the basal level of NO present before NO is generated. A change in that basal NO level will affect all NO mediated pathways with no threshold.

A critically important pathway regulated by NO is ATP production via oxidative phosphorylation, and ATP concentration via soluble guanylyl cyclase. NO inhibits O2 reduction by cytochrome oxidase in mitochondria. All oxidative production of ATP occurs only in mitochondria. Cells can derive small amounts of ATP from glycolysis by converting glucose into lactate, however it takes 19 times more glucose to generate the same ATP via glycolysis than from oxidative phosphorylation.

Glucose is generated in the liver via gluconeogenesis. Stored glycogen is released, or amino acids from proteins are converted to glucose with some efficiency. The kidney has some capacity to make glucose too. Glucose can also be made from lactate, glycerin and a few other small carbohydrate molecules and from amino acids. It cannot be made from lipid. The brain only generates ATP via oxidative phosphorylation from glucose, lactate, acetate, other small carbohydrates or ketone bodies (made in the liver). The nervous system can not utilize lipid for ATP production. Muscle can consume glucose, or lipid. Essentially every cell can consume glucose, virtually all (except for red blood cells and perhaps the endothelium) can consume lactate. Red blood cells cannot consume lactate because they have no mitochondria. Endothelial cells do have mitochondria, but they tend to use glycolysis instead of oxidative phosphorylation.

In the brain, typically neurons consume lactate, and that lactate is produced by astrocytes from glucose. Neurons preferentially consume lactate over glucose.

At rest, essentially all organs are aerobic and ATP is produced mostly by oxidative phosphorylation with the balance by glycolysis. Glycolysis always occurs, even when there is no hypoxia, but the usual contribution may be small. ATP from glycolysis can be increased some, how much is limited by glucose delivery. ATP from oxidative phosphorylation can only be increased to the extent that there are extra mitochondria to do so, that is mitochondria above basal requirements. An individual cell can increase glycolysis a lot, however that consumption depletes the local area in glucose and increases the load on the liver and kidneys to recycle that lactate into glucose. The entire organism cannot greatly increase its production of ATP through glycolysis because there isn't enough glucose transport capacity to do so. To double ATP via glycolysis requires 2x the glucose. To double the ATP of glycolysis via increased oxidative phosphorylation requires 1.05x as much glucose. Glucose is carried in the blood stream which circulates through the vasculature. The red blood cells are confined to the vasculature, which represents only a small fraction of the body. Only the endothelium is in contact with the blood. The balance of the body gets glucose from plasma, which circulates much more slowly in the extravascular space. This plasma, or lymph contacts every cell, and that is how each cell picks up molecules that do not diffuse rapidly. O2, CO2, NO and other very small molecules diffuse sufficiently rapidly that they do not need to be convectively carried by the lymph. Virtually everything else diffuses sufficiently slowly that it must be carried. Certainly albumin, insulin and glucose must be convectively transported to reach cells not in contact with blood.

Glucose and insulin are actively transported into cells via special transporters. Activation of the insulin receptor causes the recruitment of additional GLUT transporters and so increases glucose import. However, there are obviously limits to how much glucose transport can be increased. Each GLUT transporter takes up some cell surface area, and the cell needs other transporters and other proteins in the cell surface. Lymph circulation is quite sluggish, and at most carries the glucose concentration of the blood (which is easily measured). Obviously the glucose level in the lymph must be lower because cells consume glucose as the lymph moves past them. For ATP via glycolysis to be doubled, the glucose flux to the cell must be doubled, which (at the same lymph flow rate) requires twice the glucose, or a doubling of the blood glucose level. I suspect this is the main reason for the hyperglycemia and insulin resistance of the metabolic syndrome. Due to low NO there are insufficient mitochondria; replacement ATP must be generated by glycolysis, more glucose can only be delivered by inducing hyperglycemia. Insulin resistance has to be induced too, so that some insulin and glucose gets to the cells that are farthest from a capillary. It needs to be remembered that the glucose and insulin levels in the extravascular space immediately adjacent to the vast bulk of cells are the levels that are actually important (not the value in bulk blood). However glucose and insulin levels in the space between capillaries is extremely difficult to measure.

Just as glucose only gets to cells farthest from a capillary if the intervening cells don't consume it, so to insulin only gets to those cells if the intervening cells don't consume it. Hyperglycemia and insulin resistance are seen as necessary features to deliver glucose and insulin to cells not in contact with blood.

Note, this view of the metabolic syndrome (hyperglycemia and insulin resistance are physiologically adaptive to maintain cell energy status) is counter to the "conventional" view that hyperglycemia is pathological. In my opinion, the "conventional" view is mistaken because of the mistaken notion that homeostasis is a real physiological effect. It is not. Homeostasis is a dogmatic, false belief for which there is zero evidence, zero supporting data, and zero physiological basis to expect it to be correct. Cells did not evolve to control physiology to be "the same", they evolved physiology to survive, and any and every parameter that can be changed is "fair game", and can be made lower or higher if necessary for cell survival. The myth of homeostasis arose because there were no techniques to measure what was going on inside cells on the time scales that are important (for virtually all parameters (more than 99.99% anyway) that is still true). The default assumption of stasis is simple. Simple but wrong. There is no parameter that physiology holds constant. Parameters regulated via feedback control (essentially everything important) require a deviation from a setpoint, and then compensatory response(s) to return the parameter to the setpoint. Even the most tightly regulated parameter cannot be "static"; there must be fluctuations in it. The only defensible default position is that we do not know what the concentration is, or how it changes over time until it is measured.

A modest decrease in ATP from mitochondria (5%) requires a doubling of glucose delivery to make up for it by glycolysis. When cells can't make enough ATP, they die. Either by apoptosis if the ATP fall is slow, or by necrosis if the fall is rapid. If the cells "too far" from a capillary can't get enough glucose, they will die, one at a time. This would be extremely difficult to detect via histology or biopsy. It is only the cells that are "too far". But when the do die, the immune system has to clear the debris, and that is the likely source of the chronic and systemic inflammation that characterizes all of these diseases.

NO also regulates the spacing between capillaries. Hemoglobin is the sink for NO and the source of O2 (O2Hb). The body must be able to both generate more blood vessels when there are not enough (angiogenesis), and ablate blood vessels then there are too many. The only way that "too many" blood vessels can be detected is via low NO due to close proximity to O2Hb. High O2 can't work because the highest the O2 level can get is the atmospheric level. Low NO from any mechanism is going to increase the spacing between capillaries (I think this is what leads to systemic sclerosis, fibromyalgia and Raynaud's). The only way a cell can get more O2 is by generating superoxide, pulling down the NO level so cytochrome oxidase pulls down the O2 level and more O2 diffuses down the gradient. Low NO then prevents mitochondria biogenesis. Potentially leading to a vicious circle and eventually to chronic insufficient mitochondria, aka chronic fatigue. If the NO level is already low, there is no inhibition of cytochrome oxidase that can be released, so generating superoxide only causes damage, it doesn't increase O2 delivery, O2 consumption or ATP generation.

When NO is low, blood vessels characteristically take on a "tortuous" morphology. This occurs (discussed earlier) when there is feedback and the flow affects the morphology and vice versa. It is a sign that the natural regulation of blood vessel spacing and morphology is becoming unstable and is about to fail.

Relatively few organs are capable of a high metabolic rate, they are muscle, brain, liver, kidneys. Every organ that can have a high metabolic rate does so via oxidative phosphorylation.

Muscle can operate anaerobicly. First on stored phosphates, creatinine phosphate, second on stored glycogen via glycolysis. Normally, when muscles are doing glycolysis, they are also oxidizing substrates. Some of the lactate is exported into the blood, and blood lactate levels go up. That lactate can be taken up and oxidized by other organs, such other muscles, the brain, can be recycled into glucose in the liver or kidneys, or can be taken up by fat cells and converted into fat. Lactate can be taken up by muscle and converted into pyruvate and excreted into the blood. Lactate can also be converted into glucose in fast twitch muscle (and stored as glycogen), but presumably not while the muscle is generating work. There is no mechanism for the body to excrete lactate, so either it is oxidized, or converted to glucose or to fat. All cells can make lipid and do so on a regular basis to maintain the cell membrane. Ectopic fat, that is fat in places it isn't "supposed to be", is a serious symptom. Fatty liver is pretty common, fatty arteries are bad, fatty skeletal muscle is more serious, fatty heart muscle, fatty kidneys and fatty pancreas are very serious. Production of lactate in muscle and consumption of lactate elsewhere, slightly increases the maximum ATP production of muscle. The muscle gets the ATP from glycolysis, but the reducing equivalents produced when lactate is turned back into pyruvate to feed into the citric acid cycle is done where the reducing equivalents can be consumed elsewhere.

A common cause of ectopic fat in the liver is alcohol consumption. The classic explanation is that alcohol is metabolized by alcohol dehydrogenase which generates NADH in excess of what the liver can easily handle. The liver then turns those reducing equivalents into fat to get rid of them. When lactate is converted to pyruvate so it can be fed into the citrate cycle (or converted into glucose), it also generates reducing equivalents.

Normally, reducing equivalents are removed is via oxidation and generation of ATP. However this requires mitochondria. What if you don't have enough mitochondria to dispose of the lactate? Don't make so much lactate? The problem is, cells have to make ATP, and if they don't have mitochondria to make ATP they will do glycolysis which generates lactate.

An interesting property of lactate, is that it can induce acute anxiety. Anxiety is a state of heightened awareness of danger. Lactate is produced by muscle acting anaerobicly. Presumably, increased lactate is a sign of impending metabolic crisis, better to have a lower threshold for being "careful", when one is in a near metabolic crisis. An interesting observation about panic attacks is that the frequency and severity sometimes drops remarkably during pregnancy. I suspect this is due to increased mitochondria number during pregnancy, gearing up physiology to deal with the metabolic stress of late pregnancy, delivery and lactation. Increased mitochondria means more ATP from oxidative phosphorylation, and less from glycolysis, resulting in less lactate and greater capacity of the liver and kidneys to clear lactate via glucogenesis.

I suspect that the nausea of morning sickness is actually due to elevated NO levels, so as to foster mitochondria biogenesis, and to maximize basal NO levels during the first trimester where embryonic differentiation is occurring. It is during differentiation that the highest fidelity of DNA replication and control is required. High NO levels mean low superoxide levels, and less potential for oxidative damage to DNA. Much of the enteric nervous system is nitrergic, nausea is exacerbated by placebos, indicating nausea is made worse by elevated NO levels. Many factors involved in neural development, neurogenesis, proliferation, differentiation, neuron trafficking, axon migration, involve nitric oxide. Including very "simple" things such as neural tube closure to the much more complicated things that are going on. Earlier blogs discuss how changes in maternal basal NO level may "program" fetal physiology and so affect adult physiology. This is known to occur in multiple organ systems, the Barker hypothesis. It likely occurs in the brain as well. It is in utero that most of the brain structural anatomy is established. That is the only time that major changes in brain function can be "hard wired" in.

"Stress" is a physiological state distinguished from "at rest", by the presence of a stressor that the organism must respond to. There are a large number of potential stressors, and a more limited number of responses. Virtually all of these responses are adaptive in the short term, and maladaptive in the long term. It is obvious that adaptive responses to stress must be maladaptive in the long term, otherwise cells and organisms would have evolved to be in them continuously. Stress invokes a number of physiological pathways.

In an earlier blog I posted about the placebo effect, and how placebos are what switch physiology from the "fight or flight" state to the "rest and relaxation" state. During the "fight or flight" state, organisms and cells are operating in emergency overload conditions, and cell repair is put off because of the need to divert all resources to "running from a bear". The "fight or flight" state is normally an acute physiological state, which the body stands down from as quickly as possible. "Fight or flight" is a low NO state, to minimize inhibition of cytochrome oxidase and so maximize potential aerobic ATP production.

In cells, virtually everything is powered by ATP. Proteins are synthesized using energy from ATP, lipids are synthesized, ions are pumped across membranes, muscles are moved, proteins and organelles are transported by ATP powered motors, proteins are phosphorylated, proteins are folded and unfolded, damaged proteins are sorted and disposed of by ATP powered proteases. Several billion years of evolution have resulted in ATP control systems that are extremely well regulated, and the details of which remain largely unknown. The details are unknown because of the extreme complexity of the systems, and the very small size of individual cells where the regulation takes place. There are hundreds of thousands if not millions of pathways, all of which are individually controlled exquisitely well under an extremely diverse range of conditions. Many (if not most) of these conditions do not occur during normal physiology.

What is the highest priority when running from a bear? Escape from the bear, obviously. Everything else is of lower priority, low enough that if it doesn't help in running from a bear, it can be put off. Does your body need to repair cell damage while running from a bear? Prevent infections? Reproduce? Dispose of damaged proteins? Generate milk for lactation? No, all of these things can be shut off until after the bear has been escaped from and your body can "stand down" from the fight or flight state. If a few more molecules of ATP can help escape, an "optimum" ATP control system would shut down all "non-essential" systems to divert ATP (and other resources) to "running from a bear".

Reproduction, starvation
So what does this have to do with the murder of Katie McCarron? Just to remind everyone that there are metabolic states that we personally have never experienced yet our bodies remain ready to invoke if necessary. When was the last time you "ran from a bear"? Likely never. But could you if one started chasing you down the street? Of course you could, in a heart beat.

It needs to be appreciated that humans evolved. What that means is that humans today are descended only from earlier human and non-human ancestors who survived and reproduced in spite of every adversity that befell them. None of our ancestors who "ran from a bear" were caught before they reproduced. If they were caught before they reproduced, they had no descendents and so are no ones ancestor. This is an extremely important point. No organism has an ancestor that "ran from a bear" and was caught before that ancestor reproduced.

Over evolutionary time, the average number of descendents the average individual had was 2. Those descendents who survived and reproduced that is. For every individual that had more, someone else had fewer. For example, if the average number of descendents was 2.1, then over 500 generations the population would reach levels we know did not happen. (1.05)^500 = 3.9 E+10, many more people than are alive today.

We know that in the absence of birth control, women become pregnant many times. If they only had 2 descendents, either they died before having more, or the children died before reproducing, or both. How many times did females get pregnant? 5, 10, 15 times? No one knows. It seems likely that men would continue to have sex with them and they would continue to get pregnant until they died, became infertile, or went through menopause.

A major cause of death in less-developed regions is starvation. No doubt starvation was important during evolutionary time too. What behaviors might evolve to survive starvation? Remember, no one's ancestor starved to death before that individual reproduced. Only those individuals who survived starvation and then reproduced contributed to the present human gene pool.

The defining characteristic of mammals is that females generate milk for their young. For a female to generate milk, she must have the physiological resources to do so. In mice, there are definite metabolic limits to how much milk can be produced. Mice normally have litters of 8-15 pups with a mean of 11 or 12. When litter size is reduced, mice eat less food and produce less milk, but with larger litter sizes, food consumption reaches a plateau. Milk production continues to increase, but the energy concentration of the milk goes down. There are metabolic limits as to how much food mice can eat, digest, and convert into milk. Obviously there are limits for humans too.

Empirical and theoretical constraints on the evolution of lactation.

Evolution of mammals: lactation helps mothers to cope with unreliable food supplies.

Effect of variation in food quality on lactating mice Mus musculus.

To make more milk, mice increase the size of their digestive system and other organs, but only within limits. Presumably humans do the same thing.

Energetic demand of multiple dependents and the evolution of slow human growth

After giving birth, it takes some time before a women's milk "comes in", many of the details of what regulates lactation remain unknown. It is obvious that a woman's metabolic resources are limited, and so cannot increase indefinitely.

In order to make milk, food must be eaten, digested, absorbed, converted in the liver into forms that can be turned into milk in the mammary gland, transported to the mammary gland, and turned into milk. The control system monitors and regulates all of these physiological functions and adjusts the capacity of each so there are no "bottle necks" must also work properly. A schematic of a few of the subsystems is shown in figure 1.

Control of physiology
The control system(s) that regulate the metabolic capacity of each individual subsystem is probably the most important control aspect, and yet is the least understood. That control system must be capable of both increasing metabolic capacity when there is not enough and decreasing it when there is excess. For example, liver capacity in excess of metabolic demands for what the liver can do is of essentially no value because it is never used. Organisms that waste resources on unused tissue compartments have fewer resources to devote to reproduction and over evolutionary time are out competed by organisms that allocate resources more efficiently. Presumably because those systems grow many orders of magnitude in size from in utero to adult capacities, the systems are under feedback control. Only feedback control would provide effective regulation over so many orders of magnitude.

Organ size must be controlled at both ends, when the organ is too small it must be increased, and when it is too large it must be decreased. A control system that only works to make the organ larger would be unstable and if the organ could never shrink, would eventually result in a mismatch. We know that organs do shrink, so there must be a control mechanism that does it in a controlled manner.

Precisely how the control systems work, is not fully understand. That there is such a control system and that it does work extremely well is not in doubt. Presumably there is a signal from each tissue compartment that utilizes a metabolic resource to trigger the production of metabolic capacity to produce that resource in the tissue compartment that produces it. For example, the brain utilizes glucose or ketone bodies. Both of these are made in the liver. There must be a signal from the brain to trigger liver growth. Can that be a neurological signal? Probably not. Multi-celled organisms needed to coordinate metabolic activities between multiple tissue compartments even before nervous systems evolved. Presumably as more tissue compartments were added, those coordination systems were elaborated and made more complex, not replace with de novo evolved systems. Essentially every cell in the body needs glucose, there must be signal(s) that regulate liver size and physiology accordingly. The time scale needed for control is slow, on the order of days, there is likely no need for neural speed. What ever the signal is, it needs to be transmitted from each cell that consumes glucose to each cell that produces it (in principle). Because the liver is denervated when transplanted (as are all transplanted organs), regulation of glucose production capacity cannot be solely neurogenic. Similarly because the liver can regenerate on a rapid time scale, those new cells must pick up a signal by non neural means. There may be neural mechanisms as well, but non-neuronal mechanisms are sufficiently robust to be "enough". Similarly for the heart and kidney and all organs that have been transplanted. No doubt this is part of why so many different regulatory molecules are made by different organs. Angiotension is made in the heart and affects the kidneys. Similarly erythropoietin is made in the kidney and liver and regulates erythropoiesis in the bone marrow.

I suspect that many of the control pathways that regulate liver capacity to make glucose and ketone bodies are regulated by NO. The ability of the liver to make glucose does depend on mitochondria; similarly the ability to make ketone bodies from lipid also depends on mitochondria. Since mitochondria biogenesis is initiated by NO, low NO will adversely affect liver capacity to do those things. Erythropoiesis is triggered by erythropoietin, which is expressed in response to HIFa which is activated by NO. There is considerable feedback between NO and hematocrit because oxyhemoglobin in red blood cells is the sink for NO. Under conditions of isovolemic anemia, exhaled NO increases. So low NO will cause anemia as the body lowers hematocrit to reduce NO destruction and increase NO levels. I suspect that low NO resulting from normal hematocrit when Epo is used to raise hematocrit (such as during kidney failure) is the reason for increased mortality when hematocrit is raised to "normal" (13.5 vs. 11.3 g/dL). Basal NO is already low in some patients with kidney failure (some kidneys fail because they don't have enough mitochondria); still lower NO simply accelerates the process.

Lactation is extremely energy intensive. The timing of that energy consumption is not precisely clear. Much of the lipid in milk is synthesized or deposited in the breast between periods of breast feeding and is then released during lactation. The carbohydrate lactose is the major osmolite and so is necessarily synthesized at the time of milk release. It doesn't take a lot of ATP to do that, but it takes two molecules of glucose to make each molecule of lactose and that glucose has to come from somewhere. Similarly, milk proteins synthesized in the breast are made at the time of milk release. Some proteins from the blood stream (such as immunoglobulins) are transported from the blood stream to the milk.

The main storage site of protein is skeletal muscle. Dietary amino acids beyond what is incorporated into protein are deaminated and converted into glucose mostly in the liver with a little bit in the kidney. Everything else uses glucose, fat or ketone bodies for ATP production.

An interesting observation is that the higher the body fat of a lactating woman (as measured by BMI), the shorter the period that she nurses her child and the sooner she introduces complementary foods. Reduced duration of lactation is also associated with excessive weight gain during pregnancy. This would seem to be counter intuitive. If depot fat is a source of energy, presumably obese women have more energy to spare, and so should lactate longer, not shorter. However, milk has primarily 3 components, protein, lactose and fat. Lactose can only be made from glucose. Glucose can only be made from 3 carbon substrates such as pyruvate, lactate and glucogenic amino acids. Most lipids have an even number of carbons, and are broken into 2 carbon bits that are oxidized. Fat can be converted into ketone bodies, acetoacetate, beta-hydroxybutyrate and acetone. None of these can be used to generate glucose or lactose. A diet that is too high in fat isn't conducive to the production of glucose. Lactation requires a balance of protein, lactose and fat. If there is insufficient liver to generate sufficient glucose, or if the diet contains insufficient glucose precursors, appropriately nutritious milk cannot be produced. In the short term, females can draw on body reserves (stored glycogen, and then stored protein) to produce milk. However body fat can only be used to generate milk fat, it cannot be used to synthesize lactose or protein. Once glycogen reserves are consumed, the female must catabolized protein to make lactose or protein. That means drawing on skeletal muscle and other lean tissue. Under such circumstances, glucose is made from protein, via deamination, which releases ammonia, which may be converted to urea in the liver (at an ATP cost). In the "wild", some of that ammonia and urea would find its way to the skin, where a surface biofilm of ammonia oxidizing bacteria would oxidize it into nitrite and NO, which would then stimulate mitochondria biogenesis.

Glycogen is an important body reserve, and when it is exhausted there are dire health consequences. There is a drop in blood sugar, and if there are insufficient ketone bodies to support the nervous system, it will begin to die. If hypoglycemia is sufficiently deep and of sufficiently long duration, brain damage is inevitable and irreversible. Similarly, anaerobic muscle operation requires glucose and optimally glycogen. Allowing muscle glycogen to go to zero greatly reduces short term peak muscle capacity. There is a period of time during rat gestation where maternal dietary carbohydrate is essential for fetal survival. It is during the time when fetal liver accumulates glycogen.

In mink, milk fever is a serious problem, and causes significant mortality. Many of the symptoms are characteristic of the metabolic syndrome, elevated blood glucose, insulin resistance. In humans there is an inverse correlation between duration of lactation and family history of diabetes and also an inverse correlation between duration of lactation and risk of diabetes type 2.

Why is high temperature associated with milk fever? I suspect because energy physiology is becoming less efficient. To generate the same ATP with fewer mitochondria, the mitochondria potential is driven higher, which increases slip, and reduces the ATP generated per molecule of O2 consumed. The excess energy is dissipated as heat. I think this is the mechanism for increased basal metabolism observed in the hypermetabolic state of obesity, many degenerative diseases, and in the hyperpyrexia of stimulant abuse. The increased consumption of O2 and substrates does not translate into more ATP. One mechanism, expression of uncoupling protein, can severely diminish ATP levels by turning mitochondria from producers of ATP to consumers of ATP. Similarly, the Cori cycle, the recycling of lactate into glucose consumes energy which is dissipated as heat.

I think the hyperpyrexia associated with milk fever is likely "the same" as the hyperpyrexia of the stimulant drugs of abuse, such as PCP, which is frequently associated with psychosis and often violence. Postpartum psychosis and infanticide are likely specific to the postpartum period. If a woman has not had children, she may not be capable of metabolic stress induced infanticide.

It might be thought that induction of uncoupling protein in response to low ATP might be counter productive. It might be. However, briefly lowering ATP concentration, may turn off ATP consuming pathways and so produce an increased ATP supply by decreasing consumption. Normally, low ATP occurs because of excessive ATP demand (in muscle for example), and with a "normal" number of mitochondria, there is excess ATP production capacity, but the mitochondria need to operate at a higher potential to produce it. Uncoupling protein protects from the mitochondrial potential from getting too high and too much production of superoxide.

Mitochondria regulation, short term, long term, mitochondria disposal, mitochondria biogenesis
An observation which is important in my placebo effect blog is that your body will allow you to run yourself to death trying to escape from a bear. But that is for an unpredictable, unanticipatable, unforeseen, acute, severe metabolic load. Metabolic load due to lactation is not unpredictable. It would be surprising if no physiological mechanisms evolved to prevent death under those circumstances.

How does a cell respond to increased demand for ATP? The answer is fabulously well, on all time scales that are important, including seconds, minutes, hours, days, weeks and years. An outline of a few of the compensatory responses is shown in table 1. The placebo effect blog talks about acute ATP demand, what about less acute? The only source for a large increase in ATP is from mitochondria. Normally there is some excess mitochondria capacity, this is what allows metabolic rate to increase above basal levels. The number of mitochondria doesn't change in a few seconds or a few minutes, or even hours, what changes is their regulation. To generate more ATP, mitochondria increase their membrane potential, which increases the driving force for ATP production from the mitochondrial potential gradient. This also has the effect of increasing superoxide which is vectorally produced in the inner matrix, where MnSOD converts it into H2O2. Before the MnSOD destroys the superoxide, the superoxide destroys NO, which lowers the NO level local to the mitochondria and the low NO then disinhibits cytochrome c oxidase which then reduces O2 to H2O. The more active cytochrome c oxidase consumes more O2 (to a lower O2 concentration), which pulls down the O2 concentration, which increases the O2 gradient between the mitochondria and the blood vessel, so a larger flux of O2 diffuses down the concentration gradient.

So, an early response to a demand for more ATP is increased superoxide production by mitochondria. As demand goes up, the O2 flux must increase, the O2 concentration gradient must increase, O2 concentration at the mitochondria must go down, and cytochrome c oxidase must be less inhibited. The only way to do this is by removing the inhibition imposed by NO. Heart muscle can increase metabolic O2 consumption by an order of magnitude. For an order of magnitude more O2 to diffuse from the blood stream to the mitochondria, the gradient in O2 (d[O2]/dx) must increase an order of magnitude because it is only the O2 concentration gradient that drives O2 from the O2 source (blood) to the O2 sink (mitochondria). The O2 level at the mitochondria thus must drop an order of magnitude while the activity of those same mitochondria increases by an order of magnitude.

If metabolic stress is prolonged, this presents a problem. The only way a high ATP flux can be produced is by destroying NO with superoxide at the mitochondria. However, NO is the signal to generate more mitochondria. Low NO is also a low ATP concentration state, during which time cell repair is reduced. Mitochondria have a finite lifetime. After a time they wear out, accumulate damaged proteins and eventually damaged mitochondrial DNA and become dysfunctional. How are mitochondria recycled? Very carefully. Mitochondria are potentially quite dangerous. They can consume considerable quantities of substrates; O2 and organics ported in, they can generate essentially unlimited quantities of superoxide and H2O2. They contain Fenton active metals, Fe, Cu, Mn, heme, and so can generate hydroxyl radical from the H2O2 they make. Hydroxyl radical damages everything it touches. The only protection from hydroxyl radical is to not come in contact with it. Fortunately when superoxide is made, it is vectorally produced into the inner matrix, and so is separated from the cytoplasm by 2 lipid membranes. But to recycle the Fenton active metals, the mitochondria need to be taken apart. How? Very carefully. The metals are mostly coordinated by sulfur, and are very tightly held. Coordination of NO to many of these metals does inhibit the Fenton reaction. Iron nitrosyl sulfide complexes are a major storage site of iron and NO. Ensuring the local environment is low in H2O2 and high in NO may be an important factor in the timing and regulation of autophagy.

Mitochondria and all organelles are recycled by autophagy, a characteristic of all eukaryotes. Briefly the organelles to be reprocessed along with some cytoplasm are enclosed in a vacuole, protease precursors are ported in along with other lytic enzymes, the V1H-ATPase begins to lower the pH, and at the appropriate pH, the proteases become activated. Cysteine is ported in, and cystine is ported out, reducing disulfide bonds, opening the proteins up so they can be digested into little bits which are ported out.

Conserving ATP by putting off protein synthesis and the reprocessing of mitochondria is a good idea. While you are running from a bear is no time to use ATP to destroy mitochondria, even crappy dysfunctional and useless mitochondria. You run from a bear with the mitochondria you have, not the mitochondria you wish you had. One mechanism by which this is regulated is by oxidative stress inhibiting the V-H-ATPase that regulates the pH in the vacuole and so regulates the whole process. So, the oxidative stress that causes low NO also inhibits autophagy, and inhibits mitochondria biogenesis.

What happens if the state of low NO goes on for too long? The number of mitochondria that are produced is less than the number that wear out, so the number of mitochondria goes down. How far down? Good question. If it goes too far down, the cell they are in dies, most likely through apoptosis (programmed cell death). Usually a gradual and slow decrease in ATP causes apoptosis, an acute drop in ATP causes necrosis. Apoptosis is "better", in the sense that it leaves less debris and causes less damage, but it takes ATP and time to happen, necrosis doesn't.

Normally, sleep is a low metabolic state, and a high NO state. It is during sleep that most mitochondria autophagy and mitochondria biogenesis occurs. However, it is also during sleep that much of the lipid destined to be in the next day's breast milk is produced. Some lipid can be transported at low energy cost from depot fat, but some is synthesized de novo. Synthesis of lipid requires a lot of energy. Glucose must be synthesized in the liver, then lipid synthesized in the breast. If there are not enough mitochondria, then the drop in metabolic rate during sleep may not be enough to raise NO levels sufficiently for mitochondria biogenesis to make more.

At higher ATP production rates, oxidative phosphorylation becomes less efficient, there is more slip (fewer ATP molecules per molecule of O2 consumed). Substrate consumption can be increased, but the quantity of ATP produced per molecule of substrate is lower. If metabolic demand goes up faster than mitochondria biogenesis, you can (in theory) reach a metabolic state where maximum ATP production capacity actually falls because worn-out mitochondria are not replaced and the fewer mitochondria that are left are running at ever higher potentials, ever more inefficiently, and producing ever more superoxide, and wearing out ever faster. A number of disorders are characterized by a hypermetabolic state including obesity, heart failure, primary biliary cirrhosis, kidney failure. I think a hypermetabolic state is a consequence of too few mitochondria. The solution is to increase the mitochondria number by increasing NO and so triggering mitochondria biogenesis. Normally simply rest does this. ATP acts on guanylyl cyclase to increase the threshold for NO activation. When mitochondria are operating at a high potential, they generate a lot of superoxide which lowers the NO level. When ATP demand falls, the mitochondria potential falls, which stops the production of superoxide and so NO levels go up. This triggers mitochondria biogenesis but only if there is a source of NO that the superoxide is pulling down. If basal NO is already low, the NO level does not rise when superoxide production falls.

I think that in cachexia the liver doesn't have enough mitochondria to make glucose from lactate, so it makes it from alanine. The alanine comes from muscle. The metabolic load of generating glucose is shifted from the liver to skeletal muscle, turning the muscle into glucose and releasing ammonia. This ammonia can either be turned into urea (at an ATP cost in the liver), or it can be excreted as ammonia in the kidney, or on the skin where the ammonia oxidizing bacteria can turn it into NO and nitrite (raising NO levels and triggering mitochondria biogenesis).

Once the hypermetabolic state with insufficient mitochondria happens, the only way out is to reduce metabolic load, allow NO levels to increase, initiate mitochondria biogenesis, and increase ATP production capacity. If you can't reduce your metabolic load, that is if you have no reserves and need all of your metabolic capacity to supply your basal metabolic needs, then you are SOL. I think this state is commonly known as "chronic fatigue syndrome". In acute cachexia due to infection or trauma, if the underlying infection or trauma is repaired, the metabolic demand goes down, NO levels go up, mitochondria biogenesis can resume. In chronic cachexia the metabolic rate doesn't go down, so there is no way out and it is part of a terminal physiological course.

If your ATP production capacity reserves are insufficient, anything that increases ATP demand can be fatal. When people suffering from severe anorexia are refed in a hospital setting, digestion of food, and resumption of a more normal metabolic state is not easy. There have been fatalities even in a hospital setting. Typically these deaths are characterized by a hypermetabolic state just before death. I suspect that is the attempt to increase ATP production by increasing mitochondria potential which decreases the efficiency of ATP production enough that ATP production actually falls. Either that or production of superoxide from higher mitochondria potential causes induction of uncoupling protein and that causes ATP production to fall. In any case, a hypermetabolic state is a sign of metabolic crisis.

Sophie's choice
What can a female do if the metabolic load necessary to sustain her infant until weaning is unsustainable? What can a female do if there is insufficient food to sustain her infants? The female is left with a Sophie's choice. Continue down an unsustainable path until she dies (then all her children die), or make a choice of which of her children will die sooner, and which might then have a chance of survival later, or wait until they die one by one, or they all die. Putting off a decision may weaken the stronger ones and lessen their ability to ultimately survive.

Well, what did our ancestors do? None of them chose to go down an unsustainable path until they and all of their children died. If they did, they are no one's ancestor. This is an extremely important point. No organism has a single ancestor that starved to death before that ancestor reproduced.

What did Sophie do? She put off deciding until the last moment, and then impulsively chose for her son to survive and her daughter to die. Sons are frequently favored (for example as in China the ratio is now highly skewed to males) because a male can (in theory) have many more descendents than can a female. The preference for sons is well known, and is responsible for the selective abortion of females and infanticide of females. Michelle Dawson has blogged about this (as a somewhat peripheral issue). Ironically, the instinctive preference for sons in anticipation of more grandchildren means that many parents in China with a single son will have no grandchildren because there are many millions more males than females. The instinctive feeling that sons are a better reproductive bet than daughters has been rendered wrong by modern circumstances. It may be "wrong" and be known to produce an undesirable result but people still can't stop themselves from doing it. They are making the same choice that Sophie did, save a son at the expense of a daughter. To be fair to Sophie, females have other means of survival, becoming the concubine of a male. In the "wild", there is no rational reason for a male to ever kill a female who is old enough to be self-supporting. He simply uses her as a concubine. She then bonds to him via the mechanism of capture bonding. This is not to justify rape or abuse of females, but it is a behavior that "worked" in our evolutionary past (that is both males and females reproduced via the female being raped), and so we still have the ability to respond when the circumstances are appropriate, even if we have never experienced those circumstances, just as we could run from a bear if one started chasing us. Sophie's daughter was 9, old enough to be self-supporting, but young enough to have never been pregnant. The type of female that Moses ordered saved as concubines (Numbers 31:17) when captured in battle.

Acute neurological effects of metabolic and other stress: Stress induced delusions
Sufficiently severe metabolic stress causes death. Slightly less coma and less still delirium and delusions. What types of delusions might aid survival? That would depend on what the stressor was.

When one needs to run from a bear, the pain of minor injuries is of zero consequence. That is why under extreme states, the body causes the release of endorphins, compounds that dull pain while allowing one to continue running from a bear. Under extreme states, the endorphins can even induce euphoria, delusions that one is not tired, that one has great strength, that one is invulnerable, that one is omnipotent. These delusions are quite useful when running from a bear, or if the bear catches you, to fight with the bear even when the bear is many times stronger. Maybe the bear isn't hungry enough to risk getting a scratch or a poke in the eye from a psychotic human prepared to fight it. I think this is the source of the "runner's high". Does a certain level of fatigue suddenly disappear and a new more effective source of energy come online? No, that cannot happen. If it did, organisms would evolve to be in that state continuously. The runner's high is the delusion that one is not tired. One may have more energy to devote to running, but that is only because ATP has been diverted from other uses.

What does happen is akin to ischemic preconditioning. ATP production is not increased or made more efficient, ATP consumption is decreased by turning off ATP consuming pathways. Which pathways? The voluntary pathways? No, then fatigue would seem to be exacerbated. What are turned off are the involuntary pathways, the cellular repair pathways. The loss of the feeling of fatigue is a delusion. A very useful delusion when running from a bear. A very dangerous delusion when achieved through voluntary exercise, or via stimulant drugs of abuse. Overuse injury in people addicted to exercise is common. The normal pain of overuse is blocked by the delusional euphoria of the runners high. The side effects of stimulant drugs of abuse, cocaine heart, amphetamine heart, the brain damage of stimulants, all come from the reduction in ATP caused by the stimulants turning off the repair pathways. Acute alcohol consumption can cause hypoglycemia. Alcohol is metabolized by alcohol dehydrogenase which makes reducing equivalents which must be disposed of. The liver can't make glucose during that time, so blood glucose can only be maintained by stored glycogen. When that glycogen is depleted, the resulting hypoglycemia can cause brain damage or even be fatal. I suspect that many "violent drunks" are violent because of ATP depletion in the brain invoking violent behavior, the "berserker" state.

The body optimizes the various metabolic trade-offs it must make over a time horizon. Running from a bear may cause a torn muscle, which is better to avoid, because it will take time to heal, and may even cause permanent damage, however a torn muscle is infinitely better than being caught. The long term adverse effects are balanced against short term survival. In a sense, the body calculates a "discount rate", that is, an effective interest rate, to discount the future values of goods and services (i.e. the body and its functionality) versus values of those same things today. A problem with using a discount rate to value avoiding future adverse consequences is that if the discount rate is high enough, and the time frame long enough, avoiding a future adverse consequence is of negligible value today, even if that adverse consequence is quite severe.

In the running from a bear case, the discount rate is essentially infinite until one has escaped from the bear. Any future "cost" (that is a cost that can be deferred until after the bear has been escaped from) is negligible compared to escaping from the bear. How does the body calculate this? Well, under conditions of extreme stress, the body does the calculation for you, and that calculation is reflected in the different "values" that people have under conditions of rest, and under conditions of extreme stress. This is why desperate people do desperate things. There isn't time for these "values" to be weighed cognitively, and no doubt some are from deep evolutionary time before human ancestors had sufficient mental capacity to cognitively weigh such things. People don't know why they do these things, make these decisions, but one thing humans are good at is making rationalizations of why we feel certain things.

We can see this change in values quite easily in people affected by stimulant drugs of abuse. The classic example is the "crack whore", an individual who will take any risk, do any degrading thing, expose herself to HIV, hepatitis, or other diseases simply to get more crack. What the crack is doing, is invoking some of the same metabolic stress pathways that are invoked during "running from a bear". It makes living in the present moment (while on crack), more important than any future event(s). That is why individuals have the ability to do things that a person not on drugs would never do, take enormous risks, face virtually certain death from HIV, completely neglect their health, or even allow their children to starve to death. It is not that these people are being irrational, rather they are being completely rational, it is just that the "discount rate" they are using to evaluate future adverse events is near infinite. It is exactly analogous to the feeling that the next few moments of life while running from a bear are "worth" running yourself to death. Your body has to feel that way to take the enormous risks that are "worth it" to escape from a bear. Because these risk/reward calculations have to be done essentially instantaneously to be useful, they are not subject to cognitive deliberation or control. You go with your "gut". How can you deter such individuals with a risk of future punishment? You can't. The "war on drugs" has shown time and time and time again. There is no punishment you could administer that is worse than the hell-hole of a life that "crack whores" are already living. Deterrence simply cannot work when the discount rate becomes infinite. Stimulant drugs of abuse induce a state where someone feels and acts as if they have nothing to lose. That is a state where deterrence cannot work.

The concept of deterrence is implicit in the defense strategy of "mutually assured destruction". The rationale is that a rational person won't risk the certain death of millions in order for some finite possibility of a finite gain. However, if a person is in a metabolic stressed delusional state, such as the runner's high, they are not working with the same "discount" rate as at rest, and so may not come to the same decisions. It is extremely important that leaders making decisions about such things not put themselves in such delusional states by exercising too vigorously, becoming intoxicated, taking stimulant drugs of abuse or other such things.

It is the same near infinite discount rate that compels some individuals to sacrifice themselves for their companions in a moment of stress. Stimulants of abuse invoke the same physiological state. Cocaine use among mothers correlates better with symptoms associated with psychosis than does abuse of alcohol, opiates or marijuana. I think that is because cocaine invokes the same pathways as postpartum psychosis.

Many mothers would fight to the death to protect their children. A optimal choice has to weigh the likelihood of the children's' survival should the mother perish. That is, are there other reliable caretakers (siblings, extended family, grandparents, child's father, villagers, lactating females) who can and will care for the child until the child is able to fend for itself? If there are no potential caretakers, or if the mother feels they are not sufficiently reliable, then for her to have any surviving children, she must survive and either save the children she already has, or save herself and get pregnant at a future time.

In the "wild", there are two components of infant feeding, milk produced by the mother, and food that is hunted and gathered. Usually the hunting and gathering is also by the mother, but grandmothers are sometimes involved. Milk can only be provided by another lactating female, who has excess capacity, and the desire to foster the child. The usual cause of metabolic stress over evolutionary time was likely insufficient food. An adult female sufficiently known and bonded to the mother to be acceptable foster parent would likely also be affected by what ever environmental effect is causing the local shortage of food.

In evolution, the only "reward" that is selected for is survival of genes which means having relatives (especially descendents) who survive and reproduce. What organisms evolve are (for the most part) physiology and behaviors that tend to accomplish that. However, what is "needed", is not constant in time, or over different circumstances.

What triggers infanticide
I think that metabolic stress is what triggers postpartum psychosis and ultimately infanticide. It is the attempt to shed metabolic load to preserve maternal life and future reproductive capacity under severe metabolic stress. An evolved "feature" observed in all mammals. The "goal" is not so much to preserve maternal life, but rather to preserve maternal reproductive capacity, as measured in the life of her children, of their siblings born, unborn, and not yet conceived. If times are not "good enough" to provide sufficient nutrients to bring infants to weaning and beyond to when they are metabolically self-sustaining, better to put off reproduction until later, when times might be better.

Other metabolic costs, pregnancy, anorexia, depression
The metabolic "cost" of a pregnancy is a very interesting topic. In figure 2, from Energy adaptations in human pregnancy, for women from Gambia and Keneba, the energy "cost" of early pregnancy is zero. The incremental energy requirement for pregnancy in humans is quite small. This is characteristically quite different than that of all other mammals. Humans have an extremely long period of time during which the infant requires care by adults including protection and supply with food, first by lactation, and later by supply of adult-type food.

ATP is not stored; the instantaneous production always equals the instantaneous consumption. If this were not the case, then there would be rapid accumulation or depletion of ATP. Each mole of glucose that is oxidized produces about 38 moles of ATP. A 2000 calorie diet then produces some 55 kg of ATP per day. Obviously, the ADP and P are recycled, and ATP production and consumption is very precisely matched.

When there is not enough ATP, the cells can either make more, or use less, or (optimally), do both. Because it takes ATP to digest food, there may be times when there isn't enough ATP to digest food and so eating food is put off. Obviously eating cannot be put off indefinitely; neither can any other essential ATP consuming pathway. But when you are running from a bear, you put off anything and everything that you can, until you have escaped from the bear. Dietary thermogenesis, the energy required to digest food and store it in forms that can be retrieved is about 10% of the caloric value of the food.

Anorexia is a serious problem in many women. Many have actually starved themselves to death. Precisely why this occurs is unknown. There can be considerable mutual reinforcement of the behavior in the cult of "Ana". These anorectic individuals have very strong and deliberate motivation to be thin, and they are quite resistant to being told to eat, or being forced to eat. They are seemingly quite rational in other aspects of their life. Self-preservation is an extremely strong instinct, as is avoiding starvation.

Brain metabolism in anorectics is reduced over that of low weight depressed individuals, which is reduced over normal controls. Brain hypometabolism of glucose in anorexia nervosa is normalization (to some extent) after weight gain. I suspect that somehow the body gets into an ATP conservation mode, where avoiding the ATP cost of digestion is considered to be an important survival strategy, and so the brain manufactures feelings to cause this to happen, and people with very strong feelings that they must not eat develop rationalizations to justify those feelings. The rationalizations may be quite bizarre and illogical, and even quite delusional and wrong, but rationalizing the feelings that your brain is generating to survive an extreme metabolic state is an important survival factor. Just as the runners' high is the delusion that you are not tired, I think the anorectics' feeling of being "full" and not hungry is a similar delusion.

Cellular determinants of feast and famine.

Normally, the metabolic capacity of each system is closely matched to the others. Ideally, the capacity of each system is identical, that is there is no "excess" capacity in one system that cannot be utilized by the others. That excess is simply wasted because it cannot be utilized. Reserves can be tapped when physical activity is increased above basal levels. Regardless of what the reserve is, at some point that reserve will be exhausted and metabolic rate cannot be increased. The only alternative then is to start shedding other metabolic load, diverting resources to what ever activity is demanding it.

Physical activity is under voluntary control, autonomic activities are not. Fatigue and pain are symptom of insufficient metabolic capacity in the muscles, and can be caused by insufficiency in any of the subsystems supplying metabolic resources to that muscle. Autonomic systems often don't have symptoms such as pain when they have insufficient metabolic capacity because there is nothing you can do to reduce metabolic demand. An exception is the heart. Ischemia in the heart is painful. One can reduce metabolic demand on the heart by reducing physical activity. The heart will continue to pump until it kills itself from over exertion. However there is tremendous pain while this is happening, no doubt to induce the organism to reduce physical activity and so reduce the metabolic load on the heart.

What happens to other organ systems when they are overloaded? The liver doesn't convey signals of pain when overloaded. The major component of voluntary metabolic activity is skeletal muscle, which can operate on lipid which doesn't require acute liver involvement to mobilize. There isn't much voluntary activity that can be reduced to limit liver metabolic load. Digestion is a major liver metabolic load, low appetite is a symptom of many diseases. Postprandial thermogenesis is significant. Perhaps low appetite is a mechanism for reducing the metabolic load on the liver due to digestion. Not something that can be sustained in the long term, but perhaps a useful strategy in the short term.

Infanticide from the child's perspective.
A quality of life issue that many healthy adults have is not wanting to be a burden on others, in particular their families, should they become disabled. I could imagine someone feeling that they would rather die than be a burden of a certain level. In particular, an organism should evolve the characteristic of not wanting to reduce the reproductive success of themselves, or of their relatives. The "optimum" reproductive strategy would be to weight "burden" (that is the decrement in another's reproductive capacity) by the degree of relatedness.

It is considered acceptable for a person to voluntarily sacrifice themselves for another. Many parents would willingly sacrifice themselves for their children, and this is "explained" in an evolutionary sense as trying to protect the reproductive capacity of your closest relatives. Full siblings are as related to each other as to their parents as to any children they may have. Because the behavior to sacrifice oneself is to preserve the reproductive capacity of near relatives, the willingness to sacrifice should (at a logical extreme) depend on the relative reproductive capacity of each relative, weighted by the degree of relatedness. In other words, a sacrifice has equal "benefit" to the individual when the preserved genes are the same. In other words, saving an identical twin provides as much benefit as saving two siblings, parents or children, four grandchildren, half siblings, cousins. The "sacrifice", is not "life", because everyone is going to die eventually any way. The only meaningful "sacrifice" is of the potential to have descendents before one dies. Seen in that light, a postmenopausal woman can't have any more descendents, all she can do is attempt to preserve the reproductive capacity of her relatives, her siblings, her children, grandchildren and great grandchildren.

The preference for sons can then be seen as being due to the perception that the son has a greater potential reproductive capacity than the daughter, but the "cost" in terms of providing food from infancy until they are self-sustaining is about the same.

The reproductive potential of all individuals is not the same. Reproduction requires survival to a reproductive age, finding a mate, mating, having children, and having those children survive. In the "wild", each reproducing female had to accomplish each of those tasks by herself, although the finding a mate and mating may have been forced upon her by a male. In the relevance of a "Sophie's choice" type situation, in order to make an evolutionarily optimum choice, the female making the "choice", has to unconsciously weigh the likelihood that a particular child would be successful in each of these elements of successful reproduction, and then choose the child expected to be most successful.

In the context of the Katie McCarron situation, a child with autism in "the wild" would have a harder time surviving and successfully reproducing. If a mother had 2 children, one with autism and one NT, the NT child would be a better reproductive "bet", and so would likely be favored in a "Sophie's choice" type situation. This is not to condone or find acceptable such a choice, or to say that such a choice is "good", but in the context of evolution and reproductive survival, it is the "obvious" choice. A choice that (I think) the "successful mother" paradigm would force, were a mother to be put in such a "Sophie's choice" type situation.

So what choice would one of those children make? Usually, an individual always wants to live, but there are plenty of examples where individuals will sacrifice themselves so that others may survive. Katie and her sister were too young to make such a decision, but the notion of a child sacrificing themselves for a parent or a sibling is not unheard of. It would be an evolutionarily successful strategy to sacrifice oneself if that sacrifice was necessary to preserve the reproductive capacity of a sibling or parent, and that sibling or parent had a sufficiently greater reproductive capacity than the child doing the sacrificing.

A "Sophie's choice" type decision is not made cognitively, it is not a reasoned decision based on facts and logic. It is an instinctive response, a response of the autonomic nervous system. I think that under "enough" stress, virtually anyone could (and would) make that type of decision. Many people may deny they could make such a decision, but they have never been under sufficient stress to really know.

A corollary of the "successful mother" paradigm, is the "competitive mother" paradigm. This paradigm is for people not in a "Sophie's choice" type situation to thwart the "successful mother" paradigm of non-relatives. This in effect increases the reproductive capacity of the "competitive mother" by reducing the reproductive capacity of other mothers. I suspect that some of those who find what Karen McCarron did to be worthy of the death penalty is that they are being "competitive", and are trying to reduce competition by finding a justification for killing someone (though they may not be conscious of that as motivation). I think there is a component of xenophobia in some of that, treat people who are like me (and hence likely share more genes) well, and treat people who are not like me harshly.

Gender differences in acute metabolic stress induced psychosis
If the hypothesis regarding stress induced changes in the discount rate as applied to future reproductive opportunities applies, then there should be differences in how males and females react under metabolic stress, acute vs. chronic.

What about sacrifice during wartime? In modern wars soldiers fighting together are usually not closely related to each other. Was this the case during evolutionary time when the instincts of sacrifice and camaraderie evolved? Likely not. Bachelor tribes are known in other animals. Drawing from the limited geographic range accessible before modern transportation, many of the men going to prehistoric wars would be related. Who goes to war? Single men without children or wives. Single men who do not have immediate reproductive prospects. Going to war during evolutionary times was a way to obtain reproductive prospects through the capture and rape of women and the killing of her children by previous mates. A practice common in other animals where males fight each other, and where a new alpha male will kill offspring sired by the previous male to increase his future reproductive prospects. A practice ordered by God as relayed by Moses (Numbers 31:17-18). A man might risk his life in war, but if he gains a concubine who bears his children, he has made the "evolutionarily correct" decision. All humans are descended from males who made such "evolutionary correct" decisions, and from females who made the "evolutionary correct" decision to bond to the males that got them pregnant following rape via capture bonding.

I am not trying to "justify" how people behave. That a person adopts a strategy that mitigates the damage done to them does not excuse the damage in the first place. That a person attaches to someone who abused them does not make the initial treatment non-abusive.

If there is an objective "goal" and rationale behind self-sacrifice, then we can analyze it independently of the feelings of those involved. If we look at the circumstances of the neglect of children by crack mothers, the crack mothers do not appear "irrational", they are able to plan, to carry out plans, to scheme, connive, to lie, cheat and steal. Not characteristics of an inability to reason. Are they "insane"? In a legal sense, no, the legal definition of "insanity" is an inability to know the difference between right and wrong. "Insanity" is only a legal term, it has no medical use. Is a person who steals a loaf of bread to avoid starvation "insane"? No, because the person "knows" stealing is wrong, but needing to steal food to survive is sometimes looked at as a mitigating circumstance. A person who starves to death (or allows their children to starve) rather than steal a loaf of bread is (in my opinion) "insane", because a person dying is a "higher degree" of wrong than stealing a loaf of bread (provided no one starves as a consequence of the theft). Similarly, killing a human in the context of self-defense is not considered "insane" because while killing a person is wrong, self-preservation is a mitigating circumstance.

So how would a child feel about infanticide? Obviously a child would rather live, but if the mother is under such severe actual metabolic stress such that only one of them can survive, what kind of rational "Sophie's choice" would a child make? This is not a cognitive choice the child would make (children are not capable of such cognitive reasoning, but then neither are psychotic adults), it is an instinctive choice based on "evolutionary" relevant criteria. Those criteria would include the chances of the child surviving to adulthood and being able to have children compared to the chances of the child's siblings surviving (those already born and those not yet conceived). A full sibling is as related to the child as would be any of the child's children.

How to prevent postpartum psychosis and infanticide?

The key is prevention, prevention, prevention, prevention, prevention. Once a woman becomes psychotic and delusional, she cannot be reasoned with, no matter how lucid she appears. In the case of Munchausen syndrome by proxy she may actively hide what she is doing, and when caught may simply commit suicide (note quite disturbing paper). Andrea Yates reported quite delusional thoughts regarding God, Satan, and provided a bizarre rationale as to why she "needed" to kill her children to save them from a worse fate.

Delusional thoughts are not rare among parents of children with ASDs. The Mercury Malacia have quite delusional beliefs regarding the causation of ASDs, and how to "cure" them. Beliefs that have no basis in fact, science, logic, or any other evidence based system. Some of these parents have made threats against others who's only "crime" is disagreement with the belief that mercury causes autism. Discussed in Mercury Rising and blogged about by Autism Diva, Autism Vox, Kevin Leitch, and Orac. In my (non-medical) opinion, parents with delusions are at high risk of unpredictable behaviors. Unfortunately, people with delusions are usually unable to appreciate that their belief system is delusional. When people with delusions start to threaten violence, that should be taken very seriously. Delusional individuals do not have a rational belief system to fall back on and use to modulate and control their behavior.

Prevention is most effective the sooner it is implemented. The key feature in this low NO hypothesis of postpartum psychosis and infanticide is severe metabolic stress in the postpartum period. The optimum way to prevent that metabolic stress is to ensure the mother has sufficient mitochondria. This is best accomplished months before conception. The first trimester for many women is characterized by nausea, known as morning sickness. While uncomfortable and objectionable, there is no indication that morning sickness has any adverse effects on the health of the woman, the pregnancy or of the infant. Actually, there is good evidence that there is an inverse correlation between severity of morning sickness and difficulties with the pregnancy.

I think that morning sickness is a sign of high NO, and is a good thing. The most critical events that occur during the first trimester are proliferation and then differentiation of the cells that form the fetal organs, and ultimately the organs of the adult. The health of those organs both in utero and as an adult is only as good as the fidelity of DNA replication. Any errors that occur cannot be corrected. Ever. The only correction mechanism is for cells containing errors to be deleted. There are multiple mechanism to ensure that DNA replication only occurs under suitable conditions. A major mechanism is via regulation of the cell cycle. NO is involved in a number of the pathways involved. While DNA is being replicated is an extremely dangerous time for the cell. Normally DNA is wrapped around proteins that protect it, keep it from getting tangled up, and protect it from damage. The nuclear DNA is also kept inside the nuclear membrane, which also protects the DNA, particularly from damaging radicals such as superoxide.

Superoxide and NO destroy each other at near diffusion limited kinetics. Therefore one cannot have both superoxide and NO present simultaneously, unless both are being synthesized. Which ever one is in excess will destroy the one that isn't. Superoxide is sufficiently reactive to damage DNA. NO is not. The reaction product of superoxide and NO, peroxynitrite is sufficiently reactive to damage DNA, as is its decomposition product NO2 but when NO is in excess, it reacts with NO2 to form nitrite, which is benign.

NO also regulates the ATP setpoint via sGC, and a high ATP level would seem desirable during cell division. At high NO levels, mitochondria are mostly suppressed because O2 consumption by cytochrome oxidase is inhibited. Mitochondria are a major source of superoxide (to the inner matrix), which is dismutated into H2O2. NO deactivates Fenton active metals (which produce hydroxyl radical from H2O2). Hydroxyl will destroy anything it touches. With an unpaired electron, NO is extremely reactive with radicals. In virtually all cases it deactivates the radical and makes it less damaging. A high NO state would seem to be the ideal time to do DNA replication. DNA replication isn't an energy intensive process. ATP is needed to pull the strands apart, but the generation of the new complementary strands doesn't take much ATP.

During the first trimester, the fetus is quite hypoxic. I think it is because not very much fetal growth is required, there is mostly placental growth, and careful replication of DNA. The placenta only needs to survive until the baby is born, it doesn't need to have extremely high fidelity DNA duplication. I think it is better to have a low O2 level, get most ATP from glycolysis, and reduce the ambient level of superoxide, H2O2 and other potential DNA damaging species.

The critical component that must be expanded during the first trimester is mitochondria. ATP production requires mitochondria. Mitochondria in the maternal liver, kidneys, heart, and in the placenta. Mitochondria biogenesis is triggered by NO. Similarly the blood supply must be expanded. Erythropoiesis is triggered by erythropoietin, which is expressed in response to HIFa, which is activated by hypoxia, or by increased NO levels.

Mitochondria and blood have high iron contents due to the hemes that active parts of the proteins needed. If there are insufficient mitochondria or erythrocytes, then there will be metabolic stress later.

I am stopping now. I will go into more detail later if I have the time.
I had posted a comment at Kev's blog which he objected to and deleted. I have reposted it below.

I have a different take on all of this. I know nothing of any of the
players except what I have read in the media. I see postpartum psychosis
and infanticide as evolved traits to successfully deal with severe metabolic
stress in the postpartum period. I don't know if that is what happened in
this case, but I suspect so.

I have been working on a blog on the physiology behind this for some time now, and it is now at 30 pages. I hope to put it up there soon.

My focus is more on trying to prevent such things from happening in the future. If my hypothesis of metabolic stress is correct, then harsh punishment will have zero
deterrent effect. Harsh treatment of women in the postpartum period will
increase the incidence of postpartum psychosis and infanticide.

From my vantage point, I object to the notion of "justice", as if
a bad act requires some sort of retribution to counteract it. Two wrongs
don't make a right. If the conditions that women with small children find
themselves in are so harsh that the only thing that prevents infanticide is the
mother's concern of harsh punishment, then society is broken, the mother/child
unit has been destroyed and infanticide is one of the least of the problems
society will be facing.

It is his blog and he can control the content on it in any way he likes. I object to his characterization of my comment as "self serving, self aggrandising crap".

The notion that "justice" requires the finding of blame and the punishment of those who are guilty when ever something bad happens, is precisely what is causing the Mercury Malacia to blame and want to punish and destroy the pharmaceutical industry. That is what caused the burning of witches in times past.

I will post at least part of my infanticide blog today. The section on prevention is less complete, I will post that later.

Tuesday, July 17, 2007

Meme of 8 things

I was tagged by Kristina, to list 8 facts about myself. Because I was asked, I can say whiny things. If you don't like the whiny things I say, take it up with whoever started this 8 things meme. I am supposed to link back to her, and to inflict this on 8 bloggers myself. I have decided that I won't inflict this on anyone. If reading this, you want to blog about 8 things, feel free to, but I don't feel comfortable asking anyone to do it.

I actually have been very busy, working on global warming, nitric oxide, and a blog about postpartum psychosis and infanticide. I think that infanticide is a evolved feature to protect the mother's life and reproductive capacity under times of metabolic stress. Low NO mimics those times of metabolic stress and lowers the threshold for infanticide.

1. I very rarely complain, my philosophy being that of doing something rather than complaining about it. I grew up in a big family, and if someone else did something, you never criticized it, unless you were willing to do better. As a consequence, I have an extreme tolerance for many things.

2. I am single, and I don't like being single. Perhaps this relates to #1. Perhaps not.

3. I donate blood regularly. They call me essentially as soon as I am eligible again (hint: that means I am in good health, straight, don't use self-injected drugs, don't frequent sex workers, and am free from STDs, hepatitis, and HIV).

4. I eat turkey every day at least once, sometimes twice. Mostly it is for the tryptophan which is a serotonin precursor. I have had depression in the past (pre-nitric oxide) and it helped then. I see no reason to change it even though my high NO level has essentially eliminated my long term depression and I am tapering off my meds.

5. While I eat breakfast I sit in front of a 500 Watt quartz-halogen lamp ($10 from Home Depot) to prevent SAD (seasonally affective disorder) (not that I ever had it). It does boost my mood a little, it is trivial to do, so I do it.

6. I recycle. Bottles, cans, jars and flyash. The company I started to commercialize my invention for recycling flyash has now recycled well over 4 million tons of flyash.

7. I haven't watched any TV since I saw part of Superbowl 2006.

8. In the winter I set my thermostat at 60. In the summer I turn off the pilot on my gas heater and it makes an observable difference in my gas consumption.