A major implication of the low NO hypothesis of ASDs is that ASDs are actually evolved adaptive features of human physiology, that ASDs are a fundamental “stress response”, arising from maternal stress in utero and that the characteristic features of ASDs are invoked due to maternal stress. The function of these ASD characteristics is to invoke the “tool making”, and “tool using” phenotype, most characteristically expressed by individuals with Asperger’s, such as Newton, Einstein, and many other great scientists, engineers, and artists. It is well known that many organs are epigenetically programmed by stress in utero [1]. It would be surprising if the most important organ, the brain, were not.
Review of evolution
How does any trait evolve? DNA mutates, acquires new function(s), confers reproductive advantage(s), and is selected for. Evolution selects against non-reproduction from all causes simultaneously. If a trait increases survival/reproduction, evolution will increase that trait until more decreases survival/reproduction (i.e. causes death). There are no other evolutionary endpoints. All “well evolved” traits will prevent death in some circumstances and cause death in others. An overly exuberant immune response (anaphylaxis) can cause death. Anaphylaxis is complex, and exhibits complex genetics. It is not considered a complex disease because an exuberant immune response has understood benefits. Evolution has configured the immune system to minimize the sum of deaths from infection and from anaphylaxis. It is not that anaphylaxis is a “benefit”; rather an immune system capable of anaphylaxis is superior to one that is not. Stress responses are among the most conserved pathways [2]. Many of them date to billions of years ago, long before there were multi-celled organisms, long before there were mitochondria and eukaryotes. Presumably because they are ancient, they are “well evolved”, and when activated too exuberantly each stress response can and will cause death. Whether we call such a trait a “feature” or a “disorder” depends only on the circumstances.
How does a trait that is an emergent property of >100 genes evolve? Genes mutates, mutant genes confer advantageous traits, over evolutionary time organisms with those mutated genes survive/reproduce more and the mutant genes become common in the gene pool. Interactions between different genes enhance survival and advantages from different combinations increase the frequency of those combinations in the gene pool. But that is for advantageous traits. How does a disadvantageous trait evolve? It can only evolve if it is coupled to an advantageous trait that more than compensates for the disadvantage, as in sickle cell trait (which protects against malaria when heterozygous and can causes sickle cell disease when homozygous). Perhaps a negative trait could appear via a novel combination of genes. That would be a rare stochastic occurrence and could not be a cause of common disorders. A novel combination should have novel effects.
The traits of ASDs are not novel, they are characteristic of many people, with autism now having a prevalence of ~5.5-5.7 per 1,000 births [3]. ASDs present on a spectrum with variable severity even in monozygous twins. In some ASD families, all siblings are affected, and affected seriously enough that survival in the “wild” (>100k years ago) would be questionable. ASD occurs in children, long before there is the possibility of reproduction. ASD traits of sub diagnostic severity are not uncommon [4]. I suggest that all humans have some traits of ASD. It is only when those traits reach clinical diagnostic thresholds is someone said to have an ASD, and when severe, to have autism. These distinctions are purely arbitrary, much like the difference between being short and tall, but vastly more complicated.
Humans are unique for their brains and ability to use tools. Humans evolved large and complex brains only because such brains conferred survival and reproductive benefits. Human evolution was shaped mostly by events 100k or more years ago. Humans are the only extant hominin that manufactures and uses tools. The first instances of manufactured stone tools date to about 2.5 to 2.7 MYA (million years ago), and was near universal by 2 MYA [5]. Tools of perishable materials perhaps were earlier. Modern humans are good at tool manufacture and tool use. Tool use has profoundly shaped human evolution and those parts of the human genome that affect brain structures important for tool creation and use. The major structures of the brain are formed in utero and early childhood, and are then largely fixed throughout adult life. It is only in utero and early childhood that major structural changes in the brain, such as are characteristic of ASDs can develop, including larger numbers of neurons[6 ], larger brains, and increased asymmetries [7 ].
Which individuals are most adept at tool use today? It is people with Asperger’s, people with ASD. Many scientists and engineers have Asperger’s, and it is suggested that Einstein, Newton, and many brilliant scientists had Asperger’s [8]. Asperger even said “It seems that for success in science or art a dash of autism is essential.”[9] The stereotypical nerd is someone with facility at math, science and with characteristically poor social skills [10]. The mirror neuron system[11] (responsible for understanding the actions of other individuals) exhibits dysfunction proportional to ASD severity [12].
The major barrier to revolutionary scientific innovation is conventional thinking and existing paradigms [13]. What Kuhn calls “normal science”. Ideas transmitted culturally are difficult to displace even when wrong. It is nearly 150 years since Darwin’s “Origin of Species”, with overwhelming data supporting and no datum inconsistent with evolution, yet in the USA, 40% of the population believes evolution is false [14]. Some on the Nobel Committee were unable to accept relativity as valid and so Einstein received the Nobel Prize for the photoelectric effect, not relativity [15].
Cultural notions of what is appropriate affect abilities (i.e. what people think they or anyone can do). Women exposed to a hypothesis wrongly attributing mathematical ability to genes on the Y chromosome have impaired mathematics performance [16]. A degree of social isolation from disrupted mirror neurons may insulate ASD individuals from incorrect paradigms of science, technology and the peer pressure associated with cultural practices which must be abandoned to overcome the current hard times. No doubt 2.8 MYA everyone “knew” stones didn’t make good tools.
The first stone tools were not developed after committees of peers reviewed proposals and selected the highest scoring for implementation; they were developed by the “Einsteins” of the time working alone. Acquisition of nut cracking skill by capuchin monkeys (Cebus apella) using stones as hammer and anvil takes about 2 years and requires considerable repetitive nonproductive effort while watching proficient individuals [17]. No doubt repetitive trial and error was needed to acquire de novo skill(s) to manufacture stone tools 2 MYA, and such individuals were thought bizarre for “uselessly” banging stones together.
Evolutionary selection exerts its greatest effects not when times are easy, but when times are hard. It is when times are hard, that greater facility with tool creation and use would have its greatest effects on human evolution and be most positively selected for. What were “hard” times 1, 2, 3 MYA? Likely much the same as today, famine, disease, migration, and war. These all cause “stress”. Stress is a low NO state.
I propose that exposure to lowered basal NO in utero due to maternal stress (or other causes) at specific times of fetal neuronal development may produce the characteristic hyperplasia of neural structures associated with Asperger’s and other ASDs. Low NO is suggested to cause the characteristic minicolumn structure associated with autism [18] and the timing of stressors may be crucial to the development of the autism phenotype [19]. In guinea pigs, brief prenatal stress increases brain/body mass ratio, and changes adult behavior [20]. Prenatal stress increases learning ability in rats.[21] Prenatal stress does program hypothalamo-pituitary-adrenal function [22]. Low NO does cause neuronal hyperplasia [23]. The patterning of many neural structures is determined in part by gradients in NO mediating proliferation, differentiation, or apoptosis [24]. Stress in utero causes adaptive changes in the adult physiology of multiple organs. It would be surprising if it did not exert adaptive influences on the most important organ, the brain.
Table 1. lists a few pathways involving NO important in development. The list is incomplete, and is only to illustrate that the numbers of pathways involving NO as a regulatory signal is not small, numbering in the thousands, more than enough degrees of freedom to elicit many extremely complex responses, far beyond our ability to predict a priori, or even to model once completely known in complete and precise detail.
There are multiple families of pathways where NO actively modulates the development of specific brain structure via transcription, DNA methylation, the cell cycle, proliferation, differentiation, apoptosis, growth factor, and receptor mediated effects, all of which are coupled, all of which are nonlinear, and none of which are fully understood. Because these pathways are already regulated by NO, any change in the basal level will change the outcome.
Nonlinear coupled systems of even a few variables are completely intractable to understand and model. We should not be surprised to see complex effects when NO physiology is perturbed even slightly. Monoamniotic twins can be discordant for anencephaly [25] and monozygous twins can be discordant for ASDs, demonstrating the cause(s) of these are not solely genetic, and that large effects can derive from very slightly different environments in utero. The NO exposure history may be identical, but because the development is not exactly synchronous, the outcome can be completely different, as is the characteristic chaotic behavior of coupled non-linear systems.
The way that people with ASDs are treated, being bullied, is characteristic. Children with special needs are bullied more than normal children.[26] Exposure to violence and victimization by bullies does lead to increased aggression and violent behavior, [27]
Table 1. NO pathways
called the “cycle of violence” [43]. It is unlikely that bullies 2 MYA were gentler. There are reports of teenage boys being bullied, acquiring weapons and planning or committing massacres as at Columbine. In more than two thirds of cases there was clear and obvious bullying [44]. In Green Bay Wisconsin, three boys were bullied, developed and implemented a plan to fight back, with guns, bombs and home-made napalm [45, 46]. No doubt young men 2 MYA made similar plans when they were bullied. Adults bully [47] as do academics [48] as do teachers [49].
I speculate that when times got hard; people with ASDs were born, were bullied as children, left as teenagers, developed new weapons technology, came back, killed the alpha male bullies and got the females. A scenario that may have played out millions of times. Because all members of a tribe were likely related, a bully may reproductively benefit through his sister, daughter, or cousin even if he is killed. The new technology may be adopted by the tribe and benefit the inventors’ siblings even if the inventors were killed. As Max Planck said: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grow up that is familiar with it.” Once new technology is developed, be it fire, weapons, agriculture, or clothing, things get easier, stress goes down, children are born with less ASDs, until times get hard again. It is important to remember, that evolution has configured neurodevelopment to minimize death/non-reproduction from all causes simultaneously. That includes death due to inability to develop new technology from not enough ASD traits being balanced by non-reproduction from being "too geeky" from too much.
Violence against women, pregnant women and the cycle of violence
Inducing stress on pregnant women via any mechanism should have similar effects. There is an increased incidence of autism among first born. Whether that is due to first pregnancy anxiety, or stoppage, or other factor(s) remains unknown. Humans are unique among mammals for a high level of preeclampsia and miscarriage which also occurs in contemporaneous hunter gatherer societies suggesting modern environmental effects are not the cause [50]. Preeclampsia exhibits complex genetics [51]. Preeclampsia is a state of oxidative stress [52] and so is a low NO state. Eclampsia and preeclampsia may be dysfunctional extreme forms of a “feature” that induces a degree of neuronal hyperplasia in the developing fetus by inducing low NO.
Intuitively, we would expect strong evolutionary pressure against males abusing females pregnant with their fetus (were such abuse to be solely negative). I was unable to find studies documenting such behavior in non-humans. Physical and emotional abuse of pregnant women is not unknown, or even rare [53], approaching 10% of women in many populations [54]. In regions where “honor killings” occur, assault of women by their partners can exceed 50% [55] . Violence against women might be an evolved mechanism for “programming” the brain of the fetus in utero by changing the in utero environment, providing a rationale for violence against pregnant women by the father of the fetus, or by females’ relatives.
Abuse is considered to be solely detrimental, but in the “wild”, some effects of abuse could be “features”. Low birth weight is a serious problem and abuse is associated with lower birth weight [56]. Babies too large to be born vaginally can now be delivered by caesarian section, an option not available 100k year ago when a baby too large for vaginal birth would certainly die, likely killing the mother. Abuse might induce a degree of ASD, improve facility in tool use, and might foster other behaviors in anticipation of stress. The cycle of violence may be the epigenetic implementation of the adage “the best defense is a good offense”. When times are hard, rapid escalation to violence may be advantageous. Violence against women is most frequent during that couple’s hard times. So called “honor killings” of women are most frequent in regions where the cycle of violence and blood feuds are particularly strong.
This is not to suggest or imply that violence against women is acceptable. If this hypothesis is correct, it is an unfortunate circumstance of human evolution that such violence resulted in survival and reproductive benefits and so may have been selected for enough so that DNA supporting those traits has become a part of the human genome. However that benefit may only pertains in the “wild”, where death from abuse balanced survival from cephalopelvic disproportion.
Just as rape, infanticide and murder of romantic rivals can be successful reproductive strategies for males, so too may pregnant female abuse. It may be a successful strategy for females as well. A strategy some females may unconsciously use in selecting mates or in behaving toward them while pregnant. This is not to excuse or condone such violence but may explain some of the difficulty social policy has in dealing with it. These characteristics are from deep evolutionary time, and likely predate Homo sapiens (as does alpha male infanticide).
Alpha male infanticide is not unknown in current human behavior, is common in recorded history, and was once mandated by major religious traditions.[57] All humans are descended from individuals who reproduced using these strategies. No doubt under the right kind of stress, any human will have these characteristics and behaviors. The behaviors are not “genetic”, they are epigenetic. It is not that alpha male infanticide is "always" a reproductive benefit, rather a developmental program that can generate males capable of infanticide (under the "proper" circumstances) is "superior" (i.e. has greater reproductive benefit) than one that cannot. The development programs written in our genome supports these and other developmental outcomes. To prevent these developmental outcomes, we need to prevent the "proper" circumstances (where such behaviors do provide reproductive benefits) from occurring. If this hypothesis is correct, bullying will not deter such behaviors, it will make them worse. The way to prevent violent adults is to “coddle” them in utero and as children. But that is not a surprise to anyone who understands human behavior. It is surprising that it takes someone with Asperger's to appreciate it.
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57 Bible, Numbers 31:17-18.
