Theory of Mind vs. Theory of Reality: The tradeoff along the Autism Spectrum

In any great organization it is far, far safer to be wrong with the majority than to be right alone. -- John Kenneth Galbraith

If the only tool you have is a hammer, you tend to see every problem as a nail.
-- Abraham Maslow

In the land of the blind, the one-eyed man is king.

How autism provides resistance to the delusional thinking of groupthink (aka drinking the Kool-Aid).

When your primary competition is with other people, life is a zero sum game. When your primary competition is with reality, there are no limits.

The cause(s) of Autism Spectrum Disorders (ASDs) remain unknown. The complex genetic disorder hypothesis posits ASDs are an emergent disorder of multiple genes, perhaps dozens or more. How a common disorder of so many genes could evolve has not been suggested. One hypothesis is that genes associated with ASDs did confer some advantage resulting in their selection in the past, but are now detrimental. I suggest ASDs are not disorders at all, but normal (even human defining) developmental responses, particularly to stress in utero and early childhood. This fundamental human neurodevelopmental paradigm programs the brain and behaviors mediated by that brain so as to optimize survival and reproduction depending on maternal and infant stress; invoking abilities to understand, interact with and manipulate other humans when times are good, and abilities to understand, interact with and manipulate the environment via tool production when times are hard. It is hypothesized that this trade-off between Theory of Mind (ToM) and Theory of Reality (ToR) is the quintessential trade-off along the Autism Spectrum. Implications for interaction difficulties between individuals with ASDs and Neurologically Typical individuals (NTs) are discussed. Prevention and treatment are also discussed.

Background ASDs

The Autism Spectrum Disorders (ASDs) are defined and diagnosed by difficulties in communication, social interaction and by repetitive behaviors. In ASDs, there is a high (but not absolute) concordance between monozygous twins, [1] moderate concordance between dizygous twins, [2], [3] and lesser concordance between siblings. With no generally accepted environmental cause, ASDs are thought to be primarily genetic in origin with associations of perhaps 135 genes.[4] No doubt the complex effects on brain structure and behavior observed in ASDs are not mediated via a single pathway, but calls to abandon a search for a single explanation are premature. [5]

A number of single mutations have been associated with multiple cases of autism-like symptoms. I call these "autism-like" because it is not clear if the cause and sequelae of these autism-like syndromes are identical to or even similar to the common cases of autism and ASDs (which remain unknown). A good example is Rett Syndrome which is known to be caused by a loss in the MeCP2 gene which is on the X chromosome. Females have 2 copies of the X chromosome, one of which is silenced. Active MeCP2 in some cells rescues the organisms from the fatal loss of MeCP2 which afflicts males (who have only one X chromosome). RS females develop seemingly normally until 6-18 months when they develop the characteristic RS phenotype which includes autism-like symptoms, but is also characterized by non-autistic symptoms of small head size, breathing abnormalities, vascular abnormalities, scoliosis, growth retardation and others. Because the effects of MeCP2 deletion are mediated through aberrant transcription of methylated DNA, then aberrant transcription of methylated DNA is sufficient to lead to autism-like symptoms. Perhaps the symptoms of common ASDs are also caused by DNA methylation, or perhaps via a shared final common pathway triggered by aberrant DNA methylation.

Nitric oxide is a pleiotropic signaling molecule used in thousands of metabolic pathways where it regulates, ATP supply, O2 consumption, steroid physiology, transcription, axon targeting, the cell cycle, epigenetic programming and many other aspects of physiology, development and neurodevelopment. Many of the pathways observed to be abnormal in ASDs are mediated through NO signaling.

I suggest that the final common pathway mediating autism and autism-like symptoms is low NO in utero, during neurodevelopment and as an adult. Low NO is the archetypal stress response. Virtually any type of stress ultimately results in low NO which physiology uses to trigger compensatory responses. For example, oxidative stress occurs when superoxide levels are increased. Superoxide consumes NO at near diffusion limited kinetics so a high superoxide state is necessarily a low NO state. NO inhibits cytochrome c oxidase. To release that inhibition and increase O2 consumption to maximize aerobic ATP production, the NO level must be lowered. Psychosocial stress increases oxidative stress through catecholamine oxidation, ATP stress increases oxidative stress through increased mitochondrial potential necessary to increase ATP flux, xenobiotic stress increases superoxide through the cytochrome P450 pathway, immune system stress increases superoxide through the respiratory burst. Just about any type of metabolic stress would decrease NO levels and according to the present hypothesis would tend to produce a more autistic-like phenotype. This may be the mechanism for the association of copy number variations with autism. This may also be the mechanism behind the ASD-like symptoms produced by MeCP2 deletion. Females with MeCP2 deletion are mosaic. Some of their cells do have appropriate methylation readout and some do not. Presumably this differential regulation of DNA expression causes metabolic inefficiencies and metabolic "stress" due to cells being out of "sync". In a mosaic organ with non-synchronous regulation, some cells would be working harder than others, perhaps even working at cross purposes. The final common pathway of essentially every kind of metabolic stress is decreased NO.

Virtually all ASD physical symptoms are consistent with pathways regulated by NO being skewed in a low basal NO direction. I suggest that the ASD phenotype is a stress compensatory pathway mediated by low NO.

NO/ROS Balance Programs adult physiology in utero

The physiology of virtually all adult organs is known to be programmed in utero in response to a number of fetal stressors including nutrition[6] stress and hormonal factors. [7] NO/ROS balance in utero does lead to epigenetic programming of adult blood pressure in rats. [8] Stress is a low NO state. [9] The most characteristic physical feature of ASD children is a larger brain[10], with smaller and more numerous minicolumns. [11] Low NO is suggested to cause the characteristic minicolumn structure associated with autism[12] and the timing of stressors may be crucial to the development of the autism phenotype. [13] In guinea pigs, brief prenatal stress increases brain/body mass ratio, and changes adult behavior. [14] Prenatal stress increases learning ability in rats. [15] Prenatal stress does program hypothalamo-pituitary-adrenal function. [16] Low NO does cause neuronal hyperplasia. [17] The patterning of many neural structures is determined in part by gradients in NO mediating proliferation, differentiation, or apoptosis. [18] There are increased asymmetries in the brains of ASD individuals[19], suggesting differential regulation of neuronal growth when the sizes of those structures are formed in utero. Stress in utero causes adaptive changes in the adult physiology of multiple organs; it would be beyond surprising if it did not exert adaptive influences on the most important organ, the brain.

I suggest that low NO in utero, brought about by maternal stress leads to the ASD phenotype in affected individuals, and the genotype that leads to the ASD phenotype was adaptive under conditions where humans evolved, in the “wild”, but is perhaps now less adaptive due to environmental change(s). What possible advantages could the ASD phenotype hold?

The Brain is fundamentally the most Human organ

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 social animals, as are all primates. Humans are unique in their use of language with syntax and grammar to convey complex ideas. 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[20]. Manufactured 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. Similarly, communication and language has profoundly shaped human evolution and those parts of the genome that affect brain structures important for language acquisition 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 neurons can be epigenetically programmed to form the major structures in the brain with the characteristic neuroanatomy observed in ASDs such as increased asymmetries, larger numbers of neurons[21] and larger brains.

Brain size at birth limited by female pelvis: Brain optimization requires tradeoffs

The size of the newborn brain is limited by the size of the mother's pelvis through which it can be successfully born. In the absence of medical C-section, cephalopelvic disproportion results in significant infant and maternal mortality. What ever advantages a large brain at birth provides it comes to naught if the infant or mother dies. The structure and size of the brain at birth must be an evolved trade-off between the multiple tasks that brain will be called upon to perform at birth and over the life of the individual and the substantial risk during a natural birth. The only time the most fundamental aspects of brain structure can be modified is while those structures are being formed. Much of the formation of those brain structures occurs in utero, much of it in the first trimester following closure of the neural tube (which is when teratogens such as thalidomide can cause autism). Epigenetic programming of cells occurs when those cells are dividing and undergoing differentiation. Much of the differentiation in early human development occurs in the first trimester. Patterns of methylation modify DNA expression and modify the phenotype of that differentiated cell for the lifetime of that cell. Many neurons do not divide over the lifetime of the individual. NO does modify methylation through the folate pathway and so modifies DNA methylation in ways that are quite complex (for at least this one gene system). Presumably multiple genes are epigenetically modified in complex ways by this same mechanism.

Oxidative stress and low NO cause changes in DNA methylation. Presumably this is part of the normal mechanism by which stress (which results in oxidative stress and low NO) causes global epigenetic reprogramming of diverse genes in diverse tissue compartments under diverse circumstances. Psychological stress causes long lasting changes in neurological functioning as for example PTSD. The details of how psychological stresses of what types cause the characteristic neurological changes that manifest as PTSD are mostly unknown. We know it happens, so there must be physiology that supports those characteristic changes.

DNA methylation mediated through NO does influence expression of genes that are involved in some autism-like syndromes, such as Fragile-X mental retardation gene (FMR1). Aberrant readout of DNA methylation is implicated in the autism-like symptoms of Rett Syndrome (RS). Many of the symptoms of RS are characterized by physiology being skewed in the direction of low basal NO.

Fundamental brain optimization tradeoff: Theory of Mind (ToM) for Theory of Reality (ToR)

Humans are unique among animals for their abilities at communication; language making and language using and tools; tool making and tool using. These abilities are highly dependent on a large brain with substantial plasticity for self modification via learning throughout life. The relative importance of these two extremely important human behavioral characteristics is dependant upon the environment the infant is born into. The major neuroanatomy of the brain originates from structures arising during early neuron proliferation and differentiation during and after neurulation in the first trimester. These structures are then elaborated on later in utero. It would be beyond surprising if the relative aptitude of the brain for communication and/or tool making/using (including manual dexterity for manipulating objects) were not to some extent programmed in utero.

That trade-off would show up as a trade-off between abilities to understand and manipulate other humans (Theory of Mind), and abilities to understand and manipulate reality (Theory of Reality). These are the differences that are seen in people along the autism spectrum. I will discuss how a less developed ToM interferes with ASDs communicating with neurologically typical individuals (NTs) and their very well developed ToM. For the most part ASDs don't pick up the nuances of communication, particularly how it relates to motivations, beliefs and other mental states. The NT ToM forces NTs to think in anthropomorphic terms, even when it is inappropriate because they lack a robust ToR.

I spend a lot of time trying to explain this in several different ways using several different analogies. What I am trying to describe is exceedingly complex, as complex as an entire human brain. Something that complex cannot be described simply except in simplistic terms. It would be like trying to describe a library in a single paragraph.

Good times --> Need Good ToM

One hypothesis of this paper is that when times are good, and a woman's first trimester of pregnancy is characterized by low stress, then the "optimum" infant brain will be one optimized for better communication. If times are good, there will be plenty of other humans around, and the infant's primary competition for food and mates will be with other humans. Because times are good, the cultural information the adults have is working well to produce those good times. Copying that good cultural information with high fidelity is important. Good communication, a good ToM with the ability to understand and manipulate other humans is the best strategy when times are good.

Hard times --> Need Good ToR

When times are hard, a woman's first trimester will be characterized by high stress. The optimum infant brain will be skewed away from communication because during evolutionary time, hard times meant fewer humans in the territory. With fewer other humans around the need for communication is reduced. The cultural practices of the adults are not working well to produce good times. If the cultural practices are not working well, they need to be modified until they are working well. When times are hard, there won't be many other humans around because they will die in infancy. Competition will be against reality for food, shelter, and to stay alive. The adults don't know how to make good times, so that is something the infant will have to figure out for him/herself.

Theory of mind, theory of reality and theory of cognition

I will make a distinction between being able to think about something (cognition) and being able to think about that thinking process (meta-cognition) and coin a term Theory of Cognition (ToC), to denote the ability to think about and emulate different types of cognition. The term is an attempt to be analogous to ToM and ToR, which are meta-abilities to think about and compare multiple models of other minds (necessary for communication by emulating other mental states), and multiple models of potential realities. I am making this distinction because the different types of computation that humans do are not necessarily mapable onto each other.

Analogy:
Word processing ToM Theory of Mind Emulating other minds
Spread sheet software ToR Theory of Reality Emulating Reality
Operating system ToC Theory of Cognition Choosing Emulations

Trying to understand human communication with a ToR might be like trying to write a document not with word processing software but with a spread sheet. A document could be written in a spread sheet. It would be slow, cumbersome and the document wouldn't have the right formatting and wouldn't be as polished as something done in a word processor. On the other hand, a large spread sheet calculation simply can not be done using word processing software. The word processing software doesn't support the primitive functions, addition, subtraction, multiplication, etc that a spread sheet calculation requires. Some of the complex word processing functions can be emulated on a spread sheet but spell checking and grammar correction would be very cumbersome and difficult.

This is the sense that I am trying to convey, that people with a robust ToM can do good and robust communication that is nuanced, and well understood by others with a matching and robust ToM. Their shared ToM is analogous to the word processing software, and a well formatted document is analogous to human communication between individuals with a shared ToM. The ToR is analogous to the spread sheet software and the large spread sheet analogous to a highly technical ToR. A theory of cognition (ToC) would be the selection of the proper software type to do the required computations (ToM(English), ToM(French), ToM(ASL), ToR). There are multiple ToMs, each language is different to some extent, although there are other communication modes, body language, cultural signals, gestures. There is only one ToR, the one which accurately describes reality as it actually is. Individuals may have a ToR that is highly specialized and individualistic, physics or medicine for example. But all of the different ToRs all mesh into one (or should) because they all describe a single reality.

In this analogy I am trying to illustrate that a specialized piece of computation machinery may work very well for one task (word processing) and not at all for another (spread sheet calculation). If you tried to input a spread sheet into a word processor, you would get many error codes, many misspelled words; the word processing software would reject it as badly formed. A very well formed spread sheet cannot be read on a word processor. This is analogous the problem that some NTs have with understanding people with ASDs.

Normal background "housekeeping" features can impede communication. Many types of different word-processing software have automatic spell checking. If a word is spelled wrong, the software will change the spelling to match the spelling to one of the words in its dictionary. If the word is not misspelled, but is simply not in the dictionary, the software can't recognize it and will change it anyway. This is a type 1 error, a false positive. The software falsely identifies a character string and modifies it to match its default identity. This is an inherent property of specialized pattern recognition systems. There is a trade off of type 1 errors (false positive) for type 2 errors (non detection). If you don't have access to modify the "error correction function", it may be impossible to type certain strings because the error correction keeps changing them. In certain word processing software this can be extremely annoying and make writing outside the scope of the software impossible. If the software won't let you have certain character strings in your document, you can't write about them. If your ToM won't let you have certain ideas, you can't think about them. Appreciating that your ToM doesn't have the capacity to think certain thoughts is extremely difficult.

Being unable to conceptualize ideas is not uncommon. There are people who believe in the literal truth of ancient texts and are unable to conceive that they do not accurately describe reality, irrespective of what data can be collected today. These beliefs are from a ToM, shared with others of their community. Such beliefs did not arise from observations of reality, they were told to individuals by other individuals who believed them. Those false beliefs are derived by those false beliefs being communicated to the individual and so shaping their ToM. Such beliefs are often extremely resistant to change.

Learning can be looked at as modification of the brain's neural network so the neuroanatomy can support what ever new idea it is that is being learned. Usually this takes a long time and is quite difficult. Learning physics or mathematics is difficult because the normally developing neural patterning doesn't support that type of thinking the way it supports language. I will discuss this more later.

A mother's necessity makes her child an inventor.

Maternal stress --> fetal development along autism spectrum --> Asperger phenotype

The hypothesis of this paper is that low NO in utero causes development along the autism spectrum so as to program the brain in utero to one that supports a better ToR. Precisely the phenotype that is needed when mothers are stressed and so times are hard. What ever technology and cultural practices are being used, they are not working well enough and so new ones need to be developed.

Which individuals are most adept at tool use today? It is people with Asperger’s, people with ASDs. Many scientists and engineers have Asperger’s, and it is suggested that Einstein, Newton, and many brilliant scientists had Asperger’s. [22] Asperger even said “It seems that for success in science or art a dash of autism is essential.” [23] The stereotypical nerd is someone with facility at math, science and with characteristically poor social skills[24]. The mirror neuron system[25] (responsible for understanding the actions of other individuals) exhibits dysfunction proportional to ASD severity. [26]

The major barrier to revolutionary scientific innovation is conventional thinking and existing paradigms. [27] 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. [28] 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. [29]

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. [30] 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 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. [31] No doubt repetitive trial and error was needed to acquire de novo skill(s) to manufacture stone tools 2 MYA, and such individuals had to ignore criticism that they were bizarre for “uselessly” banging stones together.

These culture notions are transmitted through the robust NT ToM. To avoid being adversely influenced by potentially incorrect ToMs, ASDs require a weaker ToM, a ToM that perhaps allows some communication, but one that can easily be ignored, resulting in the ability to ignore the "Kool-Aid" which is a stronger version of groupthink. The delusional world views that some NTs have can become extremely compelling to them,, such that they are unable to perceive that it is delusional, particularly when a charismatic leader with a strong ToM (essentially the definition of a charismatic leader) imposes it on his/her followers. More on this later in the discussion of cargo cult science.

ASD individuals developing skills unrecognized as useful by NTs must possess a compulsion to acquire those skills despite peer pressure that such skills are useless. Many ASDs acquire skills that NTs think are useless, fascination with train spotting, bird watching, collecting, virtually every savant ability is acquired to a degree that NTs do not find useful (if they did, then NTs would acquire such skills to that degree and it would not be thought of as savant). Language and communication is the "savant" skill of NTs. NTs possess a skill at communication (with other NTs) that ASDs cannot hope to master. Just as ASDs sometimes have skills that NTs cannot hope to master. Just as elite athletes have skills that non-athletes cannot hope to master. A society with the ability to use the best skills of a highly variable and diverse group would be better able to cope with adversity than a society where all individuals had the same average abilities. Not every individual in the village needs to be proficient at making stone tools, provided there are enough proficient individuals and the tools their skills produce can be traded for other things.

Cognition: Non-algorithmic calculation

Cognition in human brains is done by neural networks, the fundamental details of which are mostly unknown. Some cognitive abilities (such as savant calendar) are known to be non-algorithmic because the errors are not always the same, and the time for performing the calculation is not asymmetric depending on calculation direction the way a computation performed using an algorithm would be. [32] It is likely that most if not all other types of human cognition are non-algorithmic.

I am using algorithm in the sense that an algorithm is what a Turing machine executes. An algorithm is a series of instructions that when acted upon manipulate data and perform a calculation. The computers that people are familiar with are algorithmic. Calculators use a calculating engine (the processor) to operate an algorithm (the software) to manipulate the data. In general the data does not modify the software or the processor while the computation is in process, and given the same data, the same processor running the same software will produce the same output each and every time the calculation is performed.

Neural networks are inherently non-algorithmic in the sense that there is no "algorithm" explicitly being implemented by the neural network. A neural network may be used to implement an algorithm. For example, humans and other animals have the ability to do approximate mathematical operations such as comparison. Two groups of objects can be compared and the one with the larger number can be selected even when the members of each group have not been counted. This selection can be made by individuals unable to count and even by animals. This selection is non-algorithmic. An individual able to count is also able to count the members of each group and then tell which group is larger by comparing the two values. The person, who can count, knows that the counting algorithm produces a more reliable comparison than the non-algorithmic visual comparison. The person who cannot count does not know how to implement the counting algorithm.

Human brains are not optimally configured to run algorithms. A processor that can run algorithms is in essence emulated in a human brain to run the algorithm under consideration, such as counting or multiplication. The form that the data is in may greatly limit what algorithms that data can be manipulated with. For example multiplication using Arabic numerals is easy. Multiplication using Roman numerals is exceedingly difficult. There is essentially no algorithm for multiplying Roman numerals, individuals use a look-up table. Learning algorithms takes considerable time and effort for many individuals.

Communication requires a Theory of Mind

Exactly how neural networks in the brain configure and reconfigure themselves to do the computations that certain cognitive tasks require is unknown. Presumably there is some type of feedback that modifies the network when sub-optimal results are achieved so as to configure the network to produce better results. How this occurs is unknown, but for language acquisition, some conclusions as to how this optimization works can be made which I discuss below. What I want to emphasize the compulsive aspects of language acquisition. People do not choose to acquire the language they acquire as children, their brains acquire it (or synthesize it de novo) for them.

All communication requires two parties, a sender and a receiver. The sender must have a mental concept, translate that mental concept into a communication medium, transmit that message to the receiver, who must receive and then translate that message back into a mental concept. In that sense, all communication is only the transmission of representations of internal mental states. For there to be communication, the mental concept must necessarily be mapable onto the neural structures of both individuals. If one party is not able to represent the mental concept in their brain, the concept cannot be communicated either from them or to them. In a sense, communication is the transmission of data that allows the receiver to identify and map that concept into a mental representation, in effect the receiver is doing pattern recognition on the data stream and generating a mental representation, in effect a pattern of thought either generated de novo, or a familiar pattern previously used.

In this sense, communication can only occur between individuals with a shared Theory of Mind. This is the sense that I am using ToM in this paper, the emulation of the cognition of another individual to achieve a mapping of the mental state of one individual with the mental state of another individual. The possible fidelity of that mapping determines the possible fidelity of that communication. If a mental state cannot be mapped onto another individual's ToM, then that mental state cannot be communicated to that individual.

Pattern recognition is a well recognized ability. All systems encoding pattern recognition are subject to different forms of error. There is the type 1 error, the false positive, the error in wrongly identifying a false instance as positive. There is also the type 2 error, the false negative, the error in missing the correct identification of a correct instance. In a general sense any pattern recognition system can be made more sensitive, that is with a reduced type 2 error, but then there is an increased type 1 error and there are more false positives.

A type 1 error is getting the attempted message wrong; a type 2 error is missing the attempted message. Since communication is a two-party interaction, the "fault" of miscommunication cannot be attributed to either party, the "fault" lies in their interaction.

Many human interactions engender other types of error. There is no generally accepted definition of what is a Type 3 error, but one definition is "the error committed by giving the right answer to the wrong problem". When times are hard, and the culturally transmitted traditional information isn't capable of solving the hard times, that is an example of the right answer to the wrong problem. The time of adolescence and early adulthood is often a time of rebellion against authority, against conventional wisdom, against cultural norms. Young people are testing the limits of their culturally acquired information; testing to see what works and what doesn't. This is somewhat speculative but this might be a mechanism to reduce the cultural transmission of obsolete or dysfunctional practices. In the absence of a written language, the only cultural practices that can be transmitted are those adopted by the next generation. If the older members of the tribe live long enough to transfer their wisdom to adults past their adolescent rebellion period, perhaps the wisdom is worth transferring. If not, then perhaps it isn't and the tribe should try new approaches until that happens.

Communication and language acquisition

Social animals communicate with each other. In humans the ability to develop language is innate and the brain structures to support language and language development must be coded for genetically. Language itself must be learned or is synthesized de novo during certain periods of brain development. This point is quite important. When humans are growing up in a culture, they adopt the language of the culture, provided that the language is "well formed". If the language the adults are using is not "well formed", the children synthesize a new language that is "well formed". That is, when the children of immigrant parents grow up, they do not adopt the pigeon language their parents are speaking, they either adopt the "well formed" dominant language, or synthesize a "well formed" Creole. The various sign languages did not become "well formed" until children grew up with signing as their first language, which they modified into a "well formed" language.

The acquisition of language in this way tells us several things; that the ability to acquire language is innate, that there is a more "primitive" cognitive structure underlying language (by that I mean that the structure of "thought" has a component that is simpler than the linguistic components humans communicate with). Without a simpler and more primitive cognitive structure, the Creole could not be analyzed as it is being formed to ensure the resulting Creole has a "well formed" grammar. However, the ability to form a Creole is lost at a certain age. The immigrant parents of the Creole synthesizing children continue to speak their pigeon language. This implies that the cognitive structure that analyzes language as it is being learned and forces it to be "well formed", i.e. to conform to standard human linguistic patterns is lost (to some extent) with age. It also implies a compulsion to learn the "standard" language and a compulsion to force others to comply with the "standard".

The development of a de novo language, such as a Creole, is a collective outcome produced by a population. It is not produced by a single individual. Another way of describing it is that the population developing the language acquires a shared neural mapping of the medium of the language (sounds, gestures, etc) to neural structures producing the mental states that are the ultimate outcome of communication (that is the ideas being communicated). In this context, there is no arbitrarily correct mapping. The mapping is correct so long as it is the mapping shared by the group. In the sense of the Galbraith quote at the start what ever the majority adopts as the linguistic mapping is the correct mapping. This is a very important point. What ever the majority adopts as correct is correct; everything else is wrong.

For a single majority linguistic mapping to arise spontaneously there must be very powerful mechanism(s) to eliminate deviation from the mapping acquired by the majority. The majority acquire a shared Theory of Mind with respect to linguistic mapping. In other words, the differences between the shared Theory of Mind and that of any individuals in the population are reduced. The deviation is not reduced by changes to the shared theory of mind; the deviation is reduced by individuals adopting the shared ToM as their own. This is an important point. There is no "shared" ToM. There are only individual ToMs which correspond to the shared ToM more or less. The shared TOM can only be shared to the extent that all individuals have the same components and the same structural relationships between those components. The shared ToM reflects the "lowest common denominator"; the ToM that overlaps with everyone else's ToM is all that can be shared. I think this relates to the importance of "peer pressure" in the age group capable of forming a Creole language. If peer pressure were not so compelling, a single coherent language would be difficult to achieve.

The rigidity of an inflexible ToM maintains stability of communication, of information transmitted culturally to the next generation. If your ToM doesn't support an idea, you cannot transmit it, receive it, understand it, or even think it. When times are easy, transmitting the cultural information that led to those easy times is important. It is important to do so with high fidelity because it worked. When times are hard, the culturally transmitted information isn't working, and so needs to be abandoned or modified. The fidelity of transmission must be reduced so what ever is wrong and/or isn't working can be eliminated.

The ToM of NTs that allows them to communicate so easily with each other limits what they can communicate to ideas that are within the shared ToM. This is an extremely important point, but it is a point that NTs have an extremely difficult time understanding because they can only think using ideas that are within their shared ToM. If an individual's ToM is insufficiently flexible to map an idea, that idea cannot be understood unless the ToM changes. But there is tremendous peer pressure to maintain the shared ToM of the group and to not change it.

This rigidity of the NT ToM is what causes ideas to persist even when those ideas are wrong and the rejection of correct ideas even when well supported by incontrovertible data. Many religious ideas have no supporting evidence and are in fact demonstrably wrong. For example the idea that the Earth is less than 10,000 years old and was created in 6 days as described in Genesis. Similarly the idea of evolution is rejected without a single piece of data inconsistent with it.

Most ToM ideas are transmitted from other individuals, not generated de novo.

Conflicting compulsions for ToM and ToR

A specific ToM is only useful for communication in the context of the group of individuals that share it. The mapping of a data stream (i.e. speech or gestures) into ideas and mental states is arbitrary and the only correct mapping is the one that everyone else in the group shares. There must be a tremendous compulsion to modify one's ToM to conform to that of the group. It is this compulsion that forces the emergence of a single language in a group.

In contrast, a ToR is only useful in so far as it actually corresponds to reality. To eventually develop a robust ToR, the individual must have a compulsion to modify his/her own ToR until it does correspond with reality, irrespective of the ToR of others in the group.

Thus developing and maintaining a good ToR is in conflict with developing a good ToM. A ToM needs to remain static for individuals to be able to communicate with each other. A ToR needs to be dynamic and change when ever it is found to be in error or to be dysfunctional.

I think this is the source of much of the resistance to new ideas in human culture but also in the scientific community. These concepts are laid out by Thomas Kuhn in his book, The Structure of Scientific Revolutions. Most scientists do what Kuhn calls "ordinary science", where they work within the paradigm of their scientific field. It is difficult to work outside the paradigms of a scientific field. Any contradiction of an existing paradigm is considered extraordinary and so requires extraordinary evidence. Some individuals are unable to reject paradigms even when they have been shown to be wrong. In these individuals, their rigid ToM has locked them into a perpetual state of error, and they don't have a sufficiently robust ToC to appreciate that their thinking is faulty and in error. It is mechanisms similar to the mechanisms that enforce a rigid ToM during language acquisition that compel adherence to the faulty ToM in later life, peer pressure, appeal to authority, tradition.

Communication and ASDs

Communication in humans encompasses a number of modalities including speech, sign language, body language, written language, music, artistic expression and perhaps pheromones. Most of these have components that are learned, improve with practice and degrade with disuse demonstrating the involvement of neural structures which retain plasticity (positive and negative) even in adulthood.

Autism is defined by behaviors, behaviors related to social interactions where autistic individuals have what are called characteristic deficits which can be reliably measured. However what constitutes a deficit is a matter of perspective. One example is a "deficit" in the ability to impute anthropomorphic motivation and emotion to inanimate objects as in the work of Frith. In this research, triangles were animated and made to move in three different ways, randomly, goal directed and moving interactively with implied intentions. The two sets of purposeful motions were designed to evoke anthropomorphic responses, e.g. chasing, fighting and coaxing, tricking. Individuals were scored on how closely they matched the scripts the animators of the triangles were trying to portray.

The ASD individuals scored lower than the NTs did, and this was described as a "mentalizing dysfunction". This was taken as a confirmation that people with ASDs have an impairment in attribution of mental states. However, whose "mental state" did the ASDs have an impairment in recognizing? The "mental state" of the triangles? Was this error a type 1 error (false positive), or type 2 error (false negative)? One might say the ASDs had a type 2 error, failure to recognize the "mental state" of the triangles, but one could (more correctly I think) say that the NTs had a type 1 error of falsely attributing a "mental state" to obviously inanimate triangles.

There is no intrinsically correct representation of the mental state of triangles. Triangles do not have mental states. The only way that a mental state can be attributed to triangles is via anthropomorphic projection of human-type intentions onto inanimate objects. In most circumstances this would be a Type 1 error; falsely observing anthropomorphic attributes in inanimate objects. It could also be thought of as a type 3 error, wrongly using a human based anthropomorphic model where it is inappropriate. This type of projection is not uncommon. Imputation of motivation and intentions to inanimate objects was at one time the basis for the religious belief that demons and spirits inhabit and animate virtually every object.

Inappropriate invocation of anthropomorphic feelings is a large part of the entertainment industry. Many cartoons are stylized after humans and many humans develop grossly and dangerously wrong ToR based on these erroneous ideas. In regions where bears are endemic, campers feeding bears is a serious problem. People assume that the anthropomorphic representations they have seen on TV are representative of how bears will react in real life. There have even been cases where a parent has applied peanut butter to a child's face so a bear cub would lick it off to obtain cute pictures.

This relates to the second quote, "If the only tool you have is a hammer, you tend to see every problem as a nail." If the only cognitive structures you have to think with are the cognitive structures of human emotions and communication, trying to figure out the properties of inanimate objects would consist of trying to ascribe human motivations and intentions to those inanimate objects and trying to figure out what they would do next in human terms.

Savant cognitive abilities

A striking feature of some people on the autism spectrum is that in some instances they have narrow and highly superior cognitive abilities. Human mental abilities have distributions in the population, with "normal" abilities being distributed "normally". Usually people with autism are somewhat lower on intelligence tests such as WISC, but with somewhat higher scores in block design. When intelligence tests without a communication component such as Raven's Progressive Matricies are used, some autistic individuals score much higher, in some cases as much as 70 percentile points higher (n=7). [33] That is 70 percentile points higher. Such a lack of congruence between tests is sufficient to show they are not measuring the same thing and we shouldn't use the same label to denote what the different tests are measuring even if there is good correlation among NTs. That correlation can only be spurious.

The distribution of intellectual abilities is "normalized", that is differences are measured and then scaled to fit on a distribution. That scale is arbitrary, and does not reflect any sort of absolute scale of difficulty.

As social animals, humans live in societies, larger communities of humans where there can be specialization and division of labor. It is this specialization and division of labor that has allowed humans to collectively master many technologies. Presumably different mental tasks are optimized by different neural structures. Dispersion in mental abilities requires dispersion in neural structures.

Savant abilities are not rare among people on the autism spectrum, and sometimes occur in individuals with profound disruptions in other cognitive abilities. This shows that to some extent, some cognitive abilities are independent of each other. Presumably superior performance in some cognitive tasks and inferior performance in others represents a trade-off of abilities along multiple spectra. The brain is limited in size, its computation capacity is limited, relative cognitive abilities of individuals will depend on the myriad details of the neurodevelopmental path that individual took.

Communication is "savant" ability of NTs

Many ASDs have savant abilities, which demonstrate that what ever part of the brain is providing those cognitive abilities has superior performance to the corresponding part of NT brains with lesser performance. The one area where NTs are universally better than ASDs is in communication. I suggest that communication is the savant ability of NTs, and that NTs have traded reduced abilities on ToR and ToC for enhanced ability in ToM.

The difficulty in relations between ASDs and NTs is that NTs don't appreciate that the ToM they are using for communication is a savant ability that ASDs don't share, and shouldn't be expected to be able to emulate. An ASD can't emulate the NT savant ability to communicate any more than an NT can emulate an ASD savant ability at mathematics. If you don't have the brain structures that can do the computations, you can't emulate the behavior. You might be able to fake how it sounds, but because the fundamental neural structures are not present, it is just an act and can't have the actual content.

Trying to think about Reality with a ToM is like doing Cargo Cult Science

Richard Feynman coined a term, Cargo Cult Science, to describe the practices of people who may be doing what they call experiments, but they are missing the fundamental intellectual honesty to be actually doing science. The term comes from the observation that tribes in the South Pacific would observe westerners arrive and set up landing strips which would bring aircraft laden with cargo, all sorts of goods that seemed to appear like magic. Along the lines of Arthur C. Clarke's observation that "any sufficiently advanced technology is indistinguishable from magic". They tried to understand the source of this cargo and how to get cargo for themselves using their understanding of reality. They generated a Cargo Cult, and proceeded to adopt rituals to try and cause cargo to appear.

This is really an excellent metaphor for trying to think about a subject with the wrong approach. Their thinking was that such good cargo had to come from the Ancestors, but the Ancestors would only bring such good cargo if they were communicated with in the right way, which the westerners knew how to do, so copy them and the cargo would appear. They built landing strips, control towers and populated them with radio control operators, but to no avail.

Explaining that their approach was wrong would fall on deaf ears. They don't have the background to understand where the cargo actually came from. They had anthropomorphized their observations and reduced them to the human terms they could understand using their ToM. They didn't come to their beliefs via facts and logic, facts and logic won't dissuade them from their beliefs.

Obviously there are multiple individuals involved, a leader and followers and the leader may achieve lots of things even if no cargo shows up. Presumably it is the charismatic persuasion of the leader using the leader's ToM that causes the followers to believe the leader. Simply by leading the effort to obtain cargo the leader achieves status over the others. Even when doing something completely useless and wrong, the society holds together if all of the members share the same ToM. Individuals not sharing the conceptualization of obtaining cargo by building airstrips would not fit in.

To people who have savant mathematical ability, those without it who are trying to emulate mathematical abilities can be seen as trying to do cargo cult mathematics. They can go through the motions, but don't have the ability to generate the content. Similarly, ASDs who try to communicate with NTs are doing cargo cult communication. They can go through the motions, but there is a lot of stuff that is being missed.

Neurological structures required to support an idea

The only ideas that an individual can think about are ideas that can be mapped into that individual's neural network. To learn a new idea, either the neural structure present is sufficiently flexible that the new idea can be mapped into it, or the neural structure must be modified until the new idea can be mapped onto it.

The process of learning a new idea must include as the first steps, the process of modifying the neural networks of the brain such that they can support the new idea being learned. Often the first step is "unlearning" ideas that are wrong. I think that this modification of the brain to support new ideas is why learning takes such a long time. New neural structures need to be made.

All mental representations require some level of neuronal "overhead" to be sustained. The details of how the brain does that are not understood. While the capacities of the brain are large, they are not infinite, and at some point trade-offs must be made.

Socially isolated individuals develop on an autism-like pathway.

All important physiological systems are under feedback control (that would be all physiological systems). Presumably an organ as important as the brain is also under feedback control, and this is reflected in the improved efficiency obtained through practice at certain mental tasks.

Presumably if there is a trade-off of ToM vs. ToR, then isolated individuals with no need for a ToM would develop a more robust ToR. This does appear to be the case in multiple organisms including humans, monkeys and rodents.

The classic work on socially isolated monkeys was done by Harlow in the 1960's, [34] and present animal welfare regulations would make such experiments problematic. Some monkeys were raised with no social contact at all, even with their mothers. Such monkeys were profoundly affected and exhibited rocking behaviors, self-injurious behaviors and profound disruption in abilities to interact with other monkeys. They were termed autistic by the experimenters.

Surprisingly, some of these socially isolated monkeys exhibited superior cognitive abilities. What is especially interesting is that these superior abilities were termed "deficits" by the experimenters. [35] Socially reared monkeys were conditioned with a tone and a startle stimulus. A redundant lamp was then paired with the tone. Socially isolated monkeys conditioned to the redundant light, the socially reared monkeys did not. The experimenters characterized the non-conditioning of the socialized monkeys to the redundant signal of the light as "blocking" the isolated monkeys then exhibited what was termed a "deficit" in blocking. Why the experimenters chose to use the term "deficit" to refer to a superior ability tells us something about the experimenters and their expectations about the socially deprived monkeys, not the monkeys.

Rhesus monkeys raised in social isolation have superior learning performance to those raised in social environments. [36]

Involvement of nitric oxide in social interactions and communication

The archetypal social interaction in mammals is the bonding of the mother to her infant. All mammals exhibit this behavior and have exhibited it for as long as mammals have suckled their young. The first social interaction all mammals have is with their mother. Even mammals thought of as primarily non-social do have this social interaction.

NO is involved in the development of the bonding and smell recognition that occurs in ewes within 2 hour of giving birth. Inhibition of nNOS blocks formation of that olfactory memory, and this blockage can be reversed by infusion of NO into the olfactory bulb. [37] Oxytocin is essential in the formation of normal social attachment in mice. [38] Reduction in oxytocin release following epidural anesthesia in heifers preceded a reduction in maternal bonding type behaviors[39]. Activation of the oxytocin receptor causes activation of nitric oxide synthase. [40] The connections that mediate maternal bonding can occur in the space of a few hours[41], limiting the distance over which axons must migrate to form these new connections.

Why NO is the signaling molecule that mediated the neural remodeling to cause maternal bonding makes evolutionary sense. Lactation is extremely energy intensive. If a mother does not have the metabolic resources to generate sufficient milk of sufficient nutritional quality to sustain her infant until it is weaned, she (and her infant) is better off not bonding to her infant and abandoning it. Spending metabolic resources on a reproductive attempt that will fail will reduce the success of potential future reproductive attempts. A failed reproductive attempt has no advantage either to the mother, or to the infant. An infant's best reproductive strategy in those circumstances is to do what ever increases the likelihood that the infant's mother will have a successful reproductive event later, so that the non-surviving infant may have a surviving sibling.

I discuss this at length in my blog on infanticide. Using NO as the positive signaling molecule to mediate maternal bonding directly couples maternal bonding to energy status. The low NO of metabolic stress directly reduces the degree and fidelity of maternal bonding. In extreme metabolic stress (the most important states for maternal bonding to be blocked) the maternal instinct turns from nurturing to infanticide. It needs to be appreciated that infanticide under conditions of extreme metabolic stress is as much a "maternal" instinct as is nurturing when times are better. I see infanticide as the brutally hard state that desperate metabolic stress induces in postpartum women.

Social isolation reduces NO generating neurons in the brain

When rodents are raised in a socially deprived setting, the numbers of NO producing neurons in some parts of their brains are reduced. [42] A reduction in basal NO in the brain due to development under socially isolated circumstances makes sense. Many social interactions are mediated via NO mediated pathways, including bonding and other pathways mediated through oxytocin. If the environment one is growing into is non-social, social neural pathways have little or no survival benefit. Better to develop the neural structures that will be useful.

Socially isolated individuals retain sufficient neural plasticity to partially recover

Social isolation at birth produced monkeys with profoundly disrupted social abilities. Experiments demonstrated that some of the disrupted social abilities could be restored. This involved the use of "therapist" monkeys, usually socially raised normal monkeys that were substantially younger than the isolated monkeys. [43] In females, a socially isolated female could recover somewhat and be an improved mother following pregnancy and raising an infant however many times the first born infants did not do very well but mothering did improve with subsequence births[44] demonstrating plasticity in neural networks mediating mothering behaviors during pregnancy and/or mothering activities. Since maternal bonding is the archetypal communication pathway for mammals, this suggests that other fundamental communication pathways have plasticity also.

With NO being involved in bonding, improved bonding and mothering interactions with subsequent births is consistent with increased neurogenic nitric oxide as a causal mechanism. If a non-social environment becomes social, reconfiguring neural structures to cope with social interactions would be advantageous.

Potential for treatment

I suggest an analogous treatment for ASD individuals may be to incorporate them into play groups with significantly younger NT children that are at similar developmental stages, but with sufficient adult supervision that nothing untoward can happen.

Doing this in the context of increasing NO levels via the techniques I am working on my have important therapeutic effects.

References:

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Suggestion to reduce antibiotic resistant skin infections

in Hospitals, Nursing Homes and Hospices using topical ammonia oxidizing bacteria

Skin and wound infections involving antibiotic resistant organisms are serious problems in medical care. Hospitals and nursing homes present difficult infection control challenges because diverse patients carry different organisms and presenting different immune system status. The large influx of patients, staff, visitors and supplies, with diverse resident microorganisms ensures that a hospital is an open system in terms of microbiology. It is suggested that introducing and maintaining a dominant population of autotrophic ammonia oxidizing bacteria in the hospital and patient environment may significantly reduce hospital transmitted infections while also reducing selection for antibiotic resistance.

The conventional approach to infection control is the liberal use of soap and detergents to remove soil, use of chemical disinfectants [1] including oxidants such as bleach, iodine and hydrogen peroxide; cell membrane disruptants such as alcohols, cationic surfactants and phenolics and the rare and judicious use of antibiotics. Antibiotics are agents which interfere with a microorganism's internal metabolism in a fairly specific way (as opposed to non-specific oxidants and membrane disruptants). Some antimicrobial agents are being used indiscriminately such as triclosan, which inhibits lipid synthesis in target organisms.[2] Use of triclosan containing cleaning products does lead to increased resistance of exposed microorganisms to triclosan and also to other antibiotics [3] (the therapeutic and statistical significance of this is complex, a single resistant clone may be medically significant even if most clones stay susceptible). Use of antibacterial household products does not reduce the incidence of disease symptoms. [4]

Antibiotics should be used sparingly because use eventually leads to antibiotic resistance. Every time an antibiotic is used, organisms are exposed to different levels as the administered dose is absorbed, transported throughout the body, and finally metabolized or excreted. If the exposure level is less than the toxic dose, the organism will survive and if resistant will pass that resistance down to its descendents. Non-target non-pathogenic organisms can develop resistance, and this can be transferred to pathogens via plasmids. Even non-antibiotic disinfectants, such as pine oil can cause broader resistance to antibiotics through upregulation of multi-drug resistance pathways. [5] These are ATP powered transporters which excrete target compounds including antibiotics. Upregulation of these efflux pathways can cause broad spectrum resistance to many antibiotics and chemical disinfectants. [6]

In addition to the problem of resistance, killing all microorganisms including non-pathogens leaves those niches completely open for the next organism that appears. Re-inoculation of surfaces cannot be avoided because microorganisms are ubiquitous in the environment and on patients. An adult human contains more bacterial cells than human cells. [7] Mostly in the gut, but every surface exposed to the external environment including the skin, mouth, gut all have characteristic resident microorganisms. The resident commensal microbiota is a normal part of what protects against infection by pathogenic organisms. When that normal flora is disrupted, as with systemic antibiotics, the now empty niche can be colonized by pathogens, as for example a yeast infection following antibiotics.

Many pathogenic organisms can survive long term on dry inert surfaces, days, weeks and even months. [8]

I am working with organisms previously unrecognized as commensal Autotrophic Ammonia Oxidizing Bacteria (AOB). AOB are widely known in the environment, where they perform the first step in the process of nitrification, the oxidation of ammonia to nitrite. They are found in virtually all soils and all sources of water including ground, surface and sea water. I have found that AOB live on the external surfaces of many eukaryotes, where they provide a first line of defense in keeping those organisms from acquiring surface infections.

AOB are obligate autotrophs. They derive ATP only from oxidation of ammonia into nitrite and are incapable of deriving ATP from oxidation of organic compounds. There has been no report of an infection with any of these organisms and it is likely that an infection is not possible. They produce no toxins, and have no transporters to excrete them. They are slow growing with optimum doubling times of ~10 hours. They are incapable of growth on any media used to isolate pathogens.

The major product of commensal AOB is nitrite, produced from ammonia in sweat or bodily secretions. Acidified nitrite is a very potent anti-microbial and has been shown to kill antibiotic resistant organisms such as MRSA and VRE. [9] The normal pH of the skin is about 4, sufficiently acid that nitrite disproportionates to NO and NO2 and sufficiently acid that nitrite has potent antimicrobial effects. AOB are virtually completely resistant to nitrite, acidified nitrite, NO, even NO2 at levels that would be acutely toxic to other organisms (e.g. 600 ppm NO, 100 ppm NO2) [10]. Acidified nitrite is synergistically (~100x) toxic to some organisms in the presence of H2O2 and lactate. [11] Lactic acid bacteria are a large class of commensal organisms, particularly on the skin and vagina where some of the most persistent produce H2O2 [12], and because they lack hemes are fairly resistant to NOx toxicity. It is our hypothesis that AOB are natural human commensal organisms, and in conjunction with Lactic acid bacteria provide a first line of defense against skin pathogens for humans and for many eukaryotes.

AOB are associated with corrosion of natural stone, particularly calcareous stone. [13] The mechanism seems to be production of low pH via oxidation of ammonia to nitrite, the low pH then traps more ammonia from the atmosphere and the low pH causes loss of NO/NOx. Too low a pH reduces NH3 availability to the bacteria, too high a pH causes loss to the atmosphere. The growth rate is higher on calcareous rock likely because as the rock dissolves it releases trace minerals needed for growth. The only substrates needed are ammonia, CO2, O2 and minerals.

While NO/NOx species are broadly antimicrobial, the main mechanism for preventing surface infection may not one of organism death (which organisms can evolve resistance to) but rather disruption of quorum sensing (evolved resistance to disruption of quorum sensing is much more difficult and may necessitate loss of pathogenicity). .

Many microorganisms communicate by what is called quorum sensing. [14] Organisms producing a specific chemical which diffuses away, but when a sufficient number of clones of the organism are present the local concentration builds to a level that triggers a change to a different phenotype. Usually this transition is associated with the expression of virulence factors, adherence, toxins, exporters, proteases, biofilm formation. If these virulence factors are not expressed, the organism remains non-virulent even if it is a virulent strain. Virulence factors can only cause disease if they are expressed. Even transient interference with quorum sensing blocks formation of abscesses by Staphylococcus aureus. [15]

Gram-negative bacteria often use acyl homoserine lactones as quorum sensing compounds. Some eukaryotes interfere with these signals as part of their defense against infection. These interference mechanisms include oxidation [16] by hypochlorite, superoxide and NOx, and displacement by halogenated furanones. [17]

Nitric oxide is a signaling molecule used by some biofilm formers to transition from a biofilm phenotype to a planktonic type. That is, low NO triggers the transition to form a biofilm and high NO inhibits it. Bacteria in biofilms are much more resistant to antimicrobial agents both antibiotics and antiseptics. The inhibitory concentration in a biofilm is higher sometimes by more than a factor of 500. [18] Many infections particularly persistent infections are characterized by the formation of biofilms [19] which is not surprising because therapeutic doses cannot be arbitrarily increased to counter the increased resistance of biofilms. Nitrite inhibited the formation of biofilms by Staphylococcus aureus and Staphylococcus epidermidis, and caused dissociation of biofilms already formed. [20] When formation of quorums sensing compounds is blocked, even agents that are virulent pathogens exhibit reduced dissemination and reduced mortality. [21] The main virulence factor of Staphylococcus epidermidis is formation of a biofilm and this is triggered through quorum sensing. [22]

An advantage of the AOB as commensal organism suppressing heterotrophic pathogenic organisms is that AOB have very simple genomes [23] and an almost complete inability to metabolize organic compounds. It is quite likely that they would be extremely slow to evolve resistance to antibiotic compounds (if at all) because they lack precursor metabolic pathways that can be adapted to metabolizing them. If they are unable to evolve resistance, they would be unable to transmit that resistance via a plasmid to a pathogen. Because they grow ~30 times slower (10 hours vs. 20 minutes), if they could evolve resistance they would do so much slower (if at all).

It is expected that AOB are safer than the lactobacilli which are commonly consumed in large quantities as yogurt and which are specifically used as probiotics. [24] Very rarely liver abscesses and endocarditis has been attributed to lactobacilli strains which have been indistinguishable from those used by the patients as food. [25] These associations are thought to be opportunistic infections rather than primary infections. [26] Introduction of some Lactic acid bacteria into nude athymic mice does not cause illness. In any case AOB don't excrete any proteases to degrade structural proteins and are unable to metabolize animal products if they did (unlike Lactic acid bacteria). AOB are obligate aerobes and so can't colonize the gut. The only place they can live is on the external skin, where they can live long term (years) subsisting only on natural secretions (unpublished data). During long term growth on human skin AOB do suppress other bacteria including bacteria that cause body odor (unpublished data).

Many pathogens express urease which hydrolyzes urea into ammonia raising the pH of infected skin and tissues. If this ammonia were oxidized into nitrite by AOB, they would lower the pH. If the skin did become infected, any infectious organisms would metabolize proteins into amino acids and then deaminate them releasing ammonia. An AOB biofilm would oxidize that ammonia into nitrite and NO, killing or inhibiting the organism. The pH of the site where the infection is would be high due to the ammonia released. The pH dependence of surface tension (lower at high pH) would wick those fluids to regions of low pH, where the AOB are turning the cation (ammonium) into an anion (nitrite). This is thought to be a major factor on the skin where natural pH gradients distribute sweat to regions of highest AOB activity. The lowest pH that AOB can attain is limited by the availability of ammonia (ionized ammonium is not metabolized) and the decomposition of nitrous acid. A pH below 4 cannot be generated by AOB.

I have been growing these bacteria in an organic free media simulating human sweat, distilled water plus minerals and ammonia. The only source of organic is what the AOB fix from CO2 utilizing the ATP they derive by oxidizing the ammonia to nitrite. The growth media ends up being about 40 mM in nitrite, perhaps 20 times levels observed in vivo in human saliva (2 mM) [27]. Human saliva naturally contains nitrite derived from nitrate concentrated 10x over plasma levels in saliva then reduced to nitrite by tongue commensal bacteria. This nitrite is a normal part of the antimicrobial system of the mouth and gut. [28] Mice and rats have survived for years on drinking water containing 5,000 ppm sodium nitrite (72 mM) [29].

In a hospital or nursing home setting there are many surfaces which cannot be sterilized. The surface in closest proximity to a patient's wound is the patient him/herself. Patients cannot be sprayed with disinfectant for a variety of reasons, and no disinfectant is self-renewing the way a natural biofilm is. An agent that was completely natural, sufficiently mild, odorless, which actively suppressed bacteria via mechanisms which did not lead to resistance and was self-renewing could be a useful addition to normal infection control procedures. One method of use might be to spray the patient down after bathing. Another use might be to apply to surfaces after cleaning. Perhaps applying to surfaces not cleaned as regularly, the undersides of beds, walls, floors. Perhaps applying to bedding and garments.

A major problem is incontinence and skin injury due to ammonia from hydrolysis of urea in urine. AOB oxidize ammonia to nitrite, suppressing the heterotrophic bacteria that hydrolyze urea to ammonia. Formation of nitrite lowers pH, turning toxic ammonia into non-toxic ammonium. The pH can't get below about 5-6 because the availability of ammonia goes down (they don't utilize ammonium). NO and nitrite are vasodilators and would be expected to increase circulation in affected regions. The NO/NOx level can't get to locally toxic levels because hyperemia occurs first which then carries the NO/NOx away.

This is an approach that may have some advantages for in patient long term care.

[1] McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999 Jan;12(1):147-79. Review. Erratum in: Clin Microbiol Rev 2001 Jan;14(1):227.

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[6] Poole K. Efflux-mediated antimicrobial resistance J. Antimicrob. Chemother., July 1, 2005; 56(1): 20 - 51.

[7] Xu J, Gordon JI. Inaugural Article: Honor thy symbionts. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10452-9.

[8] Kramer A, Schwebke I, Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review. BMC Infect Dis. 2006 Aug 16;6:130.

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[11] Kono Y, Shibata H, Adachi K, Tanaka K. Lactate-dependent killing of Escherichia coli by nitrite plus hydrogen peroxide: a possible role of nitrogen dioxide. Arch Biochem Biophys. 1994 May 15;311(1):153-9.

[12] Vallor AC, Antonio MA, Hawes SE, Hillier SL. Factors associated with acquisition of, or persistent colonization by, vaginal lactobacilli: role of hydrogen peroxide production. J Infect Dis. 2001 Dec 1;184(11):1431-6.

[13] Mansch R, Bock E. Biodeterioration of natural stone with special reference to nitrifying bacteria. Biodegradation. 1998;9(1):47-64.

[14] Schauder S, Bassler BL. The languages of bacteria. Genes Dev. 2001 Jun 15;15(12):1468-80. Review.

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[18] Olson ME, Ceri H, Morck DW, Buret AG, Read RR. Biofilm bacteria: formation and comparative susceptibility to antibiotics. Can J Vet Res. 2002 Apr;66(2):86-92.

[19] Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999 May 21;284(5418):1318-22. Review.

[20] Schlag S, Nerz C, Birkenstock TA, Altenberend F, Götz F. Inhibition of staphylococcal biofilm formation by nitrite. J Bacteriol. 2007 Nov;189(21):7911-9.

[21] Lesic B, Lépine F, Déziel E, Zhang J, Zhang Q, Padfield K, Castonguay MH, Milot S, Stachel S, Tzika AA, Tompkins RG, Rahme LG. Inhibitors of pathogen intercellular signals as selective anti-infective compounds. PLoS Pathog. 2007 Sep 14;3(9):1229-39.

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[23] Chain P, Lamerdin J, Larimer F, Regala W, Lao V, Land M, Hauser L, Hooper A, Klotz M, Norton J, Sayavedra-Soto L, Arciero D, Hommes N, Whittaker M, Arp D. Complete genome sequence of the ammonia-oxidizing bacterium and obligate chemolithoautotroph Nitrosomonas europaea. J Bacteriol. 2003 May;185(9):2759-73.

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Delusional Nonsense

As a scientist concerned about the rampant disinformation being put out on the web, and as someone very concerned about scientific literacy and the education of children to be scientifically literate, I feel I must blog about the travesty of disinformation being put out by Ben Stein and the Discovery Institute.

I interrupt my regular blogging to post the obligatory links of Ben Stein's movie aka the crappy Creationist movie (oops I mean expelled the movie aka Intelligent Design or ID movie) Expelled to the Expelled Exposed web site. PZ Myers has many of the details.

Evolution is one of the scientific theories that there is the most evidence for. The largest amount of evidence is in the DNA of living organisms. Every bit of the DNA that has been analyzed so far is completely consistent with evolution and with common descent. Just as DNA testing is extremely reliable for determining relatedness of children to their parents, it is also reliable in determining relatedness of more distant relatives. Even very distant relatives to humans, such as E. coli.

Evolution of ASDs as invoking tool using phenotype

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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45 http://www.jsonline.com/story/index.aspx?id=498353 (accessed 12/25/06)

46 http://www.jsonline.com/story/index.aspx?id=498527 (accessed 12/25/06)

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57 Bible, Numbers 31:17-18.