Autism Spectrum Disorder describes a complex of many symptoms that appear in children, often first noticed by parents when the child is three years old. Some report having noticed a change in what they thought was normal development much earlier. New research shows that there may be indicators other than behavior that might help us to intervene and possibly prevent the worst of symptoms.
An NPR report on some of the genetic research sparked my wish to wrangle with some of the assumptions being made by many researchers. Much of the discussion of autism centers on genetic “causes,” despite the fact that genes do not “cause” anything. However, genetics research can give us many insights into how the brain is put together. I also present new research that suggests an environmental association and criticize both kinds of research for not asking the right questions.
Updated: 17 Sept 2014
Comment on “Autism Risk ‘High’ For Kids With Older Sibling With The Disorder Autism Rates Higher in Siblings” on All Things Considered for 15 Aug 2011, where I address medical scientific research methods used in this case and in others, discussing the role of toxins and genetics as “causes” of this disorder of the nervous system.
A new study (Ozonoff et al 2011) which observed the incidence of autism in siblings found that a baby with an older sibling with autism will also develop autism in 15-20% of families. If the newborn is also a male, then he will develop autism in 25% of cases (9% in females). In families with two or more autistic children, a new arrival will develop autism in 33% of cases. Even though the likelihood of being born without autism is higher, the number of cases of autism is significantly higher than the incidence in the general population where no siblings have autism (about 0.9%).
The implications are that families with children diagnosed with autism can expect a higher risk in new additions to their families. Instead of waiting to see if the new baby develops autism, parents can be pro-active and start looking for the signs earlier as well as take action to try new therapies on their children. The report mentions how such behavioral therapy has helped autistic children to communicate better than thought possible.
My Comment Posted at NPR
This study (Ozonoff et al. 2011) and the study on autism in fraternal and identical twins (Hallmayer et al. 2011) are contributing to the argument in favor of environmental, and not genetic causes of autism. In the case of the fraternal twin study (Hallmayer et al. 2011), the environment that is considered is the uterine environment, where both fraternal and identical twins share something in common, but there is reduced shared genetics in the fraternal twins.
If environmental toxins are the real culprit here, then they have to be taken so seriously that we understand how they could cause damage inside the body. Most people think that finding a gene associated with autism means that it could be passed down from one generation to the next. That will happen only if the gene is carried inside an egg or sperm. Most people assume that every cell carries the same genes everywhere in the body. But they do not if some are exposed to mutagenic toxins and others are not. If researchers find a gene associated with autism we have to understand better the environment-gene equation. Finding a gene is not such a simple process, since it matters which tissues are being tested. People might think that genetics seems to be more likely the culprit, since “risks” of autism are higher if a sibling has it, and fraternal twins raise that risk to even higher levels. However, if children are exposed to the same toxin in the environment, then an important control has not been met in either of these studies. See my blog post “Genetics, Toxins and Autism” at https://marthalhyde.wordpress.com/2011/08/16/genetics-toxins-and-autism/ for more on this discussion.
Environment is the Trigger for Genetic Expression
The development of autism has been looked at from both environmental and genetic sides. Most studies have looked for a list of obvious major organic toxins that have clear effects on the liver, spleen, kidney and nervous system in people of all ages. They assume that if toxins caused autism that they would also cause other problems in people of all ages. When people have looked for genetic “causes”, they generally examine cells of the autistic person and compare them with cells of other people without autism to see which genes are different.
The benefits of science have come from very careful experimental testing of hypotheses. These are controlled experiments, where a participant is exposed to a “manipulated” situation to see if there is a different response than expected. Sometimes the same participant is used for both the experimental manipulation and as a “control,” where no manipulation has occurred but otherwise, circumstances of the test are the same. Sometimes there are “matched” participants, i.e., participants who are similar in any way imaginably involved in an hypothesized “cause,” but one is manipulated, and the other serves as the “unmanipulated” control.
Scientists may find many genes “associated” with autism, but none have been found to cause “autism.” Thus, the word “cause” needs to be very carefully applied. There have been no experiments done which replaced normal genes in children with autism-related genes that “caused” the appearance of autism in these “normal” children. That study would be unethical at the least. No animal models for autism have been developed and used in such an experiment, either. In fact, genes do not “cause” anything to happen, they just regulate protein production in each cell. Since all geneticists know that genes only provide a blueprint which is acted upon by the environment, we must suspect that some environmental interaction with genes is occurring during the time period when the brain becomes disorganized as found in autism.
When geneticists test a parent for the possibility of passing dangerous genes to their offspring, most sampling procedures for genetic tests assume that every cell in the body carries the same genes. Such an assumption only works if we can also assume that mutagens are not attacking most of the cells that the researcher samples. This is not the case, since we carry mutagenic toxins inside our bodies, and are exposed to mutagens all around us. Therefore, the most exposed areas of the body, including the skin on the outside, and that lining all orifices (mouth, nose, ear, orbits, urethra, anus and vagina), and the ductal lining of the pores in the skin, could all hold mutated cells because of such exposure. The most common method of obtaining genetic material is a scraping of skin cells from the lining of the mouth.
How to Prepare a Wet Mount Microscope Slide With Human Cheek Epithelial cells, from YouTube
Furthermore, there are readily available pathways for entry of toxins into the inside of the body: breathing, swallowing, entering the brain via the eyes (Toxins and the Eyes), crossing the thin epithelium lining the cheek, tympanic membrane of the ears, and gut epithelium, and travel within the body via the connective tissue highways that make up the hypodermis (What is the Hypodermis?). Toxins can travel through all sub-epithelial space, as well as along all blood vessels, nerves, lymphatics, connective tissue investing all organs, following all vascular and nervous routes to their internal regions. Some toxins could get into the bone marrow easily, without entering the blood vascular system because they could follow the connective tissue that surround the capillaries, and which enter the bone via nutrient foramina. Once inside the bone marrow, these toxins could then get into the blood supply, if they happen to have the right charge, the correct size, and do not damage the blood vessels. See my post Toxins for more information on toxins in the body.
So samples of the mouth, nose, or other orifices, those taken of blood, or biopsies of fat, spleen, liver, heart, lungs, or of any other organ, might also show effects of toxic mutagens, to a greater or lesser degree. Only if the researcher took biopsies of many different kinds of tissue, along with the usual blood sample, cheek scraping, and tested each sample separately, could anyone suspect that an autism-related gene might have passed down from one generation to the next. But even this assumption still may be wrong if such widespread presence of a gene is found.
If the mother has the toxin, it is also highly likely that the toxin is dispersed throughout the uterine endometrium, since it is largely made up of connective tissue during the early proliferative phase (pre-ovulatory) of the uterine cycle. In this way, after fertilization, when the embryo is burrowing into the highly thickened endometrium, every cell in the embryo is exposed to the toxin, resulting in every cell in the body so altered.
In any case, there is a possibility that ovaries and testes may have mutations when there are none elsewhere in the body, and still be caused by toxins. Toxins can pool by gravitational force during sleep in the nether regions of the body, causing infertility and sexual problems, in addition to other symptoms like pelvic infections, urinary tract infections, hemorrhoids, incontinence, diarrhea, constipation, poor repair after giving birth, etc. These toxins can cause damage while en route to the gonads. Local damage repair could erase any mutagenic result, leaving the only traces of this damage in areas where the toxins do pool.
Genes vs. Environment
Since autism appears to result from something happening during the period of most brain development, most people assume that some genetic program must be the problem (also assuming that all brain differentiation is completely dependent upon that genetic program, which has never been shown in any experimental test). However, another way to look at this is to suspect that any mutated genes associated with autism are only expressing themselves in brain tissue and not anywhere else. Why? If the autism genes were expressed in other tissues, we would see other symptoms appearing later in all autistic children, which might also appear in some other children or adults who were only exposed to the same toxin later in life, after most of brain development has finished. There are enough symptomatic differences among autistic children that many of these comorbid symptoms may or may not be tied to the same genes associated with the disorganization of the brain in children with autism. The complexity of symptoms associated with autism suggests a complex cause.
Autism research, it seems, suffers from the inability to consider that all “causes” have to be controlled in both experimental and observational studies. In other words: if you do not look for a cause, you are not going to find it. Finding a strongly-associated gene is not finding the cause. I discuss the evidence concerning a cause of autism proposed by many are vaccines with mercury (thimerosal) in them in my blog post The Problem with Vaccines. Medline Plus (2014, Sept 8) does mention mercury as a possible cause of autism. However, most studies looking for strong associations between vaccines and autism have yielded negative results. This doesn’t mean that there is no association, however, because none of these studies control for every possible effect.
There have been attempts (Rzhetsky et al. 2014) to look for toxic exposures as a cause. Indeed, many of the comorbid symptoms of autism look a lot like the neuropathy that can result from exposure to mercury and other neurotoxins. This study of the incidence rates of Autism Spectrum Disorder and of Intellectual Disability (often suspected in the past of being related because of similar symptoms) found a high association of autism (as well as intellectual disability) with congenital malformations in males, which are often associated with toxic exposure (pesticides, lead, sex hormone disrupters, drugs, plasticizers, and dioxin). However, autism differs from intellectual disability in the former’s strong association with genes governing similar functions (Parikshak et al. 2013).
Rzhetsky et al. (2014) also found associations with state-mandated “rigor of diagnosis” of autism by a health care professional when a child was being considered for enrollment in a special education program, suggesting that a significant portion of the rise in autism diagnoses may result from these mandates.
Autism in Utero?
Lois Salter (2014) presented unpublished findings of a study of ultrasound scans of fetuses that were diagnosed postnatally with autism. When compared with normal children, these fetuses showed more rapid growth in head and body at the 20 week mark, well into the second trimester. The study was presented in July 2014 at the International Congress of the Royal College of Psychiatrists. A report and interview on this conference talk suggest that ultrasound scans may be helpful in diagnosing autism earlier (WebMD), but one might also suspect that autism may result from something that happens before birth.
Some have wondered if the genetic plan for brain organization was disrupted long before the parents start to see the first symptoms between the ages of two and four years. Stoner et al. (2014) examined autopsies of brains of children known to have autism, comparing them with brains of non-autistic children of the same age (2-15 years age at death). They found that autistic brains had widely distributed patches of poor development in the highly regulated formation of the layers of the neocortex in the prefrontal lobe (the area most affected by autism). These layers showed poor connections with other layers and between columns of neocortical cells.
Because much of the plan for the development of the highly organized neocortex is executed during the second trimester of fetal life, Stoner et al. (2014) concluded that autism may start to appear before birth. They also concluded that the damage was different from that seen in intellectually disabled brains, in that ten of 11 autistic brains had damage in clearly functionally-related areas strongly tied to suspected autism-risk genes (Parikshak et al. 2013). The damage in intellectually disabled brains was much more diffuse and not consistent across individuals. An excellent review of this paper, along with a video showing the method used was presented by Medical News Today (2014).
Reconciling Observations with Theory
There are several important observations to make about the Stoner et al. (2014) study. Dr. Stanley Nelson, interviewed about the implications of this study by NPR, mentioned that the researchers only found bits of tissue in the cortex showing this disorganization and wondered, “Why is the whole cortex not disorganized?” He also wondered how ten of the 11 autistic brains showed the same damage when there are so many different genes associated with autism. The fact that the damage is so consistent in ten of the brains also argues for an origin in fetal life when environmental influences are supposedly controlled better than in post-natal life. There is a realistic assumption that uterine environments are more similar across a population than post-natal environments.
The sample size is very low, and the uniformity of brain disorganization morphology may represent a common environmental cause, especially if the brains all came from the same region of the country. No one has mentioned anything about the geographic origin of the brains. The “spottiness” of the damage looks a lot like what we would expect to see if a toxin was “sprayed” across the frontal lobe in a fashion that might occur if it had entered the brain case through the eyes and ate through the dura mater, dripping onto the developing brain through holes in that tough, dense connective tissue. However, if the fetus were exposed to such a dangerous toxin while still in utero (the place where, these researchers all suggest, any causative event would have had to happen), there probably would have been many obvious defects elsewhere in the body.
It is unlikely, although not impossible, that a toxin could have interacted chemically only with vulnerable cells in the developing brain. This means that it could not enter the embryo via the blood vascular system, either because it destroys its only entry way, the capillaries, or because it cannot cross the epithelial membrane that makes up the lining of all blood vessels. Because of the extra layers of protection of the fetus, it is highly unlikely that any toxin could enter the body through any route other than the circulatory system. At this time period when the brain is starting to form the neocortical organization, the beginning of the second trimester, the skull has formed a cartilaginous membrane around the brain and begun to ossify small centers of the major skull bones, frontal, parietal, and occipital bones (Sadler 2004), and thus, has no very hard tissue through which a toxin from outside the fetal body would have to penetrate. If the toxin could damage the meningeal membranes, it could also damage blood vessels and any other epithelium. Thus, it is still extremely difficult to understand how massive damage to the embryo would not have happened at the same time as toxic cortical damage.
All of the above discussion assumes that the damage to cortical organization happened in utero, as Stoner et al. (2014) assume. It would be extremely difficult to show that this is the case, unless an animal model of autism could be tested by inserting many, if not all, of the genes associated with autism into an egg and sperm, with subsequent fertilization and implantation showing that the presence of the genes seems to determine signs of autism, and that it was possible to induce autism in utero.
Stoner et al. (2014) suggest that, because research has shown that the brain can re-wire itself around damaged areas, catching signals of autism in utero may allow us to create methods for children to form the workarounds needed to develop normally. Indeed a program described in the recent NOVA episode, “Vaccines: Calling the Shots” showed how all signs of autism may be able to be overcome with early intervention.
Given that the brain has an ability to repair damage, especially early in life, we cannot rule out the possibility that the same kind of second trimester neocortical organization can be developed after birth during the period of time when the most neocortical development occurs. Indeed, we have reason to suspect that this occurs for the simple reason that the neocortex undergoes rapid mitotic activity after birth as well, creating new areas for cortical reorganization that would mimic what happened before birth. The “spottiness” of the cortical disorganization so noted by Stanley in the NPR interview might be in areas where the rapid expansion of the neocortex during the first three years of life in “spots” of mitotic activity and secondary organization into the recognized layers and columns of cells as prominent features of neocortical morphology. In this way, an environmental cause of autism could cause spotty distribution of disorganized neocortex.
Brauser, D. (2014, June 27). Routine ultrasounds may detect autism in utero. Medscape Medical News, WebMD.
Hallmayer, J. Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T. . . . Risch, N. (2011). Genetic heritability and shared environmental factors among twin pairs with autism. Archives of General Psychiatry, 68(11), 1095-1102. [Freely Available].
Hamilton, J. (2014, March 26). Brain changes suggest autism starts in the womb. All Things Considered, NPR.
McNamee, D. (2014, March 27). Autism begins in the womb, according to a new study. Medical News Today.
Medline Plus (2014, Sept 8). Autism. U. S. National Library of Medicine & National Institutes of Health.
Ozonoff, S., Young, G. S., Carter, A., Messinger, D., Yirmiya, N., Zwaigenbaum, L. . . . Stone, W. L. (2011). Recurrence risk for autism spectrum disorders: A baby siblings research consortium study. Pediatrics, 128(3), e488-e495. [Freely Available].
Parikshak, N. N., Luo, R., Zhang, A., Won, H., Lowe, J. K., Chandran, V. . . . Geschwind, D. H. (2013). Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell, 155(5), 1008-1021. [Freely Available].
Rzhetsky, A., Bagley, S. C., Wang, K., Lyttle, C. S., Cook, E. H., Jr., Altman, R. B. & Gibbons, R. D. (2014). Environmental and State-Level Regulatory Factors Affect the Incidence of Autism and Intellectual Disability. PLoS Computational Biology, 10(3), e1003518. doi:10.1371/journal.pcbi.1003518 [Open Access]
Sadler, T. W. (2004). Langman’s medical embryology, Ninth Ed. Baltimore, Md: Lippncott, Williams & Wilkins, p. 172.
Salter, L. (2014, June 27). The role of routine foetal anomaly ultrasound scans in detecting autism in utero. International Congress of the Royal College of Psychiatrists. p. 14.
Stoner, R., Chow, M. L., Boyle, M. P., Sunkin, S. M., Mouton, P. R., Roy, S., … Courchesne, E. (2014). Patches of disorganization in the neocortex of children with autism. New England Journal of Medicine, 370(13), 1209-1219.
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