Dr Deth's lab was the first to identify the D4 dopamine receptor, which has unusual structural features and
properties related to methylation.
When dopamine stimulates this
receptor it causes methylation of the phospholipids in the membrane. He got involved in autism research when Dr Martha Herbert, an autism expert from Harvard Medical School, saw this research and told
him that this was of interest to the autism community.
What is methylation?
The word “methyl” refers to a single carbon atom that can be transferred
from one molecule to another. The molecule
that receives the carbon atom is said to have been “methylated”. Methylation is a process that is so common that it affects nearly every aspect of cellular metabolism and function. It seems that poor methylation is a
fundamental issue in autism. Kids with
autism tent to have low levels of methyl donors, and many respond well to supplementation with methyl B12 (mB12). Of the 6 types of B12 in the
body, methyl B12 is the active form for methylation. Post-mortem studies have found that the levels of B12 are low in the brains of people
with autism. In order to address this, cells need to have access to enough B12 and also have enough glutathione that they can convert B12 to its active form (too much oxidative stress inhibits this process). This
way the cell can decide what is the best form and how much of different forms
to make. There is an assay now that can
measure the levels of the 6 forms of B12 in the body, but brain levels can only be measured post-mortem.
Post-mortem studies have found levels of mB12 in
the brains of kids with autism at about 25% of what they should be. This suggests that there is a
problem with the transport systems that bring B12 into the brain, which is a poorly understood process. B12, along with many other nutrients and products in the blood, is brought into the brain through a structure called the Choroid Plexus. These structures, one in each of the 4 ventricles of the brain, are part of the blood-brain barrier (BBB) and selectively transport certain nutrients and other things from the blood into the cerebrospinal fluid (CSF). There are certain proteins that attach to B12 and other things and actively carry them across the BBB. Dr Deth is currently studying this process to understand better how this process works.
Dr Deth's research directly shows that heavy metals such as mercury and lead interfere with methylation, which has led to him testifying in front of congress on the issue of vaccine safety, as well as testifying as an expert witness in the federal vaccine court. He says that since then, the science has further validated this hypothesis and has fleshed out much of the specific details of how this interference occurs. In particular the growing field of epigenetics has shed a lot of light on this connection. Epigenetics is the study of how genes are turned on and off to regulate biological function and development, and this regulation of gene activity is controlled by methylation. Epigenetics is the mechanism that orchestrates development, from the moment of conception throughout our lives, including development of the brain. So if something interferes with methylation it can profoundly interfere with the process of development.
Epigenetics is what links the environment and exposures that we get to our genetic
expression. Environmental factors
impinge on anti oxidant status, which then impinges on methylation, and
methylation *is* development.
Environmental factors include mercury, lead, RoundUp, pesticides, etc. Genes influence a person's risk of being
harmed by these environmental factors, but the genes themselves are not the "cause" of the autism (in most cases). Among many researchers there is a
predetermined certainty that autism must be genetic so they keep looking for the genes over and over despite the lack of results.
Sample sizes of 10,000 genomes have not turned up any consistent findings, and these researchers then say they just need a larger sample size- maybe 50,000 genomes. Yet you can look at 30 to 50 kids with autism and measure their glutathione
levels and find marked differences in these kids. This finding (of low glutathione) happens all
over the world, wherever autistic kids are studied. What are the factors leading to the low
glutathione, which then causes poor methylation and epigenetic problems during development?
Understanding of autism causality is moving
away from a “single agent” hypothesis to a complex interplay between susceptibility to injury and exposure to multiple contributing factors. Early theories that mercury and thimerosal
were involved are still true, and pointed to a mechanism of causality that is
very complex and which has been validated and is now better understood. Now that we know the mechanism, we can see
how other factors also come into play. When gluten and casein are digested, they result in peptides with opiate
activity, and research has shown that these peptides interfere with the uptake of cysteine from the GI tract. Cysteine is necessary for cells to produce glutathione- availability of cysteine is what determines how much glutathione is made. This results in oxidative stress and damage to the DNA, via poor methylation.
What is oxidative stress?
Oxidation is the ability to use electrons that we get from food to make energy. As we metabolize nutrients in our food, our mitochondria use the process of oxidation to make ATP, which is our source of energy. They do this by converting oxygen to water. About 3 to 5 percent of the oxygen molecules
that go through this process, instead of becoming water, become other oxygen species
and are able to oxidize other biological molecules that we don’t want to be
oxidized. ReDox balance
is a balance between oxidation molecules and anti-oxidant molecules. Oxidative stress is the condition of having
too many oxidizing molecules and not enough anti-oxidant molecules. Oxidation damages various proteins and even
DNA. In 2008, Dr Deth published a paper called “The Redox Methylation Hypothesis of Autism”, in which he laid out the connections between the pathways that make
anti-oxidants and the pathways that support methylation. In response to oxidative stress, the body can
down regulate methylation to restore balance. Methylation can help to heal some of the damage to DNA via changing gene
expression, but this is not always enough. Autism is a spectrum because when methylation
goes wrong, it affects so many areas of the body, and we each have our own
genetic variability so we will each show this damage a bit differently. Each person must receive treatment tailored
to them as an individual.
The dopamine D4 receptor is critical for attention. Dopamine and D4
receptors can synchronize different neural networks that might otherwise not be
synchronized together, and to tune their frequency of activity. Frequency is how fast the neurons are
firing. Higher frequencies are more
metabolically demanding. When you are
attending to something, dopamine and the D4 receptor make the circuits involved in what you are paying attention to shift to a higher frequency,
the gamma frequency, which is 30-80 hz. The D4
receptors are located in certain cells in the brain called parvalbumin
expressing GABAergic interneurons. Those
cells develop post-nataly as the individual's capacity for attention develops. By 4 to 5 months of age babies begin to be able to
pay attention to things. Problems
with methylation could affect attention through this process. Certain mutations in the gene for the D4 receptor is the biggest
risk for developing ADHD. When asked if this connection between the parvalbumin expressing intern neurons and the ability to pay attention could suggest that people of higher intelligence are more at risk for developing autism, Dr Deth explains that once you correct the
underlying metabolic problems in autism the person's actual intelligence can become revealed. He goes on to explain his theory that people who are at
the highest risk form environmental induced neurodevelopmental injury are
people whose genes are poised for intelligence, but intelligence in the brain
is a risky undertaking, making the cells are more vulnerable. It’s a trade-off. These are more likely to suffer from an
environmental injury. The parvoalbumin
cells are the most sensitive cells because their high firing rate means that they have a high metabolic rate, which means that they create more damaging oxidative byproducts (also called reactive oxygen species). (My thoughts here- this also means that these cells are more dependent on mitochondrial function so may be more sensitive to mito dysfunction).
Dr Deth has written a book called Molecular Origins of Human Attention in which the role of dopamine and D4 receptors is more fully explained.
Additional papers by Dr Deth that discuss methylation and redox imbalance in autism:
"Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks."
"While autism is still a mysterious developmental disorder, expansion of research efforts over the past 10 to 15 years has yielded a number of important clues implicating both genetic and environmental factors. We can now assert with a measure of confidence that contemporary autism reflects the combined impact of multiple environmental factors on the processes that regulate development in genetically vulnerable individuals. Since epigenetic regulation of gene expression is acknowledged as the most critical factor in development and DNA methylation (the addition of a carbon atom at discrete locations) is the fundamental event for epigenetic regulation, dysfunctional methylation can be considered as a likely cause of autism. Since methylation activity is highly sensitive to oxidative stress (an abnormal redox state) and many environmental factors promote oxidative stress, we have proposed a redox/methylation hypothesis for autism causation. The narrative herein describes the evolution of this hypothesis, which is essentially a series of linked discoveries about how the brain uniquely relies on oxidation and methylation to guide its development and to carry out its cognitive functions."
