Antabine (Anatabloc) and Autism - a Supplement or a Drug?

This is another post prompted by a comment received on this blog.

My 15 year-old daughter has classic regressive type ASD. I started her on an anti-inflammatory, Anatabloc, over a year ago and it allowed me to take her off atypical anti-psychotics ( she was on them for aggression) Do you know anyone else using this dietary supplement?  

I found this very interesting and so I did some quick research.

Anatabloc was until very recently sold in the US as a supplement, it was withdrawn from sale by the producer following a corruption trial and a dispute with the FDA over approvals.  Nobody is saying the supplement does not work, rather it is a drug.

Anatabloc, supplement at center of McDonnell trial, to be taken off the market

Anatabloc

Anatabloc was sold as an anti-inflammatory supplement based on a substance called Anatabine, found in tobacco and in lower concentrations in green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes.

Anatabine has been studied in animal models and in cells to see if it might be useful for treating nicotine addiction and inflammation, and has been studied in models of diseases characterized by inflammation, such as Alzheimer's Disease, thyroiditis, and multiple sclerosis.

On a biochemical level, it appears to be active against certain nicotinic acetylcholine receptors.

Regular readers will recall extensive earlier posts on the cholinergic system and nicotinic acetylcholine receptors.

IBS, IBD and Autism, leading to Cholinergic Signaling and the Vagus Nerve

Nicotine Patches -Autism, Alzheimer's and MCI

Biomarkers in Autism: The Cholinergic system – In need of caffeine & nicotine or maybe just choline

The conclusion of all those posts was that, most definitely, in some people’s autism, an effective strategy is to adjust the cholinergic system.  Possible methods include:-

·        Vagus nerve stimulation – still in development

·        Nicotine patches – cheap and effective in some people

·        Two Alzheimer's drugs Donepezil and Galantamine, that are acetylcholinesterase inhibitors

So at first it seemed that Anatabloc may be “just another” cholinergic drug.  However on analyzing the patent submitted by the producer, it seems there may be an alternative mode of action.

Patent for Antabine use in Autism

METHODS OF ADMINISTERING ANATABINE TO TREAT AUTISM SPECTRUM DISORDERS AND SEIZURE DISORDERS

32| Anatabine is an alkaloid present in tobacco and, in lower concentrations, in a variety of foods, including green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes. Without being bound by this explanation, data presented in Examples I and 2 below indicate that anatabine reduces transcription mediated by nuclear factor B (NFKB). NFKB is a transcription factor which operates in cells involved in inflammatory and immune reactions.

The nuclear factor NF-κB pathway

NF-κB is seen as being clinically significant in cancer and inflammation.

The NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules.  

NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs.

Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others. It is important to note though, that elevation of some NF-κB inhibitors, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.  Elevated NF-κB has also been associated with schizophrenia.

I take the, perhaps unconventional, view that schizophrenia is adult-onset autism.  It has already shown that in terms of genetics, there is a great overlap between these two conditions.

The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia.

CONCLUSIONS:

Schizophrenic patients showed activation of the cytokine system and immune disturbance. NF-kappaB activation may play a pivotal role in schizophrenia through interaction with cytokines

The Nuclear Factor NF-κB Pathway in Inflammation

Abstract

The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-κB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway. NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease. In this article, we discuss the role of NF-κB in inflammation in light of these recent studies.

Clinical trials using Anatabloc

The producer behind Anatabloc is well advanced with clinical trials, as you can see below.

http://clinicaltrials.gov/ct2/results?term=anatabloc&Search=Search

I suspect that Anatabloc will disappear as a supplement and reappear a few years later on as an FDA approved drug for various conditions.

Conclusion

It is a pity that Anatabloc has been taken off the market.

It looks plausible that it could be effective in other people’s autism, not just the reader of this blog.

For the time-being, other than taking up smoking, a good source would be those tasty sun-dried tomatoes.

P.S.


Having re-read this post and taken a closer look at the patent and the company, I wonder if the original comment is genuine.  The patent is not very convincing and in Table 1 on page 44 it is quoting Wakefield et al, as one of only two sources that link inflammation to autism.  I could have written a much better patent application myself.

Adaptive Behavior and Autism

Today’s post is rather off subject, since it is not about GABA or complex pathways mainly researched for cancer.  It is about struggling to put on your shrunken socks, that shirt that was left inside out, or finishing your Lego by yourself.

Adaptive Behavior / Coping Skills

Most people never need to think about adaptive behavior; it just comes naturally.  When adaptive behavior is very weak, then daily life becomes a challenge.

Adaptive behavior is a type of behavior that is used to adjust to another type of behavior or situation.  Adaptive behavior reflects an individual’s social and practical competence of daily skills to meet the demands of everyday living.

Adaptive behavior is often measured by psychologists using the Vineland Adaptive Behavior Scale .

This post looks as adaptive behavior and some ways to improve it.

What prompted this post was a recent post on the excellent Simons Foundation blog:-

In fragile X syndrome,coping skills decline with age

Fragile X is rare, but is associated with autistic behaviors and often MR. It is viewed as the most widespread single-gene cause of autism.  Fragile X is frequently used by autism researchers because there is a mouse model of it.

In fact what the study showed was that the acquisition of coping skills in fragile X is much slower that with typical children and as they get older, the wider the gap becomes.  They do not lose their existing coping skills with age.  This fits perfectly with how Deborah Fein, my favored Neuropsychologist, describes skill acquisition in autism. 

Her chart below is actually more optimistic than how she actually describes it.

It is from an excellent lecture video  available from the MIND Institute

She is just past half way down the long list of lectures.

Fein’s small “recovered” group has a spurt of development that allows them to catch up. This is extremely rare, but evidently can happen.

By interfering with Nature’s chosen path, as is the objective of this blog, we should be able to change the trajectory of skill acquisition.  

  

ABA and Adaptive Behaviours

One of the good things about the ABA approach is that it includes, and indeed prioritizes, developing adaptive behavior, in the form of daily living and self-help skills and developing fine and gross motor skills.  

The “bible” of skills to teach is “The Assessment of Basic Language and Learning Skills - Revised (ABLLS-R)”, when starting with a young, non-verbal child, the document is extremely daunting.  But looking back, it really does have all the key skills and what order to teach them.

People only slightly familiar with ABA might think that it is the opposite of “adaptive”, since ABA is teaching you to follow exact rules and instructions.  So what happens when the situation is slightly different? Then what?

Some of these situations are predictable, like what to do when you are brushing your teeth and the toothpaste tube is empty.

The options might include:-

1.     Start screaming
2.     Give up
3.     Ask for help
4.     Brush with water alone
5.     Find a new tube of toothpaste

I think that the early emphasis on fine/gross motor skills helps the brain develop pathways that can later be used for more complex processes.  So insisting on learning to catch a ball, control a pencil, stack colored block in order is much more important than it may seem.

ABA may be teaching the brain to structure itself, which may be a pre-requisite for it to become more adaptive later on.

 

Motor skills and adaptive behavior skills in children with ASD

Thanks yet again to funding from the Simons Foundation, the following study looks at just this very subject.  The abstract is rather better laid out than the copy of the full version that I managed to locate.

The relationship of motor skills and adaptive behavior skills in young children with autism spectrum disorders

Abstract

Objective

To determine the relationship of motor skills and adaptive behavior skills in young children with autism.

Design

A multiple regression analysis tested the relationship of motor skills on the adaptive behavior composite, daily living, adaptive social and adaptive communicative skills holding constant age, non-verbal problem solving, and calibrated autism severity.

Setting

Majority of the data collected took place in an autism clinic.

Participants

A cohort of 233 young children with ASD (n = 172), PDD-NOS (n = 22) and non-ASD (developmental delay, n = 39) between the ages of 14–49 months were

recruited from early intervention studies and clinical referrals. Children with non-ASD (developmental delay) were included in this study to provide a range of

scores indicted through calibrated autism severity.

Interventions

Not applicable.

Main outcome measures

The primary outcome measures in this study were adaptive behavior skills.

Results

Fine motor skills significantly predicted all adaptive behavior skills (p < 0.01). Gross motor skills were predictive of daily living skills (p < 0.05). Children with

weaker motor skills displayed greater deficits in adaptive behavior skills.

Conclusions

The fine and gross motor skills are significantly related to adaptive behavior skills in young children with autism spectrum disorder. There is more to focus on and new avenues to explore in the realm of discovering how to implement early intervention and rehabilitation for young children with autism and motor skills need to be a part of the discussion.

Full Text is Here

Fine and gross motor skills were predictive of those important adaptive/living skills.

Does this mean that by improving fine/gross motors skills you will improve adaptive/living skills? This comes to the recurring issue of correlation and/or causality.  Since this my blog, we can apply that overriding factor which is “common sense”, and say yes, in most cases, it will.

Our Experience of Adaptive Behavior

After a few years of ABA, adaptive behavior did gradually improve, albeit from a baseline of near zero.

It is clear from the literature that some children do not respond to ABA; I think it is really a case that they do not respond to anything.  In these children overcoming the biological origin of their autism is a prerequisite for meaningful progress.

It is also likely that the earlier a biological intervention is made the better the final outcome.  Typical kids can spend twenty years in education and so the more time an autistic child has in full time education with a “re-tuned” brain the better.  Adaptive behavior typically emerges/develops from birth to early childhood, a time when many with ASD are not “present”. 

If you can progress with ABA, then additionally treating the biological dysfunctions should boost the learning trajectory.

Only recently though did I start to observe some spontaneous developments.  Getting dressed after swimming, when your feet are still a little damp, it can be hard for anyone to put their socks on, so I am really pleased that Monty, aged 11 with ASD, now manages all by himself.

In the not too distant past, untangling his inside out jeans, re-attaching the half detached belt would have been the source of great frustration.  You could use ABA to train somebody to untangle their jeans and thread their belt neatly, but we never did.  This he is figuring out all by himself.

Another recent example is his latest Lego model.  We are big Lego fans, but in the earlier times Monty was more interested in “crashing” his Lego than playing with it.  It was a case of build it, crash it and then somebody else look for all those tiny pieces. 

His latest toy plane has extremely fiddly little stickers that you have to stick on the bricks.  If you do not get them lined up nicely, you have to pull them off and start again.  It really is a test of both fine motor skills and patience.

So I was assuming that when Monty came to the stickers, either he would not bother or he would ask for help.  But no, he just said “stickers” and stuck them on.

Things are definitely changing for the better.  

Tics, Ticks, Autism - Wnt signaling & PAK1

I was interested to receive a comment from a reader of this blog who finds that the anti-parasite drug Ivermectin has a major impact on her child’s  autism, debilitating tics and OCD (Obsessive Compulsive Disorder).

Regular readers may recall that when looking at so-called PAK1 inhibitors, which look like the Holy Grail for both common cancers and autism, it turned out that two already exist.  One is an old anti-parasitic drug called Ivermectin and the other is a substance found in certain types of bee propolis from Brazil and New Zealand.

It then turned out that a handful of “alternative” practitioners in the US are already using Ivermectin for autism, but for entirely different reasons.  They believe that various parasites exist inside the children and cause/exacerbate autism.

I thought this was intriguing and quite likely another case of “the right therapy, for the wrong reason”.

Tics and Ticks

Tics are those sudden, repetitive involuntary actions that can vary from annoying to debilitating.

Ticks are tiny parasites that like to attach themselves to your skin, they can fall from trees/bushes or attach themselves to skin as you pass through long grass. Some ticks carry Lyme Disease.

Tics are common in autism, PANDAS, PANS and many forms of OCD (Obsessive Compulsive Disorder).

It seems that some “alternative” practitioners in the US are treating PANDAS and PANS on the assumption that it is caused by Lyme Disease.  Others are recommending “de-worming” for autism, on the assumption that intestinal parasites are to blame.

Here is a link to somebody writing about these alternative practitioners, for those who are curious.

My take

This all sound highly odd to me, partly because it seems that you have to keep taking the de-worming tablets for the long term.  With regular mild parasites found in developed countries, drugs therapy can eliminate the parasites.  In some tropical climates more aggressive parasites exist that are almost impossible to eradicate 100%.

So regular de-worming of humans in the United States, in 2014, sounds bizarre.

On the other hand, you cannot dispute when somebody finds their child’s tics and OCD have disappeared with the de-worming therapy and that they return when the therapy stops.

Is it, as I suggested in the early posts, that the PAK1 inhibiting properties of Ivermectin are behind its effect?  Hopefully yes, but I am not sure.  So I will take a look at Ivermectin and see if it has any other properties that could impact autism, tics and OCD.

Ivermectin - not just for your dog

Most people would only come across Ivermectin at the vet, but there is much more to it.

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Discovered in the late-1970s, originating solely from a single microorganism isolated at the Kitasato Institute, Tokyo, Japan from Japanese soil, Ivermectin has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found.

The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms. The disease causes visual damage for some 1–2 million people, around half of who will become blind.

Lymphatic Filariasis, also known as Elephantiasis, is another devastating, highly debilitating disease that threatens over 1 billion people in more than 80 countries. Over 120 million people are infected, 40 million of whom are seriously incapacitated and disfigured. The disease results from infection with filarial worms

Modes of Action

Let us look at the various modes of action proposed for Ivermectin.

1.     GABA

Initially, researchers believed that Ivermectin blocked neurotransmitters, acting on GABA-gated Cl⁻ channels, exhibiting potent disruption at GABA receptors in invertebrates and mammals.

In mammals the GABA receptors occur only in the central nervous system (CNS), i.e. in the brain and the spinal cord. But mammals have a so-called blood-brain barrier (BBB) that prevents microscopic objects and large molecules to get into the brain. Ivermectin, while paralyzing body-wall and pharyngeal muscle in nematodes has no such impact in mammals.  Consequently Ivermectin is much less toxic to mammals than to parasites without such a barrier, which allows quite high safety margins for use on livestock, pets and humans.

2.     Glutamate

Subsequently, researchers discovered that it was in fact glutamate-gated Cl⁻ channels (GUCl⁻) that were the target of Ivermectin and related drugs.

3.     Reversing Immunosuppression

The growing body of evidence supports the theory that the rapid parasite clearance following Ivermectin treatment results not from the direct impact of the drug but via suppression of the ability of the parasite to secrete proteins that enable it to evade the host’s natural immune defence mechanism.

Researchers discover how key drug kills worms in tropical diseases

In a major breakthrough that comes after decades of research and nearly half a billion treatments in humans, scientists have finally unlocked how a key anti-parasitic drug kills the worms brought on by the filarial diseases river blindness and elephantitis

Regular readers will recall that a beneficial parasite therapy in inflammatory diseases is the TSO worm.  This worm also modulates the host’s immune system so as not to be ejected.  This calming of the over activated immune system appears to be beneficial in several conditions and possibly autism.

4.     Inhibitor of Wnt-TCF Pathway

Recent cancer research has shown the Ivermectin has a highly unexpected property; it can block a pathway called Wnt-TCF on which many cancers are dependent.

The river blindness drug Ivermectin and related macrocyclic lactones inhibit pathway WNT-TCF responses in human cancer

Wnt signaling is also a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS), in other words oxidative stress, known to cause DNA and cellular damage.

Perhaps aberrant Wnt signaling is involved in the mechanism of autism?

Well it appears to be the case.

Role of a novel Wnt pathway in autism spectrum disorders

The canonical Wnt signaling pathway in autism.

 Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism.

5.     Inhibitor of PAK1

We already know from earlier in this blog, that Ivermectin is a PAK1 inhibitor.  Blocking PAK1 should prevent several common cancers, according to researchers at MIT, who also suggest that autism cannot occur without PAK1.\

Not entirely surprisingly, if you look into the cancer research you will see that PAK and WNT are interrelated.

p21-Activated kinase (PAK) interactswith Wnt signaling to regulate tissue polarity and gene expression

Wnt signaling is mediated by three classes of receptors, Frizzled, Ryk, and Ror. In Caenorhabditis elegans, Wnt signaling regulates the anterior/posterior polarity of the P7.p vulval lineage, and mutations in lin-17/Frizzled cause loss or reversal of P7.p lineage polarity. We found that pak-1/Pak (p21-activated kinase), along with putative activators of Pak, nck-1/Nck, and ced-10/Rac, regulates P7.p polarity. Mutations in these genes suppress the polarity defect of lin-17 mutants. Furthermore, mutations in pak-1, nck-1, and ced-10 cause constitutive dauer formation at 27 °C, a phenotype also observed in egl-20/Wnt and cam-1/Ror mutants. In HEK293T cells, Pak1 can antagonize canonical Wnt signaling. Moreover, overexpression of Ror2 leads to phosphorylation of Pak1. Together, these results indicate that Pak interacts with Wnt signaling to regulate tissue polarity and gene expression.

So there at least five possible effects that Ivermectin can have.

Too much Ivermectin is not good

According to the literature in the developing world, there are 200 million people (http://onlinelibrary.wiley.com/doi/10.15252/emmm.201404084/abstract) currently taking Ivermectin, which is provided free for river blindness; some of those have been using the drug for over 20 years - so much is known about it.

It is suggested that at excessive doses, Ivermectin starts to cross the BBB and then affects the neurotransmitter GABA.  Ivermectin stimulates the release of the GABA in the presynaptic neurons and enhances its postsynaptic binding to its receptors. This increases the flow of chloride ions in the neurons, which causes hyperpolarization of the cell membranes. This on its turn disturbs normal nervous functions and causes a general blockage of the stimulus mechanisms in the CNS. The resulting cerebral and cortical deficits include mainly:

• Ataxia (uncoordinated movements)
• Hypermetria (excessive or disproportionate movements)
• Disorientation
• Hyperesthesia (excessive reaction to tactile stimuli)
• Tremor (uncoordinated trembling or shaking movements)
• Mydriasis (dilatation of the pupils); in cattle and cats also myosis (contraction of the pupils)
• Recumbency (inability to rise)
• Depression
• Blindness
• Coma

So, too much Ivermectin is not a good idea.

So why is Ivermectin good for Tics, OCD and Autism?

At low doses Ivermectin does not cross the BBB (blood brain barrier), but in autism it appears that the BBB can be more permeable than it should be.  So possibly Ivermectin produces an increase in GABA, like that caused by Valproic Acid.  Some people with autism find Valproic Acid very beneficial.

Perhaps those glutamate-gated Cl⁻ channels (GUCl⁻) play a, yet unidentified, role in autism.

Or, perhaps we got it right and PAK inhibiting property is what matters. 

Perhaps being an PAK1 inhibitor will also make it a Wnt inhibitor, or maybe not, worth checking though?

Perhaps the MIT guys got it wrong and it is Wnt rather than PAK that we should be focused on? 

I hope the blog reader that prompted this post does indeed give the bee propolis a go and see if it has the same effect as Ivermectin.

Cancer

Having said in an earlier post that I will not try and out-smart the cancer researchers, I will just say that the extremely cheap drug Ivermectin does seem to have some potent anti-cancer properties.  

I know that cancer drugs are supposed to be hugely expensive.

An earlier post mentioned Ivermectin’s positive effect on Leukemia, but it seems that the WNT-TCF Pathway is involved in very many cancers.  This is not to mention that just being a PAK1 inhibitor should be enough to prompt further interest.

Conclusion

Well it looks like Dr Wu and Dr Klinghardt have indeed got the therapy right, but I believe for entirely the wrong reasons. By promoting themselves via organisations like Autism One, they are almost guaranteed to be ignored by mainstream doctors and researchers. The therapy will therefore remain on the fringe, with the quacks and cranks.

From my perspective, what really matters is whether a therapy works.  We can always later on figure out why it works.  So thank you Dr Wu and Dr Klinghardt.

GABA’s role in Neurodevelopment – Oxytocin and Bumetanide

This is a very brief post to direct those of you interested in the role of GABA, the neurotransmitter, towards a very recent open access review paper by Ben Ari.

In particular, people considering Oxytocin or Bumetanide to treat autism may find it interesting.

The GABA excitatory /inhibitory developmental sequence: a personal journey

The Knudson Multiple Hit Hypothesis in Cancer, leading to the emerging Peter Multi-Mutation Matrix Theory of Autism

  

In Autism the more complicated research and emerging diagnostic tools seem mainly to relate to things like genes and CNVs (Copy Number Variants).  To understand this in detail, a PhD in genetics might be helpful; but once you realize that nobody fully understands this emerging area of science, we may still be able to draw some usable insights, that have not been noticed by the autism research community.

The focus of research is on cancer; autism remains in a backwater.  However, what research there is on autism and genetics does seem to show rather more overlap with the mechanisms and pathways seen as being behind cancer than you might have expected.  This, combined with the very odd sounding finding by that Nobel Laureate at MIT, that neither cancer nor autism can develop without the presence of a substance called PAK1, makes me interested to look at the cancer research.

Then you notice after only a few minutes of research, that there are numerous instances where cancer and autism share common “abnormalities”, including:-

·        PTEN a protein that is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers. PTEN acts as a tumor suppressor gene.

·        Tumor protein P53, known as the “guardian of the genome" because of its role in conserving stability by preventing genome mutation.

We have the fact that in autism there are numerous abnormalities in various human growth factors, which again has overlaps with irregular cell mutation/proliferation in cancer.  These same growth factors are implicated in aberrant mTOR behavior, another target of cancer research.

In addition, two conditions involving tumors, often in the brain, are comorbid with autism, namely Neurofibromatosis and Tuberous Sclerosis Complex (TSC).

Can so many links in the mechanisms behind cancer and autism be coincidence?

While I do like to think of autism in terms of my earlier Venn diagram,

  

there will be another way to look at autism, which will look quite different.  It will be a list of genes whose function has been either been completely disrupted, partially disrupted or not affected. This matrix would then define a person’s unique autism phenotype.

It will be a long list of genes and so there will be many thousands of possible permutations, explaining why each person with autism seems to be unique.  When you have met a person with autism, you have done just that, met one person.  The next one will be distinctly different, but still be labeled autistic.

Some of these genetic abnormalities were rare “de-novo” mutations, other were inherited from the parents, some came from epigenetic disruption either in-utero, after birth, or indeed from earlier generations (we save seen how epigenetic changes can be passed through the generations).   This epigenetic change is the mechanism whereby the environment, what you eat, where you live and how you live, may affect both your genes and those of your successors.

As the number of mutations exceeds the adaptive capacity of the brain, then strange dysfunctions will appear.  When taken together, these dysfunctions appear as what we call “autism”.  Some single gene mutations are sufficient to produce autism, for others further genetic damage may be needed.

So the link with cancer seems to be about the control of mutations.

There are many very clever people whose working lives are dedicated to cancer research, so I doubt we will be able to out-smart them.

When it comes to autism research, I am much more optimistic that there are likely many unturned stones and unnoticed or lost connections.  So I expect there will be little gems among the PAK inhibitors, mTOR inhibitors etc.

Back to Cancer

Today’s post will not be complicated; it is more about common sense, a Finnish amateur historian and a thoughtful cancer researcher called Alfred Knudson.  Some variants of “their” cancer hypothesis are now being applied to autism.

First Came Nordling

The origins behind Knudson’s cancer hypothesis, rather surprisingly, come from the work of a Finnish architect with an interest in history and statistics, called Carl Nordling.

  

His multi-mutation theory on cancer was published in the British Journal of Cancer in 1953. He noted that in industrialized nations the frequency of cancer seems to increase according to the sixth power of age. This correlation could be explained by assuming that the outbreak of cancer requires the accumulations of six consecutive mutations.

A NEW THEORY ON THE CANCER-INDUCING MECHANISM.

Then Came Knudson

Later, Knudson performed a statistical analysis on cases of retinoblastoma, a tumor of the retina that occurs both as an inherited disease and sporadically. He noted that inherited retinoblastoma occurs at a younger age than the sporadic disease. In addition, the children with inherited retinoblastoma often developed the tumor in both eyes, suggesting an underlying predisposition.

Knudson suggested that multiple "hits" to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two "hits" had to take place before a tumor could develop, explaining the age difference.

It was later found that carcinogenesis (the development of cancer) depended both on the activation of proto-oncogenes (genes that stimulate cell proliferation) and on the deactivation of tumor suppressor genes (genes that keep proliferation in check). Knudson's hypothesis refers specifically however, to the heterozygosity of tumor suppressor genes. Simply proposing that a mutation in both alleles is required, as a single functional TSG is sufficient.

The Two-Hit Theory of Cancer Causation

Source: http://www.fccc.edu/research/research-awards/knudson/index.html

Now to Apply the Multiple Hit Model to Autism

In the case of cancer it has been found that for mutation to occur it is necessary for two genes to be activated/deactivated.  The first gene is activated and tells the cells to proliferate; the second gene that should be stopping the cells proliferating has to be turned off.  Both genes have to malfunction for cancer to be possible.

In the following, science heavy, autism paper they conclude that the data suggests a “Multiple Hit Model of Autism Spectrum Disorders”.

It also suggests that some of the gene mutations are doing damage, while other mutations are actually positive, trying to counteract the effects of the damaging mutations.

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

“Finally, our analyses suggest the interesting possibility that deleterious mutations of neuronal genes (e.g. SNTG2 and MYT1L) could potentially counteract the effect of synaptic deleterious mutations (e.g. SHANK2). The identification of risk and protective alleles within the same subject is one of the main challenges for understanding the inheritance of ASD.”

Coming back to the “easier” research, which comes from psychologists rather than geneticists, takes us to a paper about those people with autism who do not fare well during and after puberty.

A Two-Hit Model of Autism - Adolescence as the Second Hit

Abstract

Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a “first hit” that sets up a neural system that is “built to fail” in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the “second hit” that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence.

Double-tap Autism

Regular readers may recall a recent post about what I termed Double-tap autism.

The second tap was not adolescence, rather a viral infection in early childhood, occurring in someone with classic early onset autism.

Double-tap Autism – perhaps an important variant

The Peter Multi-Mutation Matrix Theory of Autism

There will of course have to be a Peter Multi-Mutation Theory of Autism and it will necessarily have to include therapeutic implications.  Hopefully, it will show that once sufficient mutations have been pharmacologically countered, the adaptive capacity of the brain may be able to overcome those that are left.

It does appear from the research that some mutations are occurring to counter the effect of the damaging mutations, perhaps in a form of self-repair process.

To establish exactly what has happened in any individual the best way would seem to be through proteomics, which is the science surrounding how genes produce the various proteins that actually give them their biological effect. By analyzing the various proteins you can see what genetic mutations have actually happened, as opposed to analyzing the genes themselves that would tell you only what might happen.  

Also, by genetic testing, to what extent can you detect genes that have been only partially disrupted?