Belgrade, Busby Babes and the Wakefield MMR Saga

On 5^th February 1958, Manchester United played away to Red Star in Belgrade.  What is remembered is not the match, but the flight home; having stopped to refuel in Munich, the plane crashed on take-off with 23 fatalities and 21 survivors.

Matt Busby, the Manager, survived the accident and ten years later he led a new team of Busby Babes to win the European Cup.  Bobby Charlton and Bill Foulkes survived the crash and played against Benfica in that final.

Why am I telling you about this?  The reason is the air crash investigation that followed.  It was convenient to blame the pilot, Captain James Thain.  The German enquiry blamed him for not deicing the wings and claimed that this ice prevented the plane from taking off, as it reached the end of the runway.

For ten years Thain tried to clear his name and insisted there had been no ice on the wings and that a deep layer of water and slush on the runway caused the accident.  Finally, Harold Wilson, the then British Prime Minister, backed his call for a new investigation.  At that second inquiry, it was shown that Thain had been right all along.  The wings were not iced up, but the runway had not been properly cleaned and the crash was inevitable.  The plane could not gather enough speed to take off and crashed into a house at the end of the runway.

Thain had been a convenient scapegoat and died aged 54, the 24^th victim of the crash.

The truth did come out in the end and it was recently the subject of an excellent documentary by National Geographic.

Do vaccines cause autism?

I was surprised last week when my mother, a retired doctor,  asked whether I thought the MMR vaccination caused autism .  My reply was along the lines of “maybe sometimes, but we will never know”.  A year ago, I would have simply said “of course not”.

Monty, autistic and aged 9, also flies from Belgrade to London, and sometimes via Munich.  Planes have got much bigger and safer and airports are much better prepared for bad weather.  Flying will always have a risk and all drugs have an element of risk; so naturally vaccines also have a risk.

From a public health perspective, it is clear that vaccines save millions of lives and so any risk is vastly outweighed by the overall benefit.

If you were Bill Gates, who is nobly trying to eradicate polio from the planet (he now has the added problem of the Taliban killing the vaccination teams in Pakistan), what would you say about Andrew Wakefield and his linking of autism to vaccines?

Not surprisingly he gets referred to as a fraud and that his research was rigged and that later research proved him wrong.  Now can we get back to eradicating polio!

In the big picture Bill is definitely right; Andrew Wakefield may also be right, but will he ever get a fair chance to prove it?  Captain James Thain waited ten years, I think Andrew Wakefield will need to wait much longer.

It sounds highly plausible that injecting a combination of vaccines preserved in a solution with mercury (the mercury has now replaced by a much larger amount of aluminium) might cause an adverse reaction in the brains of a small number of subjects; perhaps ones with a slightly permeable blood brain barrier (BBB).  Rather than trash this hypothesis, it would have been better to fully investigate it and perhaps develop safer vaccines.  As in Munich, there has been an investigation, but I was rather shocked reading comments of researchers familiar with those studies.

I would agree with Bill that Andrew Wakefield could be seen as a danger to public health, but what if he is also right.  Does it matter?  If you are touched by autism, then yes; otherwise probably not.

Back to Spock

I mentioned a few posts ago that I had been to see the latest Star Trek movie with Ted, aged 12, and his friend Adrian “Mole”.

While saving a planet, but endangering the Starship Enterprise, Spock commented that “the interests of the many outweigh the interests of the few”.  Bill would concur, and so would Peter.

The conclusion is that if you are one of the few, you are on your own.  Do not wait for the Enterprise, or anyone else, to help you.  Help yourself.

I have no idea whether Andrew Wakefield is right, but at least on my blog he gets a chance to present his case. Here he is responding to a recent measles outbreak in South Wales.

Angelina Jolie or Destiny’s Child?

At the time of writing this post Angelina Jolie’s aunt has succumbed to the same cancer that killed Angelina’s mother and she announced that she also carried the same defective gene.  She opted to take pre-emptive action and, in effect, cheat a nasty early death from breast or ovarian cancer.

I have read so much research into autism, that it is pretty clear to me, that you could calculate an Autism Risk Factor (ARF) for prospective parents, if you really wanted to.  Would you really want to?  I expect those with direct experience of autism might be in favour, the others probably would not even bother to answer the question.  Since few truly autistic people have children, it is really more of a question for their siblings; do they want Destiny’s Child?

It may sound depressing, or something to do with eugenics, but actually it does not have to be.  I am not suggesting the sort of genetic and chromosome testing that is already routinely done for conditions like Down’s syndrome.  I am talking about the kind of lifestyle changes that ideally a woman who smokes, drinks heavily or takes drugs, should take when she wants to have a child.

If your ARF puts you at risk, then you would receive a list of lifestyle changes, you should take to minimize the risk to your future child.

 

Autism Risk Factor (ARF)

I am not qualified to develop the ARF, but I am confident enough to highlight two of the factors that should go into it:

 

1.     Maternal & paternal family history of autoimmune diseases

Auto-immune diseases including, but not limited to, history of type 1 diabetes, rheumatoid arthritis, celiac disease and hypothyroidism.  Here is some supporting evidence, for those who are interested:-

·         Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders

 

·         Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism

 

2.     Maternal & paternal stress capacity

This risk factor is my invention.  I used to only really think about mechanical stress, but now I know all about physiological stress, psychological stress and that big one, oxidative stress.  It seems, remarkably to me, that the latter three types of stress are in fact one and the same.

Put another way, physiological stress, psychological stress and oxidative stress are reflections of each other.  If you have got one, you will have all three.

The good news is that can use obvious visible cues to spot people will a low stress capacity and you could even then confirm it with a laboratory test of their oxidative stress (GSH redox level).

I recently took four short airplane flights and I observed people with chronic nail chewing (male) and obsessive nail filing (female) sitting beside or in front of me; it looks like about 5% of the flying population.  If you added the non-autistic people with mild stereotypy (stimming) like foot flapping, and those with Trichotillomania (compulsive hair pulling, that we learned about in the posts on GSH/NAC) you would have a large proportion of those people living in some degree of potentially damaging oxidative stress.

I think the maternal stress capacity would be most relevant, but the fetus’s own stress capacity is also important, and some of that clearly comes from the paternal side.

Conclusion

So the conclusion for Ted, aged 12, is to grow up and find a nice calm girlfriend and buy a large supply of NAC, just in case.

 

 

 

The Swedish Disease

Ted, (aged 12, and supposedly “normal”) and his brother Monty (aged 9, and now steadily becoming more “normal”, as this blog progresses) go to the same school as a Swedish family.  In Ted’s class is a Swedish girl, Charlotte, and her younger brother is in the Primary school along with Monty.  I have been both surprised and impressed, by how nice the kids in Primary are to kids with any kind of special need.  However, once they make the big leap to Secondary, they stop being so nice; it becomes cool to be critical and even cruel.

Ted’s Swedish friend, Charlotte, was explaining to their class that her younger brother had something called Attention Deficit Hyperactivity Disorder, but it was OK, because he only had 10% ADHD.  Ted of course then replied “and you have got the other 90%”.  Some of the other things they get up to are far, far worse; one reason why I put Monty down a couple of years in Primary.

But, the Swedish Disease is not ADHD.

During my research, I recently came across some references to so-called “Somali autism clusters”; this caught my attention and so I decided to delve deeper.

It seems that following the descent of Somalia into becoming a failed state, many refugees have been welcomed by the United States and Sweden, in particular.  In the US there are now communities living in Minneapolis and San Diego.  Not long had they arrived in their new homeland, when they started to produce large numbers of autistic children; sounds odd does it not?

Swedish researchers got on the plane to Minneapolis in the US, to launch a joint investigation and it was reported that Dr Wakefield wanted to go to San Diego to investigate.  The Swedes did not come up with an explanation that convinces me.  I think I have a much better one, and one that Dr Paul Ashwood, from the University of California might agree with.

The Swedish Somalis said they had never encountered autism before and so they named it the “Swedish Disease”.  The Swedish researchers concluded that since both Sweden and Minneapolis are far north, where the sun does not shine so much, the autism was the result of a lack of vitamin D.  That sounded odd to me; what about the cluster in San Diego that Dr Wakefield wanted to get in touch with?  Last time I was in California, the sun hardly ever went away.

A much more likely explanation is related to the immune system.  I have never had the pleasure of touching down in Mogadishu (the capital of Somalia, in case you did not know) but I did travel extensively in some poorer parts of Asia.  The level of hygiene and cleanliness in rural parts of India would really shock most westerners; the most effective strategy is just not to eat anything.  I came back 9 pounds lighter.

In my recent posts, I showed how the immune system plays a major role in the predisposition of children to autism; to me it is hardly surprising that first generation Somali children, born in ultra-clean Sweden and America, have a high incidence of disease related to the immune system, and to neuroinflammation in particular.  I dare say they never had much asthma in Somalia either.

The parents’ immune system has been toughened by all manner of parasites, bacteria and virus and has no doubt evolved to be prepared for it.  The children inherited their parents’ immune system, but it has stopped being challenged by any kind of serious attack.  Then in utero, or in very early childhood, a big oxidative shock came along and the immune system went crazy and over-reacted (a cytokine storm); massive neuroinflammation caused permanent brain damage and autism was the result.

It’s just my theory, but if you ever read that Somali immigrants are complaining about asthma and food intolerance, it might just be right.

More recently, the Swedes did a very large study looking at autism in all their immigrant population, here is an interesting link discussing the study:- 

Swedish study dissects autism risk in immigrants

 

A Cytokine Storm? Mr Spock

I have recently started learning the workings of the human immune system, while 12 year old Ted (“normal” except for a Star Wars obsession) has been discovering Star Trek.  Last weekend we went to the cinema with Adrian “Mole” to see the latest release.  Mr Spock made one interesting observation, regarding what can happen when the interests of the many outweigh the interests of the few; this will be the tittle of a forthcoming post about the fate of Dr Wakefield and his vaccine theory.

Cytokines

Cytokines really do exist, even though they sound like something from science fiction.  They are signalling molecules associated with inflammation.  Several inflammatory cytokines are induced by oxidative stress.  The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidant stress, makes them important in chronic inflammation.  In extreme cases, there is a downward spiral of inflammation making it worse and worse.  The Spanish Flue in 1918 and SARS in 2003 are given as examples of such deadly cytokine storms.

The Research

There is a vast amount of research about the role of cytokines in autism and some very good work has been done by Paul Ashwood.  Finally, I have found an Englishman, even though he has gone to live in California, publishing some really high quality and useful research.  It turns out he is a colleague of Dr Wakefield.  Much of Paul Ashwood’s research is not available for free.  This one is:-  The role of immune dysfunction in the pathophysiology of autism

This paper is very readable and shows how a dysfunction of the immune system is without doubt a major part of the autism story. In typical post-Wakefield fashion, nobody wants to stick their necks out and draw usable, if only hypothetical, conclusions; it is easier to just suggest further research.

All the research shows high levels of cytokines in autistic subjects in the brain, spinal fluid, blood and in the gut.  Recent research also shows high levels of cytokines in the siblings of autistic people:- Plasma cytokine profiling insibling pairs discordant for autism spectrum disorder

The researchers comment:-

Thus, the lack of significant differences between sibling pairs discordant for ASD found in our study is in line with the results of previous studies. It is possible that a common immunogenetic background shared by siblings might eventually lead to different clinical outcomes when an environmental stress (for example, prenatal exposure to environmental toxins, viral and bacterial infections, parental microchimerism, etc.) occurs during development.

This last finding was deftly understood by 12 year old Ted, who commented, “Well Dad, you nearly had two autistic children”

Well isn’t he a chip off the old block.

Peter Interpretation

So combining this knowledge with my other readings, drew me to the logical conclusion that the inherited immune dysfunction, combined with the oxidative shock, so well described by Chauhan et al,(in the 400 page book) most likely resulted in a cytokine storm that damaged the brain, and autism resulted.  Due to the feedback loop of the cytokines, the neuroinflammation continues for life.

This then led me to research cytokine storms, to see how the cycle could be stopped and some kind of homeostasis reinstated.  I did not expect to find an answer, but I did.   

First we have to introduce new terms, TNF and TNFR.

TumorNecrosis Factors (TNF)

Tumor necrosis factors (or the TNF family) refer to a group of cytokines whose family can cause cell death or apoptosis.  19 members of the TNF family have so far been identified; the one that caught my eye was OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production.

A tumor necrosis factor receptor (TNFR), or death receptor, is a cytokine receptor that binds TNFs.  The matching TNFR for the TNF OX40L is called OX40 (also known as CD134).

OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response due to its ability to enhance survival. OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo. T helper cells (type 1 and 2) are white blood cells that play a major role in the immune system
OX40 has been implicated in cytokine storms.

Cause of the Cytokine Storm

When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.  Normally, this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs.

TNF inhibitors and Cytokine Storms

The cytokine storm is kept going by the TNF cytokines.  So if these cytokines could be inhibited the storm might abate. An existing medication developed for arthritis called a TNF-alpha blocker was proposed as a possible drug. Corticosteroids and NSAIDS (Non-steroidal anti-inflammatory drugs) have been found ineffective.

In 2003 researchers at Imperial College demonstrated the possibility of preventing a cytokine storm by inhibiting or disabling T-cell response. A few days after T cells are activated, they produce OX40, a "survival signal" that keeps activated T-cells working at the site of inflammation during infection with influenza or other pathogens. OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. A combined protein, OX40- immunoglobulin (OX40-Ig), a human-made fusion protein, prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with an immune overreaction while allowing the immune system to fight off the virus successfully. By blocking the OX40 receptor on T-cells, researchers were able to prevent the development of the most serious flu symptoms in these experimental mice.  Sadly, it appears this discovery has been abandoned by the small company that tried to develop it.

And now for the shock …

In 2009 researchers in China found that a statin induced down-regulation of OX40 and OX40L in a concentration-dependent manner.

Simvastatin reduces OX40 and OX40 ligand expression in human peripheral blood mononuclear cells and in patients with atherosclerotic cerebral infarction.

"These findings improve our understanding of the anti-inflammatory and immunomodulatory properties of simvastatin"

Antioxidants have been successfully trialled in cases of Acute Respiratory Distress Syndrome (ARDS), which is another example of cytokine storm.  Organ damage was reduced and there was an improved survival rate.

Conclusion

It would seem that the combination of antioxidant and statin is about as good a combination as is currently possible, to dampen down the remaining effects of a cytokine storm, which is the extreme case of neuroinflammation.

By skill, or luck, this combination is exactly what I am trialling with Monty.

   

Peter Hypothesis Regarding the Cause of Autism

Peter Hypothesis Regarding the Cause of Autism,

 The Predisposition of some Children towards it and Implications for Treatment

Autism is a spectrum of behaviours and disorders that result from damage and subsequent malformation of the developing cerebellum.  The damage in classic autism occurs in utero, whereas in the case of regressive autism, there is a second oxidative shock that occurs around a key point in brain development, triggering the onset of autism.  The cause of the cerebral damage is an oxidative shock from one or more of a variety of possibilities, not limited to, maternal stress and infection during pregnancy and toxins such as mercury crossing the blood brain barrier (BBB).  Individuals with autism, and many of their close relatives, have a predisposition to the condition, due to an inherited over-reactive immune system.

The immune system may have become over-reactive to infection partly due to a lack of the on-going attacks, for which it has evolved.  This may be another case for the well documented “Hygiene Hypothesis”, in which a little bit of dirt, rather than an apple a day, keeps the doctor away.

The result is that while in modern society the likelihood of an oxidative shock has increased, the immune system has become so relaxed, due to a sterile environment, that it becomes over-activated when confronted by a severe oxidative shock.  A cytokine storm then rages and the resulting severe neuroinflammation and oxidative damage causes permanent brain damage.  The brain tries to repair itself, but as it continues to grow, it deforms.  A milder neuroinflammation typically continues throughout life and this aggravates the observed autistic behaviours.

In very rare individuals with mild autism, a “recovery” can be observed.  This is most likely the result of successful behavioural therapy of some kind and the on-going neuroinflammation subsiding, for reasons unknown.    In cases where brain damage is substantial, as is generally reported to be the case in classic autism, “recovery” is somewhat fanciful; optimal outcome is the realistic goal of therapy.

A secondary inherited/genetic factor may eventually be proved to be the permeability of the BBB (blood brain barrier).  This would play a role in both the initial oxidative shock reaching the cerebellum and in the following cytokine storm.  Cytokine molecules are particularly large and those released from outside the brain should struggle to enter it.

Vaccination damage is just one of many possible causes of oxidative shock that could trigger regressive autism; it cannot be the cause of classic early onset autism.  Milder cases of autism, and indeed ADHD, are caused by milder cerebral damage and milder on-going neuroinflammation.

Implications of the Hypothesis

1.       At risk mothers should avoid possible oxidative attack

The overactive immune system is measurable (the simplest and cheapest test is the C-reactive protein test; but cytokine testing would be conclusive) and this knowledge could be used to reduce further cases of autism, by identifying at risk mothers.  The threat of oxidative damage could be reduced by de-sensitizing the immune system during pregnancy (risky, but possible), or perhaps better, by meticulously avoiding oxidative damage during pregnancy, in those in the high risk group.  Most likely, the lack of a “successful” oxidative attack during pregnancy would reduce the likelihood of a secondary shock later on that could tip the balance towards regressive autism.

2.       Reset the immune system

Increased exposure to pets, mild intestinal parasites and dirt in general, would reverse the modern trend towards an unprepared and then over-reactive immune system.

This would have the secondary benefit of reducing the prevalence of a wide range of 21^st century conditions including asthma, food allergies, eczema and even gastrointestinal sensitivity and arthritis.  These are all linked to neuroinflammation and/or an overactive immune system.

3.       Therapy & Treatment

Once the brain damage has occurred we are left with the challenge of how best to manage it and achieve “optimal outcome”.  Now that we have a plausible hypothesis, this will greatly help us (me) finding effective therapies, some of which will be novel.

Therapy needs to take advantage of neuroplasticity, particularly in the very early years, to maximize the potential of the damaged brain.  Intensive early behavioural intervention has been proved to be effective and neurological explanation is that the brain’s own plasticity is being exploited to develop new pathways within it.  In other words, start an ABA programme.

Targets for pharmacological intervention:- 

•     Reduce the on-going neuroinflammation / oxidative stress   

•    Treat secondary issues arising from the malformation of the brain

            ·         Ion channel and neurotransmitter (GABA, glutamate etc.)  malfunction

            ·         Hippocampus malfunction, leading to a cascade of hormone errors (CRH, 
                      TRH, AVP, Oxytocin, Cortisol etc.)