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Friday, 22 June 2018

Learning about Autism from the 3 Steps to Childhood Leukaemia




Special baby yoghurt to prevent childhood leukaemia, would quite likely also reduce the severity/incidence of some autism by permanently modulating the immune system.

Today’s post is about Leukaemia/Leukemia, another condition like autism, that is usually caused by "multiple hits".  It makes for surprisingly interesting reading for those interested in understanding autism.  
Leukaemia is a group of cancers that begin in the bone marrow and result in high numbers of abnormal white blood cells. Symptoms may include bleeding and bruising problems, feeling tired, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells.
Cancer research is making some great strides and, being English myself, I am pleased that some of the cleverest research is being carried out in England; the epicentre is the Royal Marsden Hospital/Institute of Cancer Research. Sadly, there is no such centre of excellence for autism research in England, or anywhere in Europe.  The best autism research usually comes from the US, Canada and increasingly China; the exception being bumetanide/NKCC1 research in France.  
Now straight to leukaemia and yoghurt.


Professor Mel Greaves from The Institute of Cancer Research, London, assessed the most comprehensive body of evidence ever collected on acute lymphoblastic leukemia (ALL) -- the most common type of childhood cancer.
His research concludes that the disease is caused through a two-step process of genetic mutation and exposure to infection that means it may be preventable with treatments to stimulate or 'prime' the immune system in infancy
The first step involves a genetic mutation that occurs before birth in the fetus and predisposes children to leukemia -- but only 1 per cent of children born with this genetic change go on to develop the disease.
The second step is also crucial. The disease is triggered later, in childhood, by exposure to one or more common infections, but primarily in children who experienced 'clean' childhoods in the first year of life, without much interaction with other infants or older children.
Acute lymphoblastic leukemia is particularly prevalent in advanced, affluent societies and is increasing in incidence at around 1 per cent per year.
Professor Greaves suggests childhood ALL is a paradox of progress in modern societies -- with lack of microbial exposure early in life resulting in immune system malfunction 

The same paradox applies to autism and is likely a big part of why medical autism is increasing in prevalence, once you adjust for some foolish doctors moving the goalposts of what is autism.


Here is another easy to read summary of what Professor Grieves is saying.


Our modern germ-free life is the cause of the most common type of cancer in children, according to one of Britain's most eminent scientists. 

Acute lymphoblastic leukaemia affects one in 2,000 children.
Prof Mel Greaves, from the Institute of Cancer Research, has amassed 30 years of evidence to show the immune system can become cancerous if it does not "see" enough bugs early in life. 
It means it may be possible to prevent the disease
Combined events
The type of blood cancer is more common in advanced, affluent societies, suggesting something about our modern lives might be causing the disease. 
There have been wild claims linking power cables, electromagnetic waves and chemicals to the cancer.  That has been dismissed in this work published in Nature Reviews Cancer
Instead, Prof Greaves - who has collaborated with researchers around the world - says there are three stages to the disease
§  The first is a seemingly unstoppable genetic mutation that happens inside the womb
§  Then a lack of exposure to microbes in the first year of life fails to teach the immune system to deal with threats correctly
§  This sets the stage for an infection to come along in childhood, cause an immune malfunction and leukaemia
This "unified theory" of leukaemia was not the result of a single study, rather a jigsaw puzzle of evidence that established the cause of the disease. 
Prof Greaves said: "The research strongly suggests that acute lymphoblastic leukaemia has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed."
Evidence that helped build the case included:
§  An outbreak of swine flu in Milan that led to seven children getting leukaemia
§  Studies showing children who went to nursery or had older siblings, which expose them to bacteria, had lower rates of leukaemia
§  Breastfeeding - which promotes good bacteria in the gut - protects against leukaemia
§  Lower rates in children born vaginally than by caesarean section, which transfers fewer microbes
§  Animals bred completely free of microbes developed leukaemia when exposed to an infection
This study is absolutely not about blaming parents for being too hygienic. 
Rather it shows there is a price being paid for the progress we are making in society and medicine. 
Coming into contact with beneficial bacteria is complicated; it's not just about embracing dirt. 
But Prof Greaves adds: "The most important implication is that most cases of childhood leukaemia are likely to be preventable." 
His vision is giving children a safe cocktail of bacteria - such as in a yoghurt drink - that will help train their immune system
This idea will still take further research. 
In the meantime, Prof Greaves said parents could "be less fussy about common or trivial infections and encourage social contact with other and older children".
Good germs
This study is part of a massive shift taking place in medicine. 
To date we have treated microbes as the bad guys. Yet recognising their important role for our health and wellbeing is revolutionising the understanding of diseases from allergies to Parkinson's and depression and now leukaemia.


Childhood Leukaemia Incidence is Rising

The overall prevalence of all types of leukaemia is about 1.5%.
Today we are just looking at one sub-type, acute lymphoblastic leukemia (ALL). It usually occurs in children aged 2 to 5 and if not treated promptly is fatal within a matter of months.
ALL is the most common type of childhood cancer. Approximately 3 of 4 children and teenagers who are diagnosed with leukemia are diagnosed with ALL. It is most common in children younger than 5, with most cases occurring between the ages of 2 and 4.
The prevalence of ALL is increasing while that of adult leukaemia is static.





While nobody ever talks much about it, ethnicity clearly is very relevant to autism incidence. It is not just about wealth and poverty; some ethnic groups are more prone to certain diseases than others. In the case of childhood leukaemia you have the most risk if you are a white Hispanic American.
In the case of autism, it looks to be parents who are Non-Hispanic White Americans who have the highest risk and if you are Jewish and high IQ the risk goes up further.

It is not all about genes
In about 10% of autism you can trace the cause back to a single miscreant gene, or entire chromosome, but for most autism it is much more complex.
For many genes, an error does not mean that a related dysfunction is guaranteed to occur it just makes you predisposed to that dysfunction. As we see with childhood leukaemia, most children with the miscreant gene never develop that cancer. Only 1% of all the children with the risk gene develop the cancer.  
This is one reason to be very careful opting to carry out Whole Exome Sequencing (WES), because you will likely discover genetic mutations that are associated with all kinds of possible conditions, but quite possibly none of the dysfunctions have, or will ever, occur in that person.
There are some genetic conditions that invariable do occur, but most often there are tell-tale physical signs. A short little finger (pinkie) is one I was discussing recently with someone, to help them narrow down a possible diagnosis.

Dr Grieves' full paper 
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)–runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.  

Childhood acute leukaemia is the most common paediatric cancer in developed societies, accounting for  one- third of all cases, with a variable incidence rate of 10–45 per 106 children per year and a cumulative risk of ~1 in 2,000 up to the age of 15 years1. The most common paediatric leukaemia, acute lymphoblastic leukaemia (ALL), is an intrinsically lethal cancer, as evidenced by a universally adverse clinical outcome before effective therapy was developed. Currently, however, cure rates for ALL using combination chemotherapy are around 90%, making this one of the real success stories of oncology. While this is a cause for celebration, the current treatment remains toxic, traumatic for young patients and their families, and carries some long- term health consequences. It is unfortunate that we have remained ignorant as to the cause of ALL. The open question as to whether this cancer is potentially preventable is  therefore important.

Most cases of childhood ALL are potentially preventable. But how? Lifestyle changes including day care attendance or protracted breastfeeding in the first year of life can be advocated but would be difficult to achieve. A more realistic prospect might be to design a prophylactic vaccine that mimics the protective impact of natural infections in infancy, correcting the deficit in modern societies. Reconstitution or manipulation of the natural microbiome or helminth injections are strategies under consideration for early- life immune disorders in modern societies, including autoimmune and allergic conditions. Oral administration of benign synbiotics (bacteria species such as Lactobacillus spp. and oligosaccharides) can have profound and beneficial modulating effects on the developing immune system. The results of those endeavours might inform approaches for preventing BCP- ALL. Cross collaboration of scientists working in disparate fields of early- life immune dysfunction — allergy, autoimmune disease and ALL — would be beneficial.

Other modulators of risk in childhood aLL 
In addition to patterns of infectious exposure and inherited genetics, other factors are likely to contribute to multifactorial risk, including diet and chance. For acute lymphoblastic leukaemia (aLL) as well as acute myeloid leukaemia (aML) and most other paediatric cancers, risk is significantly and consistently elevated in association with higher birthweights or, possibly, accelerated fetal growth. a plausible interpretation of this link is that higher weight, possibly orchestrated via insulin-like growth factor 1 (iGF1) levels, may provide a greater number of cells at risk. iGF1 potentiates expansion of B cell lineage progenitors. Recently, evidence has been presented, using mouse models of aLL, that a restricted diet can have a risk- reducing impact. intermittent fasting was shown to block expansion of leukaemic cell populations and progression of disease. the effect operated via attenuation of leptin receptor expression on leukaemic cells, possibly enforcing differentiation. Diet or calorie intake may, therefore, have a modulating impact on risk of aLL, reinforcing the likely multifunctional nature of causation of aLL, as in cancer in general. random events or chance get short shrift in cancer epidemiology, but it has long been recognized that contingency and chance pervades all of biology. Some posit that a substantial number of cancers are due to chance alone, but this has been contentious. Chance is likely to be an ingredient in each and every cancer, including childhood aLL. this is because inheritance of risk alleles is a lottery at conception, because exposures including infections, at particular times, may or may not happen and because mutational mechanisms alter genes independently of their function.

Conclusion
Professor Grieves looks like my kind of academic/researcher. We came across another such one, Dr Peter Barnes, also English, who is known for translational research in asthma and COPD. What matters is applying/translating research, not making a good living publishing inconsequential research, editing a journal and being on the board of some charities. In the real world, results are what count.  
In the academic world it seems to be quantity of publications that matter.  I vote for quality over quantity.
Intestinal bacteria are clearly a fundamental part of human health, but to fully understand the implications will take many decades of research. Even today, we can see the critical importance of exposure to a wide range of bacteria very early on life and indeed during pregnancy.





12 comments:

  1. Whats everyones thought about this new drug: L1-79, a tyrosine hydroxylase inhibitor

    http://www.mdmag.com/medical-news/fast-track-designation-granted-for-l1-79-in-treatment-for-autism-spectrum-disorder

    I think its friggin crazy what these guys are experimenting with on people with autism/asd, sounds like a great way to induce parkinsons and aggrevate adhd like symptoms... my mouth literally fell open, I have emailed the pharma company asking for a reason behind why they think their drug should work and HOW.

    If you consider that things such as calorie restriction, exercise and even hdac-inhibition actually upregulate tyrosine hydroxylase and the importance of dopamine in social functioning and learning.

    Once again Im disgusted by this company they better have a damn good explanation in their response to the message I submitted on their website!!!

    Not sure where to post it, so I have put it here

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    1. Hi Aspie,many kids with autism have diminished Comt activity which means higher baseline dopamine levels resulting in hypomanic behaviour, tics and OCD. My son had tardive dyskinesia with risperidone chronic use, due to dopamine receptor blockade.But reducing dopamine levels in the brain is another thing. Iam using Bcaas to do this but would use a tyrosine hydroxylase inhibitor.Tyler is the one who can clarify this.
      Valentina

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    2. Drugs rarely only do one significant thing in the body/brain. Also, I posted about this a month or so ago a few blog posts back in the comments.

      As you well know if there is excessive extracellular dopamine in the brain, to prevent receptor desensitization you will want to normalize dopamine levels somehow. There are several different enzymes in the dopamine synthesis pathway, and tyrosine hydroxylase is the most practical one since it is responsible for converting tyrosine to L-DOPA while AADC involves creating dopamine from L-DOPA as well as serotonin from 5-HTP, among being involved in other enzymatic processes on top of that. As far as the brain goes, your other options are to block tyrosine from getting into the brain (BCAA therapy), or else block dopamine receptors explicitly (risperidone).

      We all know the problems with antipsychotics in how non-selective they tend to be with regards to the various classes receptors they affect which is why the next best thing I think is BCAA's. Who knows if this drug will be proven safe and effective and does not have too many side effects, but it is at least a good chance at being a better band-aid than BCAA's and likely being far less damaging than chronic use of antipsychotics like risperidone.

      Even if this drug is successful, it will likely be very expensive so that only upper-middle class and wealthy families in my country will be able to afford it so if I were you I would not worry too much about it one way or another.

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    3. Ok Tyler, will continue with BCAAs, it seems that will not be easy to find a better alternative.
      Valentina

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    4. Valentina....

      Tardive dyskinesia is a serious matter, on top of that you seem to forget (which Tyler allready also has highlighted) that BCAA's lower serotonin aswell.
      Not to mention they effect nmda (to be more precise, they ACTIVATE nmda channels).
      My guess is people who benefit from BCAA's actually have high serotonin and low nmda activity at baseline.

      With regards to comt, I have no clue for classic autism, but I have done a 23andme test (and so should people on this board before randomly giving drugs their kids as its like finding a needle in a haystack else for a proper drug that works) and this showed that I have the comt warrior gene. FYI this means that I have LOW dopamine.
      Please keep your kid save...

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    5. Aspie, you can replace any lost serotonin from BCAA's using 5-HTP which readily crosses the BBB, while if you only want to lower serotonin in the brain you can use mucuna pruriens which is essentially natural L-DOPA. When I first started the therapy I resupplemented both 5-HTP and mucuna pruriens as all I was attempting to do was block high levels of L-Kynurenine from getting into the brain. I am not going to repeat all of the reasoning for this as you can find it all in past comments here, but in the end I found it was best for my son to not even bother with 5-HTP and mucuna pruriens.

      Last but not least, the hyperbole concerning COMT status is more or less a cottage industry on the internet and the conclusions some sites make have little or nothing to do with the actual science concerning the subject. The same goes with the litany of MTHFR tests, even though a very small number of people can have other multiple complications with folate metabolism that warrants further scrutiny.

      What seems to matter most are gene networks, not specific gene variants themselves except in some rare conditions. Some scientists even believe now that complex features like height or intelligence may involve pretty much all of our genes, especially as only 1.5 percent of our DNA actually codes for proteins while the other 98.5 percent does many other interesting things. In fact, a paper this week showed that a transposon which comprises 20 percent of your DNA and was previously thought to be junk and parasitical in nature is necessary for vertebrates to get past the 2 cell stage of division. It is thought that we have such a huge amount of this transposon because its redundancy is integral in making sure that this very early and important step in development transpires.

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    6. Thanks Aspie,don´t think I haven´t had doubts about BCAAs.I asked Tyler and he told me that they are safe because the excess is excreted in the urine.The truth is that without them i wouldn´t have been able to stop risperidone. But my questions remain and are:Is there a chance of overstimulating NMDA receptors and cause neurotoxicity with chronic use? Also i don´t know if BCAAs can alter microglial cells and their response to inflammatory signals. Certainly my son has a disturbed immune system and really want to keep him safe.
      Valentina

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    7. Yeah Tyler im aware of mucuna, I tried it once, it did help a lot but I was kind of worried about tollerance and or being dependant on it (its l-dopa after all in the extract...). On top of that it is best taken with a dopa decarboxylase inhibitor, EGCG from greentea being one.

      5HTP, my body seems to get benefits on acute dosing for sleep, but several days in a row makes me sick tbh, its a 100% NO-GO for me!

      Reuteri atcc 6475 is allready known to shift tryptophan pathways towards indole production (this should mean less serotonin will be in my body).

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    8. @Valentine,

      While the animal study done with BCAA clearly shows it activates NMDA keep in mind that the amounts they used in that study was outrageously high. On top of that most people in autism seem to be deficient in the branched chain amino acids.

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  2. Baby formula, yoghurt, green tea, pu-erh tea, wine (resveratrol)... And what now?

    We had guests at midsummer, and one of the bottles left after the party ("sour beer") mentioned that the beer was fermented with Lactobacillus. As my mind is always focused on translational medicine nowadays it got me thinking. Alchol-free beer, with gut-friendly bacterial strains and perhaps some B-vitamins...
    Maybe I just got a little too creative. :)

    /Ling

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  3. Off this topic but this is fascinating:

    http://news.berkeley.edu/2018/06/25/crispr-reduces-autism-symptoms-in-mice/

    MTEP/MPEP? Lithium?

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  4. How do one know if a compound has to be divided in more than one daily dosage? Is it as simple as halflife being somewhere over 16 hours?
    I'm kinda stuck with a lot of capsule dividing, and if I could go down to one daily dosage instead of two that would save me a lof of time.
    At the moment it is pterostilbene and bacopa that are causing a lot of activity, but it would be nice to know for future interventions too.

    /Ling

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