Showing posts with label Leukemia. Show all posts
Showing posts with label Leukemia. Show all posts

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.

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.

Monday 28 November 2016

Leukemia, IL-6 IL-10 and an Autism Flare-up

Leukemia/Leukaemia  is cancer that begins in the bone marrow and result in high numbers of abnormal white blood cells.

I received a comment on this blog a long time ago from a parent whose child had initially responded well to some of the autism therapies suggested on this blog. Later on all the therapies stopped working.  That child also has leukemia.

We now know this is a common event when you start treating autism, some comorbidity arises that blocks the effects of those therapies.  In my son’s case it is a simple pollen allergy, but it can be all kinds of inflammatory conditions such as colitis, IBS, IBD, GERD, celiac disease, juvenile arthritis, mastocytosis etc.  This list goes on, but now I know why it includes leukemia.

I do not consider epilepsy, or indeed cognitive dysfunction, as comorbidities.  Epilepsy is periodic extreme neuronal hyper-excitability, whereas in much autism there is chronic neuronal hyper-excitability.  Not surprisingly, chronic neuronal hyper-excitability can develop to periodic extreme neuronal hyper-excitability.  So I see epilepsy as a natural progression from childhood autism, but one that perhaps could and should be prevented.

Earlier on writing this blog I thought that genetics and cancer pathways would be beyond its scope, but in apparent absence of anyone much else publicizing the connections with autism I revised my view.

It has been known since 1930 that leukemia is comorbid with Down Syndrome (DS).  DS is caused by caused by the presence of all, or part of a third copy of chromosome 21 this leads to over expression of 300+ genes.  DS is usually easy to diagnose based on physical appearance .  The gene over-expression frequently leads to autistic behaviors and somewhat less frequently to various types of leukemia and in later years early onset Alzheimer’s.  The good news is that DS  children with acute myeloid leukemia (AML), and in particular the acute megakaryocytic leukemia (AMkL) subtype, have exceptionally high cure rates.

The particular gene that is over-expressed in DS and can cause leukemia is called HMGN1.

DS is increasingly rare in Europe, but quite common in the US due to differences in parental choice regarding the termination of pregnancies identified as high risk of Down Syndrome.

I think it only fair to consider leukemia as a possible comorbidity of autism, since may people with DS do indeed exhibit autistic behaviors.

There is no quality data to say how common leukemia is in non-DS autism.

Leukemia and Cytokines IL-6 and IL-10

I do consider the pro-inflammatory cytokine IL-6 to be public enemy number one of autism, while the anti-inflammatory cytokine is a potential friend.

There are different types of Leukemia, but it appears that IL-6 and IL-10 play a key role and at least in acute myeloid leukemia can predict the outcome.  Generally speaking leukemia is associated with elevated IL-6 and in particular when there is a relapse.

Acute myeloid leukemia (AML) blast cells frequently produce interleukin-6 (IL-6) 

Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels

An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

So we can infer that a leukemia relapse will likely lead to a worsening of autism driven by an elevation in the level of the pro-inflammatory cytokine IL-6.  This would account for why the autism drugs “stopped working” in the case of our reader.

We could then ponder that a therapy that reduces IL-6 and increases IL-10 might help keep some types of leukemia in remission.

This is altering the Th1/Th2 balance which was the target of our reader Alli from Switzerland who did decide to spend many hours reading the oncology research to understand all those cellular signaling pathways.

For those interested in why DS increases the risk of leukemia, scientists at the Dana-Farber Institute in Boston have figured this out, at least in the case of one common form of Leukemia.

If only some more of the clever people studied autism.