Oxaloacetate and Pepping up Bioenergetic Fluxes in Autism and other Neurological Diseases



BHI as a dynamic measure of the response of the body to stress
In this scheme, healthy subjects have a high BHI with a high bioenergetic reserve capacity, high ATP-linked respiration (AL) and low proton leak (PL). The population of mitochondria is maintained by regenerative biogenesis. During normal metabolism, a sub-healthy mitochondrial population, still capable of meeting the energetic demand of the cell, accumulates functional defects, which can be repaired or turned over by mitophagy. Chronic metabolic stress induces damage in the mitochondrial respiratory machinery by progressively decreasing mitochondrial function and this manifests as low ATP-linked respiration, low reserve capacity and high non-mitochondrial (e.g. ROS generation) respiration. These bioenergetically inefficient damaged mitochondria exhibit increased proton leak and require higher levels of ATP for maintaining organelle integrity, which increases the basal oxygen consumption. In addition, chronic metabolic stress also promotes mitochondrial superoxide generation leading to increased oxidative stress, which can amplify mitochondrial damage, the population of unhealthy mitochondria and basal cellular energy requirements. The persistence of unhealthy mitochondria damages the mtDNA, which impairs the integrity of the biogenesis programme, leading to a progressive deterioration in bioenergetic function, which we propose can be identified by changes in different parameters of the bioenergetics profile and decreasing BHI.

Source:  The Bioenergetic Health Index: a new concept in mitochondrial translational research


Bioenergetic is today�s new buzz word; it is again all about getting maximum power output (ATP) from your mitochondria, which we looked at from a different perspective in a recent post.


A simple lack of ATP inside the brain seems to be a feature of many kinds of neurological problem. 
Oxaloacetate (OA or OAA) is another interesting potential treatment for a wide range of neurological disorders from Alzheimer�s and ALS to Huntington�s and Parkinson�s. There are no effective treatments for any of these conditions and little has changed in decades.
OAA, at high doses, and in animal studies, does have some very interesting effects, but they are perhaps too wide ranging, because some may be helpful and others not. OAA is interesting but no panacea.
OAA is sold as a supplement in low doses. It changes so many things, I think it is not surprising that some people find it beneficial, whether it is for Bipolar, ADHD or something else.
I think at higher doses, where there is a measurable impact above and beyond the OAA you have naturally in your blood, there might be some benefit as a treatment for mitochondrial disease. That would mean most regressive autism and some Childhood Disintegrative Disorder (CDD).
So we can consider OAA as another potential therapy for bioenergetic dysfunction. We have come across many potential therapies already in this blog.
Here is a schematic summary of what OAA does.



OAA effects and inter-effect relationships. OAA, a bioenergetic intermediate, affects bioenergetic flux. This produces a number of molecular changes. CREB phosphorylation and CREB activity increase, which in turn promotes the expression of PGC1 family member genes. AMPK and p38 MAP phosphorylation increase, and these activated kinases enhance PGC1a co-activator function. PGC1-induced co-activation of the NRF1 transcription factor stimulates COX4I1 production, while PGC1-induced co-activation of the ERRa transcription factor stimulates VEGF gene expression (61). OAA-induced flux changes also stimulate the pro-growth insulin signaling pathway and reduce inflammation. The pro-growth effects of increased insulin pathway signaling and increased VEGF, in conjunction with a more favorable bioenergetic status and less inflammation, cooperatively stimulate hippocampal neurogenesis.

You may recall from earlier posts that PGC-1a is the master regulator of mitochondrial biogenesis. 
The PGC-1a protein also appears to play a role in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.
The PGC-1 a protein interacts with the nuclear receptor PPAR?. PPAR? has been covered extensively in this blog; agonists of PPAR? do seem to be therapeutic in some autism. Many drugs that are used to treat Type 2 diabetes work because they are PPAR? agonists.
It is not a surprise that Oxaloacetate (OAA) lowers your blood sugar. 



Bioenergetics and bioenergetic-related functions are altered in Alzheimer's disease (AD) subjects. These alterations represent therapeutic targets and provide an underlying rationale for modifying brain bioenergetics in AD-affected persons. Preclinical studies in cultured cells and mice found that administering oxaloacetate (OAA), a Krebs cycle and gluconeogenesis intermediate, enhanced bioenergetic fluxes and upregulated some brain bioenergetic infrastructure-related parameters. We therefore conducted a study to provide initial data on the tolerability and pharmacokinetics of OAA in AD subjects. Six AD subjects received OAA 100 mg capsules twice a day for one month. The intervention was well-tolerated. Blood level measurements following ingestion of a 100 mg OAA capsule showed modest increases in OAA concentrations, but pharmacokinetic analyses were complicated by relatively high amounts of endogenous OAA. We conclude that OAA 100 mg capsules twice per day for one month are safe in AD subjects but do not result in a consistent and clear increase in the OAA blood level, thus necessitating future clinical studies to evaluate higher doses.

In addition to being proposed for the treatment of AD and diabetes, recent preclinical research has also identified OAA as a potential therapeutic agent for stroke, traumatic brain injury, amyotrophic lateral sclerosis, and glioma [15], [16], [17], [18]. The clinical safety data we now report should prove relevant to efforts intending to translate results from these preclinical studies to the clinical arena. Our study also informs our attempts to develop OAA as a treatment for AD. Overall, we conclude that although OAA 100 mg capsules twice per day for one month are safe in AD subjects, because a consistent and clear increase in the OAA plasma level was not observed future clinical studies need to evaluate higher doses.

Experimental: Oxaloacetate (OAA) active capsule containing 100 mg OAA and 100 mg ascorbate, taken daily  

Experimental: Part 2 - Oxaloacetate (OAA)2 gram/day 
Participants take 2 grams of OAA per day for period of 4 weeks

Participants take 2 capsules Jubilance 100 mg Oxaloacetate/150 mg Ascorbic Acid blend per day

Oxaloacetate is an energy metabolite found in every cell of the human body. It holds a key place in the Krebs Cycle within the mitochondria, providing energy to the cells. It is also a critical early metabolite in gluconeogenesis, which provides glucose for the heart and brain during times of low glucose. It is critical to human metabolism, proper cellular function and it is central to energy production and use in the body.
Oxaloacetate may affect Emotional PMS through multiple mechanisms. During PMS, there is a large increase in glucose utilization in the cerebellum of the brain in women who are affected with emotional mood swings. Oxaloacetate supplementation has been shown to support proper glucose levels in the body. Having an excess of oxaloacetate allows gluconeogenesis take place upon demand, thereby fueling the brain, and perhaps meeting cerebellum glucose need.
In addition to oxaloacetate's ability to support proper glucose regulation, oxaloacetate affects two chemicals in the brain, GABA and glutamate. Altering the GABA/Glutamate ratio can affect mood. Oxaloacetate supplementation can reduce glutamate levels in the brain via a process called "Glutamate Scavenging". In addition, oxaloacetate supplementation was shown to increase GABA levels in animal models. By both lowering glutamate and increasing GABA, the GABA/Glutamate ratio is affected, which may also help women with Emotional PMS.
This study will investigate oxaloacetate's effect on Emotional PMS using patient completed surveys to measure depression, anxiety, perceived stress, and aggression, and statistically compare these results against placebo (rice flour) and baseline measurements.

An interesting old paper from 1968 was recently highlighted to me by a friend, it  shows that sodium oxaloacetate is particularly effective in treating type-1 diabetes.  In type-2 diabetes the effect range from none/minor in most  to a profound effect in a minority.
The meaning of �treating� was reducing blood sugar levels.
This study was the result of identifying the active substance in the plant euonymus alatus sieb, which has known blood sugar lowering effects.



Introduced from northeast Asia in the 1860s. Widely planted as an ornamental and for highway beautification due to its reliable and very showy fall foliage coloration. Numerous cultivars are available.
Other states where invasive: CT, DE, IN, KY, MA, MD, MO, NH, NJ, OH, PA, RI, VA, WI, WV. Federal or state listed as noxious weed, prohibited, invasive or banned: CT, MA.

Here is the interesting Japanese paper from 1968: 

There are more recent studies on the Euonymus alatus plant:

Euonymus alatus (E. alatus) is a medicinal plant used in some Asian countries for treating various conditions including cancer, hyperglycemia, and diabetic complications. This review outlines the phytochemistry and bioactivities of E. alatus related to antidiabetic actions. More than 100 chemical constituents have been isolated and identified from E. alatus, including flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids. Studies in vitro and in vivo have demonstrated the hypoglycemic activity of E. alatus extracts and its certain constituents. The hypoglycemic activity of E. alatus may be related to regulation of insulin signaling and insulin sensitivity, involving PPAR? and aldose reductase pathways. Further studies on E. alatus and its bioactive compounds may help to develop new agents for treating diabetes and diabetic complications.

A total of 26 flavonoids have been isolated and identified from E. alatus. The main structure types include flavonoid, flavanone, and flavonol. The aglycones of flavonoid glycosides isolated from E. alatus include quercetin, kaempferol, naringenin, aromadendrene, and dihydroquercetin. The flavonoids are mainly distributed in the leaves and wings of E. alatus
There is no mention of oxaloacetic acid.
The active components in protecting experimental diabetic nephropathy as mentioned above have also been suggested to be concentrated in ethyl acetate and n-butanol fractions [36, 40], though the nature of these compounds is still not identified. 
Euonymus alatus (E. alatus) has been used as a folk medicine for diabetes in China for more than one thousand years. In order to identify major active components, effects of different fractions of E. alatus on the plasma glucose levels were investigated in normal mice and alloxan-induced diabetic mice. Our results show that ethyl acetate fraction (EtOAc Fr.) displayed significant effects on reducing plasma glucose. In oral glucose tolerance, EtOAc Fr. at 17.2 mg/kg could significantly decrease the blood glucose of both normal mice and diabetic mice. After 4 weeks administration of the EtOAc Fr, when compared with the diabetic control, there were significant difference in biochemical parameters, such as glycosylated serum protein, superoxide dismutase and malondial dehyde, triglyceride, and total cholesterol, between alloxan-induced diabetic mice and the control group. Additional histopathological studies of pancreatic islets also showed EtOAc Fr. has beneficial effects on diabetic mice. Chemical analysis with three-dimensional HPLC demonstrated that the major components from EtOAc Fr were flavonoids and phenolic acids, which had anti-oxidative effects on scavenging DPPH-radical in vitro. All these experimental results suggest that EtOAc Fr. is an active fraction of E. alatus and can prevent the progress of diabetes. The mechanism of E. alatus for glucose control may be by stimulating insulin release, improving glucose uptake and improving oxidative-stress.

Oxaloacetic acid
You already have Oxaloacetic acid in your body, you make it.
Oxaloacetic acid (also known as oxalacetic acid) is a metabolic intermediate in many processes that occur in animals. It takes part in the gluconeogenesis, urea cycle, glyoxylate cycle, amino acid synthesis, fatty acid synthesis and citric acid cycle. Oxaloacetate is also a potent inhibitor of Complex II.

Conclusion
This post was prompted by our reader LatteGirl, who was asking about the supplement BenaGene and ketones. BenaGene contains 100mg of OAA and the company behind it is the sponsor of some the current OAA clinical trials.
The BenaGene supplement is sold by some companies that sell ketone products, but I do not really see big connection between OAA and ketones.   
If you can materially increase the plasma level of OAA, you really would expect numerous changes to occur.
Depending on what might be wrong with you, OAA might provide a net benefit, but it all looks very hit and miss. 
Treatment of all neurological disorders from ALS, Alzheimer�s to depression currently is remarkably hit and miss. Most serious disorders have only very partially effective treatments, but they do get FDA approval nonetheless.
The OAA research suggests its effect is from �altered bioenergetic fluxes�. You might be wondering what this actually means, since it sounds like pseudoscientific mumbo jumbo. What this really means is that for one reason or another there is a shortfall in energy (ATP) to power your cells.

�Perturbed bioenergetic function, and especially mitochondrial dysfunction, is observed in brains and peripheral tissues of subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI) (1,2), a clinical syndrome that frequently represents a transition between normal cognition and AD dementia (3). Neurons are vulnerable to mitochondrial dysfunction due to their high energy demands and dependence on respiration to generate ATP (4). Mitochondrial dysfunction may, therefore, drive or mediate various AD pathologies.�

Impaired energy (ATP) production can be caused by a deficiency in one of the mitochondrial enzyme complexes (often complex 1), but it could be caused by too few mitochondria (each cell needs many) or it could be caused by a lack of fuel (glucose or ketones), or oxygen.
Glucose crosses the blood brain barrier via a transporter called GLUT1.
GLUT1 deficiency leads to epilepsy, cognitive impairment and a small head (microcephaly). It can be treated by adopting the ketogenic diet, where ketones replace glucose as the fuel for your brain and body.
Oxygen freely crosses the blood brain barrier, but sometimes there is not enough of it. To increase the amount of oxygen that is carried in the blood, mountaineers and the military sometimes use the drug Diamox, which changes the pH of your blood, among other effects.
The brain's blood supply is via microvasculature/microvessels. This does seem to be impaired in autism, according to the research, resulting in unstable blood flow to the brain. 
Thyroid hormones are generally seen as regulating your basal/resting metabolic rate, so rather like your idle on your car, when you do not press the accelerator/gas pedal.  If the idle rate is too low your car will stall in traffic.
Thyroid hormone has many other effects and these are very important in the brain, particularly during development. A lack of the T3 hormone will lead to a physically different brain, whereas in adulthood it just causes impaired function which is reversible.
Thyroid hormones T3 and T4 can cross the blood brain barrier. The prohormone T4 is converted into the active hormone T3 within the brain. Some research suggests that T4 may have a direct role in the brain, rather than simply being a source of T3.

Thyroid receptors in the brain
TRa1 encompasses 70�80% of all TR expression in the adult vertebrate brain and TRa1 is present in nearly all neurons
It appears that windows in brain development may exist where T4 itself may act on TRa1.
Thyroid Hormone (TH) endocrinology in the CNS is tightly regulated at multiple tiers. Negative feedback loops in the hypothalamus and the pituitary control T3 and T4 output by the thyroid gland itself. Further, multiple phenomenon functions together to modulate the transport of circulating TH through the BBB, and multiple transporters act together to directly alter TH availability in the CNS itself. Additionally, conversion of intracellular T4 into T3 by deiodinase 2, inactivation of both T3 and T4 by deiodinase 3, and, the ability of different TR isoforms and different coregulators to respond directly to T4 versus T3 further regulate the CNS response to TH. 


The thyroid hormone receptor subtypes TRa and TR� are expressed throughout the brain from early development, and mediate overlapping actions on gene expression. However there are also TR-subtype specific actions. Dio3 for example is induced by T3 specifically through TRa1. In vivo T3 regulates gene expression during development from fetal stages, and in adult animals. A large number of genes are under direct and indirect regulation by thyroid hormone. In neural cells T3 may control around 5% of all expressed genes, and as much as one third of them may be regulated directly at the transcriptional level. Thyroid hormone deficiency during fetal and postnatal development may cause retarded brain maturation, intellectual deficits and in some cases neurological impairment. Thyroid hormone deficiency to the brain during development is caused by iodine deficiency, congenital hypothyroidism, and maternal hypothyroidism and hypothyroxinemia. The syndromes of Resistance to Thyroid Hormones due to receptor mutations, especially TRa, cause variable affectation of brain function. Mutations in the monocarboxylate transporter 8 cause a severe retardation of development and neurological impairment, likely due to deficient T4 and T3 transport to the brain.   

Thyroid hormones are essential for brain maturation, and for brain function throughout life. In adults, thyroid diseases can lead to various clinical manifestations (1,2). For example, hypothyroidism causes lethargy, hyporeflexia and poor motor coordination. Subclinical hypothyroidism is often associated with memory impairment. Hypothyroidism is also associated to bipolar affective disorders, depression, or loss of cognitive functions, especially in the elderly (3). Hyperthyroidism causes anxiety, irritability, and hyperreflexia. Both, hypothyroidism or hyperthyroidism can lead to mood disorders, dementia, confusion, and personality changes. Most of these disorders are usually reversible with proper treatment, indicating that thyroid hormone alterations of adult onset do not leave permanent structural defects.
The actions of thyroid hormone during development are different, in the sense that they are required to perform certain actions during specific time windows. Thyroid hormone deficiency, even of short duration may lead to irreversible brain damage, the consequences of which depend not only on the severity, but also on the specific timing of onset and duration of the deficiency (4-8).
Hypothyroidism causes delayed and poor deposition of myelin

Pep up your Bioenergetic Fluxes
Within this blog we have encountered a wide range of methods that might help put correct a deficiency in power available to the brain.
      Improve brain microvasculature function (Agmatine)

      Ensure central basal metabolic rate is high enough (T3 hormone)

      Increase D2 (lower oxidative stress, kaempferol) if centrally hypothyroid

      Increase number of mitochondria (activate PGC1alpha)

      Ensure adequate mitochondrial enzyme complexes for OXPHOS

      Ensure adequate glucose transport via GLUT1

While I still feel Bioenergetic Fluxes sounds like something very quack-like, it is the valid terminology and it does look important to many neurological conditions.
In Monty, aged 14 with ASD, Agmatine has worked wonders, in terms of being far more energetic. I assume the effect is via increasing eNOS (endothelial nitric oxide synthase) and this has improved blood supply. We saw that blood flow through microvasculature/microvessels is impaired in autism.  We also saw that in mouse model of Alzheimer�s, Agmatine has a similar positive effect; this also seems to apply in at least some humans with Alzheimer�s.  

Diabetes
We can certainly add Oxaloacetate to the long list of substances we have come across in this blog that may well be therapeutic in diabetes. In the case of Oxaloacetate, it is type-1 that seems to uniformly benefit, whereas in type-2 diabetes some benefit and some do not.
It is amazing that in type-1 diabetes, only insulin is routinely prescribed, when so many things can increase insulin sensitivity and reduce the severe complications of this type of diabetes.
In the case of type-2 diabetes, you can halt its progression and, for the really committed, we saw how you can reverse it.
If a common, life-threatening, condition like diabetes is not fully treated, no wonder nobody bothers to treat an amorphous condition like autism.







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.





Ketones and Autism Part 4 � Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1�

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD ea...