Robert Naviaux is the real deal and his theory on the Cell Danger Response is fascinating [1]. In addition to ASD, he recently made a significant discovery in the characterization of Chronic Fatigue Syndrome as a metabolic illness [2].
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.
Schizophrenia is basically symptoms of permeability of the blood brain barrier. Whole proteins pass through and mess things up. Similar to automimmune disease. Why else are those diseases on the list the only ones increasing in pravalence, and all others are decreasing (infectious, cancerous, viral, etc.). ASD is neuroprotective and tightens those cell junctions, with behavioral drawbacks. All these things are interrelated, the issue is they can be caused by 100k different contributing factors and susceptibilities.
If the diagnosis rate (incidence) increases, and people aren't dying rapidly, then the prevalence would surely increase as well. Unless you're using prevalence in the context of total people affected by a disease, regardless of whether or not they were diagnosed.
Wait, how was Chronic Fatigue not a metabolic illness? I always assumed it was a mitochondrial disfunction from the way it was described in the literature.
There was an infamous clinical trial called "PACE" that purported to show that psychotherapy (CBT), along with exercise ("graded exercise therapy", or "GET") gradually increased beyond one's initial limits, was an effective treatment for chronic fatigue. The idea is that CFS patients do not have a metabolic illness; rather, they are suffering from self-reinforcing "unhelpful beliefs" that cause them to fear and avoid physical activity. Even the very act of attributing one's chronic fatigue to a physical illness is itself pathologised (and is to be attenuated via CBT) under this framework.
However, the PACE trial was a complete bodge; the protocol and criteria for classifying "recovery" were changed during the trial (to the point that a patient that got worse could nevertheless be classified as having "recovered), the outcome measures were subjective and self-reported (which are liable to be affected by CBT or other forms of social pressure), and conflicts of interest were not reported to participants.
Re-analyses of the data were thwarted by the fact that the researchers did not publish anonymised trial data, which violated the requirements of one of their funding sources and the requirements of one of the journals in which they published. There were plenty of methodological criticisms of the trial (http://www.virology.ws/2015/10/21/trial-by-error-i/) but the actual trial data was still not available. Academicians and patients alike unsuccessfully tried to get access to anonymised PACE data for years, and the PACE researchers did their absolute best to prevent that from happening -- including labelling legitimate requests for anonymised trial data (that they were obliged to publish) and criticism of their study as "vexatious" and "harassment" in a BMJ feature article (https://doi.org/10.1136/bmj.d3780). The Information Commissioner's Office ordered the PACE researchers to release the trial data, the researchers appealed that decision -- and got laughed out of court. The tribunal concluded that there indeed was a very strong academic interest in the data being released, that it was sufficiently anonymised to prevent re-identification, and went as far as to say that the PACE researchers were overly disparaging of patient groups and skeptical researchers -- and that legitimate requests for trial data and criticism of the PACE study did not constitute harassment.
Given how hard the PACE researchers tried to prevent release of the anonymised trial data, the results of the independent re-analysis (http://dx.doi.org/10.1080/21641846.2017.1259724) should not be too surprising. There was no basis for an in-flight change to criteria and protocols and CBT/exercise did not provide a statistically significant change in recovery. There are other serious issues with the PACE study's methods that are addressed in http://www.virology.ws/2017/03/13/an-open-letter-to-psycholo... or in the independent reanalysis linked (and there's a quite decent timeline and overview of the PACE trial here: http://me-pedia.org/wiki/PACE_trial).
Serious biological research (not nonsense by CBT-obsessed wankers who lie with statistics) into CFS continues and there's indeed many findings on potential biomarkers for CFS -- more keeps getting published, 10.1186/s40168-017-0261-y nor 10.1186/s12967-017-1161-4 weren't there last time I looked into this, for example. There's robust evidence of biomedical anomalies in CFS patients -- far more than enough for CFS to be considered a legitimate medical syndrome and not a psychiatric/psychological/"somatic" syndrome. That we haven't yet identified a biomarker useful for diagnosis nor know an aetiology certainly shouldn't disqualify CFS from being a medical syndrome!
Since there's plenty of evidence against the PACE trials' findings -- why do CFS patients object to it? After all, papers regularly do get proven wrong or have their findings revised, it's kinda how science operates. It's not the actual publication of the PACE results that have caused harm -- it's how the results were used. Since PACE was the first clinical trial of its scale on CFS patients, its findings ended up single-handedly defining clinical policy, treatment recommendations, and public policy relating to welfare and insurance. CBT and making patients do physical exercise is infinitely cheaper than any sort of medical treatment; and if the PACE trial happened to find that those will help people with CFS "recover" and get back to work, well, that's just a happy coincidence. That CBT is useless and excessive physical exercise harmful to CFS patients is immaterial; there's research that says it helps, so if you're a recalcitrant patient who complains, you're clearly not doing the CBT or the exercise enough! Similarly, the mere belief that CFS has a physical (and not psychological) cause is explicitly called out as one of the "harmful beliefs" that CBT is to neutralise -- disagreement with the treatment method (or familiarity with current medical research) is itself a sign that you're not taking CBT seriously.
It is not just through treatment guidelines (and denial of medical access beyond CBT and forced exercise) that the PACE results have materially harmed patients. Extremely unusually for a clinical trial, PACE was funded by the UK DWP -- and could not have returned better results to justify the DWP's agenda of cutting disability spending: http://www.centreforwelfarereform.org/uploads/attachment/492... . The DWP wanted findings to show that CBT and GET would get disabled people off benefits; and the PACE researchers (by changing the protocol/criteria halfway through) handed that to DWP on a silver platter. That CBT/GET are, in reality, useless (at best) is immaterial here -- DWP doesn't give a flying fuck whether people actually do get better or even manage to survive without disability benefit, they only needed these published findings to justify benefit cuts.
>(not nonsense by CBT-obsessed wankers who lie with statistics
I'm not sure if you realise that you're posting "hateful bollocks" as Dan puts it, but for the benefit of the other posters here I'll address your not-quite-so-bollocks points.
The main criticisms of the PACE trial were the measures of recovery, but recovery wasn't even measured in the main trial -- it was a secondary paper, and even the authors admitted that there are various measures of recovery.
There have been quite a lot of trials into CBT and GET in CFS, and overall there is a small-to-moderate effectiveness for the treatments. Long term followup from the PACE trial is consistent with the other trials...patients undergoing CBT and/or GET improve more quickly than patients getting "standard" treatment.
If you actually look at the research from people involved in the PACE trial, you'll see they have in fact done a lot of biological research (and have stated many times that the HPA axis and immune system are almost certainly involved). It is unfortunate that they chose to give the dubious theories about illness beliefs and deconditioning as the basis for the PACE trial. However just because the trial had a bogus theory behind the treatments doesn't mean they don't actually work. Also, having biological abnormalities doesn't rule out CFS being psychosomatic (as all psychosomatic illnesses will by definition have physical symptoms). In fact, given that CFS has been shown to be triggered by stress in the majority of cases, and given the abnormalities found in the stress system that mirror the effects of chronic stress, a psychosomatic explanation seems quite plausible.
> There's robust evidence of biomedical anomalies in CFS patients -- far more than enough for CFS to be considered a legitimate medical syndrome and not a psychiatric/psychological/"somatic" syndrome.
You make many good points, but this billious bit of hateful bollocks discredits the cause. It's far too common to hear CFS activists claiming "my illness is real, it's not in my head". It's hateful, it's beyond fucking stupid, and it needs to stop.
You dismiss entirely the severity and biological causes of illnesses like psychosis or bipolar. You dismiss entirely the debilitating nature of psychological illness such as OCD.
In 2010 psychiatric, neurologic, and substance misuse disorders were the leading cause of YLDs, and were over 10% of DALYs. (And the MH component was over 56%.
I don't think that's a fair characterization. If someone says they suffer from bipolar illness, you wouldn't assume that their "real" problem was that they had a sprained ankle. Similarly someone complaining of CFT shouldn't be assumed to have a mental health problem instead. That doesn't diminish the severity of either kind of problem.
Dan was just referring to the comment about mental/psychological illnesses being "not real". You bring up a different point (but that is still not an excuse for this attitude).
It should be added that there was major controversy about whether CFS was psychological in nature long before PACE, including a big public/media bustup around the 90s in the UK (and likely elsewhere) between CFS sufferers and many GPs.
Quick Googling to fact check this does seem to illustrate a bias by multiple world governments to marginalize those suffering from this, without any real scientific basis to do so.
Maybe it's my philosophical materialism, but I've never found that to be a satisfactory alternative explanation for anything. What can explain a psychological disorder other than underlying physical disease? Attributing a disease to psychological disorder is indistinguishable from saying "we don't understand what causes this."
>What can explain a psychological disorder other than underlying physical disease?
It's well established that the causality works both ways, i.e. physical illnesses can cause psychological symptoms, and psychological factors can cause physical symptoms, e.g.:
- fever-causing illnesses cause "sickness behaviour" consisting of depression, anxiety, fatigue, brain fog and other symptoms, causing by pro-inflammatory cytokines.
- exam stress has been shown to significantly increase EBV antibodies.
- psychological stress causes significant changes to the immune system through the effects of cortisol and adrenaline (the two main stress hormones are also two of the main immune modulators).
- psychological stress causes a release of TNF-a (a pro-inflammatory cytokine that is involved in sickness behaviour).
- fear causes bowel movements, due to the fact that the HPA axis (the main stress system) also influences bowel motility.
>Attributing a disease to psychological disorder is indistinguishable from saying "we don't understand what causes this."
Not really. If there are factors that point to psychological causation, it should be considered as much as other possible causes.
> What can explain a psychological disorder other than underlying physical disease? Attributing a disease to psychological disorder is indistinguishable from saying "we don't understand what causes this."
It might be ultimately reducible in this way, but the treatments for various psychological conditions are often very different than physiological problems.
Right, but that's also often just due to limitations in science. All psychological problems are physical, they're just very complex physics and chemistry of the brain which we still don't understand and have no medicated or surgical ways of altering for the better.
Just as you can heal a muscle injury with simple rehabilitating exercises, some psychological injuries can be rehabilitated similarly with exercise of the brain. That doesn't change the physicality of it.
This might help some aspects of ASD. Hopefully. However I do not see how it will reverse the altered neural migration occurring early in development, for example, unless it is administered in infancy or earlier while in the womb..
For those of you who read the side effects on the Wikipedia page, the article addresses 'em:
> Unlike treatment for African sleeping sickness, which involves multiple, higher doses of suramin over a period of time and frequently results in a number of adverse side effects ranging from nausea and diarrhea to low blood pressure and kidney problems, researchers said the single, low dose of suramin used in the ASD trial produced no serious side effects beyond a passing skin rash.
> It is also common to experience various sensations in the skin, from crawling or tingling sensations, tenderness of palms and the soles, and numbness of hands, arm, legs or feet.
That's an intriguing symptom, given that many inflammatory/autoimmune conditions cause peripheral neuropathy. I wonder if what is being described is the "unblocking" of peripheral nerves, causing a flood of signal-distorting noise as they re-join the nervous system.
Small sample sizes aren't necessarily damning. E.g. if you gave 5 rabies patients a treatment and they were all instantly cured, that would be extremely strong evidence it worked. Because rabies is 99.999% fatal and the chances of 5 randomly chosen people being cured by coincidence is basically 0.
In this case, for example: "We had four non-verbal children in the study, two 6-year-olds and two 14-year-olds. The six-year-old and the 14-year-old who received suramin said the first sentences of their lives about one week after the single suramin infusion. This did not happen in any of the children given the placebo." That seems promising and worth further study.
Many idiotic statements (such as yours) would be prevented if English language speakers agreed to a global moratorium on the use of the words "objective" and "subjective" until such time that it could be verified that 99.999% of the population could use them in regular discourse in non-idiotic ways.
And still:
“This work is new and this type of clinical trial is expensive,” he said. “We did not have enough funding to do a larger study. And even with the funding we were able to raise, we had to go $500,000 in debt to complete the trial.”
From TFA: "Suramin works by inhibiting the signaling function of adenosine triphosphate (ATP), a nucleotide or small molecule produced by cellular mitochondria and released from the cell as a danger signal. When CDR is activated, the effect of extracellular ATP is similar to a warning siren that never stops. Suramin inhibits the binding of ATP and similar molecules to key purinergic receptors, according to Naviaux."
Are there any other substances out there that inhibit ATP signaling?
If you said "purinergic signaling" then yes. I think the one used quite often is clopidogrel (plavix) that inhibits the ADP receptor on platelets to prevent them from aggregating.
As far as I know, though, the drugs studied that inhibit purinergic signaling have only been approved for anti-platelet purposes.
I vaguely remember ATP from GCSE biology - and in my head it's related to energy production in cells... I'm curious whether that's merely poor memory or not
We could just Google this....but ATP adenosine triphosphate is the preferred energy source in the cellular energy cycle. A phosphate gets broken off when a cell uses it leaving ADP which is... Something something, I forget the rest. It's more expensive for the body to extract energy from ADP.
Some of us don't. The article mentions a "14-year-old who had not spoken a complete sentence in 12 years".
As an autistic adult, it's really frustrating how high-functioning autistics and caretakers of low-functioning autistics constantly talk past each other and refuse to acknowledge that the other exists.
As one of the aformentioned caretakers I can attest that a certain narrowing of focus on one's own issues is part of the deal. I also have an autistic adult friend who is constantly dismayed by the focus on child autisim, so I can relate to what you are saying.
The focus on children is likley caused by the medical siloing of patients into pediactric and adult. Also researchers may want to focus on harm reduction, ie by preventing or amelirating autisitic symptoms in children it is likley to also prevent the downstream effects to their nervous systems. But certainly if researchers want to get a better understanding of treatment efficacy, adults should also be included in trials.
Our current diagnostic grouping of symptoms into an autisic spectrum is imperfect, I would be very supprised if autisim as we understand it today is caused by one thing. So if this research becomes a treatment it will likley only be benificial for a certain percentage.
[1] http://naviauxlab.ucsd.edu/wp-content/uploads/2016/09/cell_d... [2] http://naviauxlab.ucsd.edu/wp-content/uploads/2016/08/PNAS-2...