Dr Ben Marlow looks at the way cells in the body cause the stress and anxiety seen in autism – and wonders if the future may hold a medication or therapy to calm it all down.
Since the beginning of August, my wife and I have been trying to toilet train our eight-year-old son Freddie. He has severe autism, learning impairment and other medical challenges I have previously written about in this publication.
Spending large amounts of time taking him to the bathroom has really crystallised for me just how stressful he finds the world he lives in. The noise of the toilet flush, reflections in the mirror, sitting on a cold toilet seat – all of these provoke fear. Pupils dilate, face flushes, pulse quickens and the intense ‘sympathetic drive’ of ‘fight or flight response’ overwhelms. Adrenaline and cortisol surge, resulting in intense crying, raging or other emotions.
Stress: the impact it has not just on the nervous system, but also on all other parts of the body (the gut, glucose homeostasis and our immune system) is, for me, the key unifier in the broad umbrella diagnosis that is autism.
No matter what the level of autism (including non-verbal and associated learning difficulty, as with Fred), stress and anxiety impacts all. It’s largely from the oversensitive response to the world around us, or ‘superpowers’ that many are born with but don’t need.
Cellular stress
What if we were to dive deeper into this stress response, looking at a cellular level, and try to find a therapy that turns the volume on this signalling down? What becomes apparent if we do this is that there are many other disease areas that have this heightened ‘cell danger response’ (CDR).
Professor Robert Naviaux (based at the departments of Medicine, Pediatrics and Pathology at the University of California, San Diego) introduced the concept of the CDR in 20141. His lab discovered the molecular basis of Alpers syndrome, which is the oldest Mendelian (where there are traits passed from parents to offspring) form of mitochondrial disease (a disorder that occurs when the energy-producing parts of cells fail to work properly).
His lab was also the first to show that defects in a human DNA polymerase (an enzyme that duplicates the genetic information stored in DNA) could cause human disease. The team’s current research focuses special attention on the crossroads of innate immunity, inflammation, somatic cell genetics (studying mechanisms of inheritance by using cells in culture), and metabolism in chronic disease.
Naviaux’s theory is: ‘The cell danger response is the evolutionarily-conserved metabolic response that protects cells and hosts from harm (from pathogens, chemicals, physical stressors).’1
He explains that when danger is detected, the mitochondria alter cellular metabolism to shield the cell from further injury, downregulating as a protective mechanism. Mitochondria decrease oxygen consumption and stiffen their membrane to limit the spread of pathogens. They also release antiviral/antibacterial chemicals and a molecule called ATP, which acts as a warning messenger to other cells so the ‘danger response’ is propagated throughout the body.
This ATP is a very good messenger and spreads the warning rapidly: it impacts the immune system (mobilising the innate immune response), changing utilisation of sugar (first described as the ‘Warburg effect’2), using the sugar quickly but very inefficiently to help fuel the stress response.
Naviaux postulates there are several stages. Once the danger has been dealt with by the body system, there should be a restorative healing phase; however, in some diseases the individual becomes stuck in the ‘danger phase’, which stops healing and leads to chronic illness, Alzheimer’s, chronic fatigue/ME or autism. The body becomes ‘over responsive’ and ‘oversensitive’ to harmless triggers, which cause the flood of extracellular ATP (eATP) and puts the body on high alert. The stress never gets turned off.
Drug tests
A drug that has an impact on this ATP stress signalling is suramin. It’s an inhibitor of purinergic signalling (which is when purinergic receptors in the cell or nearby cells regulate cellular functions). It stops the eATP signal reaching other cells by binding to and blocking the receptor.
Suramin was first synthesized in 1916, making it one of the oldest manufactured drugs still in medical use. It is used to treat African sleeping sickness (trypanosomiasis), and remains on the World Health Organization list of essential medications.
Based on the CDR theory and early research on mouse models of autism, a clinical trial was devised and carried out. In the 2017 SAT-1 trial3 (Phase 1/II), 10 boys aged from five to 14 were randomised to take either a placebo or a 20mg/kg infusion of suramin. The treatment group saw improvements in an ADOS score (a way of assessing autism) and secondary measures of language, social interaction and an observed reduction in restricted behaviour.
A second Phase II trial was carried out in 2021 by biopharmaceutical company PaxMedica. It involved more participants: a total of 52 boys aged from four to 15 who were randomised into three arms – 10mg/kg suramin, 20mg/kg suramin, and placebo.
The study measured outcomes using an Aberrant Behaviour Checklist and Clinician’s Global impression (CGI). The primary outcome measure, the Aberrant Behaviour Checklist, did not yield a significant result in comparison to placebo, aside from a subset analysis for the younger participants with milder symptoms. A subset analysis of an already small sample size must be viewed with caution. The secondary outcome, the Clinician’s Global Impression, did reveal a significant benefit in the lower dose of 10mg/ kg compared to placebo.
The future
Having a medication or therapy that can ‘turn the volume down’ on the amplified stress response seen in autism could have a significant impact on quality of life and development. It could also see a reduction in the common health comorbidities seen in autism. Suramin and molecules that work on this cellular stress response could also potentially have an impact outside of research into autism. It could impact research into other chronic diseases linked to stress, exaggerated immune response and metabolic compromise, such as Alzheimer’s and chronic fatigue.
REFERENCES
1 Naviaux, RK: ‘Metabolic features of the cell danger response’, Mitochondrion, 2014 May;16:7-17. doi: 10.1016/j. mito.2013.08.006. Epub 2013 Aug 24. PMID: 23981537, https://pubmed.ncbi.nlm.nih.gov/23981537/
2 Vallée, A, Vallée, JN: ‘Warburg effect hypothesis in autism spectrum disorders’, Mol Brain 11, 1 (2018), https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-017-0343-6
3 Naviaux, RK et al: ‘Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial’, Ann Clin Transl Neurol, 2017 May 26;4(7):491-505. doi: 10.1002/acn3.424. PMID: 28695149; PMCID: PMC5497533, https://pubmed.ncbi.nlm.nih.gov/28695149