April 30, 2022 7:00 am

The science of how to heal is growing rapidly.

Dr. Naviaux published a journal article that organizes the current knowledge on the cell danger response.

I consider it a seminal work and one of four groundbreaking theories that form the basis of how I restore health.

histamine intolerance, mast cell activation, medicines, antidepressants, brain fog, alison vickery, health, australia


Health happens on a spectrum.

At one end of the spectrum, the body can seamlessly maintain health. It does this through what Naviaux calls the health cycle.

If you have pricked your finger with a lancet or seen your finger bleed and repair itself, this is an example of the body seamlessly maintaining health.

At the other end of the spectrum, the body can no longer address stressors as cells and organs have stopped functioning, and a disease process is underway.

It does so when over time as more and more cells fail to be repaired such that organs begin to fail. This is where medicine excels.

In the middle of these two extremes, the body attempts to restore health by running health and cell repair programs, and we experience symptoms.

I like the analogy of a sailing boat rocking under strong winds (stressors) and rough seas (cellular capacity).

The boat’s rocking (including releasing histamine) is the boat trying to sail upright (by running the cell danger response cycle).

Unblocking the health cycle allows the boat to sail upright once again.


The Four Stages

Naviaux has suggested four distinct stages of healing based on distinct cellular characteristics.

The four stages are the;

Health cycle,

Cell danger response 1 (CDR1),

Cell danger response 2 (CDR 2), and

Cell danger response 3 (CDR3).

Naviaux has also provisionally organized over 100 conditions into each stage, providing a working hypothesis on where targeted solutions can promote healing.


histamine intolerance, autoimmunity, mast cell activation, cell danger response, Alison Vickery, Health, Australia

The Health Cycle

I have previously covered the foundations on which the health cycle depends.

This includes; circadian rhythms, metabolic flexibility, attending to physical stressors, and perceived stress.

The significance of the health cycle is that the body knows what to do.

Overall, no supplements (other than detoxification) are needed in the health phase.


The Cell Danger Response Cycles

The health cycle was not designed to handle continual exposure to sources of threats and stress.

When the total stressor load exceeds the health cycle’s ability to restore health, the body moves through three stages of the cell danger response.

The cell danger response is a primitive mechanism that protects cells and ourselves from harm. When our cells encounter a level of threats that exceeds the cell’s capacity for homeostasis, the mitochondria release ATP from the cell.

The extra-cellular ATP binds to purinergic receptors on the cells’ surface, initiates the cell danger response, and amplifies inflammation.

Purinergic receptors are found on cells throughout the body, including mast cells. Importantly, ATP not only degranulates mast cells, but mast cells also release ATP when they degranulate.

These stages are characterized by:

1. The HPA Axis

When a cell is stressed, the mitochondria respond by sending alarm signals to over 22 stress response systems.

Changes to the hypothalamic-pituitary-adrenal (HPA) axis are a hallmark of the cell danger response. They commence on CDR1 and resolve on exit from CDR3 to the health cycle.

Adrenal support is frequently needed as part of the first stage of the cell danger response.

The involvement of the HPA axis can be assessed with a DUTCH test.


2. The Mitochondria

The mitochondria generate the energy-rich molecule adenosine triphosphate (ATP). ATP has two roles. Within the cell, it produces energy. Outside the cell, it signals that there is a threat, starts the cell danger response, and triggers inflammation within the body.

Naviaux categorizes the cell danger response into three different mitochondrial responses; glycolysis (CDR1 blockage), aerobic glycolysis/pyruvate (CDR2 blockage), citric acid cycle, and oxidative phosphorylation (CDR3 blockage).

At the time of stage 2, the mitochondria are likely struggling and need support.

An organic acid can measure mitochondrial function. I like running this test with the Vibrant America Micronutrient Test to target mitochondria nutrients.



3. The Autonomic Nervous System

At CDR1, the cell gains cell autonomy to quarantine and repair itself. Healing remains incomplete until CDR3 is completed and cells reintegrate and take up their organ-specific role.

I like to use the analogy of the mitochondria being the fuse, the autonomic nervous system being the electrical wiring, and the brain being the switchboard. When a cell is stressed, the mitochondria blow a fuse and block communication.

This cell autonomy remains until CDR3. The last step of CDR3 requires the cell to re-establish bi-directional communication with the brain via the autonomic nervous system.

Only then can the health cycle be re-established. This is why I consider autonomic response testing so crucial.

The autonomic nervous system helps to determine whether a cell is functional or not. It can also determine whether the autonomic nervous system itself as a whole is overwhelmed by a total load of stressors.

Autonomic response testing provides precision around what the autonomic nervous system is trying to resolve and what will rebalance or bring the autonomic nervous system back online.

Restoring Health

Naviaux’s four distinct stages of healing provide a hierarchy.

Naviaux has also provisionally organized over 100 conditions into each stage, providing a working hypothesis on what support is needed at each stage.

This support potentially includes:

Cell danger response 1 (CDR1) – pyrroles, acetylation, methylation, uric acid, and adrenal support.
Cell danger response 2 (CDR 2) – mitochondrial support.
Cell danger response 3 (CDR3) – anti-purigenic support (typically with suramin).

There is a very high correlation between these stages and what I see in my client base. Notably, many of my clients have pyrrole and acetylation issues that are switched on by the cell danger response and switched off once homeostasis is restored, and not necessarily a diagnosis.


LifeWave Patches

LifeWave patches work on the energy body and restore balance to the autonomic nervous system, which is so vital to the cell’s danger response.

Over the last year or more, I have been refining my use of the LifeWave patches based on this cell danger response theory as follows:

This support potentially includes:

Cell danger response 1 (CDR1) – a kidney/adrenal protocol
Cell danger response 2 (CDR 2) – mitochondrial support using the X39 and X49 patches.
Cell danger response 3 (CDR3) – when little if any supplements are tolerated, I find that the patches can be used to address underlying stressors that would otherwise be treated with medicines or supplements.

The LifeWave patches are the most effective way of supporting the energy body.



The importance of the cell danger response to me is not in identifying medicines or mast-cell stabilizers but in providing a clear pathway to restore health.

Diagnoses and medications make for lifetime clients and are good for business. They are not necessarily good for health.

Having worked within this model since this paper was first published, I firmly believe that it provides a hierarchy that explains how ill health progresses and how we can heal.

We can either wait and do nothing or wait for a disease process. Or we can get busy supporting our body to restore health.


Additional Reading

Meyer, Joel N., et al. “Mitochondria as a target of environmental toxicants.” toxicological sciences 134.1 (2013): 1-17.

Naviaux, Robert K. “Metabolic features of the cell danger response.” Mitochondrion 16 (2014): 7-17.

Naviaux, Robert K., et al. “Antipurinergic therapy corrects the autism-like features in the poly (IC) mouse model.” PloS one8.3 (2013): e57380.

Naviaux, Robert K. “Oxidative shielding or oxidative stress?.” Journal of Pharmacology and Experimental Therapeutics342.3 (2012): 608-618.

Naviaux, Robert K., et al. “Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial.” Annals of clinical and translational neurology 4.7 (2017): 491-505.

Naviaux, Robert K. “Antipurinergic therapy for autism—An in-depth review.” Mitochondrion (2017).

Naviaux, Robert K., et al. “Metabolic features of chronic fatigue syndrome.” Proceedings of the National Academy of Sciences 113.37 (2016): E5472-E5480.

Theoharides, Theoharis C. “Extracellular mitochondrial ATP, suramin, and autism?.” Clinical Therapeutics 35.9 (2013): 1454-1456.

Theoharides, Theoharis C., et al. “The “missing link” in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells.” Autoimmunity reviews 12.12 (2013): 1136-1142.

Adinolfi, Elena, et al. “The P2X7 receptor: a main player in inflammation.” Biochemical pharmacology (2017).

Kurashima, Yosuke, et al. “Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors.” Nature communications 3 (2012): 1034.

Wu, Shu-Jing, Yuan-Shuai Liu, and Jian-Yong Wu. “The signaling role of extracellular ATP and its dependence on Ca2+ flux in elicitation of Salvia miltiorrhiza hairy root cultures.” Plant and cell physiology 49.4 (2008): 617-624.

Fulkerson, Patricia C., and Marc E. Rothenberg. “Targeting eosinophils in allergy, inflammation and beyond.” Nature reviews Drug discovery 12.2 (2013): 117.

Bartlett, Rachael, Leanne Stokes, and Ronald Sluyter. “The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease.” Pharmacological reviews 66.3 (2014): 638-675.

Ochoa-Cortes, Fernando, et al. “Potential for developing purinergic drugs for gastrointestinal diseases.” Inflammatory bowel diseases 20.7 (2014): 1259-1287.

Faria, Robson, et al. “Action of natural products on P2 receptors: A reinvented era for drug discovery.” Molecules17.11 (2012): 13009-13025.

Vafai, Scott B., and Vamsi K. Mootha. “Mitochondrial disorders as windows into an ancient organelle.” Nature 491.7424 (2012): 374-383.

Safiulina, Dzhamilja, and Allen Kaasik. “Energetic and dynamic: how mitochondria meet neuronal energy demands.” PLoS Biology 11.12 (2013): e1001755.

Parikh, Sumit, et al. “A modern approach to the treatment of mitochondrial disease.” Current treatment options in neurology 11.6 (2009): 414-430.

Nicolson, Garth L., and Michael E. Ash. “Lipid replacement therapy: a natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function.” Biochimica et Biophysica Acta (BBA)-Biomembranes 1838.6 (2014): 1657-1679.

Lane, Nick, and William Martin. “The energetics of genome complexity.” Nature 467.7318 (2010): 929-934.

Nunnari, Jodi, and Anu Suomalainen. “Mitochondria: in sickness and in health.” Cell 148.6 (2012): 1145-1159.

Vasquez, Alex. “Mitochondrial medicine arrives to prime time in clinical care: nutritional biochemistry and mitochondrial hyperpermeability (“leaky mitochondria”) meet disease pathogenesis and clinical interventions.” Integrative Medicine: A Clinician’s Journal 13.4 (2014): 44.

Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat. Immunol. 2007; 8: 11–13

Matzinger, Polly. “The danger model: a renewed sense of self.” Science 296.5566 (2002): 301-305.

Ryu, Shi Yong, Min-Ho Oak, and Kyeong-Man Kim. “Inhibition of mast cell degranulation by tanshinones from the roots of Salvia miltiorrhiza.” Planta Medica 65.07 (1999): 654-655.

Zhang, Jun, et al. “Effects of puerarin on the inflammatory role of burn-related procedural pain mediated by P2X7 receptors.” Burns 39.4 (2013): 610-618.

Wareham, Kathryn J., and Elizabeth P. Seward. “P2X7 receptors induce degranulation in human mast cells.” Purinergic signaling 12.2 (2016): 235-246.

Sibaev, A., et al. “Iberis amara L. constituents reduce excitatory cholinergic and inhibitory purinergic neurotransmission.” Planta Medica 76.12 (2010): P618.

Zhang, Jun, et al. “Study of baicalin on sympathoexcitation induced by myocardial ischemia via P2X3 receptor in superior cervical ganglia.” Autonomic Neuroscience: Basic and Clinical189 (2015): 8-15.

Shemon, Anne N., et al. “Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor.” British journal of pharmacology 142.6 (2004): 1015-1019.

Ruprecht, Ruth M., et al. “Suppression of retroviral propagation and disease by suramin in murine systems.” Proceedings of the National Academy of Sciences 82.22 (1985): 7733-7737.

Balzarini, Jan, et al. “Comparative inhibitory effects of suramin and other selected compounds on the infectivity and replication of human T cell lymphotropic virus (HTLV-III)/lymphadenopathy?associated virus (LAV).” International journal of cancer 37.3 (1986): 451-457.

Hamidpour, Rafie, et al. “Antipurinergic therapy with suramin as a treatment for autism spectrum disorder.” J. Biomed. Sci5.14 (2016): 10-4172.

Mahoney, C. W., A. Azzi, and K. P. Huang. “Effects of suramin, an anti-human immunodeficiency virus reverse transcriptase agent, on protein kinase C. Differential activation and inhibition of protein kinase C isozymes.” Journal of Biological Chemistry265.10 (1990): 5424-5428.