Understanding The Cell Danger Response
- The cell danger response is an ancient metabolic response to ‘threat’.
- The cell danger response encompasses many facets of cellular function: inflammation, oxidative stress, innate immunity, and the ER stress response.
- The cell danger response is maintained by extracellular nucleotide (purinergic) signaling.
- Chronic persistence of the cell danger response may be the cause of many chronic diseases.
- Antipurinergic therapy (APT) may be effective in many chronic disorders – as proven in animal models (see treatment section below)
What Is The Cell Danger Response?
The cell danger response is an evolutionarily conserved metabolic response that protects cells, and thus the host, from harm. It is triggered by physical, chemical, or biological threats that exceed the cells capacity to cope with the threat.
The resulting metabolic mismatch between the available resources of the cell, and functional capacity of the cell, produces a cascade of changes in cellular function. Some of these changes include: electron flow, oxygen consumption, redox, cell membrane fluidity, lipid dynamics, bioenergetics, carbon and sulphur resource allocation, vitamin availability, metal homeostasis (such as heavy metals). (source)
What Should Normally Happen?
After the danger has been eliminated or neutralised, anti-inflammatory and cellular regenerative pathways should be activated to reverse the cell danger response and to heal. When the cell danger response persists, whole body metabolism and the gut microbiome are disturbed, resulting in multiple organ systems being impaired, and chronic disease. (source)
What Conditions Have Been Associated With The Cell Danger Response?
These disorders include autism spectrum disorders, 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, traumatic brain injury, epilepsy, suicidal ideation, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis. (source)
Features Of The Cell Danger Response
Mitochondria fragment under conditions of the cell danger response leading to ineffective control and propagation of intracellular calcium transients. When cells are injured and mitochondrial proteins are released to the extracellular space, these proteins can trigger inflammation. (source)
When mitochondrial oxygen consumption decrease, oxygen rises and activates reactive oxygen species (ROS) production. Increased oxygen, superoxide and hydrogen peroxide trigger inflammation via NFkB. (source)
Sulphur metabolism is shifted such that glutathione is consumed liver phase two detoxification reactions, and the amino acid cysteine is diverted to reduce hydrogen sulphide. (source)
In the face of normal body stores of calcium and phosphorus, vitamin D metabolism is altered significantly by the cell danger response. A mitochondrial P450 enzyme, the 1α hydroxylase, in the kidney is required to activate 25-Hydroxyvitamin D to hormonally active, 1,25-Dihydroxyvitamin D. Another mitochondrial enzyme, the 24α-hydroxylase, is used to inactivate vitamin D. The mitochondrial enzyme, 24α-hydroxylase, is increased by cell danger threats like endotoxin.
This decreases the concentration of active vitamin D and contributes to the cell danger response by increasing inflammation, but also increases the risk of developing of autoantibodies that may include anti-thyroid antibodies, and may contribute to the development of other autoantibodies like anti-folate receptor antibodies. (source)
Folate and Vitamin B12
The metabolism of folate and vitamin B12 is tightly interconnected with mitochondrial function, sulfur metabolism, methylation (among other things such as glycine). Ultimately the flux through alternative pathways of folate, glutathione, and methionine metabolism is determined by cellular redox. (source)
The fluidity of the cell membrane is the result of thermal packing of fatty acid side chains. In general, the shorter and more polyunsaturated the side chain, the more fluid the membrane. Reciprocally, the longer the carbon side chain, and the more saturated, the stiffer the membranes become. Under conditions of the cell danger response, the cell membrane is stiffened by progressive replacement of shorter polyunsaturated lipids with longer, more saturated lipids. (source)
Low plasma levels of the active metabolite of vitamin B6, pyridoxal 5′-phosphate (PLP) are a common feature of inflammation and the cell danger response. This may impact histamine metabolism (see more below) (source)
The chronic activation of the cell danger response alters both the gut microbiome and the availability of nutrients. For example, in children with autism, the expression of intestinal disaccharidases is decreased so that the microbiome of the colon receives a larger number of simple disaccharides like sucrose, lactose, and maltose. This may result in IBS like symptoms due to excessive fermentation. (source)
My Interview with Dr. Neal Nathan
How To Treat The Cell Danger Response
“What is really important is that we restore biochemical balance in order to turn off the CDR alarm.” Neil Nathan
When the abnormalities appear later in childhood or young adult life, and have not persisted long enough to produce structural abnormalities, there is a chance that many disorders currently thought to be static, irreversible, and poorly responsive to treatment, or even degenerative, might actually be dynamic functional states that respond well to anti-CDR treatments. (source)
Firstly the danger has to have been eliminated or neutralised.
The next step is to address the relevant metabolic features of the cell danger response whichcan be addressed individually with specific treatments, or more globally with a combination of supplements, dietary and activity changes, or with adaptogen therapies. (source)
However, since the cell danger response appears to be a functional response that is coordinated by purinergic signaling, a new chapter in complex disease therapeutics can be imagined in which the pharmacology of purinergic antagonists is expanded, natural products are sought, and new anti-inflammatory drugs are developed that selectively target one or more of the 19 known classes of purinergic receptors. (source)
Stressed cells release purinergic signaling molecules, like ATP – you may have heard about ATP as the ‘energy currency’ of the cell. These molecules activate the process of inflammation, and this, in turn, stimulates the body to make more cortisol. What’s interesting here is that this process is independent of the pituitary gland. This process is set off directly by the cell danger response.
Of all the features listed here, this one may be the most immediately amenable to treatment and is critical in the rebooting of the cell danger response.
Suramin is a purinergic blocking agent. Dr. Naviaux has published a ground breaking preliminary study of its benefits.
Methylation is altered as part of the cell danger response, meaning that supporting methylation is an obvious thing to consider
Optimising Key Nutrients
Key nutrients to consider are:
- Addressing vitamin D intake following the measurement of vitamin D in the blood.
- The addition of lysine to the treatment program, if warranted.
- Addressing vitamin B6.
- And the amino acid tryptophan.
The cell danger response stimulates histidine decarboxylase – an enzyme that is involved in histamine metabolism and dependent on vitamin B6.
Looking at histamine production is therefore critical.
Restoring The Gut Microbiome
Restoring an imbalanced gut microbiome is not as simple as adding back missing species of bacteria. The physical habitat, often called the terrain, of the gut and the nutrients delivered (i.e food) must be durably changed in order to produce a durable change in the complex microbial ecosystem. (source)
You may like to read my blog What Does A Healthy Microbiome Look Like.
Dr. Nathan in his book Toxic mentions he has used two specific forms of magnesium – magnesium taurate and magnesium glycinate – with great benefit over the years. If the deficiency is profound, with intracellular magnesium levels measuring below 31.0 mEq/L, oral magnesium may be insufficient, and intravenous magnesium administration may be necessary.
Giving phosphatidylcholine intravenously has been a wonderful adjunct treatment, helping to strengthen and heal nerve tissues and membranes.
Amino Acid Supplementation
In multiple research studies, Marty Hinz, MD, has shown that the use of 5-HTP and L-tyrosine, when used with cofactors and other amino acids, especially cysteine, dramatically improved a wide variety of illnesses. This is particularly true of neurodegenerative diseases, such as Parkinson’s, but applies to depression, anxiety, chronic fatigue, and fibromyalgia as well.
Hyperbaric Oxygen Therapy (HBOT)
Long used for treating divers with decompression illness, hyperbaric chambers also are used in conventional medicine for treating serious infections that are not responding to the usual antibiotic approaches and for healing wounds that are not healing properly. We are increasingly finding HBOT to be of value in helping to turn off the inflammatory response, and physicians are using it to treat Lyme disease and autism.
Additional Treatment Options
Frequency Specific Microcurrent
My interview with Marina Townsley:
The Gupta Program
My interview with founder Ashok Gupta: