Cells can get stuck! 

Cells can get stuck in a reaction that was intended to heal the body. When that backfires, it becomes the problem instead.  I spoke of this a bit in an interview with Dr. Serrafino about FSM and how it can reboot your system from the cell danger response.

A toxin can trigger a series of reactions of cell danger leading to inflammation, immune dysregulation, hormone dysregulation, GI imbalances, pain, insomnia, fatigue and weight gain.

Dr. Shoemaker expanded his model to include CIRS as seen in many chronic conditions (Mold, Lyme, PANDAS, fibro, autism, etc).  We begin to realize there is a common denominator in all of these conditions. Given each person’s unique biochemistry, age and genetic predispositions, the same insult to the body can create a wide variety of symptoms.

Published in 2013, Dr. Navio termed the complicated biochemical abnormalities seen in inflammatory that is a deeply engrained primitive response by a cell being threatened by an infectious agent or toxin. He uses a virus entering a cell as an example and outlines a sequence of events the cell uses to respond to this threat via the cell danger.

This is termed the Cell Danger Response, or CDR.

The mitochondria and organelles detect the presence of an intruder as a diversion of electrons, or voltage drop, and decrease of electron flow within mitochondria. Mitochondria react to this drop almost instantly to decrease their oxygen consumption.

The oxygen concentration within the mitochondria within the mitochondria rises, making cellular redox chemistry more oxidizing to shield the cell from more injury.

This is a protective mechanism. 

This is a deeply engrained mechanism that is deeply ingrained within our cells.

This rise in mitochondrial oxygen concentration triggers 8 events within the cell as a result of the cell danger response.

1. The cellular metabolism shifts to prevent hijacking and assembly of cellular resources from intracellular pathogens. Viruses have to take advantage of host resources to make resources to make materials it needs to thrive. It cannot make what it needs for itself.  So, our cells have learned to attempt to deny the invading virus what it requires to grow and thrive, preventing replication.
2. Cell membrane stiffens to prevent the virus or other pathogen from leaving the cell. Basically, the cell is committing suicide for the greater good with the hope that the virus will be unable to spread to other cells.
3. Cell releases antiviral and antimicrobial chemicals into the areas around tot cell to further limit the spread of infectious agent
4. Autophagy and mitochondrial fission increase to remove intracellular pathogens
5. DNA methylation and histones are changed to alter gene expression. The invader cannot methylate- which is needed to make or repair DNA. This prevents them to replicate DNA and RNA without hijacking our methylation chemistry.  S we shut or own methylation chemistry to limit the virus
6. Endogenous retroviruses are mobilized to produce genetic variants. We attempt to change our genetics to make ourselves less susceptible to the attacker.
7. Neighboring and distance cells are warned- an alarm of the danger response
8. The behavior of the host is altered to limit the spread of infection-fatigue forces us to rest, we sleep more to conserve energy.

The next step is the understand the vital chemical reactions of the body affected by these protective events. And grasping the imbalances triggered by the microbe or toxin to give us a blueprint to start healing.

Turning off the CDR alarm relies on understanding the biochemical shift delineated by the CDR.

1. Stressed cells release ATP to activate the process of inflammation by activating the NLRP3 inflammasome that stimulates the body to make more cortisol, independent of ACTH. That means this cortisol production is separate from the pituitary gland to regulate stress hormones. It is set up directly by CDR.
2. Sulfur metabolism shifts so that glutathione is consumed in an attempt to regulate detox. Cysteine is diverted to making hydrogen sulfide and taurine. This process interferes with methylation a key component for restoring chemical balance.
3. Vitamin D metabolism is altered. Vitamin D plays a role in dealing inflammation and preventing autoimmunity. Threats of danger CDR (from exotoxins too) can increase activity of 24 a-hydroxylase that decreases concentration of active vitamin D and increases inflammation and risk of autoimmunity. This is why it is important to run both the stored (25 OH) and active (1,25 OH) vitamin D. I discuss Vitamin D assessment in more detail in part 1 of this blog. 
4. CDR directly stimulates the enzyme histamine decarboxylase (HDC). This enzyme is dependent on B6 to produce histamine (from histidine) which is important for mast cell and eosinophil cell functioning in their coordination of allergy and antiparasitic immunity
5. When CDR is activated, RBC and heme centers are released from damaged cells, interfering with porphyrin synthesis
6. The metabolism of the amino acid tryptophan can be altered in several ways in response of CDR. By hydroxylation, it may be converted to serotonin or melatonin (normal reaction). By dioxygenase pathway, it may be converted to KY or QA which produces more inflammation. Elevated levels are associated with anxiety, depression, heightened pain sensitivities and other psychological issues.
7. Effects of CDR are strongly regulated by effects of lysine. It turns out that dietary lysine is an antagonist of the gut serotonin receptor 4 and opposes CDR and anxiety.  Taking oral lysine can reboot CDR.
8. CDR produces low plasma level of P5P- the active form of B6. Pyridoxine is another name for B6.  A deficiency in P5P shifts metabolism of tryptophan to ward quinolinic which promotes inflammatory process, maintaining CDR.  This can be measured on my Nutreval panel.
9. Under healthy conditions of metabolism, toxic metals do not accumulate, since we can excrete them. When CDR is activated, the internal milieu is changed. Heavy metals can accumulate and heavy metal toxicity which adds to their overall toxicity. We can measure this in my Nutreval and also hair tissue mineral analysis.
10. When the host is sick the gut microbiome is sick. When chronically activated, the CDR alters the habitat of the bowel, with shifts in the bowel. Leaky gut occurs from chronic inflammation and dysbiosis, increase in food allergies and possibility for opportunistic infections.  I can measure the gut microbiome and integrity in my BiomeFX test.  I can also measure your food sensitivities on my P88 food sensitivity test that measure IgE, IgG and complement which gives you a good analysis of different pathways to how certain foods may be burdening your immune inflammatory response.

The CDR is initially adaptive and coordinated by the close interplay of mitochondria and cell. As it persists, it may become maladaptive once the initial danger is gone.  If the cell cannot turn off the alarm, the CDR becomes part of the problem rather than the solution.

Once the danger has passed, unless the alarm can be turned off, this process can persist. 

First, once the danger has passed, if the body is dealing with an infection or toxin, if remains untreated, turning off the alarm will be difficult.  Attempts to tell cell it is no longer in danger will go nowhere.  If mold toxicity is not treated, attempts to turn off CDR are not effective.  First you need to treat it before you can do any rebooting rebooting strategies.

Identifying and treating the causes of CDR are important.  Otherwise, you are unable to reboot your system to reverse this process.

Mitochondrial shift

In 2017 paper, Dr. Navio explains there are 2 different types of mitochondria. M1 and M2.  Using the blueprint of understanding CDR gives us a clear method on how to proceed.  CDR can shift mitochondrial function so that M2 mitochondrial functions are converted to M1 function.

M1 mitochondria are specialized to created oxidative shielding response triggered by CDR and perform dozens of antiviral and mitochondrial functions.  This requires a shift from M1 back to M2.  Sometimes the cell does not realize its ready for the shift and gets stuck in M1.

Using the CDR as a model for diagnosis. Metabolic features of chronic fatigue syndrome, Dr. Navio realized liquid chromatography to measure 612 chemicals in CFS patients.  CFS patients show deficiencies in just a few.  The biochemical profiles in these deficiencies are different in men and women.

Benefits of fasting

While this subject has not received much attention, humans have evolved two different systems.  In the summer, food is plentiful, and ancestors gained weight. In the winter, people ate less, and the cellular metabolism regrouped.  Winter on the frontier- mending and repairing what needed to be done for the arrival of spring.  We have evolved two different biochemistries based on how we metabolize foods in winter and summer.

There two main pathways of this energy shift.

• MTOR– facilitates protein synthesis and growth by using new nutritional materials to promote rapid growth.
• AMPK- optimizes energy efficiency and stimulates the recycling of cellular of cellular materials for repair.   These shifts can be stimulated by fasting.

The pathways stimulated by AMPK support regeneration and are anti-inflammatory as they work to break down damaged proteins, lipids, DNA and RNA.  What this means is that if we cannot cycle naturally between summer and winter metabolism, we get stuck. We are losing our natural movement and need for winter metabolism.

For patients whom inflammation is a key player, the distinction between summer and winter metabolism takes on added importance. CFS, fibro, Lyme, mold, chronic viral infections all share persistent inflammation the body feels powerless to control.  IF we could reestablish the natural balance between summer and winter metabolism, can we shut of these inflammatory signals.

Fasting could stimulate the transition to winter metabolism.  Most people are often put off by this as they find fasting difficult.  I personally have been a big proponent of fasting and do longer 3-4 day fast a few times a year, and daily intermittent fasting of 14-18 hours.  However, beginners can try intermittent fasting (Skip dinner- modified fast of 16 hours). For some patients, a fast of this duration would be beneficial to assist in this shift. For those with diabetes should only fast under medical supervision.

Biochemical pathways 

When it comes to biochemical imbalances, there are common abnormalities in various found across the board with patients with chronic disease.

The most common abnormalities are found in the following pathways:

• Phospholipids
• Sphingolipids
• Purines
• Riboflavin
• P5P
• BCAA
• Microbiome
• Peroxisomes
• Proline
• Cholesterol
• Arginine
• Fatty acid oxidation
• Bile acids
• Serine metabolism

This could be an adaptive cellular response to control the spread of intracellular bacterial infection.

According to Dr. Nathan, this complicated biochemistry will be the future of medicine in just a few years.

Dr. Navio’s lab is pioneering Metabolomix testing.  This process we have been discussing about 600 biochemical substances can be measured using blood specimen.  I currently use the Nutreval for assessing patient’s Metabolomix.

Our old standby, the CMP will be viewed as inadequate to provide the information needed.  Repeating the same test is the definition of insanity.  This is often the testing most physicians still rely on, and frankly, it is ancient.

A shift in how we treat these patients 

Using the CDR should be used as a model for treatment.  Treating methylation is an obvious component of treatment. So is addressing vitamin D intake following appropriate measurement. So is addition of lysine and assessing and treating gut microbiome. So is assessing vitamin B6 and addressing intake and amino acid tryptophan. So is assessing histamine production and heme metabolism (Chapter 5 and 6). And these are only the basics following the 8 biochemical shifts delineated by the CDR.

The good news is, we have ways to assess your unique individual needs.  This is done with tests I run routinely in my clinic called the Nutreval and Hair Tissue Mineral analysis. This gives us the full Metabolomix picture that provides a blueprint that provides us the full biochemical evaluation of your deficiencies and excesses specific to you.  This will allow me to provide tailor made treatment protocols for your needs front and center.  This takes away the education guesses.  This is going to be the future of medicine, in my opinion.

To learn more about how my testing can help you with resetting the cell danger response, visit my website here.