The Cell Danger Response

Welcome to Christian Natural Health with naturopathic Dr. Lauren DeVille.

Christian Natural Health is the podcast on how to get and stay healthy.

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Welcome back to another episode of Christian Natural Health.

Today I'm going to be talking about the cell danger response.

As a naturopathic doctor, I am trained to think of chronic disease in terms of the therapeutic

order.

Treatment has to follow a particular sequence of steps for optimal results, and the more

sensitive the patient, the more critical the sequence becomes.

If you step on a thorn, for instance, it'll hurt and your foot will swell up around

the area of the intruder in an attempt to expel it and repair the damage.

The appropriate treatment for this pain isn't to take an Advil and to try to forget about

it, or to ice the foot, or to just use crutches, it's to pull out the thorn, naturally.

In chronic systemic disease, if the initial trigger is an external toxin, first you have

to get out of the toxic environment.

Once you've done that, the next step is to supply any missing building blocks required

for healing, clean water, fresh air, sleep, exercise, a healthy diet, etc.

Sometimes this alone is enough to restore health, and the healthier the person, the more

often this is the case, but sometimes subsequent steps in the therapeutic order are still necessary.

I recently became aware of an analogue of this process in the literature called the

Cell Danger Response, described in multiple papers over the past decade or so by Robert

Neville.

It strikes me as similar to the therapeutic order, but with a much more robust description

of what is happening at the cellular level.

Here's what it is.

A healthy cell can typically deal with minor damage during the normal sleep cycle, clearing

out metabolic waste and initiating cellular repair.

The Cell Danger Response only gets triggered when the damage exceeds this threshold.

Neville describes three stages of the CDR, four if you include restoration to health.

Stage one, CDR one, involves a cellular disconnect from the organism at large, going offline as

it were from a functional standpoint, as well as inflammation and energy conservation

to deal with the threat.

Stage two, CDR two, is the repair stage.

Cells revert to undifferentiated stem cells to proliferate and replace what's been damaged.

Stage three, CDR three, involves new cell differentiation and instructs regarding an

instruction regarding their new function in the tissue and organism as a whole.

Neville described these stages via metabelomics, which is a process by which many biological

metabolites are measured at once from a single tissue sample.

This allows the researcher to look for patterns not single markers to tell a bigger story

of what's going on after cellular damage occurs.

This is useful because it helps to reframe chronic illness in terms of which stage of

the CDR they might be stuck in.

This understanding may help to clarify which specific therapeutic modalities might be warranted

and in what sequence.

Many chronic diseases go back to mitochondrial dysfunction, but I've noticed in practice

that even when I have a good reason to believe that this is the case, mitochondrial support

products or procedures in many cases yield less than impressive results.

The CDR concept helps to put in context why this is the case.

The mitochondria are where the CDR starts.

They sense a threat, be it physical, chemical, or infectious, and they respond by spilling

ATP, the body's energy currency, outside the cell, as well as various precursors and

breakdown products of ATP, such as ADP, oxygen, reactive oxygen species, and other metabolites

from further upstream.

The mitochondria are bleeding out, essentially, but they're doing it because continuing with

business as usual, typical tissue function, would ignore the threat and would likely result

in cell and tissue death.

Some cell death can be the targeted healthy house cleaning autophagy, but that's not

what this would be.

This is a threat against otherwise healthy cells.

In other words, this is cellular defense mode.

Typical metabolism in the mitochondria involves the conversion of glucose into ATP with the

help of oxygen.

It's called oxidative phosphorylation, and it's quite efficient.

But in the stage of CDR1, the cell doesn't want to convert oxygen to ATP for energy, and

indeed, it's just gotten rid of its cache of available ATP.

Instead, it wants the oxygen to make reactive oxygen species, pro-oxidants, to attack the

danger source, whatever it is.

Neville uses the analogy of converting the mitochondria from power plants to battleships.

The goal here is to get rid of the eminent threat with minimal collateral damage.

This still requires some ATP, but not nearly as much as normal tissue function, so the

cell switches to anaerobic without oxygen respiration, producing lactic acid as a byproduct.

The CDR2 is the second phase of the cell danger response.

Once the acute danger is gone, the next phase involves repairing and replacing any tissues

damaged in the fight.

Depending on the tissue involved, sometimes local stem cells get activated and begin the

differentiation process, and tissue with slower turnover mature cells revert back to stem

cells so that they can proliferate and repair the damage.

When this occurs, the mitochondria flip back to aerobic with oxygen, respiration, but not

the typical oxidative phosphorylation of a healthy cell.

Instead, stem cells enter Warburg metabolism, best known as the way that cancer cells locally

generate energy.

All rapidly dividing cells do this, because what they need most isn't energy for normal

function.

Rather, they need building blocks to make more, more cells.

Normal mitochondrial function oxidative phosphorylation involves breaking glucose all the way

down to CO2, which we exhale, but that's a waste of carbon for a cell that needs it for

a building material.

In Warburg metabolism, oxygen is available, but the cell chooses to make lactic acid instead.

This is both to regenerate NAD, the oxidized form of NADH, which is otherwise known as

vitamin B3, which is necessary to continue to produce ATP, and also because lactate then

can get recycled into building blocks for the new cell.

CDR3, the third phase.

At this point, the new tissue is built and the new cells differentiate into their roles

and establish connections with their neighbors.

The mitochondria should flip out of Warburg metabolism and back to oxidative phosphorylation.

They should also begin to restore sensitivity to outside signals, like hormones, during

the CDR cycles, since the cells are offline, they aren't sensitive to systemic hormonal

signals.

The main signal necessary to bring tissue stuck in CDR3 back to health is signaling from

the vagus nerve.

Chronic CDR activation essentially communicates to the body that it's not safe, inherently

activating the sympathetic nervous system and rendering the tissues resistant to signals

from the parasympathetic nervous system at the same time.

This likely explains why some people who are clearly locked in a pattern of autonomic

nervous system dysfunction don't always respond to vagus nerve stimulation, somatic therapies

and the like.

These therapies are designed to send the signal to the body, you're safe, you can function

normally again.

But this will only work if the dysfunctional cells have completed CDR3 and are stuck there.

If they're stuck anywhere upstream, it's not either not true, maybe the tissue isn't

safe, if they're still in toxic environment or struggling with a rampant infection, or

the signal can't yet get through.

So the second part of this, I'm going to go ahead and put in the same podcast.

So just as a quick summary, the three phases of the cell danger response, it's a cycle

in which the cells take themselves offline from the rest of the body in order to protect

themselves from a threat and to repair.

CDR1 involves a shift from energy production to oxidative stress in order to fight off

the invader.

CDR2 involves tissue proliferation for healing.

CDR3 involves new cell differentiation, connection to neighboring cells and reestablishes

normal cell metabolism and sensitivity to outside signals.

So how cells get stuck in one of the CDR phases?

The healthier and more vital a person or the tissue is, the more readily injured cells

can enter and complete the CDR cycle with total resolution.

But if any cells fail to complete the cycle and reintegrate, this might create a weak

link, susceptibility to later injury.

I often express this to patients like this.

Whenever you get stressed, whatever your weak link is, that's what breaks.

On a systemic level, re-exposure to a toxin, your body has seen before, tends to trigger

a faster and more extreme response than the first time.

I see this most often with Sir's chronic inflammatory response syndrome from biotoxins.

Chronic CDR1 activation.

Those get stuck in CDR1 due to ongoing inflammation from a real ongoing threat.

You're still in a toxic environment or you still have an infection.

A perceived ongoing threat, an MPO myelopiroxidase chronic overactivation fits here, or chronic

hypersensitivity of the purinergic receptors that first responded to the extracellular ATP.

Sometimes, the oxidative stress involved in normal CDR1 initiation can actually damage

the enzyme needed to shut CDR1 off.

This may happen when the CDR gets initiated in an already inflamed environment, such as

in cardiovascular disease and metabolic syndrome.

In these cases, the oxidative damage secondary to the metabolic problem might prevent resolution,

and thus, building blocks for membrane repair, phosphatidylcholine and essential fatty acids

might be beneficial.

Exercise has been shown to help regulate that enzyme that shuts the CDR1 off called

CD39, so this can be a meaningful intervention at this stage.

Corsitin and Resveratrol also help to regulate CD39 as do T regulatory cells.

The most relevant supplement that modulates T regulatory cells is, in this capacity, is

vitamin D3.

Adenosine, a breakdown product of used ATP that accumulates throughout the day, also boosts

CD39 production.

Caffeine notoriously blocks adenosine receptors, so if someone is stuck in CDR1 and they drink

a coffee or another caffeine source, it might be worth taking a holiday from it for a few

weeks to clear out the pipes and resensitize the adenosine receptors.

Already damaged mitochondria can also trigger ongoing oxidative stress, which can damage

the CD39 enzyme.

I suspect selective antioxidants that might clean up excessive reactive oxygen species

might shine here like molecular hydrogen.

Traditional mitochondrial supplements tend to favor oxidative phosphorylation, which

is inappropriate at this step, and a vote noted that it can, in some cases, even make

things worse.

Knowing that the original insult is gone, Lotus Naltrexone can really shine at resetting

a chronic stress response, too.

According to Navveau, diseases that fit a chronic CDR1 activation pattern include

SERS, chronic inflammatory response syndrome, chronic infections of all kinds, allergies,

and asthma.

Chronic CDR2 activation.

The tissue proliferation phase might go awry if mature cells attempt to revert back

to stem cells but fail, then they can become senescent or zombie cells.

A few of these can still be beneficial to the overall process, triggering inflammatory

cytokines that can help to perpetuate healing, but too many of them can halt the danger response

cycle, the cell danger response cycle, and it can get stuck here.

If this is the case, fasting can be helpful to trigger autophagy.

Warburg metabolism characteristic of CDR2 occurs in the presence of oxygen that isn't

explicitly used for ATP production, and this extra oxygen appears to be part of the signaling

process for tissue remodeling and regeneration, which implies that hyperbaric oxygen can

be helpful if someone is locked in unresolved CDR2.

However, as excessive reactive oxygen species characterized CDR1, HBOT can potentially be

harmful if someone is stuck in that phase rather than in CDR2.

Because Warburg metabolism runs on glucose, someone's stuck in this phase might do well

on the ketogenic diet to switch the metabolic fuel from glucose to fat.

According to Navveau, diseases that fit a chronic CDR2 activation pattern include metabolic

disorders like diabetes, hypertension, heart disease, peripheral vascular disease, elevated

uric acid, fatty liver, and some phybrotic disorders like pulmonary fibrosis and kiloids,

irritable bowel disease, Crohn's ulcerative colitis, and cancers, of course.

Chronic CDR3 activation.

The tissue remodeling phase may fail to progress to resolution if the world now signals fails.

What this looks like depends upon what the tissue is supposed to do, but ultimately it means

the tissue is no longer actively inflamed and no longer actively remodeling either.

This might occur due to senescent cells that made it through CDR2, but DNA damage renders

them non-functional.

Since the parasympathetic nervous system is required to send the all-clear signal treatments

that stimulate the biggest nerve are indicated here, even in the absence of overt-disautonomic

symptoms.

Nicotine patches might be useful for this population for the same reason, though that's speculative.

But along these lines, healthy social connections and support are huge for sending safety signals

to the body.

This pro-resolve and mediators SPMs also fit here.

Their whole purpose is to clear out the metabolic waste left over after a conflict so that resolution

can occur.

Direct mitochondrial support is more likely to be beneficial here, too, including red light

therapy to try to restore normal oxidative phosphorylation.

According to Navos, diseases that fit a chronic CDR3 activation pattern include neuropsychiatric

conditions like autism, OCD, anxiety, depression, bipolar schizophrenia, pans and pandas,

Parkinson's, Alzheimer's, multiple sclerosis, Tourette's ALS and traumatic brain injuries.

Many autoimmune conditions, Lupus, scleroderma, showgrins, polymyalgia, rheumatica, ankle

losing, spondylitis, Hashimoto's and rheumatoid arthritis.

Chronic pain syndromes like fibromyalgia, alodinia, complex regional pain syndrome, eye diseases

like macular degeneration, presbiopia, presbacuses, chronic migraines and headaches, psoriasis,

eczema, and more.

So the therapeutic order of naturopathic medicine revisited.

Navos makes the point that the normal health cycle requires adequate nutrient intake, waste

and toxin removal, restorative sleep, and connections to nature and other people.

Particularly CDR1 maps clearly onto the first step in the therapeutic order of naturopathic

medicine.

This is what the order is, though.

Identify and remove the obstacle to cure from the environment, give the body the building

blocks that it needs to heal, stimulate the vital force, address and support we can

damage systems, correct structural integrity, address pathology with nutraceuticals, address

pathology with pharmaceuticals, and last suppress symptoms with pharmaceuticals only when necessary.

But that's all big picture.

The CDR offers a fascinating peak at what might be going wrong at the cellular level, depending

upon the disease process in question.

I hope that as more studies are done, it will become increasingly clear how we might help

to hit a reset button in each case.

So there are two studies or two articles that this comes from.

I'll link to both of them in the show notes and thank you for joining me and I'll see

you next week.

Americans have a big healthcare problem.

Over 100 million citizens carry medical debt while paying for overpriced and complicated

health insurance.

As Christians, we don't have to pay for a broken system.

Christian health care ministries is an alternative to health insurance at half the cost, plus

you can enroll at any time.

Find up to health insurance with a biblical solution.

Join CHM today by visiting CHministries.org-slash-wellness.

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