As a naturopathic doctor, I’m 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 this 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 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. (More on this in Part 2 of this article.)
I recently became aware of an analog of this process in the literature, called the Cell Danger Response (CDR), described in multiple papers over the past decade or so by Robert Naviaux. 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.
The Cell Danger Response Cycle
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 damage exceeds this threshold.
Naviaux describes three stages of the CDR–four if you include restoration to health. Stage one (CDR1) 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 (CDR2) is the repair stage: cells revert to undifferentiated stem cells to proliferate and replace what’s been damaged. Stage three (CDR3) involves new cell differentiation, and instructions regarding their new function in the tissue and organism as a whole.
Naviaux described these stages via metabolomics, 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 illnesses 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.
The Trigger to Enter the CDR: Purinergic Signaling
Many chronic diseases go back to mitochondrial dysfunction—but I’ve noticed in practice that even when I have good reason to believe 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.
(Sometimes cell death can be the targeted, healthy “housecleaning” 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.
CDR1: The First Phase of the Cell Danger Response
Typical metabolism in the mitochondria involves the conversion of glucose into ATP, with the help of oxygen (called oxidative phosphorylation)—and it’s quite efficient. But in this stage, 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); it wants the oxygen to instead make reactive oxygen species (pro-oxidants) to attack the danger source, whatever it is. Naviaux uses the analogy of converting the mitochondria “from powerplants 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.
CDR2: The Second Phase of the Cell Danger Response
Once the acute danger is gone, the next phase of the cell danger response 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. In 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 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 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 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, aka 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 of the Cell Danger Response
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 cycle, since the cells are “offline,” they aren’t sensitive to systemic hormonal signals.
Restoration of the Health Cycle from CDR3
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 either not true (maybe the tissue isn’t safe, if they’re still in a toxic environment or struggling with a rampant infection), or the signal can’t yet get through.
In Part 2, we’ll discuss how cells can get locked into one of these phases and fail to heal, how to recognize the block, and (at least theoretically) what to do about it.
