Is there Finally a Unifying Lens for Understanding CIRS?
Maybe!
The Cell Danger Response gives us a framework to better understand CIRS and other complex chronic illnesses. In today’s post, we do a deep dive into Dr. Robert Naviaux’s Cell Danger Response framework. What it is, how it affects you, and why it may be the most useful framework we have for understanding stubborn cases of CIRS and mold illness.
Expert Recap: What is the Cell Danger Response?
The Cell Danger Response, as described by Dr. Robert Naviaux, is a new way of looking at chronic illness. When danger is detected, the body’s cellular powerhouse, the mitochondria, switch from energy production to defence. This is an evolutionary response that protects cells from harm. In a healthy body, when the threat is gone, the body will go through a cycle that returns the mitochondria to normal. However, if this cycle is interrupted, the body is stuck in the cell danger response loop. Cell Danger Response is connected to CIRS if we consider an ongoing mold exposure to be the reason the body is stuck in CDR.
CIRS and the Cell Danger Response
If you treat complex chronic illness long enough, you start to suspect that the diseases we name so confidently (like CIRS, CFS, long COVID) may actually be features of something deeper than the assigned label. I’ll tell you with confidence that most patients that walk through my door come in with a litany of labels describing their symptoms: IBS, CFS, MCAS, MCS, POTS, CIRS.
Are these six unique illnesses?
Or, could there be a single underlying process that is wearing different masks?
Dr. Robert Naviaux, a physician-scientist at UC San Diego who founded its Mitochondrial and Metabolic Disease Center, has spent his career describing what that underlying process might be. He calls it the Cell Danger Response (CDR for short) and in my view it’s one of the most clarifying ideas in modern medicine for anyone trying to understand why some people get sick and never recover.
This post draws exclusively on Dr. Naviaux’s own published work. Let’s get into it!
What is the Cell Danger Response?
I’ll do my best to ensure you don’t need a medical degree in order to understand the CDR. In short, the Cell Danger Response is the metabolic response, formed through evolution, that protects cells and hosts from harm. The CDR is triggered when a cell encounters a chemical, physical, or biological threat that exceeds its capacity to maintain a stable environment. (source)
The CDR is not a disease. It’s a protective, adaptive defence. The CDR is what a cell does when the danger it senses is greater than its ability to function normally. This is protective design formed through evolution. Our cells have done this for hundreds of millions of years.
CDR is, by design, protective and life-saving.
Knowing this should reframe the way you look at your illness.
CDR and fatigue
Let’s take the common CIRS symptom of fatigue. What if we viewed your fatigue as an adaptive and protective mechanism? If your fatigue is protective, the solution is not to force your cells into producing more energy. Instead, we need to ask, what are your cells trying to protect you from?
The sentinels within your cells that detect threats are your mitochondria. If you took any middle or high school biology class, you were probably told that the mitochondria are the “power plants of the cell”. And they are. But they’re so much more than that. Dr. Naviaux tells us that they are also your cell’s threat detectors. They continuously monitor the environment and respond instantly to danger by shifting their activity from healthy energy production to cellular defence.
Dr. Andrew Heyman describes this shift in your mitochondria as moving from power plants to battleships. When a mitochondrion senses that something is wrong, it triggers a coordinated set of responses that evolved to help the cell survive microbial attack or physical harm. (source)
The Cell Danger Response pathway
What follows the detection of threat or harm is not a single switch, but a cascade of events. Dr. Naviaux catalogues changes across an enormous range of cellular systems:
- Electron flow,
- Oxygen consumption,
- Redox state,
- Membrane fluidity,
- Lipid dynamics,
- Bioenergetics,
- The allocation of carbon and sulfur,
- Protein folding,
- Vitamin availability,
- Metal homeostasis, and more. (source)
One of his most useful observations is that the CDR is the thing that a long list of separately-named stress responses are all describing from different angles.
This is why the idea is so unifying. Fields that thought they were studying different phenomena have, according to Dr. Naviaux, been studying the same conserved response with different instruments.
Could it be that CIRS, long COVID, MCAS, and other complex, chronic illnesses are all part of the larger cell danger response?
Let’s dig deeper!
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How a protective response becomes a chronic disease
If the CDR is protective, why do people stay sick?
When the cells are functioning within the health cycle, once the danger is eliminated or neutralized, two things happen:
- A choreographed sequence of anti-inflammatory and regenerative pathways switch on to replace lost cells and restore normal function.
- The cell stores a metabolic memory of the exposure. This results in durable changes in mitochondrial mass, in cellular protein and lipid content, and gene expression through epigenetic modification. (source)
The CDR is supposed to be a phase you pass through on the way back to health.
The disease state arises when the cell does not complete the return back to health. Dr. Naviaux describes how, under conditions set by a mixture of host genetics and the character, timing, magnitude, and frequency of the exposure, a dysfunctional form of the CDR can persist. In his later work he frames this as a healing cycle with stages that must be completed in sequence; when the cycle is blocked, healing cannot finish.
Dr. Naviaux states:
Chronic illness results when cells are caught in a repeating loop of incomplete recovery and re-injury; a state where they’re unable to fully heal. (He argues) this biology sits at the root of virtually every chronic illness. (source)
The cell, sensing ongoing or repeated danger, never gets the all-clear signal. It stays in defence mode. And a cell stuck in defence is a cell that cannot do its job. If this is multiplied across multiple tissues and organs, then we have a chronic, multi-system illness.
The CDR is your body at war
Dr. Naviaux uses a relevant metaphor when the CDR is activated:
Cells do what nations do when they go to war…
- Harden their borders.
- Stop trusting their neighbours.
- Restrict the exchange of resources.
If you have a body full of cells that have stopped cooperating with each other, you have a body dealing with chronic disease.
The CDR and your Environment
There’s one more piece of Dr. Naviaux’s framework that makes it tailor-made for thinking about mold illness and CIRS: the environment. If you’ve read any of my previous work, you know I strongly believe that healing will never occur until we’ve solved for the environment. Meaning that your indoor air quality needs to be free from ongoing biotoxin exposure.
Your mitochondria regulate the CDR. Chemical pollutants in the environment (think mold, endotoxins, or actinobacteria) lower the threshold for CDR activation. When there’s persistent activation of the CDR, there’s an inhibition to healing which, over time, leads to chronic illness. (source) In other words, your environment can prime cells to trip into danger mode more easily, and to stay there.
Dr. Naviaux frames the CDR as a universal response to environmental threat or injury, and emphasizes that once it’s triggered, healing cannot complete until the choreographed stages of the response return to a state of readiness. (source) If you’re reading this article from a CIRS-aware point of view, you know exactly how the environment plays a role in your healing. With that in mind, we now turn our attention to where and how the CDR and CIRS intersect.
Where the Cell Danger Response and CIRS overlap
Now to the heart of it. The similarities between CIRS and the CDR:
CIRS and the CDR share a similar architecture when it comes to the trigger.
CIRS occurs when a biotoxin exposure in a susceptible individual sets off a self-perpetuating inflammatory response that won’t shut off. Let’s break down CIRS from a broader perspective:
- The existence of an environmental threat.
- A body and immune system that can’t return to baseline.
- A defensive response that becomes self-sustaining.
Is that not the Cell Danger Response?
By my read, that is the Cell Danger Response described at the level of the whole person. The CDR offers a cellular and metabolic POV for exactly the phenomenon CIRS describes clinically: a response that should have been temporary, getting stuck in the ‘on’ position indefinitely.
The mitochondrial and metabolic layer of the cell danger response
The CDR sheds new light on the most common symptoms of CIRS: profound fatigue, exercise intolerance, unrefreshing sleeps… These can be explained by the mitochondrion’s shift from energy production to defence. When the danger response is chronic, the cell is, by design, not making energy at full capacity. That reframes “fatigue” from a vague symptom into a predictable consequence of cells stuck in defence mode.
The metabolomic evidence.
Dr. Naviaux’s research further breaks down the CDR into three stages. (source) CDR1 is the acute stage whereas stages 2 and 3 are the more chronic stages.
As I read it, the picture that emerges is of a response that has moved past its acute, inflammatory, hypermetabolic opening phase into a chronic, conserved, hypometabolic persistence state. I liken this to the body battening down for a long siege rather than fighting an acute fire. For CIRS, this maps onto something I see constantly: the difference between the acutely inflamed patient and the hypometabolic, treatment-resistant patient who seems metabolically burnt out.
The CDR framework predicts that these are different phases of one process, not different diseases.
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How thinking in CDR terms can help
So how does this help us clinically?
The CDR reframes treatment.
In CIRS and mold illness, our goals are to remove the threat, bind the toxin, and suppress inflammation. Great. That helps us out of CDR1, 2, and 3 but it might not restore the cells back to readiness.
Part of Dr. Shoemaker‘s genius is that VIP is more than an anti-inflammatory compound. It’s a signal of safety to your cells. It’s the “all clear” sign to help them return to health.
If you’re a patient that has tried VIP but it didn’t help, you’re likely still in an early CDR state. You need to go back to identify what sort of “threat(s)” your mitochondria are still detecting in your environment.
The CDR focuses on the scarcity of energy production.
Lots of us in the mold-illness space are hyper-focused on inflammation. Great. That’s definitely an essential part of treatment. But we can become blind to the simple fact that most of the patients suffering from a chronic illness have mitochondria that aren’t making energy properly.
The CDR puts mitochondrial function and the hypometabolic state at the center. I love this. It aligns with what patients actually report. And it’s why I often start treatment by supporting energy production, not just chasing inflammatory markers.
The CDR helps the clinician better structure treatment.
Every CIRS patient knows that you cannot force a defensive cell to heal on your schedule. Throw Modafinil or Vyvanse at this and you’re only going to make things worse. Same goes for detox or antimicrobial protocols. Pushing aggressive interventions onto a patient that is metabolically suppressed will backfire. The CDR framework provides a mechanistic reason for the “go low and slow” caution that experienced clinicians must use with sensitive patients.
CDR is a unifying theory.
The CDR gives a single story that connects the environmental exposure, the immune activation, the mitochondrial energy crisis, and the failure to heal.
The limitations of the CDR
I want to close this article by stating that the CDR is by no means an all-purpose cure for complex, chronic illness. I believe it is the start of an improved understanding in the chronic illness world. An understanding where mitochondria are in the spotlight. This is a needed change.
To be clear, the CDR has not had any clinical validation. It is a theoretical framework. There have not been any clinical studies to see how the CDR maps onto CIRS treatment. At present, the Shoemaker protocol remains the best we’ve got (by a wide margin) for CIRS treatment. But I do feel the CDR can help clinicians better understand when we get stuck on complex cases.
If VIP isn’t moving the needle for a patient, that’s important data. If you’re dogmatically following the Shoemaker protocol, you’ll probably throw more VIP at the problem (I did that for years). And you’ll be left with a patient that doesn’t recover. By bringing in Dr. Naviaux’s work, you can see when a patient is still in the CDR. VIP will never signal safety when there’s still an ongoing exposure. So, you need to circle back to identify where an ongoing source of “danger” is occurring.
If you’re a clinician or a patient that is stuck, I invite you to integrate the CDR framework into your thinking. My hope is that it inspires new ideas about recovery.
Mark Volmer has attained the highest level of Shoemaker Protocol certification, and is one of only two of Canada’s Shoemaker Protocol practitioners. The Shoemaker Protocol is the only scientifically proven method of treating CIRS.
