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Newsletter #18

Part I of the Cell Danger Response 2.0

In the next few newsletters I would like to delve into Dr. Robert Naviaux’s latest discussion of the Cell Danger Response which he published just recently in the journal Mitochondrion titled: “Metabolic features and regulation of the healing cycle—A new model for chronic disease pathogenesis and treatment.” (Those readers who wish to read this paper in its entirety can find it at):

As always, Dr. Naviaux’s writings are so full of poignant observations and connections that in order to even begin to do justice to them, I will need to tease them apart and present them in segments, as I plan to do today.

The first observation that I would like to comment on is his thought that an organism can become so used to feeling a certain way, that when those feelings begin to change, that organism can actually experience those changes (even when they are healing and clearly beneficial) as a threat to their “normalcy” and they can resist those changes because they experience them as uncomfortable. I think this is a profound understanding and it adds another dimension to the complicated picture of symptoms that our patients describe to us.

To be more specific, what I am saying here is that patients may become so physiologically habituated to their daily experiences of how bad their bodies feel, that any change is interpreted by their bodies as a kind of withdrawal. While the term addiction might be too strong here, this would be akin to an addict withdrawing from something they are
addicted to and experiencing sweating, palpitations, pains, fatigue, and insomnia as they begin the withdrawal process.
I had never thought about this before, but on reflection, I think that sometimes when patients begin to improve, they will describe “Herx” like symptoms. They may, in fact, be experiencing a physiological withdrawal, which might look like a Herx reaction or detoxification. Since these reactions have been part of their lives for so long, I suspect that I, and my patients, have immediately jumped to the interpretation of those symptoms in the framework they know, but perhaps we have been sometimes wrong, and that these may actually be withdrawal symptoms as they move forward in healing into a new physiological state?

This thought will give me a segue into discussing more of the new material abstracted from Dr. Naviaux’s paper.

First, let me briefly remind readers of some of the important components of the Cell Danger Response which I describe in more detail in Toxic: Heal Your Body…..

The mitochondria are the organelles inside of cells which monitor
safety (as well as provide us with life-giving energy). The mitochondria do this by responding to tiny changes in electrical voltage within each cell that are triggered by threats, most notably toxins and infectious agents. When these threats are perceived, the mitochondria set off a series of choreographed biochemical changes that have been designed, over the millennia of our evolution, to protect us from those threats. Dr. Naviaux calls this process the Cell Danger Response.

His first paper, describing this process in detail, in the journal Mitochondrion, in 2013, provided us with a model of how the cells, and then the whole organism, responds to threat. When functioning properly, the threat is neutralized and the cells return to their normal functioning. But when those cells do not perceive any let-up to that threat, they get “stuck” in the biochemical response to that threat, and will continue to signal “danger” and remain in an inflamed state for a prolonged period of time. This model provided us with a breakthrough in our understanding of many chronic illnesses, as we could now begin to look for the “stuck” places and do something about it.

His new paper takes this several steps further. Dr. Naviaux now puts this Cell Danger Response as simply the first step in what he calls theHealing Cycle. Again, this initial response, now termed CDR 1, represents the body’s effort at containmentof this threat. If those efforts at containment are not completely successful, and get stuck, Dr. Naviaux lists a number of specific disease conditions that will result from that physiological state in which the innate immune system is spinning on itself and cannot move forward. Some of those include allergies, asthma, chronic infections, (e.g. Lyme disease), Gulf War illness, and mold toxicity. Metabolically, the cells are stuck in glycolysis, which is a less effective method for extracting and utilizing energy. The mitochondria actually change from the healthy M2 mitochondria to M1 mitochondria and the differences in mitochondrial structure can be clearly observed by those who are looking for it.

When the cells have achieved some successful degree of containment of the toxins or infections, it can then move through a checkpoint into the next stage of the cell danger response, termed CDR 2. In this stage of healing, which is one of proliferation, the damaged cells from the first stage can be replaced with healthier cells and begin to regenerate. The major metabolic process here is now aerobic glycolysis, which is a far more efficient way for the cell to generate and utilize energy.  Here the mitochondria are in yet another structural mode, M0. The illnesses which can be attributed to this phase of the healing cycle are proliferative disorders such as diabetes, hypertension, heart disease, BPH, inflammatory bowel disease, cancers and leukemias.

When the cell has successfully moved through this phase of healing, it passes another checkpoint and shifts into the CDR 3, which moves the mitochondria back into their more normal M2 structure, and uses oxidative phosphorylation (a more comprehensive form of energy generation). This phase is primarily devoted to differentiation and development, and illnesses in which the cycle is “stuck” here include Chronic Fatigue Syndrome/ME, Fibromyalgia, Autism spectrum disorders, Neuropathic pain syndromes, Anxiety, Depression, Bipolar, OCD, Psoriasis, Eczema, Hashimoto’s thyroiditis, and others.

I would like to refer back to my initial discussion that some symptoms may represent a physiological withdrawal as one shifts from one stage of the CDR to another. If a patient spends many years “stuck” in the CDR 1 and then begins to move through to the next stage, (as they are healing), we can now understand that they may have become so physiologically habituated to their altered chemistry in CDR 1, that they experience this change as a withdrawal phenomenon and may actually have symptoms that reflect this withdrawal. You can understand that this would be confusing to both patient and provider. When, finally, we are making progress and we are excited that we are moving through the healing cycle, how disappointing to feel worse! However, if we understand this (which I am beginning to, with Dr. Naviaux’s help) if we do not freak out and get upset by what appears to be setback, and correctly understand this as a withdrawal process, this will help us to help our patients comprehend what is happening to them and smooth out that transitional process (which is what it is) so they can move forward with less worry and concern that something “bad” is happening to them. We can use this information to help them to understand that this is simply a predictable part of the healing process.

Another important point here is that this is not a clean, linear process. The mitochondria are not all in one state of metabolism…..they can be in different states in different cells or tissues of the body. Similarly, the named illnesses here are not linear, and these illnesses may have components of CDR 1, 2, and/or 3 at any given moment in time. The body is a mosaic of biochemistry, and it should not be viewed as,“ah, this whole organism is in CDR 2, so I will use CDR healing strategies to move them forward.” We must use all of our clinical acumen to help to discern which phase is predominating, and as Dr. Naviaux warns us in paragraph 19;  Dangers of tonic, single-stage CDR interventions:  “Chronic treatments for pain and inflammation syndromes associated with CDR 1 diseases may increase the risk of diabetes and cardiovascular diseases (CDR2-associated disorders), and/or autoimmune disease (CDR3-associated disorders). Subdivisions within each of the CDR stages are likely to exist. For example, the fact that statin treatment for cardiovascular disease increases the risk of diabetes suggests that these two disorders belong in functionally separate divisions within the CDR 2.”

Dr. Naviaux’s evolving map of the Cell Danger Response is exciting and, at the same time, daunting. A great deal more research needs to be done to help us to understand these biochemical shifts, the check points, and potential therapeutic strategies as we graduate into an entirely new model of understanding chronic illness and how to work with it.
This is the future of medicine.

I welcome any questions you may have and would be happy to post
answers in future newsletters.

I was inspired to write about this subject when I recently re-read one of my favorite books, Big Magic: Creative Living Beyond Fear, by Elizabeth Gilbert. What Elizabeth Gilbert is writing about is essentially creativity—-how to find it and nurture it—and how important it is to our spirit to make it an integral part of our daily living. In that context, she writes: “Do you have the courage to bring forth the treasures that are hidden within you?” And, while she is talking about creative treasures, that same statement can also be seen as relevant to having the courage to live the productive life you were given as your birthright. Are you going to let your illness take that away from you, or are you going to “hunt to uncover those jewels—-that’s creative living. The courage to go on that hunt in the first place—that’s what separates a mundane existence from a more enchanted one…..I’m talking about a life that is driven more strongly by curiosity than by fear.”That got me thinking that healing is not that much different, conceptually. In the face of prolonged debilitating illness, we must face those fears, with courage, to get well. Mobilizing our courage to create something (which is laden with potential fears) is not so different than mobilizing our courage to heal.

At first glance, one might wonder why it would take courage to get well. After all, wouldn’t everyone want to get well from an illness or injury?  So why would it take courage, as opposed to your basic pluck or fortitude or even common sense? “Of course I want to get better… you think I am enjoying feeling this lousy?”

But, like most things in life, healing is quite a bit more complicated than a simple desire to get well. And, as an illness does not resolve quickly, and lingers, this gets more complicated still.

So, when someone begins to realize that they are not well, their first assumption is that this is going to be temporary, like, say a nasty viral infection. When that presumed viral infection does not resolve after several weeks, then several months, it begins to dawn on that individual that something more serious is going on and that they are going to have to start working on it.

They go to their primary care physician, who runs some basic testing, and they are surprised to hear that “everything is in the normal range.” Perhaps, they are told, if they are more patient, their symptoms will indeed go away on their own in another month or so.

When this does not happen, then they begin, understandably, to become a bit more worried. What, actually, is causing this illness?

What if I don’t get better?  What then? After a while, they begin to realize that their primary care physician is not able to help, and they go to specialists or to functional/integrative physicians to dig deeper. Perhaps they are fortunate enough to get a clear diagnosis and to then begin effective treatment. But, more often in my world, they are given dozens of different diagnoses: Chronic Fatigue Syndrome/ME, Fibromyalgia, Mitochondrial Dysfunction, Methylation Dysfunction, Lyme Disease, Chronic Viral Infection, SIBO, Parasitic Infections, Genetic Disorders, Neurotransmitter Deficiencies, Heavy Metal Toxicity, Multiple Chemical Sensitivities……and worse, “No one could have all of those symptoms so this must be psychosomatic” and they are offered an antidepressant and the opportunity for psychotherapy. After several months to years of treatment attempts, they may be somewhat better, or not better at all, or worse.

By now, they have spent thousands of out-of-pocket dollars, and financially they begin to worry about how much more this may cost them. Now, that niggling little worry about getting better has become a much louder voice adding additional concerns about whether or not they will have to live with this for the rest of their early lives. Now, their family and friends have begun to wonder whether this is all “in their head” and how long they, too, will have to put up with this prolonged fatigue, cognitive impairment, anxiety and depression and …… they have entered a rabbit hole which can be hard to climb out of.

This is where courage comes into play. I am increasingly aware that as I try to help my patients navigate the turbulent waters of this journey, I need to remind them about how to find their bravery again. It requires faith (in themselves, their support systems, and the universe) that despite the difficulty of their journey, there is a reachable end in sight. That if they are strong enough to survive it thus far, they surely have the strength to go the rest of the way.

For some, the hardest part of their journey comes after they have started to improve and realize that they now have the opportunity to reclaim their lives and live it fully. Having lived a life of illness for so long, do they have the courage to embrace this opportunity?  Yes, it is scary to have to step up to the plate, but also, how wonderful!  Can they move past their fears (What if……?) and envision a life filled with joy, wonder, vibrant health and creativity?
I hope so.

 Happy New Year, everyone.  May this usher in a year filled with healing, prosperity, and love….and peace.