Is the Cell Danger Response the Theory of Everything?

I was spurred by the recent news release from the Open Medicine Foundation to read more about Robert Naviaux from UCSD, the lead investigator of the new metabalomics study. Dr. Naviaux published a paper in 2014 which provides an elegant explanation of possible causes of many chronic conditions including ME/CFS, FM, ES and Chronic Lyme Disease. Just as Dr. Stephen Hawking and others are looking for a “Theory of Everything” to explain the physical principles of the cosmos, Dr. Naviaux has developed a unifying theory of how cells respond to threats.

What follows is my review of Dr. Naviaux’s recent work. His work provides an entirely new paradigm (new to me at least) and a new way of looking at chronic disease. The abstract of the paper can be found at: http://www.ncbi.nlm.nih.gov/pubmed/23981537 The full paper can be downloaded free of charge at:

http://www.sciencedirect.com/science/article/pii/S1567724913002390

The crux of Dr. Naviaux’s theory is that cells have a limited number of ways to respond to threats whether they be from an infection, change of temperature, change to acid/alkaline balance, exposure to man-made chemicals, heavy metals or psychological trauma. The mitochondria are at the centre of a universal cell response called the “cell danger response” (CDR). During the CDR, changes occur in many aspects of cellular function and these changes can be identified by measuring affected molecules in blood, urine and cerebral-spinal fluid using metabolomics technology. Measuring these molecules is the aim of the newly funded study that Dr. Naviaux will be leading through the Open Medicine Foundation.

What is the Cell Danger Response? The CDR is present in all animals and every class of animal virus has the machinery to try to evade or neutralize this mitochondrial danger alarm system. Mitchondria contain 1500 proteins and catalyze over 500 chemical reactions. They sense threats which cause changes to electron flow. All of the above threats (infective, chemical and psychological) change the electron flow in cells. When electron flow changes cells are injured.

When a cell is injured by a virus or other threat, ATP and other molecules leak out of the cell and warn the other cells of the danger. These neighboring cells then undergo changes to protect themselves against the danger. Mitochondria rapidly decrease their energy production and the level of oxygen in the cell rises because it is not being used. This oxygen rich environment blocks the building of molecules like DNA and RNA which are critical both to the cell and the infecting virus. Virtually all of the cell responses which you may have heard of like the oxidative stress response, methylation, gut function and immune response and many you may not have heard of are part of this unified cellular response to danger.

And there is more...

In nature all species are exposed to seasonal variations in food supply; summer being a time of plenty and winter a time of time of scarcity. The ease of finding food in summer turns on the “summer genes” which leads to the growth of new molecules and cells. This is all well and good in some tissues like the skin and liver where new growth is constant and when the animal is exercising regularly to catch or find food. But in the absence of adequate exercise and in tissues such as the heart and brain where few new cells develop, the push towards growth causes old and damaged molecules – cellular garbage – to accumulate.

In nature, this period of summer growth is balanced by winter. In winter, different genes are in charge and the body focuses on recycling existing molecules knowing that outside resources are scarce. The “winter genes” protect against modern diseases such as diabetes, cancer and heart disease. In modern times in developed countries we live in constant summer – food is available all the time. As a result, the “winter genes” that focus on recycling and degrading cellular garbage are rarely turned on. The result is cellular inflammation and chronic disease.

When a cell has been infected by an organism or faces other dangers, the electro-chemical processes shift towards the “cell danger response” which is similar to the “endless summer” picture.

Even after a cell recovers from the CDR (there are mechanisms for it to recover), it stores a memory of the experience much as the brain stores memories of life experiences. This cellular memory may make the cell more prone to going back to the dysfunctional state. Furthermore, Dr. Naviaux suggests that in certain circumstances, the CDR can persist even after the original danger is past – in other words get stuck. This could explain the “hit and run” hypothesis of ME/CFS I have discussed in previous newsletters in which an individual becomes ill after an infection and the “illness” persists even after the infection is gone. I have wondered lately whether the same could be true for “Chronic Lyme Disease”.

The CDR is thought to be perpetuated by purinergic signaling (adenosine di- and triphosphate and uridine di- and triphosphate). Research is underway to find drugs to modulate the purinergic receptors. Dr. Naviaux published a paper in 2013 in which 16 aspects of function in a mouse model of autism were corrected with a purinergic receptor blocker which has been used in humans to treat African Sleeping Sickness.

There is only one paper I know of looking at purinergic signaling in ME/CFS. This is a paper by Alan and Kathy Light previously discussed in an oral presentation I gave several years ago. They did not find increased expression of two purinergic receptors after exercise in individuals with ME/CFS compared to healthy controls.

Why am I calling this the “Theory of Everything”? Because pathological persistence of the Cell Danger Response (CDR) is implicated in many diverse conditions including: autism, ADD, food allergies, asthma, bipolar disorder, PTSD, traumatic brain injury, diabetes, heart disease, cancer, Alzheimers disease, Parkinson’s disease and most autoimmune diseases (eg. MS, Rheumatoid arthritis, Lupus). Which condition develops depends on the age of the animal, the nature of the danger, the health of the animal at the time of exposure and the animal’s genetic makeup to name only a few factors.

The good news is that some conditions thought to be irreversible may respond to therapies which dampen or reverse the Cell Danger Response. With scientists of Dr. Naviaux’s quality drawn to the field, one can only be hopeful.

Author: Eleanor (Ellie) Stein MD FRCP(C)

I am a psychiatrist with a small private practice in Calgary and am an assistant clinical professor in the faculty of medicine at the University of Calgary. Since 2000, I have worked with over 1000 patients, all with ME/CFS, FM and ES. My passion for this field comes from my own struggle with these diseases, my desire to improve my health and then pass on what I learn. My goal is for every patient in Canada to have access to respectful, effective health care within the publicly funded system.

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