Review Mitochondrial and metabolic features of salugenesis and the healing cycle, 2023, Naviaux

Highlights

• Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery.
  
  
• Salugenesis, the healing cycle, the integrated stress response (ISR), and the cell danger response (CDR) each describe different aspects of the same biology.
  
  
• The healing cycle cannot progress without programmatic changes in mitochondrial function needed for local and organelle-to-organism signaling.
  
  
• The rise and fall of extracellular ATP (eATP) after stress or injury is a key driver of salugenesis and the healing cycle.
  
  
• The rising tide of chronic disease can be traced to impaired salugenesis, incomplete healing, pollution, and ecosystem changes caused in part by anthropogenic factors.
  

Abstract

Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery. Salugenesis is the automatic, evolutionarily conserved, ontogenetic sequence of molecular, cellular, organ system, and behavioral changes that is used by living systems to heal. It is a whole-body process that begins with mitochondria and the cell. The stages of salugenesis define a circle that is energy- and resource-consuming, genetically programmed, and environmentally responsive. Energy and metabolic resources are provided by mitochondrial and metabolic transformations that drive the cell danger response (CDR) and create the three phases of the healing cycle: Phase 1—Inflammation, Phase 2—Proliferation, and Phase 3—Differentiation. Each phase requires a different mitochondrial phenotype. Without different mitochondria there can be no healing.

The rise and fall of extracellular ATP (eATP) signaling is a key driver of the mitochondrial and metabolic reprogramming required to progress through the healing cycle. Sphingolipid and cholesterol-enriched membrane lipid rafts act as rheostats for tuning cellular sensitivity to purinergic signaling. Abnormal persistence of any phase of the CDR inhibits the healing cycle, creates dysfunctional cellular mosaics, causes the symptoms of chronic disease, and accelerates the process of aging. New research reframes the rising tide of chronic disease around the world as a systems problem caused by the combined action of pathogenic triggers and anthropogenic factors that interfere with the mitochondrial functions needed for healing. Once chronic pain, disability, or disease is established, salugenesis-based therapies will start where pathogenesis-based therapies end.

Open access, https://www.sciencedirect.com/science/article/pii/S1567724923000351

 

This is above my head a bit when reading, and I'm not quite there really on assuming ME/CFS is necessarily a state of hypometabolism/hibernation this is an interesting read for putting different aspects out in different sections.

Towards the end in section 26 it was interesting to see slightly different conditions being talked about, which of course highlights the ongoing burden of the lump and dump approach there has been pushed for ME/CFS (and any of the other things that got dumped under there) and then the cheek of funding it as if it is not only just one condition, but didn't need extra funding for the sorting out that miscategoriations and then effects of bad treatment. It is like a double-injury of creating a pot with little funding made impossible to sift.

Which is a shame because it does feel like really interesting possibilities that will impact other illnesses could come from work that looks into the areas that might be needed to unpick ME/CFS, so potentially whole new areas of medicine being funded that are worthwhile and of course my preference would be for the huge sums given to BPS kingdoms to stop being wasted and at least redirected into setting up that proper worthwhile science.

But, rant over, I can't help seeing the stumbling blocks when it comes to the possibilities talked about below. It is great if there are some ideas of what could be tried, but what will be the methodologies if ME/CFS is a collection of different things - because the lowest-common-denominator approach of trials is a bit of an issue if, as per some of the things mentioned in section 26, there are different underlying things going on that could look the same on the surface (and indeed the more that is unpicked maybe the more differences and types there are). Is there good examples of where this has been worked through for other conditions, with atypical and different types etc?

 

Paths to treatment seem attainable. What's the holdup on drugs like suramin?

"... most cases of chronic disease are not caused by an active threat... [They] result from incomplete healing and recovery after a threat or injury has passed...[an] inability to actively extinguish the... (metabolic memories) triggered by a past life-threatening exposure."

"Pathogenesis-based treatments are inherently disease-specific. In contrast, salugenesis-based treatments are inherently non-specific because they target the process of incomplete healing that is a shared root of many different chronic illnesses."

"The absence of parasympathetic autonomic safety signals leads to hypersensitivity to local purinergic (ATP-related) danger signaling and slows healing."

"Early antipurinergic therapy after injury has been shown to prevent pathological chromatin remodeling, inhibit inflammation, and rescue damage in spinal cord neurons, microglia, and astrocytes"

"Antipurinergic drugs like suramin, pannexin 1 (PANX1) channel blockers, and other salugenesis therapies are part of induction therapy to reboot healing. They are not meant to be taken for life."

 

To me this is like saying that pulling the choke out is the solution to everything - wet spark plugs, dirty petrol, snapped fan belt, flat battery... which it isn't.

I doubt suramin will cure anything much.

 

You still need to pull the choke out on a spanking new Honda 2.5HP outboard motor. But I admit that they don't have fan belts.

 

Is that your feeling about the whole conceptual framework / set of ideas, or just suramin specifically?
I appreciate the article is 33 pages, and I haven't even attempted to read it yet! Just always curious about your take on the big theories..

 

The framework. I just don't think this is real medical science I am afraid. All the experience we have is that people do not get better until you deal with the individual disease. Once you have done that they tend to get better just fine without toxic additives.

 

I agree. I read it through yesterday and thought there were many interesting points. Also undoubtedly true that we do much better with acute disease and do very poorly at curing chronic disease ("Medicine - Volume II"). I won't have understood many details in depth, but I thought I followed the overall discussion OK. However I couldn't help but feel I was reading something of a religious text, trying to induce an epiphany in the reader (I'm grossly exaggerating here, but almost more scientology than science, even while discussing some great scientific concepts). There was also too much emphasis on BPS for my liking, but perhaps I'm overly biased against this.

Yes I think the mitochondria are front-and-centre but I don't think it's a systems biology problem, where the organism has got stuck in a failed healing cycle and that mind-brain-body integrated signalling is wrong/lost, with resulting pathological local tissue cell-autonomous behaviour. I much prefer the idea that something specific is pathological and generating a blood-borne effect, resulting in eg mitochondrial fission in multiple cells. I just don't think we understand the mechanisms underlying these chronic diseases: in the specific, not in the general as proposed here.

 

Whatever happened to the replication study Naviaux was doing years ago as a follow up to his 2016 metabolomics paper? It’s been 10 years or radio silence so it’s safe to assume the findings did not replicate even after years of torturing the data.

 

I was a patient subject in that study. I repeatedly reached out to OMF asking when that study would be published. Eventually after a few years they became annoyed that I kept asking them and they told me that the data had been shared within the OMF science community and implied that was sufficient as far as they were concerned. They didn't really say it wasn't gonna be published but they didn't say it was gonna be published either.

 

I'm fairly certain that in my case the healing cycle is broken. I'm young, in my 20s, and yet it took me 8 months to recover from a lumbar puncture. I spent months unable to leave the bed because i had to lay completely horizontally 24/7. Wounds on my skin, even if minor, take a long time and heal very abnormally leaving permanent keloid scars. If this is what was happening in my brain, it would make perfect sense. If there is something wrong with tissue modeling, it would explain why it's impossible for me to learn or concentrate, or build muscle.

Unfortunately, researchers only care about publishing papers so it will take a long time to know if there's something to this. It doesn't matter what is actually wrong with the patients - Naviaux got to publish his papers and get his salary so he is all good. Maybe he is right, maybe he is wrong, but it doesn't matter because he published. And doctors don't care about us either because they can say psychosomatic and their job is done too.

 

Maybe they should rename themselves to "closed medicine foundation". If we don't publish negative results we will keep running in circles forever.

 

That’s really disturbing. Implies they are covering up negative results.

 

We are a little off topic but a few years ago Ron Davis was very publicly saying that publishing paper was slowing his work and that he wanted to push on the research, just not publish. At the time he wanted to develop his nano needle, and the capacity to test hundreds of samples at a time ( as I remember it). Then came the problems of not getting NIH funding and being vocal about it.

Back to Naviaux’s theory. It’s getting more and more like an alternate universe, and at best, a downstream effect of the real problem.

 

Publishing negative results is absolutely essential for scientific progress.