Do not go gentle into that good night

Cells in the body dying of necroptosis obey Dylan Thomas — “Do not go gentle into that good night” all sorts of inflammation ensues around the cell, and systemically if enough die that way at once.

Cells dying from the first discovered form of programmed cell death e.g. apoptosis disobey.  They die very quietly producing no inflammation, and are quietly munched up by phagocytes.  Just how this happens has been a huge mystery.

Well one way to figure out what is going on looks at a phagocyte before it meets an apoptotic cell and afterwards.  Quite a bit it turns out.  The brute force technique looks at the changes in our 20,000 or so protein coding genes.  They found increased expression in 886 and decreased expression in 966, some 9% of our total.  How do you make sense of that.

This is typical of the brute force approach to any condition (e.g. cancer, infection, vascular disease), and shows you just how hard it is to figure out what is going on from the mass of data produced.

The authors of Nature vol. 580 pp. 130 – 135 ’20 (https://www.nature.com/articles/s41586-020-2121-3.pdf) were far cleverer than that.  What they did was cause a bunch of cells to go apoptotic at once and then the “supernatants and cell pellets from apoptotic cells and live cell controls were subjected to untargeted metabolomic profiling against a library of more than 3,000 biochemical features or compounds.”

Then by a huge amount of work they found 6 metabolites released by the apoptotic cell  which when given together which could switch macrophages (a type of phagocyte)to the non-inflammatory state (e.g. the one above producing all those gene changes).

Then they pared the number of metabolites doing this down to 3 (spermidine, guanosine monophosphate and inosine monophosphate). They call this cocktail of metabolites MEMIX-3.

They get out of the cell dying of apoptosis because the executioner (caspase) chops up a protein channel on the cell surface (pannexin1), allowing the 6 metabolites to escape.  A rather parsimonious suicide note wouldn’t you think.

It gets better. MEMIX-3 obviously is an anti-inflammatory agent, and they showed that it attenuates arthritic symptoms and prevents rejection of a lung transplant.

Brilliant work, and possibly one of great therapeutic import.

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Comments

  • Mark Thorson  On April 8, 2020 at 10:18 pm

    How weird! Two of these molecules are widely used food additives. The food-industry names of GMP and IMP are disodium guanylate and disodium inosinate. They are flavor enhancers. A 50/50 mixture of GMP and IMP has about 10X the flavor enhancement punch of MSG. I’m sure it says something fundamental about our sense of taste that the maximum effect occurs at the 50/50 mixture, but I don’t know what it means. GMP and IMP are powerful flavor enhancers on their own, and I have done experiments to confirm that the maximum effect really is at 50/50. There’s a synergism with MSG, so maximum economy is to use all three. On the other hand, in my experience GMP/IMP alone produces a brighter flavor than MSG alone or in combination, so best flavor is to use GMP/IMP without MSG. On the other hand, during my experiments I developed peripheral neuropathy manifested as a numbness in the tops of both feet which took nearly a year to resolve. During that time, I was like a human Geiger counter for GMP/IMP. I could eat one tortilla chip with a flavor package that included GMP/IMP and my feet would flare up. If I were your liability lawyer, I’d say stick with MSG monotherapy.

    • luysii  On April 9, 2020 at 9:48 pm

      Well maybe the GMP and IMP shut down your macrophages who should have been doing housekeeping on your peripheral nerves — neuropathy usually starts in the longest nerve fibers.

  • Mark Thorson  On April 9, 2020 at 7:16 pm

    Something I forgot to mention about GMP or IMP. It might be both of them or maybe just one of the two, but there’s something in there that acts as a mild stimulant, like caffeine. It’s also possible there couild be a contaminant in the material I bought. Before buying chemicals and planning my experiments, I read every scrap of information I could get about these molecules from Stanford — all their libraries including chem, bio, and med school. Nothing I found mentioned either the peripheral neuropathy or the stimulant effect. I suspect they may have undiscovered properties that could be risky. I would not use them if I were a food manufacturer.

    • luysii  On April 9, 2020 at 9:49 pm

      Doubtful that there was a contaminant in the GMP/IMP you took, if exogenous GMP/IMP in a flavor package could cause a flare.

      • Mark Thorson  On April 10, 2020 at 1:29 pm

        Good point, it probably was the intended material unless contamination is rampant in the industry. I probably was influenced in my thinking by the outbreak of eosinophilic myalgia linked to tryptophan which probably was caused by a contaminant. I never heard a definitive end to that story — only that it might have been caused by a methylene-linked dimer or a contaminant called “peak X”.

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