Scientists Discover How To Halt and Control Cellular Death Process – Previously Thought To Be Irreversible

A composite image of a cell throughout pyroptosis. Credit: Gary Mo

A study published by researchers at the University of Illinois Chicago describes a new method for analyzing pyroptosis — the process of cell death that is usually caused by infections and results in excess inflammation in the body — and shows that process, long thought to be irreversible once initiated, can in fact be halted and controlled.

The discovery, which is reported in Nature Communications, means that scientists have a new way to study diseases that are related to malfunctioning cell death processes, like some cancers, and infections that can be complicated by out-of-control inflammation caused by the process. These infections include sepsis, for example, and acute respiratory distress syndrome, which is among the major complications of COVID-19 illness.

Pyroptosis is a series of biochemical reactions that uses gasdermin, a protein, to open large pores in the cell membrane and destabilize the cell. To understand more about this process, the UIC researchers designed an “optogenetic” gasdermin by genetically engineering the protein to respond to light.

“The cell death process plays an important role in the body, in both healthy states and unhealthy ones, but studying pyroptosis — which is a major type of cell death — has been challenging,” said Gary Mo, UIC assistant professor in the department of pharmacology and regenerative medicine and the department of biomedical engineering at the College of Medicine.

Mo said that methods to examine the pyroptosis mechanisms at play in live cells are difficult to control because they are initiated by unpredictable pathogens, which in turn have disparate effects in different cells and people.

“Our optogenetic gasdermin allowed us to skip over the unpredictable pathogen behavior and the variable cellular response because it mimics at the molecular level what happens in the cell once pyroptosis is initiated,” Mo said.

The researchers applied this tool and used florescent imaging technology to precisely activate gasdermin in cell experiments and observe the pores under various circumstances. They discovered that certain conditions, like specific concentrations of calcium ions, for example, triggered the pores to close within only tens of seconds.

This automatic response to external circumstances provides evidence that pyroptosis dynamically self-regulates.

“This showed us that this form of cell death is not a one-way ticket. The process is actually programmed with a cancel button, an off-switch,” Mo said. “Understanding how to control this process unlocks new avenues for drug discovery, and now we can find drugs that work for both sides — it allows us to think about tuning, either boosting or limiting, this type of cell death in diseases, where we could previously only remove this important process.”

Reference: “Gasdermin D pores are dynamically regulated by local phosphoinositide circuitry” by Ana Beatriz Santa Cruz Garcia, Kevin P. Schnur, Asrar B. Malik and Gary C. H. Mo, 10 January 2022, Nature Communications.
DOI: 10.1038/s41467-021-27692-9

Co-authors of the Nature Communications paper, “Gasdermin D Pores Are Dynamically Regulated by Local Phosphoinositide Circuitry,” are Ana Santa Cruz Garcia, Kevin Schnur and Asrar Malik, all of UIC.

The research was funded with grants from the National Institutes of Health (P01HL060678, R01HL090152, R01HL152515, T32HL007820, P01HL151327).

Cell BiologyInflammationPopularUniversity of Illinois at Chicago
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  • Sekar

    Very Interesting.

    Triggered some thoughts for consideration. Some are way out in left field.

    1.If I remember correctly, the Human Body replaces all the cellsin its body every seven years.

    2. Sodium and Pottasium balance is critical for life. Sepsis indicates that sodium – Pottasium balance has gone awry in the human ecosystem.

    3 Calcium supplements are very importantfor bone. The porosity of bones increases when there is calcium deficieny. Affects female gender more than male. Have always wondered about bone marrow transplants.

    Now coming to the article. Very good work.

    1. The Human and mammalian system is fairly complex. Good to know that GSDMD a;one is responsible for calcium flares in macrophages and fibrobalsts. Was wondering about T-Cell Responses.

    2.To get a more comprehensive understanding of the human ecosystem immunity (and also mammmalian) connect the Sodium – Potassium Balance and long-term regulation in humans and mammmals. The new born baby get mothers milk and calcium from the same. I wonder whether such breast fed babies are healthier during their lifetimes than bottle fed milk with artifical milk powder. Would be interesting research.

    3. The size of the pore and its opening and closing and time span for the same triggered the following thought. When do the quantum effects get triggered in the Biological Systems. Nano chemistry and Quantum Physics. At Nano levels?

    4 Kinetic Response from cummulative calcium is interesting. Maybe, potential to manage the same exists by bringing in Sodiumand Potassium into the mix? May provide Clues to manage inflamation responses better , which protects the Human Ecosystem frm invading horedes of bacteria, viruses and pathogens. Didnt quite understand the Interleuken effect.

    5.Optogenetically activated signals emenated largely frm circular pores. Triggered the following thought. Quantum effects explanation by “Physics Girl” in You-Tube. Maybe the Binary On/Off Switch being developed for Quantum Computing can be useful if deployed in Medicine? The role of lipid layers is interesting.

    6. Have always wondered about the Neuron and its role in regulation of the brain. The fact that electrical signals and its importance in human health is extremely importanthas has been known for quite some time, especially for the Nervous system.

    7. Spatial Biochemistry is a new field. The finding that less temporal alignment and longer effectiveopening time for spore membrane triggered the following thought. Brownian Motion. Have always wondered if such motion is much more aligned in live biological system and if so, how are they are aligned in biological systems.

    8. The Wortmanin pre-treated cells showing less variability triggered the following thought. Does Bio magnetism exist in biological systems which can enable such alignment? I suspect it does.

    All these views expressed are personal and not binding on anyone

  • Matthew T G

    And who do you think will have access to the better part of that. Sure as hell won’t be the average Joe. All I see is a way for the rich to live longer.

  • Nunya

    I’m quite glad I could never afford something like this as a “common person” as I would jump off a bridge before I allowed anyone to keep me alive to serve them for another 50 years.

  • Antony J. Blinken

    “Quote: boosting or limiting, this type of cell death…”

    Thank you, the Military’s biochemical warfare division will be in touch with your funding shortly. Please consider methods of dispersal, delivery and targeting of large populations through / air, water supplies etc. for rapid (instantaneous?) cell death. Specifically Homo sapiens, with specific species genus / race / ethnicity / lineage / individual genetics.

    Yours sincerely, Antony J. Blinken

  • John

    All things start out benefitting the better off first but, eventually trickle down.. It may not in our lifetime but it’s still exciting.

  • J.H.W.

    Yes, it is a well known fact that breast milk if even fed for a minimum of two weeks produces a much healthier human. But you were on to something there though..enfamil and other brands are know to cause gas-“issues” but as well..Inflammation in babies to a severe degree. I do believe it is a chain reaction.. iodine \salt/potassium.. are important for balances signaling/communications between cells/neurons\axioms. Etc. But… magnesium and calcium operate together.. if one is out of whack than the other can’t do its job. Point…dehydration on a molecular level..a domino effect for bad enzyme proclivities.. etc. Thus causing bad signaling within the neural system. This matters significantly considering…the “off” switch can easily be tripped through this discombobulated communication. 99% of humans are clinically deficient in these fundemental areas that effect hydration levels.
    I which does induce inflammation…as well environmental stressors ..depending on the average nervousness of the individual. “Knowing you are terminally ill” is all it takes to drive a person into a natural state of deficiency. Fear=hyper vigilance =major depletion of sugar/potassium levels. Leaving a high salt output… which leaves me to ask. Though I’m sure all of these are equally important.. one who is undergoing treatment such as chemotherapy…can be clinically deficient in sodium chloride to the points of hallucinating. Which is contrary to my for mentioned theory. But significant at the same time. Due to the balances thereof. High salt =swelling. For some. But the opposite for others. I suffer low salt. And swell due to stressors…and where I began…is where I end.. milk has high sugar content. I get relief. After hyper vigilance..by going for milk…(reduces inflammations in my gut) and pickle juice….for swelling in my feet…(same causes) if I dont.. its lights out for me, and my body goes all tardic-kenesis on me. My point is.. yes…everything is a two way system. All things are on a balanced spectrum. This idea kinda reminds me of a (new born ~ as a cell) when it auto-aborts. (Dead cell) this relates to …neurotoxins vs. Endorphins… one depletes…and causes depressions=dehydration.
    The other regenerates…and drives…calcium and magnesium to do their thing. Which also relates to my tardic-comment. I believe in as above so below….that cell picture looks just like a nebula-or galaxy… I consider these the same fundamentally on a grander scale. Can a cell self abort due to malevolent signaling, from environmental causes…thus.. opening the pathways for bad bacteria!/pathogens to enter the pores or linings..in the first place… then causing this cycle to amplify.?

  • Sekar

    Very Interesting.

    Triggered some thoughts for consideration. Some are way out in left field.

    1.If I remember correctly, the Human Body replaces all the cells in its body every seven years.

    2. Sodium and Pottasium balance is critical for life. Sepsis indicates that sodium – Pottasium balance has gone awry in the human ecosystem.

    3 Calcium supplements are very important for bone. The porosity of bones increases when there is calcium deficieny. Affects female gender more than male. Have always wondered about bone marrow transplants.

    Now coming to the article. Very good work.

    1. The Human and mammalian system is fairly complex. Good to know that GSDMD alone is responsible for calcium flares in macrophages and fibrobalsts. Was wondering about T-Cell Responses.

    2.To get a more comprehensive understanding of the human ecosystem immunity (and also mammmalian) connect the Sodium – Potassium Balance and long-term regulation in humans and mammmals. The new born baby get mothers milk and calcium from the same. I wonder whether such breast fed babies are healthier during their lifetimes than bottle fed milk with artifical milk powder. Would be interesting research.

    3. The size of the pore and its opening and closing and time span for the same triggered the following thought. When do the quantum effects get triggered in the Biological Systems. Nano chemistry and Quantum Physics. At Nano levels?

    4 Kinetic Response from cummulative calcium is interesting. Maybe, potential to manage the same exists by bringing in Sodium and Potassium into the mix? May provide Clues to manage inflamation responses better , which protects the Human Ecosystem from invading horedes of bacteria, viruses and pathogens. Didn’t quite understand the Interleuken effect.

    5.Optogenetically activated signals emenated largely form circular pores. Triggered the following thought. Quantum effects explanation by “Physics Girl” in You-Tube. Maybe the Binary On/Off Switch being developed for Quantum Computing can be useful if deployed in Medicine? The role of lipid layers is interesting.

    6. Have always wondered about the Neuron and its role in regulation of the brain. The fact that electrical signals and its importance in human health is extremely important has has been known for quite some time, especially for the Nervous system.

    7. Spatial Biochemistry is a new field. The finding that less temporal alignment and longer effective opening time for spore membrane triggered the following thought. Brownian Motion. Have always wondered if such motion is much more aligned in live biological system and if so, how are they are aligned in biological systems.

    8. The Wortmanin pre-treated cells showing less variability triggered the following thought. Does Bio magnetism exist in biological systems which can enable such alignment? I suspect it does.

    All these views expressed are personal and not binding on anyone

  • maxx

    Misspelled fluorescent in 7th paragraph & that sidetracked me from the article, took me out of the moment. Had to go determine if author meant bursting into flower or actually fluorescent, with an “fluor…”.
    Other than that, good info.

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    30 trillion in debt