TeachableMedicalNews article 02082023

Teachable moment in classrooms:

  1. cellular basis of life chapter – concept of one gene, one protein
  2. cellular basis of life chapter – concept of gene mutation leading to protein malfunction
  3. cellular basis of life chapter – role of mRNA in protein synthesis
  4. nervous system chapter – pain receptor neurons detect chemicals of tissue damage
  5. blood chapter – the heme is the oxygen-binding part of hemoglobin

The news item:  Recently the following report appeared:

Gene silencing medicine transforms crippling pain

The NHS is set to fund innovative therapy that patients say has given them their lives back.

The article states that two sisters suffered tremendous pain from acute intermittent porphyria, and even opioid pain killers couldn’t block the pain. The article also states that the sisters received the injected givosiran drug which provided pain relief, and that the drug silences a gene, so buildup of a toxic protein is prevented.

So, Why Do I Care??  Constant, chronic pain prevents people from carrying on with their daily lives. Because traditional pain management approaches may not work on such patients, alternative pain relief methods are being explored. Porphyria is one of those disorders where pain relief may eventually come from the molecular understanding of the causation of pain. If the gene silencing approach is successful, it would be reasonable to explore it’s use for other disorders, and that might benefit many patients.

Plain English, Please!!!  First, let’s talk about what porphyria is. The heme part of hemoglobin is an organic chemical shaped as a large ring. That large ring is constructed by linking together small chemicals. That is similar to an assembly line that makes cars.  Each factory worker adds a piece to the half-finished car. The ring called heme is made on a molecular assembly line where the workers are enzymes. If one enzyme is missing (because of genetic mutations) the assembly line behind that worker keeps on humming, and partially completed ring pieces accumulate in the cell.  In the case of the disorder called porphyria the partially made ring is called amino levulinic acid (ALA). The sisters in the article suffer from such a genetic mutation, and ALA has accumulated in their bodies.

Second, let’s talk about why porphyria causes pain. The large amount of ALA spreads throughout the body of porphyria patients, and damages neurons, the liver, and the kidneys. The damaged cells leak their inner chemicals, and those leaked chemicals trigger nerve impulses from pain receptors. When those nerve impulses reach the brain, we feel pain.

Third, let’s talk about how gene silencing works.   It makes sense, that if we could slow the action of the first workers/enzymes in the assembly line, then we would slow down the accumulation of ALA. Those enzymes in the heme assembly line are made, just like other proteins, using a messenger RNA (mRNA) that guides the construction of the protein in a ribosome.  Imagine mRNA as a string of letters forming a message on a long banner. The RNA interference (siRNA) drug givosiran covers up a part of the banner. When that happens, the ribosome cannot read the mRNA message, and cannot make the enzymes for the heme assembly line. Fewer enzymes on the assembly line means less ALA in the body, which means fewer damaged cells, and, thus, less trigger for pain.

 

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