A critical role for mTORC1 in erythropoiesis and anemia
Excerpt 1): “Cells must coordinate their rate of growth and proliferation with the availability of nutrients. mTOR , a serine-threonine kinase, is one the key proteins responsible for nutrient signaling in eukaryotic cells. mTOR is activated by conditions that signal energy abundance, such as the availability of amino acids, growth factors, and intracellular ATP. Activated mTOR then phosphorylates a set of downstream targets that promote anabolic processes, such as protein translation and lipid biosynthesis, while suppressing catabolic processes such as autophagy [1].”
My comment: That fact links the availability of nutrients to RNA-mediated cell type differentiation in all cells of all tissues of all organs and all organ systems via the conserved molecular mechanisms. The mechanisms epigenetically link the sensory environment to pheromone-controlled cell type differentiation in species from microbes to man during their life history transitions. Simply put, cells must have nutrients to proliferate. They cannot coordinate their growth rate when they are starving to death. That fact makes the nutrient-dependent microRNA/messenger RNA balance the most obvious link to the physical landscape of DNA in the organized genomes of all species.
Evolutionary theorists continue to claim that the genomes are organized in the context of mutations, natural selection and the evolution of biodiversity. Although no evolutionary event has ever been described and only RNA-mediated events have been detailed, some people seem to prefer to believe in pseudoscientific nonsense about protein biosythesis and degradation. Fortunately, most medical laboratory scientists know that pseudoscientific nonsense may kill people.
For example see:
Two case studies and a review of paroxysmal cold hemoglobinuria
Yesterday, I spoke about this with Misty, a medical technology student. I learned later from a former technologist who became a physician’s assistant that Misty had ‘aced’ her most recent test in immunohematology/blood-banking/transfusion medicine. I discussed this with Misty and we concurred: No matter how much laboratory professionals learn, there will always be cases where what is not known alters patient outcomes.
In these two case studies, the authors link what appears to be antibiotic-induced receptor-mediated changes to an acquired hemolytic anemia via medication-induced changes in the microRNA/messenger RNA balance and RNA-mediated events that differentiate cell types via amino acid substitutions. Unlike Misty, some students may believe cell type differentiation is caused by mutations and natural selection. Yes, indeed, Richard Lenski’s works with E.coli have been meaningfully interpreted to make it appear that they support a ridiculous theory. See: The Man Who Bottled Evolution. That report misrepresents this fact: The organisms were competing for a carbon source, as all organisms must do. Without a source of nutrients, they starve to death. They do not evolve inside or outside bottles. See for example: “…in medium with glucose and acetate as carbon sources, E. coli cells preferentially metabolize glucose and excrete acetate until the glucose is depleted and then undergo a diauxic switch to acetate consumption [32].” This fact is reported — with my emphasis — as “…each population consisted of generalists competing for two different sources of dietary carbon (glucose and acetate), but after 1200 generations they had evolved into two coexisting types each with a specialized physiology adapted to one of the carbon sources.” I am reminded that medical laboratory scientists who often are generalists may also compete to find the diagnosis that best fits into the context of a disease or disorder. It may be a matter of ego, but the competition is more likely to be a matter of which professionals can collectively provide the best information to the attending physician.
If the problem with cell types that led to the aquired anemia was manifested in sickle-cell anemia, most people would have been taught by evolutionary theorists that the genomic instability that led to the ecological adaptation was caused by a mutation, which somehow spread throughout human populations in geographic regions where malaria was or still is endemic. That is an example of how evolutionary theory continues to kill people. Theorists don’t seem to know anything about biophysically-constrained nutrient-dependent RNA-mediated events and amino acid substitutions, which differentiate cell types in all cells of all individuals in all species via stabilization of DNA. That is why evolutionary theorists typically attribute the biodiversity of cell types to mutations, natural selection, and the evolution of more than 1180 human hemoglobin variants.
If medical laboratory scientists did that, no tests for the cell type variants present in the anemia manifested in the two cased presented above would ever have been developed. Two children (one 23 month-old and one 4-year old) would have not been diagnosed with paroxysmal cold hemoglobinurea (PCH). Both would have received transfusions or died. Only one received a transfusion, and fortunately both children lived. That’s because a test for PCH was developed in 1904. When the 4-year old manifested the symptoms and same results of testing, no transfusion was requested. Kudos to those who adeptly recognized the pattern in these two children.
What is the problem? Medical laboratory professionals are taught to recognize patterns; evolutionary theorists are not.
In this case, the acquired hemolytic anemia makes it clear that consideration of the biophysically-constrained thermodynamics of protein biosynthesis and degradation should be the first consideration. Antibiotic-induced changes in these receptor-mediated nutrient-dependent thermodynamic cycles appear to initially help with the natural genetic engineering of organism-level thermoregulation in the management of infections and fever in both children.
The antibiotics did not cause mutations in the bacteria or in the children. However, two to three weeks later the children presented with the acquired hemolytic disease. Was the disease acquired due to a virus that led to a bacterial infection or the antibiotic used to treat the symptoms? Could an earlier diagnosis of PCH have been made in the 23-month old to avoid the requirement for transfusion? An earlier diagnosis is not likey if the medical professionals are taught to believe in the evolution of antibiotic resistance or to believe that evolutionary events somehow differentiate cell types.
Cell type differentiation is nutrient-dependent and RNA-mediated. It is controlled by the metabolism of nutrients to species-specific pheromones that enable self versus non-self recognition as clearly as does testing in the blood bank. Unfortunately, some evolutionary theorists portray the Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, as if it were a mutation that was fixed in certain populations via natural selection. How can they suggest that given what is known: “There are two DARC protein polymorphisms, the FY*A and FY*B alleles, that differ by a single amino acid. A third polymorphism, FY*O or the Duffy-null allele, is a DARC promoter region single nucleotide polymorphism (SNP) that effects the loss of Duffy antigen protein expression on red blood cells [5].” — Hodgson et al (2014)
Medical professionals probably understand what most theorists cannot. Cell type differentiation is nutrient-dependent and pheromone-controlled via RNA-mediated events, which explains why medical professionals may laugh at any attribution that links a fixed amino acid substitution to perturbed protein folding, which theorists claim also causes the loss of Duffy antigen protein expression on red blood cells. Most medical professionals have trouble believing in a hypothesis that links mutations to amino acid substitutions and protein biosynthesis, but also to the loss of those proteins. Medical professionals should be wary of anyone who tells them that mutations lead from protein biosyntheis to fixed amino acid substitutions and also the elimination of amino acid substitutions and proteins in different human populations. For example, watch out for Masatoshi Nei. He states that “…genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world.” Kick him out of your lab before he kills someone with an incompatible blood type with his theory. Tell him on his way out that nutrient-dependent RNA-mediated events differentiate cell types and you have the test results that prove it. If you must do so, first take him to the microbiology department and experimentally test how long any bacteria lasts without a supply of nutrients.
Show him how that cell types of E. coli show up in different colors on different types of media if he needs to be convinced that the morphology of the colonies is nutrient-dependent and pheromone-controlled via quorum-sensing.
If medical professionals refuse to believe in the pseudoscientific nonsense of neo-Darwinian theory, experiences in microbiology, transfusion medicine, and other departments, may lead to more interest in obtaining a thorough patient history. Most of us would not hesitate to obtain that history if any problem occurred in any aspect of testing — even with a cold agglutinin that appeared to cause hemolysis. Some of us may link antibiotic use to the hemolytic disorder by what is currently known about RNA-mediated events that differentiate cell types via amino acid substitutions in populations with different hemoglobin variants.
“What’s a hemoglobin variant?” — an evolutionary theorist might ask. “I learned that mutations cause different cell types associated with skin pigments in different populations of humans so that — as mutant humans — they could survive in regions where malaria was, or still is, endemic.
We need to keep the evolutionary theorists out of the lab and ignore them when we are inside or outside the lab. We need to tell them that they may be causing patient deaths by preventing the early diagnosis of disorders that may or may not require treatment with blood transfusions, or with antibiotics if the diagnosis of the disorder is made quickly. Try this, tell the evolutionary theorists that the diagnosis of PCH requires the same test that has been used since 1904. Ask why they don’t know that RNA-mediated events link nutrient-dependent amino acid substitutions to cell type differentiation. Tell them they have contributed to deaths from disorders caused by population geneticists who knew nothing about cell type differentiation in any species. They simply assumed that mutations caused the morphological and behavioral differences and taught others who have continued to tout that pseudoscientific nonsense for more than 100 years. They wouldn’t know the difference between an ecological adaptation and a mutation if they saw one macroscopically, in a test tube, or under the microscope.
