I don't know how you would test drugs on some cells in order to find a cure for ME/CFS? I mean, it's not like cancer, where you just want to kill the cells, so you can see if things worked. Or like some intracellular infection, where you can see if you eliminated the pathogen.
I don't think we have anything to hang our hat on in terms of finding something clearly wrong with cells that we can then fix.?
I don't want to become the defender or spokesperson for this technique, but it does proceed based on that premise: we dont know what's wrong, so take an unbiased approach to see what drug makes things look like healthy cells again.
Walder used it in diabetes, he told me. Here's a couple of his papers that argue this process is useful when you're groping round in the dark (my emphasis added).
Gene expression signature: a powerful approach for drug discovery in diabetes
Smithamol Sithara 1 ,
Tamsyn M Crowley 2 ,
Ken Walder 1 ,
Kathryn Aston-Mourney 3
Affiliations
Abstract
Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of antidiabetic drugs; however, those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease, and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally,
the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved. Therefore, the approach of designing new drugs aimed at a specific molecular target is not optimal and a more expansive, unbiased approach is required. In this review, we will look at the current state of diabetes treatments and how these target the disease symptoms but are unable to combat the underlying causes. We will also review how the technique of gene expression signatures (GESs) has been used successfully for other complex diseases and how this may be applied as a powerful tool for the discovery of new drugs for T2D.
. 2023 Dec 31;15(1):2165368. doi: 10.1080/19382014.2023.2165368.
Identification of reversible and druggable pathways to improve beta-cell function and survival in Type 2 diabetes
Smithamol Sithara 1 ,
Tamsyn Crowley 2 ,
Ken Walder 1 ,
Kathryn Aston-Mourney 1
Affiliations
Abstract
Targeting β-cell failure could prevent, delay or even partially reverse Type 2 diabetes. However,
development of such drugs is limited as the molecular pathogenesis is complex and incompletely understood. Further, while β-cell failure can be modeled experimentally, only some of the molecular changes will be pathogenic. Therefore, we used a novel approach to identify molecular pathways that are not only changed in a diabetes-like state but also are reversible and can be targeted by drugs. INS1E cells were cultured in high glucose (HG, 20 mM) for 72 h or HG for an initial 24 h followed by drug addition (exendin-4, metformin and sodium salicylate) for the remaining 48 h. RNAseq (Illumina TruSeq), gene set enrichment analysis (GSEA) and pathway analysis (using Broad Institute, Reactome, KEGG and Biocarta platforms) were used to identify changes in molecular pathways. HG decreased function and increased apoptosis in INS1E cells with drugs partially reversing these effects. HG resulted in upregulation of 109 pathways while drug treatment downregulated 44 pathways with 21 pathways in common. Interestingly, while hyperglycemia extensively upregulated metabolic pathways, they were not altered with drug treatment, rather pathways involved in the cell cycle featured more heavily. GSEA for hyperglycemia identified many known pathways validating the applicability of our cell model to human disease. However, only a fraction of these pathways were downregulated with drug treatment, highlighting the importance of considering druggable pathways. Overall, this provides a powerful approach and resource for identifying appropriate targets for the development of β-cell drugs.
I'm not sure that is a clear sign of low risk.
