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In 2005 we discovered that previously-thought insoluble proteins could in fact be solubilized in unsalted water.Since then,this discovery has offered us and other groups a powerful tool to characterize insoluble proteins,and we have further addressed several fundamental and disease-relevant issues.The results reveal:1) The fact that all insoluble proteins including membrane proteins are soluble in unsalted water,but get aggregated upon being exposed to ions,logically suggests that ions existing in the background play a central role in aggregation,thus called dark mediators.2) By minimizing the mask of the pre-existing buffer/salt ions,we found that by contrast to the current belief,anions are able to bind proteins with high affinity and specificity,and different salts have very diverse effects on protein dynamics.3) Unlike misfolded proteins,which still retain the capacity to fold into well-defined structures but are misled to off-pathwayaggregation,unrefoldable and insoluble proteins completely lack this ability and will unavoidably aggregate in vivo with ～150 mM ions,thus designated as intrinsically insoluble proteins (ⅡPs).IIPs may largely account for the wastefully synthesizedDRiPs which were estimated to be ～2％ in yeast and up to 30％ in human genomes.4) Very recently,we decipher that insoluble proteins are all membrane-toxic because they have high potential to partition into membranes to form helical conformations driven by both amphiphilicty and hydrophobicity.Our results thus resolved the paradox that aggregation of specific proteins is characteristic of many human diseases and aging,yet aggregates have been increasingly found to be unnecessary for initiating pathogenesis.To attack membranes might represent the common first step for various kinds of aggregated proteins to trigger familiar,sporadic and aging diseases.The homeostasis of aggregated proteins including IIPs in vivo is the central factor responsible for a variety of human diseases including aging.5) Our discovery also implies a solution to the chicken-and-egg paradoxfor the origin of primitive membranes embedded with integral membrane proteins,if proteins originally emerged in unsalted prebiotic media.