A historical and evolutionary perspective on the biological significance of circulating DNA and extracellular vesicles

Abstract

The discovery of quantitative and qualitative differences of the circulating DNA (cirDNA) between healthy and diseased individuals inclined researchers to investigate these molecules as potential biomarkers for non-invasive diagnosis and prognosis of various pathologies. However, except for some prenatal tests, cirDNA analyses have not been readily translated to clinical practice due to a lack of knowledge regarding its composition, function, and biological and evolutionary origins. We believe that, to fully grasp the nature of cirDNA and the extracellular vesicles (EVs) and protein complexes with which it is associated, it is necessary to probe the early and badly neglected work that contributed to the discovery and development of these concepts. Accordingly, this review consists of a schematic summary of the major events that developed and integrated the concepts of heredity, genetic information, cirDNA, EVs, and protein complexes. Cir-DNA enters target cells and provokes a myriad of gene regulatory effects associated with the messaging functions of various natures, disease progression, somatic genome variation, and transgenerational inheritance. This challenges the traditional views on each of the former topics. All of these discoveries can be traced directly back to the iconic works of Darwin, Lamarck, and their followers. The history of cirDNA that has been revisited here is rich in information that should be considered in clinical practice, when designing new experiments, and should be very useful for generating an empirically up-to-date view of cirDNA and EVs. Furthermore, we hope that it will invite many flights of speculation and stimulate further inquiry into its biological and evolutionary origins.

The diverse origins of circulating cell‐free DNA in the human body: a critical re‐evaluation of the literature

“…With characteristics similar to that of actively released cfDNA and its proposed functional roles, it thus was proposed that metabolic DNA may serve as a precursor DNA component of virtosomes (Gahan et al, ; Aucamp et al, ). Additionally, referring back to Darwin's gemmules, in 1889 Hugo de Vries introduced intracellular Pangenesis, theorising that Darwin's gemmules have an intracellular messaging rather than heredity role (Schwartz, ).…”

Extracellular DNA in natural environments: features, relevance and applications

“…1). As part of virtosomes, exDNA shows the ability to migrate to different parts of the body, enter target cells and alter their physiological properties such as the immune response, by sharing antigenic information (Anker et al 1984; Aucamp et al 2016; Skog et al 2008). Peters and Pretorius (2012) highlighted that this active release and uptake of nucleic acids is a characteristic of all organisms and cell types, and that in contrast to the neo-Darwinian dogma, physical and behavioural traits can be inherited through this cycling.…”

“…Peters and Pretorius (2012) highlighted that this active release and uptake of nucleic acids is a characteristic of all organisms and cell types, and that in contrast to the neo-Darwinian dogma, physical and behavioural traits can be inherited through this cycling. This is because there has been found evidence that not only somatic but also germ cells might be subject to genetic and epigenetic modifications via exDNA (intensively reviewed and discussed by Aucamp et al 2016). In this context, it has been hypothesised that the exDNA in human blood vessels might derive to a large extend from metabolic DNA, which is—as opposite to the stable genetic DNA—a specially synthesised low-molecular-weight fraction of DNA involved in the regulation and performance of RNA production and other cellular functions.…”

“…On the one hand, the functional role of exDNA inside the human body and especially the blood vessels is to serve as an intercellular messenger in the shape of virtosomes (Gahan and Stroun 2010), spreading the immunological information about pathogenic invaders but also supporting the dissemination of malignant information causing oncogenesis, cell invasion, metastasis and the development of resistance against radiotherapy and chemotherapy (Aucamp et al 2016). On the other hand, exDNA has been shown to act as a trap for invading pathogens in the shape of NETs, being in that way a part of the innate immune system and combatting an infection.…”

“…The occurrence, relevance of exDNA and possible exDNA-derived therapies in the human body (reviewed by Aucamp et al 2016; Cooper et al 2013; Thierry et al 2016);…”