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. CirDNA 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.

Keywords: Genometastasis; Inheritance of acquired characteristics; Lateral gene transfer; Metabolic DNA; Pangenesis; Virtosomes.

Fig. 1

Chronological summary of the key events that led to the discovery and characterization of cirNAs and EVs from 428 bc (a) to date (b). The research topics include inheritance theories (represented by triangles), Pangenesis and graft hybridization studies (diamonds), the inheritance of acquired characteristics (chevron), genetic material and inheritance (squares), soma-to-germline information transfer (crosses), metabolic DNA (circles), EVs (half circles), cirDNA (stars), the bystander effect (rectangles), mobile protein complexes (arrow), and cancer progression and/or metastasis (plus)

Fig. 2

Przibram and Steinach’s somatic induction research [50]

Fig. 3

Chronological summary of the events that led to the discovery and elucidation of nuclein as hereditary material in genes [83, 212, 213]

Fig. 4

Studies that contributed to the discovery and elucidation of Pelc’s metabolic DNA. a Ficq and Pavan [133] ’s discovery of DNA synthesis in the chromosomes of R. angelae larvae was the first indication that DNA played a very active part in the larval development. Polytene chromosomes are generated by the repeated replication of the chromosomes, followed by the alignment of the multiple copies of sister chromatids along their lengths, forming distinct banding patterns [214]. Pelc [132] later observed similar patterns of heavily and weakly labelled nuclei in mouse tissues and attributed the occurrence to the renewal of parts of genetic material that is highly active in the cells of an organ, similar to the puffing of chromosomal bands in R. angelae. b DNA metabolism in DNA bodies was also associated with Pelc’s metabolically active DNA and Ficq and Pavan’s chromosomal puffs by Lima-de-Faria [141]. Lima-de-Faria produced a detailed elucidation of DNA and RNA metabolism in the DNA bodies of Acheta domesticus oocytes in 1968 and proposed that the DNA released during the disintegration of the DNA body at the end of diplotene serve as information carriers [140, 141], theoretically making Lima-de-Faria not only the first to officially use the term metabolic DNA, but also the first to connect metabolic DNA to genetic messaging and cirNAs. c Pelc connected metabolic DNA with the macronuclear DNA of ciliated protozoa in 1970, giving reason to believe that metabolic DNA served a similar protective purpose towards genetic DNA as macronuclear metabolic DNA would protect micronuclear genetic DNA from alterations during transcription [–161]. d Schematic summary of key characteristics of Pelc’s metabolic DNA which share striking similarities with macronuclear metabolic DNA. The breakdown or removal of copied genes from polytene chromosomes during the larval development, the release of DNA and RNA from DNA bodies during disintegration, and the regular degeneration of old macronuclei and synthesis of new macronuclei during meiosis result in the release of nucleic acids into the nucleus, cell, and circulation, indicating a connection between Pelc’s metabolic DNA and cirNAs as suggested by Lima-de-Faria [141] and later by Gahan et al. [5]

Fig. 5

Series of studies that influenced Pelc’s research on metabolically active DNA and the development of Pelc’s hypothesis on metabolic DNA