Unravelling the nexus: Towards a unified model of development, ageing, and cancer.

This work presents a comprehensive model that aims to unify our understanding of embryogenesis, ageing, and cancer. While there have been previous attempts to construct models separately for two of these phenomena (such as embryogenesis and cancer, ageing and cancer), models encompassing all three are relatively scarce, if not entirely absent. The model's most notable feature is the presence of driver cells throughout the body, which may correspond to Spemann's organisers. These driver cells play a vital role in propelling development as they dynamically emerge from non-driver cells and inhabit specialised niches. Remarkably, this continuous process persists throughout an organism's entire lifespan, signifying that development unfolds from conception to the end of life. Driver cells orchestrate change events through the induction of distinctive epigenetic patterns of gene activation. Events occurring at young age drive development, are subject to high evolutionary pressure and hence carefully optimised. Events occurring after reproduction age are subject to decreasing evolutionary pressure: for this reason, such events are "pseudorandom" -deterministic but erratic. Some of these events lead to age-related benign conditions, such as gray hair. Some lead to serious age-related diseases, such as diabetes and Alzheimer's disease. Furthermore, some of these events might perturb epigenetically key pathways involved in driver activation and formation, leading to cancer. In our model, this driver cell-based mechanism represents the backbone of multicellular biology: understanding and correcting its functioning may give the chance to solve a wide range of conditions at once.

Embryogenesis, morphogens and cancer stem cells: putting the puzzle together.

This paper describes a model which puts together three key elements of cancer theory: the analogies between embryogenesis and carcinogenesis, the role played in both processes by morphogens and related pathways, and the recently emerged paradigm of cancer stem cells. The model is called Epigenetic Tracking. Originally conceived as a model of embryonic development, it was later extended to interpret other aspects of biology, such as the presence of junk DNA, the phenomenon of ageing and the process of cancer formation. In this work we deepen our vision of carcinogenesis, and propose a novel hypothesis on the role of morphogen-processing pathways. According to the hypothesis, the interplay of these pathways leads in stem cells to the production of new transcription factors, which act as drivers of cellular differentiation. The disruption of these pathways, caused by mutations in specific genes, would represent the first and most distinctive event in the carcinogenic process. Our hypothesis allows us to make testable predictions on patterns of gene mutations involved in carcinogenesis. Our hypothesis also suggests that cancer stem cells can stay dormant until they are activated in a process that resembles activation of stem cells during tissue repair or at a specific time during development.

A model of evolution of development based on germline penetration of new "no-junk" DNA.

There is a mounting body of evidence that somatic transposition may be involved in normal development of multicellular organisms and in pathology, especially cancer. Epigenetic Tracking (ET) is an abstract model of multicellular development, able to generate complex 3-dimensional structures. Its aim is not to model the development of a particular organism nor to merely summarise mainstream knowledge on genetic regulation of development. Rather, the goal of ET is to provide a theoretical framework to test new postulated genetic mechanisms, not fully established yet in mainstream biology. The first proposal is that development is orchestrated through a subset of cells which we call driver cells. In these cells, the cellular state determines a specific pattern of gene activation which leads to the occurrence of developmental events. The second proposal is that evolution of development is affected by somatic transposition events. We postulate that when the genome of a driver cell does not specify what developmental event should be undertaken when the cell is in a particular cellular state, somatic transposition events can reshape the genome, build new regulatory regions, and lead to a new pattern of gene activation in the cell. Our third hypothesis, not supported yet by direct evidence, but consistent with some experimental observations, is that these new "no-junk" sequences-regulatory regions created by transposable elements at new positions in the genome-can exit the cell and enter the germline, to be incorporated in the genome of the progeny. We call this mechanism germline penetration. This process allows heritable incorporation of novel developmental events in the developmental trajectory. In this paper we will present the model and link these three postulated mechanisms to biological observations.

A hypothesis on the role of transposons.

Genomic transposable elements, or transposons, are sequences of DNA that can move to different positions in the genome; in the process, they can cause chromosomal rearrengements and changes in gene expression. Despite their prevalence in the genomes of many species, their function is largely unknown: for this reason, they have been labelled "junk" DNA. "Epigenetic Tracking" is a model of development that, combined with a standard evolutionary algorithm, become an evo-devo method able to generate arbitrary shapes of any kind and complexity (in terms of number of cells, number of colours, etc.). The model of development has been also shown to be able to produce the artificial version of key biological phenomena such as the phenomenon of ageing, and the process of carcinogenesis. In this paper the evo-devo core of the method is explored and the result is a novel hypothesis on the biological role of transposons, according to which transposition in somatic cells during development drives cellular differentiation and transposition in germ cells is an indispensable tool to boost evolution. Thus, transposable elements, far from being "junk", have one of the most important roles in multicellular biology.