Abstract
Ionizing radiation is a peculiar perturbation when it comes to damage to biological systems: it proceeds through discrete energy depositions, over a short temporal scale and a spatial scale critical for subcellular targets as DNA, whose damage complexity determines the outcome of the exposure. This lies at the basis of the success of track structure (and nanodosimetry) and microdosimetry in radiation biology. However, such reductionist approaches cannot account for the complex network of interactions regulating the overall response of the system to radiation, particularly when effects are manifest at the supracellular level and involve long times. Systems radiation biology is increasingly gaining ground, but the gap between reductionist and holistic approaches is becoming larger. This paper presents considerations on what roles track structure and microdosimetry can have in the attempt to fill this gap, and on how they can be further exploited to interpret radiobiological data and inform systemic approaches.
Highlights
When investigating the mechanisms and outcome of the radiation insult to a cell, as the basic structural and functional unit of a living organism, one is confronted with a peculiar kind of perturbation: ionizing radiation action proceeds through stochastic, discrete energy deposition events, occurring over a very short temporal scale and a spatial scale such that critical cell targets as the nuclear DNA and chromosomes can be severely damaged[1, 2]
The biological outcome of the exposure strongly depends on the clustering of energy deposition events at such scales, in turn related to the radiation quality under investigation[3]
This largely accounts for the success of mechanistic approaches in radiobiological research, as track structure and microdosimetry studies, though often limited to the characterization of energy deposition, initial damage and its complexity: the further correlation of these quantities to late radiobiological endpoints usually requires a phenomenological modeling approach, and the intrinsic variability in energy deposition at the target level is not always taken into account
Summary
When investigating the mechanisms and outcome of the radiation insult to a cell, as the basic structural and functional unit of a living organism, one is confronted with a peculiar kind of perturbation: ionizing radiation action proceeds through stochastic, discrete energy deposition events (excitations or ionizations), occurring over a very short temporal scale (up to 10-15 s) and a spatial scale such that critical cell targets as the nuclear DNA (double helix diameter ~2 nm) and chromosomes (linear dimension of a domain ~1 μm) can be severely damaged[1, 2]. The biological outcome of the exposure strongly depends on the clustering of energy deposition events at such scales, in turn related to the radiation quality under investigation (i.e. densely vs sparsely ionizing radiation)(3) This largely accounts for the success of mechanistic approaches in radiobiological research, as track structure (and nanodosimetry) and microdosimetry studies, though often limited to the characterization of energy deposition, initial damage and its complexity: the further correlation of these quantities to late radiobiological endpoints usually requires a phenomenological modeling approach, and the intrinsic variability in energy deposition at the target level is not always taken into account (e.g. when extracting only the average of microdosimetric distributions and not their shapes). Bioinformatics analysis of vast -omics datasets, together with the development of new methods to perform an integrated analysis of different radiobiological endpoints, are promising to gain further insight into these mechanisms Taken altogether, these considerations beg the following questions: what roles for track structure and microdosimetry, and, more in general, for the study of radiation-induced initial events, in radiobiology today? This section includes selected examples of track structure and microdosimetry calculations that, to some extent, present aspects of novelty, and might point a way forward for the application of such approaches to gain new insight for the interpretation of radiobiological data
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