April 2022 EMM Editor's Choice Article

Of time, space, and linear models

The April 2022 EMM Editor’s Choice article is “In vitro relationships of galactic cosmic radiation and epigenetic clocks in human bronchial epithelial cells,” (https://doi.org/10.1002/em.22483) by Jamaji C. Nwanaji-Enwerem, Philippe Boileau, Andres Cardenas.

Science fiction writers such as Isaac Azimov may have led us to forget how inhospitable space really is. Outside of the protective cocoon of the Earth’s magnetosphere, protons and ions fly through space near the speed of light, tearing through shielding and shredding DNA in its track.

In their recent paper, Nwanaji-Enwerem and colleagues attempted to quantify the genomic wear-and-tear effect of being exposed to space radiation (Nwanaji-Enwerem et al. 2022). The question the authors asked is: “How much faster do cells age when exposed to space radiation?” An elegant and straightforward question, that leads to a not-so-straightforward answer.

The authors used a publicly available dataset from human cells exposed to space-relevant types of radiation. Specifically, they looked at the most plastic, modifiable part of the genome: the epigenome. Except for rare mutations occurring in a stochastic manner, the DNA sequence is stable through time. The methylation marks providing context to the sequence, however, are highly responsive to their environment. The authors used three different algorithms using hundreds of epigenetic DNA methylation alterations previously validated to reflect cellular aging, what are called “epigenetic clocks.”

So: more radiation, more aging? For one of these three clocks, the answer was a statistically robust “yes.” That clock, the epiTOC2 model, effectively tracks aging through estimates of cell divisions. However, that is also where the clear answers stop. The epiTOC2 model could only demonstrated significant increases in aging for 56Fe particles, the most potent type of radiation. In the case of X-rays and 28Si radiation, no such association was demonstrated. A second and third clock which track aging in cell divisions and days, respectively, did not respond to radiation. Is epiTOC2 a better clock? If so, why would it fail to track the damage due to the two other types of radiation?

In this work, the authors made a very reasonable assumption: more radiation, more aging. They used a linear no-threshold (LNT) model to evaluate the relationship. However, this is not a completely resolved question in radiation biology (Weber and Zanzonico 2017). In fact, many indications point to a non-linear relationship between radiation and biological effects, particularly at low doses. There are at least three other competing models: one where low doses of radiation have larger effects than in the LNT model (hypersensitivity), one where low doses have smaller effects than in the LNT model (threshold), and finally, one where low doses have a beneficial biological effect (hormetic). The lowest dose analyzed in this study is 0.1Gy, which is the poster child for low radiation doses, straight in the middle of that uncertainty zone.

Our scientific tools are infinitely better at describing linear relationships. Personally, Nwanaji-Enwerem and colleagues effectively convinced me that there is a relationship between radiation exposure and aging. But as much as I wish that radiation followed a linear no-threshold model, this study also hints that our best tools are probably a square peg in a round hole when it comes to looking at the relationship between dose and effect.



Nwanaji-Enwerem, Jamaji C., Philippe Boileau, Jonathan M. Galazka, and Andres Cardenas. 2022. “In Vitro Relationships of Galactic Cosmic Radiation and Epigenetic Clocks in Human Bronchial Epithelial Cells.” Environmental and Molecular Mutagenesis 63 (4): 184–89. https://doi.org/10.1002/em.22483.

Weber, Wolfgang, and Pat Zanzonico. 2017. “The Controversial Linear No-Threshold Model.” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 58 (1): 7–8. https://doi.org/10.2967/jnumed.116.182667.

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