The efficacy of protons to cause cell death varies as the protons travel through the patient, reaching a maximum at the end of range. However, current clinical practice assumes that this potential to cause cell death is constant across the proton range, quantified by the relative biological effectiveness (=1.1).

This assumption is known to be incorrect. Although, clinical results still show a benefit over conventional photon therapy with this assumption in place, this is thought to be due to the better physical dose distribution. That being said, better knowledge of the variable RBE effect can help us to further increase the benefits offered by protons. The variable RBE is thought to be, in part, a result of the increased DNA damage at the distal end of the proton range.

My research focuses on understanding the mechanisms by which protons cause DNA damage and lead to cell death. This can be achieved through simulation. Simulations allow for a huge number of repeats with reliable statistics, as well as the analysis of experimentally unobservable phenomena. The simulations require use of code to model the proton transport and interaction with biological targets.

The transport of protons, and other ions, is simulated with the open source Monte Carlo toolkit Geant4 (GEometry ANd Tracking), originally developed at CERN for detector testing. Recent developments by the Geant4-DNA collaboration have extended the toolkit’s capabilities; allowing for accurate physical interactions and better particle tracking at lower energies. Geant4-DNA is also capable of simulating the production and tracking of reactive oxygen species for use in studying the effects of indirect DNA damage.

Combining the physics and chemistry of Geant4-DNA with biological targets of varying complexities allows us to develop simulations capable of determining DNA damage. Crucially, double strand breaks (DSBs) can be determined. It is thought that failure to repair these DSBs is the mechanism that leads to cell death. Within the group we are particularly interested in scoring this DNA damage with the conventions of nanodosimetry. This will offer a link between the physics of the proton beam and the early biological effects.

Biological targets currently implemented within the group are the DNA double helix, the chromatin fibre, models of plasmid DNA, and a model of the cellular nucleus. 

Nicholas Henthorn is a research associate within the PRECISE group. He has a B.Sc. in Physics, an M.Sc. in Medical Physics, and a PhD in mechanistic modelling for proton therapy. His work is focussed on the simulation of DNA damage with a relevance to proton therapy. These simulations aim to uncover the mechanisms of physical and chemical damage that result in biological effect.