Towards Predictive Computational Models of Oncolytic Virus Therapy: Basis for Experimental Validation and Model Selection

Oncolytic viruses are viruses that specifically infect cancer cells and kill them, while leaving healthy cells largely intact. Their ability to spread through the tumor makes them an attractive therapy approach. While promising results have been observed in clinical trials, solid success remains elusive since we lack understanding of the basic principles that govern the dynamical interactions between the virus and the cancer. In this respect, computational models can help experimental research at optimizing treatment regimes. Although preliminary mathematical work has been performed, this suffers from the fact that individual models are largely arbitrary and based on biologically uncertain assumptions. Here, we present a general framework to study the dynamics of oncolytic viruses that is independent of uncertain and arbitrary mathematical formulations. We find two categories of dynamics, depending on the assumptions about spatial constraints that govern that spread of the virus from cell to cell. If infected cells are mixed among uninfected cells, there exists a viral replication rate threshold beyond which tumor control is the only outcome. On the other hand, if infected cells are clustered together (e.g. in a solid tumor), then we observe more complicated dynamics in which the outcome of therapy might go either way, depending on the initial number of cells and viruses. We fit our models to previously published experimental data and discuss aspects of model validation, selection, and experimental design. This framework can be used as a basis for model selection and validation in the context of future, more detailed experimental studies. It can further serve as the basis for future, more complex models that take into account other clinically relevant factors such as immune responses

Guilt and Child Soldiers

The use of child soldiers in armed conflict is an increasing global concern. Although philosophers have examined whether child soldiers can be considered combatants in war, much less attention has been paid to their moral responsibility. While it is tempting to think of them as having diminished or limited responsibility, child soldiers often report feeling guilt for the wrongs they commit. Here I argue that their feelings of guilt are both intelligible and morally appropriate. The feelings of guilt that child soldiers experience are not self-censure; rather their guilt arises from their attempts to come to terms with what they see as their own morally ambiguous motives. Their guilt is appropriate because it reaffirms their commitment to morality and facilitates their self-forgiveness