Small Applied Research Project

Coarse-grained funnel model of early cellular responses for improved accuracy of prediction of chronic diseases (Funnel)

Today, long-term hazard assessment of nano-sized ultrafine particulate matter (PM) relies on slow and expensive animal testing (in vivo). Any alternative method requires mechanistic insight into disease development, covered by the OECD’s concept of Adverse Outcome Pathways (AOP).

Problem

Two AOP frustrations preventing development of alternative tests:

molecular-level complexity VS limited validation data,
material-agnostic events VS material-specific triggers

While the AOP describes the disease development as a chain of material-agnostic key events, early cellular responses are obviously material-specific and involve thousands of molecular components and pathways, simply too costly to be unravelled for each material. Besides, that level of detail cannot be integrated into any general prediction model as it needs to be calibrated against limited in vivo data, available for only up to 100 different nanomaterials.

SOLUTION

Refocus AOP key events: from molecular to functional perspective:

shift the focus of cellular responses from molecular level to the level of functional units (i.e. organelles) to reduce the complexity of the early evolution pathways by 10 orders of magnitude, matching the size of the in vivo dataset for calibration,
adapt our in-vitro-to-in-silico translation platform and prediction model, recently developed at our spin-out company Infinite, to funnel material-specific early events towards material-agnostic disease evolution, revitalising the AOP value for animal-free disease prediction.

IMPACT

Covering the widest possible range of modes-of-action (MoA), reliable safety testing of any material will boost the material safety assessment, now hindered by the limited animal testing capacity, to allow novel nanomaterials, crucial e.g. for green transition and medicine, to safely reach consumers.