We ran a clinical project, Insignia (www.mutationsignatures.org), between 2013-2018, recruiting patients with DNA repair/replication defects, aging syndromes and neurodegeneration, and people who have been exposed to environmental/occupational mutagens, to gain biological insights into mutational phenomena in these patients. We have a repository of iPSCs from these patients and are studying their normal, non-cancerous cells to understand the steps that lead to their disease phenotypes.
We use directed differentiation to generate 2D and 3D models of different tissues from patients with DNA repair disorders and in isogenic engineered knockouts to understand the basis of acquired changes in somatic cells that lead to age-related phenomena such as neurodegeneration.
Mutagenesis is not necessarily disease-associated, indicating that cellular ability to preserve homeostasis in spite of exogenous DNA damage, DNA repair/replication abnormalities, physiological stresses or by-products of metabolism, is extremely high. Here, we strive to understand how human cells coordinate physiological responses to the extensive amount of damage that our DNA is exposed to.