Paola Scaffidi obtained her PhD from the Open University of London, working at Dibit San Raffaele Institute in Milan, Italy with Marco E. Bianchi. Her PhD work led to the identification of the chromatin protein HMGB1 as a major danger signal released by damaged cells, which triggers inflammatory responses. She then moved to the US National Cancer Institute to work in Tom Misteli's laboratory, first as a postdoctoral fellow and then as a staff scientist.
Her postdoctoral studies focused on the premature ageing disease Hutchinson-Gilford Progeria Syndrome and aimed at elucidating how nuclear architecture affects genome function. These studies showed that global epigenetic alterations are associated with both premature and normal ageing and opened avenues for therapeutic intervention to treat the disease.
As a staff scientist, she initiated a new area of investigation focused on elucidating how epigenetic mechanism and cellular reprogramming affect initiation and maintenance of solid tumours.
She joined the Cancer Research UK London Research Institute (LRI) in 2014 to lead the Cancer Epigenetics group. In 2015, the LRI became part of the Francis Crick Institute.