[8] At the University of North Carolina at Chapel Hill, Sharpless ran a basic science laboratory that utilized genetically engineered mice to study cancer and aging, and was co-founder and co-director of the UNC Lineberger Mouse Phase I Unit.

[12][13][14] The biomarker assay was commercialized by a clinical-phase biotech company called Sapere Bio (formerly HealthSpan Dx), founded by Sharpless and his team.

[16][17] He is also one of the founders of G1 Therapeutics, listed $GTHX under the NASDAQ, which is a clinical-stage biopharmaceutical company developing small-molecule therapies for the treatment of patients with cancer.

Extending upon this work, Sharpless' team developed the p16LUC model, a genetically engineered mouse that 'glows' upon activation of the p16INK4a promoter due to insertion of firefly luciferase in place of the endogenous gene.

[18] Use of this system revealed the activation of p16INK4a in tissues surrounding nascent tumors, allowing scientists to non-invasively visualize the formation and progression of spontaneous cancers in living animals.

Specifically, Ned's lab has used the p16LUC allele to understand how low dose toxic exposure over a lifetime can affect the rate of molecular aging.

[26] In 2013 Sharpless and his lab cataloged a large list of circular RNAs in human cell lines and mouse tissues using a whole genome sequencing strategy employing RNase R digestion.

[8] Sharpless has authored or co-authored more than 170 original reports, reviews and book chapters recorded in the PubMed.gov database[28] and has served as an editor of Aging Cell and the Journal of Clinical Investigation.