Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes.

Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4α). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4α in both lymphoblasts and pancreatic ß-cells, including compounds that physically interact with HNF4α. Compounds including US Food and Drug Administration-approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from ß-cells. This method may suggest therapeutic hypotheses for other nonblood disorders.

Perturbational profiling of nanomaterial biologic activity.

Our understanding of the biologic effects (including toxicity) of nanomaterials is incomplete. In vivo animal studies remain the gold standard; however, widespread testing remains impractical, and the development of in vitro assays that correlate with in vivo activity has proven challenging. Here, we demonstrate the feasibility of analyzing in vitro nanomaterial activity in a generalizable, systematic fashion. We assessed nanoparticle effects in a multidimensional manner, using multiple cell types and multiple assays that reflect different aspects of cellular physiology. Hierarchical clustering of these data identifies nanomaterials with similar patterns of biologic activity across a broad sampling of cellular contexts, as opposed to extrapolating from results of a single in vitro assay. We show that this approach yields robust and detailed structure-activity relationships. Furthermore, a subset of nanoparticles were tested in mice, and nanoparticles with similar activity profiles in vitro exert similar effects on monocyte number in vivo. These data suggest a strategy of multidimensional characterization of nanomaterials in vitro that can inform the design of novel nanomaterials and guide studies of in vivo activity.