Unexplored therapeutic opportunities in the human genome

Abstract

A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.

Figure 1 |. Target development level categories applied to the human proteome.

a | Percentages of the whole proteome are shown in the inner ring. Percentages of each target development level (TDL) category for selected major protein families are shown in the outer ring, with the T_clin category expanded. Inner ring colours are as follows: T_dark, black; T_bio, red; T_chem, green; and T_clin, blue. b | TDL distribution across protein families, coloured by TDL category. Data show 3,644 proteins that have a confirmed disease association according to the Online Mendelian Inheritance in Man (OMIM) database. The enzyme category excludes kinases, which are considered separately. GPCR, G protein-coupled receptor.

Figure 2 |. Patterns of target development level distribution across different data: visualizing the knowledge deficit.

a | The three criteria used in establishing the target development level are to the left, and their independent validation by four other data types are to the right. For PubMed abstracts, Gene Reference Into Function (RIF) annotations, antibodies, Gene Ontology, R01 grants and patents, the score for each target is the count of those entities associated with the target, normalized between 0 and 1. The values for the Harmonizome data availability score were computed differently, as described in the main text. See FIG. 1 for colour codes and Supplementary Table S4 for further details. b | Patterns of scientific curiosity: STRING database access counts by target development level (January–December 2016).