Road Map for Discovery
A new study finds that that nearly 40 percent of the human genome remains largely unexplored, which could dramatically impede the search for new drug therapies.
The dearth of research tends to be self-perpetuating, because scientists know they are more likely to be successful and funded by querying those areas of the genome that are already relatively well described.
As a first step toward solving the problem, a team of U.S. and European scientists has proposed an elegant method for categorizing the genome according to how extensively genes – and the proteins they code for – have been studied. The new classification scheme also suggests what steps would be needed to establish whether these proteins are likely targets for an array of novel drug therapies.
The work was carried out as part of the Illuminating the Druggable Genome (IDG) project, a National Institutes of Health Common Fund initiative. The findings are highlighted in “Unexplored therapeutic opportunities in the human genome,” published in the February 23, 2018, issue of Nature Reviews Drug Discovery.
“Almost 9,000 proteins are not currently being subjected to NIH-sponsored research,” said lead author Tudor Oprea, MD, PhD, professor and chief of the Translational Informatics Division in the University of New Mexico’s Department of Internal Medicine. “This study attracts attention to that situation. We hope to encourage scientists and funders to explore the unknown.”
Oprea led a team of researchers from the IDG Knowledge Management Center in an exhaustive review of a wide array of genomic, proteomic, chemical and disease-related data in order to track the target development level (TDL) of human proteins.
The researchers proposed grouping human proteins into one of four TDL categories:
- Tclin (for “clinical”) represents the most-studied proteins, ones that have known interactions with approved drugs and for which there is an identified mechanism of action. These represent just 3 percent of the human proteome.
- Tchem (for “chemical”) includes proteins that are known to bind to small molecules with relatively high potency. This group accounts for 6 percent of the proteome.
- Tbio (biology) refers to proteins for which there is experimental evidence of disease relevance, and some understanding concerning their structure and function, but which have not been fully developed as drug targets. About 53 percent of the proteome belongs to this category.
- Tdark (referring to the “dark” genome”) includes all proteins that do not meet the criteria for inclusion in any of the other categories. “[T]hese are proteins for which there is the least current knowledge and a low number of specific molecular probes available,” the authors said. “Some represent unexplored opportunities within the druggable human genome.” These proteins account for 38 percent of the proteome.
The authors note that funding to study the dark genome has been scarce, in part because research is often based on “artificial distinctions,” in which problems are segregated by organ or disease. “This distinction breaks down in nature, as we are likely to observe the interplay between the same genes and pathways regardless of organ, albeit in a context-specific manner.”
Their proposed classification scheme “provides a convenient way to partition human targets that highlights the focus (or lack thereof) of science and drug discovery efforts on different targets.”
Oprea said the fact that drug targets for which small molecules are currently known represent only around 10 percent of the human proteome “underlines the extent to which we don’t fully understand human biology. There’s a lot more work to be done.
The Knowledge Management Center includes researchers from the NIH National Center for Advancing Translational Sciences, the University of New Mexico, the University of Miami, the University of Copenhagen, the European Bioinformatics Institute and the Icahn School of Medicine at Mt. Sinai. Other collaborators on this paper are from Yale University, the University of North Carolina, the University of California, San Francisco, Baylor College of Medicine, the University of Zurich, as well as IQVIA and AstraZeneca.