From chemical genomics to personalized medicine—tackling the genotype to phenotype problem

Molecular BioSystems is dedicated to publishing research at the interface between chemistry and systems-level science. This is a growing and changing interface and encompasses all kinds of different science, which is one of the reasons I am particularly excited about the potential of this journal. This broad mandate involving both chemistry and biology means Molecular BioSystems will address basic research that’s ultimately relevant to clinical and personalized medicine.

In my own field of yeast functional genomics, a number of us have become interested in linking bioactive compounds to their cellular targets and the possibility of doing so on a large-scale. Perhaps our most powerful resource for deciphering the cellular roles of bioactive compounds is the yeast deletion mutant collection. This genome-wide set of strains provides a simple system for deciphering the target pathways because compound activity can be linked to specific genetic alterations, which enables us to infer the cellular role of the compound. Analogous genome-wide mutant collections are being constructed for other microoganisms, including many pathogens, and RNA interference (RNAi) knockdown systems are extending this research to more complex mammalian cells.

Indeed, widespread application of this type of chemical-genomics approach offers the potential to develop chemical probes targeting the majority of all pathways in a variety of different cells. Nevertheless, this ambitious goal remains a long way off and will continue to be so until we generally establish closer working relationships between chemists and biologists. Personally, I would argue that the chemical diversity provided by natural products is going to play a major role in establishing our full repertoire of biologically active chemical probes and that we should consider a common pairing of systems-level functional genomics research groups with natural product chemists. Interestingly, this pairing is becoming even more obvious with the application of next generation sequencing to metagenomics and the cataloging of gene clusters that encode the relevant metabolic pathways involved in natural product biosynthesis.

Given diverse collections of bioactive compounds, chemical-genomics approaches should enable us to identify hundreds of highly specific chemical probes. But it doesn't stop there because, as we all know, things are always more complicated than they first appear. The response of a given individual to a specific chemical perturbation remains widely varied because, at least in part, their particular phenotype remains determined by their own particular genotype. The genotype-to-phenotype problem is becoming more apparent as we begin to catalog whole genome sequences for numerous individuals. A mechanistic understanding of this problem remains a major hurdle for human geneticists and one that is critical for the development of personalized medicine.

We hope that readers/authors will help to ensure that Molecular BioSystems remains central to providing solutions to some of these problems.

Charles Boone, PhD

Chair, Molecular BioSystems Editorial Board

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