By establishing a library of individual yeast genes, each cleverly tagged with its own molecular barcode, an international team of molecular geneticists has designed a valuable resource for pharmaceutical research with advantages over previous approaches.
The research team, including Minoru Yoshida at the RIKEN Advanced Science Institute in Wako, and Charles Boone at the University of Toronto, Canada, developed the library in which each yeast gene is copied and attached to two unique single stranded DNA molecules that act as barcodes. This enables researchers to efficiently identify each gene.
The yeast-based chemical-genomics approach, presented recently in Nature Biotechnology by Yoshida and colleagues (1), is useful because many medicinally important drugs target fundamental biological processes that are conserved between yeast cells and higher organisms.
Using the team’s approach, all the gene-carrying units, or plasmids, in the yeast are carefully constructed individually, as opposed to conventional genomic libraries that are created from random fragments of DNA. Each plasmid carries a single yeast gene as well as two 20-nucleotide barcodes that identify it. The library comprises plasmids for almost 5,000 genes and covers approximately 90% of the yeast genome.
Other approaches to examine the genetic influence of potential drugs have limitations such as needing high volumes of test compound, which can be of limited availability, or being labor intensive.
Most significantly, the newly created gene catalogue will enable researchers to identify at the genetic level the precise modes of action of specific compounds that are being screened as potential pharmaceuticals. The library can be used to efficiently identify mutant genes that confer resistance to a test drug by comparing cells that show resistance and susceptibility to the compound. Determination of the mutant genes leads to the identification of the functional impact of a potential drug.
In a demonstration of the usefulness of the library, Yoshida and colleagues identified the gene responsible for conferring resistance to a novel class of compounds with pharmaceutical potential. Identifying this gene enabled the team to characterize the mechanism of action of these molecules and to determine that they are antifungal compounds, a property not detected by other techniques.
An essential but challenging step in the development of small molecules into therapeutic drugs is identification of their cellular target. “Using this library, our group intends systematically to study chemical–genetic interactions in which an altered gene dosage or gene mutation leads to a change in cellular response to a bioactive compound,” says Yoshida.
Ho, C.H., Magtanong, L., Barker, S.L., Gresham, D., Nishimura, S., Natarajan, P., Koh, J.L.Y., Porter, J., Gray, C.A., Andersen, R.J. et al. A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds. Nature Biotechnology 27, 369–377 (2009).
The corresponding author for this highlight is based at the RIKEN Chemical Biology Department, Chemical Genomics Research Group
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine