AsianScientist (Dec. 17, 2015) – Researchers at Singapore’s Agency for Science, Technology and Research’s (A*STAR) Institute of Medical Biology (IMB) and Singapore Immunology Network (SIgN) have identified a new paradigm for the identification and evaluation of genes for cell survival. By challenging long-held notions on gene essentiality and drug development, the study published in Cell could help predict future drug resistance.
Traditionally, basic and applied genetics have relied on the core concept of gene essentiality, which states that certain genes are essential for a cell’s survival. When the cells in question are cancer cells or pathogenic microbes, drugs can be developed to block these essential genes and so eradicate these harmful cells.
Yet, drug resistance, in which cells mutate and render the drug ineffective, is on the rise. Examples include antibiotic resistance and chemotherapy resistance, the latter being a leading cause of cancer treatment failure. The rising trend of drug resistance suggests that cells can in fact adapt to the inactivation of some of these seemingly essential genes.
The problem is exacerbated by the long timeframe of drug discovery and inability to predict future drug resistance at the early stages of drug development. Very often, companies spend billions on developing a single drug candidate, only to discover several years later during clinical trials or even after approval, that resistance can occur.
In fact, the success rate of clinical trials globally is estimated to be as low as 25 percent, partially due to the high number of drug candidates found to be resistible only during trial stage. This represents the loss of time and resources which could otherwise have been used to develop more effective drugs and therapies.
Now, A*STAR scientists have redefined the underlying concept of gene essentiality by putting forth a new genetic paradigm.
Previously, genes were divided into non-essential ones that are dispensable for cell viability, and essential genes that are required for cell survival. The new study found that essential genes can be further split into two kinds—one being the kind that cells need for survival, known as ‘non-evolvable’ essential genes, and the other being those that cells can find ways to survive without, by an evolutionary process of mutation and selection. Genes belonging to this latter class were termed ‘evolvable’ essential genes.
Cells knocked-out of one of these ‘evolvable’ essential genes need to adapt very quickly so as to survive. Through examining approximately 1,000 essential genes in yeast, the team found that cells were able to adapt so quickly because they mutate to change their number of chromosomes.
In so doing, they change the relative balance of genes in their genome and use alternative pathways to perform the original function carried out by the missing gene. This also explains why the presence of extra chromosomes has been reported commonly in chemotherapy-resistant cancer cells and drug-resistant fungi and parasites.
This study holds great potential to improve the current drug discovery and development process, with applications for illnesses varying from cancer to infectious diseases. Drug candidates can be tested to see if they are in fact targeting ‘non-evolvable’ essential genes.
This would then suggest a lower possibility of drug resistance since cells would not be able to adapt to the loss of these genes. With this new paradigm, drug resistance can be predicted at the discovery stage and resources can be optimized to develop more effective drugs that can save lives.
Dr. Giulia Rancati, Principal Investigator at IMB and corresponding author of the paper, said, “We are thrilled to challenge a longstanding paradigm in genetics, especially one with such clinical implications. The next step will be to translate these findings in pathogenic fungi and human cells, and to find non-evolvable essential genes as novel antifungal and chemotherapy targets, respectively.”
The article can be found at: Liu et al. (2015) Gene Essentiality is a Quantitative Property Linked to Cellular Evolvability.
Source: A*STAR; Photo: Mehmet Pinarci/Flickr/CC.
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