Singapore – Agency for Science, Technology and Research (A*STAR)’s 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 holds great potential to predict future drug resistance, thereby saving lives and optimising the use of resources. The study was published on 25 November 2015 in the online issue of Cell.
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, so as to eradicate these harmful cells.
Yet, drug resistance, in which cells mutate and render the drug ineffective, is on the rise. According to a recent World Health Organization (WHO) report, “antibiotic resistance is happening right now, across the world.”[1] Other examples include chemotherapy resistance, which is a leading cause of cancer treatment failure[2], or the recent spread of antifungal drug-resistant fungi[3]. The rising trend of drug resistance suggests that cells can in fact adapt to the inactivation of some of these seemingly essential genes.
Drug discovery is a long-drawn process that takes many years from development stage to first-in-man clinical trials. Currently, there is no way 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 that resistance can occur. In fact, the success rate of clinical trials globally is estimated to be as low as 25 per cent, 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 optimised 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.”
Professor Rong Li, Bloomberg Distinguished Professor of Cell Biology and Chemical & Biomolecular Engineering at Johns Hopkins University (JHU), and a world renowned expert in cellular asymmetry, division and evolution commented, “This is a fantastic study that takes a systematic approach to re-define the essentiality of gene function, taking into account the cell’s adaptive potential. The findings demonstrate high-level plasticity across the genome-wide molecular network toward a range of genetic perturbations.”
Both corresponding authors of the study, Dr Giulia Rancati and Dr Norman Pavelka, Principal Investigator at SIgN, are recipients of the A*STAR Investigatorship, a prestigious research award designed to attract the most promising young researchers around the world to do independent research at A*STAR. This breakthrough therefore attests to the world-class quality of R&D by researchers under the programme, and the strength of the award in nurturing leading scientific innovators.
Notes to Editor:
The research findings described in this media release can be found in CELL, under the title, “Gene essentiality is a quantitative property linked to cellular evolvability”, by Gaowen Liu1,2, Mei Yun Jacy Yong1, Marina Yurieva3, Kandhadayar Gopalan Srinivasan3, Jaron Liu1, John Soon Yew Lim1, Michael Poidinger3, Graham D. Wright1, Francesca Zolezzi3, Hyungwon Choi4, Norman Pavelka2,3,*, Giulia Rancati1,2,*
1Institute for Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
2School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
3Singapore Immunology Network (SIgN), A*STAR, Singapore 138648, Singapore
4Saw Swee Hock School of Public Health, National University of Singapore (NUS), and National University Health System, Singapore 117549, Singapore
*Corresponding Authors
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About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and Research Institutes, the wider research community and industry. A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities primarily located in Biopolis and Fusionopolis.
About A*STAR’s Institute of Medical Biology (IMB)
IMB is one of the Biomedical Sciences Institutes of the Agency for Science, Technology and Research (A*STAR). It was formed in 2007, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life.
IMB has 20 research teams working in three primary focus areas - stem cells, genetic disease, and skin biology. The teams work closely with clinical collaborators as well as industry partners, to target the challenging interface between basic science and clinical medicine. IMB’s strategic research topics are targeted at translational research to understand the mechanisms of human disease so as to identify new strategies for disease amelioration, cure and eradication and to improve health and wellbeing. Since 2011, IMB has also hosted the inter-research institute Skin Biology Cluster platform, and leads major strategic funding programs in rare genetic diseases and in skin biology. In 2013 IMB became a founding institute of the Skin Research Institute of Singapore.
For more information about IMB, please visit www.imb.a-star.edu.sg.
About A*STAR’s Singapore Immunology Network (SIgN)
The Singapore Immunology Network (SIgN), officially inaugurated on 15 January 2008, is a research consortium under the Agency for Science, Technology and Research (A*STAR)’s Biomedical Research Council. The mandate of SIgN is to advance human immunology research and participate in international efforts to combat major health problems. Since its launch, SIgN has grown rapidly and currently includes 250 scientists from 26 different countries around the world working under 28 renowned principal investigators. At SIgN, researchers investigate immunity during infection and various inflammatory conditions including cancer and are supported by cutting edge technological research platforms and core services.
Through this, SIgN aims to build a strong platform in basic human immunology research for better translation of research findings into clinical applications. SIgN also sets out to establish productive links with local and international institutions, and encourage the exchange of ideas and expertise between academic, industrial and clinical partners and thus contribute to a vibrant research environment in Singapore.
For more information about SIgN, please visit www.sign.a-star.edu.sg.
[1] http://www.who.int/drugresistance/publications/infographic-antimicrobial...
[2] http://chemocare.com/chemotherapy/what-is-chemotherapy/what-is-drug-resi...
