GENOMIC TECHNOLOGIES

RNA TECHNOLOGIES

The Genome Institute of Singapore has a strong programme on studying RNA and its diverse processes. The programme studies RNA beyond its primary sequence and utilises high throughput technologies to study RNA structure, RNA editing and RNA modifications in different diseases. This extends outside of the traditional view of targeting DNA and aims to understand and utilise the properties of RNA as a potential drug target.

The GIS RNA programme is also integrated with Singapore health agencies and other institutions and universities to improve human health.

While much effort has been focused in the last decade on studying how DNA and protein contribute to gene regulation, recent studies have shown that RNA plays important roles in almost every cellular process. Beyond its primary sequence, RNA can fold into complex secondary and tertiary structures, and are extensively processed and modified in diverse cellular functions. Errors in post-transcriptional processes such as folding, alternative splicing and RNA editing can result in the development of cancer and neurological disorders. We aim to utilise and develop high throughput technologies to study how RNAs work inside cells, in order to target RNA for disease treatment.

We work closely with several technology platforms in GIS, including the Genome Analytics Core, High Throughput Sequencing Platform, GERMS Platform and the Genome Innovation Laboratory. In collaboration with other computational groups within GIS, we develop novel analysis tools to study new datasets on RNA function. We also collaborate with other biology groups within GIS to study RNA under different developmental and disease processes. This extensive network of interactions has enabled us to develop new technologies to study how RNAs interact with other molecules globally, as well as how they could be regulated through RNA editing.

By continuing to develop and apply new technologies, we hope to discover new functions in this major class of macromolecules in diseases to facilitate better treatment.

CRISPR AND NUCLEIC ACID EDITING

The Genome Institute of Singapore is rewriting life. We do this by developing the most exciting technologies to massively change DNA in human genes, correcting the root causes of diseases, and synthesising new genomes from scratch.

Our work contributes to what has been called ‘the biggest biotech discovery of the century’ by the MIT Technology Review - the CRISPR-Cas technologies. At GIS, our work is pushing the limits of CRISPR-Cas technologies for genome (DNA) and transcriptome (RNA) engineering.

New CRISPR-Cas advances enable the creation of genetic change faster, better, and cheaper than ever before. These breakthroughs open up compelling avenues to directly remedy disease-causing genes. Combined with the ease of massive parallelisation, we now dissect entire genomes letter-by-letter, so as to illuminate disease vulnerabilities, drug modes of action, and combat viruses.

We further engineer the Cas protein with novel function-conferring effector domains that include transcription regulators, epigenetic regulators, fluorescent proteins, and deaminases, each of which allows us to create a unique functional change to the genetic location of choice.

Together, these multiple applications of CRISPR-Cas underscore its widespread utility, and promise a future of new diagnostics and medicines. At GIS, we continue to unlock the full potential of CRISPR-Cas technology by resolving the most outstanding obstacles impacting its use. Our work is making CRISPR-Cas more potent, more specific, more broadly applicable, easier to use, and safer. In doing so, we are inventing the new generation of research tools and molecular therapeutics.

Our work is part of a future where new life forms are created from the most fundamental building blocks. We develop new molecular machines that read, write, assemble, and repair DNA, so that we can engineer life direct from design. We interface the biological with the physical so that we can interconvert binary instructions with DNA sequences. We generate mini human organs harbouring new genetic blueprints. We build living things from imagination.

These technologies dramatically impact our future in how we rapidly combat disease outbreaks, manufacture biologics and medicines, disseminate cures, realise our imagination, and answer the hardest questions in what defines life. The Genome Institute of Singapore develops these cutting-edge technologies to answer these most pressing challenges facing our world.

LIQUID BIOPSY

Liquid biopsy refers to a non-invasive diagnostic test or technology that can identify conditions related to the tumour by detecting biomarkers in fluid samples such as blood or urine. This is differrent from traditional tissue biopsy which uses tumour tissues to serve a diagnostic purpose. As fluid samples, mainly blood of cancer patients, can be routinely and easily obtained from cancer patients, it has the potential to revolutionise cancer management by providing real-time monitoring and diagnosis of tumour. Liquid biopsy is gaining widespread interest in the area of cancer research and diagnosis, where genomic alterations have been shown to drive tumour progression and influence tumour response to treatment therapy.

Cancers accumulate genomic alterations as the tumour progresses. With the development of large-scale biologic databases, powerful technologies for patient characterisation and computational tools for big data analysis, the majority of the driver oncogenes have been uncovered. As we move into the era of precision medicine or individualised treatment therapy based on biologic behaviour of tumour, liquid biopsy, which has the ability to diagnose tumour and monitor its progression without the need to obtain tissue biopsy, is becoming one of the most exciting developments in cancer management.

At GIS, we use a wide variety of advanced, contemporary technology platforms to detect ultra-low frequency genomic alterations from the blood of cancer patients. We work with various national hospitals and clinics to discover novel blood-based biomarkers from cancer patients which can be used for clinical applications such as disease monitoring, prognosis and evaluation of therapy response.

Most recently, we have identified a novel blood-based biomarker strongly associated to breast cancer relapse. Our team at GIS is developing a liquid biopsy blood-based assay to detect circulating tumour DNA, which can potentially be used in the clinic to identify high risk relapse patients, monitor treatment response, as well as a companion diagnostic for future drugs.

GIS is also actively involved in the national liquid biopsy programme (CaLiBRe: Cancer Liquid Biopsy for Real-time diagnostics and early intervention) to profile the blood of cancer patients from diagnosis to relapse, in order to identify emerging genomic alterations as early as possible. We aim to develop innovative liquid biopsy genomics assays which can be implemented in the clinics to benefit cancer patients. With our CAP (College of American Pathologists)-accredited facilities, we have the complete framework to develop and validate our research discoveries into functional liquid biopsy assays for clinical applications.

SPATIAL TRANSCRIPTOMICS

The transcriptome of a cell contains a wealth of information about the cell’s current state as well as its recent history. An individual’s stem cells, skin cells, and neurons all have the same genome, but differ in their gene expression profile.

While next-generation sequencing is a powerful technology that can reveal the complexity of the human transcriptome, transcripts analysed need to be extracted from tissues, thus destroying their native spatial relationships. Yet, the tissue context of gene expression is of tremendous biological importance – most physiological processes take place under intricate cellular coordination and proper cell-cell interactions are vital for tissue health. If we can map the transcriptome of all the cells from an intact tissue, we can examine, at the most fundamental level, how different cell types in the mammalian tissues work together.

Multiplexed fluorescence in situ hybridization (FISH) is an attractive approach for spatial transcriptomics (ST), and has recently been implemented under various schemes, such as cyclic single-molecule FISH (smFISH), sequential FISH (seqFISH), and multiplexed error-robust FISH (MERFISH). In particular, we showed that MERFISH can be used to spatially image hundreds to thousands of RNA species within single cells.

Currently, laboratories in GIS are interested to develop new ST technologies and apply them to answer questions in both healthy and pathological tissues.