Accelerating genomic discovery: from pharma to farmer

Genome sequencing – analysing all of an organism’s genetic information at once – is having a transformative effect across the biotechnology industry. The technology required to sequence a genome is more accessible than ever, in part due to a rapid decline in cost and an increase in speed over the past 15 years. In 2014, three genomics centres, including the Kinghorn Centre for Clinical Genomics at the Garvan Institute of Medical Research in Sydney, acquired Illumina HiSeq X Ten systems, which has the capability to sequence a whole human genome at a base cost below US$1000. Such high-throughput technologies are generating a wealth of genomic data, and are providing an increasingly valuable information source for both medical and agricultural research. 

The pathway for the translation of medical research has traditionally been linear – discoveries are made in research that inform the development of a new drug or diagnostic test, which is then approved for use in the clinic after many phases of clinical trials. Recently, and especially with regard to genomics research, we are seeing a shift towards a more cyclical translation pathway of clinically driven research. Increasingly, candidates for genomic research are being identified in the clinic and their genomic data is being used to inform their own clinical care. Similarly, diagnostic information is playing a crucial role in discovery stages, leading to a blurred boundary between research and the clinic. This shift in the traditional research paradigm means that genomic discovery is playing a role at all stages of the translational pathway, rather than just at the beginning. 

Many drug trials are adding translational arms alongside more traditional clinical endpoints so that the biochemical mechanisms that underpin clinical observations can be explored in depth. Others are using genomic information to stratify patients and inform how the trial is run. The Molecular Screening and Therapeutics (MoST) clinical trials being carried out at the Garvan Institute of Medical Research in Sydney use molecular information from tumours to match individual patients with treatments targeted to their specific cancer type. The trials also contain multiple clinical sub-studies of novel treatments, and patients are stratified into sub-studies based on what treatment is most appropriate for their tumour. The MoST trials sit between a traditional Phase I toxicity trial and Phase II efficacy trial, and represent the future of trial design in cancer, as genomic profiling of tumours will be essential for the next generation of targeted therapeutics. 

Tailoring treatments based on a person’s genetic make-up promises an era of better patient outcomes from more targeted and effective therapies. For this reason, pharmaceutical companies are beginning to incorporate genomics at all stages of the drug- development pipeline – from discovery through to late-stage clinical trials. 

In 2016, AstraZeneca launched its Centre for Genomics Research with the aim of compiling genome sequences and health records from two million people over 10 years. AstraZeneca intends to discover rare variants associated with diseaseand response to treatment, and will use the data to inform drug development across their entire portfolio, which includes complex diseases such as asthma and diabetes. Much of the genetic contribution to complex diseases remains unexplained, and large-scale sequencing projects such as this could uncover the impact of rare variants that have not previously been identified. 

Agricultural research is also undergoing a genomic revolution to combat rising populations and climate change. The rate of annual yield increases from major staple crops must more than double by 2050 to keep up with population increases. Conventional breeding, which involves selection based solely on phenotype over a number of generations, is expensive and time- consuming. A rapid and efficient selection system is needed for the development of high-yielding and climate-resistant crop varieties for the future, and this is where genomics is becoming a powerful tool. 

Genomic selection is becoming routine in crop improvement.

Genomic selection involves estimating the genetic worth of a plant by comparing its genomic profile with those of others that have grown in the same environment. This requires large reference libraries of molecular markers and phenotypic information to be built, but can save significant time and money in the long run by increasing the accuracy and efficiency of selection. Genomic selection is becoming routine in crop improvement, particularly for cereal crops, such as maize and rice. We are seeing a lot of genomic research that is focused on building or refining reference libraries for other crops, to accelerate the uptake of this technique. 

A similar approach to breeding is being used for livestock, and is responsible for the dramatic increases in livestock productivity over the past 50 years. For example, milk production in Holstein cows doubled from approximately 6000 kilogams in 1960 to 12,000 kilograms in 2000 – and 75 per cent of this change was genetic. 

Libraries of genome-wide markers are being used to predict performance traits of breeding stock, which allows producers to optimise the profitability and yields of their herds by making strategic breeding decisions. Genomic selection of livestock has been used commercially for more than a decade, so most of the work in this area is focused on adding to, or refining, the existing reference libraries. 

A key project is the 1000 Bulls Genome Project – an international effort to construct a large database of genetic variants from 1000 ancestor bulls ofthe most important domestic cattle breeds. The first 234 genomes sequenced have yielded 28.3 million variants, including several associated with embryonic loss and lethal chondrodysplasia. This type of database is invaluable for producers looking to maximise the health and viability of their herd. 

Genome sequencing has moved from a prohibitively expensive and time-consuming research technique to a powerful tool for shaping the future of biotechnology. We are already seeing genomic information being used for the development of targeted therapeutics, the stratification of patients in clinical trials, and the improvement of crop and livestock breeding. 

Additionally, we are seeing the emergence of pioneering genomics-focused companies, such as Australia’s Genome.One, which provides genomic sequencing and genomic analysis to accelerate innovation in the biotech sector. Importantly, as the cost of sequencing continues to decrease, the amount of genomic data available for research will increase exponentially, providing even greater opportunities for researchers to realise the value of genomic information in their field. 

By Andrew Stone, Head, Cohort sequencing and analytics, Genome.One

This article was first published in Australasian BioTechnology, the journal of AusBiotech, April 2018, Volume 1, Number 1; 65-67.

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