Finding the Needle in the Haystack with Synthetic DNA

Finding the Needle in the Haystack  with Synthetic DNA
3D render of DNA strands on a technology abstract background

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Twist Bioscience is a cutting-edge synthetic biology company whose proprietary technology might be the real twist—a method of producing synthetic DNA by “writing” it on a silicon chip. Clinical OMICs Editor-in-Chief Chris Anderson sat down with CEO Emily Leproust, Ph.D., an early pioneer in the high-throughput synthesis and sequencing of DNA who has designed and developed multiple commercial synthesis platforms to streamline microarray manufacturing and fabrication, to learn more about how Twist’s technology is impacting oncology research.

What is your technology and how does it differ from others?

Twist Bioscience is leveraging the power of our disruptive silicon-based DNA writing platform to make industry-leading NGS Target Enrichment panels used to identify a variety of genetic variations. We have built panels for DNA and RNA sequencing, and our newest tools will focus on solving how to detect the epigenetic state of cancerous cells from liquid biopsies. The current technology, offered by others, just doesn’t have the level of sensitivity, flexibility, or confidence that’s needed. The way we’re addressing the problem is with our Hybrid Capture Target Enrichment, which is used to detect very low levels of various states of methylated DNA molecules. Hybrid capture introduces oligonucleotide probes into a genomic sample and ‘pulls out’ the DNA of interest through hybridization to enrich the sample before sequencing. The alternative is amplicon-based PCR, which can be extremely complicated when it’s highly multiplexed and usually results in an overabundance of PCR duplicates. Those duplicates are redundant, need to be removed from the analysis, waste sequencing, and give an inflated coverage rate. Also important to note is that with Hybrid Capture Target Enrichment versus Microarray, there is the sequencing advantage so you know the methylated state of every base with single-base resolution.

What makes Twist stand out?

Our Hybrid Capture Target Enrichment technology provides a uniform capture and high library saturation of the molecules of interest without a complicated library preparation process or redundant sequencing. It also enables extreme customization of any target. It’s so simple—you can specify the targets that you want to be captured, and we create a panel that requires no further optimization. Our high-fidelity, double-stranded DNA (dsDNA) allows us to capture both the sense and antisense strand for a more robust enrichment, and we focus on the design algorithm to accurately boost the correct concentration of each probe, which is why we’re able to achieve a very uniform capture.

What advantages do your technologies provide to researchers and clinicians, and how can they help them in their work?

We help researchers and clinicians find the needle in a haystack. When developing liquid biopsy assays for diagnosis, companion diagnostics, or minimal residual disease (MRD) monitoring, sensitivity and accuracy of variant detection is critical. The customizability of our dsDNA hybrid capture probes is what makes our system so widely accessible. The flexibility of our probe design enables a small-to-large target region. Now, with our technology, clinical researchers are able to order custom probes and detect not only the sequence of their variant of interest, but also its epigenetic state. If a particular gene is hyper- or hypo-methylated, that will be identified systematically, even with ctDNA.

What do you consider the sweet spot(s) in the market for your technologies?

Early detection cancer screening, low mutant variant detection, and minimal residual disease (MRD) are three main applications where our technology is being used, and where epigenetics and somatic mutations come into play. All of these rely on rare variant detection in liquid biopsy, and we’ve recently added detection of methylated DNA. Every disease is going to have a different set of genomic variants that could be informative, so customization of an assay is critical. That’s why we focused on making it easy to order a panel of custom targets for a completely customized assay. We want researchers and clinicians to only sequence what they need, and not what they don’t, saving them both time and money.

What can you tell me about the company’s plans for the coming year?

This year we will conduct a full launch of our custom methylation detection panels to aid in early detection cancer screening by identifying differentially methylated regions (DMRs) to analyze hypo- or hyper-methylated targets in cancerous cells. We have early access researchers generating some incredible results. We’re also building custom panels for those investigating MRDs. The thought is that clinicians will first use our exome assay as a first-pass screening method, and use the results to create a very specific, smaller panel for targeted liquid biopsy monitoring. Using this approach, treatment decisions would be more informed, and patients could be screened for relapse.

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