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Biomodal Expands Sequencing and Sample Prep Method to Read the 'Six-Base Genome'


NEW YORK – Biomodal has launched a new version of its epigenetic sequencing and sample prep assay that enables researchers to distinguish between unmodified, methylated, and hydroxymethylated cytosines.

According to the Cambridge, UK-based company, which rebranded from Cambridge Epigenetix last year, the new Duet Multiomics Solution evoC product, launched this week, allows for single-base resolution sequencing of the four standard DNA bases, 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC) from the same DNA molecule and in the same workflow, removing the need for repeat sequencing. Typically, a sample is sequenced multiple times when measuring epigenetic marks: once to measure the DNA bases and again to decipher the methylation marks.

The company's first product, called Duet Multiomics Solution +modC and released last year, enabled customers to determine modified cytosines but did not distinguish between 5mC and 5hmC.

To read out the six bases, sample DNA undergoes a series of proprietary enzymatic transformations. First, complementary strands are synthesized that remain attached to the original DNA strands. Modified Cs are then enzymatically protected while unmodified ones are deaminated and converted to Ts. The DNA is then sequenced on any type of short-read sequencer and processed using software that resolves paired bases from the sample and copy strand into one of six states: A, C, G, T, 5mC, and 5hmC.

Biomodal published its method in Nature Biotechnology last year. While that study focused on five-base sequencing, it also showed the feasibility of six-base sequencing.

The company recently presented data for the Duet evoC assay at the Precision Medicine World Conference, analyzing gene expression in archived colorectal cancer (CRC) patients and healthy controls. Gene expression signatures distinguished CRC from healthy controls and identified several enhancers relevant to CRC genes, as well as genes implicated in CRC.

"We are working with early-access customers to build and refine further models using existing data in additional cell types and organisms," CEO Peter Fromen said, "so they could choose to use Duet evoC in the future to predict and understand gene expression without performing additional standard or nascent RNA-seq experiments."

Fromen added that the applications of this technology are wide-ranging, from developmental biology to minimal residual disease (MRD) and therapy response monitoring. He did not disclose the list price for the Duet evoC.

"You could envision [this] technology [being] utilized in a liquid biopsy application," he said, "say, MRD, where the customer is interested in whole-transcriptome data, in addition to methylation profiling, plus somatic mutations, to look at the impact of a therapeutic intervention."

Fromen said that there is "a ton" of interest in being able to assay methylation state in the oncology space, where hydroxymethylation information is often lacking.

Several academic researchers have been using the Duet evoC over the past few months as part of an early-access program.

Sarah-Jane Dawson, a clinician-scientist at the Peter MacCallum Cancer Centre and the Centre for Cancer Research at the University of Melbourne, said that her lab currently uses the assay to study the genomic and epigenomic landscape of circulating tumor DNA in liver cancer.

"The comprehensive genomic, 5mC, and 5hmC characterization is providing novel opportunities to utilize these features for ctDNA detection and to track serial ctDNA changes to understand and optimize treatment approaches in this disease," she said via email.

Dawson said the Duet evoC technology has helped her lab streamline its ctDNA analysis from limited samples.

"The technology has allowed us to obtain accurate and comprehensive genetic and epigenetic data at single base pair resolution in a single workflow," she said.

Another early user, Sonia Gandhi, a professor of neurology at University College London, said that capturing methylation signatures in postmortem brain tissue might help researchers better understand how aging renders the brain more vulnerable to disease.

"The common neurodegenerative diseases of the brain are age-related, and yet the way in which the aging process interacts with the neurodegenerative processes are largely unknown," she said in an email.

"Due to the elevated levels of 5hmC in the brain," she explained, "the ability to differentiate it from 5mC becomes crucial for a more accurate evaluation of differential methylation between samples from disease and healthy individuals. We anticipate that this distinction will enhance our understanding of the intricate relationship between methylation changes and gene expression."

Biomodal might face competition from direct DNA methylation sequencing approaches that don't require enzymatic conversion of DNA prior to sequencing, such as those from Pacific Biosciences and Oxford Nanopore Technologies.

PacBio, for example, provides five-base sequencing on its Revio platform using HiFi sequencing. Aaron Wenger, PacBio's senior director of product management, said that in addition to the four standard DNA bases, plus 5mC, the Revio system detects a number of other methylation marks, such as 6mA and 4mC.

"Since it is fundamental to HiFi sequencing," Wenger said, "methylation detection does not require any upfront library prep or specific sequencing chemistry."

He also mentioned that while methylation patterns provide a good indicator of which genes are "on" versus "off," they don't provide quantitative measures of expression levels, nor information on specific isoforms, both of which can be assayed via techniques such as full-length RNA sequencing. 

Fromen said that the tight correlations between Duet evoC results and nascent RNA do provide an accurate estimate of gene expression levels. Additionally, he said that the Duet evoC can cut out much of the background noise present in most RNA-seq data, particularly single-cell RNA-seq data.

He added that company has numerous other products in its development pipeline. "We're nowhere close to being finished here," he said.