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Phase Genomics Revs Up Product Development for Hi-C Assay Applications With Eyes on Cytogenetics

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NEW YORK – Phase Genomics, a startup commercializing next-generation sequencing-based chromatin conformation assays, is preparing to develop test kits for use in human cytogenetics and epigenetics. The firm has also upgraded its metagenomic sequencing product to improve discovery of phages and mobile elements.

The firm has applied for a patent titled "systems and methods for karyotyping by sequencing" and has received two small business innovation research phase I grants worth a combined $3.9 million from the National Human Genome Research Institute and the National Institute of Child Health and Human Development. In one of the grant abstracts, the firm explained plans to create a Hi-C-based test for use in the reproductive health market.

Phase also has partnered  with Qiagen to explore epigenetic applications of its Hi-C technology, Phase Genomics CEO Ivan Liachko said. In October 2020, Qiagen licensed Hi-C patents from Phase, enabling the former company to sell EpiTect Hi-C kits in the US.

"We're exploiting this technology in every possible way we can," Liachko said. "We're sort of a crucible for invention. Usually, internal conversations have to deal with which products we're not going to be developing."

Cytogenetics is just one of several directions in new product development at the University of Washington spinout. Phase has also added new capabilities to its metagenomic sequencing platform, giving researchers the ability to resolve phage genomes and even connect them to their bacterial host.

Liachko declined to provide more detail on the development of human health applications but said the firm plans to share more information at the end of the year.

As its product list grows, so does the Seattle-based company. Despite the pandemic, the company has more than doubled its headcount to 25 people. The firm's kits have sold well during the pandemic and services have done even better, according to Liachko. "A lot of labs were shut down, so they were outsourcing work," he explained. Liachko described revenues as "robust" but declined to provide specific numbers. He noted that between sales and grants, the firm hasn't had to consider raising more funds.

"That may change," he said. "Interested parties are always welcome to talk to us. We're not openly fundraising now but that doesn’t mean were not talking to people. We are always looking at all sorts of opportunities."

Based on the SBIR grant abstracts, the firm's efforts on detecting chromosomal aberrations are focused on making a computational pipeline that can "reproducibly call chromosome aberrations" as well as making the Hi-C protocol work with multi-well plate handling. It is also working on validating the method using patient samples.

Hi-C, the firm said, can "detect the breadth of chromosomal aberrations at high resolution and low cost."

The firm's new ProxiPhage analysis software for its ProxiMeta metagenome deconvolution platform may also touch on human health, though indirectly.

"Phages have a range of uses as therapeutics, and they also give us a more comprehensive view of microbiology and microbial interactions," Chris Mason, a genomics researcher at Weill Cornell Medicine, said in an email. His lab has used the new phage discovery aspect of ProxiMeta in a study of stool samples. But most metagenomic sequencing methods are only able to identify phages in a microbial community if sequence fragments are already in a database, and even in that case, the methods have a hard time assemblign them into genomes. Matching phages to hosts is even trickier.

"Most methods either miss these interactions completely or give incomplete maps of such interactions," Mason said. "Long-read platforms and cross-linking protocols exist, but they are nascent."

"The twin grand challenge — to capture full genomes and to link newly discovered viruses to their hosts — are major roadblocks for the field," Matthew Sullivan, a microbiome researcher at Ohio State University, said in a statement. His lab collaborated with Phase on a study posted to BioRxiv on June 14. The researchers reconstructed 205 viral genomes from a single human stool sample and found hosts for 180 of them." Promisingly, these early findings suggest that Phase Genomics’ proximity ligation approach may solve both these problems," he said. Sullivan declined to comment further, citing the fact that the study was not yet peer-reviewed.

Phase's ProxiMeta product now offers a view into the phage genome blind spot. "Viruses have Hi-C links inside their genomes and Hi-C links to their bacterial hosts," Liachko said. "We're able to deconvolve and bin these little virus genomes and connect them to their hosts using only Illumina data." The kit, which costs $490 per sample and includes the updated computational analysis, also can annotate, bin, and track mobile genomic elements such as plasmids. Phase developed it with help from yet another grant from the National Institutes of Health worth $1.7 million. Because the company considers it an extra feature, it eschewed an early-access program; however, a few customers did participate in the alpha phase of product development.

"These [viral genomes] are very accurate," Liachko said. "To allay worries that it's just junk being binned together, we mapped our viral genomes against a long read assembly from the same sample and found that 96 percent [of them] were congruent with their long read counterparts," meaning only 4 percent of genomes had 10 percent or more sequence contamination relative to the long read version of that viral genome.

Phage recovery can improve by three to four times over traditional annotation methods, he said. "You can get more phage genomes out of a short-read assembly with this method than you can get out of a long-read assembly, on a dollar-per-dollar basis."

Mason said he hasn't yet analyzed his data, so he could not confirm that level of performance. "It's not crazy, though — very possible," he said.

"Clinicians, researchers, and microbiologists can all utilize this information right away, and it can give them a better view of a microbial system, phage therapy's impact, or a clinical case," Mason said.

Liachko added that the firm will continue to expand but probably not add more employees until the end of the year. "It depends on how certain product development efforts come out," he said.

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