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10x Genomics Acquisitions Point Towards New In Situ Analyisis Platform

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NEW YORK – After acquiring ReadCoor and Cartana, firms developing in situ genomics technologies, 10x Genomics is "definitely" planning to develop its third platform, CEO Serge Saxonov said.

The Pleasanton, California-based single-cell and spatial genomics firm is committed to investing in the technologies, Saxonov said, adding that the new platform will offer complementarity to researchers already using either of the existing platforms. "A lot of discoveries with Visium or Chromium can be followed up on and explored further using in situ approaches," he said.

How long development will take and how much money 10x is planning to invest is unclear. But observers predict that R&D investment will bring Cartana's reagents onto the instrument developed by ReadCoor. "It's an educated guess, but this seems like a logical combination … and would attract a lot of interest," said Toon Swings, a life science technology specialist at the VIB Tech Watch team, which helps researchers access emerging technologies.

Cartana's chemistry is more powerful, especially when it comes to sensitivity, he said: their reagent kits, which are already commercially available, are about 10 to 30 percent as sensitive as fluorescent in situ hybridization. By comparison, fluorescence in situ sequencing (FISSEQ), the technology underlying ReadCoor's platform, "is less than 1 percent efficient and sometimes lower," noted Jeroen Aerts, VIB Tech Watch's spatial genomics expert. "But people want to have a nice automated device," which ReadCoor has now developed, he said.

Swings and Aerts agreed that in situ genomics would be complementary to existing 10x technology. They helped arrange the use of Cartana tech in a study published in July in Cell that paired it with spatial transcriptomics, the technique that 10x's Visium platform is based on. VIB sent samples to Cartana to be processed at its Stockholm lab, they said.

In the study, researchers from Belgium's KU Leuven and the VIB Center for Brain & Disease Research analyzed "the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques" in a mouse model of Alzheimer's disease. Using spatial transcriptomics, they found early alterations in gene expression networks related to myelin, the nerve sheath, and later alterations in a multicellular network of plaque-induced genes involving oxidative stress, lysosomes, and inflammation. They used Cartana's in situ sequencing to confirm the gene expression alteration at a cellular level in both mouse and human brain sections. The authors did not respond to a request for comment.

"This is really the next frontier in single-cell research," Aerts said. "A lot of researchers have generated single-cell RNA sequencing data through 10x and want to know where those genes or cell phenotypes are located in a cellular context."

On 10x's radar

Saxonov said that in situ genomics has been on 10x's radar "for a number of years" and that the firm had invested in R&D itself. "The key questions have always been the maturity of the technology and the maturity of customer interest," Saxonov said. "More recently, those started making progress."

The firms also come with more than 110 patents that 10x believes to be foundational for doing in situ analysis. Which specific patents those include is not clear. ReadCoor had secured an exclusive worldwide license from Harvard to market FISSEQ.

The ReadCoor acquisition for $100 million in cash and $250 million in stock, which closed Tuesday, is vindication for Decheng Capital, Partner Victor Tong said. After meeting with ReadCoor cofounder Richard Terry in 2015, Decheng Capital quickly decided to fund the company and led both the $23 million Series A and $30 million Series B financing rounds.

"Around 2015, single-cell products were on the cusp and about to take off," Tong said. "We thought that ReadCoor was an extension of that." But convincing others of the potential wasn't always easy.

"For the first three years, people in the field still did not really understand the true power of spatial-omics or what you can do with it. It was difficult to explain to investors on Wall Street," Tong said. But that started to change earlier this year at the Advances in Genome Biology and Technology conference in February, where ReadCoor launched its platform and 10x and NanoString held seminars on their spatial genomics products.

Cartana, spun out of Sweden's Science for Life Laboratory in 2017 and acquired in August for $41.2 million, is based on barcoded padlock probes that target nucleic acids of interest. The probes are amplifiedin situ using rolling circle amplification followed by sequencing-by-ligation, also directly on the tissue. Every gene or transcript readout is coupled to a cartesian coordinate and transcript counts depend on how cells are segmented. The method can reveal which cell types a particular transcript shows up in, or conversely, the transcripts that a predefined set of cells may contain.

10x Genomics declined to provide interviews with Cartana's leadership. Company officials noted that Cartana would join its Stockholm facilities. "We plan to bring aboard everyone" from Cartana, Saxonov said. "At this point, the teams are staying."

10x declined to say how it would handle any existing Cartana customers. The in situ sequencing reagent kits have already been marketed to customers, the VIB Tech Watch team said. For €4,000 ($4,707) the library prep kit readies up to five samples — defined as a 1 cm2 area — with up to 600 genes per sample, while an €8,000 large kit can process 15 samples. The padlock probes, which work with fresh frozen and formalin fixed, paraffin embedded samples, can be obtained in predefined neurology and immunology panels at €2,000. Custom probes are also available at €300 per gene, with four probes per gene.

After prep, the method requires the in situ sequencing kit, which adds adapter probes and fluorescent labels, priced at €2,500 for the small kit and €4,000 for the large.

"This can become very expensive, depending on the number of samples you have," Swings noted.

Saxonov stressed that it's still early for in situ genomics and the firm has no timelines yet for platform development. "In situ is just an emerging field and for the most part has been done in individual research labs," he said, noting that this meant 10x does not have much competition yet.

Vizgen, a Harvard spinout commercializing multiplexed error-robust fluorescence in situ hybridization (MERFISH), developed by Xiaowei Zhuang, could be a competitor in this market. "All these technologies deal with the same thing," Aerts said. Vizgen uses a different chemistry offering high capture efficiency and high multiplexing, "but ultimately they want to achieve the same goal," he said.

"Vizgen is a more powerful technology than padlock probes," Aerts said. As reported by GenomeWeb, Vizgen claims it can measure 80 percent of mRNA in a sample. But Saxonov said "it's still very early and not clear how much progress has been made outside of the lab where the technique was first developed."

And in situ transcriptome accessibility sequencing (INSTA-seq), described in a preprint posted to BioRxiv in August 2019 from the lab of Je Lee, a researcher at Cold Spring Harbor Laboratory who contributed to the development of FISSEQ, is another method that could soon be available. As reported by Biocompare, Lee is collaborating with Gene Yeo of the University of California, San Diego to automate that workflow.

Elsewhere, spatially resolved transcript amplification readout mapping (STARmap), developed at Stanford University, is another lab-based method for in situ transcriptomics.

Though the methods are far from perfected, they point towards a way to home in on important transcripts in single cells, or even distal parts of cells. By combining wider single-cell or spatial approaches with targeted in situ ones, "you can think about discovering new subsets of cells in the brain or tumor microenvironment," Aerts said.

Even further down the road, 10x envisions the new platform finding use in the molecular pathology lab. "The in situ form factor is a nice fit for clinical applications in the long run," Saxonov said.

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