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Acuity Spatial Genomics to Develop Platform for In Situ Analysis of 3D Genome Organization

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NEW YORK – Acuity Spatial Genomics, a new venture backed by analytical instrumentation firm Bruker, seeks to be the go-to option for the spatial analysis of genome organization.

With licenses to technologies developed in the lab of Harvard University Professor Ting Wu, Acuity will develop instruments and assays to offer an in situ look at chromatin architecture, the positioning of chromosomes, and gene position within a chromosome, among other features of DNA in the cell, at single-cell and subcellular resolutions. Studies from Wu's lab have suggested their methods could provide spatial resolution of at least 40 to 60 nanometers while imaging genomic regions ranging in size from several kb up to 1 Mb or more. Acuity also plans to provide project services.

The company is majority-owned by Bruker and Bruker Nano President Mark Munch will also serve as Acuity's CEO. The firm could draw on Bruker's expertise in imaging, fluidics, and  platform design. "There are certainly some synergies that exist," Munch said. "How much of that expertise Acuity really needs is yet to be determined." Bruker did not disclose the size of its investment. Munch also declined to provide further details on product and services development and release timeline.

When ready, Acuity will launch into a market it values from $3 billion to $5 billion, though Munch said that market size estimation was an attempt to be "prudent."

The underlying technologies, namely varieties of oligo fluorescent in situ sequencing (OligoFISSEQ), were the fruit of a collaboration between Wu's lab and Bruker that dates back to at least 2016.

Wu's lab had been working on a concept called Oligopaints, synthetic probes built around a middle section that hybridizes to a nucleic acid, here DNA, and flanking regions that provide other functionality. Oligopaint-like probes are also used in multiplexed error-robust fluorescence in situ hybridization (MERFISH), the method being commercialized by spatial transcriptomics firm Vizgen, another Harvard-associated startup.

In OligoFISSEQ, the flanking regions contain barcodes that are read out in multiple ways: sequencing by ligation, sequencing by synthesis, and even hybridization. Wu's lab published a paper on the method and its uses for 3D genome mapping in August 2020 in Nature Methods.

The technology is made possible by the current capability to synthesize Oligopaint probes at lengths up to 200 bases. "When we started doing this, you could maybe get high-quality oligos 60 bases long," Wu said. Approximately 30 bases are required for genome homology, leaving only 30 for the additional functionality. Longer oligos "greatly enable us to use the nongenomic sequence to load up on capabilities," she said.

When Acuity is ready to launch its platform, it will target the market for basic research on genome organization, which has so far been serviced by next-generation sequencing-based assays, such as Hi-C, available commercially from firms like Arima Genomics and Dovetail Genomics. The data output from Acuity's platform could be complementary to data from both Hi-C assays and numerous new spatial transcriptomics methods, Munch said. Acuity could also face competition from another new in situ DNA analysis method developed by researchers at the Broad Institute and the Massachusetts Institute of Technology, whose commercialization strategy remains undisclosed.

In the Nature Methods paper, Wu and colleagues showed OligoFISSEQ is compatible with imaging hundreds to thousands of cells, producing genome maps of 129 targets across all chromosomes and traced the path of X chromosomes through 46 regions. They also described combining OligoFISSEQ with Oligo Stochastic Optical Reconstruction Microscopy (OligoSTORM), setting the stage for super-resolution imaging of genomes that Acuity will build on as part of OligoFISSEQ HD.

"There's subcellular, and there's really another level of subcellular, and that's what we're talking about with OligoFISSEQ HD," Munch said.

"Not even pushing it that hard, we were able to accelerate imaging of 66 spots by 36 times in just one try," Wu said. She predicted that with additional development, the imaging time and data storage demands of technology could be decreased by up to 1,000 times. With that, we have opportunity to think about the entire genome at this resolution." Her lab is currently attempting to scale the number of targets by 10 times or more.

Those features will push applications looking at signatures of genomic organization in many biological systems. "A lot of basic research is just trying to understand the structure-property relationship," Munch said. Of course, many researchers are also trying to understand how 3D structure relates to disease, especially in oncology and neurology.

Wu said the technology has potential for use in diagnostics, suggesting that OligoFISSEQ could be used anywhere karyotyping is used. "Those kinds of diagnostics are very powerful for all kinds of diseases, but they're expensive and difficult to do. You really have to be exquisitely able to detect changes in grey-on-grey images," she said. OligoFISSEQ has the ability to target particular metaphase chromosomes, which can simplify that process, she said.

The technique could also look at genome folding and provide insight on enhancers, promoters, or even chromosome translocations, which often cause cancer. The method could screen for disease states this way.

Those types of applications are not so far away, she suggested. "One reason we're not there already is our limited capacity to look at a lot of the genome quickly and cheaply. The issue is not so much conceptual; it literally is the hands-on bottleneck of having enough funds and being able to look at enough genome and quickly," Wu said. We know which cells to look at and we have a good idea what we want to look for." With OligoFISSEQ, "we've started to open up the bottleneck a bit," she said.

Munch said that when it launches Acuity will focus on the research, not diagnostics, market but said it isn't due to limitations of the technology.

"We have so much great work to do on the basic research side, in terms of pushing science, that's really what needs to be the focus for now," Munch said.

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