Leveraging multiplexed error-robust fluorescence in situ hybridization (MERFISH) technology, Vizgen has developed MERSCOPE, a high-resolution platform for spatially profiling the transcriptome. This image depicts how MERSCOPE can generate displays from whole sections (9 × 7 mm), to wide fields of view (200 × 200 µm), to subcellular views (12 × 12 µm).

Systems that seamlessly integrate single-cell transcriptomics analysis and tissue imaging will facilitate deep studies into biological pathways and disease mechanisms. No longer will it be necessary for investigators to resort to poorly integrated (cobbled together) systems, which are more likely to introduce variable results. No longer will it be necessary to destroy samples, either to perform next-generation sequencing or generate disassociated cells for single-cell analysis.

A seamless system, an in situ analysis platform, is available from Vizgen. “[Our platform] can look directly at the cells in a tissue slice without having to tear apart the tissue,” says George Emanuel, PhD, Vizgen’s co-founder and director of technology and partnerships. “[It] can measure hundreds of genes to see details such as where RNA transcripts are expressed within the tissue.”

The platform is called MERSCOPE, and it incorporates multiplexed error-robust fluorescence in situ hybridization (MERFISH) technology. The platform is fully automated to simultaneously measure the copy number and spatial distribution of hundreds to tens of thousands of RNA species in individual cells.

Taking a distinctive approach

Spatial analysis platforms have been developed by other companies, notes Terry Lo, president and CEO of Vizgen. However, he asserts that these companies “haven’t provided a platform for single-cell resolution, which is key to generating the depth of data needed. Other academic methods are very specialized and require expert labs that are immersed in the field. The broad research community, therefore, has a real hunger for a spatial transcriptomics platform.”

MERSCOPE was announced last March at a virtual event, Advances in Genome Biology and Technology (AGBT) 2021, and it is scheduled to ship this summer. “MERSCOPE takes the MERFISH technology and packages it into an easy-to-implement spatial genomics instrument,” Lo points out. “This is the first platform to deliver single cell–level molecule genomics information in a spatial context.”

MERSCOPE offers combinatorial labeling, sequential imaging, and barcoding, and it enables hundreds of genes to be profiled with hundreds of thousands of cells in one instrument, without the need for sequencing.

The big concepts that set Vizgen’s MERSCOPE solution apart from current MERFISH technology workflows being used in the research community are microscopy and standardization. “A very advanced level of microscopy is involved to run these measurements,” Lo elaborates. “If you’re trying to do this yourself, you would have to configure the microscopy in a technically complex way, and getting it right isn’t trivial.” He adds that fully automating (and thus standardizing) this instrument eliminates the trial and error, “taking a lot of the burden from the user.”

“This is a full solution from point of sample to result,” Lo emphasizes. “We’ve established and standardized the entire workflow with its own core materials—probes and imaging reagent kits, for example—to enable more repeatable and robust results.”

In terms of analysis, Vizgen takes a targeted approach, focusing on specific genes of interest. “When faced with analyzing the full transcriptome for approximately 30,000 genes, it becomes overwhelming to understand what’s important,” Lo says. “We expect to target more than 500 genes in the first-generation MERSCOPE platform, and to gradually expand that number.”

Supporting ambitious applications

“[MERSCOPE] is true spatial transcriptomics,” Lo insists, “and people are still learning what insights they can get from this technology.”

MERSCOPE performs combinatorial labeling, sequential imaging, and error-robust barcoding to enable hundreds of genes to be profiled within hundreds of thousands of cells in a single instrument run. The platform includes validated or custom gene panels, reagents and consumables, automated analytical instrumentation, and data visualization software.

Early adopters are using it to investigate the tumor microenvironment and how cells there interact with other cells to affect disease progression. Another key application area, Emanuel says, is the study of “neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, where a lot remains unknown.”

Alpha versions of MERSCOPE are in use at the Broad Institute, Harvard, and the Rockefeller University, generating data that has been informing studies that will be discussed in upcoming publications. “We’ll have a short beta program for external launch (in late spring/early summer), followed by a limited launch this summer,” Emanuel details. By the end of the year, MERSCOPE will be available broadly. “In the future,” he remarks, “we want to make it translational for use in clinical applications.”

Rising from a sound foundation

MERFISH, the foundational technology behind MERSCOPE, was developed in the lab of Xiaowei Zhuang, PhD, the David B. Arnold Professor of Science and director of the Center for Advanced Imaging, Harvard University. When she published a paper in Science explaining the technology in 2015, it garnered significant attention.

“The inflection point came in 2018 with the publication of another paper in Science,” Emanuel recalls. “It showed that super-resolution microscopy broke the resolution barrier and was a practical way to visualize and discover cellular structures. It showed that there was novelty to the technology and that you could do with many cells what had (at the time) been done only with single cells.”

After that, Lo adds, “People tried implementing MERFISH on their own, so we thought there would be commercial demand.” The company was formed and funded with a $14 million Series A round. Since then, he continues, “We’ve put the technology into a user-friendly solution—engineering a closed-box system and improving reagents and overall methods to facilitate the process from gene panel design all the way through image processing, analysis, and visualization.”

Growing despite disruption

Just as the company was getting off the ground, COVID-19 hit. “We were trying to establish a pathway toward commercialization, so COVID-19 was quite disruptive, injecting additional uncertainty,” Lo acknowledges. Nonetheless, Vizgen thrived. Nature Methods named spatially resolved transcriptomics as the Method of the Year in 2020, citing Vizgen’s spatial genomics technology.

Now the company is expanding its facilities to manufacture the reagents used in its instrument. It plans to triple its staff this year (to 60). “We’ve had a lot of support and excitement to build out the company from researchers as well as investors,” Lo says.

Rapid growth, in fact, is one of its greatest challenges. “Because there’s such high demand for this technology, we need to scale very fast, so we’re building the organization very quickly,” he continues. “That’s not easy.”

Vizgen is building a strong scientific team and continues to work closely with the original MERFISH developers, two of whom—Emanuel and Jiang He, PhD—joined the company. Additionally, Zhuang is a scientific consultant along with fellow co-founders David Moffit, PhD, also of Harvard, and David Walt, PhD, who is the scientific founder of Illumina and Quanterix.

As Vizgen grows, Lo and Emanuel say they will continue to improve on the already fully functional MERFISH platform with additional versions of reagents and higher cell throughput, “tailoring the platform as customers’ needs arise.”

“We’re seeing the evolution of spatial transcriptomics right now,” Lo declares. “The big question is what this technology will mean in terms of accelerating scientific knowledge, and how to make it move even faster. The answers will be groundbreaking.”      

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