This past Thursday, May 6, Vizgen launched their MERFISH (Multiplexed Error-Robust Fluorescence in situ Hybridization) Data Release Program and released the first available dataset, the Mouse Brain Receptor Map. Researchers can access the dataset and future data releases for free through Vizgen’s website. After the launch, I had the opportunity to speak with Terry Lo and George Emanuel to discuss the announcement, MERSCOPE, and the spatial omics industry overall. You can find a transcript of our discussion below.
Terry Lo is the President and CEO of Vizgen and has guided the company through the launch of their first platform, MERSCOPE. Prior to joining Vizgen this past year, Terry pioneered the early success of spatial biology and mIF at PerkinElmer and later Akoya Biosciences.
George Emanuel, PhD is a founding member of the Vizgen team and the Director of Technology & Partnerships. Over the past decade researching biophysics at Harvard, George has developed high-throughput spatial profiling technologies, including extending MERFISH to profile 10,000 genes in a single sample.
Congratulations on launching the MERFISH Data Release Program this past Thursday and all the exciting Q1 announcements! For our readers who may be less familiar with Vizgen and MERFISH, can you tell us a few sentences about the technology, the company, and your vision?
Terry: Thank you, it has certainly been an exciting time for Vizgen! The launch of our MERFISH Data Release Program is a huge milestone for us as a company and for the scientific community. MERFISH is a spatially resolved single-cell transcriptomics profiling technology developed in Professor Xiaowei Zhuang’s Research lab at Harvard. With MERFISH, individual transcripts from 100’s to 1000’s of genes are directly visualized within intact tissues, enabling spatial single cell atlassing. MERFISH technology was first published in Science in 2015 and has since seen broad adoption in the research community with more than ten peer-reviewed publications to date.Vizgen was founded to commercialize a solution for MERFISH to make it easier for labs to apply the technology to advance their research. The Vizgen MERSCOPE Platform provides a streamlined end-to-end solution for generating MERFISH data through ready-to-use reagents, software, and an automated instrument with integrated fluidic handling and fluorescence microscopy. Spatial genomics is an area we feel will play such an important role in enabling our understanding of biological systems and finding future cures and ways to overcome disease. We believe our MERSCOPE platform is positioned to help lead this next generation of genomics, and our mission is to deliver the best spatial genomic solutions to the research community.
The research community has definitely been very active in propelling this industry, and spatial omics technologies have obviously generated massive interest over the past year, and a lot of that appears to now be shifting towards in situ approaches. What are the differences that will drive MERFISH’s value against competing solutions?
George: By expanding the multiplexing capacity of smFISH, the gold standard for quantifying RNA copy number, MERFISH is able to detect nearly all of the copies of the targeted transcripts while greatly expanding the multiplexing capacity to transcriptome-scale and while maintaining the strengths of an image-based technology. Since many functionally relevant genes are expressed at only a few copies per cell, the ability to detect as many copies as possible is critical. Our high detection efficiency enables us to detect lowly expressed genes very easily, genes which may be missed with single-cell sequencing approaches today. Additionally, since MERFISH is an imaging-based approach, it readily provides information across a whole tissue slices rather than targeted regions. In a single instrument run, MERSCOPE can characterize hundreds of thousands of cells. MERFISH achieves this with direct imaging—there is no need for any downstream sequencing or 3rd party instrumentation. MERFISH also offers significant improvements in resolution, localizing each RNA transcript with 100nm accuracy across the full tissue slice for a true high-resolution imaging based approached. This not only allows the researcher to make discoveries based on single cell expression profiles across the tissue but gain an even deeper understanding of the intracellular biology.
You mentioned there isn’t an absolute need for downstream sequencing or other instrumentation, but how do you see technologies like MERFISH integrating with traditional sequencing or proteomics imaging technologies? How do you think multi-omic analysis will impact the adoption of the MERSCOPE?
George: We see technologies like MERFISH as complementary approaches to traditional sequencing in some sense. With a gene panel guided by the results of single cell sequencing, MERFISH is able to map out the spatial organization of the cell types identified through sequencing. Since substantial resources have already gone into single cell sequencing, cell types of many different tissues have already been well characterized. Understanding their spatial organization is the next step towards creating cell atlases and understanding the biological relevance of the catalogued cell types.We appreciate the importance of both protein and genomics information, but while there are a number of technologies already commercialized on the proteomics side, there hasn’t been a true spatial genomics platform available yet.Transcriptomics by nature is more quantitative than proteomics and has a more readily expandable multiplexing capacity. Since probes for spatial genomics can be designed computationally to bind to the target transcript with high specificity using established transcriptome annotations, spatial genomics does not require the extensive antibody screening and validation necessary to construct multiplexed proteomics panels. This enables the analysis of more targets than with protein assays, and without the same obstacles that exist with finding and utilizing validated antibodies in proteomic approaches.Terry: Building on what George just mentioned, both transcriptomics and proteomics offer important information, but there is a big gap in the availability of spatial data on gene expression as opposed to protein expression, and spatial gene expression data can be directly compared to single cell sequencing data. Transcriptomics is unlocking a new plethora of information that will help determine how cells are different, how they respond, how they interact with each other and more.
Circling back to the MERFISH Data Release Program, what insights do you expect to be generated with the Mouse Brain Receptor Map? What other tissue or sample types would benefit from a similar program, perhaps in oncology?
Terry: The Vizgen Mouse Brain Receptor Map is the largest publicly available data set for spatial genomics available to date, containing half a billion transcripts and nearly a million cells, and we think this marks a major step forward in the advancement of spatial genomics. For the first time, spatial genomics data is accessible to review and leverage into research, and this data was generated on an integrated platform that can actually be brought into your lab.The map contains the full MERSCOPE output from measurements of a 483 gene panel including canonical brain cell type markers, GPCRs, and RTKs across three coronal brain slices with three biological replicates for each slice. This mapping of full coronal slices with biological replicates demonstrates a measurement that hasn’t been achieved before. Researchers looking at the data can map out GPCRs across the whole brain while maintaining the spatial and cellular context, learning which cells are expressing which GPCRs in which spatial positions of the brain.We believe this could be a valuable resource to guide and support ongoing research on the importance of GPCRs in the brain to unlock new insights. For example, driving a better understanding of which of these GPCRs have clinical relevance, but may have been overlooked by other technologies.This dataset is also intended as a showcase for researchers in other fields so they can begin to understand the depth and quality of the data that is now available in spatial genomics and how this may apply to their research questions.One area we will focus on for future releases is human tissue data, for example human cancer tissue. We are already working on datasets with human and mouse tumor samples to showcase the versatility of MERFISH for oncology applications. MERFISH supports the mapping of biological systems with high gene throughput, accelerating the ability to uncover how biological systems are functioning. This plays a critical role in preclinical research. We have seen success with the brain already, and in oncology we hope it can get us closer to better and more predictive cancer treatments.In addition to Vizgen generated data, we are working towards building a repository of MERFISH measurements demonstrating how our collaborators are using MERSCOPE to advance their research. We have collaborators finding success with a variety of human and mouse sample types including liver, heart, bladder and more. Our goal is to build a repository of easily accessible, well catalogued MERFISH data.
This dataset includes the transcripts of nearly 500 genes—more than 500 million transcripts across more than 700 thousand cells. How important do you believe AI- and ML-based analysis techniques will become in the near term to make sense of these hyper-plexed datasets?
George: AI and ML tools have become increasingly more prevalent in the space. Since spatial genomics is still an emerging field, it’s impossible to say which computational tools will yield the most relevant biological insight. We see some groups starting to apply ML tools, but many algorithms still help researchers understand and interpret their datasets. MERFISH does generate a large amount of data, and we do think predictive AI and ML models could greatly benefit from incorporating the comprehensive spatial profiling enabled by MERFISH.
Continuing on that theme, how often do you hear about the importance of improved bioinformatics solutions from your customers? Do you believe that it will be the primary barrier to adoption of spatial omics technologies?
George: Tools to easily understand these large datasets are essential for adoption of spatial omics technologies. We have built a visualization tool to interactively explore the data and we will continue to expand the bioinformatics capabilities of our solution in the future. Since MERFISH is an emerging technology, there are also many opensource tools in development to perform different types of analysis on the data. Through the data release program, we are feeding data into these tools to support this expanding bioinformatics development. At the same time, we see MERFISH data building on single cell measurements. Researchers who already have experience working with single cell data can easily perform the same analysis on MERSCOPE data, but now with spatial context.
Continuing with the theme of analysis, how important has developing the bioinformatics been for MERFISH, and how important was it to develop a sample-to-answer platform solution?
George: Where spatial genomics is still new, and we know there are so many things that can be done with the data, we want to keep parts of the workflow open, while also providing our own visualization tool. We imagine that researchers will end up using the data in ways we may not even have anticipated yet. It is important to our team to ensure that our data is available in easy to load formats and compatible with tools being developed by the academic community—and by releasing a full MERSCOPE dataset, we hope we can inspire the development of new opensource tools to extract new biology from these rich datasets. Our philosophy is that we want to provide open and easy to use data formats so the research community can determine where MERFISH is needed most, and what applications and analysis to build over it. This is also why it was so important to us to build a sample-to-answer platform. The fully integrated solution offered with MERSCOPE includes custom gene panel design, imaging, data processing and visualization. We know that MERFISH can still be daunting to some researchers who may have been investigating their own homebrew solutions, and our hope is that MERSCOPE solves these complexities.
Following up on the latter half of that question, how important will simplified workflows be in driving the adoption of a technology like MERFISH in translational and clinical settings?
Terry: Very important. What we’ve designed today focuses on discovery, early translation, and preclinical research. Data generated from these research activities will be necessary to inform what applications and indications are most appropriate for future clinical use. The workflows intended for downstream large scale clinical trials and clinical applications are potentially very different, and a MERFISH platform to support this is part of our future roadmap. We are enabling researchers at this stage to understand what is important in this evolving spatial genomics field, and we will continue to build on the capabilities to leverage the expansion into translational and clinical markets.
Finally, rounding out our conversation, what have been some of the most exciting results that you have seen come out of spatial profiling platforms?
Terry: We are right on the cusp of a new age of thrilling discoveries enabled by spatial genomics. As an example, a team of researchers from Harvard profiled RNA inside individual neurons at the genome scale with super resolution using MERFISH this past year. This was the first demonstration of MERFISH’s ability to discover new biology beyond pure mechanism of action, and there are many more discoveries coming down the pipeline.It has also been exciting to us to see that there has been reproducible spatial genomics data being generated on these different platforms in a way that researchers are able to collaborate. It is clear that the research community is ready for a true spatial genomics platform to continue generating new data for the overall advancement of human health. In just a few short months our MERSCOPE platform will be available through our limited summer release and it’s so energizing to think about the future discoveries that it could enable, especially in the context of what has already been demonstrated. We feel that our MERSCOPE platform will be a leader in reproducible, error-robust, validated data and is the true spatial genomics platform that the research community has been waiting for. The possibilities are endless.