Developing new tools to accelerate spatial genomics and drug discovery

insights from industryDr. George EmanuelCo-Founder and Sr. Director of Technology & PartnershipsVizgen
In this interview, we speak to Dr. George Emanuel, Scientific Co-Founder at Vizgen, about their new MERSCOPE Platform and how it is accelerating the field of drug discovery through combining both single-cell and spatial genomics.

Please can you introduce yourself and tell us about your role at Vizgen?

My name is George Emanuel, and I’m a scientist driven to develop new technologies to facilitate biological insight. I believe the current era of biological understanding is enabled by advances in the underlying imaging, genomics, and computational technologies that have allowed us to understand aspects of biology that would have been nearly impossible to understand with technologies from even a couple of decades ago. Continued technical innovation will continue to fuel the engine of biological discovery and improved human health.

In 2019, I helped cofound Vizgen, where we developed the MERSCOPE Platform that we started shipping in 2021, and I am currently working within the company as Sr. Director of Technology and Partnerships to continue moving the technology forward.

Vizgen is dedicated to pioneering the next generation of genomics by providing researchers with tools to gain new insights into the biological systems that govern human health and disease. As an innovative and forward-thinking company within the genomics landscape, what role do you believe it plays in accelerating the field of drug discovery?

With the inherent complexity of biology, it’s not trivial to figure out what mechanism might work best to target a certain to treat a given disease. Not only may the molecular mechanism of the disease function differently depending on the cellular context, such as neurons compared to macrophages, but the mechanism may have varying downstream phenotypes based on spatial arrangements, such as cell-cell interactions, or based on vicinity to various tissue structures. With preceding technologies, pieces of the picture could be measured directly, and the full landscape could be pieced together. But, with new technologies, such as the MERSCOPE Platform, enabling highly multiplexing spatial genomics through MERFISH Technology, a larger piece of the picture can be uncovered within a single experiment. Hopefully, more direct insight will allow researchers to more efficiently understand what’s happening within a diseased tissue, which types of drugs may most efficiently revert the disease mechanism, and monitor the drug’s efficacy and safety.

Genomics

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The drug discovery sector has seen incredible advancements in recent years, largely due to the COVID-19 pandemic. Despite this, there are still many challenges the sector faces. What do you believe to be some of the biggest challenges researchers currently face in drug discovery, and how can new tools such as your MERSCOPE Platform help to overcome these?

Despite advances in some areas of drug discovery accelerated by COVID, on the whole, drug discovery continues to be incredibly challenging. We don’t know biology well enough to predict how a given drug may impact the complex network of interacting molecules within a biological system. To predict the impact of perturbations, directly observing what’s happening across a biological tissue is a critical step, and that’s where MERSCOPE™ comes in.

MERSCOPE opens a window into the biology that was not previously possible by spatially mapping gene expression with single-cell resolution. This opens the path to improved drug discovery. You can consider this in the context of the tumor microenvironment – the ability to understand how gene expression of subtypes of T cells, B cells, or macrophages changes based on the types of cells in their immediate vicinity allows researchers to track and characterize cell-cell interactions that may be perturbed to create more effective treatments.

The Vizgen MERSCOPE Platform

Your latest product, MERSCOPE, is the first high-resolution in situ platform combining both single-cell and spatial genomics. Why did you choose to create a platform that combined both these disciplines?

MERSCOPE merges two previously distinct lines of research—genomics and biological imaging. On the side of genomics, technologies from the last two decades have enabled researchers to understand gene expression across the full genome with increasingly finer compartmentalization all the way down to the level of a single cell but with little or no spatial context. On the other hand, with standard imaging technologies, researchers often only label and measure a few biomarkers at once but can still uncover important biology by examining the spatial organization of those biomarkers.

MERSCOPE brings the power of genomics to traditional imaging technologies. Researchers can now measure hundreds of biomarkers using entirely custom panels targeting exactly the genes they are interested in and map their spatial organization across full tissue slices with single-cell resolution. Since either side of technology, genomics or imaging, has proven to be essential for modern biology, merging the two naturally provides a complete picture of the biological system and a more direct pathway to understanding what’s happening across the biological tissues.

Can you tell us how this platform works and some of its various applications within research, especially concerning neuroscience and infectious diseases research?

The MERSCOPE Platform is able to measure so many target genes with such high spatial resolution by using Multiplexed Error-Robust Fluorescence in situ Hybridization (MERFISH) technology. MERFISH is a technology based on single molecule FISH (smFISH), where individual transcripts are stained with fluorescent dyes so they can be detected under a high-resolution fluorescence microscope. With smFISH, each copy of each targeted transcript shows up as a fluorescent point within the microscopy image, so by computationally identifying the spots in the image—like finding the stars in an image of the night sky—you can map out the gene expression across the entire sample with single molecule accuracy. But, across a biological tissue, you need to look at hundreds or thousands of relevant genes to fully understand what each cell within the tissue is doing.

MERFISH builds upon smFISH by introducing a binary encoding scheme to greatly increase the number of genes that can be measured simultaneously. Rather than measuring the genes one at a time, each gene is assigned a unique barcode, and the barcodes are measured using sequential rounds of hybridization and imaging. From the images that are acquired, we can then identify which barcode is present at each position in the sample by mapping the pattern of fluorescence intensity measured to the barcodes assigned to each targeted gene.

With MERFISH, each of these combinatorial barcodes is also error robust, so the transcripts can still be identified accurately even with stray fluorescence across the sample. By mapping the expression of hundreds of genes simultaneously, the researcher can now get enough information to very finely characterize and map cell types across a complex organ and how they change within disease models or understand how infectious pathogens affect different cell types within the host tissue.

Alongside its many applications within research, it also offers unrivaled detection efficiency at subcellular resolution. How important is this when undertaking spatial genomics research, and what other advantages does your MERSCOPE Platform offer?

MERSCOPE was designed from the ground up to achieve high data quality. Researchers need research tools they can rely on to produce biological insight, and the quality of the data directly impacts the level of confidence they can have in the biological results. When it comes to transcriptomics, the critical parameters are sensitivity and specificity.

Sensitivity, also characterized as detection efficiency, is the ability to detect as many transcripts within the tissue from the targeted genes as possible. Many functionally relevant genes are expressed at single-digit transcript copies per cell, which, when combined with a low-sensitivity platform, could result in them dropping out of the measurement and important biology remaining hidden. Specificity refers to the fraction of transcripts identified from the measurement corresponding to true transcripts within the biological sample. Low specificity coincides with many inaccurate transcripts, obscuring the true biological signal.

To achieve the most biologically relevant spatial genomics measurement, MERSCOPE was designed with optics optimized for single molecule detection, allowing us to detect more light from each individual molecule and for each molecule to appear smaller on the imaging system. This allows us to optimize the amount of information we’re able to detect per cell and achieve both high sensitivity and high specificity that yields high consistency when benchmarked against previous genomics technologies.

How MERFISH Technology Works

Your MERCSOPE Platform is also the only solution for MERFISH technology, allowing a seamless workflow from sample preparation to data visualization. What are the benefits of having a streamlined workflow in place when often conducting complex research?

Researchers need to generate data that provides new biological insight easily. We integrated MERFISH technology with tools to streamline the process from custom gene panel design all the way through downstream data analysis to deliver the first commercial end-to-end spatial genomics solution with single-cell resolution. The MERSCOPE Platform solution covers everything a research lab needs to be able to focus on uncovering biology rather than the technical details of the technology.

You showcased your MERSCOPE Platform at Neuroscience 2022, an exhibition bringing together over 25,000 people from the life sciences community. How important are in-person exhibitions to both companies like yourselves as well as researchers looking for new ideas?

In-person exhibitions are an invaluable forum for the scientific community, both for companies like Vizgen to introduce new products and research tools and also for us to learn about the current state of the art of the research community. The tools we develop have to be valuable for the community and conferences such as Neuroscience 2022 provide a unique opportunity for the company to be able to directly interact and learn from thousands of researchers within a few days.

Are you hopeful that your MERSCOPE Platform will contribute to the field of drug discovery? What would this mean for the improvement of human health and disease?

Some of the largest opportunities and challenges for new drug development coincide with the areas we see MERSCOPE could provide new insight to help move the fields forward—neurodegenerative disease and cancer.

Both the brain, with the complex interactions between hundreds of distinct cell types, and tumors, with complex cell-cell interactions as the body tries to fight the malignant tissue while the tumor works to suppress it, have intricate spatial organizations that likely have fundamental roles in the progression of either class of disease. I’m excited to see what researchers might uncover with the MERSCOPE Platform and what it could mean for finding a path to cure these devastating diseases.

Drug Discovery Concept

Image Credit: metamorworks/Shutterstock.com

What is next for Vizgen? Are you involved in any exciting upcoming projects?

The exciting aspect about being at the cutting edge of technology is that it requires relentless innovation to maintain that position and best serve the scientific research and drug development communities. At Vizgen, we intend to do just that, relentlessly pushing the technology forward. The MERSCOPE Platform started shipping in the summer of 2021 and was the first of its kind that enabled spatially mapping tissues with a true single-cell and single-molecule resolution.

It’s great to see how it is already enabling new biological insight across a rapidly growing user base, but we have also continued to add key new features, including the ability to measure both RNA and protein within the same sample and FFPE tissue compatibility. The MERSCOPE instrument is a foundation for continually providing new functionality to the community, all on the same hardware.

We have many new products in development towards this end that I’m excited to launch, including expanded gene multiplexing capacity, enhanced cell identification, additional target analyte flexibility, and tools to streamline downstream data analysis. Along with the new product development efforts, we often release new datasets that showcase the platform's new functionality.

Where can readers find more information?

https://vizgen.com/resources/

About Dr. George Emanuel

George Emanuel, Scientific Co-Founder, Senior Director of Technology & Partnerships

George has spent the past decade developing high-throughput spatial profiling technologies including inventing a technology for pooled imaged-based screening of genetic variant libraries and extending MERFISH technology to profile 10,000 genes in the same sample.

George received dual undergraduate degrees in Applied Math and Molecular Biology from the University of Colorado and a Ph.D. in Biophysics from Harvard University.

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