While most industries slowed down in response to the global pandemic in 2020, the field of spatial omics certainly did not. Established companies and startups continued to announce products, engage in M&A activity, and democratize their technology beyond pure innovators. While this field had its origins in hyper-plexed imaging, companies have shifted towards providing spatial transcriptomics products after the launch of 10x Genomics’ Visium platform in 2019. You can find 2019’s Year in Review here, an overview of the underlying technologies these companies provide here, and the result of our 2020 AGBT survey here.
Arguably the company which set off the spatial transcriptomics craze (along with NanoString, discussed below) with the launch of the Visium Spatial Gene Expression platform, 10x Genomics has continued to roll out the technology and announced planned improvements (e.g., added compatibility for IHC, FFPE compatibility, targeted panels). The biggest news for this year, though, did not come from the success of Visium, but from two adjacent acquisitions (ReadCoor and Cartana AB) for in situ analysis during the summer and fall. The two acquisitions bring more than 100 patents which will likely be utilized to develop a new platform for in situ analysis.ReadCoor started 2020 with a strong Series B raise of $30M and launch of their RC2 platform at AGBT but brought the field to a fever pitch with their $350M acquisition ($100M cash and $250M in stock) in October. The company was founded as the exclusive worldwide provider of FISSEQ, a technology developed by the Church Lab at Harvard’s Wyss Institute. The technique is able to visualize the whole transcriptome at single nucleotide resolution by converting RNA into cDNA and cross-linking the amplicons into a matrix. These matrices are then able to be imaged using a number of different fluorescent sequencing techniques. While the platform developed by ReadCoor is automated and easy to use, experts have noted the efficiency of the instrument can be extremely low (1% range), which is where Cartana AB potentially factored into 10x Genomics’ roadmap.Cartana AB is a spin-out of the SciLifeLab in Stockholm—the same center which spun out Spatial Transcriptomics, the company acquired by 10x Genomics to develop Visium. The company focused on bringing reagent kits to the market instead of a platform and had successfully launched the product line. Prior to the acquisition, Cartana was listed as a full partner on three of the six European Human Cell Atlas projects, and the company was selected over other potential providers like NanoString and 10x Genomics. While Cartana was acquired for a smaller sum of around $40M, the underlying technology may be key to a potential 10x Genomics in situ analysis platform. Many experts believe the IP from both companies will be used in combination, as the reagents from Cartana could address some of ReadCoor’s shortcomings, but only time will tell.
The Visium readout of a breast cancer slide shown with (left) and without (right) the H&E overlay. Visium was utilized to highlight 10 population clusters based on gene expression to then be mapped back into the spatial organization of the tissue. Image courtesy of 10x Genomics.
Akoya has continued to grow its install base for the CODEX platform and more clinically focused Phenoptics portfolio to more than 500 instruments, backing up more than 100 publications in just 2020. Of the research completed using Akoya’s platforms, I personally find the AstroPath Program at Johns Hopkins to be particularly interesting. Despite its critical importance, data analysis has been an afterthought in the field of spatial omics, and this is reflected by the relatively limited tools that have been made available to researchers for image analysis—experts we’ve spoken to have stated that a single run of a hyper-plexed instrument could take up to two years to analyze in complete depth, given the potential iterative process of reanalyzing data for new potential insights. In AstroPath, though, The Johns Hopkins University School of Medicine and the Henry A. Rowland Department of Physics & Astronomy have collaborated to apply astronomy algorithms to the Phenoptics platform to identify and optimize predictive phenotypic signatures. While the Phenoptics instruments operate at a significantly lower plex but higher throughput than CODEX, the work could one day help alleviate the limitations of today’s analysis methods for hyper-plexed instruments. In addition to this research, the company launched Proxima, a cloud-based image analysis software solution. Akoya, among a handful of other companies (such as AI-based companies like Nucleai), is trying to emphasize the importance of generating insights rather than data.
A multiplex image shown without (left) and with (right) nearest neighbor analysis. Implementing analysis methods such as this one has led to the discovery of distinct cellular “neighborhoods” within the tumor microenvironment. Image courtesy of Akoya Biosciences.
Fluidigm similarly continued to grow the install base for its Hyperion Imaging System (imaging mass cytometry) to more than 100 active units and more than 65 total publications. The company’s lawsuit against Ionpath is ongoing, but many aspects of the case beyond patent infringement have been dropped. While the Hyperion is one of the foundational technologies for hyper-plexed spatial omics, it has not generated revenues that map to the enthusiasm in the space. This is in part due to the fact that the (imaging) channels that the company addresses don’t ideally map to the customers with the deepest pockets today, namely genomics customers. However, some researchers have found instruments indispensable in the fight against COVID due to the high plexity and limited sample availability.
Imaging completed by the Dexi Chen Lab at the Beijing Institute of Hepatology looking into the inflammatory response to respiratory distress syndrome in COVD patients. Dexi Chen, PhD, MD, has stated “Imaging Mass Cytometry with CyTOF technology is our method of choice for these studies because the limited samples are very valuable.” Figure courtesy of Zhang et al., 2020 (doi.org/10.7326/L20-0227).
In response to the COVID-19 pandemic, Ionpath increased focus on its services business, as they expected capital equipment budgets to be delayed during the global pandemic for the purchase of instruments like the MIBIscope. This decision has led to a large increase in their services business which is expected to have grown six-fold this past year, with continued growth expected for 2021. The company also named a new CEO, Sander Gubbens, in August and successfully raised a Series B of $18M in September. With the additional funds the company is expanding its sales force as well as investing in the further development of advanced analysis systems (e.g., ML, AI) for the MIBIscope. Interestingly, the Series B also expanded the number of investors beyond Samsara Biocapital and Genoa Ventures and included an investment from Bruker Corporation. Released in a statement following the investment, Bruker Executive Vice President Dr. Rohan Thakur found synergies between their existing MALDI TOF mass spectrometers and Ionpath’s MIBIscope. Bruker hopes the investment and collaboration will accelerate the adoption of these technologies for pathology applications. With the now established service business and a (hopefully) waning pandemic, Ionpath is ramping up sales and manufacturing for their MIBIscope Instrument and associated antibody panels for 2021.
Ductal carcinoma in situ (DCIS) cells shown with 9 markers of cell lineage. The publication found that 17 of the top 20 predictive factors of disease progression were spatial and were only elucidated by MIBI and not traditional molecular techniques—a strong endorsement of spatial imaging technologies. Image courtesy of Ionpath & Risom et al., 2021 (doi.org/10.1101/2021.01.05.425362).
NanoString announced the development of another spatial omics platform, dubbed the spatial molecular imager (SMI), which is expected to launch by 2022. This instrument will be tailored towards offering single-cell and subcellular resolution with targeted content, as the company's GeoMx DSP is focused on high plex, high throughput applications. During the announcement, Brad Gray (CEO, NanoString) stated the total addressable market for both the GeoMx and SMI platforms to be more than $12B, with around half of that being dedicated to diagnostic testing. While there is significant excitement in this market and we do expect it to continue to grow rapidly, we believe this estimate to be aggressive on the clinical side. Regardless, the SMI platform is an exciting development, as NanoString expects the platform to effectively have unlimited plexity for RNA, and proteins will only be limited by the number of validated antibodies (currently ~6,000). More news from NanoString on the SMI platform is expected at AGBT 2021, and a service for the technology is also expected to be launched this year.While the SMI may be creating significant buzz today, NanoString's growing GeoMx DSP install base of more than 150 systems backed up by 30+ publications also experienced some exciting announcements through 2020. The company continues to expand the systems capability and portfolio of content with over 300 validated protein assays and the recent announcement of a Whole Transcriptome Atlas. Alongside the atlas, the company also released the first NGS-enabled GeoMx assay, the Cancer Transcriptome Atlas panel. The panel covers 1,800 genes and can include the analysis of custom genes as well. NanoString also partnered with the Oregon Health & Science University to develop new protein assays for breast cancer. Nanostring and the DSP appear to have consolidated a solid lead in the space for the coming years.
The images above highlight the difference in the output of the SMI (left) and DSP (right). While the DSP output is tailored towards exploring tissues at high plex, the SMI output is capable of highlighting RNA markers of interest at a sub-cellular level, unlocking research not easily addressed today. Note the DSP slide on the right includes the background image of the fluorescently labeled slide with the regions of interest for profiling in red and green. Images courtesy of NanoString
Rebus Biosystems (formerly Optical Biosystems)
Rebus Biosystems ended the year on a high note closing a $20M Series B funding round in November. The company is targeting spatial transcriptomics with its proprietary synthetic aperture optics (SAO) system. The technology is cyclical, meaning different genes are targeted over multiple scans / runs using smFISH, and the images are then compiled to show up to 30 genes simultaneously. While the technology is not yet commercially available, you can utilize an early access service through the company.
Vizgen, a spin-out of the Zhuang lab at Harvard, started the year by landing a $14M Series A funding round in January. The company is commercializing MERFISH (multiplexed error-robust fluorescence in situ hybridization), which, based on available publications, may have superior performance capabilities over key competitors (NanoString’s GeoMx and 10x’s Visium) through higher resolution (publications have gotten to ~100 nm) and higher detection efficiency. These technological advantages (e.g., single cell resolution) could expand the capabilities of spatial omics, and potentially address questions that currently have only been able to utilize single cell sequencing with the advantages of spatial context. Vizgen is currently developing a platform solution with end-to-end support from sample preparation through data analysis, intended to vastly simplify the implementation of MERFISH, and alpha units have already been placed at five sites, including the Broad Institute and at Rockefeller University. Historically, the complexity of the workflow has sometimes taken years to properly implement into a lab, and Vizgen has taken this into account by developing a simplified platform.
As highlighted in the image above, Vizgen’s MERFISH technology is capable of elucidating genomic information across entire tissue sections as well as at the sub-cellular level. Image courtesy of Vizgen.
Lunaphore Technologies, a Switzerland-based company developing the COMET all-in-one staining and imaging platform, raised an additional $26M in funding through their Series C round in the spring. The company noted it will be utilizing this financing to expanding its offerings to the US market. While the 40-plex instrument is not yet available, pilot units will be made available through a Priority Access Program in the near future. RareCyte introduced a new instrument, the Orion, to jump into the spatial omics market. The instrument is capable of scanning for 21 markers simultaneously, which is on the low end of plexity for this market, but the technology makes up for this by enabling rapid imaging (<3 hrs), high resolution (300+ nm), and having a small footprint.Resolve Biosciences ended the year on a high note with a $24M Series A funding round in December. The company is utilizing this financing to develop and commercialize its Molecular Cartography technology. The company is still early in the development phases but is planning on launching an early-access service offering in the coming months.Also, we may have missed your company—if you would like to see your (or another) company added to the list to track for future articles, please let us know!We expect 2021 to continue to bring exciting developments in the spatial omics field as two distinct markets have emerged—spatial transcriptomics and hyper-plexed tissue imaging. Growth in the body of research focused on spatial omics has exploded over the past year, with the number of articles published more than doubling. Be on the lookout for more news this year and at AGBT in a couple of months, as we expect many exciting announcements at the virtual conference.Disclaimer: the order of companies is not a ranking, and they are listed alphabetically; Some of the companies listed in this article may be DeciBio Consulting clients or customers.Publication search term: (akoya AND codex) OR phenoptics OR "co-detection by indexing" OR "codetection by indexing" OR cycif OR "t-cycif" OR (nanostring AND dsp) OR "digital spatial profiling" OR (nanostring AND geomx) OR (geomx AND dsp) OR fisseq OR "fluorescent in situ sequencing" OR readcoor OR "imaging mass cytometry" OR (fluidigm AND imc) OR (fluidigm AND hyperion) OR macsima OR (ionpath AND mibi) OR "multiplex ion beam imaging" OR mibiscope OR "spatial transcriptomics" OR merfish OR "multiplexed error-robust fluorescence in situ hybridization"