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The rapid growth of the spatial transcriptomics market has been led by the introduction of higher-plex, higher-throughput solutions. Building on ISH workflows and utilizing NGS and higher-resolution imaging-based methods have driven recent developments in spatial transcriptomics.

Providing the highest-plex commercialized solutions for RNA and/or protein spatial biology is barcode-based in situ capturing techniques utilizing NGS readouts. While only one segment of the spatial transcriptomics market, the rapid adoption of these solutions for discovery and translational research have proven customer appetite for new high-plex spatial transcriptomics solutions and the applications made possible using such techniques, enabling a new era of spatial biology.

Speaking with IBO about spatial transcriptomics tools, Anoja Perera, Director of Sequencing and Discovery Genomics for the Stowers Institute for Medical Research, a biomedical research organization, said, “Spatial transcriptomics is an extremely powerful application that allows a researcher to not only study the transcriptome of single cells, but at the same time get the spatial location within a tissue.” She is also optimistic about the funding environment, citing her own experience. “At our institute, we are funded by an endowment and funding for equipment has been fine. I am seeing a few of my researchers writing grants to use spatial methods in their research.”

NanoString Technologies

Leading the emergence of the high-plex spatial transcriptomics market has been two companies, 10x Genomics and NanoString Technologies. NanoString introduced its GeoMX Digital Spatial Profiling system in 2019. In February, the company commercially launched the Whole Transcriptome Atlas (WTA) for humans covering over 18,000 protein coding genes. In May, the company released the mouse version of the assay.

Brad Gray, CEO of NanoString, described spatial biology as building upon the single-cell biology revolution. “What single-cell biology didn’t do is let you understand where each of those individual cells resides in tissue. So that gave rise to spatial biology, which is just at its very birth right now,” he stated. In 2020, the company released its first assay, the Cancer Transcriptome Atlas for the Illumina NGS readout. “NanoString was the first [company] to have a major platform launched in the spatial biology space, and we focused initially on what we call translational research,” noted Mr. Gray.

The market has definitely advanced since the company’s initial entry in the space. “You move from a period where you’re explaining to scientists what spatial biology is to a period where you know you’re answering questions. [Scientists] are ‘pulling’ now. They’re saying, ‘Tell me about this. I’ve heard of that,’” explained Mr. Gray.

For the GeoMx, oncology has been a primary area of adoption, but the market is expanding with applications in more research areas, such as neuroscience, developmental biology, fundamental immunology and infectious disease. “I expect over time non-oncology applications will outnumber oncology applications,” said Mr. Gray.

The expansion of the spatial transcriptomics market in general is further indicated by the launch of new platforms. Next year, NanoString will introduce the Spatial Molecular Imager, which will feature imaging-based detection, marking the development of higher-resolution solutions. The two product platforms illustrate the market’s growth opportunities as labs look to adopt multiple spatial transcriptomics technologies. “In the end, customers will have both; they’ll have high-throughput whole transcriptome profilers, [and] they’ll have lower-throughput, high-resolution imagers,” commented Mr. Gray. In addition, he believes all imagers will be differentiated by plex.

Asked about challenges in the spatial transcriptomics market, Mr. Gray highlighted cost and awareness. “What limits the pace at which spatial biology can be adopted? I think one is capital equipment budgets… And the other is just getting the word out, and the best ‘word’ are those in the scientific literature that don’t come from the companies that have been in the technology, but come from the scientists who used it to discover things.” Another area where further development is needed informatics. “These systems generate terabytes and terabytes of data; the imagers in particular,” he said. “Within NanoString, the largest group in our R&D organization now is our software group.”

Regarding the NanoString GeoMx DSP, Ms. Perera told IBO, “NanoString is a good option for a pathology lab. However, for an academic setting where we might work with different organisms, this might not be the best solution.” But she found the software a positive. “A nice thing about NanoString seems to be the software and imaging capabilities.”

Regarding her comments, a NanoString spokesperson told IBO, “Two-thirds of the GeoMx systems sold to date have been in academic research settings.” He also said that since the launch of WTA and the release of the Mouse WTA, NanoString now offers universal spatial RNA assays that address the vast majority of the total addressable market.”

10x Genomics

10x Genomics began shipping its spatial biology system, the Visium Spatial Gene Expression Solution, in 2019. Later this year, for the Visium, 10x Genomics will launch a highly multiplex protein assay for simultaneous protein measurements in the same tissue section, adding to lower-plex protein detection capabilities already available. Initially introduced for fresh frozen tissues, this year, the company launched a solution for use with FFPE slides.

Visium offers a non-targeted approach to spatial transcriptomics, enabling hypothesis-free research. “That’s what makes Visium differentiated from some of these other methods—you don’t have to pick regions of interest within a section or a sample,” observed Nikhil Rao, PhD, 10x Genomics’ Director of Spatial Platforms.

Visium applications include oncology. In addition, the number of Visium neuroscience publications is also increasing. “What the researcher was trying to do [in one study] was show that by mapping that layer of the brain, they can then make better calls about specific neuro-psychiatric disorders, like schizophrenia and autism,” noted Dr. Rao.

With the introduction of Visium FFPE, one of the technology’s challenges has been met. “We launched last June Visium for FFPE, and this is really the first time there’s been unbiased gene expression from entire tissue sections for formalin fixed paraffin embedded samples,” explained Dr. Rao.

10x Genomics has also heard from customers about their need for single-cell resolution. To meet this need, the company will next year launch the Visium HD Spatial Gene Expression solution, which will offer single-cell resolution. “I think one of the big use cases for Visium HD that we’re excited about is particularly relevant in oncology, where you can imagine having a tumor and immune cells attacking the tumor and are able to look at every single one of those immune cells and define what cell types those are,” said Dr. Rao. Like Visium, Visium HD is expected to add protein compatibility in the future.

10x Genomics has also invested in in situ sequencing technology (ISS) (ISS is a technique where the tissue or cell is sequenced in the section) with the purchase of ReadCore FISSEQ Fluorescent ISS and Cartana’ ISS reagent kits (see IBO 10/15/20). The company will use the technologies to develop a new ISS solution, which will be designed to provide a high-throughput, high-plex, single-molecule resolution, targeted approach to both RNA and protein target localization without NGS, including imaging of entire tissue sections. This is part of 10x Genomics’ larger strategy. “Thinking about Visium as discovery and translational, we see in situ being translational into early pre-clinical, studies,” said Dr. Rao.

Regarding her experience using Visium, Ms. Perera commented on the cost, “First, you need to optimize the tissue and permeabilization for a cost of ~$1,500. Then you can perform the actual experiment for about $5,000–$6,000 not including sequencing costs.” However, Ms. Perera highlighted the total lower cost of ownership. “The benefit of Visium is that it can be used for any organism and doesn’t require a capital purchase as long as you have access to a cryo, microscope and a sequencer.”

Dr. Rao responded to her comments, stating the 10x Genomics is continuously improving products. “First, we aim to remove the tissue optimization step in the future. In fact, we expect that the next versions of Visium will eliminate the need for this step, removing the initial investment and upfront, labor-intensive steps.

SLIDE-Seq

Ms. Perera highlighted her use of SLIDE-Seq, a non-commercialized technique. “This method was developed by Fei Chen’s group at the Broad and we have been collaborating with them. We get close to ‘true’ single-cell resolution as the beads are 10uM in size,” she commented.

 

 

 

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