Breaking Boundaries with NanoString’s Digital Spatial Profiling
Recently we had a conversation with key members of the scientific leadership team at NanoString. Joe Beechem, the Senior VP of Research & Development, and Alessandra Cesano, Chief Medical Officer, talk about their perspectives on the impact of Digital Spatial Profiling (DSP) Technology.
NS: How would you describe your role at NanoString Technology?
Alessandra Cesano (AC): My role, and my passion, are to bring research and development tools to clinical medicine to better serve patients and improve patient outcomes. Joe and I talk a lot—usually, Joe is the creator of the technology and the visionary of what is possible. As the CMO and a former clinical oncologist, my response is usually, “This is great, but what can I use it for? How can it have a future impact in the clinical world?” Digital Spatial Profiling (DSP) is an example of this collaboration.
NS: Why is it important to incorporate spatial information into profiling experiments?
AC: Spatial context is particularly relevant in immuno-oncology and neuropathology because of the nature of heterogeneous tissue. The position of cells is an important indicator of their biological function. With today’s technology, when we homogenize tissue we lose that individual cellular location and the geographical component of information. Where the cells are and how they talk to each other is important to understand both biologically and clinically.
Joe Beechem (JB): To collect spatial information in research studies, we’ve developed Digital Spatial Profiling Technology, a digital assay that measures multiple variables at the same time and allows us to take a snapshot of the complex biology happening in the tissue.
NS: What is the importance of providing this information in a digital assay?
JB: Historically, research has been based on analog technology, meaning taking measurements by averaging. In all digital chemistry, we measure not by averaging but by counting individual molecules. We have developed a digital technology that works in tissue, is spatially resolved, allows us to multiplex, and is capable of monitoring entire pathways simultaneously.
NS: What is the biggest challenge facing immuno-oncology today?
AC: It is now accepted that the immune response to cancer is affected by multiple factors—some related to the tumor (epigenetic), some related to the host (genomic), and some due to the microenvironment. All these factors converge to determine the timing and magnitude of the immune response. The biggest challenge is integrating all of that information from different analytes into one single assay that allows you to understand the mechanisms of immune evasion in an individual patient sample. That can potentially influence patient management and therapeutic strategies. The ability to do a deep dive into the biology, collect all the information into a single assay, and ultimately bring it to the bedside is what we are driving towards.
JB: We have now entered an era where the medicines being used to treat disease are very complex. They respond to a multitude of inputs so it’s incredibly important to have digital, quantitative assays that allow you to measure these various components.
NS: How does Digital Spatial Profiling (DSP) fit into all of this?
AC: The tumor microenvironment is a melting pot of tumor cells and immune cells; their spatial positioning is very important. It’s not random– it is dictated by their function and their activity. So the capability of adding a spatial component, particularly in immuno-oncology research, and then taking digital measurements of proteins and RNA is unique. It helps to understand the mechanism of immune evasion at the level of a single tissue sample as well as provides insight into the mechanism of action of drugs for translational research. It overcomes the current limitations of immunohistochemistry and fluorescence imaging, such as the limited plex and quantitation, and expands the ability to look at more than just proteins with spatial resolution.
NS: What has been the biggest breakthrough in the design of DSP?
JB: It started on a whiteboard when we began to think about designing a new instrument. Everyone else was trying to put a lot of multiplexed assays into the tissue, and that’s a limiting return. You’re never going to be able to measure all those things in the tissue with traditional immunohistochemistry. We took the opposite approach—we designed small, simple molecules to go into the tissue that is spatially resolvable using indexing oligos attached to protein and RNA probes via a UV photocleavable linker. The light from the Digital Spatial Profiler brings that information out from the tissue, allowing single molecule quantification off-tissue. We turned the whole word of microscopy upside-down.
NS: It sounds like both molecular biologists and pathologists can benefit from DSP.
AC: In addition to the spatial component of DSP, you can measure the function of the cell in a multiplexed fashion that is not reachable with any other technology. The molecular will benefit from the spatial information DSP provides when measuring macromolecules. Pathologists familiar with looking at slides will see that multiplexing and digital profiling can increase what they can learn from a single tissue section. That’s where the fusion happens.
NS: Now that you have this powerful new technology, what’s your ideal experiment?
AC: I am very excited about bringing DSP to immuno-oncology research as a routine tool. It is perfectly suited to help us understand the changes in the tumor microenvironment both before and after treatment. This can be used both in profiling samples from patients that respond positively to the treatment and samples from patients that do not. Mechanisms of immune resistance will be diverse and will require different combinations of treatments, and we don’t have a good understanding of that today. The ideal experiment will be to get a biopsy before and after a patient receives a certain treatment. Then knowing the clinical outcomes and looking at the molecular changes as a response to therapeutic pressure will tell us more about the mechanisms of immune evasion. In turn, this may shape patient management in terms of therapy and follow-up.
JB: We can ask almost an unlimited number of questions that were impossible to ask before. For example, we can ask what entire biological pathways are happening in this little region of space on that particular tumor? How do those pathways change when I look at the other side of that tumor? What are these invading immune cells doing? How are they activated, and what is the tumor doing to try to turn them off? There are so many high-level biological questions that we can begin to evaluate using DSP.
NS: What’s next for DSP?
AC: The goal and mission for NanoString is to develop tools that help us understand the biology underlying disease and the mechanisms of action of the drugs we use to treat them. With these tools, we could get answers that are actionable and clinically relevant for the patient. That is the impactful future we strive for.
Watch the full interviews with Alessandra Cesano and Joe Beechem.
Find more information on Digital Spatial Profiling.
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