Paradigm-Shifting 3D Biology
Imagine being able to analyse DNA, RNA, and protein data from a single sample using just one instrument. Not only would that cut the time it takes to run those tests individually, it would also cut the noise and ambiguity around using different platforms and samples. It would open up an exciting opportunity to understand biology at a greater level of detail, and change how we think about research. Excited? So were we, because that’s exactly what NanoString Technologies are making possible today.
At the 2017 ASHG annual meeting, the team from NanoString will be showing off the paradigm-shifting 3D Biology™ technology, and presenting case studies demonstrating how it’s already allowing researchers to do more. To find out more, we asked Niroshan Ramachandran , Senior Director of Product Management at NanoString Technologies, to run us through the technology and how it’s going to be on show at the event.
FLG: At ASHG this year, you guys are talking about 3D Biology™ and The Next Generation of Genomics Tools. NanoString is one of the big names when it comes to industry-shifting genomic technologies, so a talk title like that is pretty exciting. Can you talk us through what 3D Biology actually is?
NR: The definition of 3D Biology Technology from NanoString’s perspective is that we’re enabling scientists to measure and analyse DNA, RNA, and protein from a single sample on a single instrument. As scientists, we have historically been trained to think about the one-dimensional approaches. We get as much information from DNA sequencing as we can, get as much information from RNA profiling as we can, or get as much protein information as we can. 3D Biology is a new paradigm where we’re trying to think about how to form multi-analyte experiments where we extract information from the relevant targets but also the relevant analytes. Historically, the way we would do this is we would carry out single analyte experiments sequentially, and we would start with a DNA assay followed by a RNA assay second, and then the protein assay third. We often do that because we have to do them on separate platforms. You’re often trading off between sample consumption so you would start off with the assay that is the least sample-consuming and then move towards the higher value test that is highest sample consuming. And so ultimately the goal of 3D Biology, and the assays that relate to that, is to give you the freedom to be able to extract information whether it be DNA, RNA or protein and not have to trade off on the amount of sample. The shift is really going from the sequential experimental paradigm to the simultaneous paradigm to be able to analyse multiple analytes.
FLG: When you consider where we were just a few years ago, it’s staggering to think about where we are now. Why are we seeing such an increased rate in technological development these days?
NR: Usually, we see a new technology emerge that highlights a new capability and allows you to get information that you couldn’t before. That drives a discovery phase where there is new biology revealed. Then it starts to plateau, and the next technological innovation comes. It disrupts and you get to see biology in a different way. Sequencing was a part of that, NGS another one, and mass spectrometry did that for us. I almost see that there is a cyclical nature where we oscillate from a technology boom to a biology boom. The thing that we are seeing now is sequencing becoming more mainstream. We’re getting to a point of diminishing returns where we sequence as many samples as we can. You see that most people are starting to look for the next type of capability to obtain even more information from than they got from their NGS platform.
In the market place, more and more platforms are coming out that look at the different dimensions of data analysis. Technologies that are looking to get more information out of the protein, RNA, and DNA at the same time. We’re also starting to see more technologies that enable spatial information. We’re looking to get higher sensitivity and higher resolution data from spatial information. These are all areas that sequencing couldn’t address, so now we’re seeing new technologies coming out that are trying to go where sequencing can’t go. This is very exciting for us in terms of the new types of biology we can uncover.
FLG: Our understanding of cancer has developed to a stage that we recognise it as a disease that really acts at a molecular level. Something like 3D Biology is just about the perfect tool to help us attain tremendous insight into how it behaves and its associated biomarkers. How are the 3D Biology products being used in Cancer Research now, and what kind of impact do you think they can have?
NR: We are starting to know more about the mechanism of action and how the pathways are working and what the important targets may be at the genotype level in terms of what single nucleotide variants (SNV) are important, what RNA targets we should be looking at, what protein targets and even phospho-protein targets. For example, all the NGS based experiments to date have consistently revealed the key targets we ought to focus on. Now we’re in this phase where we can leverage this discovery to perform more targeted studies that reveal something about the biological outcome of a molecular system.
Looking at 3D Biology the applications fall into two buckets, especially in oncology. One is drug development – drug developers are looking to see what pathways are being deregulated or upregulated, and trying to understand how that can translate into new targets, or mechanisms of action, or mechanisms of resistance. 3D Biology ties together the genotype and phenotype information, which are so tightly linked in oncology. For each sample, you can now genotype it and look at the mutational status and marry that to response to a therapy and look at the RNA level, the protein level, and the phospho-protein level. The phospho-protein level is extremely important to drug developers, and it’s information you can’t get from sequencing. So now you can get all of that with the least amount of technical noise, as it’s all done on a single platform with a single chemistry.
The other bucket is an application that came to us as an interesting surprise. There has been a lot of conjecture over the level of concordance between RNA and protein. Do they concord or not? If they don’t concord, is it due to technical differences between different platforms and chemistries? It’s hard to decipher if the true biology is being captured. So, we started to do some tests using 3D Biology. We found that concordance does indeed vary. Sometimes the concordance is 80-90% and sometimes 20-30%. The average will range from 40-60%. Knowing that the concordance or discordance is the true biology makes this really interesting. From a biomarker perspective, if you were to come up with an entire RNA panel or an entire protein panel, you would miss the biology that contributes to the discordance. But having an integrated panel is more potent. There are some companies out there that are investing time and effort into designing multi-analyte signatures whether it be for diagnostics or companion diagnostics. I think this is a new frontier of capturing more biology with a smaller number of targets through mixing of a number of analyte classes.
FLG: As well as having great applicable technology, you guys do a great job getting it out there. Rather than showing up to meetings, pitching up a stand and selling at the crowds, you have a strong emphasis on education and productive engagement with the scientific community. How would you describe NanoString’s relationship with its customers and potential customers?
NR: It probably stems from our mutual respect. The most common feedback from our customers is that they appreciate the support we provide for them through the entire experimental process, from when they run those experiments and generate that data. We’re very collaborative. Our teams are very technical and very scientific, so customers often enjoy having that dialogue with us. The interesting thing is, the relationship is more of a pass-forward relationship. Our customers often teach us what the need is and tell us what and where the scientific gaps are. That often inspires us to go and think about new technologies. An example of that is that we’ve developed a platform called Digital Spatial Profiling that’s inspired by all the questions that our customers ask us. In some cases, our customers actually develop some of these new technologies themselves. A perfect example of that is our protein chemistry that was developed at Massachusetts General Hospital. So sometimes our customers do a great level of innovation on our platforms, so that’s where we have that mutual respect. We collaborate with them to explore new capabilities of the platform. The flipside of that is, they then go on to tell others about how they’re using the platform. If you see us at conferences, either we will communicate on behalf of our customers using the platform, or customers are very happy to come to meetings and present their results.
The thing that really differentiates us is that a lot of our products, especially the content and data analysis, are truly steeped in strong scientific foundation. They are based on publications. We look at biological frameworks and systems that key opinion leaders have laid out, and we use that to build products so they make biological sense and are biologically relevant. I think the fact that we are so technical and scientifically orientated means that the products resonate more with our customers.
FLG: ASHG is the biggest show out there for Human Genetics. Who do you hope comes to your luncheon seminar, and what are you hoping they leave with?
NR: The interesting thing about 3D Biology is that it’s paradoxical in some ways- often when you talk to scientists about measuring DNA, RNA, and protein there’s a level of obviousness to it. We have been taught to know what the importance of those three analytes is. It feels natural to want to measure them together. And on the flipside of this, it’s surprising that we haven’t had capabilities to measure these three analytes in a relatively straight-forward manner- they’ve all been distinct disciplines for a long time. If you look at publications out there, most of multi-dimensional analysis is performed with several instruments coming together. Bringing all that data together is difficult for any single scientist to perform multi-dimensional analysis and gain meaningful insights. The goal of the session at ASHG is to show a case study where scientists can run through two or three biological experiments by looking at genotype and looking at the phenotype and trying to bring all that information together drawing insights.
The example shows the use of patient-derived xenographs from a breast cancer research model. Samples are treated with a series of drugs and monitored over time. We map the genotypes, and start to correlate genotype with response to therapy and the respective changes at the RNA, protein, and phospho-protein levels. So our customers can start to understand how easy it is to think about these analytes, and put them together in a biological context. It allows them to ask the right question of each type of analyte holistically.
My hope is that people will see the example, understand how it works, and really get their creative juices flowing. We want them to start thinking about how they might be able to use 3D Biology for samples they already have in the fridge, freezer, or biobank to generate new perspectives and insights. The new hypotheses they might generate will be really exciting for all of us.
NOTE: FOR RESEARCH USE ONLY. Not for use in diagnostic procedures.
So there you have it. You’re not just able to do more with less, you’re able to do a lot more with less. To find out more, make sure you stop by booth 601 and visit the NanoString Technologies team to get hands on with 3D Biology™, and click here to register for their Luncheon Seminar:
Thursday, October 19, 2017, 12:30 PM – 1:45 PM
Hilton Orlando, Lake Nona, Lobby Level
Title: 3D BiologyTM and The Next Generation of Genomics Tools
Speakers: Joseph Beechem, PhD, Sr. VP of Research and Development, NanoString
Justin Balko, Pharm.D., Ph.D. Assistant Professor of Cancer Biology. Leader of Molecular Oncology, Center for Cancer Target Therapies Vanderbilt University Medical Center
Title: Challenges with gene expression profiling in a biotech setting, and recent technical advances with NanoString PlexSetTM
Speaker: Matthew Goddeeris, Senior Scientist, Translational Biology, Mitobridge