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Professor Ulf Landegren Discusses Advances in Spatial Biology and 3D Sequencing

A profile picture of Professor Ulf Landegren.
Credit: Gustav Cedar, adapted by Technology Networks.
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Read time: 4 minutes

Dr. Ulf Landegren, professor in the Department of Immunology, Genetics and Pathology at Uppsala University, has made significant contributions to the development of antibody-based proximity extension assay (PEA) and in situ proximity ligation assay (isPLA) technologies.

These techniques have majorly advanced the landscape of proteomics and spatial biology, and his research has also led to the creation of several spin-out companies, including Olink and Navinci.

Landegren is a scientific advisor at Single Technologies, which was founded in 2014. Single Technologies has developed a 3D sequencer that, paired with its imaging technology, can improve throughput, reduce the costs of sequencing and do spatial genomics in 3D.

In a recent video interview, Landegren shared his perspectives on the future of spatial biology, discussed novel developments in 3D sequencing and outlined why this approach is capturing the attention of researchers worldwide.

Q: Can you discuss recent developments in spatial biology?

A: My laboratory has developed a technology that has very high accuracy and can tell us where mutant DNA is located. Mutant DNA or RNA can be very important, because they are really specific markers of malignant cells.

Proteins tend to be rather poor markers of malignancy in spatial analyses because they are not so different between malignant and benign cells. But, if you can pinpoint the mutations, then you have a way of finding:

  • Where the malignant cells are
  • How they are infiltrating
  • Whether they are approaching the line where a surgeon made a cut
  • How the mutations have evolved over time

You start with a handful of mutations and the tumors mutate all the time, so eventually the tumor accumulates more and more, and you can see the clonal history of a tumor, spatially distributed. So, DNA analysis can be very interesting.

RNA, of course, is even more interesting, because RNA gives you the identity of the cells. This [research area] is already well underway and there are lots of technologies to sequence RNA, but the faster you can read them out with Single Technology’s approach, or similar, the better.

Protein [science] is yet another area, and I've been arguing that the in situ proximity ligation technique of our spin-out Navinci has advantages over other protein detection techniques, because we can improve the specificity and we can look at more complex features of the protein, such as interactions, modifications and so forth.

On top of that, of course, anything else that you are interested in and where there are enough different events that you want to distinguish, typically can be encoded as DNA – that's done more and more now. We have the epigenome, so we want to know which parts of the genome are accessible for the transcription machinery, even if they're not currently being transcribed, which ones are ready to be transcribed? That's what you learn at the level of the epigenome, you study the nucleosomes and a technology called ATAC-seq can tell you which parts are not so hidden from view, but that are active and can be accessed by the transcription machinery. These are just some examples where we want to use DNA readout to learn more about biology.

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Q: Why is 3D sequencing interesting?

A: Sequencing started as a one-dimensional problem. You run gels and see in what order the nucleotides arrive. That only went so far. It actually gave us the whole human genome using this relatively primitive technology. Running enough of these linear reads, we eventually got there.

But, shortly after the genome was sequenced, there was a whole generation of new technologies called massively parallel sequencing or next-generation sequencing, and the general feature of them is that you sequence things in two dimensions.

You distribute your products in an area, you don't go linearly, but you can access massive amounts of templates; and once you realize that, then it's very obvious that the next place to go is the third dimension. If you can pack things in the third dimension, then you can really have large numbers of objects to sequence.

This, of course, requires a number of other technical solutions, such as how to image that number of products accurately and very quickly.

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Q: Why would it be interesting to read out in situ proximity ligation assay in 3D?

A: If we can use the Single Technology approach or 3D sequencing, then we can build images of the three dimensions of the cells, wherein the cell protein activity is going on, how it is distributed and what are the protein actions.

We may want to follow signaling pathways, for instance, from the point where a signal is given to a cell by a cytokine, activating a cell surface receptor, until the signaling via relays reaches the nucleus, where gene transcription begins – we want to measure all those steps. We also want to see [in tumor tissue], which of those steps have been interrupted, or which ones have become augmented. On top of that, we also want to do that as a function of the drugs that we treat cells with. We want to really be able to pinpoint, exactly at what step does my drug interfere?

All of these things mean that we have thousands and thousands of samples, each with millions of cells, for which we want to look at thousands of protein events – that multiplies to very large numbers, which translates to a need for Single Technologies.

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The above content is a transcription of Professor Ulf Landegren’s video interview. It has been edited for clarity and flow to ensure a better reading experience. While every effort has been made to preserve the original content and meaning, some minor adjustments have been made to improve readability.

About the interviewee

Dr. Ulf Landegren is a professor in the Department of Immunology, Genetics and Pathology at Uppsala University. Throughout his career, he has made significant contributions to the development of antibody-based proximity extension assay (PEA) and in situ proximity ligation assay (isPLA). Landegren’s research has also led to the creation of several start-up companies in the proteomics and spatial biology space.