The sequencing microscope - a path to look at the molecules of biology

Introduction

The goal of biological research is to understand how life works. Although progress is fast, there seems to be an infinity of things we do not understand. When it comes to understanding tissue from the bottom up, our knowledge leaves much to be desired. Feynman claimed that “It is very easy to answer many of these fundamental biological questions; you just look at the thing!” Well, the problem is that looking at the thing is the problem.

Challenges in Microscopy

Microscopy might never give us the possibility to directly see DNA or RNA sequences. For this, the community has evolved extraordinarily powerful sequencers. Today, one person can routinely read millions of sequences on a weekly basis. Likely soon, we will read billions of sequences daily in small labs. However, this, in itself, will not allow us to just look at the thing.

Proposal for a New Approach

We argue in this proposal that by using the sequencer itself as a microscope, we will get much closer to actually seeing what is going on in biological systems. Researchers have started in this direction by coupling microscopy and sequencing data from the same sample, but that is a temporary solution.

Technology Overview

Here, we propose a technology for inferring images using sequencing data alone, bypassing the need for advanced microscopy and leveraging the potential of the exponential growth of sequencing technology.

1. We use DNA seeds and perform a reaction in situ that allows these seeds to copy themselves locally.
2. This is analogous to phylogenetic reconstruction, but instead of inferring ancestry, we infer relations of amplicons to spatial locations in tissue.

Innovative Methodology

By using a unique approach, we derive spatial information connected to RNA transcript information directly in situ. This allows for a non-targeted spatial transcriptomics technique that is as simple as running a PCR.

Expected Outcomes

When successful, this approach will enable us, and others, to learn the inner secrets of biological systems at a significantly faster rate.