In situ genotyping
September 15, 2013
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We have glimpsed the future of genetics and it is colorful
Two papers showed up in the last issue of Nature methods that caught my attention: I mean Levsesque et al of U Penn and Ke et al. from Stockholm University. I’m generally biased towards methods papers and I find them WAY more interesting than your run-of-the-mill biology papers. But why these two papers? I have a conviction… I say conviction because until now there was very little to back it up: the future of biology rests not just in our understanding the populations of cells and observing the “average” phenotypes/phenotypes, but rather a single-cell approach is required to understand all the complex dynamics upon which biological systems thrive. FIrst came single-cell sequencing… then came single-cell barcoded RNA-seq… and now single-cell in situ genotyping/sequencing is here.
There is a magic to watching cells shine under a microscope… there is a feeling of vindication… of assurance. But it is not just that. A cell is already an “average”; an average of paternal and maternal genetic information. And FISH-based methods enable us to distinguish between them. More importantly, in addition to quantity (which to be fair is not its strongest suit), we get a feel for localization in different compartments.
Granted I’ve never done a FISH experiment. So I really don’t know how much of this is real and how much of it cherry-picking. But I’m sure if we can get there, it will be illuminating. And I don’t mean that we should drop the population for single-cells… I think we’ll be in for a surprise. I think we’ll understand, at last, how stupid a single cell is. We’ll know that individual cells make a lot of mistakes and it is the averaging effect of a population that results in a coherent behavior. In other words, I’m not interested in studying single-cells per se, but rather I want to know about them so that I can have smarter models of a population. The same way a thought forms in our brains despite many erratic firings of individual neurons, I want to know how stable phenotypes emerge in spite of, not because of, single-cell variations. Only then we’ll know which pathways are consistently crucial for a single cell and which ones are meaningful only in the context of a population.