I've been editing this article about "brain mapping" and connectomics, and I'm just stunned by how quickly the cost estimates to map, say, a mouse brain have plummeted in just the last couple years. It actually seems feasible that we could map the entire human brain -- all 86... billion neurons, and their connections -- in this lifetime. In the 1970s, Sydney Brenner started mapping all the connections between neurons in C. elegans. His team sliced the worm into thin pieces, took photos using an electron microscope, and manually traced and reconstructed each synapse for 302 neurons total. This project took more than a decade of work, and it cost about $16,500 to reconstruct each neuron. Scaling this up to a human brain boggles the mind. Electron microscopy remained the norm in connectomics for decades, because it was the only option available to see synapses at a resolution high enough to be able to trace their paths. Each electron microscope costs several hundreds of thousands of dollars, though, and you need lots of them to map even a mouse brain in a reasonable timeframe. In 2023, the Wellcome Trust released a report estimating how long, and how expensive, it would be to map the mouse connectome (~70M neurons). They estimated that imaging alone would cost $200-300M, and that proofreading (or ensuring that traces between neurons are correct) would cost $7-21 BILLION. (A human can only manually trace about 1 mm of neuron per hour.) Also, the images would occupy about 500 petabytes of data, and getting those data would require 20 electron microscopes running in parallel for about 5 years, continuously. They estimated the whole project would take about 17 years of work. This is, understandably, insane. But now it seems like there's an actual path toward mapping the full mouse brain in about five years for ~$100M dollars. There have been three major breakthroughs in the last year or so: 1/ Expansion microscopy, first developed in 2015, showed that it's possible to "enlarge" the brain by about 5x using a swellable polymer. But an improved method increases this number to >20x expansion, meaning we can now expand brains and image neurons much more easily using cheap light microscopes, rather than expensive electron ones. 2/ E11 Bio (a nonprofit research org) developed protein barcodes that get delivered into brain tissue; each neuron gets a unique combination of barcodes. These cells are then stained with colorful antibodies, which stick to a matching protein barcode, causing each neuron to light up in a distinct color. This makes tracing neurons so much easier. 3/ Google Research released PATHFINDER this May, an AI-based neuron tracing tool that can proofread about 67,200 cubic microns of brain tissue per hour, with very high accuracy. It works on electron micrographs, but something similar could be presumably be developed for the E11 / colorful tag approach. This is an extremely exciting time for neuroscience. (C. elegans connectome below.)show more

Niko McCarty.

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