Today, with
@E11BIO, I am excited to announce PRISM, a new, scalable technology for mapping brain circuits. Within 10 years, technologies like PRISM will enable us to understand fundamental brain functions, fight brain disorders, and maybe even achieve upload. Enormous congratulations to the entire team at E11, my former academic lab at the Crick, our collaborators at MIT and the Max Planck Institute, and more.
Within the brain, neurons are tangled up like 100 billion microscopic headphone cables, impossibly knotted together. Mapping brain circuits requires tracing each and every neuron throughout the entire brain volume and seeing where they connect -- an extraordinarily laborious task, even with the help of AI. More importantly, with existing methods, if you lose a single slice of imaging data or if there is a single defect in the tissue processing, it can become impossible to reconstruct circuits. With PRISM, we have figured out how to get each neuron to express a molecular barcode that can be read out at any point along its length, greatly simplifying the process of reconstruction and allowing us to reconstruct circuits even when there are gaps in imaging. We use a combination of protein barcoding, expansion microscopy, multiplexed antibody staining, and new reconstruction algorithms to improve reconstruction accuracy by nearly an order of magnitude, achieve reconstruction across gaps, and achieve simultaneous morphological imaging and imaging of synaptic proteins. PRISM requires significant additional development, but it seems likely that this kind of molecular barcoding will be necessary for brain mapping to scale.
This work has been a long time coming.
@Andrew_C_Payne and I began working on the technology that eventually became PRISM as graduate students at MIT, with
@bobae_an and our PhD advisor,
@eboyden3.
@AdamMarblestone and I invented the concept of Focused Research Organizations largely as a way to support projects like PRISM. Once Andrew had started E11 and once I had started my lab at the Crick, Andrew and I continued to work together closely, with
@syrosa_park in my lab gathering some of the critical datasets for the paper. There is much more to do, but scalable brain mapping is coming, and
@E11BIO is leading the way.
@E11BIO is excited to unveil PRISM technology for mapping brain wiring with simple light microscopes. Today, brain mapping in humans and other mammals is bottlenecked by accurate neuron tracing. PRISM uses molecular ID codes and AI to help neurons trace themselves. We discovered a new cell barcoding approach exceeding comparable methods by more than 750x. This is the heart of PRISM. We integrated this capability with microscopy and AI image analysis to automatically trace neurons at high resolution and annotate them with molecular features.
This is a key advance towards economically viable brain mapping - 95% of costs stem from neuron tracing. It is also an important step towards democratizing neuron tracing for everyday neuroscience. Solving these problems is critical for curing brain disorders, building safer and human-like AI, and even simulating brain function.
In our first pilot study, we acquired a unique dataset in mouse hippocampus. Barcodes improved the accuracy of tracing genetically labelled neurons by 8x – with a clear path to 100x or more. They also permit tracing across spatial gaps – essential for mitigating tissue section loss in whole-brain scaling. Using molecular annotation, we uncover an intriguing feature of synaptic organization, demonstrating how PRISM can be used for systematic discovery 🧵