We Shall Finally Map The Brain - EP 36 Andrew Payne
Timestamps are as accurate as they can be but may be slightly off. We encourage you to listen to the full context.
Podcast Summary
This episode features Andrew Payne, co-founder of E11 Bio, discussing his groundbreaking work on brain imaging and connectomics. The conversation explores the challenges of mapping complete neural networks (connectomes) and how E11's innovative PRISM technology uses color-coded neurons to dramatically reduce the cost of brain mapping. (05:30) Payne explains how their approach combines expansion microscopy with molecular barcoding to make neurons distinguishable, potentially reducing tracing costs by 100-fold compared to traditional electron microscopy methods.
- Main themes: The evolution from simple organism connectomes (C. elegans, fly) to the ambitious goal of mapping mammalian brains, the bottlenecks in current brain imaging technology, and how new approaches could revolutionize neuroscience research and therapeutic development.
Speakers
Andrew Payne
Andrew Payne is co-founder of E11 Bio, a focused research organization dedicated to developing next-generation brain mapping technologies. He completed his PhD at MIT under renowned neuroscientist Ed Boyden, where he worked on expansion microscopy and connectomics. Payne also trained in George Church's lab at Harvard, bringing genomics expertise to brain imaging challenges. A Canadian from Toronto who studied engineering physics at University of Toronto, Payne's personal experience with chronic pain and arthritis drives his mission to understand brain disorders as "connectopathies" - disorders of neural wiring.
Key Takeaways
Scale Up Through Team Science and Focused Research Organizations
Payne realized that solving connectomics challenges required more than individual graduate student projects - it needed coordinated teams of 10-15 specialists working together. (40:00) E11 Bio operates as a "focused research organization" (FRO), combining startup urgency and vertical integration with nonprofit public benefit goals. This approach allows for the coordination needed to tackle complex, pre-commercial scientific challenges that require multiple disciplines working in concert. The model proves that some scientific problems need dedicated organizational structures rather than traditional academic or commercial approaches.
Transform Black and White Problems into Color-Coded Solutions
The core breakthrough involves making every neuron in the brain a different color, solving what Payne calls "the ultimate color by numbers problem." (34:27) Traditional electron microscopy produces grayscale images where all neurons look similar, making tracing extremely difficult. By using viral delivery of fluorescent proteins in combinatorial patterns, E11 can create over 260,000 distinct color combinations, allowing researchers to follow individual neural pathways like following colored wires rather than trying to untangle identical gray ones.
Address the 98% Cost Bottleneck in Neural Tracing
Current connectomics faces a massive bottleneck: tracing neurons through images accounts for 98% of the total cost of mapping brain circuits. (15:27) Even the recent fly connectome required 33 person-years of manual annotation despite AI assistance. Payne's approach aims to reduce tracing costs by 100-1000 fold by providing additional molecular information that helps AI systems automatically correct errors and trace connections more accurately. This cost reduction is essential for scaling from individual connectomes to the many brain maps needed for comparative studies.
Leverage Expansion Microscopy to Bridge Resolution Gaps
Expansion microscopy, developed in Ed Boyden's lab, physically enlarges brain tissue by 5-20 times while preserving structure with 99% accuracy. (35:58) This technique solves a fundamental problem: light wavelengths (500+ nanometers) are too large to resolve synaptic connections (tens of nanometers), but expansion physically separates overlapping structures. This allows researchers to use light microscopy's color capabilities while achieving the resolution previously only possible with electron microscopy, opening new possibilities for multi-modal brain imaging.
Target Medical Applications Through Understanding Connectopathies
Payne conceptualizes many brain disorders as "connectopathies" - diseases of neural wiring rather than just chemical imbalances. (20:44) By comparing healthy and diseased brain circuits, researchers could identify specific wiring patterns that cause conditions like chronic pain, schizophrenia, or Parkinson's disease. This approach offers new therapeutic targets for drug development and brain-computer interfaces, potentially helping the one in three people who will experience brain disorders. The goal is moving from treating symptoms to correcting the underlying circuit dysfunction.
Statistics & Facts
- One in three people in the world will experience a brain disorder at some point in their lives. (21:02) This statistic, mentioned by Payne, underscores the massive medical need driving connectomics research and the potential impact of understanding brain wiring disorders.
- The recent fly connectome required 33 person-years of manual annotation to correct AI-generated neural traces. (16:03) This demonstrates the enormous human effort still needed despite advanced computer vision, highlighting why cost reduction in neural tracing is critical for scaling to larger brains.
- Current connectomics methods can distinguish about 100 different colors using traditional fluorescent proteins, while E11's PRISM technology can create over 260,000 distinct combinations using 18 different protein variants. (45:54) This represents a thousand-fold improvement in the ability to uniquely identify individual neurons in dense brain tissue.
