New paper @pai_vaibhav: onlinelibrary.wiley.com/doi/10.1111/wr… #bioelectric repair of eye, heart, and gut defects from a range of chemical teratogens and even from mutations of a key neurogenesis gene Notch! Molecular or drug (human-approved) methods repair defects in multiple germ layers. 🧵:
Super excited about this; here's context of how we got here via Pai's prior papers, & ties of this biomed-focused project to basal cognition field. Regulative development or regeneration needs to be able to ascertain correct vs. incorrect morphologies. How could cell groups do
that? Model nature.com/articles/s4159… but basically, think of image recognition by visual systems - can other body tissues act like retinas to process bioelectric info? We originally looked at the voltage prepatterns in the nascent frog brain and saw that teratogens screw up brain
form & function by making the normally precise brain prepattern fuzzy jneurosci.org/content/35/10/…. W/ Alexis Pietak, we built and analyzed a computational model: which channels could be targeted to sharpen it? Literally a contrast enhancer nature.com/articles/s4146… = HCN2 channels
were identified, and amazingly, introducing new HCN2 *or opening existing ones with drugs* (no need for gene therapy) rescued very severe brain defects in the tadpole model, including restoring normal IQ (performance in learning assays). HCN2 even cleans up wild-type embryos
(no teratogens) to make them much more uniform and perfect-looking, reducing normal developmental noise by sharperning voltage compartment boundaries. We next found (frontiersin.org/articles/10.33…) that this effect can work at a distance (Vmem signals from remote tissues):
can fix brain by changing Vmem of the ventral cells! Now, that's brain - what do we do for other organs? We had started with a model based on careful quantitative measurements of bioelectrics in the nascent brain region. But we can't (yet) image heart or gut - they're internal
and opaque. So, how do we formulate a new model to choose intervention for those body systems? Turns out, the same HCN2 trick works! We didn't need to remake an organ-specific model. So, with this latest paper, now we know: 1) computational models can help pick interventions for
complex birth defects that do not require precise spatial targeting or genome editing, 2) this can be done with already human-approved electroceuticals (but new channel drugs always welcome too), 3) the effect can be exerted from a distance in the body, 4) the same strategy can
be used for multiple body systems without knowing all the details for every tissue, 5) at least some hardware (e.g., Notch mutation) problems can be addressed "in software" (bioelectric drugs). Next: mammalian (mouse) embryos, & generalizing to other methods to modulate
how bioelectric info is processed by tissues. Comput. modeling + #bioelectricity -> regenerative medicine. Thank you to many collaborators (including lots of undergraduate students who participated in this series of papers), and to the tadpoles for teaching us important lessons.
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