Genetic Neuroengineering Group (Wickersham Laboratory)

We are specialists in developing genetic techniques for neuroscience, to provide more powerful and precise ways of studying the organization of the brain, and potentially to provide clinical neurology with more effective ways of treating disorders of the brain.

Specifically, we invent techniques for targeting neurons based on their synaptic connectivity and gene expression patterns in order to cause them to express genes that allow the neurons to be studied and controlled by neuroscientists and clinicians.

Targeting Neurons Based on Their Connectivity -- One focus of our work is on engineering systems for identifying and manipulating neurons that are directly synaptically connected either to a targeted single neuron or to a genetically-defined neuronal population of interest. The first system for such “monosynaptic tracing” was invented by Ian and colleagues at the Salk Institute in 2007 and has become a widely used technique in neuroscience, remaining the best (or even only) way of identifying cells directly connected to a targeted neuronal group without prior information. The original system, based on rabies virus, is not without its drawbacks, however, and we are currently improving it dramatically. In one arm of the work, we are developing a version of the system that is completely nontoxic to neurons: whereas the first-generation rabies virus is toxic to neurons on a timescale of ~2 weeks, a second-generation rabies virus that we have developed leaves neurons alive and completely healthy indefinitely. In a second arm of the research, we are developing systems for anterograde monosynaptic tracing: whereas the existing monosynaptic tracing system only identifies neurons directly presynaptic to a targeted neuronal population, the systems that we are developing are for identification, study, and manipulation of those neurons that are directly postsynaptic to the targeted cells. Both of these efforts should result in techniques that are transformatively useful for neuroscience.

Targeting Neurons Based on Their Gene Expression Patterns -- A second major focus is on devising ways of targeting important subtypes of neurons for expression of transgenes in the brains of animals that have not been genetically modified, with the eventual goal of allowing the use of our novel techniques in human patients. Therapies such as deep brain stimulation (DBS) can be life-changing for patients suffering from diseases such as Parkinson’s Disease, but it relies on nonspecific electrical stimulation of all neurons and processes within the vicinity of the electrode, often causing severe deleterious side effects. Neuroscience is far ahead of neurology in the precision with which neuronal populations can be stimulated: in the last decade, neuroscience has been revolutionized by the invention of “optogenetics”, or the control of neurons using light alone by means of special genes encoding “opsins” that can be expressed in the neurons to be controlled. Optogenetics is only useful, however, when the opsins can be specifically expressed in functionally meaningful groups of neurons, instead of nonspecifically within all types of neurons in a given part of the brain. Because the best current way of restricting opsin expression to specific neuron types is to use genetically modified rats and mice, this requirement has meant that optogenetics has so far been used almost exclusively in rodents, and has not been available for therapeutic purposes in human patients at all. We are currently engineering systems for targeting specific, functionally meaningful, and clinically important neuronal subtypes for expression of optogenetic genes. Our hope is that this will result in a new paradigm for targeted optogenetic deep brain stimulation in human patients.”