Plant biologists, bacteriologists, protein biochemists, and other scientists have widely studied opsins at the basic science level since the 1970s. Their goal has been to find out how these compact light-powered machines work. It was clear to one of us (Boyden) around a decade ago that opsins could, if genetically expressed in cells that signal via electricity (such as neurons or heart cells), be used to alter the electrical activity of those cells in response to pulses of light.
Such tools could thus be a huge benefit to neuroscience. They could enable scientists to assess the causal role of a specific cell type or neural activity pattern in a behavior or pathology, and make it easier to study how other excitable cells, such as heart, immune, and muscle cells, play roles in organ and organism function. Furthermore, given the emerging importance of neuromodulation therapy tools, such as deep brain stimulation (DBS), opsins could enable novel therapies for correcting aberrant activity in the nervous system.
What might be called the “example phase” of this econeering field began about 10 years ago, when several papers suggested that these molecules might be used safely and efficaciously in mammalian cells. For example, foundational papers in 1999 (by Okuno and colleagues) and 2003 (by Nagel and colleagues) revealed and characterized opsins from archaebacteria and algae with properties appropriate for expression and operation in electrically excitable mammalian cells. Even within these papers, basic science examples began to lead directly to bioengineering insights, demonstrating in the case of the Nagel paper that an opsin could be expressed and successfully operate in a mammalian cell line. In 2005 and 2007, we and our colleagues, in a collaboration between basic scientists and bioengineers, showed that these molecules, when genetically expressed in neurons, could be used to mediate light-driven activation of neurons and light-driven quieting of neurons. In the few years since, these tools have found use in activities ranging from accelerating drug screening, to investigating how neural circuits implement sensation, movement, cognition, and emotion, to analyzing the pathological circuitry of, and development of novel therapies for, neural disorders.
Now this econeering quest is entering what could be called the “classification phase,” as we acquire enough data to predict the ecological resources that will yield tools optimal for specific bioengineering goals. For example, in a paper from our research group published in Nature on January 7, 2010, we screened natural opsins from species from every kingdom of living organism except for animals. With enough examples in hand, distinct classes of opsins emerged, with different functional properties.
We found that opsins from species of fungi were more easily driven by blue light than opsins from species of archaebacteria, which were more easily driven by yellow or red light. The two classes, together, enable perturbation of two sets of neurons by two different colors of light. This finding not only enables very powerful perturbation of two intermeshed neural populations separately– important for determining how they work together–but also opens up the possibility of altering activity in two different cell types, opening up new clinical possibilities for correcting aberrant brain activity. Building off of data from and conversations with many basic scientists, we then began mutating these genes to explore the classes more thoroughly, creating artificial opsins to help us identify the boundary between the classes. Understanding these boundaries not only gave us clarity about the space of bioengineering possibility, but told us where to look further in nature if we wanted to augment a specific bioengineering property.