This story is not exactly accurate. I was a grad student in the Miesenboeck lab when optogenetics was invented there. Here's what happened behind the scenes. I rotated there in 2001, and Gero said, "Don't tell anyone, but we're stimulating neurons with light." I thought WTF?!? 1/
Based on that statement alone, I joined the lab immediately. Boris Zemelman was using an insect opsin to stimulate neurons in culture, and it worked, but it was slow. Susana Lima was trying to get it working in Drosophila, but it wasn't working well. Boris's paper came out in 2/
early 2002, and ChR1 came out. I thought let's use ChR1 to stimulate neurons, and we did back-of-the-envelope calculations and figured the currents were too small. Boris started using the P2X2 system with photocaged ATP, which also worked in vitro. Then Susana used it in 3/
flies, and it worked beautifully. I remember the lab meeting where she showed a video of a decapitated fly, and she pipetted a drop of ATP onto the neck stump. The headless body took off and flew away. I was like WTF did I just see? Then she did it with light, and that worked 4/
too. Around that time ChR2 came out, and in the original paper it worked in mammalian cells in vitro. So I thought we have to get this in vivo ASAP. But the big question was, would this opsin work without retinoid molecules that are generated by a whole biochemical pathway in 5/
the retina? We didn't think they would, so I did a set of experiments showing you could retinoid-load flies without toxicity. Then @adamcchang and I made some transgenic ChR2 lines, and it was a bit of a struggle getting high enough expression, but it worked beautifully in 6/
@adamcchang larvae. In parallel, I made the E123S and E123T mutants, in an attempt to red-shift the spectrum. This was at the very beginning of 2005. We were trying to figure out how to package the in vivo ChR2 results because we didn't have a scientific result, and we didn't want it 7/
@adamcchang to be just a technical paper. The spectral mutants I made had smaller currents, and I wasn't sure they were useful. Then, in late 2005, the Boyden and Deisseroth paper came out, and we were completely stunned. I had considered doing that experiment, but I didn't think it would 8/
@adamcchang be a publishable result to show something in vitro, much less a Nature Neuroscience paper. We already had it working in vivo at that point. But that's how it goes. The main result of the B&D paper was that the ChR2 worked with very minimal retinoid supplementation. The main 9/
@adamcchang problems with ChR2 were 1) the presumption that it would require exogenous retinoids, and 2) the currents were too small. The problem with Pan's paper, aside from coming out too late, was that it was in the retina, where we knew the retinoids existed. It failed to address the 10/
@adamcchang biggest unsolved problem that we thought would prevent ChR2's use in the CNS. Turns out we were wrong, both about the retinoid requirements and the currents being too small. Gero's lab had also made a Cre-dependent ChR2 mouse line at the time the B&D paper came out, but the 11/
@adamcchang expression was too low. We didn't foresee AAVs, which enable a huge number of transgene copies per cell. Then, by 2006, after the B&D paper came out, Gero announced the lab was moving to Oxford, and I thought f*ck that, I'm going back to med school. So I wrapped things up and 12/
@adamcchang graduated, and @adamcchang and I never published the first in vivo demonstration of ChR2, and I never published the E123T mutant that the Deisseroth lab published three years later in Neuron as "ChETA". So that was pretty much the biggest mistake of my career. We didn't 13/
@adamcchang anticipate how big optogenetics would become. I'm over it now, but it took a while. Looking back, I don't think Boyden and Deisseroth got too much credit, but I still think Gero hasn't gotten enough. I know there was also another Drosophila group using it in vivo at about the 14/
@adamcchang same time as us. I guess the only points I have to make are 1) there were more people doing this sort of work back then than people are aware of now, and it's a little weird how credit gets assigned; and 2) Pan's work failed to address what we thought was the main barrier to 15/
@adamcchang using it in the CNS, and he wasn't the only one using it in vivo back then. So this article gives him a little too much credit IMO. 16/16
@adamcchang p.s. IMO, the "invention" of optogenetics was Boris Zemelman's 2002 Neuron paper. ChR2 was the ~5th generation of optogenetic technology.
@adamcchang p.s. IMO, the "invention" of optogenetics was Boris Zemelman's 2002 Neuron paper. ChR2 was the ~5th generation of optogenetic technology.
P.p.s. I should mention that Herlitze et al also published a paper that was similar to B&D’s, but better, a few months later, and there was also a C elegans group that showed ChR2 in vivo very early on as well, and others I’ve forgotten. Many different groups.
p.p.p.s. I don't mean to devalue the contribution of Boyden and Deisseroth's groups because they have done a huge amount to push the field forward. However, I think the bulk of those contributions came after the 2005 paper, in the refinement and dissemination of the technology.
