Technology developed for high-energy physics has led to the discovery of a retinal cell that eluded biologists for 40 years.
The 512 electrode array, inspired by silicon microstrip detector technology in ATLAS, records the electrical activity of retinal neurones.
ATLAS expertise have crossed over to biology enabling the discovery of a retinal cell type that may help humans see motion. The research, carried out by ATLAS collaborators at the University of California, Santa Cruz, and by neurobiologists at the Salk Institute in La Jolla, California, appeared in the 10 October issue of the Journal of Neuroscience and may help open biologists’ eyes to the uses of techniques developed in high-energy physics.
At least 22 different types of primate retinal output cell are known from anatomical studies, but the functions of only a handful of these have been determined. The cells discovered have been called upsilon retinal ganglion cells and the team speculates that they are used to see moving objects and patterns. High-density electrode arrays and associated electronics, inspired by the silicon microstrip detector technology used in ATLAS to track the charged particles coming from collisions, were used to measure their distinct responses to visual images. The upsilons’ large light-sensitive areas and very sharp, rapid, and non-linear responses to changing patterns of light suggested that they were movement detectors.
The retina is the coating at the back of the eye that transforms arriving photons of light into electrical signals that it sends to the brain. The upsilon cells, part of the last layer of cells that send signals along the optic nerve, have been eluding biologists for 40 years. “These upsilon cells make up maybe a few percent of the output cells of the primate retina, and the chances of finding them are small as they’re so rare,” explains Alan Litke, senior author of the paper.
The experiment involved focusing a movie onto the retina and comparing this visual input with the electrical output from the retinal cells. Finding the rare cells required a huge number of electrodes within a small space, and so involved a miniaturisation process that was familiar to the CERN collaborators.
A critical part in the miniaturisation was amplifying, filtering, and reading out these electrode signals at high density. A set of multichannel integrated circuits, designed by ATLAS collaborator Wladyslaw Dabrowski and his team from the AGH University of Science and Technology in Krakow, Poland, allows 512 tightly packed electrodes to probe the retina, as opposed to the 61 previously, or just one of early experiments. The increase in electrodes meant a greater number of neurons could be probed at once, allowing researchers to monitor hundreds of cells at once, rather than just one or a few. “Finding one of these upsilons would be rare, and if you find a cell with unusual properties, you think maybe there’s something wrong, maybe it’s sick,” explains Alan. “What you really want to see is a mosaic of cells with similar properties and then you start to believe.”
ATLAS expertise was also employed in designing the software, which had to be designed from scratch as the amount of data collected was a huge step up for traditional neurobiology, though small compared to LHC standards. Dumitru Petrusca, one of the main software developers of the ATLANTIS event display program for ATLAS, undertook this task and was the first author of the upsilon paper.
Thanks to this software and technology, the neurobiologists, in collaboration with the physicists, are able to look at the bigger picture to gain a more complete idea of the vision process. “Traditionally, neurobiologists looked at just one neuron at a time. But to understand how a neural system, such as the retina or the brain, really works, we need to see the patterns of electrical activity generated by many neurons. Just like in ATLAS it would be near impossible to get at the underlying physics by looking at just one particle per event. You want to see the whole event because then you can say, for instance, there are two jets of particles with this total mass, and that’s the decay of the Higgs.”
For Alan, the processing and encoding of information is just one part of the puzzle of how the retina works. Another is how it gets wired up: “It’s a three-dimensional wiring problem. The upsilon cell connects to all these other cells and layers and we want to find out how the cells know where to go, how they connect to one another and make the right connection. It would be like the thousands of cables in ATLAS growing out of the pit and finding their way to the right control room, rack of electronics, crate and finally module, all on their own.”
Related projects include retinal prosthesis: using electrode array technology to electrically stimulate retinal output cells, using input from a video camera, to bypass the degraded photoreceptors in patients with macular degeneration. Small arrays that give some basic vision are already being trialled in six blind patients by Mark Humayun and his team at the University of Southern California.
This result may open up further opportunities for transferring expertise and techniques from high-energy physics to biology. “It’s not just the upsilon, it’s the combination of the technique and the discovery,” says Alan. “Biologists are rarely aware of the technologies developed for high energy physics, so one way to bring this to the attention of the neurobiological community is to have an interesting neurobiological result. Now we’ll see where it takes us.”
Ideas that spring from the meeting of minds
Progress is not often a scientific activity alone, but is helped on its way by chance meetings and cafeteria conversations. Whilst working at SLAC and watching his children learn to walk, talk and develop, Alan Litke wondered how silicon microstrip detector technology could be applied to understanding the fascinating depths of the brain, but without a scientist’s “six degrees of Kevin Bacon” the research wouldn’t have happened. “I had some pretty crazy ideas, but in the end one of the post-docs in my group had a neighbour who was a neurobiologist at Stanford and who was working in the lab of someone who was one of the world experts on the retina. So I started to help in any way I could.” And he hasn’t looked back. In the past some of the best science has comes from collaborations with those outside a tradition and this one has already made great steps in unravelling the mysteries of the retina.