CHLAMYDOMONAS REINHARDTII is not an obvious subject for high-profile research. It is a pear-shaped, single-celled alga which swims around ponds propelled by two flagella. As a photosynthetic organism, which subsists by converting visible light into chemical energy, it often uses those thin appendages to swim towards sources of light. When doing so it is guided by a reddish patch made of protein known as an eyespot. And, in an example of the potential value of even the most off-the-wall scientific research, studying exactly how this eyespot works has led to both a new scientific field, called optogenetics, and this year’s Nobel prize for physiology or medicine.
Optogenetics permits neuroscientists to use light to instantaneously activate individual brain cells. It has thus transformed neuroscience by making it possible to work out exactly what particular cells are doing. That enables researchers to investigate both basic neurobiology and the neural basis of illness.
The story begins in the 1990s with Peter Hegemann, then of the Max Planck Institute for Biochemistry in Martinsried, Germany. Dr Hegemann was studying Chlamydomonas’s electrical response to light. He found that it was 20 times faster than the equivalent response of a human eye. In a human retina, one protein molecule detects light and then, via a chain of molecular interactions, triggers another, known as an ion channel, to create an electrical signal. Dr Hegemann hypothesised that in his alga that convoluted process was being compressed.
Testing his guess with the tools then available proved hard, until the blossoming science of genomics came to his rescue. A team of Japanese researchers had produced a map of the DNA of Chlamydomonas, showing that it included two genes resembling those for light-sensitive proteins in some other organisms. This insight was confirmed when Dr Hegemann enlisted the assistance of a colleague, Georg Nagel, then at the Max Planck biophysics campus in Frankfurt. Dr Nagel, who shared the prize, inserted the DNA of the two newly identified genes into some frogs’ eggs, which then turned out the desired proteins in quantities large enough to test. Just as Dr Hegemann had predicted, they turned out to be light-stimulated ion channels.
Realising what they had, Dr Nagel and Dr Hegemann then tried inserting one of the genes, for a protein now known as channelrhodopsin-2, into kidney cells harvested from hamsters and from human embryos. That worked, too. They had, in other words, discovered a way of making mammal cells light-sensitive.
This bit of story was then completed by the third of this year’s laureates, Karl Deisseroth, then at Stanford University. It was he who conceived of putting channelrhodopsin-2 into cells whose raison d’être is the transmission of electrical signals: neurons. When the idea was tested, cultured rat neurons not only responded when exposed to light, but could also pass signals on to their neighbours.
The paper announcing this finding was published in 2005, but other researchers were also exploring similar ideas. Three years earlier, Gero Miesenböck, then at the Memorial Sloan-Kettering Cancer Centre in New York, had done similar work using a light-sensitive protein from a fruit fly. Dr Miesenböck, as an audience member at Monday’s announcement observed, might have serious reason to be miffed.
Regardless of details of priority, though, the subject has since exploded. Dr Deisseroth’s lab led the way, first by repeating what had been done in cultured rat cells in living mouse brains, and then by inventing the trick of using extremely thin optical fibres to illuminate, and thus stimulate, groups of neurons. In combination, these tricks let the researchers control the movements of a mouse’s whiskers.
Optogenetics has since been the subject of thousands of papers. It is being used in laboratory animals to investigate depression, schizophrenia, blindness, deafness, dementia, addiction and anxiety. There is even an attempt to use it to restore vision in people with a form of blindness called retinitis pigmentosa. Great oaks from little acorns grow. Or, in this case, little algae.
