Prestigious award for the pioneers of optogenetics
Dieter Oesterhelt, Emeritus Director at the Max Planck Institute of Biochemistry, is being honoured with the Lasker Basic Medical Research Award 2021 together with Peter Hegemann and Karl Deisseroth
Dieter Oesterhelt from the Max Planck Institute of Biochemistry, Peter Hegemann from Humboldt University and the U.S. American Karl Deisseroth from Stanford University will receive the Albert Lasker Basic Medical Research Award 2021 for the discovery of light-sensitive proteins in the membrane of unicellular organisms and their use in the development of optogenetics. The work of Oesterhelt and his colleagues also paved the way to new medical applications. The Lasker Awards are considered among the most important biomedical research prizes in the USA and are each endowed with 250,000 US dollars. Ninety-five Lasker Laureates have also received the Nobel Prize, including the three Max Planck researchers Georg Köhler (Nobelprize in Medicine 1984), Ernst Ruska (Nobelprize in Physics 1986) and Christiane Nüsslein-Volhard (Nobelprize in Medicine 1995).
Curiosity, a thirst for insight and, last but not least, a chance observation – these are sometimes the decisive elements for a successful scientific discovery. In the early 1970s, Dieter Oesterhelt detected retinal in the cell membrane of the archaebacterium Halobacterium salinarum. As a component of the protein rhodopsin, retinal is involved in the visual process in the retina of most vertebrates, including humans. Now, surprisingly, it was discovered in a halobacterium. But as is so often the case in research, Oesterhelt’s pioneering discovery was met with incredulity. In a conversation with the historian of science Matthias Grote, Dieter Oesterhelt recalls: "In fact, I met with disinterest and even complete disbelief from my colleagues. [...] Even Nobel Prize winner Feodor Lynen, my doctoral supervisor as well as my boss at the time at the Biochemistry Department of the University of Munich, was not particularly enthusiastic about this new topic. [...] When I once outlined my theory of the biological function of the new molecule on the blackboard for him, he came up with the beautiful phrase: 'Mr. Oesterhelt, I don't believe it, but I certainly hope that you’re right."
The publication submitted to Nature was returned with the remark that while the experiments were sound, the analogy with rhodopsin was far-fetched. "At the time, it was simply unacceptable to find retinal some-where other than in an eye," the scientist says today. And so the first publication on bacteriorhodopsin, as the authors had christened their molecule, appeared in 1971 in the journal Nature New Biology.
Light-driven proton pump
The newly discovered protein was a light-driven proton pump. In a sense, the retinal embodies the heart of the molecule, which forms a fine channel in the membrane of the archaebacterium. The retinal is suspended in the middle of this "pore" and works there, as it were, as a "piston": under the influence of light, it transports protons, i.e. positively charged hydrogen ions, through the bacteriorhodopsin channel out of the interior of the cell to the outside. This creates a gradient, a proton concentration gradient between inside and outside, and an electrical potential is built up across the membrane. The process is similar to charging a battery.
This system, known as the purple membrane because of its colouration, is – next to the chlorophyll system of green plants – the second light-energy-conversion principle of living Nature. "In other words, evolution invented the fundamental process of photosynthesis not once, but twice. Once with the eubacteria, via which this technique then came to algae and green plants – and once with the archaebacteria, to whom the older patent for this invention presumably also belongs", says Dieter Oesterhelt.
New tool for research
Forty years after Oesterhelt's groundbreaking work, the bacteriorhodopsin he discovered and the channelrhodopsin discovered in the green alga Chlamydomonas by his former research group leader Peter Hegemann (now a professor at Humboldt University in Berlin) are gaining ground as new tools in neurobiology. Important contributions in this field have also been made by the third honoree, Karl Deisseroth at Stanford. This made it possible to study neurons and their circuits non-invasively and with unprecedented resolution. Optogenetics, as the new technology is called, enables researchers to introduce the building instructions for light-switched proteins into cells by means of gene transfer. This makes it possible, for example, to control the activity of brain cells by switching on or off the ion flows conducted through the channels with light.
Dieter Oesterhelt says about his student Peter Hegemann, who studied the chloride pump halorhodopsin as his doctoral student: "[He] was incredibly tenacious and made a great number of discoveries. For this work he received the Otto Hahn Medal of the Max Planck Society. [...] In the USA with Ken Foster, he took up the search for comparable proteins in algae and found that they function more like molecular channels than like a pump, but that they can also be specifically controlled with light. He then tirelessly pursued this topic with his own research team for five years at the Max Planck Society and subsequently at the University of Regensburg in the 1990s.”
Benefits for medicine
The work of Dieter Oesterhelt, Peter Hegemann and Karl Deisseroth has helped to further develop technologies to study brain function, contributing to a better understanding of neurodegenerative diseases and mental illness. And for the first time, they are also opening up possibilities for perhaps curing a previously incurable disease: Retinitis pigmentosa. It starts with deficits in seeing in the dark because the rods die off; later, the cones lose their sensitivity to light, which eventually leads to blindness. Botond Roska, who works at the Friedrich Miescher Laboratory in Basel and was awarded the European Körber Prize in 2020, has incorporated light-sensitive protein channels from algae and bacteria into still intact cells of the retina of patients so that they can take over the task of the light receptor cells. The clinical data, published in Nature Medicine in May 2021, show for the first time that optogenetic methods can restore partial vision to a blind person.
"This illustrates what staying power scientists need to push a new development out of a self-imposed goal of basic research", says Oesterhelt. "I cannot emphasize enough how important it is always to be open to chance, and to keep pursuing even that which at first may appear to be insignificant." If the young biochemist had not followed his curiosity 50 years ago, despite the skepticism which met his work – who knows if the groundbreaking technology of optogenetics would even exist today?
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