Illustrations by Murat Yükselir
It’s a curious fact that many of the greatest innovations in medical science are simply rediscoveries of phenomena or substances first exploited eons ago by other species, often those occupying some of the lowliest branches on the tree of life.
So it was that Peter Hegemann, a professor and head of biophysics at the Humboldt University of Berlin, became fascinated by the ability of pond algae to sense and respond to sunlight to regulate photosynthesis.
The algae “go up if it’s too dark and go down if it’s too bright,” explained Dr. Hegemann, describing the yellow coloured “eye spots” that the algae use to facilitate this trick. “These are probably the most abundant eyes in nature.”
Starting in the late 1980s, Dr. Hegemann’s curiosity about the algae would eventually lead to the discovery of channelrhodopsins, special proteins that the algae employ to turn light into electrical signals. Then, in 2005, Karl Deisseroth, a newly hired assistant professor at Stanford University, and graduate student Ed Boyden, now a professor at the Massachusetts Institute of Technology, published a paper showing how a gene for making a channelrhodopsin could be inserted into the DNA of a neuron, effectively creating a brain cell that could be turned on or off with a pulse of light.
The resulting technology, dubbed optogenetics, has since been used in animals to provide scientists with a stunningly effective and direct way to understand how the brain is wired, opening a new window onto the mechanics of sensation, memory, emotion and a panoply of other complex neural operations that define our experience of the world. It has now earned Dr. Hegemann, Dr. Deisseroth and Dr. Boyden each a Canada Gairdner International Award for the discovery, the Gairdner Foundation announced on Tuesday.
Two other international winners, Davor Solter, an emeritus researcher at the Max Planck Institute of Immunobiology and Epigenetics in Germany, and Azim Surani of Cambridge University, U.K., have been recognized for an earlier and separate finding that first showed how some of the DNA we inherit from our parents comes with an extra layer of information that is key to understanding a variety of developmental diseases.
The $100,000 Gairdner International Award is considered the most prestigious Canadian science prize that can be won by non-Canadian researchers. About a quarter of those who have received the prize in previous years have gone on to win a Nobel.
A light touch
The enthusiasm with which researchers have taken up optogenetics and now use light to control and study brain cells has already turned Dr. Deisseroth and Dr. Boyden into neuroscience superstars and co-winners of a 2015 Breakthrough Prize for their efforts.
Applications of the technique are frequent headline grabbers, such as last year when researchers at Yale University showed that they could use optogenetics to turn on aggression in mice or, in 2016, when Philippe Séguéla of McGill University and colleagues were able to switch off pain-signalling neurons specific to one localized region of a mouse’s body.
The method has “drastically changed our way to understand what brain circuits are engaged in what behaviour,” Dr. Séguéla said. He added that the new science the Gairdner winners spawned is moving so rapidly now that new applications from just a few years ago, such as the McGill team’s use of optogentics to study circuits related to touch and temperature, “are almost a mundane now.”
Dr. Deisseroth, who is also a practising psychiatrist, was motivated by a desire to understand mental processes at the neuronal level to make the brain less of a black box. What he needed was a precision tool for activating individual neurons. With Dr. Boyden, who had a background in electrical engineering, he decided that light offered an attractive trigger for such a tool. It could be focused and applied without having to touch a target cell, and it could be shut on or off easily. But could brain cells be made to respond to light by coaxing them to produce channelrhodopsins?
“Many things could have gone wrong,” Dr. Boyden said. “The molecules could have been toxic. They could have been too weak or too slow. They could have caused side effects.”
Instead, the very first version of the experiment work surprisingly well. Late one night in August of 2004, Dr. Boyden recorded their genetically modified mouse neurons firing in response to light shining on them through a microscope. It was just the first of many steps toward a full toolkit for the optical manipulation of neurons.
“It took about five years. … It was quite stressful. But our focus was on the end goal,” said Dr. Deisseroth, describing some of the challenges and the skepticism he and his team faced while optogenetics was developed into a practical technology for brain science now used in thousands of labs around the world.
For Dr. Hegemann, whose contributions were made well upstream of the application of optogenetics, the Gairdner Award signifies a recognition of the importance of basic science for disparate fields of research that end up connecting in unexpected ways that can change lives.
“This is not predictable,” he said. “But it’s how breakthroughs are produced.”
The defining breakthrough of Davor Solter’s career began with a question. Can the embryo of a mammal be coaxed to develop if both sets of its chromosomes come only from the female or male parent?
Asexual reproduction — known as parthenogenesis — occurs naturally in many life forms, including a few species of fish, amphibians and reptiles. In the early 1980s, claims by Austrian researcher Karl Illmensee that he had created live mice in the lab from only one parent’s DNA spurred a scientific controversy that ended when other scientists, including Dr. Solter, who was then at the Wistar Institute in Philadelphia, and Dr. Surani, working independently at Cambridge, failed to reproduce the results.
The outcome of their work was more interesting than the original controversy, because it contradicted the basic biological premise that we have no way of discriminating between the genes we inherit from our mothers and fathers (apart from the obvious case of the Y-chromosome, which can only be passed from the father).
“The broad conclusions that we came to is that the parental chromosomes have a memory of their parental origin,” Dr. Surani said. “That’s why I describe this as ‘genomic imprinting.’”
Eventually, the cause of genomic imprinting was revealed to be a set of chemical tags — which geneticists call “marks” — that are stuck to a few key genes, some from the mother and some from the father. The tags mean that in those cases only one copy of a gene is functional. This carries a built in health risk, because if that gene is faulty, the other copy from the other parent cannot step in to prevent disease. A number of disorders, including Beckwith-Wiedemann syndrome, have since been linked to the discovery.
Both Dr. Solter and Dr. Surani published their findings in 1984. The two are credited with opening the door to epigenetics, the field that reveals we are not just the products of our DNA, but also of how our DNA is influenced and regulated by a myriad of other factors.
In the case of the parentally specific genes, scientists are still debating why evolution produced such a set up in mammals. Because some of the genes in question have a bearing on placental development, one theory suggests that paternal and maternal genes are at war in the developing embryo, with paternal genes pushing all-out for that particular embryo’s success while the maternal genes are more parsimonious in favour of self-preservation and prospects for future embryos.
Whatever the explanation, the discovery provided a hard-won glimpse at the complex mechanisms underlying mammalian reproduction, Dr. Solter said.
“It took me almost forever to believe that what we were getting is true,” he added.