Our brain is a large collection of neurons that constantly send charged particles around to each other to communicate. How is it possible that together these brain cells are capable of the most complicated tasks? Karl Deisseroth, professor of bioengineering and psychiatry at Stanford University in the United States, has developed pioneering techniques to shed more and more light – literally – on this question. In 2020, he received the A.H. Heineken Prize for Medicine for his work.
It is a summer’s day in 2007. A mouse unsuspectingly scurries around in a plastic container in a laboratory at Stanford University. Via a fibre optic cable in its brain, the mouse is attached to a laser, but as long as this laser is off, it doesn’t seem to really care. When Karl Deisseroth and colleague Feng Zhang press the button on the laser, the mouse suddenly begins to walk in circles. Continuously anti-clockwise, as if he were a speed skater. Then the laser is switched off. The mouse scurries around comfortably in its plastic container again, as if nothing had happened.
This was a defining moment in Karl Deisseroth’s career. ‘When I saw that we could control an animal’s behaviour instantaneously, in a precise, fast, and safe way, I knew we really had something on our hands,’ he says. The mouse ran its laps thanks to optogenetics, a technique for using light to control groups of nerve cells. The mouse experiment eventually resulted in a technique that brain scientists use worldwide to study the activity of the nerve cells of living mammals in detail. All this to answer the one question: how do our experiences, feelings, and actions arise from the behaviour of individual nerve cells?
‘From a young age I was curious about the mind,’ says Deisseroth. ‘I was always intrigued by emotions: where they come from and how they can be generated by words or experiences. Initially, I wanted to be a writer, but at university I became more and more interested in biology. I learned how to crack incredibly complex problems by looking at the cellular level to see what is happening. This approach had already transformed immunology, cancer biology, and developmental biology. That made me curious to see if we could apply this to the brain. Perhaps by looking at the level of nerve cells, we could understand where feelings come from and what their physical form is in the brain.’ With this in mind, Deisseroth developed several pioneering techniques that allow us to use light to look at the brain in action at the cellular level, and even to influence it.
For the first technique, optogenetics, Deisseroth took his inspiration from the ocean – from algae to be precise. These unicellular organisms are naturally sensitive to light. Under the influence of light, channels open in the cell wall, allowing ions to flow into the cell. Some algae species change shape as a result and move toward the light. Deisseroth came up with the idea of implanting the section of DNA that is the code for creating these light-sensitive channels into animal nerve cells. When (positive) sodium ions flow into a nerve cell, they ‘turn on’ the neuron. Negative ions, such as chloride ions, turn off a nerve cell. If nerve cells create light-sensitive ion channels thanks to the algal DNA, you can turn them on or off with light, was the thought.
Deisseroth was not immediately convinced that this would work. No one had ever put algal DNA into mammalian nerve cells. Still, he managed quite quickly to get a few Petri dishes full of nerve cells to take up the algal DNA and create ion channels. He then shone light on half of the Petri dishes, not exposing the other half for control. ‘There were more activated neurons in the exposed dishes than in the unexposed ones,’ Deisseroth says. ‘The effect was small but significant. At that moment, I realised what was possible. The big question was: how do we get this into the brain of a living mammal?’
Deisseroth used viruses to get the genes into the nerve cells. The main difficulty here was to control which cells received the gene and which did not. ‘If all the cells get it, there’s no point: you want to be able to control a specific group with light,’ explains Deisseroth. After years of further development, he managed to place the light-sensitive genes in the right part of the motor cortex of a mouse, and to implant a fibre optic cable there as well. The right motor cortex controls movement to the left. When Deisseroth and colleague Zhang shone laser light on these nerve cells via the fibre optic cable, they were activated. As a result, the mouse had no choice but to run anti-clockwise.
Now, it is possible to turn on specific nerve cells with light of a certain wavelength and turn them off with a different wavelength. This can be done in a variety of different mammals, including humans. If you do this while an animal is performing a task or having an experience, you can research step by step which cells play a role in which processes. For example, you can turn off a different group of cells each time someone performs an exciting task and see what the effect is on heart rate and breathing, among other things. ‘We are now applying optogenetics to understand how complex states such as anxiety are created by the actions of cells,’ Deisseroth said.
If you know which nerve cells play a role in these processes, you can treat people with anxiety disorders more specifically, for example. ‘In psychiatry, we have many different types of medication, but they don’t act on specific cell types. As a result, there are always side effects. In principle, you can use treatment with brain stimulation techniques more and more precisely, but we can’t yet take full advantage of that precision, because we don’t yet have that a deep understanding of the brain. So, the understanding that emerges from optogenetics can improve these kinds of treatment modalities.’
Deisseroth explores how anxiety, an emotion that he was no stranger to early in his career, is made up of different parts of the brain. ‘I used to be very nervous about giving presentations at large scientific conferences. My heart was racing, I was very nauseous, and I suffered from sweating and rapid breathing. In addition to these physical manifestations, I just felt bad.’ Years later, using optogenetics, Deisseroth was able to investigate very precisely which areas are responsible for these different components, and how they interact. ‘This result was exactly what I had hoped for most,’ says Deisseroth. ‘We really understand how our complex inner states are physically constituted in the brain.’ Similarly, Deisseroth looks at other complex states and diseases, such as sleep, addiction, depression, hunger, thirst, Parkinson’s, and epilepsy.
Turning nerve cells on and off offers wonderful possibilities, but of course it also raises ethical questions. Think of the mouse, a mammal with free will that suddenly only runs anti-clockwise. ‘We can use optogenetics to study very precisely things like aggression, motivation or memory, but also influence them,’ says Deisseroth. ‘At the touch of a button, we may be able to change the behaviour and feelings of a free-thinking person in the future. We have to think carefully about what is desirable and what is not.’
The first direct application of optogenetics in medicine focuses on a less sensitive topic. ‘Vision scientist Botond Roska put one of our optogenetic tools into a human retina,’ Deisseroth says. ‘After many years of development, last year he managed to give a blind person back a bit of sight in this way. So, there are extraordinary applications. But I still think the greatest impact is in fundamental science, through which we learn to understand the human brain.’
The second pioneering technique for brain research was introduced by Deisseroth in 2013: hydrogel tissue chemistry (HTC). With this technique, Deisseroth and his colleagues can make brain tissue from deceased animals and humans transparent. They do this by removing the fatty substances from the brain and replacing them with a transparent gel. This allows them to study the brain in three-dimensional form, with all connections intact, where previously the brain always had to be sliced. They can also attach fluorescent labels to specific cell types, causing different types of nerve cells to light up in different colours. ‘We can dive into the individual nerve cells,’ says Deisseroth, ‘and see: what is this cell connected to? And more importantly: what proteins does this cell produce? Together this offers a lot of information about their function in the whole.’
With HTC, Deisseroth and colleagues can detect abnormalities in the case of specific brain disorders, such as autism, epilepsy or Alzheimer’s disease, and research the causes. In Alzheimer’s, for example, it is known that clumps of protein form in the brain. But exactly how these are formed, and in what way they cause problems in neurons, is not yet known. This also raises the question of exactly on what to focus a treatment. Using HTC, Deisseroth and colleagues hope to learn more about the precise mechanism at the level of individual cells.
Sum of parts
The brain consists of an unimaginable number of cells with a staggering number of connections between them. So, some research is still needed before we can understand the brain in all its complexity. But is it theoretically possible, using optogenetics and HTC, to one day fully understand, and perhaps even control, the brain? Deisseroth smiles. ‘This is one of my favourite topics of conversation. I often think about it: what if we could control every single cell in a human brain? Technically, it would be very difficult. The human brain is simply too large to use light to control each individual cell. But in other animals, such as zebrafish, we are getting close. Zebrafish are transparent and have a much smaller brain than we do. Yet their brains are amazingly similar to ours. And it may well be that we will soon come to the point of complete control.’
In addition to the practical challenges, philosophical questions arise. Can you fully describe all of our behaviour, every thought, and every feeling as a composite of its components, the cells? ‘This question quickly leads to a paradox,’ says Deisseroth. ‘Suppose you could do it: you have a person look at a beautiful deep red colour, which evokes an emotion. You measure exactly what each nerve cell is doing. Then you remove the red colour and mimic that exact brain activity with optogenetics. The question is whether that person would experience the same feeling. If you assume that this is the case, then there are crazy consequences.’
‘If you mimic brain activity in each nerve cell, the connections between nerve cells are no longer relevant. Normally, cells exert influence on each other through these connections. The visual input of the red colour in your eyes spreads out into a pattern of activity in lots of different nerve cells. But we now control all those nerve cells ourselves with exactly that same pattern of activity. So then you might as well remove the connections. You could even remove all the cells from the head and spread them all over the universe. But if you do that, is there still a human being who feels something? This thought experiment indicates that we do not yet understand at all what a subjective experience really is.’
Karl Deisseroth (Boston, 1971) studied biochemistry at Harvard University in the United States and trained as a psychiatrist at Stanford University, also in the US. He received his doctorate in neuroscience from that same university. Since 2012, he has been a professor of bioengineering, psychiatry, and behavioural sciences at Stanford University. In addition, he treats patients one day a week as a psychiatrist at Stanford University Medical Center. He is also a researcher at the Howard Hughes Medical Institute in Maryland. In addition to the A.H. Heineken Prize for Medicine, Deisseroth received the Breakthrough Prize in Life Sciences, the National Academy of Sciences Lounsbery Award, the Kyoto Prize in Advanced Technology, and the Lasker Award in Basic Medical Research for his work, among others.
Karl Deisseroth develops techniques for using light to study the brain. He researches how complex states such as fear, addiction, epilepsy or depression are composed of the behaviour of individual nerve cells. Deisseroth developed optogenetics, which allows light to turn groups of nerve cells on or off. He also introduced hydrogel tissue chemistry, of which the CLARITY and STARmap methods are well-known components. With these techniques, brain researchers can make brain tissue from deceased mammals transparent. This allows the brain researchers to map out all the connections between brain cells very precisely, allowing them to detect abnormalities in specific brain disorders, such as autism, epilepsy, and Alzheimer’s disease.