The “tangle of spaghetti”, as neuroscientist Karl Deisseroth describes the wiring of the brain, has posed a singular challenge to researchers: how do you navigate an opaque mesh of 80 billion neurons to decipher brain activity — emotions, memory and learning — or identify diseased circuitry that manifests as autism or schizophrenia?
Now, two path-breaking techniques devised by Prof. Deisseroth and his colleagues at Stanford University are changing the way we see, understand and control the brain. The first technique “illuminates” the brain, enabling researchers to manipulate electrical activity. In a process called “optogenetics”, specific targetted cells are infused with a gene that directs the production of a light-sensitive protein (derived from algae or other microbes) that can then turn brain cells on or off in response to a focussed light signal.
The second is a “transparent brain” engineered through a method called “CLARITY”. This process makes brains transparent, by building a hydrogel inside the brain, removing lipids that make the brain opaque. This allows scientists to study the wiring of a three-dimensional brain in its entirety, without having to laboriously dissect and reassemble tissues as has been the practice.
Prof. Deisseroth, who is D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioural Sciences at Stanford University, was recently awarded the prestigious Life Sciences Breakthrough Prize for 2016. He spoke to Divya Gandhi in Bengaluru, where he begins a three-city lecture tour as part of the Sixth Annual Cell Press-TNQ India Distinguished Lectureship Series. Excerpts:
Laboratories around the world have begun using optogenetics to study and manipulate the brain. Are there specific disorders that the technique has proven particularly useful in shedding light on?
One of the most exciting things for me about this whole field is that I get to see corresponding principles with my own clinical practice. In the clinic, I see patients with treatment-resistant depression and also those with autism spectrum disorders. And these are really challenging and complicated clinically but they have certain symptoms — symptoms you can study in animals. And another big example is anxiety. Anxiety is a prominent feature of depression and is also a major problem in autism spectrum disorders. We can study anxiety in a very reliable way in mice. And that’s been probably one of the biggest success stories. Optogenetics is sorting out how anxiety works in the brain, what are the pathways and cells that cause it or control it, and how it is all put together. Anxiety is complicated. We know there are lots of parts to anxiety. There is the heart rate change and the breathing rate change and there is the avoidance aspects. Optogenetics has helped sort out how all those parts are assembled.
Not least because of the lack of academic opportunity, doctors in India tend not to go in for a PhD, something that critically undermines cutting-edge research. As a clinical psychiatrist and a neuroscientist doing front-end research, what would you recommend to encourage more physician-researchers in India?
One thing that makes it work well in the U.S. is the existence of a very well-defined MD-PhD training programme that is supported by the government. It really helps to attract some of the best people to the programme because you get support through medical school and through graduate school from the federal government. The other thing is, at a later career stage, making sure there are employment opportunities, where one only practices in a clinic one or two days in a week, because to really make competitive advances in research you need to spend most of your time doing research.
How did you go about creating a see-through brain? And have there been any significant, or unexpected, discoveries through CLARITY?
Around 2009, optogenetics was working really well in controlling neurons with light. But we noticed that we couldn’t quite make the final intellectual step in understanding how the wiring of the brain causes behaviour. With optogenetics, it is like roughly knowing where the parts are in a computer but not knowing the detailed circuit diagram.
The central nervous system is the hardest thing to make transparent and the reason is that the nervous system uses electricity to communicate and it has to create insulated wires to send all that electricity around, and the way the brain makes insulation is through lipids or fats and those scatter photons. So it is almost impossible to make a living transparent brain. You can slice it up into several thin sections and try to reconstruct, which is the standard way of doing it. But that’s difficult and takes a long time. So we thought: how could we keep the brain intact and make it transparent? So we had to remove the things that are making it opaque — the lipids and fat. But that would normally be destructive and cause the whole thing to dissolve, so we had to build a new kind of support for the brain while we removed the fat. We developed a chemical engineering trick by basically building a gel within the brain that gives it the support it needs when we remove the lipids and see through the brain.
The new insights have been pretty exciting actually. CLARITY has been developing faster than optogenetics. But even in just the last year, labs around the world are using CLARITY to make new discoveries. We have been surprised to see certain patterns of wiring and connections across the brain that we didn’t know were there. It has also been used in human brain tissue — Alzheimer’s brains for instance — and seen some interesting patterns.
In India, a country of over a billion people, we have, according to guesstimates, just between 3,000 to 8,000 psychiatrists. Is that a worrisome statistic, and is there an ideal ratio?
The best thing under these circumstances would be figuring out how to train general practitioners to at least recognise the disorders and know enough about the medications to provide. Of course, psychiatrists are best because they have spent the most time thinking and learning the about the ins and outs — but this may be the best short-term solution.
In 2010 you wrote about the stigma that surrounds psychiatric disease, “just as a cancer diagnosis once carried more stigma than it does now.” Would you say there is a growing awareness about mental illness now and, by extension, less prejudice around it?
I think that is happening. There is detectably, in the U.S., a more open discussion and less stigmatisation of psychiatric disease but it is not yet where it needs to be. A couple of things seem to help with reducing prejudice and stigma. If people really understand how something works, then they tend not to assign prejudicial or superstitious explanations. The general public in the U.S. is getting a deeper knowledge and understanding of psychiatry as biological. There has also have been individual people writing books and speaking out and sharing their experience with psychosis, depression or drug abuse. People aren’t hiding, they are coming out, saying “this is me”.
divya.gandhi@thehindu.co.in
