The coronavirus pandemic has been a disorienting kind of emergency. It is a generation-defining cataclysm, but for many of us the day-to-day reality has been lonely, even dull. It is a call to action, but the most useful thing most of us can do is stay at home. Covid-19 is a disease that attacks the lungs, but it has also worsened mental health while causing a drastic reduction in patients seeking care for depression, self-harm, eating disorders and anxiety. Whatever path the pandemic takes from here, says Karl Deisseroth, the pioneering American neuroscientist, psychiatrist, bioengineer and now author, “Coronavirus has affected us all and it has changed us all. There’s no doubt about that.”
Deisseroth, 49, is talking in the lush, squirrel-filled garden of his house in Palo Alto, northern California, where he has spent much of the pandemic looking after his four young children. But he has had much else on his mind. He has been finishing his book, Connections: A Story of Human Feeling, an investigation into the nature of human emotions. He has been meeting with psychiatric patients over Zoom as well as putting in night shifts as an emergency hospital psychiatrist. And he has fitted all of this around his day job, which is using tiny fibre-optic cables to fire lasers into the brains of mice that he has infected with cells from light-sensitive algae and then observing what happens, millisecond by millisecond, when he turns individual neurons on or off.
This is the basic methodology of optogenetics, a technique that Deisseroth pioneered in 2005 with his team at what is now the Deisseroth Lab at Stanford University. It has been widely recognised as one of the great scientific breakthroughs of the 21st century. In essence, he found a way to activate or deactivate individual brain cells with incredible precision – which in turn has brought about a revolution in neuroscience. Optogenetics is now its own field, its techniques and principles used in hundreds of laboratories across the world to advance understanding of the circuits of the brain and the consequences of conditions such as schizophrenia, autism and dementia. Mostly this is done by running experiments on animals – literally dialling up or down the circuits that control aggression, for example; however, the possibilities appear almost endless. Last month, the Swiss neurologist Botond Roska published a study that showed how he had used optogenetic principles on a human retina to partially restore the sight of a blind person.
Deisseroth has another great leap forward on his CV, too: see-through brains. In 2013, his team figured out a way to drain away the opaque fatty matter in a mouse brain and instead suspend all the brain cells in a scaffold of hydrogel, a transparent, jelly-like substance that allows for extraordinarily detailed brain imaging – a significant leap forward from the standard fMRI scan. He came up with the concept while changing a nappy.
Shaggy-haired and unhurried, Deisseroth more resembles a bassist in a west coast rock band than a leading scientist – and the way he tells it, all of his hi-tech questing grew out of his childhood ambition to be a poet. “That was my first love and vocation – I wanted to be a writer,” he says. He once crashed his bicycle as he was attempting to read a volume of Gerard Manley Hopkins while pedalling. “I was always intrigued by how words stir emotions, how they can lift us up and bring us down, how they serve as very potent symbols. If you look at it, one route to understanding how those symbols are transformed into feelings might be looking at how the brain works. So I got very interested in neuroscience.”
But he arrived at neuroscience via psychiatry. The two fields are usually seen as distinct – brain v mind – but the insights gained in consultations with patients have seeded many of Deisseroth’s experiments. “Anybody can read a diagnostic manual and see a list of symptoms, but what really matters to the patient is a different story,” he says. “It’s what allows me to think: what are the correspondences that we can do in the laboratory? How can inspiration flow both ways?”
Connections is Deisseroth coming “full circle”, he says, back to his “original and greatest love” – writing. It is a revelatory book. Peppered with quotes from Jorge Luis Borges and Toni Morrison, it leaps from wasp evolution to autism, the origins of mammalian fur to self-harm in borderline personality disorder patients, music to dementia, casually blowing apart any crude arts-science dichotomies as it does so. At times, it recalls the case histories of Oliver Sacks, at times the sweep of Yuval Noah Harari’s Sapiens – though Deisseroth says a closer model is The Periodic Table by the poet-chemist Primo Levi. He writes with an evident love of words – but also, with a lucid line of scientific inquiry. What are feelings? How do they work? Why do we have them? How do new feelings evolve? And why are they so often maladapted to our circumstances?
“Feelings are responses to information in the world – but as we all know, they follow their own trajectory,” Deisseroth says. “They coalesce and disappear with time. Sometimes we’re not even conscious of them.” While we are still far from even a sketchy understanding of the physical nature of feelings, optogenetics is beginning to give us a handle on how and why they arise. “We can not only record from the activity of tens of thousands of neurons while the processes that correspond to feelings are happening – we can directly turn up and turn down the representation of these feelings with great precision. We can make an animal more or less anxious or aggressive or maternal or hungry or thirsty. And all of that neurobiology maps on to this fundamental question of what a feeling is.”
There are many moments where Deisseroth’s case histories echo the strange times we are living through. One of the more perplexing stories concerns Alexander, a wealthy, well-adjusted American man with no history of mental illness whose retirement happened to fall around the time of 9/11. Alexander was nowhere near New York when the attack happened and knew no one involved. But two weeks afterwards, while on holiday in Greece, he began to display “classic mania”. He was extraordinarily joyful; he drastically cut down on his sleep (he felt no need); he had increased libido. When he returned home, he volunteered for the US Navy and started training for war, climbing trees, practising his aim, reading military strategy, insisting to his baffled wife and children that he was better than he had ever been.
For Deisseroth, the case was a sort of parable (Alexander turned out OK, by the way). “Why does this susceptibility to mania exist? Is there a value to it – if not to the person, then to the community, or to the species? Is that something that was more valuable at a different time in the long march of evolution?” He speculates that the manic state – “in some ways the highest expression of what a human can be” – was a circuit in the brain waiting to be tripped; and perhaps such states have helped humans cope with war, famine, climate emergency or pandemics in the past. What we think of as mental illness may be an evolutionary adaptation – or an attempt at an adaptation – that helped past communities survive. “Nothing in biology makes sense except in the light of evolution,” as the great geneticist Theodosius Dobzhansky wrote.
This leads Deisseroth to ponder the case of Joan of Arc in medieval France – a female teenage peasant who, like Alexander, appeared to be an inappropriate vessel for such mania, but nevertheless managed to make a national impact. “The altered state has been historically important. Even if it’s maladapted for the individual it can be transformative for the community.”
It’s hard not to think of the thousands of people triggered by conspiracies – imagined emergencies concerning 5G masts, vaccinations, the deep state. “This is the complexity of the world we live in contrasting with the distant and recent past. But the context is all wrong. We would all love to be called to action during coronavirus. But there’s not much that any individual can do.”
In another chapter, Deisseroth contrasts two patients with extreme “social and non-social brain states”. Aynur was an extraordinarily friendly, open and and talkative Uyghur woman who started to experience suicidal thoughts when she learned, while living in Europe, that her husband had been interred in a Chinese concentration camp (she had to infer this from phone conversations with her parents, who couldn’t risk telling her directly). As an extreme extrovert, the loss of her deep social bonds had destroyed her.
Meanwhile, Charles, who was on the autistic spectrum, shrank from human contact: he suffered panic attacks in social situations and could not meet anyone’s eye, associating eye contact with a “negative-valence subjective internal state” (ie feeling bad). Deisseroth was able to treat his anxiety and panic attacks, but the eye contact issue was unchanged. However, through talking to Charles, he was able to get to the “real essence” of the problem. It wasn’t that eye contact made him anxious. It was that too much social information was conveyed through eye contact – and Charles found this overwhelming.
“Hearing him state this was a transformative moment for me. We were able to bring those ideas to the laboratory and study and even quantify in bits per second how certain changes that happen in autism can affect information handling in the mammalian brain. It kind of unified all the threads very powerfully in a way that a paper or a study or a questionnaire would never have been able to do.”
It’s no surprise that the pandemic has been very challenging for those of us who, like Aynur, have deep social bonds with friends, family, even colleagues. Computer technology, which reduces our multilayered, multisensory human interactions sometimes to a single bit of information – to like or not to like? – is a poor shadow of our usual social contact. “One reason Zoom meetings can be so exhausting is we have to work much harder to create our model of the other person – and that’s before we get on to multiple people,” Deisseroth says. “Social interaction is one of the hardest things to do in biology. Think of all the information coming in, not just the language and body language but the model you form of the other person’s wants and needs, which you then have to adapt as the conversation progresses – it’s a huge information processing task. Zoom makes that much harder.”
However, for people like Charles, communicating remotely can have its benefits. Deisseroth believes it is wrong to see autism as a limitation of the mind. “People with autism do have challenges forming a model of what’s going on in the minds of others. But it’s not a fundamental limitation. They have certain structures and arrangements in their brain that can work it out – but it is hard for them to keep up with the information rate of a social interaction. In a different time scale, there is so much they can do to thrive.” Digital communication that does not take place in real time, for example email or chat functions, can be of huge benefit – and some people with autism have indeed found the slower pace of lockdown beneficial.
Meanwhile, the reach of mental health treatment is now far greater thanks to the adoption of digital technologies. “Unquestionably we’re going to suffer a tsunami of mental health issues as a result of the pandemic, but in the long run I hope that accessibility of mental health care will be greatly enhanced by what we’ve gone through. If there is a silver lining, that might be it.”
Deisseroth believes that another lesson we should learn is not to focus all of our scientific efforts on narrowly defined goals – such as treating a particular disease. “Our instinct is always to keep our funding streams and our support efforts directly aligned with those needs of the moment. The danger of that is, first of all, our understanding is so incomplete that that level of targeted effort usually won’t work. And we won’t make the enormous, transformative change that upends everything.” Connections is, among other things, an argument in favour of the cross-pollination of ideas and of scientific freedom – following science for the sake of science. The great leap forward of optogenetics rested on a 19th-century botanist’s notes on the light-sensitive algae he had found in a saline lake in Kenya – “and he was studying them because they were beautiful and for no other reason”, Deisseroth says. “One could never have predicted that this would one day give us the ability to turn on and off cells in the brain and come to a causal understanding of which connections and projections set up our motivational structures. And stories like that turn up again and again in science.”
Situated as he is in the heart of Silicon Valley, I wonder if it’s a source of frustration to him that so many of the finest minds of his generation have decided to train their intellectual capacity on selling online advertising for the tech giants – as opposed to bettering the health of mankind.
He gives a wry smile. “It is a little … disconcerting. You’ll see brilliant people from Stanford going into very high-powered jobs all focused on getting some small fraction more clicks on some little piece of advertising. I’ve spoken to some of them. They don’t necessarily feel that good about it.”
He is particularly concerned about the enormous investments that Facebook and Google are now making in brain science. “That is not altruistic. They are not doing this for us. They are doing it for them. A lot of people are concerned by that. These companies have a veneer of public service – and the tools that a company like Google has made available have had a positive impact. But even Google Maps, as we well know, still serves their interests. We have to understand that.”
For all the pressures of the pandemic, he has relished the time he has had to spend with his children, who are aged five to 12, “exercising, solving math puzzles, writing poetry, trying to come up with cures for diseases …” He also has a son from an earlier relationship, who is now in medical school. It was only while writing the book that he realised how much the experience of being a father had infused his work. He made the breakthroughs in optogenetics while struggling with single fatherhood; he describes an early clinical encounter with a girl suffering from brain cancer as the inspiration for his work; and it so happens that his wife, Michelle Monje, is now a specialist in brain cancer in children.
“All of these experiences are very charged with emotion, because of the things I was experiencing at the time. But I didn’t realise how tightly they were linked to the challenges of single fatherhood and the emotional storms that come with that until I had written the book. I came to see how this was a unifying theme in my life: the child that might be lost, the child that might be found.”
Indeed, optogenetics has helped bring about a deeper understanding of parenthood itself. “It really does change you. That structure is there just waiting for the switch to flip. It’s not a new connection that’s formed, it’s there, waiting to be activated.” When new parents talk of being “rewired” or “reprogrammed” after birth, they are being more accurate than they realise. He points to the research of Catherine Dulac at Harvard, who has mapped out parenting circuits in mice. “There is one connection that governs the drive to find the young if they’re separated and another that governs the drive to protect and care for the young. The overall state of parenting is assembled from all of these various parts. That is just beautiful. That’s inspiring.”
Throughout the pandemic, he has been attempting to come up with a unified theory of the self by studying dissociative states. What truly excites him are the “big principles” of the brain. “Anything can have parts. The real magic is how the properties of the system arise from the parts. We won’t get to a truly deep understanding potentially for decades. But we’ve at least set the stage. And we have to push it as far as we can.”