Recent Interview

‘Your expectations influence how you perceive the world’

Our brain determines the way in which we perceive the world. From the immense flow of information reaching our senses, it selects exactly those signals that are relevant. It uses our past experiences, memories, and goals. Cognitive scientist Kia Nobre unravels how our brain manages this. She received the C.L. de Carvalho-Heineken Prize for Cognitive Sciences for her research.

We may not always realise it, but the way in which we perceive the outside world is different for everyone. Our brain is constantly busy making predictions, selecting relevant sensory signals, and linking signals to information from our memory. ‘What we pick up from the external sensory stream is strongly shaped by our previous experiences, our memories, and also by our goals and motivations at a given time,’ says Kia Nobre, professor of translational cognitive science at Oxford University.

The reason: There are too many possibilities and distractions in the world to guide effective behaviour. Our brain therefore focuses our attention on the signals that are most relevant to us. There is also a huge amount of information available from within, in the form of memories. ‘Selecting and synthesising the relevant signals amidst all these distractions is essential for building coherent sensory perception, understanding and producing language, and performing everyday tasks like cooking or driving,’ says Nobre. The big question is how our brain manages this. Nobre is trying to unravel this step by step with experiments in which study participants perform specific tasks while their brain activity is measured.

Anticipation is an important part of her research. Instead of letting all the information flow in and checking for relevance, your brain proactively focuses your attention on something. Early research considered how the brain focusses on specific places in the world around you – so-called spatial attention. In the 1990s, Nobre and colleagues described a network of brain regions involved in controlling spatial attention in the human brain. In addition to spatial attention, your brain can also focus your attention selectively on specific moments in time. Nobre and her colleagues were the first to study this capacity in the human brain. ‘The most important finding is a fairly simple observation,’ says Nobre. ‘The brain can anticipate and prioritise a sensory stimulus based on its timing.’

Nobre studies this so-called temporal attention with experiments in which she gives people simple tasks while studying their brain activity. The study participants are shown various pictures and are asked questions about one of the pictures afterwards. ‘We sometimes tell people in advance when the picture we are going to ask them about will appear. Sometimes we don’t tell them, and sometimes we give them the wrong information,’ says Nobre. If people know in advance which picture they should focus on, they can answer the questions better afterwards. This is partly because your brain prepares itself when you expect a specific event, so you absorb the information better. These preparatory signals can be seen when you measure people’s brain activity. ‘If you know the timing of the event, then preparation is optimal at that precise moment.’

Attention is not only focused on the outside world. Most attention researchers investigate how the brain prepares for information coming in through the senses. However, Nobre showed that in order to perform tasks, it is also very important to focus your attention on specific items in your working memory. The working memory contains information that we actively keep available in our brains. Nobre was the first to develop experimental studies to examine this, and she has identified the network of brain areas involved, as well as relevant brain signals. Here, too, temporal attention plays a role – your brain can ensure that information from your memory is available at exactly the right moment to guide your behaviour. Nobre’s research has transformed working memory from a fixed and rigid repository into a flexible and dynamic system for bridging sensory experience, goals, and actions.

Revolutionary technologies
Nobre uses various technologies to visualise the brain and measure brain activity. She was among the first to use several revolutionary technologies. For example, early in her career she measured brain activity from electrodes placed within the brain. This was possible because she worked with epilepsy patients who had been implanted with these electrodes because medication was unsuccessful. ‘We could measure human brain activity directly,’ says Nobre. ‘That in itself was extraordinary. But we also made an amazing discovery: when we showed people words, brain areas reacted that were way outside the known language network. It was completely different from anything in the textbooks. But it was so tangible and real, you could see the response in the brain immediately. It was an incredible thrill to discover something completely unexpected.’ Nobre’s discoveries in this area were major breakthroughs in understanding the language network in the human brain.

A full understanding of the human brain requires measuring brain activity systematically, in healthy people performing different types of tasks. For this, you want to measure brain activity in a harmless way from outside the brain. Nobre has been a major figure in using and advancing methods for recording and analysing signals from the scalp to understand cognition. She was also a pioneer in using functional MRI to image brain activity. fMRI can map out which brain areas are active by detecting the oxygen-rich blood flowing to these areas.

Sometimes large scanners are not even necessary: Nobre has recently developed new methods of tracking where a person’s attention is focused in their mind just by measuring changes to the eyes. For example, she and her colleagues could tell by measuring tiny involuntary eye movements if someone was focusing on a picture to the left or right of the grid they were holding in memory. Even the pupil diameter can be telling. Nobre showed, for example, that people’s pupils become smaller or larger when they focus on a light or dark item held in mind.  ‘So, we can actually read things about the human mind just by looking at the outside, at the face.’

Alzheimer’s and Parkinson’s
Nobre uses the knowledge she gains about the brain to research what happens in the case of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. ‘Brain imaging tends to be the standard go-to method in clinical human neuroscience,’ says Nobre. ‘For example, in Alzheimer’s disease, researchers look at the reduction of tissue in the hippocampus and related areas, or they use positron emission tomography (PET) to look for specific molecules that are characteristic of degenerative processes. However, by the time structural changes are visible, it is already late in the degenerative process. We want to develop much earlier, sensitive markers of disease risk and onset. That is why we are exploring the promise of brain recording methods like magnetoencephalography and electroencephalography, better known as MEG and EEG. These allow us to measure the actual brain activity in real time. We can get readouts of how well functional networks are performing, like subtle changes to their dynamics or rhythms, and detect if the system is not working optimally at a much earlier stage.’ Nobre compares this to an athlete who develops an injury. It is much better to detect small changes in their running rhythm or movement early on, rather than noticing it when they are in too much pain to run.

The collection of brainwaves, measured using sensors in different locations, appears as a series of squiggly lines on Nobre’s computer screen. Nobre looks at different aspects of this brain activity. ‘Some brain networks have characteristic rhythms,’ she says. ‘This is the case, for example, with the motor system, which controls movement. We are trying to see if changes take place in those rhythms.’ Nobre also takes series of snapshots of so-called brain states, taking a photo, as it were, of briefly held stable patterns of activity, like poses, the brain takes. These basic states reveal something about what the brain is working on at that moment. ‘So, you say, for example, the brain is in the so-called beta state for 20 milliseconds, and then it goes to another state for 100 milliseconds, and then it comes back again,’ Nobre explains. ‘You can then see whether a brain network has been active for too long, or not long enough. Or perhaps the period of time between two states is too long.’ This research is still in its early stages, but Nobre has already found differences in brain activity in the motor systems between people with Parkinson’s and healthy people. ‘I think these little squiggles will reveal a lot more as we learn to understand their language better.’

CV
Kia Nobre (Rio de Janeiro, 1963) grew up in Rio de Janeiro and studied neuroscience at Williams College in Williamstown. In 1993, she received her PhD in neuroscience from Yale University. After a postdoc at Yale and a research position at Harvard Medical School, she moved to the United Kingdom in 1994. She became a faculty member of the Department of Experimental Psychology and a tutorial fellow at the University of Oxford, and was promoted to professor of Cognitive Neuroscience in 2006. Since 2010, she has been director of the Oxford Centre for Human Brain Activity. In 2014, she became the first Chair of Translational Cognitive Neuroscience. Nobre is a member of the British Academy, Academia Europaea, and National Academy of Sciences in the USA. In addition to the C.L. de Carvalho-Heineken Prize for Cognitive Science, awards she has received include the MRC Suffrage Science Award, the Broadbent Prize, and the APS Mentor Award.

Research
Kia Nobre studies how our brain combines signals from our environment and our memory to shape experiences. Among other things, she focuses on how our brain can concentrate on the most relevant signals from the environment and the relevant items in our short-term memory. She also studies how different areas of the brain communicate with each other, and how this brain activity is coordinated. Nobre uses various technologies to visualise the brain and measure brain activity while study participants perform tasks. She is also developing methods to detect neurodegenerative diseases at an early stage.

Heineken Prizes
Every two years, Heineken Prizes are awarded to five renowned international scientists and one artist. In 1964, Alfred Heineken established the Dr H.P. Heineken Prize for Biochemistry and Biophysics as a tribute to his father. Later, Heineken Prizes for the Arts, Medicine, Environmental Sciences, Historical Sciences, and Cognitive Sciences followed.

Video

‘My works are the residue of a ritual process’

The Dr A.H. Heineken Prize for Art 2022 is awarded to Remy Jungerman. The Surinamese-born artist combines elements from different cultures in his sculptures, paintings, and installations. Materials and rituals from Africa and North and South America form the basis of his work and he incorporates them in a modernist way. The jury praises his recognisable and unique style and the stratification in his work that makes the viewer think.

When I walk into Remy Jungerman’s studio, I am surrounded by an impressive collection of colours, materials, and geometric shapes. ‘This work is not yet finished,’ Jungerman says immediately, pointing to a panel against the wall. ‘But I actually think it is quite beautiful as it is. Sometimes it is difficult when you have to let go of a work.’ It is a panel on which he has stuck black and yellow chequered strips of fabric in different directions. In many of his works, Jungerman uses this type of chequered fabric, which comes from the culture of the Surinamese Maroons – descendants of escaped enslaved people who live in the Surinamese rainforest. On his panels, Jungerman forms exciting rhythmic and geometric spectacles by covering the fabrics with porcelain clay and then scratching the chequered pattern into the clay. In this way, his work brings together the culture of the Maroons, his ancestors, and Western modernism.

This connection can also be found in his sculptures and installations. ‘I look at geometries and patterns that travelled from Africa to North and South America via the transatlantic slave trade,’ says Jungerman. ‘I try to tell new stories with them. This cultural reference is an important theme in my work. From that perspective, I seek a connection with modernism. People often think that my inspiration comes from De Stijl. But it is the other way round. I draw my inspiration first and foremost from the chequered patterns of the Maroons’ textiles and the Winti religion to which they adhere. The grid that I build is not related to Mondriaan, but to these textiles. Perhaps this is also because, as a child, I could not go to the museum to see works by Mondriaan, Malevich, or Agnes Martin. That came later when I was at art school. But in the end, I did consciously use modernism as a tool to tell my story.’

First encounter
Remy Jungerman grew up in Moengo, a small town in the middle of the rainforest in Suriname. He was already creative as a child. He was brought up on making things. ‘My home situation was a creative source,’ says Jungerman. ‘But this source was actually more about making utensils and working behind the sewing machine. For example, we made frying spoons, which we sold to earn something extra. But we also made everything ourselves: a new body for the washing machine, a rabbit hutch, an extension onto the house. I also made a lot of my own clothes using the sewing machine.’ Jungerman did not have the opportunity to visit museums and galleries there, but he remembers his first encounter with art well. ‘I was 8 or 9 when I saw an exhibition by Moengo sculptor George Barron, who made very beautiful, polished mahogany sculptures. I was totally flabbergasted. I thought, wow, if a human being made this, I want to be able to do that too.’

But it took some time before Jungerman himself ended up in art. It was only after studying mechanical engineering and working as the head of a mechanical workshop at a telecommunications company that he ended up at art school. ‘I am actually very glad that I had that preliminary phase in which I learned the techniques,’ he says. ‘That is why I can build large sculptures without them collapsing. The hanging sculptures I showed in Venice, for instance, were quite complex structures.’

Own interpretation
Jungerman is referring to Visiting Deities, one of the works he created when he represented the Netherlands at the 2019 Venice Biennale art exhibition. He built the installation around a long table, filled with blue-and-white and black-and-white chequered textiles used in Winti rituals, treated with porcelain clay. ‘I put them on a dry seabed or riverbed, with cracked earth,’ says Jungerman. ‘This calls back to the silent stories of the transatlantic slave trade, which ended up at the bottom of the sea. In the hanging sculptures above the table, people could see ships. I did not have that in mind when I made it.’ Jungerman drew his inspiration from an oracle, an object carried by two people on a wooden stick, covered in textiles in the middle, which is used in Maroon culture on important occasions. For example, to introduce newborns, pray for the harvest, make legal pronouncements, or for pilgrimages. ‘I thought, if I analyse the meaning of the oracle, it will result in these sculptures. And I as a person am also part of that analysis – the fact that I studied at the Academy for Higher Art and Culture and the Gerrit Rietveld Academy, that I studied both western and non-western art history. But that is a very complicated approach. It is easier to think because of their shape: these are ships.’

Jungerman does not mind that people give their own interpretation of his work. ‘I think it is great. And it is primarily the first impression. If you take a longer look, you reach different interpretations. For example, I also added three water samples to the work: one from the Cottica, the river in the region where I was born in Suriname; one from the Amstel, near to where I now live; and one from the Hudson, where I often am when I am in New York. Historically, too, these three places have a triangular relationship: New York first belonged to the Netherlands, who traded it with Great Britain for Suriname. Of course, it is a lot more complicated, but that is why I am what I am today. There is a connection there. The table is a Kabra Tafra, an offering table that you set for the ancestors. I thought it was important to install this table in Venice. The Giardini, where the Biennale is held, has always been a glorification of the colonial past. There, all the rich countries could exhibit the wealth they had amassed from free labour through their colonies. As someone who comes from former colonial territory, I wanted to use the table to purify the space, and in doing so, to start the conversation.’

Richness
Yet Jungerman does not make his work primarily to show this dark history. ‘I do not find that indictment so important; to me, it is more important to look at what the richness is from which I can draw. Other people might take more of a political, activist stance, but I prefer to celebrate culture.’ Part of that richness also lies in the many rituals that colour the Maroon culture. ‘I think it is important to look not at the moment of the act, but at what remains after the act. For me, that is the work of art. I use materials that come from the ritual context, such as fabrics and clay. I take them with me to the studio, and there a work of art is created from the material. I also see creation in the studio as a ritual process, and the work of art is actually a residue of that act.’

The textiles that Jungerman uses are all from the Winti religion, the Afro-Surinamese religion that the Maroons, among others, adhere to. They wear these chequered textiles in different colour combinations for all kinds of rituals. He uses the textiles in combination with kaolin, a porcelain clay. The Maroons use this material during rituals to purify bodies and objects. ‘In installations or sculptures, I sometimes use other objects that are used in rituals,’ says Jungerman.  ‘For example, bottles of Dutch gin used in libations, or chickens used in sacrifices.’ Limiting himself to those materials with a specific source is very important to him. ‘You can probably buy similar textiles here in the Netherlands, but I think it is important that they are symbolically worn by Suriname. Perhaps some of the textiles are now manufactured in the Netherlands and shipped to Suriname. But I bought them in Suriname, and they made the journey from Suriname to the Netherlands. I like that.’

Enclosed interior space
In addition to the origin of the material, the titles Jungerman gives his works are also important. ‘Sometimes they are titles of rituals or names of Maroon clans’, he says. ‘Or, for example, of geographical locations where Maroons settled. When I make cubes, they have an enclosed interior space. That interior space is as important to me as the outside of the sculpture. Before I close the cube, I sometimes place pieces of textile there, or I say words into it, for example, of those geographical locations. I think that kind of thing sets this apart from the modernists or De Stijl. The intention is different.’

The connection with the Maroons is very personal for Jungerman. On his mother’s side, he is descended from the Bakabusi, a group of Maroons who lived in the interior of Suriname. ‘The chief, Broos, is my great-great-uncle. But I call him my great-great-grandfather, because in that context he is important as a kind of father figure.’ One photograph was made of Broos, which Jungerman has also used in his work. ‘There are six other Maroon groups, but I use the Bakabusi, to connect to the wider Maroon culture through them.’

Plans for the coming period
Jungerman is currently exhibiting at the Kunstmuseum in The Hague, the Goodman Gallery in London, and at the Katonah Museum of Art in New York. He is also staying in New York for an extended residency in the International Studio and Curatorial Program. ‘I am very much looking forward to the coming period,’ says Jungerman. ‘And it is as if this prize has come at exactly the right time. Although it is always the right time to win a prize,’ he laughs. ‘But I am so keen to continue my research into the journey of geometries from Africa to the Americas and how they influenced the aesthetics of the Surinamese Maroons. In addition, I want to study the Gee’s Bend quilts from the American South, in which similar geometries are used. I now have the opportunity to do so.’ These quilts were made by women from the isolated African American community of Gee’s Bend. This community lives in a large bend of the Alabama River in the US state of Alabama.

‘In New York, you have the Schomburg Center for Research in Black Culture,’ says Jungerman. ‘American anthropologists Richard and Sally Price have done a lot of research on Maroon culture. All the textiles and objects they have collected can be found at this centre. There was an advertisement in the New York Times, in which they say about an exhibition of the Maroon shoulder cloths: “If we didn’t tell you it came from the Suriname rain forest, you would think it was modern art.” These textiles had an enormous influence on me when I studied at the art academy in Suriname, and they still do. I now have the chance to go there and touch and smell those shoulder cloths. I want to study the similarities between the geometries of the Maroon shoulder cloths and the Gee’s Bend quilts and use them as inspiration for my new work. My dream is to have a major exhibition at MoMa in New York or Tate Modern in London. And I want to exhibit recent work from this research and some of these textiles (shoulder cloths and quilts) to tell the big story of the journey of geometry from the African continent to North and South America, through the aesthetics of the Maroons in relation to the Gee’s Bend quilts. The quilts are so well made, some look like paintings.’

CV
Remy Jungerman (1959, Moengo, Suriname) is a visual artist. He studied at the Academy for Higher Art and Culture Education in Paramaribo in Suriname and continued his education at the Gerrit Rietveld Academy in Amsterdam. He was an artist-in-residence at Art Omi in New York in 2013 and at the International Studio & Curatorial Program, also in New York, in 2018. Jungerman co-represented the Netherlands at the Venice Biennale in 2019 with the exhibition ‘Measurement of Presence’. Jungerman has exhibited frequently in the Netherlands and abroad, including at the Kunstmuseum Den Haag; Prospect 3, the New Orleans Contemporary Art Triennial; the Brooklyn Museum in New York; and the Havana Biennial in Cuba. In late 2021 and early 2022, he curated a major solo exhibition at the Stedelijk Museum in Amsterdam, entitled ‘Behind the Forest’.

Research
Remy Jungerman creates sculptures, paintings, and installations in which he combines elements from different cultures. Materials, traditions, and rituals from Africa and North and South America form the basis of his work and he incorporates them in a modernist way. Specifically, he draws much inspiration from the Maroons of Suriname. He uses, among other things, textiles from the Winti religion, to which the Maroons adhere, and kaolin, a porcelain clay used in this culture during rituals to purify objects and bodies. In his large installations, he also uses other materials from rituals. He wants to use the aesthetics of these materials to tell new stories. All his work contains a stratification that makes the viewer think.

Heineken Prizes
Every two years, five renowned international researchers and one artist are awarded the Heineken Prizes. The first of the prizes, the Dr. H.P. Heineken Prize for Biochemistry and Biophysics, was established in 1964 by Alfred H. Heineken, as a tribute to his father, Dr. Henry P. Heineken. To this award were subsequently added Heineken Prizes for Art (1988), Medicine (1989), Environmental Sciences (1990) and History (1990). Alfred Heineken’s daughter, Charlene L. de Carvalho-Heineken, continues this tradition. The C.L. de Carvalho-Heineken Prize for Cognitive Science (2006) is named after her. The prizes are made available by the Alfred Heineken Fondsen Foundation and the Dr. A.H. Heineken Foundation for Art. The Royal Netherlands Academy of Arts and Sciences (KNAW) takes care of the nomination and selection process.

Video

‘We live because we constantly die’

Most of the time, body cells die a silent, programmed death, but sometimes they burst like a balloon while loudly asking immune cells for help. Biomedical scientist Vishva Dixit unravels the underlying processes of the various forms of cell death, laying the foundation for treatments of various diseases such as cancer, Alzheimer’s, and sepsis. For his research, he received the Dr A.H. Heineken Prize for Medicine.

Every second, a million cells in our body die, amounting to one kilogram of dead cells per day. Our body rids itself of these cells because they are old, damaged or mutated and replaces them with new cells. This cleansing process is essential to life, but it walks a thin line. If too few cells die, mutated cells accumulate, which can lead to cancer. When more cells die than our bodies can replace, it leads to degenerative diseases such as Alzheimer’s. Vishva Dixit, vice-president of Early Discovery Research at the South San Francisco biotechnology company, Genentech, a member of the Roche Group, studies the mechanism responsible for the process of cell death. Because the better we understand it, the better we can understand diseases such as cancer and Alzheimer’s.

‘We live because we constantly die’, Dixit says. ‘For a long time, it was a great mystery exactly how our cells were made to die, and what the nature of the assassin was.’ He entered the field of cell death research at an interesting time. In the early 1990s, researchers discovered a ‘death receptor’ on the cell surface, activation of which ultimately led to cell death. But how exactly was not at all clear. In addition, American biologist Robert Horvitz discovered a gene that played an important role in programmed cell death in the C. elegans worm, which won him the Nobel Prize in 2002. For many years, it was unclear what the gene’s precise function was, but eventually it was discovered to code for a protease: a so-called ‘molecular scissors’. Once activated, these scissors shred the contents of the cell, causing the cell to die. ‘We began to wonder whether such a protease was involved in other organisms, including humans,’ says Dixit. ‘So, we did an experiment with a protein that is produced during infection with the cowpox virus. This protein inhibits the family of proteases. When we stimulated the death receptor in the presence of this inhibitor, the cells did not die, but without the inhibitor they did. From this we could conclude that a protease from this family had to play a role in cell death.

Years later, they identified the specific molecular scissors that cut up the cell. They called it Yama, after the Hindu god of death. Today, this protease is known by the somewhat more boring name of ‘caspase-3’. But a big question remained: how does the death receptor activate the molecular scissors? ‘The receptor had no obvious way of signalling. It looked like nothing we had ever seen,’ says Dixit. He eventually discovered that there were a few intermediate steps: the receptor eventually activates the molecular scissors via various intermediary adaptors. The knowledge of this signalling pathway forms the basis of several pioneering treatments that can be found in hospitals today. For example, this knowledge has been used to improve immunotherapy in cancer patients, by ensuring that immune cells initiate this chain reaction, killing cancer cells.

The kilo of cells that die in your body every day doesn’t hurt a bit. But in addition to this ‘silent’ form of cell death – apoptosis – there is also ‘loud’ cell death: necrosis. This occurs, for example, in the case of a cut, infection or burn. Dying cells alert immune cells to come and clear away the danger: they trigger an inflammatory response to destroy, for example, the pathogens. Dixit discovered that cells have different sensors for specific forms of danger, but that they trigger the inflammatory process in the same way.

These findings are important for treating sterile inflammation – inflammation without a pathogen, such as a bacterium, virus or parasite. ‘Sterile inflammation is at the heart of many first world diseases,’ says Dixit. ‘For example, they are behind atherosclerosis (hardening of the arteries), which leads to heart attacks. Furthermore, sterile inflammation accelerates degenerative diseases such as arthritis and Alzheimer’s disease. Our dream is to find a way to inhibit sterile inflammation without inhibiting the inflammatory response as a whole, because that makes you very susceptible to pathogens.’

Because damage to the cell membrane triggers sterile inflammation, you can target the receptor that detects that damage, known as NLRP3. For a long time, it was thought that it would not be possible to develop inhibitors for that receptor specifically. ‘But Mohamed Lamkanfi, a former postdoctoral researcher in my lab, demonstrated in 2017 that this was indeed possible,’ says Dixit. ‘He used analogues of sulphonylurea, a class of molecules used in the treatment of diabetes. These inhibitors were not very powerful; he needed a very high concentration. But because he demonstrated that it is possible, other researchers entered the field to develop more powerful inhibitors. And today, there are a number of NLRP3 inhibitors in clinical trials for the treatment of sterile inflammation.’

Blood poisoning
Sometimes there is a pathogen involved, to which the body reacts far too violently. This is the case with sepsis (blood poisoning). Bacteria such as Salmonella or E. coli cause an extremely severe inflammatory response. ‘Seven million people die of sepsis every year,’ says Dixit. ‘And despite all efforts, there is still no effective treatment.’ But there is hope: Dixit discovered that there is an alternative signalling pathway through which sepsis occurs. This opens the door to new methods of treatment.

In his research, Dixit frequently uses mice that have been genetically modified so that they lack one specific gene. By comparing them to mice that do have the gene, you can find out in which processes the gene plays a role. But in 2011, he accidentally discovered that mice widely used in the research field, on which hundreds of papers are based, were missing not one, but two genes. They not only lacked the gene for caspase-1, an enzyme that triggers an inflammatory response, but also the gene for another enzyme: caspase-11. ‘All the conclusions drawn about caspase-1 could just as easily apply to caspase-11,’ says Dixit. ‘We began to wonder what caspase-11 does, and modified mice so that they only lacked the gene for caspase-11. We found that these mice did not respond to a class of bacteria that includes salmonella and E. coli. So, we could conclude that these bacteria activate caspase-11, but we did not yet know how. The big surprise was that one specific molecule in the bacteria was responsible for this: LPS (lipopolysacharide). And this was the very molecule that was already known to be responsible for the majority of septic shock.’

Alternative route
The American immunologist Bruce Beutler had previously identified another receptor that responded to LPS and it was thought to mediate sepsis, for which he was awarded the Nobel Prize in 2011. But shortly thereafter Dixit, in 2013, discovered that there is another pathway to sepsis. In fact, he and his research group showed that this pathway is much more important, at least in mice. ‘If you can develop an inhibitor for caspase-11 or one of the proteins in the cascade, then you have a new opportunity to find a treatment for this disease,’ says Dixit. ‘My fondest hope is that we can find drugs that act on this pathway, reducing the disastrous effects of sepsis on mankind.’

Dixit is currently studying in greater detail what necrotic cell death looks like. ‘We are taught that this cell death is like a water balloon that you stick a needle into: it bursts, and the liquid is hurled in all directions. We recently discovered that a membrane protein, NINJ1, greatly accelerates this explosive process. The big mystery is: why? My hypothesis is that pathogens such as intracellular bacteria and viruses are rapidly ejected out of the cell so that immune cells can promptly clear them away. Moreover, in doing so, in one fell swoop, the bursting cell denies intracellular bacteria and viruses of the home they need to replicate. This is just a hypothesis; I could be completely wrong. But that’s the wonderful thing about research – you get to ponder things like that and then find out if you’re right.’

CV
Vishva Dixit (Kisii, Kenya, 1956) studied medicine at the University of Nairobi in Kenya. In 1981, he moved to the United States for a medical residency training programme at Washington University in St. Louis. In 1986, he was hired as faculty by the pathology department of the University of Michigan, where he was appointed a professor in 1995. Beginning in 1997, he held various positions at the biotech company, Genentech. He has been vice president of the Early Discovery Research Department since 2005. Between 1999 and 2008, he was also an adjunct professor of pharmaceutical chemistry at the University of California, San Francisco. Dixit has more than 50 patents to his name.

Research
Vishva Dixit studies how our bodies regulate the process of programmed cell death (apoptosis). He discovered which enzymes are involved in this process and how they activate each other in a chain reaction. This knowledge is used, among other things, to improve immunotherapy for cancer patients, with immune cells initiating this chain reaction, killing cancer cells. Dixit also studies necrosis, the cell death that occurs, for example, after a cut, burn or infection. Dying cells alert immune cells to come and clear away the danger: they trigger an inflammatory response. His findings have the potential to lead to improved treatment of arthritis, Alzheimer’s, and sepsis, among others.

Heineken Prizes
Every two years, Heineken Prizes are awarded to five renowned international scientists and one artist. In 1964, Alfred Heineken established the Dr H.P. Heineken Prize for Biochemistry and Biophysics as a tribute to his father. Later, Heineken Prizes for the Arts, Medicine, Environmental Sciences, Historical Sciences, and Cognitive Sciences followed.

Video

Climate change dampens oceanic carbon sink

Oceans absorb a significant proportion of the CO2 emitted by humans from the atmosphere. Therefore, oceans have a significant effect on the amount of greenhouse gases in the air and, consequently, on the climate. But the service that the seas provide to humankind is under threat: climate change is making the oceans less and less efficient at absorbing CO2. Corinne Le Quéré, professor of climate change science at the University of East Anglia in the UK, accurately maps out the complex interaction between the oceans and the atmosphere. In 2020, she received the Dr A.H. Heineken Prize for Environmental Sciences for her work.

Every day, climate scientist Corinne Le Quéré uses advanced models to study how the world’s oceans respond to the changing climate. A little ironic: she only saw the ocean for the first time when she was eighteen. But her interest in the environment had already been aroused. ‘I grew up in the middle of the forests in Canada,’ says Le Quéré. ‘I was always very close to nature and often went camping in the wild during the holidays. My entire childhood was the true Canadian holiday that everyone dreams of. When I first saw the ocean at 18, it was fascinating, but my interest had already been piqued from growing up so close to nature, enjoying the weather and the elements.’ When Le Quéré went to university in the 1980s and 1990s, environmental science was still an unknown field of research. Le Quéré studied physics and went on from there to study oceanography and climate.

‘The oceans are doing us a great service,’ says Le Quéré. ‘They absorb about a quarter of the CO₂ that we emit and therefore have a dampening effect on climate change. But this carbon reservoir is in turn susceptible to climate change, through changes in sea surface temperature, wind strengths, ocean circulation, and marine ecosystems.’ Le Quéré maps out this complex interplay and translates it into computer models, with which she studies how these processes have changed in the past, and what we can expect for the future.

In the depths
The oceans currently act as a so-called carbon sink: a carbon reservoir that absorbs more carbon than it emits. As a result, they slow down climate change. But at the same time, this carbon sink function is under threat from climate change. To understand why, it is first useful to know why the oceans currently act as a carbon sink. Human CO₂ emissions increase the concentration of CO₂ in the atmosphere. This leads to a difference in the ‘pressure’ of CO₂ between the atmosphere and the ocean. To cancel out this difference, CO₂ dissolves in the ocean. ‘What makes the ocean so absorbent are the chemical reactions that convert the CO₂into bicarbonate,’ says Le Quéré. The benefit of this is that it isolates the carbon from the atmosphere. The bicarbonate is then transported to the depths of the ocean by ocean currents. This allows the ocean to continue to absorb new CO₂. This process slows down climate change through CO₂ emissions. The drawback is that this process also acidifies the ocean.’ This acidification is bad news for some organisms. For example, certain shells and fish bones may dissolve due to the higher acidity level. ‘We do not yet know what the consequences of this will be for the carbon cycle, but in any case, it will have a great impact on the ocean ecosystem.’

The factor that most determines the amount of CO₂ the ocean can absorb is the transport of carbon into the depths. Because when it is removed from the ocean surface, the concentration there becomes lower, and the ocean can absorb new CO₂. But that is not the only factor. ‘Climate change is warming the atmosphere and therefore surface water,’ says Le Quéré. ‘And CO₂ is less soluble in hot water than in cold water.’ So, it is bad news: by warming up the climate, we are reducing the ocean’s absorption capacity, which we so desperately need to limit climate change.

Against the wind
Early in her career, Le Quéré made an important discovery. She was the first to use observations to show that the efficiency of CO₂ absorption by the ocean had been reduced. ‘I analysed the Antarctic Ocean because the wind had increased there. This extra wind causes deep, carbon-rich waters to rise to the surface faster than normal. As a result, more natural carbon is emitted back into the atmosphere, and less man-made CO₂ is absorbed.’

The innovative aspect of this research was that Le Quéré did not look at measurements in the ocean itself, but rather at the CO₂concentrations in the air above the ocean. ‘We collected atmospheric measurements taken over a period of 25 years. Then we used a method called ‘inversion’. Suppose you measure the CO₂ concentration at point A and point B, and the wind blows from A to B. If the CO₂ concentration in point A is higher than in point B, you know that CO₂ has ‘disappeared’. That CO₂ has been absorbed by the ocean. So, by comparing two concentration measurements at a time, you can determine how much CO₂ has been absorbed by the ocean between those points. We collected as many measurements as possible of CO₂ concentrations around the Antarctic Ocean and combined them with weather data. This enabled us to demonstrate that the ocean’s carbon absorption had not increased, while CO₂ emissions had risen by 40%. If efficiency had remained the same, carbon absorption should have followed the emissions, but it did not.’

The hole in the ozone layer was one of the main causes of the stronger winds in the area. It changed the circulation of air and accelerated the winds. ‘This raises a new major research question,’ says Le Quéré. ‘Because climate change also increases wind strength. In fact, climate change increases the winds in all seasons, while the hole in the ozone layer does so only in summer. I am currently trying to study how much the wind will increase in the coming period, and whether the effect on CO₂ absorption will disappear when the ozone layer recovers or get worse due to climate change.’ Le Quéré studies the impact of climate change not only in the Antarctic Ocean, but all over the world. She was also the first to quantify the impact of climate change on the carbon sink function of the world’s oceans. ‘We demonstrated that it has become a little weaker due to climate change. A small part of this was due to warming of the ocean surface, but most was due to changes in the wind,’ says Le Quéré.

Ecosystems
And then there is another important factor for the carbon cycle in the oceans: ecosystems. ‘These ecosystems live in the upper part of the ocean,’ says Le Quéré. ‘But dead organisms or excrement can sink to the depths of the ocean. This is all material that contains carbon, and so a lot of carbon is transferred from the ocean surface to the depths of the ocean. This is part of a natural cycle: ocean currents eventually bring this carbon to the surface elsewhere. Initially, this cycle was evenly balanced. But acidification, warming, and oxygen depletion have affected such ecosystems. This also affects the carbon cycle.’

But how exactly is not yet clear. That is why Le Quéré creates models to map the complex interactions within ecosystems. ‘We have developed a way of representing ecosystems that does justice to the diversity in ecosystems but is not too complex to model. To do this, we divide organisms into groups that function in a similar way, for example because they all have shells, eat the same kind of food, show similar behaviour, or have a similar size.’ Le Quéré focuses on micro-organisms. ‘When we think of marine ecosystems, we often think of animals like fish or whales. But they do not affect the carbon cycle that much. The small organisms play a much bigger role.’

For each of these groups of organisms, Le Quéré and colleagues collect observations – for example, of their growth as a function of temperature or the amount of nutrients available. They do this in the laboratory or with measurements from ships. All this information is included in the model and used to calculate various scenarios. At present, they do not foresee any major changes in the carbon sink function as a result of changing ecosystems. But whether this will remain so in the long run is questionable. ‘We know that there have been major shifts in ecosystems in previous geological eras,’ says Le Quéré. ‘There have been situations in which organisms reuse all the carbon-rich material on the surface. Hardly any carbon sank to the bottom.’ Such a situation would be anything but favourable, as no carbon would be transported to the depths. ‘We are closely monitoring the ecosystems, to understand if or when this will happen again.’

Unpredictable
Modelling ecosystems is not easy. ‘You do not have natural laws like in physics,’ says Le Quéré. ‘It is much more unpredictable. You really have to observe ecosystems and try to mimic that behaviour in a model. When I first published my model based on the groups of similar organisms, two critical publications immediately responded. One claimed the model was far too complex; the author talked about “running before we can walk”. The other said that our model was far too simple. So, I thought: we have probably got it about right’, Le Quéré laughs. ‘They were both a bit right, of course. But now, some 17 years later, there are many new options. In addition to more computing power, we have, for example, underwater cameras that continuously take pictures in the ocean. With artificially intelligent computer programmes, we can detect which organisms are in a photo. This allows us to automatically process millions of observations.’

In the coming years, Le Quéré hopes to learn more about the stability of ecosystems. ‘I push my model to the limit, with, for example, extreme temperatures, acidification, oxygen depletion, or pollution, and see when the ecosystems collapse. This way, I can analyse how things go wrong in these cases. Then we can look in the ocean to see if there are any indicators that things are going in the wrong direction.’

Recommendations
In addition to her research, Le Quéré also advises governments on their CO₂ emissions and how to deal with climate change. ‘I think it is very important for scientists to speak out, to show the evidence, so that governments and people can make informed decisions. That is why, throughout my career, I have spent about one day a week making science available to the public, and especially to policy makers.’ Currently, Le Quéré has a seat on the Climate Change Committee in the UK and chairs the French High Council on Climate. These are both independent advisory bodies to the governments. ‘There is much evidence that the recommendations of these commissions have accelerated action on climate change’, says Le Quéré.

In addition, Le Quéré initiated the Global Carbon Budget with colleagues in 2004. ‘At an annual meeting of the Global Carbon Project, the alliance of all global research on the carbon cycle, we discussed what the research community could do to support policy makers. Policy makers meet annually in climate summits, but we in the scientific community only issue an IPCC report once every six or seven years. To fill this gap, we decided to publish an update every year on how much CO₂ was emitted the previous year and where that carbon ended up: in the atmosphere, the ocean, or on land.’ Le Quéré directed this publication, which was christened the Global Carbon Budget, for thirteen years. ‘It started out as a way of advising policy makers, but eventually it also proved to be a great boost for research regarding the carbon cycle.’

CV
Corinne Le Quéré (Magog, Canada, 1966) studied physics at the University of Montreal in Canada. She then obtained her master’s degree in atmospheric and oceanic sciences from McGill University, also in Montreal. In 1999, she obtained a PhD in oceanography from Pierre and Marie Curie University in Paris (now Sorbonne University). Following several positions, she was appointed Royal Society research professor of climate change science at the School of Environmental Sciences at the University of East Anglia in Norwich, UK, in 2019. Le Quéré initiated the annual publication Global Carbon Budget in 2004 and was author of several IPCC reports. She currently has a seat on the Climate Change Committee in the UK and chairs the French High Council on Climate.

Research
Corinne Le Quéré studies how the carbon cycle in our oceans is changing under the influence of climate change. Every year, the oceans absorb an average of one quarter of the CO2 emitted by humans from the atmosphere. This carbon reservoir is in turn susceptible to climate change, through changes in sea surface temperature, wind strength, ocean circulation, and marine ecosystems. Le Quéré studies the interactions between these components in the recent past, and makes projections for the future. She was the first to demonstrate that increases in winds in the Antarctic Ocean are leading to less efficient absorption of CO2, and linked this to the depletion of the ozone layer. Le Quéré currently focuses on studying the different processes and ecosystems in the sea with great details. Thanks to new measurement techniques, she can create a complex model of how marine ecosystems respond to climate change and how this affects the carbon cycle.

Heineken Prizes
Every two years, the Royal Netherlands Academy of Arts and Sciences awards the Heineken Prizes to five renowned international researchers and one artist. The first of the prizes, the Dr H.P. Heineken Prize for Biochemistry and Biophysics, was established in 1964 by Alfred H. Heineken, in honour of his father, Dr Henry P. Heineken. To this award were subsequently added Heineken Prizes for Art (1988), Medicine (1989), Environmental Sciences (1990), and History (1990). The daughter of Alfred Heineken, Charlene L. de Carvalho-Heineken, is continuing this tradition. The C.L. de Carvalho-Heineken Prize for Cognitive Sciences (2006) is named after her.

Video

The genetic copier unravelled

At any given moment in every body, many millions of cells are engaged in a complex process: copying DNA within the cell. Before a cell can start dividing, each piece of genetic material is copied with great precision. For many years, the workings of this so-called DNA replication were a great mystery. Bruce Stillman, professor of biochemistry and president of Cold Spring Harbor Laboratory in New York State, made important contributions to unravelling this mystery. In 2020, he received the Dr. H.P. Heineken Prize for Biochemistry and Biophysics for his work.

In Bruce Stillman’s office, there is a beautiful crystal on which a replica of the first lens made by Antoni van Leeuwenhoek is displayed. That lens opened the world of microbes and cells to the human eye. This work of art is the Heineken trophy he received for is pioneering research. One of the first things Van Leeuwenhoek saw through his microscope around 1670 was the sediment in beer. At first, he thought he was looking at some dead cells, but later he found he had seen yeast cells, alive and well and essential to the process of brewing beer. It so happens that Stillman owes many of his breakthroughs to an important choice: about forty years ago, he decided to start using yeast cells for his research. The yeast S. cerevisiae, which is used to make bread, wine, and beer, enabled him to identify many proteins that play a role in copying DNA in cells.
Indeed, while Stillman is enthusiastically talking about his research, many millions of cells in his body are busy. All DNA and associated proteins are copied with great precision before a cell can proceed to divide. For example, in the human body’s bone marrow alone, a billion metres of DNA are meticulously copied every minute – a feat of no small magnitude. But despite the insanely complex molecular machinery, equipped with various control mechanisms, this process sometimes goes wrong. ‘One of the reasons I became interested in the subject of DNA replication is because this process goes wrong in cancer,’ Stillman says. ‘I wanted to understand how this process really works, and what exactly goes wrong in that case.’ Stillman devoted his career to unravelling this biological copier. He and his colleagues identified many proteins that play an important role in the replication process and unravelled how they interact.

Simultaneous copying
If you want to copy a strand of DNA, you might think: I’ll just start at one end, and copy until I get to the other end. But the hard data quickly make you face facts. ‘If you only had one starting point, a so-called origin of replication, it would take months to replicate an entire chromosome’, Stillman says. ‘In reality, there are a lot of these starting points. As a result, the copying process only takes about eight hours in human cells.’
Very efficient, but this requires good coordination. First, the copying proteins must somehow know where to start copying. ‘You cannot start in the same place twice, because then you get duplicate sections’, Stillman says. ‘You cannot skip a starting point either, because then a piece of DNA is thrown away.’ One of his major breakthroughs was to unravel how this simultaneous start is managed. ‘The replication process starts with proteins binding to DNA at specific locations’, Stillman says. ‘The breakthrough that Steve Bell, a postdoc in my lab, and I made in 1992 was the discovery of the Origin Recognition Complex, which is the enzyme machinery that gets the whole process going.’

Ready, set, go!
This Origin Recognition Complex, ORC for short, is a protein that recognises a starting point in the DNA strand and binds to it. Next, ORC gathers a series of other proteins around it, many of which Stillman has also identified. All together, they form what is known as the pre-replicative complex. This complex gives ‘permission’, as it were, to start DNA replication. Once the starting signal is given, the copying proteins begin copying from the starting points. After that, the pre-replicative complex is destroyed. ‘This complex cannot then be reassembled until the fully copied and original chromosomes are pulled apart and placed in two separate cell nuclei’, Stillman says. ‘This ensures that the copying process cannot be started multiple times within one cell cycle.’
To figure out exactly how this all works, Stillman and colleagues had to find a way to distinguish between the formation of the pre-replicative complex and the actual copying of DNA. To do this, they first studied viruses that infect cells of primates. In these cells, the virus uses much the same machinery as primates to replicate its viral DNA. So, the same proteins that copy human DNA also copy viral DNA. ‘In my lab and that of my colleague Thomas Kelly, we identified many of these proteins,’ Stillman says. ‘Thanks to this research, we discovered many proteins that play an important role in the human replication process.’

Baker’s yeast
However, viruses did not solve the issue of how this replication process gets started in cell chromosomes. An important step toward unravelling this mystery was the decision to work with yeast. Stillman’s eye fell on Saccharomyces cerevisiae, a yeast used to make bread, wine, and beer. Yeast proved to be a perfect organism for his research because it allowed him to apply both biochemical and genetic techniques. ‘The reason we started working with yeast was because there was a suggestion that the starting points, the origins of replication, in yeast are defined by specific DNA sequences.’
This indeed turned out to be the case. Step by step, Stillman and student York Marahrens studied which nucleotides (the building blocks of DNA, better known by the letters A, C, G, and T) are required for DNA replication. They did this by comparing normal strands of DNA with mutated versions. ‘We identified four pieces of DNA code required for DNA replication,’ Stillman says. ‘We had origins that worked, and origins that did not work. The difference between the working and non-working versions was only one letter in the genetic code. Colleague Stephen Bell used that information to identify proteins that bound to the working origins, and not to the non-working ones.’ The proteins that bound to the working origins combined to form what they called the Origin Recognition Complex.

Good choice
In their yeast research, they discovered not only ORC, but also other proteins that together with ORC formed the pre-replicative complex, not just in yeast cells. ‘Eventually in my lab we also found the human ORC, by following the evolutionary path from yeast to humans’, Stillman says. ‘I knew at the time that this would open up a whole new field of research. But when we found ORC, we were initially very cautious. Indeed, people had previously claimed to have found the critical protein that bound to the origins. But each time, it turned out not to be true. People began to believe that no such protein existed. But thanks to our analysis with the origin mutations, the evidence was very strong. It is very rewarding to spend six or seven years working on a hypothesis that could very well be wrong but turns out to be right in the end.’
Only recently did Stillman fully realise how beneficial their choice of baker’s yeast had been. In 2020, he published a paper on the evolution of ORC. In it, he showed that baker’s yeast and some related yeasts are the only species on the planet in which the origins are characterised by specific DNA sequences. This does not occur in any other organism – fungi, insects, plants, animals. So, it would have been very difficult to find ORC with their mutation analysis in any other organism. And they just might have chosen a different organism. ‘In the mid-1980s, I was talking to yeast researchers’, says Stillman. ‘I asked them what it was like to do biochemistry with yeast. Some of them said: “Don’t do it, it’s awful.” Fortunately, we did not listen to them at the time.’

Packaging
In addition to the start of the replication process, Stillman unravelled many other aspects. ‘I vividly recall one moment from when I was working in the lab myself. I identified the protein we called CAF-1, Chromatin Assembly Factor 1, for the first time.’ CAF-1 helps to bind packaging proteins around the newly copied DNA. In the end, the DNA forms a structure together with these packaging proteins that ensures that it is stored well protected. ‘I will always remember that moment. I sat down and thought: “This is going to be really big.”’ Stillman and colleagues discovered many other proteins, including the so-called Replication Protein A, a protein that binds to a single strand of DNA to keep it from curling up during copying; ABF-1, one of the proteins that bind at locations where copying starts; and Replication Factor C, a protein that loads a protein called Proliferating Cell Nuclear Antigen (PCNA) that helps the copying machinery and CAF-1 to duplicate and package the copied DNA. Many patients with the autoimmune disease systemic lupus erythematosus make antibodies against PCNA.
‘It turns out that all these proteins do not just play a role in DNA replication’, Stillman says. ‘They also play an important role in DNA repair, DNA recombination (which occurs when mixing the DNA of two parents, among other things), and a process called checkpoint signalling. If damage is detected during DNA replication, such as that caused by UV light or X-rays, a signal is sent to stop the cycle of cell division until repair has taken place. Replication Protein A appears to be the primary signal for this.’
In case of damage, DNA repair enzymes digest the DNA strand that has damage, leaving single-stranded DNA behind. This does not belong in a human cell, where all the DNA is neatly contained in the double-helix structure. ‘Replication Protein A binds to that single-stranded DNA, and that is the signal for the temporary stopping process. The cell division cycle can only progress once the damage is fixed, by creating double-stranded DNA again’, Stillman says. ‘I am quite proud of the fact that these proteins play a role in many different processes. The impact is much broader than we thought when we started this.’
Not only environmental factors such as UV light or X-rays can cause damage. When you consider how complicated the DNA replication process is, and how many different proteins are involved, it is not hard to imagine that very occasionally something goes wrong in the copying process itself. ‘In the bone marrow alone, 500 million red and white blood cells are produced every minute’, Stillman says. ‘Multiply that by the 2 meters of DNA that needs to be copied in each cell, and that means a billion metres of DNA are copied every minute. You could wrap that around the earth along the equator about 25 times. We know today that about half of all cancers are caused not by environmental influences such as sunlight or smoking, but by the intrinsic process of making mistakes during DNA duplication. These mutations accumulate over a person’s lifetime. And even though the process of DNA replication is very accurate, if we could make it even more accurate, we could significantly slow down the onset of cancer in people’s lifetimes. It would be wonderful if we could get that done.’

Rare genetic disorder
In addition to cancer, Stillman’s research is making an important contribution to understanding a very different disease. In 2011, he stumbled upon a series of publications about a very rare genetic disorder: Meier-Gorlin syndrome. People with this condition suffer from a specific form of dwarfism. Unlike more common forms of dwarfism, in people with Meier-Gorlin the head is also smaller than usual, proportional to the small body size. But even though these patients have a brain that is about twice as small, their intelligence is not necessarily lower than average. According to the publications, mutations in DNA replication genes, which code for ORC and other proteins, were the cause of the syndrome. But the symptoms could not be explained purely on the basis of errors in the DNA replication process. ‘Thanks to our research, we now know that ORC and other replication proteins play a much larger role in the cell cycle’, Stillman says. ‘Many of these other functions were found to be impaired in people with Meier-Gorlin syndrome. So, thanks to our fundamental research, we were able to explain this syndrome.’
But what Stillman finds most valuable is this fundamental knowledge itself. ‘I have been very fortunate to be able to pursue the discoveries that end up in textbooks and are part of the knowledge of who we are and how our genetic information is passed on from one generation to the next. I find it quite extraordinary that the human genome shares gene sequences with bacteria that evolved many billions of years ago and with yeast that evolved hundreds of millions to a billion years ago. All that time, their DNA sequences were being copied to eventually produce modern species with related genes. Evolution has maintained processes that have been in place for a very long time. The proteins that copy DNA, which are similar in yeast and humans, have been doing so for a very long time.’

CV
Bruce Stillman (Melbourne, Australia, 1953) studied at the University of Sydney, and received his PhD from the John Curtin School of Medical Research at the Australian National University. He continued his career in the United States, where he started as a postdoc at Cold Spring Harbor Laboratory in New York State. He has been a professor of biochemistry there since 1985. In 1994, he became director of Cold Spring Harbor Laboratory, and since 2003 he has held the position of president there. In addition to the H.P. Heineken Prize for Biochemistry and Biophysics, Stillman has received the Herbert Tabor Research Award, The Louisa Gross Horwitz Prize, the Canada Gairdner International Award, and the Australian Advance Global Impact Award, among others.

Research
Bruce Stillman studies how the replication process of DNA works in eukaryotic cells – cells that contain a nucleus. This includes the cells of almost all multicellular organisms, such as plants, animals, and humans, as well as many unicellular organisms, such as yeast. Thanks to his research, we better understand how our genetic material is copied and how this relates to other processes in the cell. Stillman also studies where this process goes wrong in diseases such as cancer. His research provided an explanation for the rare genetic disorder Meier-Gorlin syndrome.

Video

We simplified the biosphere more and more

As humans, we are putting great pressure on all of Earth’s ecosystems. Environmental scientist Carl Folke was one of the first to realise that we can only solve this problem by examining society and nature as one. For his research on resilience of people and planet, bringing together science and policy, he received the Dr A.H. Heineken Prize for Environmental Sciences.

If you want to safely invest your savings, do not put all your money in one company, but spread it out over several companies. That way, you will not lose all your money in one fell swoop if disaster strikes that one company. Most people gladly take this advice to heart. After all, you want to manage your hard-earned money safely. But when it comes to another important prerequisite of our existence – the Earth – we as humanity do just the opposite. ‘We simplified the biosphere, the thin layer around the Earth’s surface in which all life resides, more and more,’ says Carl Folke. ‘Because of our actions, there are far fewer different types of organisms, the resilience of the entire terrestrial and ocean ecosystem has eroded.’ Folke is director of the Beijer Institute of Ecological Economics and founder and chair of the board of the Stockholm Resilience Centre. He was at the forefront of the theory that describes the resilience of social and ecological systems. ‘Many people look at resilience in the sense of recovery: being able to spring back to a certain equilibrium,’ Folke says. ‘But we look at it completely differently. We see resilience as the capacity to live with changing circumstances, and to deal with surprises.’

An important prerequisite for this is diversity. ‘In an ecosystem, all kinds of functions must be fulfilled,’ Folke explains. ‘Ideally, there should be several species performing a particular function. If one species is then eliminated, it is not a problem. In coral reefs, for example, you have species that make sure there are enough nutrients, but you also have so-called grazers. These are very important: they remove the dead coral, creating space for new coral to grow. In Caribbean coral reefs, there were originally many kinds of grazers: sea turtles, all kinds of fish, sea urchins. But due to overfishing, of these only sea urchins remained. In 1983, the sea urchins were wiped out by a pathogen. The absence of grazers prevented new coral from growing, but allowed algae to grow, and within five years the reef had been completely taken over.’

The same fate seems to befall many other ecosystems: we gradually reduce the diversity and, therefore, the resilience, after which a small shock, such as a virus or a storm, gives the system the final push towards a less desirable balance or even collapse. ‘Even if you look at the Earth as a whole, we have made the biosphere a lot less resilient in the last 60 years,’ Folke says. ‘We have greatly simplified landscapes and oceans, through intensive agriculture and overfishing, for example. In doing so, we have reduced the resilience to shocks. At the same time, climate change is increasing the shocks from extreme weather events, for example. That is not a good combination.’

Early in his career, Folke realised that you cannot solve this problem by considering humans as external factors affecting ecosystems, as was common at the time. People are not an external factor; they are embedded in the systems. Therefore, Folke linked the concept of resilience to these so-called social-ecological systems. ‘It does not make research any easier when you study social-ecological systems as a whole,’ Folke laughs. Nevertheless, he has made significant strides. Not only does he ask how the resilience of these systems changes, but he also explores how we can increase that resilience. ‘For example, we are looking at municipalities that have made a successful transformation to sustainable nature management. We can use that knowledge to help other municipalities, counties, and whole nations.’

On a larger scale, Folke recently mapped out which parties play a major role in ocean ecosystems. ‘We found that there were thirteen transnational fishing companies that together shape the food networks in the ocean. We are currently working with the CEOs of ten of them and trying to get them to stop seeing themselves purely as food producers and start seeing themselves and acting as stewards of the ocean. We are learning together how to maintain the resilience of the ocean, based on scientific understanding. We have been doing this for about six years now and it is going very well. I see this as a new kind of science, in which we use the best available scientific information to engage in dialogue with influential parties and spur them into action.’

Nature as a service provider
Folke realised during his studies that you cannot see economics and ecology in isolation from each other. ‘I initially studied business economics because we had a family business,’ Folke says. ‘But gradually I became interested in the way ecosystems support people’s lives. Gross domestic product, which measures economic progress, consists of goods and services. Back then, nature was included purely in the form of goods: raw materials. In 1983, in my master’s thesis, I was one of the first to make a quantitative analysis of the services that ecosystems provide us. I calculated what these services, such as pollination, water supply, and climate regulation contributed to our economy.’

One way we often use these days to show what the planet is doing for us is the ecological footprint: the amount of land or water surface area a population needs to sustain its consumption and waste production. Folke played a major role in developing this concept. ‘Biologist William Rees coined the term, and we developed a way to use it to illustrate the importance of ecosystems as service providers. In the mid-1980s, we began a calculation for fish farming. People thought at the time: we should not continue to empty the ocean, so we should farm fish instead. But we showed that you have to feed the farmed fish with fish caught in the ocean, fish which eat smaller fish and smaller fish eat animal plankton, and so on.’ At the base of that food pyramid are algae, which are fed by sunlight. But to ‘produce’ enough fish for the farmed fish required a sea surface area of algae production as large as 40 to 50 thousand times the surface area of the fish cages. They also made such calculations for the services of land-based ecosystems, which revealed that all of the world’s mega-cities require gigantic amounts of forest and marine systems to sustain them, for such things as food production and materials. ‘We wanted to show: whether you like nature or not, you depend on nature no matter what.’

Overloaded
Later, with his colleagues, Folke was part of introducing the concept of planetary boundaries. They defined nine different dynamic limits that humanity must stay within in order to continue to live well on the Earth’s services, for example, in the areas of warming, biodiversity, water scarcity, and ocean acidification. ‘With this, we wanted to make it clear that we depend on a healthy planet,’ says Folke. ‘A good metaphor is that of the Plimsoll mark on a ship. That is the point up to which you can load the ship, because otherwise it will sink. We are now close to the Plimsoll mark on Earth.’

Despite the pessimistic scenarios he faces daily, Folke remains positive. ‘It is a great challenge for us as humans to reconnect ourselves with the planet we live on. Sometimes you can get despondent about this because we see that positive actions are too slow. On the other hand, I would argue that we are in a kind of cultural revolution, in the way we look at ourselves as a species, in relation to the planet. You can see this in the new European Union legislation and in the actions of many companies. In the past few years, financial markets have also been trying to phase out fossil energy and move toward sustainable solutions. They are even starting to look at things like biodiversity. If you had told someone that ten years ago, they would not have believed you. But it is happening right now, and that is encouraging. So, I think we are on the right track, the only problem is that it needs to be a little faster. Whether it will be on time, the jury is still out on that. But in any case, we gave our species the name Homo sapiens, the wise human, so who knows?’

CV
Carl Folke (Stockholm, 1955) studied business economics and received his PhD in ecological economics from Stockholm University in 1990. In 1991, he became deputy director of the Beijer Institute of Ecological Economics, part of the Royal Swedish Academy of Sciences, also in Stockholm. Since 1997 he has been professor of Natural Resource Management at Stockholm University. In 2007, he founded the Stockholm Resilience Centre, together with Johan Rockström, where he has been scientific director ever since. He also became director of the Beijer Institute in 2007. In addition to the Dr A.H. Heineken Prize for Environmental Sciences, awards he has received include the Sustainability Science Award from the Ecological Society of America, the Planet and Humanity Medal of the International Geographical Union, and the Oceanographic Institute of Monaco’s Grand Medal Albert I in Science.

Research
Carl Folke studies how we can use the resources and services the Earth provides in a more sustainable way. He argues that social systems and ecosystems should not be studied in isolation, but rather considered as an integrated whole. He was instrumental in developing resilience theory for these social-ecological systems. As humans, we lower this resilience, making systems more vulnerable to disruption. Folke bridges the gap between science and policy and works with municipalities and companies to find sustainable solutions. He is at the forefront of influential concepts such as the ecological footprint, resilience, and Earth stewardship.

Video

Our scientific society is historically rare

Science and technology are an integral part of our society. But if you look at the whole history, it is quite extraordinary that science has come to play such an important role for us. Historian of science Lorraine Daston, director emerita of the Max Planck Institute for the History of Science in Berlin, examines how this development was possible. In 2020, she received the A.H. Heineken Prize for History for her work.
Our society is steeped in science and technology. Thanks to our many years of investment, scientific research is flourishing, and we are reaping plenty of benefits – directly and indirectly. For example, governments make many of their decisions based on scientific evidence. During the pandemic, we saw this more clearly than ever before. The technological marvel in our pocket – the smartphone – is here thanks to science, and many centuries of medical research have brought healthcare to the high level it is at today.

But it could just as easily have been different. If you look at history, you will see that every society has some degree of interest in its natural environment. But a society that structurally invests large amounts of money and manpower in a systematic study of that environment is a historical rarity, as historian of science Lorraine Daston discovered, both from the point of view of historical eras and from that of different cultures.
She researches how this rarity came to be: what conditions are needed to create a society in which science flourishes? In her study at the Max Planck Institute for the History of Science in Berlin, all the walls are covered with bookcases from floor to ceiling. ‘I surround myself with books, and read, and read, and read,’ Daston says. ‘I take copious amounts of notes and sort them by theme, a process I sometimes compare to chemical distillation, taking notes upon notes to locate the essential. At a certain moment, patterns reveal themselves to me, as well as a lot of new questions. With those questions, I delve back into the books.’

Fragile ecosystem
This led Daston to the discovery that there are two main conditions for richly flourishing science. ‘First, the prevailing view in society must be that science is so important that society is willing to invest heavily in research itself,’ Daston says. ‘But not only that: the career path of a scientist must also have cultural value: it must have a certain glamour factor. In every era, there are certain professions that are highly valued by society. These career paths attract the best and brightest. A second key requirement is that scientists be given sufficient autonomy and freedom. There must be institutionalisation, an organised system that protects researchers from the pressure to be immediately useful and generate economic value. Science must have a certain critical mass to bring about such institutionalisation. This institutionalisation is needed to protect the fragile ecosystem of science.’
Both conditions are currently under pressure. In highly developed countries in particular, fewer and fewer people aspire to careers in science. ‘This is a signal that the cultural standing of science is declining,’ says Daston. ‘Universities are also in danger of being overwhelmed by the demand for immediate usability and economic value. Historically, that’s not a sign of the flourishing of science. It’s a very fragile ecosystem that we need to protect.’

Bedrock layer of science
Daston also delved deeper into this ecosystem and examined the extent to which the way scientific research is done has changed throughout history. She has identified three different timelines, each with its own pace of change. ‘The first is the fastest,’ Daston begins. ‘In musical terms, you could compare the first tempo to allegretto. This is the speed of the latest empirical results, which follow each other in rapid succession. Each new issue of scientific journals like Nature or Science is filled with these hot-off-the-press scientific developments. Then there is a slightly slower timeline – andante in musical terms. This timeline consists of the various frameworks that make sense of these empirical results. An example of such a framework would be the theory of relativity or the theory of evolution. Such frameworks are not perpetual but remain in place for decades or sometimes hundreds of years.’
Daston is most interested in the third, deepest level. ‘This is the basso continuo of science – the slow evolution of fundamental practices and epistemic virtues. Examples of practices include the controlled experiment, which first appeared in the late seventeenth century; statistical surveys, a product of the nineteenth century; or computer simulations, which we have used since the late twentieth century. Once such a method is introduced, it is never lost. So, this ‘bedrock layer of science’ forms a very slow accumulation of new ways of gaining knowledge

Volcanic eruption
In general, changes on this timeline take place very slowly, but sometimes a new method appears suddenly. ‘An example is the “volcanic eruption” of probability theory in the mid-seventeenth century,’ says Daston. ‘People have been playing games of chance since time immemorial; there is archaeological evidence that the oldest civilisations were already using some kind of dice. But the idea of mathematics of probability suddenly emerged in the mid-seventeenth century. And that eruption still forms the basis for the probability theory that we use today.’
If you look purely at the bedrock layer of science, you can see beyond the boundaries of disciplines. For example, you see that statistics begins in the social sciences, as a method of describing populations. But then the method migrates to other sciences, such as the physics of gas molecules. ‘When Scottish physicist James Clerk Maxwell developed the theory of the ideal gas, he explicitly drew the analogy with a population in which individuals make contingent decisions,’ says Daston. ‘If you take those individuals together, you see a normal distribution: the familiar bell-shaped probability distribution. He compared these individual decisions of human beings to the velocities of the molecules in an ideal gas.’ Even today, there is a great deal of migration of new methods between different fields. For example, techniques from artificial intelligence can be used in many different situations, as long as you use the right training sets. Scientists use similar techniques to discover patterns in weather data, and to study whether plays were written by Shakespeare or someone else, for example.’

Emergence of photography
‘My research is constantly surprising me,’ says Daston. ‘For example, when I realised that concepts like objectivity or observation have a relatively recent history.’ Daston’s research, conducted with fellow historian of science Peter Galison, found that ‘objectivity’ as a virtue in science did not make an appearance until the nineteenth century. Before that ‘certainty’ and ‘accuracy’, for example, played a major role. The emergence of the pursuit of objectivity coincided, not entirely by chance, with the emergence of photography. Some scientific disciplines saw in the photograph the ultimate way to restrain their subjective projections onto their research subjects. ‘Objectivity is a way of trying to eliminate errors,’ Daston explains. ‘In particular, the errors that result from a scientist projecting his or her fantasies and wishful thinking onto nature,’ In disciplines such as anatomy or embryological development, for example, scientists exchanged the beautifully detailed colour drawings for blurred black-and-white photographs. Interestingly, here you can see directly that a virtue like objectivity can clash with other virtues, such as ‘accuracy’. Because a blurred black-and-white photograph may be objective, but cannot compete with a carefully executed colour drawing in perspective of an organ or stage of embryonic development for accuracy.
Photographs became more and more accurate, but this did not resolve a more fundamental clash: objectivity can also clash with the virtue of ‘truth’. ‘Truth-to-nature’ is about the underlying truths about nature, and not the properties of often variable specific manifestations. For example, in the eighteenth century, botanists such as Carl Linnaeus depicted in their drawings not one particular individual flower or plant, male or female, at a particular stage of development, but an idealised version. They were looking for the general characteristics of the species. Botanists worked with photography briefly in the nineteenth century, only to turn away from it very quickly. Photography was useless for their purposes. ‘Drawings are still often used in field guides about birds or plants for this reason,’ Daston says. ‘Biologists consider the “truth-to-nature” that a drawing gives more important than the objectivity of a photograph.’

Without exception
Daston recently completed a study on the history of rules, in the broadest sense of the word. ‘I looked at the history of rules in cookbooks, computer algorithms, manuals for warfare, game rules, traffic rules, dress code, spelling rules, laws of nature, and so on.’ Daston sought to discover underlying patterns: were there general developments on a large time scale in what a rule meant, or how it was formulated? She discovered that you can distinguish three categories of rules: rules as models, as precisely formulated laws, and as algorithms. We are still familiar with the latter two today. But rules as models were by far the most important until about the year 1800, and then largely disappeared from the scene. Such a model was an example that you could imitate but did not have to copy exactly – in much the way that role models might serve as a guide to conduct. Today, the vast majority of rules are formulated much more precisely, as ‘laws’ or ‘algorithms’.
Daston also looked at the history of exceptions to rules. ‘The interesting thing about exceptions,’ she explains, ‘is whether or not they are part of the rule. Until about 1800, rules were always formulated with a huge number of examples, exceptions, and appeals to experience and context. In a cookbook, for example, the authors tell you what to adjust if you are cooking at high altitude, or if you are using a different kind of oven. Or they make suggestions for how to replace one ingredient with another. In short, they include in the rules the fact that the world is surprising, that there are always unforeseen circumstances. But that flexibility begins to disappear after about 1800, when at least certain oases of stability emerge as a result of standardisation and globalisation. This is a world in which planning can extend months or even years into the future, in which “just-in-time supply chains” work and trains and planes are punctual.’
But how did this change come about? ‘In parts of the world, “pockets” of orderliness emerged. First, in certain cities, with Amsterdam as a shining example. By the eighteenth century, Amsterdam had become the perfect example of an orderly city in the minds of Europeans. Travelers admired its canals, waste disposal system, uniform house façades, and streetlights. Cities throughout Europe copied this model of orderliness. It took a century for this vision of urban order to be more widely realised, but because of this, around 1800, the utopian vision slowly emerged that perhaps all of society could be organised in this way.’ This was also increasingly seen in the formulation of rules: people dared to leave out all the different circumstances and exceptions.

Dynamic truth
Knowing the history of science is not only important for historians, but for everyone. We’ve seen this, for example, during the Covid pandemic. ‘It’s very disorienting for citizens, but also for policy makers, to see scientists change their minds,’ says Daston. ‘This is part of the normal and necessary process of science: in the light of new evidence, they modify their theories. But because of the limited understanding of how science works, such changes often confused the public and could be used to undermine trust in science. But the history of science shows that gathering new evidence and modifying conclusions on that basis is the necessary condition for scientific progress, not a flaw. This is one of the main messages to emerge from my research: the concept of an eternally unchanging truth, which we know from philosophy and religion, is not suitable for science. Science requires a dynamic idea of truth. Otherwise, there would be no scientific progress.’

CV
Lorraine Daston (East Lansing, United States, 1951) studied history and philosophy of science at Cambridge University in the United Kingdom and Harvard University in the United States. At the latter university, she received her doctorate in the history of science. After this, she held various positions at Princeton University, Georg-August Universität in Göttingen, and the University of Chicago, among others. Since 1995, she has been the director of the Max Planck Institute for the History of Science in Berlin, from which she retired in 2019. In addition, she continues to be connected to the University of Chicago. She has written many books about her work, including (with Peter Galison) Objectivity (2007), Against Nature (2019), and Rules: A Short History of What We Live By (2022). In addition to the A.H. Heineken Prize for History, Daston been awarded the George Sarton Medal from the History of Science Society, the Dan David Prize, and twice the Pfizer Prize from the History of Science Society.

Research
Lorraine Daston studies the historical conditions under which science flourishes in a society and the long-term development of forms of scientific rationality, such as probabilistic thinking, systematic observation, natural laws, and epistemic virtues such as truth-to-nature and objectivity. Her work translates abstract-sounding concepts into the concrete practices of doing science: making an image, conducting a statistical test, tabulating observations. She has published on a wide range of topics, from the history of probability to the wonders of nature; her most recent work has been on the moral authority of nature, the history of rules, and the origins of the scientific community.

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Light on the brain

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.

Algae genes
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.

Complex states
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.

Ethical questions
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.’

Transparent 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.’

CV
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.

Research
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.

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Music in the mind

How is it that music, at its core an abstract collection of sounds, triggers such strong emotions? And how does our brain process melodies and lyrics? It is questions like these that neuroscientist Robert Zatorre ponders daily in his Montreal laboratory. With his pioneering brain research, he even hopes to unravel what is at the heart of being human. In 2020, he received the C.L. de Carvalho-Heineken Prize for Cognitive Sciences for his work.
Robert Zatorre, professor of neuroscience at McGill University in Canada, made his first forays into music when he was about thirteen years old. He was eager to learn to play the sensational organ parts from the rock music of the 1960s, so he knocked on the door of an organ teacher. The latter, however, assured him that he had better ignore this rubbish and focus on the real thing. He took Zatorre to church and played Bach. Zatorre: ‘Afterwards I said, okay, you’re right. The rest is rubbish.’

Years later, when Zatorre combined training as an organist with studying psychology, the flame for science ignited in him as well. He wanted to discover how it was possible that music has such a powerful effect on the brain. Zatorre went on to become a pioneer in the cognitive neuroscience of music, the field that studies the effects of music on our brains. He made many groundbreaking discoveries, with important implications for neuroscience in general.
He never said farewell to the organ. In fact, in the middle of his lab is a beautiful digital organ, the sounds of which are based on an organ in Zwolle. When we visited him in Montreal, he surprised us by performing a beautiful piece by fifteenth-century Flemish composer Jacob Obrecht. Zatorre explains that the organ is the ideal addition to his lab not only because of his own background. ‘The organ is one of the few instruments for which you use two hands and two feet. This makes it ideally suited for music cognition experiments because of the coordination and flexibility required,’ he says. His two hands and two feet fly over the keys, producing beautiful sounds.

Anticipation of reward
One of the main questions Zatorre’s research seeks to answer is why music causes such strong emotions. ‘We tend to take this for granted,’ says Zatorre. ‘But how is it that we find a completely abstract pattern of sound beautiful, that it gives us pleasure, and sometimes even shivers or goosebumps? What happens in your brain?’
The mechanism behind this has only been discovered in recent years, and the research of Zatorre’s group played an important role in this. It showed that music acts on the reward system in the brain in the same way that, for example, food and sex do: through the neurotransmitter dopamine. It is pretty obvious why food and sex give us a sense of reward: we need them to survive and reproduce. Music, on the other hand, does not have such an essential function at first glance. So, why do we react to it so strongly?
‘Several things play a role,’ Zatorre explains. ‘One of the most important ones has to do with music’s ability to generate expectations, and then at times deviate from them just a little. We have long known that our reward system is sensitive not only to rewards, but also to the anticipation of rewards. If you repeatedly give a thirsty rat water after a flash of light, at some point its reward system will also respond to the flash of light itself. But what is even more interesting: if you put some sugar in the water, the reward system reacts even more strongly, because the reward is better than expected. We believe that music plays into this system of prediction, in which you have a sequence of events, and then you deviate just a little from the expectation.’

Statistical prediction
What those expectations are has everything to do with your previous exposure to music. Children do not yet have many expectations, which is why very simple songs give them a response. Adults usually find these songs boring. In order to excite their reward system, the composer and musicians have to try a little harder. Through years of exposure to music, adults have a certain statistical prediction of how music works. This can be in standard chord sequences, or melodies made up of notes from a specific scale. A good composer will occasionally put a ‘violation’ of these statistical regularities into his pieces on purpose. It is precisely these deviations that excite our reward system. ‘But the balance between predictability and surprise is very important,’ Zatorre stresses. ‘It should not be too surprising. That is why it is so hard to write beautiful music.’
That previous exposure, and the statistical information you get from it, also explains why different people like different types of music. If you are used to listening to pop music, you have a different frame of reference than if you have been listening to jazz from a young age. Differences between cultures are even greater, as Zatorre once experienced first-hand. ‘Colleagues took me to a concert in India once. I had no idea what was happening, but out of politeness I said afterwards that I thought it was very nice. But my colleagues apologized for the many mistakes the musician had made. I had no idea, it all sounded strange to me.’

Text and melody
A lot of music contains lyrics in addition to chords and melodies, and that combination puts our brains to work even harder. When we listen to a song, it sounds like a whole to our ears. But our brain processes the melody and lyrics of a song in a completely different way, in different hemispheres of the brain. Zatorre’s team demonstrated why this is. ‘Sound contains two different types of cues,’ Zatorre said. ‘The first type, called temporal cues, relates to how quickly things change in time: the rhythm of sound. In addition, you have the spectral cues: what frequencies, or pitches, are in the signal.’
Zatorre’s team filtered these cues out of a song in turn. And what did they find? When they removed the spectral information, you could follow the text easily, but the melody was completely gone. Conversely, without temporal information, the melody was easy to perceive, but the speech was incomprehensible. Zatorre: ‘Once we had shown that, the next step was to look at brain activity in the MRI scanner.’ A so-called functional MRI scan shows which brain regions are active at any given time. There is more blood flow with oxygenated blood in these regions. ‘When we had the subjects listen to the filtered songs in the MRI scanner, we saw that the left auditory cortex was able to follow the temporal cues easily (and, therefore, the speech), but not the spectral ones. And the right auditory cortex was able to follow the spectral information (and, therefore, the melody) easily, but not the temporal information.’ So, the brain processes these elements separately. How our brain then reassembles these elements into a single experience is something Zatorre hopes to find out in the coming years.

Voice recognition
Zatorre’s work is quite fundamental in nature, but that does not take away from the fact that there are all kinds of practical applications that arise from his research. For example, he showed that musically trained people are better at distinguishing speech in an environment with a lot of background noise, compared to people without musical training. He hopes to use this result to help (older) people with hearing problems. A colleague has already tried this out, Zatorre says. ‘He taught a group of elderly people, with no previous musical training, to play the piano for six months. After this, they were better at distinguishing speech from background noise. The effect was small but encouraging.’ However, this way is still a bit of a shotgun approach. Zatorre: ‘We want to find out what it is in musical training that causes this improvement. That way, you can design a teaching method specifically applied to this problem, and not just teach them to play an instrument.’
Zatorre’s group has already discovered that two different mechanisms are involved. First, as a musician, you sharpen your perception skills. ‘The ability to track information about frequencies, and therefore pitches, is more accurate in musicians,’ Zatorre explains. ‘This is because throughout their lives they often listen to different frequencies embedded in other sounds. For example, when playing in an orchestra or band, it is sometimes important to pick out one instrument among all the other sounds. This mechanism ensures that individual sounds are better registered in the brain, where in non-musicians it is more likely to become a wall of sound. The second mechanism also allows musicians to better select on which of those sounds to focus. We see more brain activity in the frontal areas in musicians. We think that has to do with control signals that are able to suppress some sounds and amplify others.’
But if you want to hear someone talk in a busy environment, you have to discern temporal information. To do this, as Zatorre’s group had previously demonstrated, you use a different hemisphere of the brain than you do to distinguish frequencies. So, why does frequently listening to different frequencies help filter speech? ‘We are not sure about that yet,’ Zatorre says. ‘Our hypothesis is that initially you mainly use the frequency information to distinguish the target text from the background. Then, you mainly need the temporal information to translate the text into the actual syllables.’

Fundamental questions
Zatorre’s other work also has important applications. For example, the better we know how music acts on the reward system, the better we can use these insights in music therapy. For example, to help regulate a less active reward system, as in depression or Parkinson’s, or, conversely, an overactive reward system, as in addiction. But Zatorre derives by far the greatest satisfaction from working with his team to explore and answer new fundamental questions. ‘When we do our experiments, we focus on very specific questions. But those specific questions are part of something much broader. Music and speech are things that distinguish us from other species. By studying how the brain enables us to produce, experience, and enjoy these things, we gain insight into what it means to be human.’

CV
Robert Zatorre (Buenos Aires, 1955) studied psychology and music at Boston University and received his PhD from Brown University in Providence in 1981. He then continued his career as a researcher at the Montreal Neurological Institute at McGill University. He has been a professor of neuroscience there since 2001. In 2006, together with Isabelle Peretz, he founded the International Laboratory for Brain, Music, and Sound Research (BRAMS), of which he is currently still co-director. In addition to the C.L. de Carvalho-Heineken Prize, Zatorre has received the IPSEN Foundation Neuronal Plasticity Prize, the Hugh Knowles Prize, the Oliver Sacks award, and the Grand Prix Scientifique from the Fondation pour l’Audition in Paris for his work, among others.

Research
Music and speech are important but complicated human forms of communication. Robert Zatorre and his team are researching how our brains process music and speech. As one of the pioneers in the field of music cognition, he uses music as a framework to explore complex cognitive functions, such as emotion, perception, movement, memory, attention, and aesthetics. For example, he demonstrated that music acts on our reward system in the same way that food and sex do. He also unravelled how and why different parts of our brain process music and speech, and he is researching how people learn music and how this process can be influenced.

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