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‘Cancer cells trick immune cells via sugars on their surface’

Cells communicate with each other through molecules on their surface. Biochemist Carolyn Bertozzi studies exactly how they do this and how to influence this communication. In doing so, she is laying the groundwork for revolutionary cancer treatments and rapid tests for tuberculosis, among other things. She recently received the Dr H.P. Heineken Prize for Biochemistry and Biophysics for her research. In early October, it was announced that she will also receive the Nobel Prize in Chemistry.

At Stanford University’s beautiful campus, full of palm trees, conifers, and countless meticulously maintained lawns, Carolyn Bertozzi is working on something that she herself regularly compares to a varied landscape: the cell surface. This surface is covered with a wide variety of molecules. Some short like freshly cut grass, some long and slow-moving, like trees in the wind. Through these molecules, cells communicate with each other. ‘When cells become part of tissue, for example, they have to organise themselves,’ says Bertozzi. ‘Muscle cells end up in your muscles, neurons in your nervous system, blood cells in your blood. Thanks to the molecules on the cell surface, these cells are in the right place at the right time.’ Sugar molecules play an important role in this. Because there is a huge diversity in the structure of sugar molecules, the pattern of sugars on the cell surface can pass on complex information.

These sugars are also essential for your immune system. ‘Your immune system needs to be able to distinguish which cells belong in your body and which don’t,’ says Bertozzi. ‘The good guys are healthy cells, which your body needs to function. But there are also bad guys – disease-causing bacteria, cancer cells, or cells infected by a virus. By tasting the sugar molecules on the cell surface, so to speak, immune cells can recognise the bad guys, and then make short work of them. They leave the good guys alone.’

But as we see in films and comic books, bad guys always find ways to avoid getting caught. For example, Bertozzi discovered that cancer cells sometimes mask the suspicious sugars on their cell surface by making large amounts of unsuspicious sugar sialic acid appear on their surface. ‘It has been known since the 1960s that the sugar molecules on cancer cells are often very different from those on healthy cells,’ Bertozzi explains. ‘One of those differences is that there is more sialic acid on the cell surface. But no one understood why. A group of receptors – proteins in the cell membrane that can trigger a reaction when a specific molecule binds to them – known as the siglec family was discovered in the late 1980s. These receptors are on immune cells and were found to suppress the activity of those immune cells when they detect sialic acid on other cells. This way, your immune cells make sure they don’t accidentally attack your own cells, which would lead to autoimmune disease. In the early 2000s, we put these two together in my lab: if cancer cells have lots of sialic acid and sialic acid can suppress immune cells, maybe the cancer cell uses that sialic acid to protect itself from our own immune system.’ This turned out to be correct, and Bertozzi has since used this insight to develop a new form of immunotherapy, which is currently being tested in cancer patients. ‘In this treatment, an enzyme mows the sialic acid off the cancer cells like a lawnmower,’ says Bertozzi. ‘The cancer cell can then no longer bind to the siglec receptors on immune cells to suppress the immune system.’

The lawnmower is not the only gardening metaphor Bertozzi enjoys using when she talks about her technologies. ‘We are also currently developing another method of immunotherapy, which works more like a chainsaw: it cuts down the longer molecules. But we don’t just cut molecules from the cell, we can also plant new ones. For example, we created polymers with sialic acid attached. We plant this combination on cells, and thanks to the sialic acid, immune cells leave these cells alone. You can use this in a transplant, for example. In that case you want to make sure that the organ you implant is not attacked by the recipient’s immune system.’

Giving up control
In addition to her work on the cell surface and immunity, Bertozzi was a pioneer in so-called bioorthogonal chemistry, which involves performing chemical reactions in a biological environment, such as a cell or an animal, without affecting that environment. For her work in this field she receives the 2022 Nobel Prize in Chemistry. ‘When we started this in the late 1990s, people said: “What are these people doing?” Chemists were used to being able to control all components of a chemical reaction – the solvent, temperature, pH, etc. But if you want a reaction to take place in a living cell or in a human cancer patient, you have to give up all that control. You can’t heat the cells to 110 degrees Celsius or add a strong acid – you will kill the patient.’

Bertozzi set out to find reactions that could take place under the conditions in human cells without disrupting the regular processes in the cell. ‘We found some reactions that were close, but not perfect,’ says Bertozzi. ‘Then we perfected them until they were completely bioorthogonal and you could perform them in cells and humans. That is how that field of research was born.’ Since then, many more people have entered the field and built on the bioorthogonal reactions developed by Bertozzi and colleagues. Currently, several biotech companies are using these reactions in human patients, for drug delivery and cancer treatment, among other things.

For example, the Shasqi company, for which Bertozzi is a strategic advisor, has developed a cancer treatment that can deliver chemotherapy drugs very precisely into the tumour. This treatment consists of two steps. First, they inject a polymer in the tumour environment. To this polymer, they have added a component that forms one half of a bioorthogonal reaction pair. They then administer a chemotherapy drug. Again, they have added an extra component: the other half of the reaction pair. This component ensures that the drug is not toxic (yet). It spreads throughout the body but does no harm. Once near the tumour, the two halves of the reaction pair click together, so to speak. They engage in a reaction that unblocks the drug. This releases the drug locally in a very high concentration. The drug kills the tumour without exposing the rest of the body to the aggressive drug. This allows you to administer higher concentrations, while the patient experiences far fewer side effects.

Trojan molecule
The original inspiration to start bioorthogonal chemistry came from Bertozzi’s research on sugars on the cell surface. ‘We wanted to image these sugars, in living cells or even in animals,’ says Bertozzi. ‘The sugars on the cell surface are long sugar chains made up of simple building blocks. And these building blocks come from the food you eat.’ So, Bertozzi took one such sugar building block, and tied an extra component to it, which again was half of two molecular clasps that could snap together. She then fed that sugar building block to cells or animals, which incorporated it into the sugar chains on the cell surface. The extra component hitched a ride without the cell noticing. Now all she had to do was add the other half of the molecular clasp, with a fluorescent molecule attached, and the sugar molecules lit up like a lighthouse in the night. ‘This was the first technology to image living cells and the sugars on their surface,’ says Bertozzi.

Recently, this led to an entirely new application: a rapid test for tuberculosis. Tuberculosis (TB) is caused by a bacterium. And like human cells, bacteria have sugars all over their surface. Bertozzi’s team cleverly exploited the fact that the sugar trehalose is common on the surface of tuberculosis bacteria, but absent on human cells. ‘We discovered that we could feed tuberculosis bacteria chemically modified trehalose and they put this all over their surface.’ As in the earlier experiment, they added a clasp to the sugar to which they could later click fluorescent molecules. ‘These fluorescent molecules have a special property,’ says Bertozzi. ‘They are not fluorescent in water, but when they reach the cell membrane, the fluorescence switches on. So, you can see the tuberculosis bacteria light up under the microscope.’ This enables rapid TB diagnoses, by examining patients’ blood or coughed-up mucus. It also allows you to monitor whether TB medication is taking effect. ‘You want to know this as soon as possible because there are drug-resistant forms of tuberculosis,’ says Bertozzi. ‘In addition, another research group has shown that you can also use this technique to detect tuberculosis cells in air filtration systems. TB is spread through the air. We may soon be able to detect TB outbreaks at an early stage, through the air filtration system in schools, hospitals or railway stations, and isolate people as soon as possible. Wouldn’t that be great?’

CV
Carolyn Bertozzi (Boston, 1966) studied chemistry at Harvard University in the United States. She received her Ph.D., also in chemistry, from Berkeley University in California in 1993. In 1996, she was appointed professor of chemistry and molecular cell biology there. In 2015, she moved from Berkeley University to Stanford University and became professor of chemistry and of chemical systems biology. Her scientific work forms the basis of more than fifty patents, and she is co-founder of several biotech companies, where her research results find their way into medical applications. Bertozzi received the Wolf Prize, the Solvay Prize, and the Nobel Prize in Chemistry, among others.

Research
Carolyn Bertozzi is developing chemical methods to study and influence the cell surface. Our cells communicate with each other through molecules on the cell surface. Immune cells, for example, can tell from these molecules whether a cell belongs in the body or not. Bertozzi discovered that cancer cells fool immune cells by presenting large amounts of a specific sugar molecule on the cell surface. She developed technologies to ‘mow down’ these sugar cells, which allow immune cells to recognise the cancer cells as dangerous and attack them. In addition, she developed many other technologies to influence proteins inside the cell and on the cell surface. In doing so, she was at the forefront of so-called bioorthogonal chemistry.

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.

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Casper van der Kooi (1990), an evolutionary biophysicist at the University of Groningen, is the recipient of the Heineken Young Scientists Award in the Natural Sciences. The jury commends his work for its scientific excellence and significant social value. Van der Kooi studies how flowers and animals, such as butterflies, get their colours and how these colours are used to attract pollinators or mates. Thanks to his work, we now better understand communication between animals, as well as between plants and animals. 

Charlene de Carvalho-Heineken established the Heineken Young Scientists Awards in 2010 to honour young scientific talent for their outstanding achievements. Since then, the prize has been awarded every two years to four highly promising young researchers affiliated with a Dutch university or research institute and who are working in one of the following domains: Medical/Biomedical Sciences, Humanities, Natural Sciences, and Social Sciences. Each laureate receives an unrestricted cash prize of €15,000 as a reward.

Plant research
Why is a daisy white and a dandelion yellow? Across the world, millions of flowers in all kinds of colours. But why do flowers have these colours, and where do they come from? This is what Casper van der Kooi studies. Plants use flowers to catch the eye of pollinators such as bees and birds, with colours playing an essential role. Van der Kooi’s research has revealed that a flower’s colour is determined not only by its pigments, but also by its internal structure. Flowers consist of several layers of cells which reflect light in different ways. The properties of these cell layers, together with the pigments, determine the flower’s appearance.

Van der Kooi also investigates how the appearance of plants evolves to make them maximally visible to their pollinators. Flowers seem to appear their colour and brightness. Accordingly, this is because not all pollinators perceive the same colours, or they see some colours more vividly than others. For instance, many insects are unable to see red. Nature, in its wisdom, has ensured that flowers that rely on insects for pollination are never red. 

Van der Kooi enjoys doing field research but is just as happy looking through the microscope at cell structures in his greenhouse in Groningen. Here, he grows plants from around the world, studying how pollinators perceive flowers and using this knowledge to discover how different flower colours are created.

Butterfly research
Lately, Van der Kooi has also been focusing on butterflies. He studies how the colours of their wings form and evolve to best attract a mate. According to Van der Kooi, what makes butterflies unique is their brilliant colours and how dynamic they are. They fly around each other, continuously reflecting light in a different way. With his team, he is investigating how butterflies’ colours combined with their behaviour determines their attractiveness to potential partners. 

Jury praises multidisciplinary research
The jury has called Van der Kooi’s research multidisciplinary approach. To enable this type of research, Van der Kooi earned two PhDs: one in computational physics and another in evolutionary biology. By combining these areas of expertise, he crosses scientific boundaries. The jury believes this makes his work unique and of high quality. He also fulfils a social role by discussing biodiversity issues as a frequent guest on radio, TV, and in newspapers. With this, he hopes to bring the abstract concept of biodiversity to life, raising awareness of its importance among a broad audience. To appeal to a younger audience, he is also working on a children’s book about plant evolution.

About Casper van der Kooi
Casper van der Kooi (1990) studied evolutionary biology at the University of Groningen. He completed his PhD in computational physics in 2015 and in evolutionary biology in 2018. Following a postdoctoral position at the University of Groningen and a Humboldt Fellowship at the University of Würzburg in Germany, he rejoined the University of Groningen as a university lecturer in evolutionary biophysics in 2023. 

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‘Pollution was seen as an inevitable consequence of development’

Today, we are facing major challenges in the areas of climate change, inequality, and health. Historian Sunil Amrith is convinced that by charting the historical development of these problems, we can tackle them more effectively. For his research on environmental, health, and migration history in South and Southeast Asia, he received the Dr A.H. Heineken Prize for History.

Air pollution is one of the most common causes of death in India today. As early as the 1940s, doctors warned of the harmful health effects of air pollution, but it has not been possible to solve this problem to date. The same is true of climate change as a result of greenhouse gas emissions. Sunil Amrith, professor of history at Yale University in the United States, is trying to understand how such problems can continue to grow for years when the knowledge is there. ‘Hopefully, this understanding will help us determine how to get out of this mess,’ says Amrith.

Amrith focuses specifically on the history of South and Southeast Asia – roughly the area between Pakistan and Indonesia. In addition to environmental and health history, he also charts the large-scale migration that has taken place in this region. A common thread in his work is inequality between and within countries, which often has its origins in colonial history. This inequality in wealth, power, and political voice continues to be felt today, causing people to face today’s challenges, such as climate change, from very unequal starting positions.

Whereas historians have been recording the history of politics, social systems, and culture for centuries, environmental history only gained a firm foothold in the 1980s. ‘Environmental history helps us better understand economic change and social history,’ says Amrith. ‘People have never been detached from nature, although that has often been the ambition of engineers and governments.’ One of the environmental aspects Amrith has studied is water. ‘In the Netherlands, you know only too well how great an effect water and water management can have on history,’ he laughs. ‘The same applies to South and Southeast Asia. Take the monsoon, for example, a highly seasonal pattern of rainfall that is very unevenly distributed over the area. It has caused great regional disparities in food security and has had far-reaching consequences for the way in which agriculture and the economy are organised.’

Rivers, too, have strongly influenced the history of South and Southeast Asia. ‘About three billion people depend on the rivers that rise in the Himalayas for irrigation, drinking water, and fishing, among other things,’ says Amrith. ‘These rivers have faced various crises, such as climate change and pollution. But damming has also caused great tensions between countries. The tendency is to build bigger and bigger dams, at ever shorter distances from each other, and higher up into the mountains.’ This increases the number of dam breaches, with all that that entails – not only for the inhabitants near the dam, but also in the countries further downstream.

‘The question is always who pays – directly and indirectly – for these projects,’ says Amrith. ‘It is not evenly distributed. In India, for example, some 40 million people have had to relocate since the 1940s due to damming and other major infrastructure projects. This is not a random forty million, but mostly tribal people. They do not have the same political voice and the same power to negotiate for compensation, let alone to prevent these projects from taking place. This is a pattern that is still relevant today. The people who consume very little, and thus have contributed very little to the global climate crisis, are often the first to suffer the consequences. Over the last twenty years, extreme weather conditions have become more frequent worldwide. Communities in South and Southeast Asia that live in informal settlements are the first to suffer, as these are often low-lying settlements with little protection from storms and flooding.’

Cumulation
Yet the relationship between devastating environmental conditions and migration is less straightforward than you might initially think, Amrith discovered. ‘About half a century ago, the idea prevailed that environmental factors determine everything, especially in poorer countries in Asia. The thinking was: if Asian workers migrate, it is because of floods or droughts. But since the 1980s, we have realised that it is much more complex: family networks, economic opportunities, and people’s dreams also play a major role. But now we have gone a bit too far – at the end of the twentieth century, migration studies no longer had any connection with the environment. This was because historians were anxious to keep away from the image of Asian migrants as an unwilling plaything of circumstances. So, when we talk about climate migration in the future, we can learn a lesson from this: there are always multiple and complex reasons for migration. Even in the case of climate change, not everyone can migrate just anywhere. Where people can go is limited by the politics, borders, and policies of neighbouring countries. There is definitely a relationship between climate change and migration. But it is always cumulative. It is not as if climate change comes out of nowhere and suddenly makes an area uninhabitable. Mostly it is about how climate change brings existing inequalities and other challenges to a head.’

Amrith studied the history of migration in South and Southeast Asia and wrote the book Crossing the Bay of Bengal, which appeared in 2015. ‘The Bay of Bengal, the north-eastern part of the Indian Ocean, was one of the most interconnected and mobile regions in the world in the 19th and 20th centuries,’ he says. ‘Historians often focus on large-scale migration across the Atlantic. But at least as many people crossed the Bay of Bengal at the end of the nineteenth century.’ Amrith showed that this migration ensured a constant circulation of cultural, religious, and political ideas. But in addition to the story of solidarity, the book also tells the story of growing division. At that time, Southeast Asia was largely in the hands of the British Empire. As more and more countries gained independence, nationalists wanted to stop large-scale migration, believing that the free movement of people was not in the interest of the newly formed countries. ‘That is also a message of the book,’ says Amrith. ‘How quickly a region held together by the movement of people can freeze and fall apart.’

Health crisis
Currently, Amrith is working on the relationship between air pollution and health in India. ‘Cities in India are among the most polluted in the world. Yet this has only recently been treated as a public health crisis. Previously, it was seen as an inevitable consequence of industrialisation and development.’ Doctors in India warned of the harmful health effects of air pollution and supported this with studies. An important question is how this nevertheless could have become such a major problem. ‘This has to do with a universal problem,’ says Amrith. ‘Since the middle of the twentieth century, the world has stuck to a specific path of development. The goal was: increase the middle class, they buy cars, and use them instead of public transport. It was supposed to provide more freedom and comfort. Cars, along with industrial pollution, are a major reason why the air pollution problem has grown so rapidly. For a long time, the idea prevailed that pollution was the inevitable consequence of welfare development. The same happened in industrialising European and North American cities in the late nineteenth and early twentieth centuries. In London, for example, there was a major smog problem. It was only after the smog crisis in the 1950s that the UK began to regulate air quality. The American Clean Air Act only really came into being in 1970. India too has had good air pollution laws since the 1970s, but enforcement is a major problem. It is outsourced to local governments that do not have the authority to do much. Yet it is not an entirely negative story. In the early 2010s, around two hundred million people in India had no access to electricity. They only had access to cheaper, more polluting sources of energy. For example, they cooked using biomass. Now, the availability of electricity in India has grown significantly, although much of it is still generated by coal. But more and more comes from solar panels. So, things are definitely moving in the right direction.’

CV
Sunil Amrith (Kenya, 1979) grew up in Singapore and then moved to the United Kingdom to study history at Cambridge University. He received his PhD in history from the same university in 2005. After working briefly as a researcher at Trinity College, Cambridge, he was appointed lecturer at Birkbeck College, part of the University of London. In 2015, he was appointed Mehra Family Professor of South Asian History at Harvard University. Since 2020, he has been Renu and Anand Dhawan Professor of History at Yale University. Among other things, he has received a MacArthur Fellowship.

Research
Sunil Amrith studies the history of South and Southeast Asia. He is interested in the close ties between the two regions, focusing mainly on the nineteenth and twentieth centuries. Among other things, he has mapped out the large-scale migration between these areas. He also focuses on the history of the environment. He recently wrote the book Unruly Waters, in which he explains why water has played such an important role in the history of South and Southeast Asia. In his work, he tries to find the historical origins of the great inequality that exists today between and within countries.

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.

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Manon van Scheppingen (1988), a university lecturer in developmental psychology at Tilburg University, is the recipient of the Heineken Young Scientists Award in the Social Sciences. The jury praises the quality and impact of her research into the influence of major life events, such as having a child and getting married, on personality change in young adults. Today, thanks to Van Scheppingen’s research, we better understand the origins of differences in personality.

Charlene de Carvalho-Heineken established the Heineken Young Scientists Awards in 2010 to honour young scientific talent for their outstanding achievements. Since then, the prize has been awarded every two years to four highly promising young researchers affiliated with a Dutch university or research institute and who are working in one of the following domains: Medical/Biomedical Sciences, Humanities, Natural Sciences, and Social Sciences. Each laureate receives an unrestricted cash prize of €15,000 as a reward.

About the study
Manon van Scheppingen studies personalities, focussing on how people think, feel, and behave. Specifically, she investigates how personality develops during adulthood and the influence of significant life events, such as having a child, getting your first job, or moving in together.

For example, Van Scheppingen explored whether the transition to parenthood leads to a more mature personality, including more self-control and emotional stability. This proved not to be the case: on average, parents were found to develop no differently from their peers without children. Nevertheless, the study did show that parenthood can indeed bring about change. For instance, she observed that some new parents, particularly mothers, temporarily experience lower self-confidence. She plans to further investigate the causes of this phenomenon in the coming period.

Another of Van Scheppingen’s discoveries is about romantic partners. Despite the common saying that opposites attract in romantic relationships, people still usually select a partner with similar personality traits. In the future, Van Scheppingen hopes to use her work to give more people insight into their own personalities, enabling them to apply this self-knowledge when making important life choices.

Jury honours social impact and multidisciplinarity
The jury praises Van Scheppingen for her multidisciplinary expertise. She knows how to make an impact with her research by combining insights from developmental psychology, demography, and sociology. She effectively reaches a non-scientific audience, sharing her knowledge through media and public lectures. In addition, the jury appreciates Van Scheppingen for the way she manages to respond to social developments, such as with her research into the development of loneliness as a result of lockdowns during the COVID-19 pandemic.

About Manon van Scheppingen
Manon van Scheppingen (born 1988) studied remedial education at VU University Amsterdam. In 2018, she received her PhD in developmental psychology from Tilburg University. During her PhD, she researched how personality develops in the context of parenthood and romantic relationships. Following a postdoctoral position at the University of Amsterdam, she has been a university lecturer in the department of Developmental Psychology at Tilburg University since 2019. 

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‘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.

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‘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

Health psychologist (1985), connected to Leiden University, has been awarded the Heineken Young Scientists Award 2022 in the field of Social Sciences. The jury praised her important contribution to improving the quality of healthcare for seriously ill patients, thanks to better communication between doctor and patient. Van Vliet’s research into how communication can help and harm patients shows a valuable translation between research and society.

The Heineken Young Scientists Awards are awarded every two years to four highly promising young researchers working in the Netherlands. The winners are selected from four fields of science: Medical/Biomedical Sciences, Humanities, Natural Sciences, and Social Sciences. The Royal Netherlands Academy of Arts and Sciences is responsible for the nomination and selection process. The award includes a cash prize of EUR 10,000 and a work of art. Previous laureates in the field of Social Sciences include Anna van Duijvenvoorde (2020) and Marie-José van Tol (2018). The award was created in 2010 by Charlene L. De Carvalho-Heineken.

About the study
Van Vliet studies forms of communication that make patients feel better, e.g., experiencing less stress and better remembering information, or feel worse when confronted with a serious illness. She is at the cutting edge of health communication, palliative care, and placebo and nocebo effects. In the laboratory, for example, she uses video vignettes to study the effects of certain ways of communicating. She also uses observational research in the medical office to look at the specific elements of communication and how they relate to patient outcomes. For example, one of her analyses shows that terminally ill patients feel better under the care
of more empathic doctors, and that they also remember more of a conversation with this type of doctor. This makes Van Vliet a versatile researcher who not only seeks answers to fundamental questions, but also knows how to translate the results into practice.

Jury praises direct application of knowledge in daily life
The jury admires the way in which Van Vliet actively engages in outreach. She regularly appears in newspapers and magazines, presents her work for professionals and other interested parties, and organises scientific events for a wide audience. Her work is also included in clinical bad-news guidelines and is thus directly applied in the consulting room on a daily basis. With her work, Van Vliet makes an important contribution to improving the quality of care for seriously ill patients.

About Liesbeth van Vliet
Liesbeth van Vliet (Lusaka, Zambia, 1985) studied clinical and health psychology at Erasmus University Rotterdam and obtained her PhD in 2013 for her research on communication during the transition to palliative breast cancer care at Utrecht University/Nivel. After her PhD, she worked for several years at the Cicely Saunders Institute at King’s College London. Currently, Van Vliet is a lecturer at the Department of Health, Medical, and Neuropsychology and KWF Young Investigator at Leiden University. In addition to the Heineken Young Scientists Award, she has also received the KNAW Early Career Partnership (2021), the Dutch L’Oreal-UNESCO for Women in Science Award (2019), and a KWF Young Investigator Grant (2018).