‘Neuropsychiatric conditions are traditionally classified according to visible, qualitative symptoms. A distinction is made between groups of patients who deviate from the norm, without the need for any biological qualification. What we do is fundamentally different. In behavioural biology, we look at the biological causes of behaviour. This transcends individual disorders: patients with very different diagnoses such as depression, dementia or schizophrenia, may show striking similarities when it comes to reduced social interaction.

One of the ways in which we try to work out whether these shared symptoms have a common biological basis is by conducting animal tests. We want to know how circuits in the brain develop and how they contribute to social behaviour. Many neuropsychiatric conditions appear very early in life, when the cortex (the area that processes outside stimuli) is still developing. Mice are perfect for such experiments, because their brains process stimuli in much the same way as human brains. In addition, mice display a whole range of social behaviours. We make EEGs, for example, or analyse the development of the brain systems of mice displaying reduced social interaction.

To translate this into human behaviour, we record the same kind of data as we would for human patients. Brain scans, blood levels, but social behaviour too. We try to observe behaviour as objectively as possible. Measuring social behaviour in patients is extremely tricky. Research of this kind usually involves questionnaires, but of course we never know whether patients have a realistic idea of their level of social interaction. To overcome this problem, we have developed an app for smartphones, which monitors user behaviour, for example, whether they leave the house, how often they make phone calls, use WhatsApp and so on. This gives us a good, objective impression of their behaviour.

We hope that these approaches will help us to understand the biological mechanisms behind social withdrawal and ultimately develop better medication for the abnormal behaviour associated with various brain disorders, such as depression, dementia and schizophrenia. We are not conducting this research on our own. One of our partners is a large European consortium working under the name PRISM (Psychiatric Ratings using Intermediate Stratified Markers). This project, funded by the Innovative Medicine Initiative (IMI), pools the resources of thirty-three universities and pharmaceutical companies (http://www.prism-project.eu/)’.

‘Good model organisms are essential for carrying out research into fundamental biological processes such as the development of diseases or ageing. As these are highly fundamental processes, a lot can be achieved with research into invertebrates such as yeast cells and worms. The basic molecular mechanisms in vertebrates and invertebrates are reasonably similar. Yeast and worms are relatively cheap and have a short life cycle. But the main advantage – the fact that they are invertebrates – is also the main disadvantage. You reach a point when you want to test your findings on vertebrate organisms that resemble humans more closely.

We often use mice in our research into ageing, but zebra fish are a good alternative. The tricky thing about studying ageing is that the symptoms we want to examine typically do not appear until late in life. This isn’t a problem with invertebrate models because they only live for a matter of days or weeks. Mice and zebra fish, on the other hand, take two to three years to age. This makes that the research proceeds at a relatively slow pace.

We are therefore in urgent need of a vertebrate model organism that ages rapidly. In recent years, we have been looking at a new, promising model organism: the killifish (Nothobranchius furzeri). The origins of the killifish have led them to develop very quickly. The fish come from Africa, where they grow in pools during the short rainy season and lay eggs right at the start of the ensuing long dry period. Their entire life cycle lasts just a few months; months in which the fish genuinely age. The brightly coloured males start to fade towards the end of the season, they lose their eyesight, move around less actively and have an increased risk of developing cancer.

In short, the fish display many of the signs of ageing that occur in humans. We also think that killifish could be an effective model for studying neurodegenerative diseases and metabolism. Research using killifish is still at an early stage; there are only a few laboratories in the world currently working with these fish. But the number is growing. At the moment, we have several hundred fish in our tanks, but our research still focuses on how best to look after them. And we are obviously looking for suitable research projects that can be modified to use killifish to speed up our research into ageing’.

‘It is vital to diagnose infections early. Once an infection takes hold, the bacteria can form a plaque or become encapsulated. This makes them inaccessible to antibiotics, and the infection becomes difficult to treat. People sometimes even need additional surgery to combat the infection. Moreover, prolonged and difficult courses of antibiotics increase the risk of antibiotic resistance.
The biggest challenge is diagnosing and localizing an early infection in a patient. In our lab, we are exploring whether we can do this by using fluorescing molecules that travel to the locus of infection, causing it to shine when illuminated.
The first step in this research is to design and build a fluorescing substance that is specific to bacterial infections. We tried taking an antibiotic molecule – vancomycin – and attaching a commonly-used fluorescent molecule. We know that vancomycin attaches specifically to the cell wall of a particular group of bacteria and not to human cells. Another advantage is the fact that vancomycin is a current and safe drug, which means that the combination molecule is probably safe too.
We now need to carry out tests on tissues and animals to check whether this combination molecule actually works in the way we hope and can be used in patients. We first tested the substance on dead human tissue. After pre-treating the bacterium Staphylococcus epidermidis with the labelled antibiotic, we introduced the labelled bacterium under the skin. Thanks to the fluorescence, this artificial infection was indeed visible through the skin. Although this demonstrated the technical success of the substance, it was still an artificial situation. A tissue model like this obviously lacks any circulation, for example.
Before moving to clinical use on patients, we conducted two animal experiments to test the effect of the substance in vivo. We conducted these experiments in collaboration with colleagues from Germany and the United States. Mice with an infected hind leg were treated with the labelled antibiotic, after which we recorded the site of fluorescence. This indeed proved to be the locus of infection, demonstrating that the principle works. The bladder also lit up, but this was not altogether unexpected because vancomycin is secreted in the urine’.

‘I chose the word “talking” carefully – it is a dialogue. And it’s a two-way dialogue: the intestinal bacteria influence our health and behaviour, but our behaviour can also change our gut flora.
The intestines have a direct link with the brain via the vagus nerve, an important neural pathway that transmits signals in both directions between the gut and the brain. Bacteria influence this communication. Intestinal bacteria are like tiny factories for neuroactive substances. They produce the same chemical substances – neurotransmitters – that our nervous system uses to communicate. These include serotonin, dopamine and noradrenalin. Since the bacterial population influences this production, it has a direct impact on the behaviour and mood of the host.
In other words, it is important to ensure a good variety of intestinal bacteria. Having adequate gut flora starts at birth. During delivery, a baby comes into contact with the mother’s vaginal microbiota. The composition of this microbiota largely determines the composition of the baby’s gut flora, which in turn influences the development of the infant’s immune system, metabolism and brain. An abnormal composition due to stress, diet, infections or the use of antibiotics will therefore affect the health of the child.
To understand these effects, researchers are studying the gut flora of mice. They examine how prenatal stress in pregnant mice, for example, affects the gut flora of newborn mice. Their gut flora shows signs of abnormality immediately after birth, but by adulthood, the microbiota of these mice is no different from that of “normal mice”. However, as soon as these mice are put under stress, their gut flora shows a strong reaction. It seems that mice whose mothers were stressed are themselves more sensitive to stress. So the bacteria in our gut appear to be one of the factors that determine whether we will become anxious or depressed.
I also study another important factor that affects our gut flora: nutrition. Our diet is very different from that of our ancestors. A prehistoric diet would have contained many more indigestible ingredients, which then served as food for the intestinal bacteria. Our current diet is threatening the existence of many of these ancient bacteria. We want to understand the implications. And whether we can limit the damage by eating more indigestible food.

Research into the interaction between intestinal bacteria and the brain is relatively new. We still understand very little about this highly complex relationship. Looking to the distant future, I think that this field may provide starting points for developing new drugs to treat mental health problems. We’ve noticed, for example, that many behavioural disorders occur in people with intestinal problems or food allergies. Take ADHD, autism or depression, for example, or certain brain diseases, such as Parkinson’s disease or Alzheimer’s disease. There is still a lot to discover in this particular field’.