Professor of molecular endocrinology Marcel Schaaf conducts fundamental research into stress hormones and their receptors, whilst also exploring applications in medication.
Friday, 5 December, late afternoon. Normally the moment at which a poem must be hastily written under intense time pressure. Not so for professor of molecular endocrinology Marcel Schaaf, who chose this moment to deliver his inaugural lecture at Radboud University, where he has been appointed since 1 February. Fittingly, he told a story about stress, in which a cortisol-laden Zwarte Piet – who is not doing particularly well – plays a central role. ‘In the lab in Leiden I often played Sinterklaas too, so it felt right’, Schaaf says a few days later in his office in Nijmegen.
A love of microscopy
Research into stress hormones or drugs derived from them – both referred to as corticosteroids – came early in Schaaf’s career. ‘As a PhD student I was already looking at corticosterone, in rats. That was more behavioural research; afterwards I shifted my focus to the molecular side. But I have had the luxury of always staying within the same subject’, says Schaaf. That focus on molecular biology also gave rise to a love of microscopy, first during postdocs in the United States and England, and later at Leiden University. During his inaugural lecture, laughter broke out in the hall when Schaaf spoke with great passion about images in which a layperson sees little more than moving dots.
Valuable
‘You might find that amusing, but it really is fascinating. You could see individual receptors moving through a nucleus. Being able to look at a single molecule in a living cell – even in a living organism now – is enormously valuable. The same applies to fluorescence microscopy. Today it might seem perfectly normal to label proteins with green fluorescent protein (GFP), but that simply wasn’t possible before.’ As well as beautiful images, this also yields a great deal of knowledge. ‘Previously we had no idea how dynamic everything is. Now we could see that the principal receptor for stress hormones, the glucocorticoid receptor (GR), first appears to scan DNA, then binds for only a few seconds before the next one takes over.’
Zebrafish
In Leiden, Schaaf also took up the zebrafish as an animal model. A fine combination, since zebrafish larvae are transparent, allowing fluorescently labelled cells or proteins to be tracked easily under the microscope. ‘It took a great deal of time to establish this model properly. We had to catch up with mice and rats; by now we have managed that. Zebrafish offer many advantages – because of their transparency, but also because behavioural studies can easily be carried out with large numbers. And thanks to CRISPR-Cas, it is now relatively straightforward to knock out a gene in zebrafish as well’, says Schaaf. Those large numbers become strikingly apparent during a tour of the zebrafish facility, with its countless tanks housing different zebrafish lines.
Mutant
Among them is a zebrafish mutant with which Schaaf’s research group recently produced remarkable embryos. GRs normally form pairs, but these are not always GR–GR pairs. The stress hormone cortisol can also bind to the mineralocorticoid receptor (MR). In addition to MR–MR pairs, MR–GR pairs also occur. ‘We have now created zebrafish embryos that are unable to form such heterodimers. This turns out to influence the effect of cortisol on behaviour. The heterodimers also appear to be important for the suppression of the immune system by corticosteroids, whilst the effects on metabolism are thought to involve homodimers instead. Our paper on this in Molecular Psychiatry goes online on 11 December, I’ve just received the proof‘, says Schaaf as he quickly checks his email. The immunosuppressive effects of corticosteroids are often the reason people are prescribed them as medication, for example in the form of prednisolone. ‘If you can create a variant without those metabolic effects, you get rid of a great many unpleasant side effects’, Schaaf explains.
Positive effects of stress
Another way to eliminate side effects may be inspired by a molecule found in ginseng roots. That molecule closely resembles prednisolone, but with a few sugar groups attached. ‘We were inspired by this to attach sugar groups to prednisolone ourselves. The resulting compound has an immunosuppressive effect, but in zebrafish with virtually no side effects. This is probably because you create a kind of slow release system: the sugars first have to be cleaved off. As a result, you always have only a low concentration of the active substance.’ Schaaf also conducts a great deal of research into the positive effects of stress. ‘Prolonged stress is harmful, but in the first two hours you actually see positive effects. If we understand why, we might be able to target that with medication’, says Schaaf.
Teaching
As a professor, Schaaf is keen to build an internationally respected research group, but in his inaugural lecture he also makes a case for greater recognition of teaching. ‘Everyone wants to teach well, but excellent teaching doesn’t get enough in return. Funding is part of the problem. I’ve sometimes thought about a system where you apply for grants for courses and are awarded money partly on the basis of your track record. That sounds frustrating and inefficient, but that’s exactly how it works for research. Perhaps we should take a closer look at both systems.’
Photo: Radboud University/Dick van Aalst