Winning two prizes in one month is not a given for every scientist, especially not this early in a career. But you have to push glycochemist Marthe Walvoort pretty hard to make her say ‘I am proud’. She particularly emphasises the importance of a stimulating environment for success.
Besides her efforts in the areas of outreach, inclusivity, diversity and helping early-stage researchers, Adjunct Professor of Chemical Glycobiology Marthe Walvoort (38) is steadily building a career based on sugars: on the one hand, the role of glycans in bacteria and, on the other, the sugar molecules in breast milk. In December, she received both the Early Career Award from the KNAW and the Athena Award from NWO. According to the KNAW, the former is intended for ‘researchers in the Netherlands who are at the start of their career and have innovative, original research ideas’. The second goes exclusively to female scientists and has an explicit role model aspect.
The jury’s last statement is difficult to dispute: during our conversation in her office at the Stratingh Institute on the campus of the University of Groningen, Walvoort shows a good smile with an infectious enthusiasm. And a hint of imposter syndrome. Laughing: ’Yes, that’s right, I can totally relate to that! Even though it doesn’t make any sense. Of course I am proud. I think I am. But I have set myself goals and we are far from achieving them. I am confident that we will get there. But at what point can you really be proud of your achievements?’
First a word about the Athena Award. In a letter to the editor in C2W | Mens & Molecule, University of Amsterdam researcher Monalisa Goswami denounced that award in 2019. She wrote: ‘Women are constantly judged on female characteristics: you’ve done some nice research, but what about your social side?’ How do you feel about that?
I kind of agree, but the prize exists, of course, for a combination of two things. Where it misses the mark a little is in the implicit suggestion that doing good and inspiring research is not enough. But I can identify with the role model aspect and I also believe that this is necessary. I am very happy with this prize.
‘Maybe I should cheer more about small steps of scientific success; after all, I do the same when my children take their first steps’
You are only 38 and already an associate professor doing notable research, with two recent awards. And you have four young children. That is remarkable, I can hardly ignore that as an interviewer. But this observation is always a little awkward, while it mainly expresses admiration.
And it wouldn’t be right not to mention it either. Many young girls wonder whether the combination of an academic career and starting a family is feasible for them, and I think it’s fine to talk about it. That is the benefit of such a prize. I gladly serve as a role model for that, it comes very naturally to me.
Then, laughing loudly: ’And it doesn’t always go well, of course! It is an exciting combination that often requires a lot of creativity. For a long time, I too thought of a scientist as someone who works 24/7. That is an outdated image, but I was also brought up with it. When I started a family, I was really afraid that I wouldn’t be able to combine it. And should I want to? But then again, would I have to stop doing what I love best because I want to start a family? Now I can show you that it is possible to do both, so I think you should talk about it.
But doesn’t this struggle also apply to young fathers?
Yes, yes, of course! Perhaps NWO should also set up a role model prize for young fathers. Just ask my partner what a challenge it is for him too. He is also busy with his job and is ambitious. So it feels a bit like we won that prize together.
The other prize, the Early Career Award, is really only for your scientific achievements. How do you look at that one?
I find that difficult. You move along the edge of what we know, which comes with a lot of uncertainties. When do you feel really confident about your research? And if you receive a prize for it, my first reflex is, ’am I that good already? That makes me doubt myself. But maybe that’s a woman thing.
So when would you describe yourself as ‘successful’?
I have indeed wondered about that and the first thing that came to mind was ‘if my students are doing well’. She points to a picture on the wall. ‘Those are my first two PhD students, they have only just finished. They both have a good job now and the fact that I prepared them for it, that is what I consider to be success. The research itself is also important, of course, but these are rarely major triumphs and mostly small steps. But perhaps I should celebrate those more often. After all, I also celebrate my children’s first steps.’
‘I’m not going to put my PhD students under pressure because otherwise I won’t meet the criteria’
Could you name an example of recent research you are proud of?
When I applied for my Veni, a new bacterial glycosylation had just been found that is involved in protein translation. If the ribosome has to link several prolines in a row when synthesising a protein, it gets stuck. Such a polyproline sequence is a kind of kink for the ribosome and the protein EF-P is then needed to pull it through. But EF-P only does that if it is glycosylated. In humans it has a standard GlcNAc sugar on it, but in these bacteria, for example in Pseudomonas, there is a rhamnose on an arginine of EF-P. That is special for two reasons, because humans do not glycosylate arginines and we do not make rhamnose.
Then I thought: we are going to make inhibitors for that! That would stop protein synthesis and kill the bacteria. Because my ultimate goal is to use this glycosylation as a starting point for new antibiotics.
We devised a rhamnosyltransferase activity assay for this purpose. But it didn’t work: none of the ten target peptides I had ordered was rhamnosylated. So what then? Then I ran into Nathaniel Martin at CHAINS and told him about this. He is, of course, a peptide expert and we figured that maybe the linear peptide we were using could have a loop. That arginine on which the rhamnose is built, is on a β-hairpin of EF-P. Then his PhD student did the cyclisation reactions and we tested them: bull’s-eye! So the rhamnosyltransferase recognises a secondary structure and there are hardly any examples of that. I found that really wonderful!
What do you find so fascinating about glycochemistry?
Many basic aspects of chemistry come together in glycochemistry, such as stereochemistry, functional groups and synthesis. And a lot of design: you have to think very carefully in advance how you want to make a certain sugar. And then there is the diversity: if you just look at the number of possibilities on the basis of the ten monosaccharides that humans can make, that is really staggering. And then bacteria have hundreds of them. They make glycan structures that are completely different from those of humans, for example to attach to surfaces. Until recently, a protein was just a protein; only now do we realise that it also contains sugars. But what do they do? We hardly know yet and that is what I find immensely interesting. And quite challenging, because contrary to DNA, RNA and proteins, there is no code to be found for glycans, except for the enzymes that take care of the glycosylation.
You say ‘challenging’, but isn’t it just extremely complicated, as is often said?
I find it very rewarding. But indeed, it is quite complicated and that is why things often don’t work out right away. Some PhD students have struggled for months because I thought that something could be made on the basis of the literature. But a young PI is a naive PI, I always say.’ Laughing: ’A number of PhD students have suffered from this.
But a bit of naivety is fine for a researcher, right?
Yes, of course! For example, we just published a nice article on sugars from Bifidobacteria which actually came out of such a naive starting point. Those bifidobacteria make exopolysaccharides for their glycocalyx, the outer layer of their cell wall. After birth, a baby is quickly exposed to bifidos, with the result that, among other things, their intestinal immune system matures and tight junctions (firm connections between intestinal cells against leakage, ed.) develop. The glycocalyx could very well be playing a role in this. We thought we could just isolate these exopolysaccharides and then do some nice tests on their function. But it was only three years later that we had optimised the method to such an extent that we could isolate them properly. At a certain point, my PhD really got tired of doing yet another test under anaerobic conditions. But it did yield a great result: those exopolysaccharides appear to be able to protect against the intestinal wall becoming more permeable as a result of the use of antibiotics.
Part of the Athena Award is also about outreach. You can often be found in podcasts, interviews, on Youtube.
Yes, the bacterial sugars are very interesting, but my line of research on mother’s milk sugars does better in the media. And I like to talk about it, sugars are already so often in the news in a negative way. There are about two hundred sugars in breast milk and they are there for a reason. But why is that? I started out quite naively again: we’re going to make them all! Then it turned out that at least dozens had already been made by chemo-enzymatic synthesis, including many in Geert-Jan Boons’ group. So I had to change my plans and I realised that I actually find it much more interesting to investigate what makes these sugars healthy: which structural elements in such a mother’s milk sugar ensure that you get a certain desired effect?
That is quite a big research question for two hundred sugars.
It is not so bad, because most mother’s milk sugars consist of the same backbone of alternating galactose and GlcNAc. Modifications such as fucose and sialic acid are attached to it. We therefore thought that the functional differences might come from those decorations. We started from that point, using a cyclodextrin as a basis, modifying it and doing assays. That way we hope to find a blueprint for a healthy sugar.’
And make better powdered milk, I presume.
Not necessarily. The discussion about breast milk and powdered milk is a delicate and complex one, but the fact is that the sugar composition in breast milk and artificial milk based on cow’s milk are very different. Cow’s milk does not contain many sugars. Alternative sugars, such as FOS and GOS (fructo- and galacto-oligosaccharides, ed.), are now often added to baby powder and these take over some of the prebiotic functions of natural mother’s milk sugars, for instance in intestinal development.
But your real goal is to find out what makes a sugar healthy?
I’m just really curious about how we can make healthier sugars. Suppose you could improve the microbiome in the gut with healthy sugars, wouldn’t that be wonderful? After all, we already know that glycans play a role in the inflammatory response in the intestines of newborns. Perhaps one day we will be able to treat chronic inflammation of the intestines, such as in ulcerative colitis, with healthy sugars. That is a real dream of mine.
‘If after five years you still can’t judge whether I am a good academic, then those six extra months won’t matter either’
Finally, back to the archaic image of the scientist who lives only for his work. How can we ensure that scientists also reach the top in other ways?
Especially if you want more women in professorial positions, you will have to accept that you will have to hit the brakes from time to time. Maternity leave, young children at home, but also taking the pressure off when someone is not feeling well. During my tenure track assessment in December 2020, we went into lockdown again and it was clear that the coronavirus was going to last even longer. The faculty offered the option of postponing my assessment, but I didn’t want to do that. If you can’t tell if I’m a good academic after five years, those six extra months won’t matter. The system works in a way that my success also depends on the success of my PhD students. But I’m not going to pressure them into working harder because otherwise I won’t meet the criteria. Then I’ll just go and do something else. Laughing: ’In that sense I have played Russian roulette, but it has turned out well.
You do need a board that looks at this issue in a modern way.
The Stratingh Institute and our department in particular are very good at this. There is a lot of understanding and flexibility. Six years ago, I was even assigned a postdoc when my lab needed setting up and I was home on maternity leave. In the beginning, that really made a positive difference. And that brings me back to the importance of role models. Adri (Minnaard, her department head, ed.) also has four children! That’s why I think it’s important to talk about it. It has helped me enormously to get where I am today.
A relatively unexplored area of molecular biology revolves around glycans, also known as polysaccharides, or - more generically and chemically less correctly - sugars. They are complex hydrocarbon compounds consisting of a branched or unbranched chain of monomers with the molecular formula CnH2nOn, or a variation thereof, such as fructose, mannose, galactose, glucosamine and mannitol. The best-known sugar monomer is glucose (C6H12O6); if you link tens to thousands of them linearly through so-called 1→4 glycosidic bonds, you get the polysaccharide amylose.
However, many glycans are much more complex than amylose and consist of numerous branches and combinations of different monomers. The picture shows a complex glycan, such as is found in human proteins via asparagine. Glycans play a crucial role in cell structure, energy storage, protein folding, signal transduction and the immune system. Glycans are found in all life on earth.
Glycan research is considered ‘complicated’, partly because it still lacks easy, widely accessible synthesis and analysis techniques, such as those that already exist for DNA and proteins. The renowned glycobiochemist Carolyn Bertozzi therefore argued earlier in C2W international for ‘a kind of glyco-service industry’ to speed up developments in the field.