The inspiration of Spinoza prizewinner Wijmenga

Text: René Fransen

Cisca Wijmenga, Professor at the University of Groningen and Head of the Department of Clinical Genetics in the UMCG, is a leading light in Dutch academic research. The latest jewel in her crown is the Spinoza Prize 2015, which is worth € 2.5 million. She started her career as a biology student in Groningen. So who inspired her during her academic career and what drives her?

‘I wanted to study something medical but was unlucky twice in the draw for medicine’, begins Wijmenga. ‘I finally decided to read biology instead. Thanks to a couple of exemptions, I found myself with a period of eight weeks to spare so I took a course unit in genetics being taught by Charles Buys.’ This geneticist from the Faculty of Medicine was a keen protagonist of molecular-biological techniques. He also wanted to identify genetic causes for diseases, something that was virtually unheard of in the mid-1980s.

‘During his lessons, I remember thinking “That’s what I want to do”,’ says Wijmenga. The course was really geared towards medical students. ‘They kept asking themselves: how will this affect the patient? But I was more interested in the fundamental mechanisms. That’s when I realized that my degree programme in biology was exactly right for me!’

Mortal sin

After graduating in biology, Wijmenga found a PhD position in Leiden, where she explored possible genetic causes for a muscular disorder. She was supervised by the geneticist Rune Frants and the neurologist George Padberg. ‘We hit it off straight away, even during the interview. Rune gave me a free rein to do my own thing and George was highly enthusiastic. I happened to mention that I needed some more patients, and he arranged for blood samples from new patient families within a week.’ Frants gave his PhD students a lot of freedom. ‘It’s a style of leadership that appeals to me. You should leave PhD students to find their own way, assuming they can cope with the freedom, of course. But that’s something you soon pick up on.’

Statistics plays a large part in genetic research. It is needed to work out which part of the DNA is linked to a particular disease when studying family trees. ‘Lodewijk Sandkuijl, a doctor who had retrained as a statistician, was there to help me. I could always rely on him.’ He died in 2002 at a relatively young age. ‘I still miss him.’

Sandkuijl taught Wijmenga one very important rule: ‘Decide which statistical analysis method you intend to use before you start. Write it down, put it in a safe place and only retrieve it once you have all the data. Apply the method exactly as you had intended. This prevents you from fishing in the data until you find something.’ He was referring to a mortal sin in statistics, which unfortunately is still being committed. Wijmenga: ‘Sandkuijl impressed this upon me right from the start. These days, we call it academic integrity.’

Five years

After being awarded a PhD with distinction in Leiden, Wijmenga took a postdoctoral position with geneticist Francis Collins in Bethesda, Maryland, USA. Collins had just taken over as head of the Human Genome Project, which aimed to analyse the complete DNA of human beings. It was the largest genetic research project of its time.

‘In his lab, I was able to study the genetic background of a specific type of leukaemia. I replicated the syndrome in a mouse and was able to discover the exact cause.’ But other events taking place in Collins’s lab proved to be even more important. He had begun to trace the genetic causes of type 2 diabetes (adult-onset diabetes). ‘Until then, we had limited ourselves to searching for simple genetic causes, i.e. a single change in the DNA causes a disease.’ But diabetes is much more complex than this: it is actually caused by the combined effect of genetic predisposition, dispersal across a large number of genes and the influence of environmental factors. ‘I was fascinated because the diseases with the greatest social impact are the most complex.’

Wijmenga was offered an opportunity to set up a research project in clinical genetics at Utrecht University. She returned to the Netherlands fired up with enthusiasm. ‘But Collins also gave me a piece of wise advice. He said that it would take me at least five years to set up something new and told me not to give up.’

Pioneering

Once she was on her own, she realized just how true this advice had been. ‘It took three years for me to acquire the project funding I needed to appoint a PhD student.’ Up until then she was mainly helped in the lab by students. ‘The only permanent positions were for me and one analyst.’

During the first year, Wijmenga kept various doors open. She turned out to have a good nose for new developments. She was one of the first people in the Netherlands to work with microarrays, a type of DNA chip that enables you to test hundreds of genetic variations in one go. She also set a PhD student to work studying genetic information in huge databases just becoming available on the internet. ‘I applied for funding from the Netherlands Organisation for Scientific Research (NWO) for this study. “We’re not sure whether this possible, but you can give it a go”, said the evaluation committee.’ She enjoys pioneering with new techniques like this. ‘I dive into new projects with a healthy dose of courage and a certain naivety; it seems to work.’

A doctor in Utrecht advised her to explore the genetic side of coeliac disease (gluten allergy), a disease that was more or less ‘discovered’ in Utrecht. This resulted in her first breakthrough in 2005: a publication in Nature Genetics about new genetic causes, and a Vici grant from the Netherlands Organisation for Scientific Research (NWO) to expand her research. Two years later, she returned to her roots in Groningen. ‘I was asked to succeed Charles Buys as Head of the Department of Clinical Genetics.’

The appointment was an honour, but it also involved heading a clinical department. ‘I was afraid that my research would suffer, but this wasn’t the case. And now I can introduce new techniques from research into clinical practice.’ A fast DNA test that enables you to find out what is wrong with children who end up in intensive care without a diagnosis, for example. ‘This is important even if a child dies, as parents can then find out whether it is likely to happen again with subsequent children.’

She also supervises junior researchers, trying to treat them in the same way that her supervisors treated her. ‘You have to give young people enough leeway to prove themselves.’ Since becoming head of department, she has become further removed from the lab itself. ‘But I still get really excited whenever someone from my group acquires their first grant, or when their first student gains a PhD with distinction.’ And she has not lost her pioneering spirit. ‘I’m currently working on a new project revolving around gut flora. These intestinal bacteria are important to good health.’ She has analysed samples of faeces from 1,500 people in the LifeLines biobank. ‘We are getting interesting results, which we will publish before long. And then we’ll scale the project up.’

LifeLines (a long-term population study involving more than 165,000 individuals living in the North of the Netherlands) is pure gold for Groningen, says Wijmenga. ‘The problem that I’m currently interested in is this: why are people healthy? In hospitals, you only see people who are ill, but of course the majority of the population manages to stay healthy for a long time. And these healthy people are part of the LifeLines cohort!’

Cisca Wijmenga (1964) has been Professor of Human Genetics at the University of Groningen since 2007. As Head of the Department of Genetics at the UMCG, she supervises approximately 250 members of staff, in both clinical practice and research. She was previously a professor at Utrecht University. Wijmenga read biology in Groningen and was awarded a PhD with distinction by Leiden University in 1993. One of her appointments was as a postdoctoral researcher on the Human Genome Project in the USA. She is author (and co-author) of more than 400 academic articles, and has more than 27,000 citations to her name. Her research focuses on the genetic side of inflammatory-related disorders, such as coeliac disease (gluten allergy) and inflammatory bowel diseases (Crohn’s disease, ulcerative colitis), as well as chronic diseases such as diabetes and rheumatism. In 2012, she was voted a member of the Royal Netherlands Academy of Arts and Sciences (KNAW). She won the Spinoza Prize in 2015, and has won numerous other academic prizes.

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