Please describe the research questions of your lab.

Our main goal is to identify mechanisms that contribute to the inception of asthma in children. We use genetics to find genes associated with asthma (i.e. PCDH1, IL1RL1), and recently also incorporated epigenetics (DNA methylation in the MedALL study) in our approaches. After identification of asthma genes or epigenes, we move on to study its function in the lab. For example, we use expression QTL and methylation QTL approaches (in blood, respiratory epithelium and whole lung) to address the association of the risk SNPs with gene expression and methylation, incorporate knock down (siRNA or Crispr/Cas9) methods in human cells or move the development of a mouse model. We recently validated one of the first asthma mouse models based on human asthma genetics: the Protocadherin-1 knockout mouse and are currently studying its phenotype.

What genetics/genomics techniques do you utilize in your lab?

Genetics:  Genome wide association studies
Epigenetics:  Illumina 450 K and 850 Epic Arrays in whole blood DNA and nasal respiratory epithelial DNA. Targeted approaches include Agena I Plex and pyrosequencing.
Genomics:  RNA sequence (either pooled cells or single cell seq) of nasal respiratory and bronchial epithelial cells, or airway wall biopsies.
Functional studies:  We do most of our functional studies in airway epithelium, both cell lines and primary cells, which we intend to immortalize or extend their lifespan.  We knock down genes using siRNA, Crispr/Cas9, or transgenic approaches.  Our mouse models include a Pcdh1 KO mouse model, as well as mice that specifically overexpress Pcdh1 isoforms in a cell specific manner.

Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?

The most important asset of my lab is that we work as a team, with dedicated translational scientists. We have a weekly systems genomics meeting of our research institute GRIAC (Groningen Research Institute for Asthma and COPD), that is attended by clinicians, immunologists/molecular biologists, geneticists, and bioinformaticians. I cannot emphasize enough that making progress in genomics is a team effort.

We use our integrated datasets in the whole lung (Lung Tissue Database), as well as in nasal epithelium (SNPs, RNA seq, DNA methylation) to quickly understand the potential role of disease SNPs on gene expression and methylation.

Our functional studies include cell adhesion models (ECIS), as well as extending lifespan of primary cells from asthma patients.

At what point in your life did you decide you wanted to be a scientist/physician?

I think I decided to become a doctor after reading a story book on the human body as a young child. I was so intrigued about how sophisticated the human body works.  I wanted to know all about it. During medical school, I was actively involved in improving medical education.  I think my interest in science came during my clerkships.  I did not take the knowledge I learned for granted, and I wanted to know how knowledge was generated.  I therefore started to do a PhD before continuing my medical training. This PhD was on asthma genetics, and I have been active in research ever since.

In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?

As a clinician, I strongly feel that the importance of a discovery can only be measured in terms of patient benefit. In respiratory genetics, we have not reached the point yet that our work is now improving the life of our patients, but this may change in the coming years. In the Netherlands, we will do a nationwide multicenter trial (PUFFIN trial) that will answer the question if we can switch to precision medicine in childhood asthma by genotyping the Arg16 variant of the Beta2 adrenergic receptor. Moreover, I think that asthma genetics has taught us that asthma only can be understood as an interaction between immune and airway structural cells (i.e. epithelium), and that epithelial integrity in lung and skin is an important mechanism that may precede inflammation. Finally, we now have good evidence that part of the heterogeneity in asthma (i.e. differences between childhood and adult onset asthma) is explained by differences in causal genes. In the next 5 to 10 years, we will see the pharmaceutical companies developing novel treatments based on findings from asthma genetics, i.e. based on the IL33- IL1RL1 pathway or TSLP.

Please describe your favorite publication involving genomics/omics that you were involved with.

We recently described the role of polymorphisms in the genes encoding IL33 (an important epithelial cytokine that detects danger signals) and its receptor IL1RL1 in the onset of asthma. [Savenije et al, PMID: 24568840].  In this paper, we described patterns of wheezing in early life and its relation to genetics. We observed that the genetic risk variants only had an increased risk of asthma in children that started to wheeze from age 3 -4 years onwards, and then continue to have persistent asthma at school-age. Moreover, we showed in two independent cohorts that children who carried genetic risk variants in both IL33 and ILRL1 were at increased risk of developing asthma.

What is your favorite aspect of ATS?

The most important aspect of ATS for me is that we form small communities of scientists that can help each other, form new collaborations, and network. I am member of the Genetics and Genomics Section and try to improve our international outreach. I think that we as scientists in respiratory genetics worldwide can work together and therefore accelerate our field.  

How could your research assist scientists and clinicians in other assemblies at ATS?

Our translational research institute GRIAC is always open to collaborations (www.griac.nl).  In the past, we have helped other groups worldwide with addressing their favorite gene/pathway in our extensive dataset.

Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?

Yes, we are always open to collaborations. Please visit www.griac.nl for more information on our research institute.