20 November 2017

Interview with Bart Westendorp

Dissecting cell fate with a sieve and a hole-puncher

Bart Westendorp

When I was little, I wanted to be an ornithologist. I thought it would be exciting to discover a new bird species and challenge the boundaries of knowledge. I’m now more of a hobby bird-watcher, yet discovery remains central to my work, where I integrate biology, technology and computer science in order to figure out how a cell’s fate is determined.

Stress can change a cell’s fate

In stressful situations, our cells need to make decisions in order to cope and adapt. Individual cells, even those in a homogenous population where all cells are alike, have subtle differences in gene expression that dictate how a particular cell is going to deal with stress. If we can map out these differences, we can figure out how some cells escape our immune system; how other cells become resistant to therapy; how to develop new drugs to prevent these runaways from taking over our body; and how to help body boost our own regenerative properties, in order to heal and repair more efficiently.

The tools of my trade include a sieve, a hole-puncher, and a highly-advanced microscope
Bart Westendorp, assistant professor
Faculty of Veterinary Medicine, Utrecht University

Our novel imaging system lets us see what’s happening inside a cell

The tools of my trade include a sieve, a hole-puncher, and a highly-advanced microscope (one of only three in the Netherlands). With these, we can look inside thousands of fluorescently-tagged cells and simultaneously capture information about their behavior at any given time point. Our unique imaging system allows us to first narrow down and select only the cells that display relevant characteristics before we dive into sequencing their RNA, which gives us a gene expression profile for those cells.

We’re currently looking for new mechanisms that cause the development of therapy resistance. Cancer cells adapt to stress during DNA replication, and gain mutations that benefit their survival. Therefore, we focus on identifying mutations and other molecular alterations that are important for cancer cells to tolerate and escape drug-induced stress. Identifying genes that are critical for the cancer cell will hopefully help us tell which molecular pathways to block to in order to more effectively stop the development of cancer.

Imaging is sharpened by sequencing and bioinformatics

For those of you who are techies, we use a sieve that separates and dispenses single cells into individual wells of a grid on a 2 cm x 2 cm black chip. This is placed under our microscope where each cell is imaged, and cells that are interesting for further analysis are noted. The chip slides over to the left side of the microscope and hovers over a multi-well plate. An ultra-fine needle acts as a hole-puncher and physically pokes a hole through the chip’s floor, releasing that particular cell from the chip into the multi-well plate. Once we’ve collected the cells we want, the micro-well plate is prepared for sequencing by Alexander van Oudenaarden’s lab at the Hubrecht, and then brought to Edwin Cuppen’s sequencing facility at the UMCU. The plate and data then returns home to us, where we perform the bioinformatics analysis, and combine our experimental data with images.