Broken glass wins biologist prestigious grant

In May, molecular biologist Geert van den Bogaart will open his lab at the Faculty of Science and Engineering of the University of Groningen. This newly appointed professor will study immune system cells, and aims to link the fundamental research in the Groningen Biomolecular Sciences and Biotechnology Institute (GBB) to clinical work in the University Medical Center Groningen (UMCG). He has just received a prestigious grant from the Human Frontier Science Program (HFSP).

Van den Bogaart studies cells of the immune system. ‘At the Faculty of Science and Engineering, a lot of work is done with microorganisms and yeast cells, but very little with mammalian cells. I was asked to fill that gap’, he explains by telephone from Nijmegen, where he currently leads his own research group as an assistant professor.

Intruder

He has his roots in Groningen though. It is where he studied biology and took his PhD in the Biochemistry and Molecular Biology group of Professor Bert Poolman. ‘Some time ago, he asked me to apply for a position in Groningen. The Faculty wants to strengthen mammalian cell biology and forge links with the Faculty of Medical Sciences.’ In Nijmegen, Van den Bogaart works on immune defences against cancer. At the University of Groningen, he plans to move towards autoimmune diseases or infections.

An important focus of his current work is the dendritic cell. This white blood cell is part of the immune system and is present in tissues that are in contact with the external environment, like the skin. It detects intruders and captures them in a process called phagocytosis. The dendritic cell ‘eats’ an intruder by absorbing it into a membrane vesicle called the phagosome. It then moves the captured intruder to a lymph node and presents it to the immune system cells, which are then activated to mount a response.

Splinters

‘We know a lot about this process, but I noticed one important question is still unresolved: how does the shape of the ingested intruder affect this entire process?’ says Van den Bogaart. He began to think about this question after a chance observation. ‘We were studying dendritic cells under the microscope. As sometimes happens, a thin glass cover slip on a microscopic slide shattered. Then I noticed that my cells had ingested micrometre-sized glass splinters.’ Fresh dendritic cells will ingest anything, in contrast to the cultured immune cell lines that are often used in research.

There are indications that shape matters: ‘Some infectious agents, like fungi, change their shape by forming an elongated hyphen inside the phagosome, and this appears to frustrate the immune response.’ Van den Bogaart has teamed up with colleagues from India and the US to study what mechanisms affect the presentation of intruders by the dendritic cells to the immune system. Together, they will receive just over one million dollars from the HFSP.

‘Stefano Sacanna from the University of New York is a specialist in colloidal chemistry who makes particles in all kinds of shapes’, says Van den Bogaart. Current research into phagocytosis is usually with killed bacteria or artificial beads – all fairly round shapes. Another aspect is that microorganisms are swallowed alive, so they may move around inside the phagosome. Inside this vesicle, reactive oxygen species like peroxides are produced to kill the intruder, and it fuses with other vesicles which contain enzymes to break it down.

Jet Engine

‘We want to find out how the shapes inside the phagosome affect the membrane fusion and whether the cell can somehow sense movement.’ To get moving shapes, metal catalysts are linked to one side of the artificial particles. They act as a kind of ‘jet engine’ which propels the particle with the oxygen from the abundant peroxide molecules. The fusion process is being studied by Shashi Thutupalli at the National Centre for Biological Sciences in Bangalore, India.

Van den Bogaart will study how particle shapes and motilities affect phagosomal degradation of the intruder and presentation to the rest of the immune system. The HFSP grant will enable all three researchers to appoint a postdoc for three years. ‘At the end of the project, we should know how the shape of an intruder affects the immune response and which mechanisms are responsible.’

Coincidence

It is no coincidence that scientists from three continents are working together on this project: ‘The HFSP encourages people to work across borders’, Van den Bogaart explains. ‘Both in the form of interdisciplinary science and of cooperating with colleagues from different continents.’ The HFSP is open to anyone in the life sciences, which makes it very competitive: out of 158 initial applications from all over the globe, only eight projects were funded.

Notably, it is the second year in a row one of the successful applicants is linked to Groningen: last year, University of Groningen neuroscientist Robbert Havekes and colleagues from Germany, South Korea and the US secured a HFSP grant for a project investigating the role of the biological clock in the effects of sleep deprivation.

To Geert van den Bogaart, the project is a flying start to his new appointment as full professor at the University of Groningen. And all because of a broken glass slide cover. As the Dutch saying has it, shards bring luck!