“We generate knowledge and insight”

Prof Peter Hordijk is working for Sanquin since 1997. He started as a staff member at the Department of Experimental Immunohematology. In 2005 he became head of the Molecular Cell Biology department. Hordijk is a specialist in the area of intracellular signaling in leukocyte transendothelial migration. The work of his group is focused on the role of small GTPases as well as specific cell adhesion molecules in the control of leukocyte and stem cell chemotaxis, leukocyte adhesion to endothelium and the modulation of endothelial integrity.

 

Could you tell us why cell migration is important for our health?
There are numerous answers to this question. Cell migration is for example important for embryonic development and it is important for forming tissues and blood vessels. For Sanquin, migration is particularly important since blood cells migrate from the bloodstream, across the vascular wall, to the tissues and the lymph nodes.
Our group mainly works on endothelial cells, which are cells that line the inside of the vessel walls and that do not migrate a lot under normal conditions. However, upon cell damage somewhere in the body they start migrating and develop new blood vessels. This can happen during long-term inflammatory processes such as atherosclerosis, but it is also observed in other vessel damages. Such migration is also relevant for tumor development, certainly in big tumors. A tumor needs nutrition to grow and therefore it needs vessels for which you need migration of endothelial cells.

What happens when the migration systems don’t work properly?
You either get too much or too little, and both situations are not desirable. Too much migration of cells from the bloodstream to the tissues causes damage. Especially white bloods cells are very aggressive cells and when they attack your own tissue they will cause only more damage. Too little migration is also not a good thing. In this case, infections are not cleared and inflammation is not fought, with all possible consequences. When endothelial cells do not migrate in the right way, you will get poor recovery of blood circulation in your tissues, which you can imagine will also lead to all kinds of problems. So in both cases it is bad news.

What are the most important lines of research/approaches that have developed in your field over the past 5 or 10 years?

New contacts between endothelial cells, identified by the cell-cell adhesion protein Vascular-Endothelial Cadherin (magenta), are targeted by microtubules (green).

What we are doing on a larger scale and what really developed over the last ten years is ‘Live Cell Imaging’. It is an important part of our research as well as for other departments in Sanquin. The last decade this technology has developed enormously. Microscopy and the use of fluorescent proteins is booming business.
We perform a lot of microscopy because it is nowadays more and more required to visualize proteins and the processes in which proteins are involved. Ten years ago this was complicated and sometimes it even was impossible. An important aspect in using microscopy is the development of so called biosensors. These are molecules that change characteristics when something happens in the cell or within the molecule itself. This often results in emitting light that was not there before or in emitting light of a different wavelength. All these technologies are so much improved in the last ten years that they became available for a lot of laboratories including ours.

Are there already groundbreaking findings done with these technologies?
The discovery and development of GFP (green fluorescent protein) which won the Nobel Prize in chemistry in 2008 was groundbreaking, also because everybody could use this technology in his or her own research. Moreover, the possibility to do high-resolution imaging in living animals (‘intravital microscopy’) has greatly improved over the past ten years and that is in a way also groundbreaking. However, such technical discoveries never happen from one day to another, it is a development over the years. We have to wait and see to what extent the use of biosensors is as pioneering. This may be a faint answer but this is how it works. We take little steps with the work we do, and looking back at what you have done in the last five or ten years or so tells you if you have made some real progress. It then becomes clear to what extend your research was pioneering.
Recently there was a publication about the formation of platelets. Due to these imaging techniques researchers could show how platelet-forming cells make long extensions which break into smaller pieces and form platelets. It was never been seen before this way, so this is really fantastic!

What is, according to you, the biggest challenge in current research in your field?
The advantage of this job is that you can decide for yourself. In research you can come up with your own challenges, but in general there are several big challenges in our field. Our type of research, analyzing and charting signal transduction pathways, is incredibly complicated. There is a lot of dynamics, changes directed by signaling, cell adhesion and cell migration. The biggest challenge is to understand how the various mechanisms in a cell work in unison. At long last, I am afraid we may be too stupid for that. It is too complicated for humans to understand since you can not make a single model that covers it all. Another complicating factor is that signaling pathways and their connections in cells are constantly changing. So it is more a conceptual challenge than a technical one. We would like to understand how everything works but our research is a part of a bigger picture. When we know a little bit more we think of ourselves as geniuses but it all depends on the type of cell you are investigating, the conditions in which they grow and more. All these variables cause a slightly different outcome every time and that makes it only more complicated.
A big challenge for our own group is to make the step from in vitro to in vivo (mice) and to ex vivo (human). The things we do in culture dishes we wish to do in human tissue/blood vessels as well and we are going to start this soon. We will use waste tissues that include small blood vessels from surgical operations. When they are not too thick we can observe them under a microscope. Unfortunately, you can not put a human under the microscope, not yet at least. But you never know where we stand in ten years from now. Maybe a new microscopy technique will be developed and perhaps then we are able to make things inside the human body visible which we can not imagine right now. I think this is a nice challenge for upcoming years.

Vascular-Endothelial (VE) Cadherin (green) marks intercellular contacts between endothelial cells. Endothelial cells contain large numbers of F-actin stress fibers that control contractility (red). Both the actin cytoskeleton and VE-cadherin control endothelial permeabilty.

Why does your line of research matter? Why should people put money into it?
Well, who doesn’t find their own research important? It is a difficult discussion. You should pay for this research because, stating the obvious, basic knowledge is important. It is often proven in the past that when we invest in it, it will bring you something in the future, only you can not predict what this will be. Fundamental knowledge works on the edge of what we know and brings us new insights in how things work. So when you do not invest in it you will undermine your own research spectrum eventually.
However, basic research is under pressure. What we do is not all pure basic research anymore; we are bending a bit towards more translational research. Nowadays there is a lot of attention for this type of research; the link between the laboratory and the clinic. Basic knowledge can lead to medicine or applications but not for the next ten or twenty years. People want to see immediate results and that is the same for subsidizers and the charity funds. People want to know where the money goes and what they get back in return. So you are a bit compelled to also do research which is relevant today, and generating basic knowledge only is not particularly popular these days.

Are you not scared there won’t be any money available in the future for basic research?
Of course! I am scared of that everyday. Only the top 10-20 % will ‘survive’ and that is a difficult situation which you must learn how to deal with. It also means that many people who start in this line of work eventually leave because they do not reach a certain level or are just not lucky. This depends on the papers you get published, the people you know, if you get your projects funded. When it all works out it is great, but it does not always go this way, which can be difficult for some.

Who or what will benefit from your research?
Again, that is difficult. You could say that over time we hope that the knowledge we generate can be used by others to develop treatment or medicine. That is not our primary job or interest; we especially generate knowledge and insight. In that context application can be very broad; we can find something that is important for many fields. In the first instance this research is important for blood transfusion. Like I said before, we look at inflammation and there are a lot of inflammatory diseases so it can be important for all those. But also stem cell transplantations, tumor development and tumor cell metastasis. That is the thing with basic knowledge; it can influence many research areas. But our primary job is to understand blood cell – vessel wall interactions.

How does your research suits Sanquin?
We have always looked at white blood cells and blood vessel walls in the context of inflammation. Inflammation can be important for blood transfusion, but is perhaps more relevant for cardiovascular diseases. Recently, we therefore also started to investigate the interaction of red blood cells and the vessel wall. Such research was never done here before and little is known about it. This is of much more relevance for blood transfusion, since you are giving a lot of red blood cells to a patient. The longer you store them the worse the quality gets; what are the consequences of this for the patient? Three PhD students from three departments are involved, and they will all look at the same problem from a different perspective and using different approaches, from very basal to clinical work. Our group will be looking at the molecular events that accompany the transfusion of red cells into patients. And this is relevant for everyone who will receive a blood transfusion.
So again this is a project in which we not only focus on the pure basic knowledge. You have to be a little pragmatic. What we do in this kind of projects is research that is relevant and we hope there is some room for research that is close to fundamental aspects we are interested in. This sometimes is a difficult balance, because not everything that we think is interesting is also relevant, and the other way around.

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