In April 2023, Minister of Education, Culture and Science Robbert Dijkgraaf officially opened the renovated Electron Microscopy Centre (EMC) in Utrecht. In what used to be a somewhat disjointed field of science, the EMC provides a hub where researchers from all the relevant disciplines have access to the expensive equipment for electron microscopy. This significant development is the result of the intensive efforts of the Perspectief consortium Microscopy Valley, with Delft University of Technology as one of the parties.
The Netherlands has traditionally been strong in the field of microscopy and its various applications. An area of just a few square kilometres, now hosts a cluster of developers of microscope technology, research groups whose work requires extensive use of microscopy, and specialised companies, including Thermo Fisher, the market leader in electron microscopy. The close physical proximity of these parties is matched by the intensity of their collaboration. ‘And this in a scientific field that used to be highly fragmented’, remarks Judith Klumperman, Professor of Cell Biology at UMC Utrecht.
Klumperman is chair of the Netherlands Electron Microscopy Infrastructure (NEMI), the Dutch research facility in which thirteen knowledge institutes have pooled their technology and expertise in the field of electron microscopy. The NEMI was awarded 17.2 million euros under the National Roadmap for Large-Scale Research Infrastructure in 2018. Since then the equipment for each particular area of expertise has been explicitly allocated to one of five research centres in Delft, Leiden, Maastricht, Groningen and Utrecht. The EMC is one of those centres and is therefore one of the important nodes in this network.
The researchers knew one another, but there was less coordination and collaboration. Everyone did everything
―
Jacob Hoogenboom
‘In the past, universities had their own labs for electron microscopy. That was generally enough, since there was less need to work together. Technological progress was not as rapid as it is now,’ Klumperman observes. ‘The researchers knew one another, but there was little coordination and collaboration. Everyone did everything,’ adds Jacob Hoogenboom, a senior lecturer at TU Delft. But with the emergence of digital microscopy and advances in materials sciences and life sciences, disciplines in which considerable use is made of electron microscopy, cooperation became essential. ‘Specialised electron microscopy calls for specific expertise, and it is very expensive. It is no longer possible for every institution to do everything itself.’
Smallest building blocks The magnification power of an electron microscope is many times greater than that of a fluorescence microscope and can identify objects that are a nanometre or less in size. The electron microscope can also produce a three-dimensional image and its speed of operation is steadily increasing. By enabling researchers to visualise the smallest building blocks of matter and of life, electron microscopy yields very important insights for science and society. For example, this advanced technology can identify abnormalities by imaging the inside of a cell. It is also used to produce better solar panels, superconductors or chips.
Microscopy Valley Hoogenboom has been working on correlative microscopy, the integration of electron and fluorescence microscopy, in Delft since 2008. The research group of Professor of Nanoscopy and Microscopy Hans Gerritsen (Utrecht University) was also engaged with the same subject. Under Gerritsen’s leadership, the two scientists launched the Microscopy Valley research programme, which received funding from NWO’s Perspectief programme in 2012. Perspectief is one of the funding instruments established by NWO to encourage researchers from various disciplines to form consortia with companies and civil-society partners for projects.
Microscopy Valley, which ran until the end of 2018, focused on developing combinations of fluorescence and electron microscopy techniques to make molecules such as proteins in cells visible. For the programme, researchers at Utrecht University, the Antoni van Leeuwenhoek hospital, Leiden UMC, Groningen UMC, UMC Utrecht, the University of Twente and TU Delft joined forces with thirteen companies, including manufacturers of microscope technology FEI (acquired by Thermo Fisher in 2016) and Carl Zeiss, and the dairy producer FrieslandCampina. Hoogenboom and Klumperman were both members of the consortium and they concur that the research programme provided an enormous impulse for collaboration in the field.
Collaboration: a natural process The collaboration already began in the design phase of the programme. Hoogenboom: ‘Twice a year the members of the consortium came together in a users’ committee to review what each was doing and to explore forms of cooperation. The process occurred naturally. Each of the participants had its own project within the programme, but there were crossovers between them. We also organised regular programme meetings with groups that used the technology in other settings and that generated new ideas.’
‘It was my first experience of active participation in a consortium and it taught me the power of collaboration,’ says Klumperman. ‘When you’re awarded a grant your first thought is how much it can mean for your own lab. But its relevance for the consortium goes further than that. You can accomplish more by working together than by going it alone. Collaborating was more enjoyable and more rewarding than I had anticipated.’
Both scientists also refer to the importance of the informal contacts between the researchers. ‘They got to know one another and became interested in each other’s work. That proved very fruitful.’
When you’re awarded a grant your first thought is how much it can mean for your own lab. But its relevance for the consortium goes further than that
―
Judith Klumperman
The programme brought together parties that would not normally meet on a regular basis. The consortium united the developers of the microscopes, the users and the companies. ‘I myself am not tech-savvy,’ says Klumperman, ‘but once you started talking to the technicians in Delft, for instance, you quickly discovered that you have a common interest. We would think about the things we want to be able to do with a microscope, while the developers of the microscopes would search for applications for the modifications they made. This meeting of minds produced results that added up to more than the sum of the parts. You were no longer working alongside each other, but with each other.’
Taking the next step In microscopy, an instrument called a probe is used to generate an image that allows the specimen to be studied. The probes for the Microscopy Valley programme had to be suitable for both light and electron microscopy. Hoogenboom: ‘Taking the next step required input from various parties. The technicians developed the instruments, the biologists studied combinations of probes with live matter and chemists developed the probes.’ The result was a new probe that works in both types of microscope.
However, conversing with scientists from other disciplines is complex and takes time, says Klumperman: ‘You speak different languages. It requires a greater effort to understand what the relevant developments are. In a consortium you have time to get to know one another and that helps to break down barriers. Particularly at the boundaries between adjacent disciplines there are unexplored issues that you can address together.’ The development of a fluorescence microscope with an integrated electron microscope is an example of that. Articles have been written about this new technique for studying cells.
According to Klumperman, the Microscopy Valley programme laid the groundwork for the establishment and funding of the NEMI in 2018. ‘Some of the funding rounds for research infrastructure attracted multiple applications for financing of research into electron microscopy.’ This meant there had to be a pre-selection procedure. Klumperman had built up a network in the field through her involvement in Microscopy Valley. ‘One thing led to another and I formed a team to write an application.’
Faster development Klumperman believes that the scientists engaged in the field now fully realise the added value of sharing costs and benefits. One of the advantages lies in the development of new microscopes. There are various aspects involved in that process, both technical and practical, for example with respect to preparing samples. Hoogenboom: ‘For example, we discuss the implications for the samples or data during the development process. This enables us to accelerate the development and application of the technology. Researchers therefore have access to new instruments sooner. The impact is immense, since in many branches of science microscopy determines the limits of what can be seen.’
‘The Covid-19 epidemic provides a good example,’ says Klumperman. ‘When it started there was a network in place to study the virus. Researchers in Leiden were then very quickly able to map its molecular structure, the image shown on television during items about Covid-19, using cryo-electron microscopy.’
Meanwhile, there are new challenges. For example, the equipment in the NEMI will have to be upgraded at some point. The researchers are therefore looking ahead for new funding possibilities. Klumperman: ‘The instruments are becoming steadily more advanced and more expensive. And the pace of development is explosive. We have to stay ahead of the game, otherwise other countries will pass you by.’ Hoogenboom: ‘We are charting a large empty expanse, as it were. The ultimate aim is to keep adding more comprehensive information, as Google Maps does by including objects such as petrol stations and restaurants.’
