Meet Linda Sandblad: Urging research to drive research infrastructure
The “Technologies Advancing Molecular Medicine” series highlights the people and activities in research technologies and core facilities in the Nordic EMBL Partnership for Molecular Medicine. In this article, we meet MIMS Team Leader, Linda Sandblad, and learn about the world-class cryo-EM facility she and her team have developed at Umeå University.
Dr. Linda Sandblad is the Director of the Umeå Centre for Electron Microscopy (UCEM) and Team Leader at the Laboratory for Molecular Infection Medicine Sweden (MIMS).
Electron microscopy (EM) has been an integral part of Dr. Sandblad’s scientific career since her PhD studies at the European Molecular Biology Laboratory (EMBL). And, her primary research interests - the structure and function of the cytoskeleton, from microtubules in her PhD and early postdoc at EMBL and intermediate filaments during her postdoc at Karolinska Institutet to cytoskeletal-like structures in bacteria since joining Umeå University - have gone hand-in-hand with EM technology development.
Dr. Sandblad traces her passion for cell biology back to her days at the Julius Maximilians University of Würzburg, “I loved cell biology in general. Already as an undergraduate student, I really liked questions about the cytoskeleton and how proteins form beautiful, symmetrical, big assemblies.” Her interest in imagery started even earlier,
Before I started biology, I was a trained photographer. Electron microscopy and photography have quite much in common. At that time, photography was about working in a darkroom and developing pictures, exactly what is needed to work with electron microscopy. You have to know how to search and focus.
From photography, Dr. Sandblad also brought with her “image memory”,
When we work with correlative microscopy, when we go from tissues to molecules, we quite often start with a big field of view. And you have to orient and recognize the shapes and landscape patterns. I feel I have a good sense for where I am and what I need to look for. And that's very useful in electron microscopy.
Dr. Sandblad’s 50/50 dual role in research and research infrastructure means that she leads and manages two teams, one in research and another that offers EM services to the academic community. Although the goals are different, the groups work together on a daily basis.
On the research side, Dr. Sandblad’s small team of postdocs and students tackle research questions related to bacterial cytoskeletal-like components and work closely on method development for electron microscopy, in general.
On the core facility side, her bigger team of research-trained scientists are employed to provide service to other researchers. Their main tasks are two-fold: 1) to hold courses for training future users and 2) to ensure the instruments are running well and to help users with sample preparation, instrument operation, image acquisition and processing.
Cryo-EM: atomic resolution in life sciences
Electron microscopy has traditionally only been able to use samples that are stable in a vacuum. Dr. Sandblad explains, “electron microscopy started in 1930, but everything had to be in a vacuum, and to put the cell under vacuum, it needed to be dehydrated.”
The cryo-EM method is “about looking at the particles of life, all different small molecules building up cells and animals, in a hydrated environment and to be able to image these building blocks and molecular machines in the presence of water,” explains Dr. Sandblad.
The technological trick for atomic resolution with hydrated samples is for water to be vitrified, i.e., converted to an amorphous solid without crystals.
Cryo-EM was developed in the 1970s-1980s at EMBL in Heidelberg. The 2017 Nobel Prize in Chemistry was awarded to three persons for their work related to cryo-EM. One was Jacques Dubochet for discovering that water can be vitrified. Dr. Sandblad explains, “that means that it is solid without crystal packing. Ice you have in snowflakes is made of beautiful crystals, but the ice that we need in a transmission electron microscope needs to be vitrified. Solid, but amorphous.”
To be able to image something that is hydrated is a powerful advancement for life sciences. “Membrane structures and enzymatic reactions are, of course, dependent on the presence of water. Cryo-EM can be used at all different levels, everything from atomic resolution of proteins, up to imaging of cells and cell-cell connections, and even small animals.” explains Dr. Sandblad.
Dr. Sandblad continues,
We can explore all the molecular machines inside a bacterium by either sectioning or lysing it, and then freezing and studying the content with cryo-EM. If you consider a functional protein complex, it will have lots of different conformations, an increase in the local topography. For cryo-EM we can have a multi reference alignment, which means that from one image we could get out several structures. So let's say a proton pump has four favourable conformations. If you treat the cryo-EM imaging and data analysis the right way you can find all of them in one go.
Dr. Sandblad applies cryo-EM technology to her own research where she is asking questions about the intermediate filament-like cytoskeletal meshwork in bacteria.
During the last few years we have focused a lot on intracellular bacterial proteins that support the organization of the cell. A bacterium is like a bag of proteins, not much for compartments, but it does have intracellular organization. We study a protein that assembles into filaments or meshworks. And we try to figure out how the monomeric, coiled coil proteins form that meshwork and how that's related to polarized growth.
Cryo-EM is essential to learning how the meshwork changes, enabling the shapes that accompany cell growth and division.
Training and serving researchers
The Umeå Centre for Electron Microscopy in Umeå has two primary goals: 1) spreading knowledge and 2) providing services.
Dr. Sandblad begins, “since we are at the university, the most important thing is actually to spread the knowledge about the method, so that PhD students and postdocs have the possibility to do state-of-the-art research.” For cryo-EM there is excellent online teaching material. Dr. Sandblad often recommends the Getting Started in cryo-EM online course offered by the California Institute of Technology (USA). The facility also offers training courses in sample preparation and image processing, and hosts students in the lab for training events.
Second, as a core facility in the academic research environment at Umeå University, Dr. Sandblad’s team offers services for research projects. Beginning with consulting on project design, the team provides advice, support, and instrument access to prepare and run samples and acquire and analyze images.
Services are available for all academic researchers on a fee-based system. However, Dr. Sandblad explains that research collaborations can develop,
When we start a project, we always start as a service. If facility staff invest a lot of their own time in method development, or do the image analysis that is related to a research question, then we sometimes set up collaborations. So that happens, but our standard way to operate is by project support and service where all users contribute with user fees.
Local, national and international collaborations are key
The Umeå Centre for Electron Microscopy is a member of CryoNet, “a network of cryo-EM facilities with additional nodes at SciLifeLab in Stockholm, Sweden, and the University of Copenhagen and Aarhus University in Denmark,” explains Dr. Sandblad. CryoNet enables training from the basics of EM to sample preparation and advanced image processing. On the Swedish side, UCEM shares project support with the cryo-EM facility on the SciLifelab Solna campus.
Local collaborations at Umeå University work seamlessly with UCEM. Dr. Sandblad explains, “we have a really good collaboration with other infrastructures, for example, the Protein Expression Platform where researchers grow their bacteria cultures in special dedicated laboratories, and then they bring it to the cryo-EM facility for sample preparation.” Researcher needs are assessed continually and Dr. Sandblad expects additional dedicated facilities for sterile cell culture in the next year.
Research drives research infrastructure
Dr. Sandblad’s demanding, dual roles in research and service require balance. Her philosophy to achieve that balance is simple: there must be a connection. She explains:
My motivation is that I believe research infrastructures have to be directly connected to research questions, and that research infrastructure has to provide what researchers need. The opposite would be dangerous. Academic research infrastructures try to adjust and operate based on the needs of the researchers.
She further details the role that researchers play:
I like the research infrastructure to stay very close to the departments with the researchers. Many of my colleagues help the facility to develop methods and apply for grants for instruments. So the research infrastructure is driven by input from the researchers. Research profits from the facility and the facility profits from research.
Keeping it all in perspective
Dr. Sandblad is reflective about her work: “imaging in life science allows us to educate. We can learn so much from seeing an image of a bacterium, or a virus or animal. We can discover the beauty of nature. And if you know more, you're better able to predict and understand nature.”
She also encourages early-career researchers to not be afraid to learn something new: “it's always worth investing time in learning a new method, and to be able to operate a microscope yourself. You can be excellent scientists by using the tools yourself.”
Dr. Sandblad’s dual roles also means that she has a lot to do, and she realizes that. But, she keeps it all in perspective: “I do one thing at the time, and try to make a good priority for each day.”
Sage advice for all.
Cryo-EM for your research project
The Umeå Centre for Electron Microscopy is a world-class facility, providing researchers with access to state-of-the-art instruments and outstanding training and project support, putting Sweden on the global research infrastructure map in life sciences.
Thanks to new funding from Vetenskapsrådet, the Swedish Research Council, Dr. Sandblad’s team is soon installing a new cryo-electron microscope, doubling the capacity in Umeå next year. She explains, “we are also upgrading the detectors, but I think that when we get the new cryo-EM instrument ready, it will give us much higher productivity. And that means that more students and postdocs can work by themselves.”
Researchers interested in utilizing cryo-EM technology can contact the Umeå Centre for Electron Microscopy. Support for projects and on-site visits may be available through Euro-Bioimaging. Nordic EMBL Partnership institutes are considered in-house users, and mobility funding from a NordForsk Infrastructure Hub grant to the Partnership may help cover costs for visits to the facility.
Director of Umeå Centre for Electron Microscopy
MIMS Team Leader