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Bioimaging – enabling Nordic groundbreaking discoveries

Cellular symmetry by Claire Hyder

The increased sophistication and versatility of medical imaging are fueling demand for the technology not just in the life and medical sciences, but across the spectrum of scientific research. The ability to not just photograph organs but also record bodily and cellular processes – and better identify trouble spots – is rapidly shaping research.

Efforts in the Nordic countries to expand, refine and share medical imaging technology have the region well-positioned as demand for more varied and detailed images continues to grow.

“Research-wise, the Nordic countries are doing very well in bioimaging,” said Professor John Eriksson, director of Turku Bioimaging, in Turku, Finland, an interdisciplinary science and infrastructure organization whose goal is to bring together bioimaging expertise in Turku and across Finland. It was founded by the University of Turku and Åbo Akademi University.

“One of the goals of this net-worked organization, is gather and to acquire state-of-the-art technologies and to promote the know-how in their use and applications,” Eriksson noted. “The main goal is to share and exchange knowledge and learn from each other. Often the best way to learn new things is to work together to benefit human health and mankind.”

Open access to state-of-the-art imaging

Turku Bioimaging began with strengths in positron imaging and molecular imaging and reorganized in 2004 so it could receive funding and became the coordinating organization of Finnish imaging. As Turku Bioimaging is physically located in Turku Centre for Biotechnology, the organization works as continuum with proteomics, systems biology, computational modeling, and software development for image data processing and analysis.

“We provide open access to all state-of-the-art imaging,” Eriksson explained. Turku Bioimaging is also part of Euro-Bioimaging, a European infrastructure organization with 29 service centers around Europe, and all have expertise areas, flagships and different technologies.

“The idea with Euro-Bioimaging is not only to provide access to technology, but also resources; we want to build up common European resources operating with the same open-access principles as those in Cern. Turku will be the headquarters of Euro-Bioimaging, partnering with European Molecular Biology Laboratory in Heidelberg and Molecular Imaging Center in Torino.”

An amazing improvement in the past 10-15 years

Among the recent developments in bioimaging is the ability to detect smaller objects and magnify them larger. “What we have seen in the past 10-to-15 years is amazing improvement in imaging, seeing gains in super-resolution,” Eriksson explained. “We can watch processes live while they’re happening and record them with high precision. Then we can combine molecular data and record things while they are happening inside the animals; there are a number of things we can record cells doing; for example, inside the internal vascular structures of a fruit fly and capillaries of zebra fish.”

Now researchers can learn more about the behavior and mechanics of immune systems and tumor growth, such as how tumors travel from their original locations, as well as watch the migration of different cell types, Eriksson continued. “They [bioimaging devices] allow you to observe almost anything within cells and tissues and watch what happens when you modify molecules. From that we can draw conclusions, so we can advance techniques in molecular biology.”

A solid standing in bioimaging

Besides Finland, Denmark, Sweden and Norway all have solid standing in the bioimaging field. Apart from Finland, very strong bioscience can be found in several other places in Scandinavia, with an especially successful bioscience cluster near Copenhagen and Malmö, with pharma companies and other biotech research firms.

“[In addition] Norway is very strong with medical imaging, in part because of collaborations with academia and industry. Also Norway is actively engaged in Euro-Bioimaging and Denmark and Sweden are considering membership,” Eriksson added.

Access to advanced applications is key

The Danish BioImaging network (DBI) is, similar to Turku Bioimaging, a national consortium of universities, research institutions and commercial companies that are interested in using bioimaging as a life science tool. Several groups and facilities around Denmark began planning the consortium out of the desire to learn about bioimaging developments throughout Denmark, particularly since bioimaging has become such an essential tool in the life sciences.

“We started meeting with people from different labs about three years ago and realized that Denmark was in need of a bioimaging network,” said Clara Prats, PhD, associate professor and head of light microscopy in the Core Facility for Integrated Microscopy at the University of Copenhagen and a member of the network’s managing committee. “We wanted to gather information of what bioimaging infrastructures were available in Denmark and information on who is doing what.”

The main groups in pre-clinical imaging, microscopy and image analysis signed agreements to collaborate over the next three years to strengthen bioimaging technology in Denmark. Over time, DBI developed more networking opportunities and now is sponsoring a PhD course, bioimaging seminars and held its first conference in November 2017.

“The community has a need for more networking, for collaboration to develop new tools and share infrastructures” Prats continued. “Bioimaging is more and more challenging, state-of-the- art applications are increasingly technically demanding and expensive. There is a need for the community to gather and share skills, knowledge and equipment to have access to advanced applications.”

A Nordic network?

Discussions have been underway about re-establishing a bioimaging network among the Nordic countries. An initiative bridging Nordic bioimaging researchers had existed, but funding ran out, Prats said. “Our aim is to connect DBI with other international bioimaging networks, such as Nordic networks and European infrastructures and EuroBioimaging.”

”Bioimaging is a very broad field that is evolving continuously at a very fast pace. Some of the current hot topics include super resolution, imaging speed, deep imaging, analysis and management of big data and, machine learning,” Prats continued.

A human cell atlas

Advances in bioimaging also helped Emma Lundberg, an associate professor at Science for Life Laboratory (SciLifeLab) in Sweden and her team create a cell atlas over 10 years, a detailed map of the human cell showing its complex structure. The cell atlas is part of the Human Protein Atlas project, an effort to determine the subcellular location of all human proteins. A collaboration among Karolinska Institutet, KTH Royal Institute of Technology, Stockholm University and Uppsala University, SciLifeLab focuses on molecular biosciences with emphasis on health and environmental research.

The Human Protein Atlas database receives about 200 000 visits per month from across the globe, according to Lundberg. “It can be used by researchers all over the world to study proteins, cell biology, human biology, and specific diseases and systems biology. It can even be used by computational scientists to try to quantify the information in the images.”

To collect the 82 374 images for the cell atlas, Lundberg’s team used confocal microscopy, which is high resolution with oil-immersion objectives, to get good resolution of all the organelles, structures and substructures in the cell, she said.

Thanks to the technology, the team was able to process 1 000 samples a week, according to Lundberg. Each protein was imaged in each of three cell lines, which are grown and stained in glass-bottomed 96-well plates and imaged at low resolution to get a sense of protein intensity and distribution. Those pictures are then fed into custom software that works out the optimal settings to capture those data, after which the samples are imaged a second time at high resolution.

At first, everything was done manually. About 30 percent of samples still have to be rephotographed manually, Lundberg estimates, to cope with the human proteome’s wide dynamic range.

A highly complex architecture of the human cell was found

One of the most significant findings stemming from the atlas creation was the discovery of a highly complex architecture of the human cell with many multi-localizing proteins, spatial variations between cell lines and single cell variations, Lundberg said.

“The classical view of the cell is a protein in one place that performs one function,” she continued. “In contrast to this, we found that as much as half of all human proteins are localized to multiple compartments in the cell. These multi-localizing proteins could have contact and site specific functions and potentially be ‘moonlighting’ in different parts of the cell. This greatly increases the diversity of the proteome and the complexity of the cell from a systems perspective.”

Lundberg’s team also discovered that as much as 16 percent of human proteins showed variation in expression at the single-cell level.

“I would say that our map illustrates the high complexity of the cell; there really are no comprehensive subcellular maps of human cells with which to compare it,” Lundberg added.

The rapid development of bioimaging

In other applications to cell studies, imaging technology has advanced to allow the study of invasive behavior of cancer cells; the use of automated imaging machines and other devices can follow the growth and other parameters of cell samples, according to Eriksson. Bioimaging also enables hundreds of drugs in different concentrations to be tested at the same time and the results reviewed after a few days. “In the past, this could have taken years,” he added.

Among the areas trending in bioimaging are the meshing of imaging and analysis, Prats noted, and other emerging areas include deep imaging, big data, machine learning/deep learning and correlative applications. “It’s a very dynamic and hot developing field of science.”

The data crunching approach is definitely a big trend, added Eriksson. “You can combine images and molecular data. If someone has been following a disease for a number of years and has metabolic samples, urine and blood samples, now they can take and rescreen small samples and combine all this data.”

The next big challenge

Storing, managing and processing all this information mined by bioimaging is the next big challenge, Prats said. “You need to have computers that can process images and huge amounts of information and you have to have people who know how to do it, bioinformatics and image analysts.”

In Denmark, a supercomputer shared among universities, the computerome, is helping with data management and computing power, other more local solutions also are coming from the private sector, as companies develop new hardware and software to help with image analysis, Prats added.

A crucial infrastructure

The evolving technology also is giving rise to new bioimaging applications across scientific disciplines. “It has always been a key technology in the life sciences; now bioimaging is getting used irrespective of what people are studying,” noted Eriksson.  “Traditionally, biochemists and biologists worked with it; now all of the disciplines use bioimaging. It’s hard to get an article published without imaging and by far imaging is the most requested infrastructure. When you ask different disciplines which technology they need most, they say bioimaging.”

Image caption: Cellular symmetry by Claire Hyder from the Turku Bioimaging competition “Life is Art”