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Seeing small, thinking big

Cellular imaging at the U of M reaches a tipping point, and a new initiative could put it over the top

The images above are single-cell thickness sections through the bodies of whole mice stained with a red-labeled antibody specific for the T-cells (white blood cells that play a central role in cell-mediated immunity). The image on the left is a negative control, the middle image is an untreated mouse showing the T-cells in the spleen and mucosal lymphoid tissue above the roof of the mouth, and the right image is a mouse vaccinated with an antigen of Salmonella typhimurium showing the proliferation of the T-cells and their migration to many non-lymphoid organs.

Microbiologist Marc Jenkins is tracking the movements of immune system cells with an eye to developing vaccines, preventing organ transplant rejection and combating autoimmune diseases. Cell biologist Mary Porter is studying the molecular motors that move substances along the highways within cells, a function critical to development and function of organs and even entire organisms. Timothy Ebner, professor and head of neuroscience, is studying how brain circuits work in the areas of the brain that control movements, and how these circuits malfunction in neurological disease.

All three of these University of Minnesota scientists are breaking ground with research that is delivering new insights in their respective fields. The impact of their research could be greatly amplified by additional investments in cutting-edge emerging imaging technologies for visualizing life at the cellular and even molecular level.

The University of Minnesota is a leader in many areas of cellular and sub-cellular biology. But faculty working in these disciplines are scattered, and imaging capability is increasingly a limiting factor in their ability to keep pace with other institutions. A new initiative would bring these researchers together to create a critical mass of users.

Cellular imaging gives researchers a close up look at a range of cell types including neurons.

Recognizing the increasingly pivotal role of state-of-the-art imaging technology in biological inquiry today, the College of Biological Sciences (CBS), Medical School and Institute of Technology (IT) are exploring the possibility of creating an interdisciplinary Initiative for Cellular Dynamics and Imaging that would bring new imaging technologies and experts to the University.

Porter is among those developing the proposal. She says the initiative would not only give researchers like her a huge boost, it would also help move the University of Minnesota toward its goal of becoming a top-ranked public research university.

“It’s a critical direction for the University to pursue,” she says. “If we’re going to lead in the biological sciences, we need cutting-edge imaging technology and expertise.”

Image is everything,” says Mark Sanders, director of the College of Biological Sciences Imaging Center. “To actually see what’s going on is essential. It’s key to understanding the complexity of systems biology at the cellular level.”

Using a confocal microscope, epithelial cells were labeled with a stain to show the location of the nucleus (red); tubulin antibodies (green) and phalloidin to reveal the distribution of F-actin (blue) following a treatment of an anti-cancer drug.

”We have exciting imaging technology,” says Sanders. “What we want to do is tie it together as a cohesive unit that combines intellectual capital as a base for building up equipment and staff with expertise in this area.”

Such a move, says CBS’ Dean Robert Elde, could take to the next level the University’s ability to pursue solutions to problems such as cancer, world hunger, antibiotic resistance and global warming.

“There is a strong correlation between breakthroughs in technology and analytical tools, and the kinds of questions that can be asked and addressed by scientists,” Elde says. “Being ahead of the curve in developing this technology will give us an advantage in applying it to vital areas of research across the University of Minnesota.” He says the University’s widely acclaimed Center for Magnetic Resonance Research (CMRR) is an example of the impact the imaging initiative could have on research. By bringing in top technology and experts, CMRR has become an international leader in advancing understanding of brain function, investigating new tools for combating cancer and more. The time is right, Elde says, to bring that kind of concerted effort to cellular imaging.

“Deciphering the human genome was the ultimate reductionist approach to biology. It lays out the parts list for any cell,” Elde says. “The way those genes and their products are assembled is what makes life work. Now we have the opportunity to take a more holistic approach.”

Driven by advances in physics, computation, digital photography and genomics, imaging technologies today are showing glimpses of life no one has seen before. Until now, the view of and within cells has been limited to static images taken after killing, preserving and staining them. But recent innovations have created revolutionary ways of looking at living things.

Like Alice stepping through the looking glass, scientists are exploring an entire wonderland beyond the former limits of microscopic resolution. Using novel imaging technologies, researchers at other institutions have been able to genetically engineer a mouse with nerve cells that appear in different colors, watch viruses hijack the cytoskeleton and observe a tumor undergo metastasis.

The University of Minnesota, Elde says, is a perfect place for building on this base. The CMRR has shown at the tissue level what University researchers are capable of accomplishing with cellular imaging. Renowned cell biology programs, computational capabilities and a commitment to biology technology collaborations lay a firm foundation, and the purchase of a state-of-the-art confocal microscope last spring provided an initial nudge toward a more comprehensive approach. The recent addition of a $2 million cryo-electron microscope to the University’s imaging equipment inventory illustrates the punch added technology can provide to research programs in a spectrum of disciplines.

Robert Elde (dean of the College of Biological Sciences), Frank Bates (head of chemical engineering in the Institute of Technology), Tim Ebner (head of neuroscience in the Medical School) and Mark Sanders (director of the CBS Imaging Center) are among the intercollegiate supporters of the Initiative for Cellular Imaging. The proposal, authored by Mary Porter (a professor in the Department of Genetics, Cell Biology and Development), would draw on existing expertise across disciplines and bring in new equipment and faculty who can create new analytical tools that will give University researchers a critical edge.

Purchased with funding from the Academic Health Center, the Office of the Vice President for Research and the Institute of Technology, the device was installed in Hasselmo Hall this summer. Molecular biologists, materials scientists, medicinal chemists and chemical engineers are lining up to use it for studies of the mechanism of muscle contraction, the structure of flagella (with implications for cystic kidney disease and infertility), development of new nanomaterials and more.

Dwight Anderson, professor emeritus of diagnostic and biological sciences and microbiology, uses cryo-electron microscopy to see molecular motors involved in assembling a bacterial virus, a key step in understanding how fundamental structures of life are assembled.

“Taking full advantage of our new cryo-electron microscope will help us rise to the level expected for the first-class research enterprise that we hope to become,” he says.

Institute of Technology faculty are enthusiastic as well. Frank Bates, Regents Professor and head of chemical engineering, is looking forward to using the cryo-electron microscope in his field-leading studies of polymers. “This instrument makes it much easier to prepare and image samples. Using our old microscope is like driving a car from the 1950s. We just can t keep up with scientists who have new models.”

What would an Initiative for Cellular Dynamics and Imaging look like? And what would it do? The proposal recommends bringing together existing faculty, postdoctoral fellows and graduate students with an interest in advanced imaging capabilities from CBS, the Academic Health Center and IT. With that group as a core, the effort would shift to adding new equipment, recruiting new faculty with the expertise to use them and creating new analytical tools.

Monthly meetings and a biennial symposium would provide forums for sharing knowledge and expertise, and for catalyzing further advances. Faculty seed dollars would encourage new collaborations. Sanders, who has sat on review panels for federal agencies that award grants for equipment and programs, says the initiative would put the University in a very strong position to gain additional resources. Initial investments in equipment are just a start. Faculty recruitment and funding for existing facilities, including the Imaging Center in the College of Biological Sciences, are part of a larger effort to attract faculty and additional funds to support the initiative’s goals.

“Ultimately the reason we’re doing research is to solve societal problems,”

Elde says. “Across that whole spectrum of issues—from biofuels to environmental cleanup to medicine—cells are the unit of life that acts. Being able to understand cells in action is crucial.”