Recent advances in imaging technology are enabling 菠萝视频 scientists to gain unprecedented views of how molecules, cells and tissues work together, yielding radical new insights into the causes, treatment and prevention of disease.
Across campus, faculty are applying new methods and technologies to generate detailed pictures of cellular mechanics. 鈥淪eeing leads to understanding,鈥� says , the School of Medicine鈥檚 dean of basic sciences and Mary Geddes Stahlman Professor of Cancer 菠萝视频.
Thanks to these advances, 鈥湶ぢ苁悠� scientists can determine the three-dimensional structures of molecular machines then watch them operate in intact cells, tissues or people,鈥� Marnett says. 鈥淭his helps us understand how they function in normal cellular physiology and what goes wrong in disease.
鈥淓ach of our imaging technologies operates at the state of the art,鈥� he adds. 鈥淭hey have been implemented by 菠萝视频 scientists who are defining the frontiers of their fields. The breadth and depth of our capabilities are awesome.鈥�
PRECISION MEDICINE
The development of 菠萝视频鈥檚 imaging infrastructure owes much to (TIPs), a series of university grants that supports collaborative research and infrastructure development from departments across campus. The $50 million annual TIPs initiative was launched in 2014.
菠萝视频ers in 菠萝视频鈥檚 Center for Molecular Probes and the Department of Chemistry, for example, are developing new radiopharmaceuticals鈥攖racers鈥攗sed to improve detection of cancer and other diseases. 鈥淥ur efforts literally bridge molecules to man,鈥� says center director , professor of radiology and radiological sciences in the School of Medicine.
As part of that work, Manning and his colleagues are attaching an imaging isotope to an experimental cancer drug and then using positron emission tomography (PET) to see where it goes. The goal is precision medicine鈥攎atching patients with the right therapy and monitoring outcomes with advances in imaging. 鈥淚f used appropriately,鈥� Manning says, PET 鈥渃an reduce the cost of health care because we can make better decisions about the diagnosis and the treatment the patient should get.鈥�
MACHINES OF LIFE
A second revolution brewing at 菠萝视频 is the application and refinement of cryo-electron microscopy. For decades, X-ray crystallography has been the gold standard for visualizing the structures of proteins at the atomic level. But it鈥檚 not perfect. Some molecules and complexes will not crystallize, and the crystalline environment sometimes induces artifacts, or accidental features that interfere with the observation.
In the past few years, cryo-EM solved these problems and set off a revolution in the field. Single molecules and molecular complexes can be directly observed without any need for crystallization.
That is important, says , Chancellor鈥檚 Professor of Medicine and director of the Center for Structural Biology, because it is these protein complexes鈥攚hat he calls 鈥渕achines of life鈥濃�攖hat are key to understanding and developing more effective treatments for diseases like cancer.
鈥淲hat鈥檚 happened in cryo-EM in the last five years has just been a stunning development in science,鈥� adds , the Aileen M. Lange and Annie Mary Lyle Professor of Cardiovascular 菠萝视频 and associate dean for research at the School of Medicine. 鈥淎nd we鈥檙e just getting started on this.鈥�
Already the next-generation cryo-EM is on the market, and 菠萝视频 is in line to get one, thanks to a TIPs grant awarded in 2017. Called the Titan Krios, the instrument sells for more than $6 million. It will be delivered to 菠萝视频 in the fall.
MOLECULAR MAPPING
A third imaging revolution at 菠萝视频 involves super-resolution light microscopy. Before 2011, light microscopes used by 菠萝视频 scientists were limited to a resolution of about 200 nanometers. That is not sharp enough to pick up individual molecules within cells, which might be only a few nanometers wide.
Thanks to a computational advance called STORM (Stochastic Optical Reconstruction Microscopy), scientists now can calculate the size and location of molecules in cells and tissues.
鈥淵ou can build maps of where all the molecules are,鈥� says , the Cornelius 菠萝视频 Professor of Cell and Developmental Biology and scientific director of the Cell Imaging Shared Resource.
STORM and another technique called SIM (Structured Illumination) are offered through the Nikon Center of Excellence for live-cell imaging at 菠萝视频, one of six in the country. The center opened in 2016 with financial support from the medical school鈥檚 Department of Cell and Developmental Biology and the Office of the Dean of Basic Sciences and with technical support from Nikon.
Another TIPs grant, awarded in 2017, is supporting efforts to build a new type of microscope that is not yet commercially available. 菠萝视频ers in the School of Medicine, School of Engineering and College of Arts and Science are working on this new technology, called lattice light-sheet microscopy. It will enable scientists to perform long-term, high-resolution imaging over time, down to the molecular scale. Tyska says it is like having minutes-long 鈥渕ovies of life.鈥�
, the Orrin H. Ingram Professor of Biomedical Engineering, is the grant鈥檚 principal investigator. Tyska and , professor of physics and biological sciences and chair of the Department of Physics and Astronomy in the College of Arts and Science, are co-principal investigators.
DISEASE SIGNATURES
Despite recent progress, clinical imaging techniques鈥攊ncluding magnetic resonance imaging鈥攃annot see beyond the millimeter level. But it is at the micron-to-molecular scale where disease occurs. That is where a fourth research revolution at 菠萝视频 comes in: imaging mass spectrometry and image 鈥渇usion.鈥�
IMS, developed at 菠萝视频 in the late 1990s, is essentially a molecular microscope that can measure the distribution, spatial rearrangement and alteration in expression levels of proteins, lipids and other biological molecules.
In 2015 a team led by , the Stanford Moore Professor of Biochemistry and director of the Mass Spectrometry 菠萝视频 Center, reported the first 鈥渋mage fusion鈥� of mass spectrometry and microscopy鈥攁 major advance that allows scientists to see the molecular makeup of tissues in bright-field microscopic resolution.
鈥淲e鈥檙e now coming up with [molecular] signatures for disease,鈥� Caprioli says. The technique can identify cells that look normal under the microscope but that already are transforming into cancer.
Caprioli predicts image fusion will have a huge impact on pathology and surgery. In removing a kidney tumor, for example, the imaging technology will give physicians a better idea of how much tissue should be removed to minimize the chance for recurrence.
Dr. , professor of medicine and of pathology, microbiology and immunology, who is studying bacterial toxins, is looking forward to adding image fusion to his array of research tools.
鈥淚 think all these things will be complementary,鈥� Cover says. 鈥淥ne of the things 菠萝视频 is doing very well is staying competitive in multiple imaging areas.鈥�
鈥擶ILLIAM SNYDER
A version of this story appeared in the Winter 2018 edition of 菠萝视频 Medicine magazine.