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30 | JULY 2016 | GENengnews.com | Genetic Engineering & Biotechnology News Technological advances have led to the development of imaging systems that integrate advanced instrumentation and refned workfows. Such imaging systems, which are capable of high throughput and low error rates, include BioTek's Cytation Cell Imaging Multi-Mode Readers. The Cytation 3 and Cytation 5 platforms incorporate both charge-coupled device (CCD) and photomultiplier tube (PMT) technology. "One can think of the Cytation as two instruments in one," says Peter Banks, Ph.D., scientifc director. "Below the microplate-loading mechanism is an inverted digital mi- croscope using CCD-based detection for brightfeld, color brightfeld, phase-contrast, and fuorescence microscopies. Above the microplate-loading mechanism is a hybrid micro- plate reader system using multimode PMT-based detectors." Cytation has been evaluated in studies involving complex cell models including a tumor spheroid, an in vitro surrogate model for metastasis. For example, Dr. Banks and colleagues examined the role CXCR4 inhibitors can play in CXCR4- mediated tumor metastasis. Tumor metastasis was quantifed by brightfeld microscopy and the Cytation imaging software. "Any sort of assay that mimics metastasis is of huge worth to oncology drug discovery," asserts Dr. Banks. "Peo- ple don't die from having a mutation in their cells. They die from tumor metastasis." Any compound that inhibits this process should be a good drug candidate to investigate as an antimetastatic drug. Looking at research imperatives more broadly, Dr. Banks and others see multiparametric analysis of disease as driv- ing the trends in imaging advancement. "Imaging methods are one of the better tools for doing phenotypic assays," he explains, "you can quantify many changes to cellular struc- ture and function using imaging through the use of various probes or just by label-free detection." Overall, what is being observed is a move toward com- bining target-based science, made popular in the last few decades, and classical phenotypic assays. "This is a more balanced approach," comments Dr. Banks. "In certain dis- eases, we have a strong knowledge of disease mechanism of action, so it makes sense to perform drug discovery through target-based approaches. On the other hand, in diseases where mechanism of action is doubtful or unknown, like many forms of cancer, I expect phenotypic approaches to be more successful." Novel PET Imaging Detectors Meanwhile, at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Anna Wu, Ph.D., professor and chair of the department of molecular and medical pharmacology, has been engineering antibod- ies for both therapeutic and imaging purposes. Antibodies meant for imaging, she points out, refect a slightly different set of engineering characteristics. Dr. Wu works with colleagues at UCLA and ImaginAb (a company she co-founded in 2007 and now serves as chief scientist) to engineer labeled antibodies. Because Dr. Wu in interested in advancing positron emission tomography (PET) imaging, she is engineering antibodies that incorporate posi- tron-emitting radionucleotides. "Each imaging modality has its strengths and weak- nesses," notes Dr. Wu. "Magnetic resonance imaging (MRI) gives you anatomical and physiological imaging, but it doesn't have the sensitivity of PET. PET has a higher reso- lution and sensitivity compared to single-photon emission computed tomography (SPECT), but it has lower resolution than MRI or CT." Dr. Wu has chosen PET because it fts well with her an- Homing In on Directed Imaging Platforms To model metastasis, scientists at BioTek Instruments used tumor spheroids that incorporated MDA- MB-231 cells and primary fbroblasts. Incubated and treated tumor spheroids underwent imaging that entailed the drawing of object masks: (A) day 1, untreated; (B) day 5, untreated; (C) day 1, treated with 250 µM oridonin; (D) day 5, treated with 250 µM oridonin. These 4× brightfeld images were captured with the company's Cytation 5 Cell Imaging Multi- Mode Reader. TRANSLATIONAL MEDICINE Ian Clift, Ph.D. Subcellular imaging technologies have come a long way. Conventional microscopy—the use of upright microscopes to detect small changes in light transmission through the cell—has been augmented by phase-contrast microscopy and fuorescence microscopy. Phase-contrast microscopy improves images by measuring changes in the refractive index within the cell. Fluorescence microscopy provides even better contrast enhancement through the use of fuorescent probes that bind to specifc molecules on and in the cell.