Top 10 Innovations 2013

Despite formidable odds, this year was a good one for life science innovation. The double punch of the government-wide belt tightening, known as the sequester, and the two-week federal government shutdown deflated institutional budgets and sowed uncertainty among investors. But new and exciting products still made their way into the marketplace. And with more than 80 products submitted to this year’s Top 10 Innovations contest, our expert panel of judges had the tall task of whittling the crowded field down to the very best. The competition proved to be so tight that this year’s Top 10 is actually a Top 12, with two ties—for the second and tenth spots. A mini-microscope that can capture networks of brain neurons firing in real time as mice engage in behaviors and a 3-D upgrade to an imaging platform that made an appearance in our 2011 Top 10, are among the winning products that embody the spirit of innovation our competition seeks to capture. Read about all the products that rose to the top of a very competitive list of submissions to The Scientist’s Top 10 Innovations of 2013. And be sure to visit www.the-scientist.com for lots of extra Top 10 information, including expanded comments from our expert panel of judges and a look at products that earned honorable mentions in this year’s contest. (left to right) BARBARA DALTON Vice president of venture capital at Pfizer, Dalton is responsible for Pfizer Venture Investments, managing the current private-equity portfolio and advising on structured-equity transactions. She began her career as a scientist and pursued anti-inflammatory drug discovery research at Smith, Kline & French Research Laboratories for 10 years. KEVIN LUSTIG Founder and CEO of software company Assay Depot and cofounder of Bio, Tech and Beyond, a nonprofit community laboratory dedicated to life science innovation. In 2001 Lustig founded Kalypsys, a biopharmaceutical company that raised more than $170 million in venture funding and has so far moved five drug candidates into clinical trials. BIBHASH MUKHOPADHYAY Manager of business development and a fellow at Johnson & Johnson’s Corporate Office of Science and Technology. Prior to joining J&J, Mukhopadhyay gained experience in venture investing at Burrill & Company, in start-ups, and as both the founder of a med-tech company and an advisor to a biotech. VAL GIDDINGS Senior fellow at the Information Technology and Innovation Foundation. Giddings is also president and CEO of PrometheusAB, Inc., a consultancy that provides regulatory compliance, media, and strategic planning advice to clients in the U.S. and around the world. He founded PrometheusAB after serving for eight years as vice president for Food & Agriculture at the Biotechnology Industry Organization (BIO). ELAINE MARDIS Professor in genetics and molecular microbiology and codirector of The Genome Institute at Washington University School of Medicine in St. Louis, Missouri, where she orchestrates efforts to explore massively parallel sequencing technologies and to transition them into production sequencing capabilities and new applications. Mardis serves on the scientific advisory boards of DNA Nexus and ZS Genetics. ERIC SCHADT Director of the Icahn Institute for Genomics and Multiscale Biology, chair of the Department of Genetics and Genomics Sciences, and the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai in New York City. He is also a founding member of Sage Bionetworks, an open-access genomics initiative designed to build and support databases and an accessible platform for creating innovative, dynamic disease models. nVista HD Inscopix COURTESY OF INSCOPIXEfforts to spy on neural activity as animals are freely moving about have been impeded by bulky equipment or limitations in human skill sets. Microscopes are often too big to mount to the head of a rodent, and electrophysiological techniques don’t allow for simultaneous monitoring of large networks of active neurons at the resolution of a single cell. Inscopix’s new mini fluorescence microscope, the nVista HD, smashes those barriers. “Basically, we are imaging at the cellular level the activity of thousands of neurons while an animal is able to freely navigate an established behavioral task,” says Scott Norviel, the company’s director of product marketing. The microscope sticks to a magnetic platform that frames a window in the skull. The detachable microscope weighs just 2 grams and can be plugged in during behavioral tasks or removed to share among a number of animals. The mice don’t seem to mind the device, says Nikita Rudinskiy, a research fellow at Massachusetts General Hospital and Harvard Medical School, who is using the microscope to research the neural correlates of dementia in the hippocampus. “They just do their normal stuff,” he says. The nVista HD carries a hefty price tag of $100,000, but since its debut in October 2012, 100 units have made it to laboratories around the world. Rudinskiy says that there’s no other technology that would offer him the ability to gather data from so many neurons over such a long time frame. “With this system you can image the same mouse, the same several hundred neurons, over days and months,” he says. “It’s amazing.” MARDIS: This is incredibly cool and will permit so much more understanding of neuronal function and neural circuits in the brain than one can ever get from a static section after sacrificing the mouse. GIDDINGS: If [this innovation] delivers it will be a major disruptive event in the history of neuroscience, potentially leading to rapid advances across multiple fronts. X-MAN Reporter Kits Horizon Discovery COURTESY OF HORIZON DISCOVERYThe X-MAN reporter kits, launched in November 2012, are essentially cell lines with built-in reporter constructs. This removes the traditional step of treating cells with reporter-bearing plasmids, which can introduce hundreds of copies of the gene of interest or its promoter. “The problem with overexpression models is that you’re obviously not expressing the reporter at the same level as the native protein or gene, and that can lead to artifactual data,” says Holly Astley, one of the Horizon scientists who helped develop the X-MAN kits. “We felt that by attaching the reporter to the gene or protein at the endogenous level, we could get around this.” There are two lines of X-MAN reporter kits: cell lines with Promega’s NanoLuc luciferase reporter, which Astley and her colleagues were confident would be detectable even at natural expression levels, and cell lines with Promega’s HaloTag, which can be used in a variety of different applications. Once the protein of interest is expressed with the HaloTag, researchers can add a fluorescent protein to visualize it, examine its interactions with other proteins, or even collect the protein of interest and any proteins that may have bound it. Molecular biologist Yaping Liu, an associate principal scientist at Merck, is using X-MAN reporter kits to look at the expression of Myc, a regulator gene that is mutated in many cancers. “We consider it a more physiologically relevant cell line to study gene expression,” Liu says. Kit prices start at $550, and include the engineered cell line along with the necessary reagents. “It works out to about $1 per assay,” says Jonathan Frampton, diagnostic product manager at Horizon Diagnostics, a business unit of the UK-based Horizon Discovery. GIDDINGS: The quantitative advances in this reporter technology should add up to a qualitative advance in researcher capabilities to image a host of metabolic activities. LUSTIG: The cell assay can be used to measure changes in expression of endogenous genes, something not possible with overexpression models in widespread use. SmartFlare RNA Detection Probes EMD Millipore COURTESY OF EMD MILLIPOREResearchers often use antibodies to sort cell types in gene-expression studies. The standard way to confirm that cells have been sorted correctly is by fixing them for microscopy or lysing them for PCR or western blotting. New SmartFlare RNA Detection Probes from EMD Millipore offer an alternative option for cell sorting by allowing fluorescent detection of internal RNA species without harm to the cell—no antibodies required. The probes, oligonucleotides specific to a target RNA that are bound to gold nanoparticles, are incubated with cells overnight. Cells endocytose the nanoparticles, which bind to their complementary RNA target, releasing a fluorophore that can be detected via flow cytometry, microscopy, or any downstream method that relies on fluorescence. The cells exocytose the particles after a few days and thus recover completely from treatment. “It’s going to revolutionize a lot of things,” says Steve McClellan, who uses the probes at the Mitchell Cancer Institute at the University of South Alabama. McClellan isolates cancer stem cells from dissociated tumors and has found that SmartFlare RNA Detection Probes, which came onto the market in January, allow him to sort out stem cells quickly and easily. He has tested nine different types of cancer, and the probes work in each one. McClellan called the preliminary data “amazing.” “Being able to work in a live-cell environment opens up a lot of opportunities,” says Victor Koong, SmartFlare product manager at EMD Millipore. The probes are priced at $645 for 250 reactions, and Koong says there should be about 900 different probes available by the end of the year. MARDIS: There are a multitude of studies that could be aided by this reagent, including cell-specific expression by gene to examine heterogeneity across multiple cells. LUSTIG: These new RNA detection probes can be used to visualize RNA expression in live cells at the single-cell level. SR GSD 3D Leica Microsystems COURTESY OF LEICA MICROSYSTEMSResearchers conducting studies that involve fluorescence microscopy can generally count on resolutions of around 200 nm. Even super-resolution microscopy, with 20 nm resolution in the XY plane, is limited by a 600–700 nm resolution along the Z axis, which does not afford a glimpse of three-dimensional molecular structure. Leica’s SR GSD 3D imaging system, released in August, solves this problem with resolutions of 20 nm in the XY plane and 70 nm on the Z axis. A cylindrical lens allows the SR GSD 3D’s software to determine whether a single point is above, below, or in the focal plane and to then combine that information into a 3-D stack. The system comes with a new 160x objective, specifically designed for super-resolution, and a SuMo (Suppressed Motion) stage, which minimizes drift. Sebastian Tille, the director of wide-field imaging at Leica Microsystems, emphasized the system’s user-friendly software, which integrates robust color correction. “Even users that don’t have a physics background . . . achieve good results in a relatively short time,” Tille says. A fully equipped system costs about $350,000. “It’s obvious that if you can see more detail in a cell, you can learn more about it,” says cell biologist Kees Jalink of the Netherlands Cancer Institute. Jalink has used the SR GSD 3D to visualize cytoskeletal organization, and describes the 3-D information gathered by this system as so good “that you can count individual molecules.” SCHADT: In this iteration of the product, 3-D visualization of cellular structures is now possible at a resolution that has formerly only been possible using electron microscopy. DALTON: This scope permits mapping signaling pathways in cells, moving visual capabilities closer to electron microscopy, and enhancing our knowledge of intracellular structure-function and molecular pathways. Prosigna Breast Cancer Prognostic Gene Signature Assay NanoString COURTESY OF NANOSTRINGOvertreatment in health care wastes money and can sometimes cause more harm than good. NanoString’s Prosigna Breast Cancer Prognostic Gene Signature Assay, introduced in February 2013, brings more detailed prognostics right to the clinic, with the goal of sparing breast cancer patients from overly aggressive treatments. NanoString’s Prosigna assay determines a patient’s risk of breast cancer recurrence by examining the gene expression profile of the patient’s tumor cells. Aleix Prat, a physician and researcher at Vall d´Hebron Institute of Oncology in Barcelona, uses the score to identify patients who might do fine without chemotherapy or radiation if they’ve responded well to endocrine therapy. The assay is also useful in research because it can identify the true biological subtype of the tumor—the only test that can, Prat says. In addition, “it captures more biological information than the set of three to four pathology-based biomarkers currently used in the clinic.” Brad Gray, the CEO of Seattle-based NanoString, says that other genomic tests can make similar assessments, but NanoString’s technology is simple enough to be used in the clinic, rather than sent to specialized labs. One kit sells for $2,000, but the instrument that performs the actual analysis, called the nCounter, runs about $250,000, at least in Europe. The company plans to introduce the assay in the United States in 2014, but isn’t yet saying what they’ll charge US customers. “There are a lot of opportunities to continue to expand the utility of the assay,” says Gray. “We think this is the first of a menu of diagnostic tests we hope to build on this system.” MARDIS: This assay has been shown to outperform the clinical testing service from Oncotype DX because more women are characterized as having a high or low risk of recurrence, both of which are clinically informative, versus “medium” risk of recurrence, which is clinically indeterminate. SCHADT: This test leverages the NanoString technology that can be run in any local lab, thus providing a path for this type of diagnostic to be run as part of existing laboratory workflows. ClearColi Lucigen COURTESY OF LUCIGENResearchers using Escherichia coli as a model organism have always had to purify their products thoroughly, due to the dual nature of the microbe—biological workhorse on the one hand, potentially deadly pathogen wielding the endotoxin lipopolysaccharide (LPS) on the other. This step is costly, time-consuming, and rarely complete. ClearColi is the first-ever line of E. coli that lacks LPS, instead expressing a nontoxic LPS precursor called lipid IVA. “We effectively eliminated endotoxin at the source,” says Uwe Mamat, a microbiologist of the Research Center Borstel in Germany, who was on the team in Ron Woodard’s lab at the University of Michigan that first happened upon a viable E. coli mutant lacking the toxin. Mamat and his colleagues published their initial results in 2006 (ACS Chem Biol, 1:33-42), after which they were approached by Research Corporation Technologies (RCT), which aims to commercialize technologies coming out of academia. RCT acquired the patent from Woodard’s group and helped the team develop the product, then licensed the technology to Lucigen, which released their first commercial product in May 2013: an LPS-free strain of E. coli for protein production. The researchers also hope to launch a plasmid-production strain by the end of the year, says RCT managing director Chad Souvignier. “The promise all along has been to develop strains that lack endotoxin activity but meet all the other performance characteristics of the strains that people use in their labs,” he says. MUKOPADHYAY: These cells allow production of proteins in E. coli without need for endotoxin removal steps, which result in loss of yield and increased costs but are not completely effective. SCHADT: ClearColi has been engineered to eliminate endotoxin and, as a result, much more cleanly produce proteins of interest in large quantities. This has the potential to significantly impact the biologics space. Humanized Bacterial Luciferase 490 BioTech COURTESY OF 490 BIOTECHMolecular biologists insert bioluminescent genes into cells to report back on any number of measures, such as the toxicity or efficacy of a drug. Firefly luciferases are popular reporter proteins, but they have one glaring deficiency: exogenous reagents must be added to target cells to turn on their glow, thus killing the cells and halting the experiment. This means that toxicity, for instance, can’t be measured continuously over the course of a drug’s dose, but only at discrete time points. Bacterial luciferase, on the other hand, “is its own little machine,” says Steve Ripp, the COO of 490 BioTech, a company that has developed a bioluminescent reporter system that requires no additional substrate to turn on the light. “No more killing your cells to get the substrate into your cell,” he says. 490 BioTech has introduced bacterial luciferase into various eukaryotic cell lines, including a number of human lines, and the reporter can be custom-made for specific experiments. “You tell us what you need, what cell line, what you want that cell line to do, and we will design it and sell it to you,” says Ripp. Costs range from $8,000 to $22,000. Although the signal is not as strong as those of other luciferases, the product works especially well for 3-D drug screens, for which assays have proven a challenge to develop, says Hal Crosswell, the chief medical officer of Kiyatec, a company that has worked with 490 Biotech on testing applications of the reporter cells. “The fact that you can monitor these in real time, continuously, without ending the experiment, is huge.” MARDIS: It transitions a critical tool from the bacterial to the mammalian world—magic! LUSTIG: This is a significant new addition to the bioluminescent assay tool kit in widespread use in pharma and academia. Eukaryotic cell lines that self-bioluminesce will enable new research approaches, including continuous imaging in cell and animal models of disease. SynVivo CFD Research Corporation COURTESY OF CFD RESEARCH CORPORATIONSynVivo is a synthetic in vivo vascular environment on a microfluidic chip. “The whole idea was to come up with a better in vitro model which actually makes use of the features and the geometry and the flow [of a real animal],” says lead developer Prabhakar Pandian. The SynVivo platform, launched in December 2012, consists of about 20 standardized chips that mimic the different vascular geometries of hamster, rat, and mouse. Several chips also contain specialized cavities for seeding cells of a particular tissue type, such as neurons, hepatocytes, or tumor cells, which scientists can use to study interactions with drugs or other circulating compounds. The chips run from $50–$150. The company will even work with researchers to develop a customized chip for an additional cost. “In the early stages of this, I thought this would be a tall order,” says Temple University biomedical engineer Mohammad Kiani, who is collaborating with the company to validate the platform, but is not financially tied to it. “But as we’ve gotten into it, we have realized that it can be done.” To construct a synthetic in vivo environment, researchers simply coat the channels of the microchip with an appropriate substrate, such as fibronectin, and then seed it with cells. Fluid then moves through the system to mimic natural blood flow. “We are very surprised that we are getting such good agreement between what we see in vivo and what’s being done in vitro,” says Kiani, who is using the technology to look at the interaction of human leukocytes and endothelial cells, to investigate therapeutic approaches to disruptions of the blood-brain barrier in children, and to replicate the interaction of tumor cells with endothelial cells during metastasis. “I think it has a lot of potential.” SCHADT: This product can recreate realistic human microvascular networks within which cells of interest can be cultured and studied in a more realistic setting. LUSTIG: This is the next step in microvascular microfluidic assay systems, enabling innovative cell-migration and drug-distribution assays that are difficult to model in other ways. NumaTac SynTouch COURTESY OF SYNTOUCHAmong its many other functions, human skin helps sense collisions when they occur. An elbow banged into a door results in a signal from the brain instructing the elbow to stop colliding with the hard surface. Robots are generally built with a metal or hard plastic exterior, which means if they hit something they are not supposed to, they have no way of sensing that they should stop or go back. Their machinery could be damaged before the action that caused the collision stops. NumaTac pads, developed by SynTouch LLC, are made of open-cell polyurethane foam—the same material used to construct injection-molded seat cushions—and contain sensors that allow robots to detect and respond to collisions. The NumaTac pads “are there when needed, like air bags. They hang out, they’re flexible, and they can be made in arbitrary shapes for whatever protection you need,” says Gerald Loeb, SynTouch CEO and professor of biomedical engineering at the University of Southern California. The price of a NumaTac pad is specific to the application and to the design of the communication network between robot and sensors. As scientists “start to put robots out into the workplace, this will become important,” says Loeb. In simulations SynTouch has shown that, with NumaTac coverage, a robotic arm that makes movements about the scale of those made by a human arm would have sufficient time to stop before it is destroyed by a collision with a rigid object. Without NumaTac, Loeb says, that robot could wind up a heap of “mangled metal.” MUKHOPADHYAY: Embedding robots with a sense of touch, with the notion that tactile feedback is critical for surgical robots. LUSTIG: This new tactile sensor is being used in prosthetic devices and surgical robots to enhance sensitivity and improve function. ADCC Reporter Bioassay Promega COURTESY OF PROMEGAAntibody-dependent, cell-mediated cytotoxicity (ADCC) reporter assays are used to assess the efficacy of monoclonal antibody therapies. Although such therapies are popular, particularly to treat cancer and autoimmune disorders, “no one is happy with the current assays,” says Jey Cheng, a senior research scientist at Promega. The bottleneck, she says, has been the variability of the human donor immune cells used as effector cells, which recognize an antibody on a target cell, such as a tumor cell, and attack it. Testing the same antibody therapy on different days, Cheng says, “it’s hard to get a repeatable result.” To develop an assay that is more reliable, Cheng’s team diverged from the usual laborious protocol of culturing cells obtained from human donors. Instead, Promega’s new ADCC Reporter Bioassay kit includes engineered human T cells developed from an immortalized cell line as effector cells, ready to thaw and use. The result is an assay that is “robust, convenient, and easy to perform,” says Mary Hu, the director of Bioassay Development and Process Analytics at Seattle Genetics. The kit costs $800 and was introduced to the market in November 2012. The major limitation of the assay is that it needs to be optimized to target the appropriate cells, “in addition to optimizing the ratio of effector cells versus target cells,” says Hu. One big benefit, she adds, is that unlike assays that use human donor cells, which can take days to propagate, all the work to assess ADCC using Promega’s kit can be done in a single day. MARDIS: This system is very innovative and likely will improve the development of these much-needed [antibody-based] drugs, which is going to be critically important. MUKHOPADHYAY: Allows investigation into presence of . . . an adaptive immune response mechanism for many commercially available oncology therapeutics, including Rituxan and Herceptin. NOMe-Seq Active Motif COURTESY OF ACTIVE MOTIFDNA methylation and nucleosome arrangement work together to exert epigenetic control of gene expression. Precisely tracking the effects of these two processes has traditionally relied on assembling separate snapshots of DNA methylation and nucleosome occupancy, the position of nucleosomes in the genome. But a new technique from Active Motif called NOMe-Seq (Nucleosome Occupancy and Methylome Sequencing) will allow scientists “to look at both DNA methylation and nucleosome positioning within the same DNA molecule,” according to Terry Kelly, the project’s R&D manager. At the start of the NOMe-Seq process, fixed chromatin is artificially methylated at GpC residues not packaged in a nucleosome. Then the cross-links are reversed, releasing the nucleosomes and any bound proteins such as transcription factors, and the DNA is subjected to bisulfite conversion, which converts unmethylated cytosines to uracil. The DNA can then be sequenced, revealing both the DNA’s methylation profile and the footprint of nucleosome occupancy where DNA was protected from GpC methylation. Introduced last November, the kits cost $650 apiece and include reagents for 10 sample reactions. NOMe-Seq “was a very attractive technology from the beginning because it allowed us, on a genome-wide scale, to be able to directly determine the nucleosome positioning with the DNA methylation status,” says Sue Clark, acting director of the cancer division at the Garvan Institute of Biomedical Research in Australia. “Previously, you could only infer by association what the relationship was between DNA methylation and nucleosome positioning,” she says. Phillippa Taberlay, a group leader in the epigenetics program at the Garvan Institute, adds that NOMe-Seq “can be applied to almost any type of epigenetic question.” GIDDINGS: If this performs as advertised, it could add a valuable tool to the analysts’ kit and shine light in some shadowed but very important places. MUKHOPADHYAY: Allows multitiered epigenetics analysis by combining high-resolution footprint of nucleosome occupancy with DNA methylation profile. Quantitative Multiplex Reference Standard Horizon Diagnostics COURTESY OF HORIZON DIAGNOSTICSValidating the results yielded by next-generation sequencing and related technologies is a significant hurdle for genomics researchers. The Quantitative Multiplex Reference Standard provides scientists with well-characterized samples of cell line or DNA variants that they can use to validate the techniques they’re employing in the lab. “[It was] very hard to get consistent mixing [of cell lines] . . . and there was no guarantee that the second time we’d go back we’d get exactly the same mix,” says cancer genomicist Erich Jaeger, who works on product development at sequencer manufacturer Illumina. The Quantitative Multiplex Reference Standard, made by Horizon Diagnostics, can cut out the time-consuming and inconsistent step of making samples of known composition. “It just really made our lives a lot simpler to have something we could go to and know that we would always be able to get these variants [at the same frequencies],” Jaeger says. The Quantitative Multiplex Reference Standard, launched in March 2013, contains a total of 30 PCR-validated mutations and can be purchased as a mix of cell lines carrying different variants, embedded in paraffin to mimic patient samples. In this form, the validation “can be included right from the beginning in terms of sample preparation,” says Chris Thorne, Reagents Group Team Leader at Horizon. “[Researchers] can work with samples throughout the whole process.” Alternatively, the product is sold as a solution of DNA containing variants of different frequencies. Paraffin-embedded sections of cells start at $40, while a solution containing 100 ng of DNA solution can be purchased for $120. GIDDINGS: Robust and validated reference standards are the essential prerequisite to enable the kind of tumor profiling that can now be imagined and which is poised to be the benchmark of the future. SCHADT: One of the first commercially available reference panels that will enable an accurate assessment of the quality of an NGS [next-generation sequencing] oncology-based assay across a broad range of detection thresholds for cancer-relevant mutations.

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