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Innovation has been a buzzword since at least the early 1990s. A Wall Street Journal article published earlier this year bemoaned the more recent overuse of the word, citing its appearance in product descriptions by soup makers, bubble-wrap manufacturers, and dried cranberry producers among more than 33,000 companies whose 2011 quarterly and annual reports featured the word. Such ubiquitous usage may be diluting the very meaning of innovation. But as the global economy searches for ways out of its current morass, the word is again fresh on many lips—innovation economy, innovation strategies, innovation officers, and the foreboding-sounding innovation gap.
With The Scientist’s fifth installment of our annual Top 10 Innovations competition we refocus on the core meaning of “innovation”—to whit: a new idea, method, or device, according to the Merriam-Webster dictionary. And this year’s crop of winning products speaks directly to this simple definition.
From a 3-D system for culturing cells and tissues and a synthetic gene service to a laboratory organization Web and iPad app (one that is coincidentally featured in this month’s Careers article “Lab 2.0” on page 67) and products that showcase the latest in rapid, cheap genome sequencing, this year’s winners exemplify true innovation. And to celebrate that spirit of inventive creativity, in which researchers and product developers push the technological envelope in order to propel science and our exploration of life, we present The Scientist’s Top 10 Innovations of 2012.
Modern pharmaceutical, chemical, and fuel companies increasingly depend on synthetic biology to produce DNA tailor-made to suit their production needs. Making synthetic genes to program microorganisms used to require a lot of time, in addition to expensive robots and other equipment, but Gen9 has developed BioFab, a new system that can quickly and cheaply produce tens of thousands of double-stranded DNA fragments of between 500 and 1,000 base pairs in length. The company’s system for “biological fabrication” couples inexpensively made small DNA fragments with patented or patent-pending chemical processes that accurately assemble them into larger DNA strands, which the platform can do in bulk. Though pricing varies with the amount of synthetic DNA and the modifications a customer needs, the cost can be less than 10 cents per base pair, which is as little as 1/5 of what some competitors charge, according to Gen9 President and CEO Kevin Munnelly. “The ability to synthesize large numbers of genes in parallel at low cost could transform the field of computational protein design,” says molecular engineer David Baker of the University of Washington, who is a customer and a member of the Gen9 advisory board.
The company, which launched this summer, currently has about 20 customers—half from industry, half from academia. Gen9’s high-throughput manufacturing process allows the company to reduce both the cost and the production time of synthetic DNA. By 2013, Gen9 hopes to singlehandedly surpass the world’s current capacity to manufacture synthetic DNA.
WILEY: Brings the cost and speed of DNA synthesis down to the point where entire vectors can be designed and assembled from scratch. A critical component needed to make synthetic biology a reality.
Ion Proton System
Human-scale genome sequencing just got a whole lot more accessible. Twelve years ago, it cost $1 billion to sequence a single human genome. By next year, using Life Technologies’ Ion Proton machine, it will take less than a day and cost $1,000 (not including analysis costs, of course).
Launched in September, Ion Proton is driven by the same semiconductor technology—which converts chemical information directly into digital data—that powers the successful Personal Genome Machine (PGM). For now, the Proton I chip sequences a human exome in a few hours. But in early 2013, Life Technologies will release the Proton II chip, designed to handle an entire human genome, from sample prep to full sequence, in 8 hours. The Ion Proton costs $244,000, and each disposable one-run chip goes for $1,000.
“We’ve piggybacked on over a decade of investment in semiconductor technology to bring a dramatic reduction in cost and increase in speed,” says Maneesh Jain, VP of business development and marketing at Ion Torrent, the sequencing technology start-up acquired by Life Technologies in 2010. By making large-scale sequencing more widely available, this machine will enable a new era of discovery, he adds.
“This will give us the capacity to quickly go after the whole exome, whereas on the PGM we were looking at 20 to 50 genes at a time,” says Christopher Corless, medical director at Oregon Health and Science University’s Knight Diagnostic Laboratories in Portland, who plans to use the Ion Proton to look for mutations in tumors that can be targeted by new pharmaceuticals. “That will be a big jump forward.”
MAZAR: This opens up all sorts of possibilities for interpretation of animal experiments, clinical trials, and the evaluation of new therapeutic interventions.
Cellular Dynamics International
This October, Shinya Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine for his discovery that injecting a few transcription factors into a differentiated adult cell can render that cell pluripotent once again. The technology revolutionized biomedical research, allowing scientists to create induced pluripotent stem cell (iPSC) models for a variety of diseases. Now, Cellular Dynamics International (CDI) is utilizing that technology to offer, via the company’s MyCell Services, iPSC lines from any patient of interest, as well as differentiated cell lines derived from the iPSCs.
“[Customers] don’t have to be stem-cell biologists to leverage this technology,” says Chris Parker, CDI’s chief commercial officer. “They can simply be interested in a disease state and get the human cells they need to answer appropriate questions.”
Paul Watkins, for example, director of The Hamner–University of North Carolina Institute for Drug Safety Sciences, is using MyCell Services to create iPSC-derived hepatocytes from patients who have survived severe liver reactions to drugs, comparing them to iPSC-derived hepatocytes from healthy donors. Ultimately, he says, the goal is to identify specific genetic profiles that indicate susceptibility to adverse drug reactions. “We have the whole exome sequence [for these patients], and we will have [the] whole genome sequence, so we know the variations that exist and have various hypotheses,” Watkins says. “But this [technology] will allow us to test, directly, those hypotheses.”
The iPSC lines are derived from CD34 cells in blood samples sent in by customers, and returned as 96-well plates of a cell type of interest. To create an iPSC line from a patient sample costs $15,000 and takes about 6 months, Parker says, but once the iPSC lines are established, it takes just 1 to 2 months to order more specific cell types derived from that line. The cost per plate for differentiated cells is approximately $1,500, with a minimum order of 20 plates.
CHANDLER: The ability to produce induced pluripotent stem cells “on demand” with high quality and purity has high potential to transform both numerous fields of life sciences research and open the door to potential medical applications.
Vanishing are the days when grad students and postdocs scribble their experimental setups and data in splotched black-and-white notebooks. Labs across the world are going digital, and Labguru is a new product that could change the way that labs chart their progress.
Labguru (coincidentally featured in this month’s Careers article “Lab 2.0”) is a digital platform, accessible via an Internet browser or as an iPad app, that stores data from different investigators in a lab, tracks reference materials, logs logistical information such as reagent inventory, and can be used to share experimental protocols and other useful tidbits. “Our biggest concern is to get labs to run more efficiently and to be more productive,” says Jonathan Gross, founder of BioData Ltd., the Israel-based company that created Labguru.
Gustavo Valbuena, a research pathologist at University of Texas Medical Branch at Galveston who studies the pathogenesis of Rocky Mountain spotted fever among other phenomena, has used Labguru in his lab for the past 9 months. After trying other software and electronic lab notebooks to organize activity and data in his lab, he found Labguru to be most effective in upping his students’ and technicians’ productivity and accountability. “What I see is that people in the lab are more consistently entering their data there,” says Valbuena, who pays about $100 per user per year for the upgraded version of Labguru. Use of the basic iPad app and Web version is free.
WILEY: This could finally start to bring experimental biologists out of the paper age and into the computer age.
Illumina has incorporated its ubiquitous sequencing by synthesis (SBS) technology into a stripped down “personal sequencer” called MiSeq—a faster, cheaper, and simpler benchtop machine that aims to bring next-gen sequencing into the mainstream.
For a 2-square-foot device it packs a lot of throughput, supporting 2x250 base pair runs and generating up to 8.5 gigabases per run. And MiSeq’s intuitive interface makes it very user-friendly. “We’ve taken what Illumina has done over the past 5 years and condensed [everything] into a really simple package,” says Jeremy Preston, Illumina’s director of product marketing. Just prepare the DNA, load the cartridge, and press “Go.”
It’s fast, too: users can prepare samples in 90 minutes and sequence an entire microbial genome in a day or less. And at $125,000 per machine—with individual runs costing from $400 to $750—MiSeq is affordable enough to use in clinical settings.
The FDA has already tapped MiSeq for use in its efforts to track food-borne pathogens. Over the next 2 years, it will also be used to track superbug outbreaks in hospitals, says Derrick Crook, a microbiologist at the University of Oxford, U.K., and coauthor of a recent pilot study into the use of MiSeq for the surveillance of C. difficile and MRSA in several UK hospitals, published in BMJ Open. “You get really high-quality sequencing in a very short turnaround time,” he says. “It’s a huge step forward.”
MAZAR: Fast, small footprint, expands ability of preclinical and clinical researchers to get genomic sequence data that can then be rapidly correlated with drug response, etc.
ONIX Microfluidic Platform
The CellASIC ONIX Microfluidic Perfusion Platform is putting a new spin on live-cell imaging. The setup looks like a rearranged 96-well plate with a glass bottom. Cells placed in inlet wells flow into a culture chamber, where they are subject to a dynamic environment designed by the user. In other plate wells, researchers can put various media, drugs, and other variables. Then, the plate is placed under a microscope and hooked up to a machine that can be programmed to control the flow of the wells’ contents via microchannels into and out of the culture chamber.
“You pipette in all your chemistry—your media, your cells—and then you go to the software and program all your automated steps,” says Alex Mok, a product manager at CellASIC, now part of EMD Millipore. “The researcher has the ability to control exactly what’s going in and what’s coming out of that chamber. . . [and] you don’t have to come in on weekends to watch your cells.”
The system, originally released in 2009, got a makeover this year, with completely revamped hardware and software, and the ability to control the temperature and gas pressure in the chamber, in addition to the chemistry. The system is perfect for use in core facilities, says Jennifer Waters, microscopy director at the Nikon Imaging Center at Harvard Medical School, which acquired an ONIX system last fall. “Because it works by pneumatics, it’s just air flowing through . . . [so] we don’t have to worry about our ONIX system being contaminated in any way with the user sample.” Plus, with several different plate types tailored to specific applications, “you can image anything from bacterial to mammalian cells,” she says.
The entire ONIX setup costs $23,000 and comes with five starter plates. Additional plates are sold in five-packs for $400.
MAZAR: If utilized in conjunction with 3-D systems, this platform could provide a tremendous opportunity to study the dynamics and pharmacology of drug delivery.
NanoLuc Luciferase Technology
Luminescence reporter assays have become indispensable tools for immunologists, cell and molecular biologists, geneticists, and other researchers seeking to shine a light on the molecular dynamics of a cell. Into the mix of luminescence options, which includes firefly luciferase and green fluorescent protein (GFP), Promega has now introduced a new fluorescent reporter enzyme called NanoLuc Luciferase, derived from an enzyme found in a deep-sea shrimp of genus Oplophorus.
The new tool offers several improvements over other luminescent reporters. Its small size—about 2/3 as large as GFP—makes NanoLuc less likely to disrupt the cellular processes researchers are using it to probe. It can also shine up to 240 times as brightly as firefly luciferase. “Bioluminescence has become one of the fundamental measurement technologies used in life science,” says Promega head of research Keith Wood. “We think with NanoLuc we’ve advanced that technology in a number of ways.”
NanoLuc user Samuel Hasson, a pharmacology research fellow at the National Institute of Neurological Disease and Stroke, agrees. Without the small size and brighter glow of NanoLuc, Hasson says that his in vitro studies of mitochondrial dysfunction’s role in Parkinson’s disease would not even be possible. “The signal that you get from the NanoLuc is much brighter,” he says. “So when you have cases of low gene expression, the level of signal you get is much higher” than with a firefly luciferase. Plus, “you perturb the natural process less when you have a smaller reporter tagged onto the mitochondrial protein.”
The DNA plasmid containing the genetic content needed to produce NanoLuc runs about $320, and the substrate used to detect the molecule’s glow is another $125, according to Kevin Kopish, global product manager for NanoLuc. Researchers can expect to pay recurring reagent costs.
CHANDLER: The increased sensitivity, small size of the protein, and the high stability could result in dramatic changes in reporter assays across many systems.
xSCELL Digital Scientific Camera
The new Photonis xSCell Digital Scientific Camera combines low-light capability, high speed, and high resolution. The camera can connect easily to a microscope—via a C-mount—shoot at 1024x1024 pixel resolution, capture images at 1000 frames per second, quickly switch to streaming video at full resolution, store up to 16GB of data, and (depending on the model) be cooled to -30 °C.
“There is a push for higher speed in modern fluorescence microscopy techniques, especially super-resolution microscopy,” says xSCell user and Yale School of Medicine cell biologist Joerg Bewersdorf. “High sensitivity down to the single-molecule level is required. The new xSCell camera, with its dramatically improved speed, represents another large step in this direction, and will help to advance the field of biomedical microscopy.”
Photonis director of imaging products Marc Neglia points out that the camera will be useful in a wide range of applications, including astronomy as well as spectroscopy and any high-throughput screening, particularly because the high-end model can be cooled to -30 °C, which helps reduce the snow-like effect on images caused by the camera’s sensors getting too hot—a common problem with digital photography.
The xSCell digital camera sells for a little more than $40,000. Having just started shipping this new model, the company has sold about 10 so far this year and expects to sell 50 in 2013.
WILEY: This camera offers a revolutionary combination of speed, resolution, and sensitivity. This should be a great boost to developing ultra-resolution microscopy technologies, which are normally limited by the slow speed of high-resolution cameras.
Morpholino oligomers (oligos) are molecules that bind to RNA and are commonly used to disrupt gene expression. To have better control over when and where target RNAs are knocked down, biotech company Gene Tools devised Photo-Morpholinos, photo-cleavable morpholinos that can be used to turn gene expression on and off in an organism or tissue culture at particular times using light. When sense Photo-Morpholinos bind to antisense morpholino oligos, the Photo-Morpholino acts as a cage to prevent the antisense morpholino oligo from interacting with its target RNA and reducing gene expression. But shine a little UV light on the system, and the Photo-Morpholino pops off, initiating gene knockdown. Or, antisense Photo-Morpholinos can directly bind the sense RNA target, but the knockdown is reversible with illumination, which cleaves and inactivates the morpholino oligo.
The technique allows researchers to look at the effects of genes in specific tissues of an organism or during different periods of development. George Eisenhoffer, a postdoc in Jody Rosenblatt’s lab at the University of Utah’s Huntsman Cancer Institute, and his colleagues used Photo-Morpholinos to knock down the gene for a stretch-activated channel called Piezo1, which they hypothesized to play a role in the extrusion of live cells from epithelial membranes as cells become overcrowded. When Eisenhoffer used a traditional morpholino for Piezo1, zebrafish embryos died very early in development. But with Photo-Morpholinos, he was able “to bypass those defects early in development,” knocking down Piezo1 only after it was not lethal to the animals. Sure enough, inhibiting Piezo1 expression later in development led to cell masses on the zebrafish’s sides, indicating their membranes had failed to properly extrude epithelial cells (Nature, 484:546-49, 2012).
The company, located in Philomath, Oregon, has sold about 30 custom-made Photo-Morpholinos since the product was launched this past summer, says Jon Moulton, a researcher at Gene Tools. At $700 for 300 nanomoles—enough to inject more than 1,000 zebrafish, for example—the product is not a blockbuster, but “we never saw this one as a big moneymaker,” he says. “It was one that our customers really, really wanted.”
CHANDLER: This could potentially dramatically change how genetic manipulation experiments are done in cell cultures as well as numerous organisms.
HubioGEM + the Wiggler
Vivo Biosciences + Global Cell Solutions
For scientists researching new therapies and conducting toxicity screening, biologically realistic 3-D cell constructs are important. But they’re also tricky. Enter HubioGEM, a product jointly developed by Vivo Biosciences (which makes HuBiogel, a human-derived biogel matrix) and Global Cell Solutions (which makes the GEM magnetic microcarrier).
Unlike animal-derived matrices, the biogel supports cells in an environment that approximates human tissue biology. Meanwhile, the microcarriers—made up of a semi-porous hydrogel filled with magnetic particles—provide magnetic control of cell clusters during collection or media exchange without interfering with analysis or screening. Together in a single mixture, they offer a better way to generate and manage 3-D tumor or stem-cell constructs that accurately mimic in vivo metabolic function.
Throw in the Wiggler—a bioreactor system from Global Cell Solutions designed to grow and maintain more robust cultures than conventional multiwell plate or mixing-flask methods, launched this October—and you have a new platform for predictive bioassays. “We’ve stacked several advantageous traits into a single solution,” says Uday Gupta, CEO of Global Cell Solutions. “The end result is healthier, longer-lasting, more manageable, and physiologically relevant cell cultures.”
Such qualities have proven “extremely valuable” for Eric Murphy, who works on cancer pharmacology at the Genomics Institute of the Novartis Foundation in San Diego, California. “We do a lot of our drug combination screens in this format now, and we’re seeing a lot of therapeutics you would have skipped over in our traditional screens,” he says. “I think it’s getting us closer to predicting what will happen in vivo.”
MAZAR: The platform proposed herein sounds like it will overcome the challenges of 2-D systems, which can be poor predictors of in vivo activity and inaccurate in their representation of tumor cell–microenvironment interactions.
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