The Scientist Top Innovations of 2008

We congratulate the winners, and welcome comments on these and other innovative technologies that are helping you generate knowledge faster than ever before.

Courtesy of Minsoung Rhee/University of Michigan, Ann Arbor

Microfluidics has made a splash in large-scale automated biopharma work, but without help from an engineer, few academic researchers can use the approach in their own work (see "Let it flow," The Scientist, January 2008).

"The trouble is, [biologists] realize microfluidics would be good, but they don't have the skill to do the fabrication," says Mark Burns, at the University of Michigan in Ann Arbor. "We wanted to give them a plastic bag full of pieces that they could assemble" to custom-fit specific projects.

Burns' graduate student Minsoung Rhee designed a set of disposable components that let researchers create their own lab-on-a-chip (Lab Chip, 8:1365-73, 2008).

Burns views the Lego-like pieces as a starter kit—once researchers find an optimal set-up, they'll probably want to have a company manufacture it for them en masse. "I view this really as a way to get people [over] the activation barrier" of harnessing the helpful capabilities of microfluidics, he says.

So far, the "assembly blocks" are only available directly from Burns, who will send researchers samples if they cover expenses. He is speaking with a company about commercializing them.

PISTON: This is exactly the right next step of moving microfluidics out of the specialists' labs and into the rank and file biochemistry and cell biology labs.

WILEY: This technology will help move biological studies to the single-cell level.

Figure Adapted from MAO et ak (2008). Image data recorded on an instrument in Prof. David Piston's Laboratory at Vanderbilt University as detailed in MAO et al (2008)

Gerard Marriott at the University of Wisconsin, Madison, and colleagues have made FRET technology capable of detecting protein-protein interactions in tissues and mammalian cells that standard FRET technology cannot spot (see "Fret-free FRET," November 2008).

The FRET technique is based on a green fluorescent protein (GFP) donor and an acceptor that exchange energy only when they are within about 8 nm of one another, making it ideal for tracking protein-protein interactions. The problem is the background. "There are 10,000 equivalents of fluorescein" in cells, says Marriott, which makes it hard to spot interactions between your target proteins.

Marriott's group changed the properties of the acceptor so that it could act like a switch. In his system, a unique wavelength of light turns "on" the acceptor at specific times, making the interaction easier to pick out from the background. (Biophys J, 94:4515-24, 2008)

So far, only Marriott's lab makes these switches (and gives them away for free). He has also developed a similar technique that can reduce background in live tissue staining, which he says biologists may prefer.

HAHN: A valuable use of switchable fluorophores to quantify low levels of FRET, this has the potential to increase sensitivity and enable the use of lower, less perturbing concentrations of sensors in living systems.

WILEY: Measures protein interactions at very low levels using a very clever FRET approach. We will be using this one ourselves.

Courtesy of Leica Microsystems

Conventional confocal instruments limit the researcher's choice of both fluorescent dyes and the experiments that can be performed with the system. Leica's TCS SP5 X white laser, released in February and featuring a white laser excitation source, generates a continuum of excitation wavelengths, ranging from 470 to 670 nm, from which up to eight simultaneous but distinct excitation lines can be selected.

"The white light [laser] is the icing on cake," says Christopher Vega, the marketing manager for Leica Microsystems in North America. "It completes the system and makes it the most flexible." This, in turn, allows optimal adjustment of the excitation line to the sample, which reduces cross-excitation and sample damage.

"The white light system frees you from compromising and allows you to make the most of every sample you put on it," Vega says, declining to provide pricing information.

HAHN: The ability to readily vary laser lines across broad regions of the spectrum has major implications. This enables the use of previously inaccessible fluorophores, provides tremendous simplification for imaging systems, and could be very valuable for multiplex imaging applications.

WATKINS: Confocal imaging approaches have always been limited by the number of excitation laser lines available to the investigator. On the emission side, spectral deconvolution has been possible for years. This laser couples excitation spectroscopy to emission spectral analysis, thereby maximizing the utility of multispectral confocal microscopy.

Courtesy of Carestream Molecular Imaging

The KODAK In-Vivo Multispectral Imaging System FX combines high resolution multispectral signaling with anatomical X-ray imaging, enabling researchers to view the movement of molecules within small animals in nearly real-time.

Consequently, this tool lets scientists study the progression of disease states at the molecular level in living animals, says Bill McLaughlin at Carestream Molecular Imaging, who helped lead the team responsible for developing the product.

According to McLaughlin, the KODAK In-Vivo Multispectral Imaging System FX, released in February, provides greater optical sensitivity than older systems by unmixing multiple fluorescent imaging signals and reducing the background noise caused by autofluorescence. The digital X-ray capabilities offer yet another advantage over previous imaging systems that only let researchers project the location of molecular changes to an animal's skin. For example, the high-resolution digital X-ray permits researchers to go from seeing molecular signals somewhere in the chest area to localizing them to specific regions of the heart or lungs.

"There's nothing out there that combines the optical—multispectral fluorescence, luminescence, and radioisotopic imaging—overlayed onto anatomical X-ray," McLaughlin says. "Nothing comes close to combining these modalities." The cost? Approximately $175,000.

HAHN: By enabling simultaneous fluorescence, luminescence, X-ray, and radioisotopic imaging, this technology greatly expands our capacities for in vivo imaging.

WILEY: Another multimodal system, but focused more on animal systems. This appears to be a very sophisticated and useful instrument.

Courtesy of Simon Cherry, UC Davis

More than a decade ago, Simon Cherry at the University of California, Davis, began working on a small animal imaging system combining two modalities with crucial qualities: magnetic resonance imaging (MRI), with its excellent spatial resolution, and positron emission tomography (PET), which can track radiolabeled tracers.

It took until this year to publish a proof of principle for the technology (Proc Natl Acad Sci 105:3705-10, 2008; Nat Med 14:459-65. 2008).

Working with a prototype, researchers are addressing areas such as cancer biomarkers, and the group is building a second prototype. "We're trying to get it into the hands of users now to see what it can do and what it can't," Cherry says, and he encourages researchers with ideas for projects to get in touch.

Ultimately, he envisions a $300,000-400,000 PET add-on to an institute's existing small animal MRI system. Meanwhile, he is working on the next generation design, which will be 25 times more sensitive—a crucial feature when looking for low-abundance molecules.

WILEY: Multimodal imaging is becoming more popular because of its power. This could be a very useful development for eventual clinical use.

PISTON: We have long wanted to combine these two modalities, but the physical constraints (i.e., no metal can get inside the MRI magnet) have frustrated these efforts. The current work is revolutionary and very clever—for the first time, it is reasonable to believe that such hybrid approaches will find their way into the research and clinical labs.

Courtesy of RIKEN Brain Science Institute

Fluorescent ubiquitination-based cell cycle indicator, or Fucci, helps biologists understand the nuances of the cell cycle. "We have already begun applying Fucci as a means for examining candidate anticancer drugs and their impact on tumor cell division and migration," says Atsushi Miyawaki of the RIKEN Brain Science Institute in Wako, Japan, in an E-mail.

Fucci works by genetically modifying cells so that they express Cdt1 and Geminin—two proteins crucial to the regulation of cell division—with red and green florescent tags, respectively. By tracking how dividing cells alternate between green and red flashes, biologists can track a cell's development through the cell cycle and terminal differentiation. Miyawaki and colleagues at RIKEN developed the technique, and RIKEN, along with the Tokyo Metropolitan Organization for Medical Research, licensed the sales rights for Fucci to MBL International.

An MBL spokesperson declined to provide a price for the technique.

PISTON: Expansion of the usefulness of genetic labeling is the current push in the field. The Fucci system is exactly that—a pre-packaged way to use the best of fluorescent protein technology in cell cycle experiments. It should facilitate clean live cell experiments by researchers who are not experts in the imaging probes or technology.

HAHN: This uses very creative engineering of fluorescent proteins to tackle an important biological problem. It will likely lead to the design of other sensors, and will be quite useful for specific applications.

Courtesy of Dover, A Danaher Motion Company

The Polonator G.007 is the first "open source" gene sequencing instrument to hit the lab market in which the instrument's software (Web ware) and specifications are freely available to the public. The new platform is also compatible with any generic reagent, eliminating the need for expensive specialized reagents designed for other platforms. This is meant to encourage a more diverse group of researchers to do their own sequencing, simultaneously bringing down the cost. Initially introduced this summer to a few labs, the Polonator is completely modular (each part can be removed and swapped) and therefore can be customized or retrofitted for any lab application.

At $150,000, the Polonator is the cheapest instrument on the market, says Harvard University's George Church, whose lab developed the technology in conjunction with Dover Systems, Plus, the tool uses five-fold less reagents than other platforms, and is the smallest instrument available.

"This is part of personal genome project," says Church. "We're trying to bring the cost [of sequencing] down, not just with instruments that are affordable, but so the whole genome experience is affordable for regular folks."

WILEY: The idea of releasing a sequencing machine as an open-development project is really innovative. It could drive software innovations and help keep down the price of this technology.

PISTON: This might be a long-term competitor to tools such as the ABI SOLiD system. Open source projects tend to rally the research base in interesting ways.

Courtesy of Sigma-Aldrich

A new custom zinc-finger protein creation service called CompoZr promises to transform the way biologists manipulate the genomes of living organisms. Invented by California biotech Sangamo Biosciences, the platform constructs zinc fingers that can target any DNA sequence provided by users with unprecedented specificity. "You can knock-out or knock-in genes to the level of a single nucleotide," says Sigma-Aldrich market segment manager Phil Simmons. "It's a level of precision that scientists haven't seen before."

Sigma licensed the technology from Sangamo in July 2007, and the company launched CompoZr worldwide in September. The process to assemble custom-made zinc-finger nucleases, or DNA-binding proteins that facilitate the targeting and editing of specific genetic sequences by causing double-strand breaks in DNA, starts with an end user specifying a particular gene sequence. Six to eight weeks (and $25,000-$35,000) later, Sigma can deliver validated expression plasmids and mRNAs that code for the exact zinc-finger nuclease the customer requested.

What took up to six months using traditional homologous recombination, positive and negative selection strategies, and a lot of clone screening, now takes something closer to one month using zinc fingers, says Trevor Collingwood, Sigma's manager of strategic business development, who helped develop the technology.

PISTON: Building transgenic animals is time-consuming and often frustrating. This approach gives us another orthogonal tool for these preparations, and it looks very promising so far.

WILEY: This is getting a lot of buzz, and could be absolutely revolutionary if it works as well as advertised.

Courtesy of Nikon Instruments

You're looking down the microscope at a cell undergoing mitosis. Gently perfusing the Petri dish with a compound you suspect affects the process, you hold your finger over the computer mouse, ready to capture the image. But instead, you're left watching in despair as the perfectly framed cell drifts out of view on your CCD screen.

Focus drift is one of the biggest challenges in high resolution and live cell imaging. In January, Nikon unveiled a solution called the Perfect Focus System (PFS), compatible with the company's TE2000 and Ti-E microscope series. "It's really a robust system," says Stephen Ross, senior scientist at Nikon, who was closely involved in PFS's development.

PFS is a hardware component that uses a half-moon shaped beam of infrared light to track optical offset and correct for it by sampling every 5 milliseconds. It holds focus both in time-lapse experiments and in short-term studies where acts such as perfusing a drug or moving a Z-stage might shift the sample. Similar systems exist, Ross says, but they don't work as well because they sample much less frequently.

A high-end Nikon microscope with all the available bells and whistles costs about $70,000, Ross estimates, and the PFS accounts for about $10,000 of that. Already, he says, it's proving popular among clients. "We can't produce this fast enough—it's enabling experiments that just weren't possible before."

WATKINS: This is invaluable for any investigator performing microscope-based live cell analyses over an extended period of time. It maintains the specimens in focus regardless of temperature or vibration, such that you can conduct experimental manipulations (e.g., reagent injections) during imaging, and continue the experiment for days.

PISTON: The idea of autofocus has been around for a long time and many attempts to build a robust version have come and gone. This one really works and is totally transparent to the user.

Courtesy of Applied Biosystems

First introduced commercially in October 2007 by Applied Biosystems, the latest and greatest version of SOLiD that came out in May 2008 can sequence the human genome for $60,000. Since it first arrived on the market, the instrument's throughput capability has doubled every three months, and as of May 2008, the system could generate six gigabases of mappable sequence data per run. According to the company, one customer has reported obtaining 13 gigabases of sequence data per run.

"SOLiD is the only genomic analysis platform which has doubled its sequencing throughput every quarter for eight quarters in a row," says Kevin McKernan, senior director of scientific operations at Applied Biosystems. Other elements that set this platform apart include its ability to read two DNA replication pathways (other platforms only read one), and two-base encoding, which can eliminate measurement errors from the sequencing data. "The SOLiD System has the potential to ultimately change not just the biotechnology landscape but every aspect of our human experience." The company has now set its sights on a $10,000 human genome by 2009, McKernan adds. But innovation comes at a price: The current model goes for $589,000.

PISTON: This system is the breakthrough on the way to a whole genome sequence that would take weeks and cost roughly $10,000. This really puts the possibility of personalized medicine in play. For research, people that never considered genomic approaches are now doing so. In so many ways, this machine changes the paradigm of how we can approach research and clinical care.

WILEY: Certainly this is the development that is likely to have the biggest impact on biology.

Correction (December 3): When originally posted, Nikon products TE2000 and Ti-E were incorrectly listed as TE200 and TEI in entry #2. We apologize for the error, which has been corrected.