ATTACK of the LAB-BOTS

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By Malorye A. Branca, Bio-IT World

“Automate” has become the new mantra for pharmaceutical technology innovators. With productivity goals soaring and investor confidence slipping, drug makers are pressed not only to deliver improved new drugs but also to do so with remarkable efficiency. These new imperatives have catapulted robotics to the head of the pharma priority list.

“Pharmaceutical companies are spending less money on discovery R&D, so they need to spend it more efficiently,” says Frost & Sullivan Inc. (Palo Alto, CA) consultant Nate Cosper. “Microfluidics, robotics and liquid-handling systems derive more value from what they already have.”

Frost & Sullivan has estimated that the world market for automated proteomics products alone would quadruple between 2002 and 2008, reaching more than $750 million US. The liquid-handling robot market, meanwhile, is set to double, reaching $1.216 billion US by 2009, according to Frost & Sullivan. “These instruments release a huge bottleneck — sample preparation,” Cosper says.

Many companies are either entering this field or expanding their presence. Some companies have to automate to meet new needs. For example, when researchers began applying DNA chips to large-scale compound profiling and toxicology studies, Affymetrix Inc. (Santa Clara, CA) started work on the GeneChip® HighThroughputArray (HTA). Using available robotic components, this new system plugs the company’s market-leading GeneChip technology into a standard 96-well microtiter plate format. By automating the slow steps, Affymetrix aims to lower the cost of large-scale studies while improving efficiency and accuracy.

Genetix Group PLC (Hampshire, U.K.) is likewise keeping up with the “more samples are better” trend. The recently launched QArraymax lets researchers quickly prepare large batches of their own glass, nylon or other-material microarrays. The arrayer can hold up to 280 source microplates and can generate up to 450 slides or microtiter plates in as little as 10 minutes. “We’ve adapted our machines to spot on the bottom of microwell plates instead of glass slides,” says CSO Julian Burke. Up to 100 protein or DNA spots fit into a single well in a 96-well plate.

Other companies are automating to expand established markets. Ciphergen Biosystems Inc. (Fremont, CA) was one of the first groups to target protein biomarker development. But, “when we first introduced the (SELDI) system, it was a chip and a reader,” explains Martin Verhoef, president of Ciphergen’s Biosystems Division. Customers had to create their own buffers and protocols. The process was faster than 2-D gels, but that’s not saying much. “It was a lot of pipetting,” he sighs.

Since then, the company has focused on automation, using standard robots from Beckman Coulter Inc. (Fullerton, CA) and Eppendorf AG (Hamburg, Germany), and following the microtiter plate format. Now, “you put the centrifuged serum in the Eppendorf, and from there it is all automated,” Verhoef says. Several hundred samples can be processed in a week.

Most importantly, Verhoef points out, automation “takes a lot of the operator out of the system.” That means less error, and better results — a key selling point.

Battle of Agencourt
The genomics boom spawned a wide range of new robots, as Agencourt Bioscience Corp.’s (Beverly, MA) laboratory illustrates. This reagent and service provider has two major advantages: its unique solid phase reversible immobilization (SPRI) nucleic acid purification chemistry, and its focus on automation. “Every step is automated,” says Brendan McKernan, vice-president of Manufacturing and Operations. “And it was conceived of that way.”

The challenge at Agencourt is to accommodate a growing client base and continually expand the range of products. “It’s easy enough to set up a pipeline process for one customer,” McKernan says.

Agencourt says it can sequence an entire human genome in a year. “We’d like to do one a day,” says vice-president and co-CSO Kevin McKernan, one of three brothers in management positions. The company’s 40-plus Applied Biosystems sequencers run more than 20 hours per day. As one instrument nears the end of a plate, a digital sign flashes overhead, signalling that it’s time for the next one.

Samples are prepped automatically with SPRI, on Beckman Coulter Biomek FX and Packard (now PerkinElmer Life and Analytical Sciences Inc., Boston, Mass.) PlateTrak™ systems. “Every piece of automation is integrated into the LIMS,” Brendan McKernan says. All the data feed into an Oracle database. Production, process management, and even proprietary reagent inventory supply are tracked electronically in real time.

Available tools are used whenever possible, but not at the cost of throughput. PCR preparation, for example, requires some custom work. “You have to minimize every possible type of contamination,” Kevin McKernan says. Otherwise, errant DNA may be amplified from dander and anything else that has floated into the hood or stuck to the pipette tips. When steel pipettes eroded under the strain of repeated sterilization and use, Agencourt staff ordered custom ceramic-coated glass tips that could withstand the procedure.

Exelixis Inc. (South San Francisco, CA) has also emphasized automation from the start, but its most unusual achievement has been the automation of functional genomics processes — one of the major roadblocks in the path from new targets to drug. The company has done large-scale studies of mutations in several critical model species, including yeast, nematode, mouse and zebrafish.

To create its genome-wide Drosophila melanogaster knockout collection, Exelixis had to generate, maintain and propagate more than 30,000 fly strains. That requires occasionally transferring the fruit flies to new quarters. To move the flies, “you have to give an aggressive flip of the wrist,” says Exelixis research head Dr. Greg Plowman, PhD. Daunted by the prospect of “flipping” about 30,000 tubes of flies once every month, the company designed a robotic system very similar to that used in high throughput screening (HTS). “Instead of vials of compounds, the robots pick up 96 vials of flies, and put them into new containers,” he says.

All of Exelixis’s automated systems leverage standard instrumentation. “You don’t want to build anything from scratch,” Plowman explains. On the data side, “everything is Oracle- and Web-based,” he says. Robo-mania is helping Exelixis stock its pipeline with drugs against novel targets, at record speed.

Chip Shot
But automating complex laboratory processes isn’t a cinch, and drug makers are unwilling to compromise when it comes to quality control, flexibility, and convenience. That’s why it’s taken so long for many of these robots to make the grade.

For example, several years ago lab-on-a-chip technology was hailed as the next breakthrough set to transform R&D. Today, barely a handful of such products are available.

“It’s not as easy as you would hope to devise successful microfluidics,” says Tony Owen, marketing manager at Agilent Technologies Inc. (Palo Alto, CA). “It’s often easy to show feasibility, but quite a different matter to make a reliable and rugged product.” Microfluidics is easily influenced by many factors, he explains, including contamination and surface effects. One of the few lab-on-a-chip products is Caliper Life Sciences (Hopkinton, MA) and Agilent Technologies’ bioanalyzer, which is so successful it has become the instrument of choice for many tasks, including preparing samples for microarray studies and PCR. Soon, Agilent will release a high-throughput bioanalyzer, called the Automated Lab-on-a-Chip. “The bioanalyzer is popular because it is fast, accurate, and it conserves sample,” Owen says. The original instrument manages a dozen samples in one run; the Automated Lab-on-a-Chip will be able to do more than 1,000, completely unattended.

Of course, automation can sometimes create another bottleneck: downstream in data management. Genome researchers at the Broad Institute (Cambridge, MA) were some of the first to automate genomic processes, and have terabytes of experience with this issue.

Stacey Gabriel heads the institute’s Human Haplotype Map Group, which aims to generate about 15 million genotypes a year using four Sequenom Inc.’s (San Diego, CA) MassArray™ system and a recently acquired Illumina Inc. (San Diego, CA) BeadLab system. The institute will generate that many genotypes again in disease studies. “One of the biggest things on my mind back four years ago, when we selected the first system, was automated allele calling,” Gabriel says. Interpreting the data from such instruments has traditionally required countless person hours. “That becomes impossible with the amount of data we are generating,” she says. “The MassArray nicely incorporated that feature.” Besides automated sample handling and allele calling, the newer BeadLab system features an integrated LIMS and bar coding, both of which are a big help in data management.

Instrument makers are also starting to realize how important the software is that controls the instruments. Traditionally, instrument makers “have not paid enough attention to the ease of use of the software,” says Josef Syfrig, Tecan Group Ltd. (Maennedorf, Switzerland) content specialist in marketing communications. A major player in liquid-handling instrumentation, Tecan recently released new instrument control software called Freedom EVOware™. The company says the new software will make it easier for anyone, from routine users to experts, to use the instruments. It also integrates easily with other vendors’ tools — an increasingly important consideration in this arena.

A startling number of slow zones have been accelerated thanks to automation. But technical bottlenecks remain.

And of course, robots also break down occasionally. “That’s where the bump is,” Gabriel says.

Good service and software can address that problem, allowing researchers to quickly pick up where they left off, but some vendors are lacking in this regard.

In the end, robots can’t actually find drugs. They are only as good as the scientists using them. But as long as they are giving researchers more time to think and plan, these automated systems are a welcome addition to the scene.