Automation & Control / Large Molecule

Designer Genes: Integrated DNA Technologies Offers Made-to-Order DNA Oligos

PC-based control platform reduces cost by $4,500 per system; smaller machine footprint effectively doubles system throughput

By Josh Olson, Beckhoff Automation

Consumers have grown quite accustomed to having the ability to customize the products they buy, from clothing to cell phone cases, to interior lighting and more. This made-to-order trend is not limited to the consumer space, however. Even biotech research organizations are utilizing highly custom synthetic genetic material to advance discovery. This type of research represents the upper echelons of scientific progress in the pharmaceutical, agricultural, academic, and other life science markets. Genetic study analyzes the basic elements of life, allowing scientists to understand biological processes and make discoveries that protect our world.

Genetic research requires synthetic nucleic acids, DNA and RNA, unique to each application. Research scientists use custom-made DNA sequences of various lengths and with unique modifications to drive genetic discovery. These custom manufactured nucleic acid sequences, or oligonucleotides, are often referred to as "oligos."

Oligos are typically short, single-stranded, synthetic DNA or RNA molecules that provide the basic tools for molecular biology research and forensics. Oligos are chemically manufactured through a process called solid-phase synthesis.

The incredible variation inherent in research requires this type of customization, often with very specific composition and on a tight timeline. Integrated DNA Technologies, based in Coralville, Iowa, fills this niche in the market, providing these customized molecular biology products for diverse application areas. From manufacturing facilities in Iowa, California, Belgium and Singapore, IDT delivers custom oligos to a global customer base, offering the highest quality and broadest product selection to ever-expanding research markets.

A manual process in the past, synthesis is now automated, much as a result of advances in robotics, computer processing and monitoring. These efforts to make their manufacturing processes faster, more precise and more efficient led to IDT's creation of the M1 DNA Synthesizer, the company's newest oligo manufacturing machine. The M1 offers a streamlined, flexible platform for custom DNA synthesis, facilitating significantly faster changeover of materials in the process. In particular, the M1 makes it easier to offer customers a wider array of options, increasing support of non-standard products, as switching time for materials has been drastically reduced with the new design.

An important factor in the effectiveness and flexibility of the M1 is the use of PC-based control and EtherCAT solutions. A product platform from Beckhoff provides a solid technological foundation for this next-gen DNA Synthesizer.

BUILDING A "BASE" FOR GENETIC RESEARCH
IDT is the largest manufacturer of custom oligo products in the world. For more than 25 years, the company has manufactured and supplied oligos for molecular biology research. Approximately 44,000 individual nucleic acid sequences leave company facilities each day, shipped worldwide to the company's 82,000-plus global customers. Each sequence is custom manufactured to the exact requirements of the customer, as Dan Brock, IDT Senior Scientist, explains: "Genetic research applications come with an inherent level of complexity in the types of oligos needed. Every one of the 44,000 sequences IDT manufactures each day is specifically tailored to the needs of the customer. Much like a snowflake, each DNA sequence we create is unique. We aspire to create each one with the highest level of quality, while efficiently getting them to our customers for their immediate use."

IDT has refined the process to an incredibly streamlined series of steps, enabling the company to receive orders as late as 1 p.m. local time and have the oligos in the hands of the customer the next morning. With this level of production volume and manufacturing speed, maintaining customer service and quality is of utmost importance. Owen Piette, Lead Automation Engineer, adds that "one of the biggest differentiators for IDT is that we do quality control on every oligo that we synthesize, which we refer to as "100 percent" QC. Our customers deserve this level of effort, and this is reflected in their experiences collaborating with IDT."

THE ANSWER IS MOST CERTAINLY "YES"
When it comes to the size or composition of a customer-requested oligo, IDT does not like to say no. Customers have an almost limitless number of options to choose from when ordering their synthetic nucleic acids.

"We work hard to provide exactly what our customers want; we look forward to the unusual, the new, and the exciting," says Brock. "If someone wants a particular product, standard or not, we'll work it out and, in almost every single case, make it happen."

As customer demands continue to grow and change, IDT has remained up to the task, continuing to offer new and exciting products. For example, the company's landmark Ultramer synthesis platform allows IDT to manufacture the longest oligonucleotides available on the market. This ability to synthesize long oligos has facilitated groundbreaking products, equipping their customers to push the limits of research farther than ever before.

Speed and space constraints were key determining factors in specifying a new controls platform. IDT pitted different control system options against one another and, when the dust settled, the Beckhoff Automation solutions was chosen. Piette explains: "The Beckhoff control system provided the right mix of price, performance and functionality for IDT's application. The mix of PC-based control and high-speed EtherCAT technology offers a robust, flexible control system solution."

Providing the processing power for the M1 is a CX2020 Embedded PC running Beckhoff's TwinCAT 3 control platform. "This control system significantly reduced hardware costs compared to the array of controls products used previously," says Piette. "We had four separate synthesizers, each with their own controller, but we were able to replace these with a single, PC-based system using the CX2020." With the Beckhoff solution, IDT was able to combine everything into a simple package, with ample room for expansion through additional I/O slices or PLC functions programmed into the software. In addition, the Windows operating system (OS) on the Embedded PC fit perfectly into the overall scheme of IDT operations.

"IDT has always embraced Microsoft OS and tools. A significant amount of our programming is done in .NET, making the IT-friendly Beckhoff system, particularly TwinCAT 3, a complementary and integrated solution," said Piette. "The company's long-standing support of the Windows system and computer science standards along with automation technologies has allowed us to easily design IDT systems on the Beckhoff platform." He added that the convergence of technologies enabled through the integration of Visual Studio in TwinCAT 3 provides a clean method for data transfer. "The incorporation of TwinCAT 3 into the widely used Visual Studio environment helps immensely when we integrate into MES systems — a key point for the data-driven nature of our customers' applications. We have a new recipe for every single synthesis, which creates huge amounts of data, so expert management of this information is integral to the success of the process."

An incredible amount of data is created by the numerous sensors in the M1, tracking every aspect of the synthesis reaction. These are necessary to help IDT scientists create nucleic acid products that conform to the exacting specifications necessary for the applications of their customers. The company constantly monitors chemicals and reagents, as well as the minute details of the reaction itself, making sure processes proceed exactly as they should. IDT found that the sub-millisecond response time of the EtherCAT industrial Ethernet system provided the necessary speed and high throughput for this type of monitoring. "The real-time throughput and high precision offered by Beckhoff's EL Series EtherCAT I/O terminals," says Ryan Witt, IDT System Engineer, "provides a previously unheard of level of monitoring functionality in our applications."

The M1 samples a wide range of Beckhoff EtherCAT Terminals from the EL and ES series, working together to provide a robust suite of I/O functionality. The 16-channel digital output terminal, for example, connects binary control signals from the controller to the actuators at the process level. Receiving and transmitting the signal at the other end is a group of digital input terminals, each offering electrically isolated signal transmission. EL3068 and EL4008 analog terminals provide additional coverage for field devices. In addition, connecting the barcode scanners used for logging and authorization is a quartet of EL6002 2-channel serial interfaces. "Overall, the EtherCAT I/O system represents a compact solution, reducing the necessary space for the networking equipment, as well as reducing required cabinet space," Witt elaborated. "As a result, IDT can squeeze four synthesizers into the space previously occupied by two."

Brock went on to discuss additional benefits, adding that they "can monitor the reaction much more closely, through all the steps of the reaction, and very accurately determine when and where any problems occur. It's almost like an EKG, where we can see the machine's heartbeat and determine any irregularities and proactively address them." Previously, IDT had to wait until the next day to be notified of issues with the machine. "Now with the real-time monitoring via EtherCAT, we don't have to wait until downstream quality control catches an error. This saves us hours in our processing time," Brock noted.

Because the process uses organic solvents, a multi-touch panel provided a solution for their application requirements. "The organic solvents we use in the synthesis process are not very plastic-friendly," says Brock. "In fact, we've gone through quite a few keyboards because of this issue. Everyone has analog-resistive touch displays, but they all have plastic fronts, so if you touch them with your glove, they just melt. The Beckhoff displays' high-quality glass construction, as well as unbeatable performance even while using gloves, offers the perfect solution for our environmental conditions."

PC-BASED CONTROL STREAMLINES EXPANSION
Overall, integration of PC-based control and EtherCAT provided the right mix of price, performance and flexibility. "Versus the other options we considered," said Piette, "the powerful centralized control solution saved us around $4,500 per system, as we did not have to purchase a separate PC or PLC for each of the four synthesizers integrated into the M1.

"The exceptional expandability was a welcome benefit, allowing us to keep our options open for upgrades as necessary. In the future, when one of our scientists comes to me with a list of requested additions or improvements to the machine, the process will be much smoother. We will be able to implement changes in a matter of months, rather than starting from scratch and pushing the timeline out a year or more," says Piette.

Form factor of the control hardware also plays into the success of the IDT integration of Beckhoff systems. "The space savings provided with the PC- and EtherCAT-based platform was immediately evident within the cabinet assembly time," Piette said. "These components pack an incredible level of functionality into a small form factor, reducing cost as well as assembly time. As clear evidence, we lowered the cabinet assembly time by 66 percent."

IDT plans to continue integrating Beckhoff technologies into their designs with projects in motion to build additional M1 synthesizers. IDT says it intends to include Beckhoff in future systems that the company believes will eventually account for as much as 60 percent of their business. As IDT keeps pushing the limits of custom DNA synthesis technology, pharmaceutical companies, the research industry and academia will certainly benefit from their commitment by receiving an answer for each unique request. By leveraging the power of PC-based control, IDT is well positioned to continue its evolution by introducing breakthrough technologies in genetic research.

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