April 15, 2016 (Vol. 36, No. 8)
Brian Handerhan Business Development Manager Parker Hannifin
Precision Systems Balance Cost and Performance, Help Realize the Promise of DNA Sequencing
The wealth of information that DNA sequencing can provide is essential to advancing many areas of biological research, including applied fields such as medical diagnosis, biotechnology, forensic biology, virology, and biological systematics. The high speed that modern DNA sequencing technology makes possible has already begun to help medical professionals gain insight into how a specific patient will respond to a particular course of treatment. It is also allowing medical information consumers to learn more about their potential susceptibility to a variety of diseases, as well as explore their ancestry.
If DNA sequencing represents the motive force driving research in the life sciences, motion systems are the muscle behind that motive force. Their use in laboratory technology is helping to unravel clues to an individual’s unique genetic code faster and with greater clarity than ever before possible.
Making Personalized Medicine Practicable
The Human Genome Project, an international project designed to determine the sequence of chemical base pairs that make up human DNA, and identify and map all of the genes of the human genome from both a physical and functional standpoint, took 13 years and roughly $3 billion to complete. Although the costs associated with DNA sequencing have come down dramatically from the project’s completion in 2003, the ability to find the genetic data necessary to deliver personalized medicine on a mass scale will depend on reducing its costs much, much further.
That’s where instrumentation developers and their technology partners play a vital role. Motion control is a particularly challenging element in this complex instrumentation, and it can make a vital contribution to cost control. The major cost drivers in DNA sequencing include:
- Labor, administration, utilities, reagents, and consumables.
- Sequencing instruments and other capital equipment informatics activities directly related to sequence production.
- Submission of data to a public database.
- Other indirect costs.
With next-generation sequencing (NGS) techniques, scientists can examine huge amounts of data concurrently and make the necessary connections between data points.
Translating the Language of Motion Control
Many instrument manufacturers have developed proprietary technologies to differentiate themselves from the competition. Their application of next-generation technology makes possible a dramatic reduction in cost to their customers, thanks to the ability to capture massive amounts of data in parallel.
NGS techniques tend to fall into one of two major categories from a motion control standpoint based on the characteristics of the motion required. The first involves a continuous scan process during which readings are taken “on the fly.” The second is more of a step-and-settle process characterized by incremental indexing steps where a reading is taken at each step.
To better understand these processes, let’s define some key motion terminology:
- Settling time—The time required for a step response of a system parameter to stop oscillating or ringing and to reach its final value.
- Following error—The position error or difference in position between the commanded position and the actual measured encoder position.
- Flatness of travel—A measurement of the deviation from ideal straight-line travel in a vertical plane (also referred to as vertical run out).
- Straightness of travel—A measurement of the deviation from straight-line motion in a horizontal plane (also referred to as horizontal run out).
- Velocity ripple—A measure of a positioning stage’s motion smoothness. This is typically measured in percent variation from a nominal value at a given sampling interval.
- Frequency response—In its most simple form, frequency response can be thought of as a measure of system stability. This includes both the system’s closed loop bandwidth and also the natural frequency of the system.
- Encoder subdivisional error—Cyclical errors resulting from the encoder read head that repeat every period of the scale.
Motion Requirements for a Continuous Scan Process
Now that we have defined the key terms, let’s put them in context. Continuous scanning is a “capture on the fly” process where “images” are captured while at least one axis is in motion.
The most critical attribute of the motion system is the constant velocity or velocity error. This is critical because of the interaction it has with the image capture and process.
Images are captured in one of two ways:
- Timing methodology is where a capture sensor is triggered based on timing calculated from the commanded velocity of the axis of motion.
- The encoder trigger method is where the capture sensor is triggered based on the linear encoder reaching its prescribed positions. Ultimately, the encoder trigger method provides the most accurate synchronization between the motion system and the image capture.
The flatness and straightness of axis travel is the second most critical aspect of the motion system (Figure 1). The image needs to be captured dynamically. Also, there is insufficient response time to allow a focusing axis to compensate for short cycle variations. The flatness and straightness must be maintained at less than 150 nm/mm of motion for optimal performance.
The biggest constraint to speeding up this process is the ability of the focusing system to compensate for the short cycle out of flatness variation of both the motion and the sample. To resolve this issue, either the reaction times of the Z-axis or the flatness of the XY-plane and the sample must be improved.
Motion Requirements for a Step-and-Settle Process
This process is about moving the sample into position and ensuring that is is stable before the image is captured. The most critical attributes are how quickly the position can be achieved and the stability with which the position can be held. As with many “optics”-based systems requiring high stability, a stepper motor with a sliding friction lead screw is often used as the driving mechanism. Because the stepper motor is an open-loop device, there’s no servo loop that can cause position hunting. A secondary encoder is often used to confirm a position as a verification step.
The biggest constraints in reducing cycle time are the speeds of which the stepper/lead screw drive technology are capable and the time required for this type of system to settle due to lack of rigidity.
The next technology transition will be to shift to linear motors with high-resolution encoders. The direct drive linear motor system offers the ultimate in drivetrain stiffness. The system would need to be designed with an encoder that has 3–10× higher resolution than the required system stability to allow for the hunting inherent in servo systems. The challenge to designing this system is the tradeoff between speed and resolution. That’s why the higher resolution encoders can become the limiting factor from a speed perspective.
With smart engineering, the cost of sequencing instruments and other large laboratory instrumentation can be amortized over three years. Other contributors to affordability for the end user are the informatics and laboratory information management systems, which cut the volume of data to be processed. These allow for quicker submission of data to public databases.
For manufacturers of genome sequencing instrumentation, automation and motion control will continue to be key subsystems for a long time to come in their race to reduce their costs (Figure 2).