Cracker is the first Asia-based competitor to formally enter the Archon X Prize for Genomics competition, which offers $10 million to the first team to sequence 100 human genomes in 10 days for under $10,000 per genome. Led by engineer Chung Fan-Chiou, the team was created in 2007 in conjunction with Taiwan’s Industrial Technology Research Institute (ITRI). The team is developing fluorescence-based optical genome sequencing technology that utilizes nanopore methodology, which they believe makes them a strong competitor in the sequencing market. BioTechniques spoke with cracker’s senior scientist Hubert Renauld about the competition and entering the genome sequencing business.
Q: Can you describe the technology you are developing?
A: Our approach relies on an innovative optical design, sequencing on top [sTOP]. A single-molecule reaction site is placed immediately on top of a multi-junction photodiode, producing an independently operable nanosequencer. Our resulting chip spans an array of millions of such nanosequencers, all operating simultaneously and each one generating data independently from its neighbors. The direct processing of light signals within the chip itself is key to the uniqueness and advantages of our technology. That is, our chip will generate data with higher levels of throughput and accuracy than technologies currently available on the market or that we know are under development. Our chip presents also the unique advantages of a low cost of manufacturing and portability. No specific production equipment is required other than that necessary to manufacture silicon chips for computer use.
Q: How does your technology improve on the other optical sequencing systems in development?
A: Most next-generation or third-generation sequencers involve microscope-like optical systems and involve taking images of an array of reaction sites over time, via scanning or real-time video taping. A huge number of image frames are then analyzed to decode sequence data from each reaction site. This is a massive computing task, which can also introduce errors during the process. All those steps are bypassed in the sTOP system. Another shortage of optical detection systems is the small field of view. Usually about hundred micrometers in size, it limits the number of reaction sites that can be monitored. On the contrary, a CPU-size chip like the sTOP chip can bear and generate data from millions of nanosequencers simultaneously. At equal rates of sequencing reaction, a 100× increase in the number of reaction sites translates into a 100× increase in throughput. Thus, simplifying the process increases not only the throughput; it is also expected to improve the data accuracy.
Q: Why did you decide to develop technology based on viewing fluorescent single molecules?
A: This technology meets both the cost and accuracy criteria. It is a mature technology that also allows for a variety of labeling solutions. It also provides us with a high signal-to-noise ratio, allowing sequence determination with confidence. The availability of a manufacturing technology is also an advantage. The non-labeled nanopore approach is a very attractive idea. However, it requires the development of a whole new process to build the core structure of the reader. On the other hand, our fluorescent labeling–based device can be easily adapted by the current semiconductor manufacturing processes; this means predictable development schedule, controllable development expense, and low cost of the device.
Q: What backgrounds do the researchers have, and how has this varied group benefited the development of this new technology?
A: Several backgrounds blend together, ranging from opto-electronics to organic-chemistry experts, from materials-chemistry specialists to molecular biologists and bioinformaticians. Commercial products or technologies—the design of which our team members have been involved in—include flat and 3-D television displays, flexible electronics supports, and gene expression microarrays. The atmosphere in the group is very relaxed; it is not surprising to see optics designers discussing with molecular biologists.
Q: What is motivating the group? The $10 million X Prize? Fame? The desire to further sequencing capabilities?
A: We are currently about 30 people strong, all with the strong and deep motivation to make a difference to our world. Different personal drivers can be found on top of this shared motivation. Fame [from] competing for the largest [monetary] prize in medical history, and the scientific aspiration to crack the “genomic code” through sequencing of many genomes are indeed present in some. In others, one can see entrepreneurial spirit, the commitment to unfold new and interdisciplinary technologies, as well as more personal motivations, like the wish to provide the best healthcare possible for the next generations, or to democratize next-generation sequencing technology.
Q: Do you think your technology will be ready for distribution earlier than your competitors in the X Prize?
A: If the final aim [is] a technology to sequence and assemble a human genome for $10,000 or less, we believe that competitors and rival technologies may reach it soon. However, we are deeply motivated by the development of a technology and a platform that will lower the cost even further, down to $1,000 and perhaps even below. We strongly believe that our technology displays three unique advantages: versatility, low cost of manufacturing, and portability.
Q: When do you estimate your group will complete the development stage of your technology?
A: Our current timeline includes the completion of a prototype by 2012, and reaching out to the market by 2015. We are now actively looking for financial support and strong partnerships, which would shorten this timeline.