ZS Genetics puts DNA under the microscope

The company has signed a three-year contract with the University of New Hampshire to develop of new preparation technologies and intellectual property for its DNA sequencing system. ZS Genetics​ is preparing to commercialise its first product, a gene expression system that uses a TEM (transmission electron microscope) to directly image and count a gene's RNA transcripts. Second in-line and aiming for a 2008 launch is its TEM-based method of conducting DNA sequencing. According to the company, the technology promises to enable the sequencing of whole genomes in days rather than months, and for thousands of dollars instead of millions. In addition, the gene expression technology could offer researchers the ability to measure the activity of thousands of genes in a single cell - with single molecule sensitivity. Sequencing technology has made a dramatic leap forward in the last year or so, with new offerings from Illumina / Solexa, 454 Life Sciences / Roche Diagnostics and Applied Biosystems all having released sequencers that are helping to drive the costs down. The original human genome project cost $3bn and took ten years before the 'draft genome' was published. Recently, the genome of Dr James D Watson, Nobel Laureate and joint discoverer of the structure of DNA in 1953 was published by 454. The project took less than two months to complete and cost less than $1m. While the aforementioned companies have predicted that costs could drop to $100,000 per genome in the near future, Thomas Abert, vice president for finance and administration at ZS Genetics, indicates that the ZS Genetics' TEM method could enter the market below that price point. "The running costs will be very low, we're projecting that our first generation sequencing is going to be running below $100,000 for a high-quality, fully assembled human genome, and that includes amortized capital costs as well, with a lot of room for future improvements,"​ said Abert. "The cost is so low because there's a lot less manipulation involved, we do a little bit of sample preparation at the beginning and then we run it through the TEM, there's no need to keep repeating steps like in other methods." ​ The preparation step involves a PCR (polymerase chain reaction) to label the DNA bases. This is required as TEM's struggle to image atoms with low atomic numbers (Zs) such as oxygen, nitrogen and carbon. ZS Genetics uses nucleotide bases labelled with heavy atoms such as bromine and iodine that can be distinguished by the TEM. Nucleotides with only one atom label are more easily incorporated into the DNA than bases labelled with large fluorescent labels leading to less label bias and greater reproducibility. In addition, because the PCR step is only conducted once not 30 times, bias and PCR amplification errors are minimised with little work. Next the sample is attached to a microarray and inserted into the TEM on a substrate holder before the system initiates its position-image-repeat cycle. Interestingly, the company believes that this cycle is limited only by the speed that the digital camera can take a picture, currently about 1.5 seconds per shot. Image analysis software process the digital data in real time with expression analysis requiring a molecule count and sequencing requiring interpreting the species of labelling atoms. Critically, the sequencing molecules will be over 10,000 base-pairs long drastically reducing downstream data processing requirements. This compares to read lengths of up to 500 base pairs on the 454 instrument. "We've taken existing, mature technologies and combined them in a unique way to allow these exciting applications. Because of this,​ our approach is to work with people that are among the best in their field and focus on developing our technology,"​ said Abert. ​"We are pleased with the results from our collaboration with the University of New Hampshire's Hubbard Center for Genome Studies as we develop what we believe will be a revolutionary technology." ​