The substrate on which the newly labeled molecules are imaged is made using semiconductor fabrication techniques. Scientists generate silicon wafers with an 11-nanometer-thick window, which is thin enough for the electron beam of the microscope to discern the DNA molecule from the substrate. ZS Genetics is also working on making even thinner wafers to boost resolution of the image.
DNA has a tendency to curl up into a tangled mass, so one of the biggest challenges has been untangling that ball into linear strands that can be read. Researchers first flow fluid through a microfluidic device with tiny channels. That device fits on top of the DNA-coated wafer. The force of the flow stretches the DNA molecules, which then stick to the silicon. An electron beam is shot through the wafer, and a camera captures the image from the other side. “The wafer is the major proprietary consumable,” says Glover. “It will be dirt cheap.”
When stretched, the DNA looks like a ladder with the bases forming the rungs. So far, the company has released images of a 23-kilobase piece of DNA using a single type of labeled base. Glover says that he and his team have also done multilabel sequencing, although he declined to give additional details.
Still, the technology has a ways to go before it’s market ready. “Lots of proof of principle methods can work in R&D, but bringing it to [market] is not trivial,” says Benes. Glover aims to have a prototype this summer that scientists can test, and a faster commercial system next year. He adds that because most of the system relies on existing technologies, it will be easy and inexpensive to upgrade the system with new cameras and software.
Longer reads will allow scientists to look at collections of genetic variations that have been inherited together, known as haplotypes. This kind of analysis can determine if a particular genetic variation has been passed down from the individual’s mother or father. Recent research suggests that in some cases, maternal or paternal inheritance can impact the severity of the disease, a phenomenon that may be more common than previously thought.