Researchers, led by University of Washington (UW) physicist Jens Gundlach, have developed a nanopore sequencing technology that is capable of reading the sequence of a single DNA molecule. In this system, the DNA is pulled through a nanopore while an ion current through the pore electronically reads the DNA's sequence. The nanopore is an engineered protein developed specifically for DNA sequencing by Gundlach's team in collaboration with Michael Niederweis, a microbiologist at the University of Alabama-Birmingham (UAB). This technology has led to a patent-licensing deal between UW and Illumina, Inc.
The licensing deal gives San Diego-based Illumina, Inc., developer of integrated systems for genetic variation analysis, exclusive worldwide rights to develop and market the nanopore DNA sequencing technology that is based on the engineered pore.
"Many companies and universities are looking at nanopore technology as one way to realize that potential, but the technology developed by Drs. Gundlach and Niederweis is among the most promising," said Christian Henry, Senior Vice President and General Manager of Illumina's Genomics Solutions business.
The nanopore was created by genetically engineering a protein pore from a mycobacterium smegmatis. The pore has an opening 1 billionth of a meter in size, just large enough for a single DNA strand to pass through, but needed to be modified to become useful for this sequencing technology.
Last year Gundlach's team published a study in Nature Biotechnology that found the combination of a genetically altered M. smegmatis pore and DNA polymerase could be used to directly determine DNA sequences using just single DNA molecules. The polymerase serves as a molecular motor that moves a DNA strand through the pore one nucleotide at a time. Their study reported a successful demonstration of this new technique using six different strands of DNA. The results corresponded to the already known DNA sequence of the strands, which had readable regions 42 to 53 nucleotides long.
While mycobacterial nanopores were first studied as potential chinks in the armor of the tuberculosis bacteria, they are now part of efforts to make genetic sequencing faster and cheaper. Gundlach believes this may lead to readily available personalized medicine, potentially revealing predispositions for a variety of illnesses, such as cancer, diabetes and addiction.
Sequencing reveals genetic variations, which partly determine each person's risk for many diseases, as well as which drugs will work best for each individual. Cancer centers are already sequencing tumors in search of variations that make some resistant to chemotherapy. And global sequencing studies seek to find the genetic contributors to a variety of conditions from autism to diabetes.
"The nanopore technique also can be used to identify subtle DNA modifications that happen over the lifetime of an individual," said Gundlach. Such modifications, referred to as epigenetic DNA modifications, may take place as chemical reactions on the DNA within cells -- and tell the cells how to interpret their DNA. While essential for proper cellular functioning, epigenetic modifications can also be the underlying causes of various undesired conditions.
"Epigenetic modifications are important for things like cancer," Gundlach said, "and being able to provide DNA sequencing that can directly identify epigenetic changes is one of the charms of the nanopore sequencing method."
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