October 15, 2013

Licensing deal marks coming of age for UAB-UW nanopore sequencing technology
Fast, inexpensive gene sequencing needed to make possible personalized medicine.

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The University of Alabama at Birmingham today announced that Illumina Inc. has licensed the rights to a DNA sequencing technology developed by a UAB microbiologist and a University of Washington physicist.

nanopore sThe patent-licensing deal revolves around nanopores first studied as potential chinks in the armor of the tuberculosis bacteria, but now part of efforts to make sequencing even faster and cheaper.

Sequencing reveals genetic variations, which partly determine each person’s risk for many diseases as well as which drugs will work for him or her. Cancer centers are already sequencing tumors in search of variations that make some resistant to chemotherapy. Global sequencing studies seek to find the genetic contributors to conditions such as autism and diabetes.

“Widespread access to genetic information will improve medical care worldwide; but in order to become part of daily, personalized medicine, DNA sequencing methods will need to become faster and cheaper,” said Michael Niederweis, Ph.D., a microbiology professor in the UAB School of Medicine and one of two researchers who developed the technology. “Our nanopore technology promises to achieve that, and we believe Illumina can transform our experimental system into a pioneering commercial technology.”

While the terms of the deal are confidential, the license gives Illumina exclusive worldwide rights to develop and market the nanopore DNA sequencing technology developed by Jens Gundlach, Ph.D., a professor of physics at the University of Washington (UW), Niederweis and their teams. The technology is protected by pending patent applications co-owned by the UAB Research Foundation and UW.

“Many companies and universities are looking at the potential of nanopore technology, but the technology developed by Drs. Niederweis and Gundlach is among the most promising,” said Christian Henry, senior vice president and general manager of Illumina’s Genomics Solutions business.

Path to a simpler sequencing technology

In every human cell, the blueprint for the body is encoded in chains of molecules called deoxyribonucleic acids or DNA. DNA chains are, in turn, composed of nucleotides, each of which includes one of four bases — adenine, thymine, guanine or cytosine. These bases serve as the letters making up the genetic code, and sequencing methods determine their precise order.

“Widespread access to genetic information will improve medical care worldwide; but in order to become part of daily, personalized medicine, DNA sequencing methods will need to become faster and cheaper,” said Michael Niederweis, Ph.D., a microbiology professor in the UAB School of Medicine and one of two researchers who developed the technology. “Our nanopore technology promises to achieve that, and we believe Illumina can transform our experimental system into a pioneering commercial technology.”  
It took The Human Genome Project 10 years and cost $3 billion to sequence the first complete set of genetic information, or genome, for one human, with the results announced in 2003. That same feat today takes a couple of days and costs about $4,000. Dramatic improvements in template preparation, sequencing strategies and image processing made this astounding leap possible in recent years, but DNA sequencing has yet to cross the threshold that will make it part of everyday medicine: to decode a patient’s genome within hours for less than a thousand dollars.

Many labs are looking for ways to replace the current processes with simpler, cheaper ones. One such approach is nanopore sequencing, which employs a pore just large enough for a DNA strand to slip through.

As the molecule passes through the pore, it partially blocks an electrical current. This enables each of the four DNA bases to generate a unique electrical signal and allows the system to identify the sequence. Bacteria evolved to have such pores in their outer membranes because they efficiently let in nearby nutrients — sugars, phosphates and amino acids — that happen to be about the same size as a single DNA nucleotide.

Niederweis started his career studying pores in a bacterial species called Mycobacterium smegmatis, a harmless relative of the bacteria that causes tuberculosis. He was fascinated with mycobacteria because their outer membranes have unique properties and are capable of protecting mycobacteria from toxic compounds, including antibiotics that kill most bacteria. Niederweis and others think such pore proteins may provide an entry point for new tuberculosis drugs, which is one of the reasons why the membrane proteins of M. smegmatis and M. tuberculosis remain major research interests in his lab. 

Previous research in other labs on another bacterium, Staphylococcus aureus, had first looked at whether a bacterial pore might be used for DNA sequencing. These earlier efforts did not work because researchers could not tell which of the four DNA nucleotide bases was passing through the pore based on the electrical signals generated. Niederweis and colleagues published the structure of an M. smegmatis pore protein in the journalScience in 2004. In 2008, Gundlach, Niederweis and their teams published an article in the Proceedings of the National Academy of Sciences showing that M. smegmatis pores due to their shape are many times more sensitive for DNA sequencing than was a previously used pore from Staphylococcus aureus.

One problem faced by the field was that DNA strands were moving through nanopores (toward an oppositely charged electrode) a thousand times too fast for the system to capture their electric signatures. The solutioncame in the form of a protein called DNA polymerase.

Within cells, a polymerase “walks” along DNA strands, reading their code as an intermediate step in carrying out genetic instructions. In the team’s system, the polymerase attaches to DNA strands headed for the pore but is itself too big to pass through. Thus, the DNA strands move through the pore as the polymerase processes them at speeds well-suited for electronic detection.

Last year, Gundlach, Niederweis and their colleagues 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 single DNA molecules.

“The UAB Research Foundation is very pleased to have licensed its nanopore technology to Illumina,” said Leona Fitzmaurice, Ph.D., director of technology transfer within the UAB Research Foundation. “As a leader in next-generation sequencing, Illumina is well-positioned to incorporate our nanopore technology into its product line and expand its customer base. Dr. Niederweis and his colleagues continue to improve their nanopore designs for use in DNA sequencing and other applications, and we’re protecting the intellectual property generated by this prolific laboratory.”

“This major licensing deal reflects the relentless drive toward innovation thriving in Dr. Niederweis’ lab and across our campus,” said Richard Marchase, Ph.D., vice president for research and economic development at UAB. “Such agreements are proof of UAB’s capacity to drive economic growth by attracting the attention of major players as they search for technologies to expand their markets and fill their pipelines.”

“I think it’s important to note that the origins of today’s announcement began years ago as part of a basic science effort to understand bacterial nanopores,” said Frances Lund, Ph.D., chair of the UAB Department of Microbiology. “Now it has the potential to jump-start the next wave of DNA sequencing technologies.”

Separate from the licensing deal, Niederweis has agreed to serve as a consultant for Illumina.

Work in the Niederweis lab has for many years been sponsored by the National Institutes of Health.
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