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Oxford Nanopore Joins EU Research Project, Improves Nanopore Transport

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Oxford Nanopore Technologies is using a €730,000 ($940,000) grant from the European Union to explore a number of potential routes for nanopore-based DNA-sequencing technology, the company said last week.
 
Separately last week, Oxford Nanopore’s academic founder, Hagan Bayley, published a paper describing an improved method for passing a DNA strand through a protein nanopore, a development that may benefit the firm’s near- and long-term commercial efforts to develop a nanopore sequencer.
 
Oxford’s EU grant is part of a multinational European research consortium called Revolutionary Approaches and Devices for Nucleic Acid Analysis, or READNA, whose goal is to develop new DNA sequencing technologies and other methods for analyzing nucleic acids (see related article, this issue).
 
Launched this summer, the four-year consortium includes 10 academic and six commercial groups in the UK, France, Germany, Sweden, Denmark, and the Netherlands.
 
It is funded with €12 million from the EU’s 7th Framework Program for Research and Technological Development (see Short Reads, this issue). Funding for the project started this summer, though its coordinators announced the consortium last week.
 
Oxford Nanopore said the funding will help it to continue developing its nanopore technology, which is based on work by Bayley, an Oxford University chemistry professor, “into an early exonuclease/nanopore DNA sequencing system.” (see In Sequence 7/1/2008).
 
The company coordinates one of seven READNA projects, called “work-packages,” that focuses on various facets of nanopore sequencing. In addition to exonuclease-based sequencing, Oxford will also explore integrating protein nanopores with solid-state materials; methods for using nanopores to study DNA methylation; and try to develop droplet-based lipid bilayer arrays for nanopore-based multiplexed genotyping.  
 
“It’s a fantastic opportunity for us to collaborate more closely with Hagan, but also a much wider group of people,” said Brian McKeown, a research manager at Oxford Nanopore who coordinates external collaborations.
 
Among the other commercial groups participating in READNA with an interest in nanopore sequencing is Philips Research, the research arm of Dutch healthcare and electronics giant Philips.
 

“It’s definitely something that will come into play more in future generations as we move towards the strand sequencing capability.”

According to the READNA website, Philips, which is represented in the consortium by Pieter van der Zaag, will be “involved in the integration of protein channels in solid state apertures,” and will be “in particular involved in the production of electronically addressable arrays.”
 
A spokesperson for Philips Research declined to comment on the company’s interest in DNA sequencing.
 
Oxford Nanopore did not reveal whether Philips currently supplies it with parts for its sequencing system that are related to the electronic readout. A spokesperson said that “sitting at the same table with them is obviously very useful.”
 
On the academic side, Bayley’s team at Oxford is joined by the group of Cees Dekker, a professor at Delft University of Technology in the Netherlands, who will help fabricate solid-state nanopores, according to the READNA website. Oxford Nanopore is keeping an eye on solid-state pores for later versions of its sequencing technology. This summer, the company licensed intellectual property relating to solid-state nanopores from Harvard University (see In Sequence 8/12/2008).
 
Another READNA participant, Kalim Mir, an investigator at the Wellcome Trust Centre for Human Genetics at Oxford, will help develop methods for amplifying DNA in emulsions and for using nanopores for sensing mutation detection, according to the consortium’s website.
 
Dekker and Mir are also involved in another project sponsored by the READNA consortium that focuses on fluorescence-based single-molecule sequencing and includes other research groups at Oxford and elsewhere.
Nanopore Transport
 
Bayley’s group, meantime, published a paper online in PNAS last week showing how it improved the frequency and efficiency with which DNA molecules pass through a modified α-hemolysin protein nanopore.
 
Oxford Nanopore, which has licensed Bayley’s innovations in the past, could use this improvement to help it develop its nanopore sequencer.
 
“It gives us the ability to very subtly change the way that we can migrate any sort of charged analyte through the pore,” McKeown said.
 
The company currently focuses on exonuclease-based sequencing, in which an exonuclease cleaves off one nucleotide at a time and feeds it through a nanopore. However, the findings of the PNAS paper will likely be even more important for later incarnations of the technology, in which a DNA strand feeds through the pore and its base sequence is read off directly.
 
“It’s definitely something that will come into play more in future generations as we move towards the strand-sequencing capability,” he said.
 
The article shows that increasing the positive charge inside the α-hemolysin pore through site-directed mutagenesis of certain amino acid residues allowed a greater number of short, single-stranded DNA to travel through the pore in a certain time and at a lower threshold voltage than had previously been observed.
 
The researchers also noticed that the changes greatly reduced the number of instances in which DNA enters the pore without translocating it immediately.
 
The problem, the scientists explain, is that only a small percentage of DNA molecules that collide with an unmodified nanopore — up to 20 percent, depending on the voltage applied — actually enter the pore and translocate to the other side.
 
Increasing the frequency with which DNA strands traverse the pore “would reduce the dead-time between reads” in nanopore sequencing, they write.
 
In addition, the engineered pores “might be used to increase the capture efficiency of individual bases during exonuclease sequencing, which would be vital for accurate reads,” according to the article.
 
Oxford Nanopore has not yet chosen to work with any of the specific modified α-hemolysin pores described in the paper, but it is “certainly something we will look at, [whether] any of these [are] going to enhance the ability of the existing pore we are working with and capture bases and bring them down in a more uniform manner,” McKeown said.  
 
According to the PNAS paper, the results from protein nanopores could also potentially be translated to solid-state nanopores, whose surface could be modified chemically. However, McKeown said, “clearly, that’s something we can do much more easily with a nanopore which is a protein species than something like a solid-state nanopore.”

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