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July 13, 2012

New positional sequencing technology could dramatically speed up gene sequencing

Although the field of gene sequencing has advanced exponentially during the past two decades, conventional technology uses light to sequence DNA. A company called Nabsys has developed a new technique that could speed up aggregate throughput by 1,000x. The technique employs using solid state detectors instead of light to sequence DNA,and should result in faster, more accurate, and more informative sequencing. In an interview with Sander Olson for Next Big Future, Nabsys President and CEO Dr. Barrett Bready, M.D. discusses how new positional sequencing technologies could be used to dramatically improve the healthcare and agricultural industries.

Barrett Bready

Question: Although it appears that the field of genomics is increasing exponentially, conventional gene sequencing techniques suffer from serious drawbacks. How do these limitations impact research?

The field of genomics is rapidly advancing, but the limitations of current techniques for gene sequencing have prevented progress in many areas. These limitations include requiring too much time for answers, inaccurate and short reads, problems analyzing DNA rearrangements such as one finds in cancers, and relatively high costs. As a result, the process of acquiring sequencing information is far from optimal, and this is significantly limiting the productivity and efficiency of researchers and physicians trying to apply sequencing to improving health.

Question: Conventional sequencing techniques employ light to sequence DNA. Why is light a sub-optimal sequencing technology?

The wavelength of light is hundreds of nanometers. The distance between base pairs in a DNA molecule is less than a nanometer. So this vast discrepancy in size causes numerous problems. It also makes the sequencing machines very complicated and expensive because of the costly lasers and cameras needed for detection. Nabsys has developed a superior approach to performing DNA sequencing called positional sequencing that detects DNA using electrical signals.

Question: Positional sequencing involves using electrical detectors instead of light?

Yes, we have come up with a proprietary method that employs solid-state materials like you find in a computer and detects the change in electrical signals when DNA passes through the silicon chips. The electrical measurements are much more sensitive than light detection and we can look at much longer pieces of DNA than conventional sequencing techniques.

Question: How does the sensitivity of these detectors compare with optical sequencing? These solid-state detectors are far more sensitive than equivalent light detectors. We get information from single molecules of DNA while most light-based systems need many thousands of molecules to see a signal. Our detectors also operate much faster than sequencing using light.

Question: This new technique Nabsys has developed allows for sequences of hundreds of thousands of base pairs to be read. Why is this important?

The reading of long DNA is a major advance because current techniques can read only a couple of hundred base pairs at most. By sequencing thousands of base pairs with each read, we can precisely identify positions of sequences and see how they fit together directly. With current technology, researchers need to piece the smaller fragments together, which is quite difficult, time consuming, and error prone. The short reads make it impossible to see how all the pieces fit together so every genome is provided as a bunch of pieces rather than a complete sequence. With long reads, we can see how everything is connected.

Question: The Nabsys method of positional sequencing uses probes. What advantage does this impart?

By using probes, we get a better signal and can look at particular parts of the DNA to find what we are looking for. So if we are examining a tumor cell, we would only need a small set of probes to map the DNA and find out if a translocation exists or not, rather than sequencing the entire segment. This saves considerable time and computing power, and should result in our method becoming a superior diagnostic tool that allows you to get as much information as you need.

Question: Nabsys claims that its probes also allow for "inherently targeted" sequencing. What exactly does that mean?

Current sequencing techniques get information from different molecules randomly. With our probes, researchers can target a specific segment of DNA for analysis. In many cases, this type of targeted analysis is exactly what scientists require to do their research.

Question: Why does processing current DNA sequencing techniques require prodigious quantities of computing power?

With current sequencing techniques, it may take billions of individual sequence reads to cover a human genome. These all have to be compared to the reference sequence to figure out where they should be compared to each other. Many of them can be placed in millions of similar locations making it very difficult and time consuming to do the calculations. Doing this huge amount of computations often requires server farms to sift through all of the data. With our approach, the sequence reads are much longer so you do not need as many and they are much easier to place relative to each other. We further reduce processing needs by using advanced algorithms so our approach can be done on a laptop rather than a server farm.

Question: How does throughput using positional sequencing compare with that of current sequencing methods?

Each detector can process DNA at a rate of 1 million base pairs per second. We can easily fit a hundred detectors on a single chip, so our aggregate throughput is many thousands of times greater than current methods.

Question: How much variation exists in DNA strands?

Every human has a different DNA sequence, even identical twins. Some of the variation does not make much difference but a lot of it does. Current sequencing methods are very good at detecting most short variants but cannot detect large scale structural differences. With positional sequencing, we can identify both short and long range differences.

Question: How will the cost of positional sequencing compare with that of current sequencing?

The cost of the positional sequencing will depend on a number of factors, so I can't give you precise costs. But I can say that for any DNA sequencing task you would want to perform, the cost of positional sequencing, should be substantially less than that of current sequencing methods. In some cases it could reduce costs by up to 4 orders of magnitude.

Question: What industries would benefit most from using positional sequencing?

This technology could greatly benefit cancer research and treatment. In cancer research, the aim is to study individual DNA molecules, to ascertain the structural variations and to determine the heterogeneity within the DNA. This can only be done by positional sequencing. This technology should ultimately lead to personalized treatments for cancer based on individualized genomic analysis of tumors.

Question: It would seem that the agricultural industry could also benefit from this.

Yes, this could accelerate the process of selecting plants with improved nutritional value and greater resistance to pests, disease, frost and drought. It does not matter whether the plants are generated by classical breeding or by directed genetic modifications. Plant genomes are especially hard to analyze with current methods so positional sequencing will be particularly valuable in this area.

Question: Will positional sequencing ultimately supplant current sequencing methods?

I believe that for the majority of sequencing tasks, it will. Current methods suffer from many limitations, and these limitations are hindering medical and agricultural research. Positional sequencing has the ultimate potential to transform the healthcare and agricultural industries.





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