DNA sequencing technology has continued to advance since the Human Genome Project, a task that took over a decade, hundreds of person years, at a cost of $3 billion. Subsequent technology developments, fueled by innovations in nucleic acid chemistry and detection have provided about a million-fold reduction in cost and equally dramatic improvement in throughput. However, much lower cost and more efficient methods for DNA sequencing will be required to make it feasible for routine healthcare practice and to reach the vision of personalized medicine. A team at IBM Research, in collaboration with researchers at 454 Life Sciences (a Roche company) is pursuing this vision with a novel idea, to sequence DNA in a solid-state device called DNA Transistor.
Several advances are currently being pursued to reduce cost and improve throughput of DNA sequencing. Ones that aim to sequence a single molecule of DNA (as opposed to the conventional chemistry based techniques of detecting reactions on a small volume of identical DNA molecules) hold the greatest potential. Amongst these, a method based on threading a DNA molecule through a pore of a diameter of a few nanometers to sequence this molecule while it translocates through the nanopore occupies a privileged place. DNA nanopore sequencing has the advantage of being a real-time single molecule DNA sequencing method with little to no sample preparation and inherently of low-cost.
At least two technical roadblocks have to be overcome to implement DNA nanopore sequencing: 1) a reliable approach to control the translocation of DNA through the nanopore; 2) sufficiently small sensors that will reliably detect individual nucleotides in a nanopore.
Researchers at IBM and 454 Life Sciences are pursuing an exciting idea to tackle both these technical roadblocks.
The device consists of a membrane composed of layers of metal and dielectric insulator, with a pore of few nanometers diameter. Voltage biases between the electrically addressable metal layers modulate the electric field inside the nanopore. This device utilizes the interaction of discrete charges along the backbone of a DNA molecule with the modulated electric field to trap DNA in the nanopore with single-base resolution. By cyclically turning on and off these gate voltages, it is plausible to move DNA through the nanopore at a rate of one nucleotide per cycle.
We call this device a DNA transistor, as a DNA current is produced in response to modulation of gate voltages in the device.
The DNA transistor is then a DNA positional controlling platform with single-base-resolution, which could be used in combination with sensor measurements that are under development by us and other research groups. By providing enough dwell time for each DNA nucleotide at the electrodes constituting the sensor, the DNA transistor allows exploration of the best electrical sensor that can resolve the difference between the four DNA nucleotides. In that sense, the DNA transistor paves the way to nanopore-based nucleotide sequencing, and personalized medicine.
Technological developments that allow sequencing a human genome for less than $1000 will have a profound impact on biology and medicine. Routine availability of genomic data, coupled with aggregation and analysis of clinical information such as treatments and outcomes will open new avenues for personalized medicine. The approach of personalized medicine is to use insights from molecular and mechanistic understanding of diseases – based on patient’s unique genome, and correlate these to evidence of treatment outcomes, to allow targeted treatment.
The ‘one size fits all’ and ‘trial and error’ approach of past will yield to evidence-based personalized medicine in future. Such precision in medicine has begun to and will increasingly manifest in various forms: segmentation of patient population into responders vs. non-responders to a particular treatment (e.g. Herceptin); segmentation of at-risk population on the basis of predicted trajectory of the disease to allow improved disease management as well as wellness management through guidance on life style choices; to eventually medicine that is tailored to the individual and targeted to the specific disease mechanism so as to maximize efficacy and minimize side effects.