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Guest Commentary: Digital sensor technologies are transforming biomedicine
by Dr. Gordon Sanghera  |  Email the author


I have devoted my career to marrying electronics and biology in the development of bioelectronic systems. Since my doctoral studies in biosensing at the University of Oxford, I have been captivated by the elegance of using bioelectronic coupling to analyze the microscopic world, and the massive technology leaps that these types of technologies may induce. Having traveled the journey of one medical transformation enabled by digital sensor technology—the management of diabetes—I believe we are poised on the brink of another, much larger revolution in digital sensing.
Perhaps no better example exists of personalized medicine—following the right treatment for the right person at the right time—than in the current management of diabetes. Diabetes, whether type 1 or type 2, is ultimately caused by disruption of insulin signaling, resulting in poor regulation of blood glucose levels that can be controlled through a combination of drugs, diet and exercise.   
Whereas the results of most diagnostic assays are acted on by physicians on a timescale of hours to days or longer, a diabetic patient may need to know his blood glucose concentration in less than 20 minutes to avoid life-threatening hypoglycemia. Critically, tight control of high blood sugar levels is essential in avoiding common complications of the disease including kidney, retinal and cardiovascular damage. As a result, approximately 6 billion glucose assays are performed by this patient population every year, a number that exceeds all other diagnostic assays combined.   
Despite obvious utility and demand, this widespread adoption of personal glucose testing by diabetic patients did not happen until decades after the development of the first home-testing systems in the 1970s. Home glucose monitoring took off, not through any fundamental advancement in the glucose chemistry underlying the technology, but through a shift from optical to electrical detection that simplified the workflow and leveraged the microelectronics revolution.
The basic chemistry behind glucose monitoring involves an enzymatic reaction that occurs in the presence of glucose to produce free electrons. The first blood glucose tests relied on additional chemistry to couple glucose oxidation to photobleaching of a dye, which could then be read by an optical device. Translating that chemistry into a system for home use created a multi-step process that involved a noticeable skin prick to extract blood (0.1 ml), blotting the blood on a strip, waving the strip about to air-dry it, timing the reaction and measuring the result in an optical meter the size of a small house brick.
A fundamental shift occurred when Professor H. Allen Hill and his colleagues at the University of Oxford devised a novel method of directly measuring the oxidative states of the glucose enzymes involved as an electric signal. This enabled them to produce a device the size of a pen and requiring only a tenth of the volume of blood (0.01 ml) that was used in the optics-based system. Interfacing the basic glucose chemistry directly into a digital system without the need for secondary reporter chemistry meant a very quick, painless, single-step process that could leverage the rapidly increasing miniaturization of microelectronics to become a barrier-free and invaluable personal tool for medical management. Current systems use a 0.001ml blood sample, resulting in virtually pain-free testing.
Like glucose detection in the 1970s, most current systems to identify single molecules rely on surrogate identification of a molecular label. Particularly common are optical technologies, usually to detect fluorescent labels. These methods can be laborious, time consuming and expensive. As in the case of glucose measurement, I believe a similarly transformative label-free bioelectronic coupling technology is at hand that is broadly applicable to single molecule detection—nanopores.  
Nanopores are nanoscale holes in membranes. Experimentally, this hole is most commonly formed by the pore-forming protein alpha hemolysin. When chambers on either side of the membrane are bathed in electrolyte and a charge is set across the membrane, the current through the nanopore channel can be measured. When a target analyte interacts with the nanopore, a characteristic disruption in current can be measured to identify that target. Through protein engineering and combination with sophisticated hardware and instrument fluidics, nanopores may be turned into high-throughput, direct electronic sensors for a variety of analytes.
Nanopores have been explored for more than 20 years in the research environment, pioneered by academics including professor Hagan Bayley at the University of Oxford and professor Dan Branton of Harvard University. However, analysis of one nanopore at a time as has been traditional in academic setting, is impractical for the industrial environment. To create a high throughput technology, a method of arraying the measurement of multiple nanopores must be developed. It is only recently that this technology been poised for industrial application and is currently under development.
One of the most prominent applications for nanopore technology is DNA sequencing; the analysis of DNA to ascertain the order in which the four standard bases appear and to gain additional information such as the description of epigenetic modifications. While the technology has advanced dramatically in recent years, today's sequencing systems may still be compared with the mainframe computers of the 1970s. Today, many systems are located in a number of large centers (genome centers and core labs) around the world that perform cost-effective DNA sequence-based experiments through efficiencies of scale. DNA sequencing is starting to be democratized but the scale and complexity of existing technologies still makes it a relatively centralized experiment.  
As the National Human Genome Research Institute noted in its $1000 genome challenge in 2004, "the ability to sequence an individual genome cost-effectively could enable health care professionals to tailor diagnosis, treatment and prevention to each person's unique genetic profile." This "race for the $1,000 genome" has been the headline of many articles in recent years. While a useful metric, when measuring the cost of a 3 billion base-pair haploid human genome sequence it is important to factor in everything; sample preparation, instrument amortisation, reagents, labor, informatics, instrument downtime and even energy. The fully factored cost today is still tens of thousands of dollars.  
If the insatiable demand for DNA information by researchers, and soon clinicians, is to be satisfied at a realistic cost, a step-change in price and complexity of workflow is needed. That is most likely to be met when optical methods are replaced by direct, electronic ones that are sensitive at the single molecule level. Nanopore sequencing fits this profile; by removing the need for amplification, fluorescent labelling, optical detection and translation of an optical signal into DNA information. Limited by silicon rather than optics, the development of nanopore-based electronic sequencers would be free to follow Moore's law of scaling-up and fulfill the vision of a mainframe-to-PC style change in DNA analysis technology. 
DNA sequence data is still largely a tool for scientific researchers, but it is taking steps towards the clinic, particularly in oncology. Reports emerged in 2009 of early personal cancer genomics, with comparison of the genomes of patients' healthy and cancer cells leading to clues about treatment strategies. Companion diagnostics exist and more are expected; a classic example is that of the breast cancer drug Herceptin, which in the United Kingdom is given purely to people who have a particular gene variant that identifies them as treatment-responsive. With the advent of lower-cost technology that allows routine large-scale analysis, we await further news of personalized medical developments such as efficacy of drugs against particular viral strains or the pharmacodynamics of drugs according to variants in human metabolic enzymes.

Beyond DNA sequencing, there are many further areas in which direct electronic analysis of single molecules might contribute towards personalized medicine and more. For example, a protein nanopore might be tailored for the identification of specific proteins, small organic molecules and ionic species.    
Just as having a simpler, cheaper methodology for DNA sequencing would catalyze the use of DNA sequence information in drug discovery processes, the same potential applies to the analysis of proteins. There is still no gold-standard platform for protein analysis during the validation and discovery phases of drug development. The platform of choice—mass spectrometry— resembles the DNA sequencer of today, requiring large start-up costs and overhead. Immunoassays can also be used to identify specific proteins, but require knowledge of which proteins are likely to be of interest from the outset. In the drug discovery phase, immunoassays are simply too expensive and cumbersome to be used for proteomic analysis.
Nanopore-based protein analysis could offer a simple, electronic and real-time tool for protein discovery, validation and potentially the same technology could be applied in the clinic. Early industrial work is underway to explore the performance of nanopore-ligand complexes for the specific and sensitive detection of target proteins.  
Another related application of this technology lies in the analysis of ion channels, the naturally occurring pore-forming proteins that regulate electrochemical balance across biological membranes. Ion channels are both drug targets (for example one of the druggable targets on the influenza virus) and sources of toxicity (for example, the hERG channel).  
The same instrumentation that reads the currents across nanopores may be used to analyze the action of drugs and potential drugs on ion channels. In the future, these methods may be incorporated into a high-throughput screening tool for routine use in research laboratories. 
Just as the development of an electrical readout for blood glucose monitoring has changed the face of diabetes management, the use of digital sensing technology in molecular analysis could have a transformative impact in many scientific disciplines.   
Gordon Sanghera is co-founder of Oxford Nanopore Technologies Ltd. He was appointed CEO in June 2005. Sanghera has more than 20 years of experience in the design, development and global launch of novel, point-of-care bioelectronic systems. At Abbott Laboratories, he held both U.K. and U.S. director level positions, including research and manufacturing process development. Before its acquisition by Abbott, Sanghera led the R&D of Medisense Inc., where he was instrumental in the launch of several generations of blood glucose systems for the consumer and medical markets. He has also developed and validated market production processes to meet with the regulatory requirements for the United States and Europe. Sanghera has a Ph.D in bioelectronic technology and a degree in chemistry.
Code: E02051003



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