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Guest Commentary: Digital sensor technologies are transforming biomedicine
02-05-2010
EDIT CONNECT
SHARING OPTIONS:
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.
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