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Biosensors are not just natural sensors that are part of life; they are sensors for biological entities including proteins, drugs, and even specific viruses. Nature does have a variety of schemes for approaching the detection of these entities. One common method is the one behind allergic response. When a body is first exposed to an allergen (a benign substance that it mistakes for a hostile invader), it is sensitized, which means that it creates antibodies that will recognize that allergen if it ever appears again. The antibodies use molecular recognition to spot the allergenic proteins and release histamine, the substance that causes your body to react by sneezing, itching, or nausea. This ability to sense larger structures, such as proteins or nucleic acids, can be remarkably important.

Glucose detection is a classic problem in biosensing. Diabetics cannot control their insulin levels; therefore, their levels of blood glucose fluctuate tremendously. If those levels get either too high or too low, their conditions can be life threatening. Currently, most Type I diabetics must actually draw blood on a daily basis, or even more often, to test for blood glucose levels. Sensing glucose molecules can be done in many ways, using optical, conduction, or molecular recognition methods. None of these have yet been shown to be compatible with an implantable simple device that could automatically, continuously sense the glucose levels in the blood. This is one of the major challenges for chemical sensing, and nanoscale structures may advance it very substantially.

DNA sensing is potentially an enormous area in which nanoscience can improve medicine. When we discussed DNA computing in Chapter 5, we talked about hybridization, the ability of DNA to bind to a complementary strand and not to bind to anything else. For instance, if we wish to sense the structure with the sequence CGCGTTC, we could do so by using a strand GCGCAAG. This means that a single strand of, say, six bases can contain 4,096 different combinations (each base can have one of four values A, C, G, or T, so a six-base sequence can have 4 x 4 x 4 x 4 x 4 x 4 possible values). Consequently, if a particular biological target such as botulism or strep or scarlet fever has a known DNA sequence, it is possible to target a short section of that DNA sequence—say a section of 10 to 15 bases—that can be uniquely sensed, without any errors, by an appropriate single-strand complementary structure. This is sometimes called a DNA fingerprint for a disease because it is virtually impossible to mistake an analyte using even a moderately long sequence. With a 15 base strand, there is only a one in one billion chance of error per strand tested.

The most striking application of DNA sensing will probably come in the generalization of the lab-on-a-chip concept. By using the powerful analytic capabilities of these dense microlaboratories, it will be possible to include several screening sensors on a chip for instant recognition of viral or bacterial DNA associated with several different diseases found in the body. Such chips could also be used to sense the presence of toxic species, either natural or artificial, in water supplies. Finally, since we now know the entire human genome, biochips could be used to sense either particular DNA signatures or particular protein signatures known to be defects that can result in disease. This would allow at-risk individuals to receive more frequent tests and attention. Multiple-sensing or sequencing of DNA is a major target in the biomedical community because it will permit tremendously advanced diagnostics. DNA sensors are clearly going to be the optimal (and maybe the only) way to respond to this challenge.

It is also possible to create sensors that take advantage of DNA recognition. The simplest sensors work by introducing a strand of DNA complementary to the analyte into a solution to be tested. If the analyte is present, it will hybridize with the test DNA and form a double strand.

Hybridization confirms that the analyte is present; finding out whether hybridization has occurred isn't trivial. We can't see the double strands without very sophisticated instruments; consequently, the determination is usually made by mass. Obviously double strands have a greater mass than single strands, though it may not be by much if the test sequence is short since each base pair weighs only as much as a molecule or roughly 1/1,000,000,000,000,000,000,000 of a gram. This is much too small to measure easily in any direct way, so it is necessary to amplify the response before it can be measured. One of the great challenges of DNA sensing is therefore to amplify the effects of hybridization so that they can be easily measured.

One way to provide this amplification is to change the optical properties of gold or silver nanodots that are attached (technically "functionalized") to the DNA. Chad Mirkin, Robert Letsinger, and their groups at Northwestern pioneered the combination of quantum optical effects (remember the changes in the color of gold upon changing the size of the gold clusters) and molecular recognition (complementary DNA binding). Their scheme and some actual results are shown in Figure 7.1.

Figure 7.1. The upper schematic shows how the nanodots in a colorimetric sensor are brought together upon binding to the DNA target (in this case anthrax). The clustered dots have a different color than the unclustered ones as is shown in the photograph below them.

Courtesy of the Mirkin Group, Northwestern University.

DNA linker DMA UnKer

By exposing the single strands of DNA that are attached to the gold nanodots, the sensor recognizes the target strands of DNA, which causes the gold nanospheres to come closer together and, as in those recurring stained glass windows, change color. Because of the color change, these are called colorimetric sensors and can be read by simply looking at them. (George Schatz's group at Northwestern has worked out the theoretical basis.) This approach is typical of the kinds of sensing methods that are used for looking for tiny fragments of DNA.

In addition to DNA, colorimetric nanosensors can use the change in color of metallic nanodots to detect other molecules. Richard Van Duyne's group at Northwestern has used nanosphere lithography to prepare tiny gold dots on a surface, as we discussed in Chapter 4. A molecular nanostructure containing a biological binding site (something like an antibody) is attached to the gold nanoparticles. The binding site is designed to recognize (chemically bind to) a particular protein analyte just as antibodies bind to biological invaders in your body. When that analyte appears in solution, it binds to the recognition site, which changes the chemical and physical environment of the gold dot, whose color is then slightly changed. This change can be measured, and the sensitivity is enormous. Van Duyne has shown that his gold nanodots can actually measure a single molecule of particular analytes.

The challenge for creating totally generalized nanosensors of this type is that, in order to be useful, sensors must not create false positive results. In the case of DNA, it is almost impossible for hybridization to occur and for the sensor to trigger if the target molecule is not present. But if you wanted to construct an explosives detector, the problem is much more complex. Nitrates, which are the molecular groups common to most explosives, are common in a variety of other common household items including hot dogs and fertilizer and can even be found within the human body. If you detected them to an accuracy of a single molecule, every single person tested would seem to be carrying a bomb. A great deal of research is being done to circumvent this problem for explosives and other common analytes.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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