Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
8.4.3 Chemographic Navigation
The human body is a cauldron of chemical complexity. Of particular interest to us here are those extracellularly occurring chemical species reliably associated with specific locations, functions, or processes that might be useful in navigation. As trivial examples, high concentrations of hormones or neuropeptides are found in the endocrine glands or in the nerve tissues; lactic acid is produced in muscles driven anaerobically; uric acid is heavily concentrated in urine in the bladder (although high blood levels may indicate gout); capillary lymph is more watery than thoracic lymph, which in turn is far richer in histaminase than cervical duct lymph (Section 188.8.131.52).
As with thermal and pressure markers, crude chemical demarcation markers may be employed to direct medical nanorobots to particular locations. Such markers may include injected chemical plumes, time release implants, remote-triggered releasers (e.g., pressure-release multi-chemical-bearing tattoos), and tissue-coded markers (analogous to radiolabeled iodine concentrating in the thyroid gland, alkali metal ions seeking out bone, or cancer-cell-targeted light-sensitive drug molecules in photodynamic therapy) -- all of which may establish useful localized chemical gradients. The principle difficulty for natural signal molecules is signal persistence, which may be relatively brief unless continuous broadcast and artificial (nonabsorbable) signal molecules are employed. Continuous broadcast creates a detection sphere of maximum radius Rmax around the broadcast emission point (Section 184.108.40.206). Use of artificial non-biodegradable molecules maximizes the signal/noise ratio. Diffusion causes small molecules to drift ~1 cell width in ~1 second, or ~1 mm in ~1000 seconds (Section 3.2 and Table 3.4); bulk flow microconvection and increased effective diffusivity due to natural stirring (Section 3.2.2) further limit positional precision.
Use of chemical beacons for chemonavigational triangulation is not efficient over large distances, since the required volume of signal chemical rises as the cube of the range. However, chemical localization may be moderately useful in close quarters. For instance, a micron-size nanorobot equipped with two antipodal chemical sensors can angularly resolve two periodic sources of dissimilar signal molecules to the limit of nanodevice rotation during a Brownian motion-limited measurement time (Section 3.2.1). A pair of 10-probe sensors taking measurements every ~1 millisec (concentration differential Dc / c ~ 20% over the full nanomedically-relevant range of Kd = 10-4 to 10-13 molecules/nm3; Section 4.2.1) can resolve Da ~ 3° of arc (Eqn. 3.2), or two chemical point-emitters separated by Xpath sin(Da) ~ 1 micron at a range of Xpath ~ 20 microns (~1 cell width) from the nanorobot.
Chemonavigation can also provide useful positional information. For example, glucose absorption in the jejunum establishes chemical gradients both in the radial and axial directions in the lumen and also across the surface of the small intestine (Section 8.2.3). If chyme leaving the duodenum starts with 1% glucose concentration and exits the upper jejunum at 0.01% concentration ~50 cm downstream, then the same 10-probe chemical sensor as above can measure 25 distinguishable glucose levels as a function of distance from the pylorus. This allows jejunal position to be estimated to within ~2 cm using glucose concentration alone.
Chemical navigation in the gut may incur significant positional uncertainties due to the large chemical variation of ingested foodstuffs, the generation and transport of gases, the volume and character of liquids consumed with the food, the state of mind (and bowel peristalsis) of the patient, the presence of biochemistry-altering disorders, and other factors. On the other hand, the results of measurements of nutrient levels in the stomach and duodenum may be broadcast downstream to jejunal nanorobots, allowing real-time assessment of the efficiency of digestive processes and thus reducing positional uncertainties. Similar gradients allow positional chemonavigation in gland ducts such as the salivary and pancreatic ducts.
Sulfate groups are more numerous on the surfaces of the rabbit aortic arch and carotid than on the surfaces of the rest of the systemic arteries, and post-staining fluorescence intensity (measuring abundance of sialyl groups in the endothelial glycocalyx) is 1.65 times higher in the carotid than in the aorta.3164 In cyto chemonavigation is possible as well. For example, intracellular diffusion gradients of O2 and ATP that appear under some conditions3068 could be useful for detecting the distribution and clustering of mitochondria.
Detailed chemomapping of individual patients may allow customization of standardized human chemographic profiles, e.g., to identify problem areas. Chemographicytes may assist in the mapping process at up to ~KHz sampling frequencies (Section 220.127.116.11; see also Chapter 19). For instance, regions of hypoxia develop in all solid tumors where rapidly dividing cells are supplied by inadequate or poorly developed vasculature. A continuously updated tissue oxygenation map allows recognition of growing hypoxic regions, permitting prompt detection of nascent tumors, myocardial and cerebral ischemia, cardiorespiratory failure, and rheumatoid arthritis (e.g., loss of fluids that provide joint oxygenation). Similarly, a whole-body map of the concentration of intracellularly sampled telomerase (or associated proteins such as TRF1/TRF2,3051,3052 Ku, and tankyrase,3053 or even telomerase mRNA levels) may provide a good first-cut toward a whole-body late-stage cancer map,* since 85%-90% of all primary tumors display this biochemical marker.3058 Cancer cells also display above-normal concentrations of b1 integrins, survivin, sialidase-sensitive cancer mucins and leptin receptors such as galectin-3, and below-normal concentrations of b4 integrins. Other examples include GM2 ganglioside, a glycolipid present on the surface of ~95% of melanoma cells, with the carbohydrate portion of the molecule conveniently jutting out on the extracellular side of the melanoma cell membrane.1403 GM2 and another ganglioside, GD2, are expressed in several types of cancer cells including small-cell lung, colon, and gastric cancer, sarcoma, lymphoma, and neuroblastoma.1403 Numerous specific markers of disease (an emerging field known as molecular epidemiology)1112 are available for detection and mapping by nanorobots.
* Telomerase is a ribonucleoprotein enzyme found principally in the cell nucleus. Telomerase is present in ciliated protozoa in concentrations of ~0.004-1 enzyme molecule per telomere;3054,3055 with 92 chromosome-tip telomeres, telomerase-active human cell nuclei may contain only 1-100 copies of the enzyme. About 10% of human cancer cells maintain their telomeres without telomerase.3056 Additionally, while telomerase is not expressed in most human somatic tissues,3057,3058 certain normal human stem cells and germline populations are telomerase positive3058-3062 and telomerase has been reported in normal human white blood cells and in some noncancerous liver diseases;3063-3065 stem cells have low but detectable telomerase activity but continue to exhibit telomere shortening throughout life,3060 hence telomerase expression per se is not oncogenic.3066
Another example is the chemographic mapping of organs. In the liver, hepatocytes located close to the portal vein (acinal Zone 1; Figure 8.26A) are bathed in blood that is comparatively rich in oxygen and nutrients, with only minimum exposure to metabolic waste products. In Zone 2, the blood is less fresh and wastes are more plentiful. In Zone 3, which extends to the central vein, the blood has little oxygen or nutrients but the highest concentration of metabolites.936 Metabolic and exocrine secretory activity creates distinct chemical and thermal gradients, clearly defining each lobule. This allows medical nanorobots to navigate between lobules by simply counting the number of lobules traversed, and to navigate within a chosen lobule by gradient averaging. Changes in measured gradients may evidence a recent ingestion of alcohol or other toxins, or may record the progression of hypoxia or cirrhosis which invariably begins in Zone 3.936
Chemical localization to specific organs or tissues appears practical (Sections 8.2.5 and 18.104.22.168), as does chemical macrosensing of systemic states. For instance, a rise in serum adrenalin accompanied by surges in lactic acid production or oxygen consumption in the lower extremities might raise the reasonable inference that the patient is panicky and possibly fleeing from something that may be chasing him. Measurement of the concentration of thiocyanate in salivary secretions can distinguish smokers (~9 x 10-3 gm/cm3) from nonsmokers (~2 x 10-3 gm/cm3).943 Measurement of leptin concentrations (a hormone secreted by fat cells) in the blood allows nanorobots to estimate the total amount of fat currently stored in the body, relative to the normal baseline of a given person.3265
Chemical tracking is also feasible. For example, a "bacterium moves through the water (or the liquid interior of your body) in a greasy cloud of its own waste products,"2973 due to the excretion of metabolic byproducts through transmembrane pores. Such microbial exhaust plumes might plausibly be detectable for distances up to ~100-1000 microns downstream, depending upon bacterial emissions, local fluid flow rates and other factors (Section 7.2.1), possibly permitting tracking and interception by medical nanorobots. Interestingly, quorum sensing among bacteria enables some microbes to eavesdrop on the chemical communications of other species.3236
Developing embryos demonstrate a sophisticated "biological positioning system" by which each cell determines its location relative to other cells to eventually produce the appropriate tissue, organ, or nerve. For example, members of the "Wnt" and "Hedgehog" families of signaling proteins help cells (in developing limbs and organs) to distinguish up from down. As another example, neuron migrations within the developing embryo are thought to be guided by chemical signposts such as the proteins reelin (released near the destinations of migrating neurons), mDab1 (which may be a docking protein activated by reelin),949 and the homeodomain proteins DLX-1 and DLX-2.950 Neuroblast cells that divide in the subventricular zone of the lateral ventricle in the brain of adult mice migrate a distance of ~3-5 mm to the olfactory bulb; these migrating neuroblasts remain organized in chains until they reach the core of the olfactory bulb, after which they separate and migrate radially as individual cells to more peripheral layers, then halt and differentiate into neurons.947 During this process, the neural precursors are not guided by radial glial or axonal fibers, suggesting chemonavigational guidance here too. Similarly, developing neurons shoot out axons whose tips are steered to their destinations by an array of guidance molecules that are fixed on cell surfaces, or are located within the extracellular matrix, or are secreted by the axon's targets -- such as the netrins (a chemoattractant group of proteins) and the semiphorins such as collapsin (a chemorepellant protein).951,1055 There is also a chemical "area code"1495 that is used for cell localization during extravasation of leukocytes from blood vessels (Section 22.214.171.124). Medical nanorobots can be programmed to follow and to interpret any such positional chemical signposts normally used by motile cells.
Chemonavigation may also be aided by the detection of isozymes -- physically distinct forms displaying the same catalytic activity that may be present in different tissues of the same organism, in different cell types, or in different subcellular compartments in a human being. Isozymes are common in the sera and tissues of all vertebrates, insects, plants, and unicellular organisms. They are commonly used in clinical diagnosis, as, for instance, to distinguish normal serum and serum from patients with a myocardial infarct or with liver disease, using a lactate dehydrogenase (LDH) electropherogram,996,3343-3348 although more recently the utility of isoenzymes in some clinical applications has been questioned.3349,3350
Last updated on 20 February 2003