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Human Chronobiology and Nanorobots
Posted on: April 12, 2005

The human body incorporates numerous biological clocks. The best-known and most-studied example is the daily (24-hour) endogenous circadian oscillator. This internal clock is normally reset by natural sunlight, which is much brighter than indoor lighting. The clock, in turn, sets the cadence for most of the other 24-hour body rhythms – for example, sleep/wakefulness cycles (e.g., melatonin), urine production, body temperature, blood cortisol and ACTH cycles, and the diurnal rhythm of mitosis in epidermal epithelium (e.g., greatest during sleep or inactivity, least during wakefulness or activity). The circadian clock stability (variation in free-running period) is ~1% in Drosophila and ~0.2% in humans.

Mammalian circadian rhythms are regulated by a master pacemaker within the suprachiasmatic nuclei (SCN) of the hypothalamus (just above the point at which the optic nerves from each eye cross in mid-brain). In humans, the SCN is comprised of ~10,000 special cells that send out electrochemical signals in a 24-hour timing pattern. Entrainment of the clock to light-dark cycles is mediated by photoreceptors in the retina, with light information conveyed directly from ganglion cells of the retina to the SCN via the retinohypothalamic tract. Mammals and other vertebrates have another independent circadian clock in each retina, possibly driven by the retinal cryptochromes CRY1 (also made in the SCN) and CRY2, producing rhythms in local physiology such as the diurnal renewal cycles of rods and cones. CRY1 is also abundant in skin tissues. Clock-resetting photoreceptors have been found in the human popliteal region (behind the knees), and such photoreceptors may exist in many different tissues throughout the human body.

The current model for a core circadian oscillator comprises, in part, a transcription/translation-based negative feedback loop in which clock genes are rhythmically expressed, giving rise to cycling levels of clock RNAs and proteins (negative elements). The proteins then feed back, after a lag, to depress the level of their own transcripts, perhaps by interfering with positive elements that increase transcription of the clock genes. In 1998, this genetic network was still in the discovery process. One ~100,000-base-pair gene, aptly named "clock," was known to produce an 855-residue protein (mCLOCK in mice, 115.7 kD) that serves as a major regulator of the ~10 other, still unidentified, genes thought to affect circadian rhythm. (One portion of mCLOCK is the same as in a related 1023-residue clock protein, dCLOCK, found in Drosophila fruit flies). Circadian rhythms will almost certainly be made up of many interconnected feedback loops that interact with the CLOCK-related core pathway. It is believed that this interconnected ensemble will ultimately determine all of the classical circadian properties – period length, temperature compensation, and resetting by light or temperature. In 1998, most chronobiologists believed that many of these outer loops would be organism specific and that only the core loop would be universal.

In addition to the 24-hour circadian oscillator, many other biological clocks have been identified in humans. For example, the 28-day menstrual cycle is timed by two ovarian clocks, each delimiting a period of 14 days. One of these two clocks is the Graafian follicle and its production of estradiol, while the other clock is the corpus luteum and its secretion of progesterone. Both are obligatorily dependent upon the proper functioning of a third clock located in the arcuate region of the hypothalamus. This clock is known as the GnRH pulse generator, which ensures the rhythmic production and release of the gonadotropic hormones into the peripheral circulation with a cyclical period of ~1 hour (±25% stability), coincident with a 1-hour cycle of hypothalamic electrical activity (±12% stability). A 90-minute clock paces the development of the somites, blocks of tissue that form in regular arrays along the spinal cord of vertebrate embryos. One regulatory gene, named "chairy," undergoes repeated 90-minute activity cycles and is known not to require protein synthesis; gene expression follows the repeating pattern even when protein synthesis is biochemically blocked. A much longer half-weekly (circasemiseptan) pattern has been observed in mitotic activity in cancer patients.

Other biological clocks abound. The stomach produces rhythmic contractions of ~3 per minute during digestion. Rhythmic segmentation contractions of the bowel at ~0.2 Hz are driven by a thin layer of specialized pacemaker cells called the intestinal cells of Cajal, which demonstrate electrical oscillations at about the same rate as the contractions. Cardiac pacemaker cells in the sinoatrial node emit a cyclical pulse that triggers a heartbeat at a ~1 Hz basal rate. The respiratory centers in the medulla oblongata produce an autonomic contraction cycle of the diaphragm at ~0.3 Hz. The human eye produces much spontaneous rhythmic dilation and constrictions, including high-frequency ocular micro tremors present in all people (mean frequency ~84-88 Hz), accommodation micro fluctuations (~1-2 Hz) with the pupil varying <300 microns in diameter, and low-frequency pupillary oscillations (e.g., ~0.2 Hz "hippus"). Electrical rhythms generated by the brain that are detectable by an electroencephalograph include alpha waves predominantly in the occipital region at 8-13 Hz, beta waves in the frontal and central areas at 18-30 Hz, delta waves at <4 Hz during deep sleep or abnormal function, and theta waves in the temporal and parietal areas at 4-7 Hz.

Individual cells display a number of oscillatory biochemical pathways as well, including calcium ion oscillations, cyclic AMP signaling, and various other cell cycles. For instance, the glycolytic enzyme oscillator, controlled primarily by phosphofructokinase, may mediate various rhythmic physiological behaviors such as slow waves of contraction in smooth muscle, electrical activity in neurons, and insulin release from β islet cells of the pancreas. In one experiment, this oscillator mediated a 55 mV voltage change in guinea pig cardiomyocytes at 0.01 Hz (±10% stability) in an almost perfectly sinusoidal pattern, although a few cells displayed oscillations with irregular phase, amplitude, or both. In another experiment, fluorescently labeled puffs of tumor-cell cytoplasm were observed being released through plasma membrane ruptures, regularly at ~0.05 Hz during a neutrophil-mediated cytolytic attack, matching the nicotinamide-adenine dinucleotide phosphate and superoxide release periods for neutrophils. By 1998, there was a growing belief that many, if not most, of the cells in an animal may possess individual biological clocks; fruit flies were already known to have clocks distributed throughout their wings, legs, and abdomen.

The human brain also possesses an interval timer that allows a person to gauge the passage of seconds or minutes to a mean accuracy of ±15%. The interval timer functions like a stopwatch and resides in the basal ganglia, a region of the brain that coordinates voluntary muscle movements. A population of neurons in the substantia nigra releases regular pulses of dopamine into an accumulator, called the caudate-putamen, a major part of the basal ganglia. These pulses are then read via neural pathways to the cerebral cortex that are known as striato-cortical loops. Other internal "alarm clocks" that reliably allow waking from sleep at desired times have been described.
For example, long ago, native American Indians of the Sioux tribe learned, after carefully controlled experiments, that they could use a full urinary bladder as a kind of alarm clock. By drinking a certain amount of water at bedtime, they found they would awaken in a specific number of hours -- drink more fluid, and they would awaken earlier from the urge to urinate; drink less, and they would awaken later.

In vivo nanorobots should be able to eavesdrop on most of these active chronobiological channels, gaining complete knowledge of the oscillator frequencies and phase settings of virtually all of the human body's biological clock systems. For example, blood plasma cortisol typically peaks in the morning (e.g., 6-23 · 10-8 g/cm3 at 8 AM), then declines throughout the day (e.g., 3-15 · 10-8 g/cm3 at 4 PM, then ~50% of 8 AM value at 10 PM). Melatonin (also detectable in saliva) cycles in the opposite direction, normally peaking at 6-7 · 10-11 g/cm3 at night and then falling to 1.4 · 10-11 g/cm3 during the day. Longer cycles are easily tracked too. For instance, blood viscosity in healthy young women shows the rhythmic variation of the menstrual cycle, probably due to changes in serum fibrinogen and globulin levels that can be measured more directly. These nanorobot-accessible readings may be used either to measure "body time" or to control it, and in some cases can recalibrate relevant onboard nanochronometers.

Environmental time cues may also be detected by in vivo nanorobots (e.g., temporal macrosensing), such as the level of illumination penetrating the epidermis (sometimes permitting inference of day or night) or the all-pervasive 60/50 Hz (U.S./Europe) electromagnetic hum generated by alternating current electrical supply systems in common use throughout the world, a crude frequency standard whose voltage can sometimes display time-of-day load-related fluctuations.

Source: Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999;
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