Foreword
Variability: from foe to friend
A summary of over 40 years of studies building a new, originally Minnesotan science with emphasis beyond circadian systems (a concept coined and documented at the University of Minnesota) upon resolving the chronome*, the lawfulness within the physiologic range in which healthy function occurs.
*Like genome, derived from gene and chromosome, omitting parts of the root words, chronome is derived from chronos (time), nomos (rule) and chromosome to describe the structure of rhythms and trends characterizing every biologic variable in its physiologic range of variation. Chronobiology splits this otherwise neglected, seemingly indivisible range into rhythms, as does fission to the "indivisible" atom.
While counting eosinophils, a white cell, in mouse blood, Franz confronted a confusing variability: without any apparent reason, a count of a hundred or more cells per mm3 of blood was followed by one near zero; or, in a different inbred strain of mice, a count of a thousand or more cells was followed by one of one hundred or so. Several kinds of blood cell counts were high at one time of day and low at another. These large changes persisted and even increased in extent when extra precautions were taken not to disturb the animals by handling them as little as possible. With one time-unspecified count of blood eosinophils, no conclusions could be drawn. The same enormous variability characterized the content of glycogen in liver or the number of cells in the state of division in this organ and other tissues. The variability remained unpredictable until Franz pursued the patterns of variation in time of these and very many other variables. Statistically, the changes became predictable.
The underlying about-24-hour cycles were uncovered. It became apparent that some of these rhythms, not strictly but approximately periodic phenomena, were of large amplitude and high reproducibility. The application of relatively simple statistical procedures to the data allowed the quantification of the underlying patterns. Thus, a heretofore vexing variability was rendered predictable. The about-daily changes were named "circadian" in order to emphasize by "about" (circa) their statistical rather than purely deterministic causality and, equally important, their built-in nature: the spontaneous rhythms had periods near (circa) 24 hours as they recurred in similar (circa) but not identical sequences and at similar (circa) intervals which, on a statistical basis, differed from their precise environmental, societal or geophysical match. This finding applied not only to the circadian system, but also to about 7-day (circaseptan) changes and their multiples and submultiples, the multiseptans, to components with still other periods, all of which changed further with age and disease. Since all these components intermodulated, it was of immediate importance to broaden focus from a single rhythmic change to various rhythms with different periods in the presence of trends. Thus, the critical lawfulness of biologic structures in time, the chronomes, was unraveled, not only for the eosinophil counts, but for the activity of the body as a whole and its resistance to various stimuli, for mitosis in different organs and tissues, and for different liver functions, related to different stages of the cell cycle.
Applications to cancer treatment followed. The fields of chronopharmacology and chronotherapy developed, based on the demonstration of the hours of changing resistance to noise, bacterial endotoxins, radiation and drugs. While originally rhythms appeared to be the exception and regulation for homeostasis the rule, the ubiquity of rhythms was documented for practically any and all variables examined, along with their critical importance. For this purpose, an emerging science developed rigorous and objective methods for the test of rhythmicity and superimposed trends and for the quantification of the characteristics (the chrones) of rhythms and trends, that constitute the chronome of a given physiological function or system. These procedures had to be applicable even when the data were not collected at regular intervals. The methodology served not only for the analysis of data but also proved to be of great value for optimizing the design of experiments. Human studies that involve thousands of people and cost hundreds of millions of U.S. dollars can now be preceded by a chronobiologic pilot investigation on a very few subjects, so that a large investment for the detection of rare effects is carried out at the right time rather than at a time when the effect may be altogether missed.
When the studies on blood eosinophil counts were repeated in mice kept under different experimental conditions such as different lighting regimens, Franz was again confronted with new sources of variability. In order to resolve this new problem, he decided to repeat the sampling on the same animals at different circadian stages in a longitudinal fashion, before and after the reversal of the temporal location of a regimen of light and darkness alternating at 12-hour intervals. He found that the timing of rhythms along the scale of 24 hours could be moved to any desirable location in time by manipulating the lighting regimen. This is how the role of the environment as a synchronizer became understood for variables such as the formation of ribonucleic acid (in liver), hormones in blood and the tolerance of potentially harmful stimuli impinging upon the body as a whole. Not only the timing of the alternation between light and darkness, but also meal timing could affect the timing of rhythms. The interactions among two or more synchronizers were clarified and social and ecologic synchronizers discovered.
The mechanism through which the alternation of light and darkness could affect rhythms was then sought. The study of blinded mice provided an answer and led to the discovery of the phenomenon of free-running. This finding in turn provided a key element to the development of chronobiology as a science sui generis. It meant that rhythms were not only an immediate response to the cyclic changes in the environment; they were not even learned in a given individual's lifetime, but they were an internal feature of organisms. The endogenicity of rhythms and their ubiquity rendered them a basic, fundamental property of life itself. These properties, first uncovered for the circadian system, were soon extended to other spectral components: the circasemiseptans, with a period of about 3.5 days; the circaseptans, with a period of about a week; the circatrigintans, with a period of about a month; the circannuals, with a period of about a year; and others.
The intermodulations among rhythms and their critical importance from an applied viewpoint as well led to the concept of the chronome, the set of multifrequency rhythms and trends with development, maturation and aging. In health, during most of adulthood, changes as a function of rhythms' stages can exceed by far changes as a function of age.
Some investigators have taken the view that rhythms are controlled by a master oscillator or pacemaker which they localize in the suprachiasmatic nuclei. Claims are made that all circadian rhythms are obliterated after bilateral suprachiasmatic enucleation. Early confirmed work by Franz had shown the critical role of the adrenal cortex in coordinating circadian rhythms in blood eosinophils, but not in serum iron. Evidence here gathered shows that some circadian rhythms can persist in one or the other system after removal of either of the suprachiasmatic nuclei (and even of the brain as a whole) or of both the adrenals. Neuroendocrine and peripheral systems intermodulate by means of feedsidewards, interactions among three or more a priori periodic entities. The modulation by the pineal or pituitary-adrenal interactions is a case in point. Periodically recurring sequences of stimulation, no-effect and inhibition by a modulator, such as the pineal, upon the interaction of an actor such as pituitary ACTH with a reactor such as the adrenal, are the results of such feedsidewards. These intermodulations occur at several frequencies, as documented for the circadian and the circaseptan ones, and play an important role in the coordination of rhythms within the organism. They coordinate the manifestation of all rhythmic behavior by the organism. Feedsidewards constitute the temporal matrix of life. Feedsidewards replace as concept and documented fact putative time-invariant feedbacks by the predictably time-variant interactions at several frequencies among a priori periodic features of the organism, Table 1.
This point of view leads to the proposition that there is merit in mapping the chronome as a way of quantifying health. To cite but one example, blood pressure or heart rate rhythms have been interpreted as a result of motor and other activity, meals, rest and/or sleep and emotions. All of these factors influence these variables but do not account for the persistence of their rhythmicity in bedrest or in weightlessness or for the fact that a blood pressure increase precedes rather than follows the daily increase of motor activity. The basic spontaneous preparation by neuroendocrine and cardiovascular activation in anticipation of daily activities must not be mistaken for a mere response to external stimuli. In this sense, certain blood pressure or other rhythm alterations resolved by the methods of chronobiometry can be interpreted as an elevation of the risk of developing one or the other civilization disease. Such blood pressure or other chronome disorder may occur within the currently "acceptable physiologic range" before disease becomes overt. There is hence an opportunity to intervene early and prophylactically in response to chronome alteration and the potential to reduce health care costs while improving the quality of care with emphasis on prevention by self-responsibility and self-help. Chronotherapy is then placed into the service of both primary and secondary prevention, while it is also useful for timing the treatment of overt disease. The following are some annotated illustrations of data underlying major concepts, facts and methods in the field of chronobiology.
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1. REALITY
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IMAGINARY
SET POINTS
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CHRONOMES: RHYTHMS, TRENDS, RESIDUALS | |
| 2.
VARIABILITY
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FOE
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FRIEND | |
| 3.
PHYSIOLOGIC RANGE
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BROAD,
RANDOM
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STRUCTURED,
PREDICTABLE (2) | |
| 4.
INACTION (left)/ ACTION (right) |
CONFOUNDER
ELIMINATION?? WISHFUL THINKING (3) |
RESOLUTION
INTO CHRONOMES OF THE "NORMAL RANGE" | |
| 5.
ENDPOINTS
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CASUAL
MEASUREMENTS MEAN +/- STANDARD ERROR (SE) STANDARD DEVIATION (SD) e.g., "THE" BLOOD PRESSURE (WITH >40% UNCERTAINTY IN DIAGNOSIS) |
TIME-SPECIFIED: . VALUES . AMPLITUDE(s) . SDS (E.G., . ACROPHASE(s) 6h, 24h) . WAVEFORM(s) . MESOR(s) . TRENDS . PERIODS . RESIDUALS | |
| 6.
SOURCES OF VARIATION
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EXOGENOUS:
RESPONSES TO EXTERNAL STIMULI
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EXOGENOUS
AND ENDOGENOUS: FOR ANTICIPATION AND PREPARATION | |
| 7.
HIERARCHY
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UP/DOWN
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COLLATERAL
(RECOGNITION OF RESPONSE RHYTHMS AND FEED-SIDEWARDS IN ADDITION TO SPONTANEOUS
RHYTHMS) | |
| 8.
TELEONOMY
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RIGHTING
AND REGULATION
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PREPARATORY
COORDINATION | |
| 9.
MECHANISM
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FEEDBACKS
ALONG AXES (UNSTRUCTURED MODULATION)
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FEEDSIDEWARDS
IN NETWORKS (PREDICTABLE CHRONOMODULATION) | |
| 10.
ANALOGY
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THERMOSTAT
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PENDULUM | |
| 11.
BIOLOGIC THEORY
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DARWINIAN
(EXTERNALLY ADAPTIVE) EVOLUTION
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INTERNALLY
INTEGRATIVE AND EXTERNALLY ADAPTIVE EVOLUTION | |
| 12.
HEALTH CARE
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OFTEN
LIMITED TO DIAGNOSIS OF OVERT DISEASE BY VALUES OUTSIDE PHYSIOLOGIC RANGE
PROMPTING, e.g., SUBSTITUTION TREATMENTS, EXCEPT FOR VACCINATION AND
GENERAL PRINCIPLES BASED ON GROUP RESULTS (DIET, EXERCISE)
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OPTIMIZATION
OF SUBSTITUTIONS, e.g., BY HORMONES OR DEVICES (PACEMAKERS) WITH DIAGNOSIS AND
TREATMENT REFINED BY NARROWED REFERENCE RANGE AND ASSESSMENT WITHIN THAT RANGE
OF CHRONORISK LEADING TO PREVENTION | |
| 13.
ANIMAL HUSBANDRY AND APICULTURE |
CONVENIENCE
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CHRONOME-BASED
TIMING
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| 14.
VALUE
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OFTEN
WASTEFUL
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INVARIABLY
COST-EFFECTIVE | |
| 15.
PERSONAL SATISFACTION
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FRUSTRATING
WORK WHEN (WITHOUT SPECIFICATION OF CHRONOBIOLOGIC TIMING, EVEN AT THE SAME
CLOCK-HOURS) ONE GETS CONFUSING AND/OR OBSCURING, EVEN OPPOSITE RESULTS FROM
THE SAME INTERVENTION
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SHEER
FUN WHEN LONG-STANDING CONTROVERSY IS RESOLVED BY ACCOUNTING FOR BOTH THE
GENETIC AND ENVIRONMENTAL BASES OF THE RHYTHMS THAT CONSTITUTE LIFE OR WHEN
DISEASE RISK DETECTION LEADS TO PREVENTION OF CATASTROPHIC DISEASE
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