Self-organized
system time:
An interdisciplinary discussion of the modelling of living
systems based on internal rhythms
(in German: Selbstorganisierte Systemzeiten: Ein interdisziplinärer
Diskurs zur Modellierung lebender Systeme auf der Grundlage
interner Rhythmen)
Deppert
W, Köther K, Kralemann B, Lattmann C, Martens N, Schaefer
J, eds, Leipziger Universitätsverlag, 2002, 393 pp.
Franz Halberg, Germaine Cornelissen, Othild
Schwartzkopff & Earl E. Bakken
Halberg Chronobiology Center, University of Minnesota, Minneapolis,
MN, USA.
Submitted:
June 6, 2002
Accepted: June 7, 2002
The major proposition of a forthcoming
series of contributions will be that the problems of our society
can only be solved by science. Volume 1, reviewed herein, implies,
by reference (in its very title) to internal rhythms, that chronobiology
is the way to do it. Many chronobiologists will agree. As the
book proposes, we need to clarify physiological processes as
mechanisms of life, from molecular to social, according to temporal
measures that (we add MAY) differ from physical time. These
time scales of internal periodic processes are described as
system time, more strictly than was done earlier by the philosopher
Herbert Hörz [1], who has the merit of
considering time horizons as well as system times. The book
discusses system time in terms of a class of PEP, defined as
a class of Periodic Equivalent Processes. According to the book,
system time is the quantification ("metering") of
time, which is carried out with the aid of a PEP class.
"Since
all living organisms possess for their survival their own temporal
organization, it follows that the temporal tuning of internal
processes in organisms can be called an intrinsic metering,
which exists without metering from the outside or by humans.
In this sense (perhaps of an internal quantification), the book's
system times are intrinsic." (Our free translation.)
A glossary, which should be read first, defines as an example
of intrinsic times, the "expression, for instance, of various
(about 24-hour) circadian rhythms, documented in all life and
in subsystems down to 'subcellular processes'".
The book recognizes in the foregoing the ubiquity and critical
importance of circadians; it explicitly deals with chronobiology,
defined as the "science of body functions" in relation
to their characteristics, that undergo, for example, a circadian
rhythm, citing a general lexicon [2]. In keeping
with the original source [3], a "Citation
Classic" of Current Contents, or a glossary in the field
[4], rhythms are viewed as intrinsic metering,
albeit the PEP approach in the book seems to restrict, perhaps
inadvertently and certainly unnecessarily, system time to that
of free-running circadian or other rhythms.
Free-running
(5; cf. 6) is not found in the book's glossary; but desynchronization
disease is included, with the proper qualification that a desynchronized
state need not be harmful. Figure 7-I-A in reference 6 on our
website (http://www.msi.umn.edu/~halberg/) shows the desynchronization
of a circadian rhythm in rectal temperature in eyeless mice,
both time-macroscopically, by eyeballing, and time-microscopically,
by time series analysis (7-I-B-D). Control mice with eyes are
seen to exhibit a regular 24-h synchronized rhythm; peaks of
the rectal temperature in these controls, subjected to a sham-operation,
and kept like the eyeless mice in light and darkness alternating
at 12-hour intervals, coincide precisely with the straight vertical
line at 8:30 pm, with only a few slight exceptions (that also
hover around the vertical line on days 3-5, 35 and 49 in Figure
7-I-A in reference 6). By contrast, peaks of rectal temperature
in eyeless mice already by the second week and thereafter occurred
clearly earlier and earlier, until they were in antiphase with
the curve of blind mice by day 22 [6]. The
same figure in [6] shows a chronobiologic serial
section (IB), thereby assessing, with its uncertainty, an advancing
phase in the eyeless mice, by comparison to a much more stable
phase in sham-operated controls, both documented in a replication
10 years later, again with their overlapping uncertainties.
The
system time for each group is now in the phase domain (IB),
only to be transferred next into the period domain, as a result
of periodogram analyses of data from control and eyeless mice
(Figure 7-I-C in reference 6, 7). The periods of controls hover
within 0.05 hours around 24 hours, whereas the periods of eyeless
animals are all different from those of controls, averaging
23.4 hours, differing further from each other much more than
do controls, a feature to be kept in mind in doing group studies.
Figure 7-I-D in reference 6 shows the timing of circadians in
serum corticosterone and liver glycogen, referred to the circadian
peak in temperature, on the left for mice, again in the phase
domain. The length of the period, whether synchronized (top)
or desynchronized (bottom), is equated to 360°. One can
thus pool data from different individuals, whatever the particular
frequency of their rhythm may be, and map internal murine timing,
as shown in Figure 7-I-D of reference 6, comparing time relations
in the externally synchronized and externally (but not internally)
desynchronized groups examined in the phase domain. Therein
the period, whatever it may be, is equated to 360°. Figure
7-I-D in ref. 6 compares the circadian system times in both
a synchronized (top) and a desynchronized (bottom) state in
a woman (right) with that in mice (left).
In
the case of studies on circadians in the laboratory, one has
a choice, among others, between synchronization by lighting
and/or other entraining agents or synchronizers generally (or
Uhrzeitgebers in the case of circadians or Kalenderzeitgebers
in the case of circannual rhythms). It seems important to remember
that by definition, external synchronizers [3]
do not "give" body time, but only synchronize internal
time with an external (usually cyclic) agent. Chronobiologists,
more often than not, determine internal phase relations at an
externally impressed frequency, as an alternative to choosing
a free-running condition, as in continuous darkness or continuous
light or after loss of a primary transducer of the synchronizer
effect, such as the eyes, with all other conditions kept the
same as much as possible. The synchronized state can be achieved
by manipulating lighting alone or by double synchronization
with light and feeding time [8]. Thereby, the
extent of change (double amplitude) of circadian rhythms can
be greatly amplified but their internal phase relations are
largely maintained when food is available, e.g., to rodents,
only early in the daily dark span [8].
When two synchronizers compete, e.g., food is available only
in the daily light span, some rhythms may be advanced, such
as that in corneal mitosis, whereas others are delayed, such
as those in corticosterone and temperature and internal phase
(read: system) relations are drastically different, as is survival
time (references in 8). On a restricted diet, the availability
of food can override the effect of a lighting cycle for certain
variables [3]. The internal endocrine time
structure of humans who eat a single daily meal as breakfast
("breakfast-only"), as compared to those on "dinner-only",
is drastically different. A shift in meal timing, while the
daily routine is unchanged with respect to other conditions,
moves the adrenal cycle, gauged by circulating cortisol, but
little, while the temporal location along the 24-hour scale
of circadians in glucagon and insulin in blood are changed very
much.
In
our hands, the mapping of human free-running in isolation from
society covered up to 267 days, while that of routine synchronized
mapping now extends up to 35 years. Moreover, under presumed
free-running conditions, a commonality of external and internal
periods, a PEP extended beyond the organism (willy-nilly, each
organism is an OPEN system) among physiological and environmental
variables points to the need to examine putative causal internal-external
interactions [9, 10, 11,
12].
The
philosophical discussion recapitulates a few – perhaps
too few – of the concerns in the development that led to
chronobiology from the early 1950s [13, 14,
15] to 1969 [3, 4,
5, 6]. The genetic basis [13],
ubiquity and mechanisms [14] and critical
importance [15] of rhythms, described earlier
by Fessard [16] as the basis of life (cf.
17), are neither documented nor mentioned. Different periods
and putatively underlying mechanisms were then (in the 1950s)
sought for different variables in different physiological entities,
as illustrated in the book reviewed herein for the heart and
circadian systems. The adrenal cortex was found to be a first
systemic mechanism for some [14], but not
all circadians [3, 4, 5,
6], that naturally led to the pituitary, hypothalamus
and pineal, on the one hand and to basic cell cycles in RNA
and DNA formation, on the other hand [18].
As longitudinal data accumulated over the past half-century,
it became clear not only that periods ranging from circadian
to circannual can be found in the same variable, as in 17-ketosteroids
[3], but also, as is the case in the heartbeat,
that a much broader spectrum of intermodulating cycles can range
from 1 second over 1 day to a 10-year periodicity in the same
person [19].
For
these reviewers, system time is the abscissa of time that covers
calendar and/or any physiological or other event-related time
from the first sample and/or the first pertinent event (such
as the onset of menstruation) to be investigated to the last
sample and/or the last pertinent event in a sequence. Any scientific
endeavor involving sampling for measurements can be planned
in the light of a time horizon [1], that summarizes,
as a chronome (from chronos = time and nomos = rule), all pertinent
prior information, with the uncertainties involved (3; cf. 1).
System time includes "rubbery time", i.e., transformations
of calendar time to a given marker time, such as the spans elapsed
between two consecutive onsets of menstruation, that each are
equated, e.g., to 360°.
Physiologist Thomas Kenner of Graz, Austria, an active discussant
in the book, has rightly described rhythms elsewhere as a feature
of everyday physiology [20]. In this context,
among others, two papers in the book's bibliography are of particular
interest, both first authored by Max Moser and last authored
again by Thomas Kenner [21, 22].
These deal with heart rate variability as a prognostic tool
in cardiology, "as a contribution to the problem from a
theoretical viewpoint". In practice as well, focus on heart
rate variability, the topic of these papers, resolves risk conditions
occurring within the otherwise neglected normal range of physiological
variability. Both an over-threshold variability (above the upper
95% prediction limit) of blood pressure, as compared to a reference
standard from healthy peers of the same gender and age, and
an under-threshold (below the lower 5% prediction limit) heart
rate variability, within the system time (of sampling) of a
week of monitoring has taught us useful lessons, yet to be tested
for use in the prevention of incapacitating disease [23,
24].
The
book considers chaos referring to teams working on nonlinear
dynamics in Potsdam and Garching, Germany, and reports on a
complexity analysis in searching for early signs of sudden cardiac
death [25]. A discussion of periodic equivalence
requires inferential statistics and the "remove-and-replace"
method, time-honored in endocrinology and applied to rhythms
[14, 26, 27].
With such qualifications we need marker rhythm statistics to
treat the cancer patient by the best compromise between cancer
system time (the best one to kill the cancer), and host system
time, to avoid the treatment's toxicity [28]
and possibly to prevent the malignancy in the first place. We
need system times along the scales of the week and year as well
as the day for immunotherapy. Vastly different cycles intermodulate
with each other to account for the difference of whether the
same total weekly dose of the drug lentinan stimulates or inhibits
a malignancy (Fig. 8-V in ref. 6).
Among
contributors to mostly discussions of presentations, four were
from philosophy, four from physics (including a physicist-philosopher);
they are joined by seven representatives of medicine (one of
them also a philosopher), one psychologist and one biologist,
at diverse stages of their careers. The book's transdisciplinary
nature, helping to tear down disciplinary barriers [29],
is its final merit. This book is warmly recommended to readers
fluent in German: it approaches an eminently transdisciplinary
problem in an interdisciplinary discussion; it recognizes beyond
narrow specialty barriers the ubiquity and indispensability
of critical chronobiological system times and horizons. Because
of their documented importance, system times and time horizons
need consideration by everybody in and beyond science.
This
review, focusing on a critical transdisciplinary field long
neglected both in physics [30] and in biomedicine,
is dedicated, with love on her birthday, June 28, to Francine
HALBERG. This radiation oncologist participated in the planning
of cancer chronotherapy as a high school student [28],
with her mother Erna, who made many altruistic contributions
to oncochronotherapy that, in the opinion of the founder of
the specialty of clinical oncology in the USA [31],
benefitted her as well. The broader challenge of treating at
times of pertinence vs. those of convenience remains in oncology
and much more broadly, in keeping with the scope of the book
reviewed herein and the broader series to follow.
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