Chronomics and chronobiology in health and disease

Abstract

Chronobiology is a branch of science that objectively explores and quantifies mechanisms of biological time structure including important rhythmic manifestations of life right from molecular level of living being, from unicellular organism to complex organism such as human being. Genetics eventually leads to genomics, concurrently the study of biological variability i.e. chronobiology leads to chronomics. GENETICS, the study of biological diversity in space CHRONOBIOLOGY, the study of biological diversity in time GENOMICS, the mapping of biological diversity in space i.e. of genomes in us CHRONOMICS, the mapping of biological diversity in time, i.e. of chronomes (from chronos, time and monos, rule ) – time structure of each pertinent variable in and around us, near and far. Chronobiology, the study of mechanisms underlying diversity in time and chronomics, the mapping of chronomes – time structures, could complement genetics. It is the study of mechanisms underlying diversity in space and also genomics, the mapping of genomes. Chronobiology allows us to approach risks, diagnosis and treatment dependent on appointment time, especially of the dynamics of time, gender, age, ethnicity and geographical location. Chronobiologic reality consists of a multifrequency spectrum of rhythms. Homeostasis, probably, needs to be replaced by an approach such as chronobiology that considers predictable variability within the physiologic range. Chronobiology hence renders predictable and exploits what otherwise is considered as exclusively random variation. Chronomics is chronophysiological genomics, not based upon the concept of the genes underlying the true blood pressure

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Indian Journal of Clinical Biochemistry, 2009 / 24 (4) 319-323
EDITORIAL
CHRONOMICS AND CHRONOBIOLOGY IN HEALTH AND DISEASE
R K Singh*
Biochemistry Department, Chhatrapati Shahuji Maharaj Medical University ( Formerly King George’s Medical University,
Lucknow- 226003, India.
Address for Correspondence :
Prof. R K Singh
Biochemistry Department,
Chhatrapati Shahuji Maharaj Medical University (Formerly King
George’s Medical University ), Lucknow-226003.
E-mail: singhrk23a@hotmail.com; raj_singh509@yahoo.com
Chronobiology is a branch of science that objectively explores
and quantifies mechanisms of biological time structure
including important rhythmic manifestations of life right from
molecular level of living being, from unicellular organism to
complex organism such as human being. Genetics eventually
leads to genomics, concurrently the study of biological
variability i.e. chronobiology leads to chronomics.
GENETICS, the study of biological diversity in space
CHRONOBIOLOGY, the study of biological diversity in time
GENOMICS, the mapping of biological diversity in space i.e.
of genomes in us
CHRONOMICS, the mapping of biological diversity in time,
i.e. of chronomes (from chronos, time and monos, rule ) –
time structure of each pertinent variable in and around us,
near and far.
Chronobiology, the study of mechanisms underlying diversity
in time and chronomics, the mapping of chronomes – time
structures, could complement genetics. It is the study of
mechanisms underlying diversity in space and also genomics,
the mapping of genomes. Chronobiology allows us to approach
risks, diagnosis and treatment dependent on appointment time,
especially of the dynamics of time, gender, age, ethnicity and
geographical location. Chronobiologic reality consists of a
multifrequency spectrum of rhythms. Homeostasis, probably,
needs to be replaced by an approach such as chronobiology
that considers predictable variability within the physiologic
range. Chronobiology hence renders predictable and exploits
what otherwise is considered as exclusively random variation.
Chronomics is chronophysiological genomics, not based upon
the concept of the genes underlying the true blood pressure
Fig 1: Variation within the physiological range can be resolved into
meaningful information, including rhythms with frequencies
covering 10 orders of magnitude, far beyond the circadian system
and seasonal changes. Non-photic as well as photic influences of
the sun have been genetically preserved in a set of photo- and
magneto- periodicities from which much can be learned. © Halberg
or the true heart rate, but replacing the historically useful
homeostatic truisms by the dynamics end points of a variable
in the biosphere and/or in its cosmos (Fig 1). Apart from
providing a better understanding of the universe, common to
both nuclear physics and chronobiology, perhaps one of the
most challenging applications of chronobiology is that of
improving the quality of health care of individuals, societies
and environments while so reducing its cost by focusing on
detecting and treating risk to prevent overt diseases again of
societies, such as homicide and war, and of individuals, such
as severe vascular disease or cancer. For such aims,
chronomics offers the opportunity to refine the definition and
assessment of health and broader normalicy positively and
individually, rather than quantifying disease as a deviation from
normalcy, negatively as the absence of disease and only for
populations, as percent morbidity and mortality. Early time
structure alternation indicates earlier risk elevation. Herein,
we try to note the cost-effectiveness of using a database of
vascular chronomes for severe disease prevention.
Chronomics specifically resolves risks of stroke and other
severe incapacitating diseases, higher than the risk associated
with hypertension and other oncological and psychiatric
disease risks.
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Indian Journal of Clinical Biochemistry, 2009 / 24 (4)
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The rhythmic structure of living organisms is partly
endogenous, genetically programmed and thus differentially
and rhythmically responsive to environmental cycles. From
the medical viewpoint, a deviation from the physiologic range
serves mainly to diagnose overt disease. Chronobiologic
considerations, in turn, aim at chronorisk assessment by
values that may lie well within the physiological range as a
step toward prevention (1). Body rhythms have been shown
to affect not only daily, weekly, monthly and yearly functions,
but also the prevalence of disease symptoms, medical test
results and even the way the body responds to drug therapies.
Ecclesiastes 3: 1-8 insists that for everything there is a season
and a time for every matter under heaven. A time to be born
and a time to die; a time to heal and a time to breakdown, and
a time to build up; a time to plant and a time to pluck up what
is planted. God has made everything beautiful in its time.
Present day chronobiologists began discovering conditions
for which there would indeed be a best time to give
medications, to make organ transplants, for malnourished to
eat, for surgeons to operate and so on. The occurrence of
disease is not a random process; rather there is a biological
time structure to it. Timing can be manipulated in much the
same way as dosing. Chronobiology offers new concepts that
can be applied for making recommendations as to when to
sample and when to treat. Some of these concepts can be
incorporated into today’s clinical practice without the need to
make major adjustments to the actual clinical procedures in
use such as the timed use of corticosteroids, oncostatics,
cyclosporine or antihypertensives and a long list of other drugs
(2-5).
Professor Franz Halberg has dedicated almost 60 years of
his active and productive life to chronobiological research;
who is known as the Father of Chronobiology. His long lasting
basic scientific work is directed, at the beginning of the new
century, to chronobiometry ( physiological and statistical
evaluation of the genetically anchored and cosmically
influenced time structures ), chronobioengineering ( collecting
physiological data by means of sophisticated equipments ),
chronobiological diagnosis of disease risk syndromes the
chronotherapy, improvement of prognosis, treatment in
different fields of medicine and last but not the least,
chronoastrobiology focusing on rhythms and broader
chronomes to explore the origins of life (6,7). It has been
understood for centuries that the movements of the earth in
relation to the sun produce seasonal and daily cycles in light
energy and that these have had profound effects on the
evolution of life. It is now emerging that rhythmic events
generated from within the sun itself, as a large turbulent
magnet in its own right, can have direct effects upon life on
earth. Moreover, comparative studies of diverse species
indicate that there have also been ancient evolutionary effects
shaping the endogenous chronomic physiological
characteristics of life. Thus the rhythms of the sun can affect
us not only directly, but also indirectly through the chronomic
patterns that solar magnetic rhythms have created within our
physiology in the remote past. According to Prof Halberg,
biological rhythms can redefine diagnosis and therapy (3). We
feel deeply honored to have had the support, cooperation and
supervision of Prof. Halberg since 1977 in carrying out our
chronobiological research. We published our first paper on
circadian rhythms ( the term coined by Prof Franz Halberg in
1959 ) of plasma 17-OHCS in different conditions in rabbits
with late Prof. K N Udupa, my mentor and teacher (8). Prof
Halberg visited our world famous, the then, Surgical Research
Laboratory of the Institute of Medical Sciences, Banaras Hindu
University in 1977 and appreciated our work and included it
for presentation during XIII International Conference of
International Society for Chronobiology in Pavia (Italia) from
4-7 September 1977 and his visit to India became instrumental
in formation/activation of our Indian Society for Chronobiology.
In the year 2003, he came to Lucknow again on my personal
invitation to inaugurate International Conference on Free
Radicals and Antioxidants in Health and Disease. In the last
10 years, the cooperation between Chhatrapati Shahuji
Maharaj Medical University (Formerly King George’s Medical
University), Lucknow and University of Minnesota, USA has
been intensive and activated our participation and inclusion
to the international project BIOCOS.
The international project on the BIOsphere and the COSmos
originated on June 30, 1997, when the Russian Academy of
Medical Sciences convened a special session at its
headquarters in Moscow to discuss and at the end of this
meeting to unanimously endorse a project on “ The BIOsphere
and the COSmos ’’ (BIOCOS). We in a worldwide project
BIOCOS, are measuring blood chemistry and looking for
repetitive and to that extent predictable changes that would
allow time treatment known as chronotherapy. This approach
by chronomics detects diagnostically the elevation of disease
risk before there is actual disease. We call it preventive
PREhabilitation to save the need for rehabilitation. The
chronome of different biochemical variables including lipid
peroxidation and anti-oxidant defense mechanisms may relate
to the efficacy and management of preventive and curative
chronotherapy. We have studied in detail the chronomics of
different physiological variables in health and disease under
tropical conditions (9-20; Fig 2a,b,c) and have demonstrated
apparently for the first time, two important findings that-

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1. the patients with gynecological malignancies, cirrhosis
of liver, gastric ulcer and carcinoma of breast had
statistically significant rhythms of studied variables, and
2. the characteristics of these rhythms were altered with
statistical significance in such patients.
Chronomes of putative anti-and pro-oxidants should be
mapped to explore their putative chronotherapeutic role as
markers in cancer chronoprevention and management of
established disease. Marker rhythm- guided individualized
chronotherapy using cancer markers for the desired effect and
host markers for the side effects remains in goal that has to
be rendered cost effective (Fig 3). We are resuming marker
rhythm guided cancer chronotherapy with kind cooperation of
Prof M C Pant and Prof. M L B Bhatt in Lucknow with University
of Minnesota, USA (21). Furthermore, we are studying the
chronomics of 7-day/24-hour BP/HR monitoring in health and
disease in our population. We measure BP/HR not only once
and not only around the clock for 24-hours, but at half hourly
intervals for 7-days. Moreover, we analyze not the fiction of a
“true blood pressure’’, but the chronome of this variable as it
is much better and much cheaper to prevent stroke even when
it involves an efficient chronobiologically interpreted 7-day/
24-hour blood pressure and heart rate monitoring.
Overswinging or CHAT (Circadian Hyper Amplitude Tension),
that is an excessive circadian variation in blood pressure (BP),
has been associated with a large increase in cardiovascular
disease risk present even in the absence of an elevated BP
itself. This usually asymptomatic condition is usually
overlooked by current practice based on spot-checks, because
to be diagnosed, measurements need to be taken around the
clock, preferably for 7-days at the outset. Once diagnosed,
however, a usual circadian BP pattern can be restored by
means of certain non-pharmacologic or pharmacologic
interventions timed appropriately. Thereby, it is possible to
reduce the risk of cardiovascular morbidity and mortality,
cerebral ischemic events and nephropathy in particular. A
number of vascular variability disorders (VVDs) could be
detected and corrected by chronobiologically analyzing
ambulatory blood pressure monitoring records ( 22-24 ).
The role of chronomics within the context of non-
communicable diseases and mental health is mostly studied
in cardiovascular variables but not limited only to the
cardiovascular system. The same methodology remains
applicable to a wide range of problems. Cancer prevention
and optimization by the scheduling of treatment administration
is another important problem. But the main focus of BIOCOS
in health promotion upon the circulation by prehabilitation is
to reduce the cost of rehabilitation by education of use of
chronobiology (Fig 4). Thorough lifelong maps of chronomes
should be generated and made available to the scientific world.
Chronomic cartography from birth to death is a governmental
task to implement, thereby serving the interests of
Fig 2 (a): MESOR map in gynecological malignancy vs health,
showing increase of circulating malondialdehyde, one aspect
desired from a putative unspecific cancer marker
Fig 2 (b): Amplitude-map in gynecological malignancy vs health,
showing non-zero circadian amplitude for malondialdehyde, an
aspect desired from a putative cancer marker, also shown by other
variables investigated in the human circulation
Fig 2 (c): Circadian timing of several studied variables with their
95% confidence limits in the human circulation in gynecological
malignancy vs health
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Indian Journal of Clinical Biochemistry, 2009 / 24 (4)
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transdisciplinary science and general public alike for the
betterment of the suffering humanity.
*Author is a member of Editorial board, IJCB and this editorial is his
tribute to Father of Chronobiology: Prof. Dr. Franz Halberg.
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Fig 3: Principles of chronoradiotherapy (top), evolved first to lower toxicity based on the discovery of susceptibility-resistance rhythms to
a variety of stimuli; eventually, we aimed for the timing of best therapeutic efficiency, goals pursued in the laboratory first, to be followed by
clinical studies of chronoradiotherapy, wherein oncostatic efficiency gained major focus. The final goal is the best temporal compromise
between effectiveness and tolerance, as shown abstractly at the top of this figure on the right. At the bottom on the left, toxicity studies
summarize a susceptibility rhythm to adriamycin with its uncertainty; in the middle, clinical studies with timing by peak tumor temperature
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cancer marker rhythms is implied at the bottom on the right. © Halberg
Fig 4: By the early detection of disease risk syndromes in the
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instituted. Such pre-habilitation in health can also complement
rehabilitation in disease. As a major goal of health care, pre-
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Chronomics and Chronobiology