Japanese Journal of Clinical Oncology 30:529-533 (2000)
© 2000 Foundation for Promotion of Cancer Research
The Temporal Organization of Life: the Impact of Multi-frequency Non-linear Biologic Time Structure Upon the Host–Cancer Balance
Director of Research and Professor, WJB Dorn Veterans Affairs Medical Center and University of South Carolina School of Medicine, Columbia, SC, USA
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ABSTRACT |
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 TOP ABSTRACT IDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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The current scientific paradigm, based upon an erroneous assumption of linear biologic reality and simple cause and effect relationships, has outlived its usefulness. In order to begin to turn the voluminous data the reductive process provides us with daily into meaningful understanding of life, it is essential to integrate these data within a complex, multi-frequency temporo-spatial framework. This rhythmic chronobiology more accurately depicts the life process, as well as its evolutionary and ongoing vital interaction with the pulsating cosmic resonance structure. Examples of the kinds of thinking and experiments necessary to exploit this new paradigm are provided.
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IDEAS ANCHORING BIO-MEDICAL SCIENCE |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Three novel ideas, each developed over more than a century, have served as the core and foundation for modern biomedical science and allopathic medicine since the mid-nineteenth century. Natural selection, genetics and the germ theory, in their broadest contexts, provide understanding of the method of the development of living systems, the underlying blueprint which is continuously modified during this endless process of development and ways of modulating these systems through molecular targeting of unseen, yet partially understood biochemical processes that regulate life. The first concept, natural selection, is the most beautiful and complete. It is by nature both temporal and spatial and deeply involves environmental (epigenetic) and genetic interrelationships. The other two ideas are essentially spatial, assuming, falsely, that the genetic blueprint and molecular targets are time invariant. Each of these ideas is thereby, incomplete.
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THE NON-LINEAR TIME STRUCTURE OF LIFE |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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A fourth idea has been emerging since 1960. This nascent idea describes the time structure of life, its chronobiology. Like natural selection, it is essentially both temporal and spatial and like natural selection, it is a fundamental description of the essential and continuous interaction between a resonating cosmic environment and the life, which evolves in time, within that resonating environment. The time structures relevant to natural selection are measured in eons. The time structures relevant to the temporal–spatial organization of life processes are measured in rhythms from microseconds in duration, to life cycle length and beyond. Rhythmic processes, such as calcium flux at the fast end and life span at the other end of this spectrum, serve as the envelope of biological rhythms relevant to the individual organisms. Lower frequency rhythms, some much lower, are also relevant to individuals as well as population dynamics and ecosystem development (e.g. solar storms 10–11 years duration and various global temperature cycles ~100–1000 years and beyond). Obviously the boundary between time structure relevant to the organism and populations and ecosystems is essentially artificial and overlapping. This leads the proponents of the idea of chronobiology to link it inextricably to natural selection. It may, in fact, be the same idea predominantly ‘in microcosm’.
Understanding life, in any meaningful sense, cannot exclude its time structure any more than evolution could be understood in the absence of an understanding of the time structure of cosmos and geos and their interactions. Despite this truism, genetics and therapy development have proceeded with virtually no thought to the nature of the temporal order of the life systems that are being therapeutically manipulated. The technical power of the tools used to describe the two- and three-dimensional patterns described by genomics and current therapy development paradigms belie the fundamental deficiency that these biological time invariant approaches carry with them. Cloning, combinatorial chemistry and high-throughput molecular targeting have yielded valuable reagents and therapeutic tools, in the absence of any understanding of the temporal organization of life. These successes do not, however, mean that a meaningful understanding of life can be achieved in the absence of tempero-spatial reintegration of biology.
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ADVANTAGES OF NON-LINEAR TEMPORAL ORGANIZATION |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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The nature of biologic time structure is non-linear and complex. Each biologic process is coordinated with every other such process through multiple interacting (multi-frequency) rhythms. The structure is a matrix of resonating inter-acting organismic and cellular pacemakers continuously timing and supporting one another to specific momentarily dominant frequencies. The rhythmic non-linear timing of systems optimizes frequency, amplitude and phase-modulated information transfer among systems and subsystems. The hierarchical matrix-based organization allows incapacitation or even destruction of one or many important organismic, cellular or molecular pacemakers without significant disruption of system time structure. The resonance structure can also, thereby, resuscitate damaged pacemakers or replace them entirely with little or no permanent system disruption. A linear system in which one or many central processes were damaged or destroyed would be much less stable than the biologic reality that has evolved to organize each living organism, population and ecosystem, in space and time.
A non-linear multi-frequency time structure has a second profound advantage over any linear system. As non-linear systems are timed and re-timed, different tasks can be accomplished by the self-same biological units (genes, proteins, organelles, cells, organisms, populations, ecosystems) at different times within these various cyles. A resonating biological system can throw all its effort into proliferation, metabolism, excretion, motility or other functions at different key times within this resonance structure, optimizing and organizing the multi-functionality essential to biological economy, which is likewise essential for life in the harsh environment colonized by life.
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CHRONOBIOLOGY’S COSMIC ROOTS AND ONGOING COSMIC TUNING |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Because of these advantages, living systems and, in fact, all living or non-living complex open systems are organized non-linearly. The prominent frequencies of this non-linear organization depend, to a large extent, upon the size of the components of the system. Small systems cycle rapidly (the electron around a proton of a hydrogen atom) while large systems resonate more slowly, the pulsating big bang/big crunch pattern, undoubtedly describing the time structure of the universe. The time structure of life is constantly reinforced, not only from within, but also from without. The frequencies of prominence in the temporal organization of most living organisms have been imprinted and are constantly reinforced by the pulsating environment. These include, among others, tidal rhythms of about half a day (circa hemidian), daily rhythms (circadian), lunar rhythms about monthly (circa triguitan), about seasonal rhythms (3 monthly), about annual rhythms (circannual) and life cycle rhythms (which differ by organism, but always include some variation upon gestation, infancy, childhood, adolescence, reproductive prime, adulthood, decline and death). All biologic processes are organized within each of these environmentally originated frequency ranges. Many, if not all, of the environmental pacemakers originally responsible for the development of genetic elements that keep time at those frequencies (half day, day, month, season, year) are still continuously available to set and reset the system and continuously reinforce these rhythmic time structures.
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CONSEQUENCES OF COMPLEX, NON-LINEAR TEMPORO-SPATIAL ORGANIZATION TO THE CONCEPT OF CAUSE AND EFFECT |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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The primal scientific drive to determine the causes of biological phenomena and the causes of disordering of biological process responsible for these phenomena is ingrained into a scientific method that has traditionally operated within a linear paradigm and employed reductionism as its primary tool. This reality has limited the kinds of questions asked and the systems used to ask them to those that lend themselves to the discovery of linear causality. Non-linear, complex associative causality, invisible to such questions and systems, is the causality truly relevant to living systems. The scientific method is equal to the task of discovery of real world causality. The linear paradigm still governing post-modern science denies the validity of pursuing and defining real multi-dimensional causal networks. In brief, cause and effect in complex resonating living systems is not a simple relationship. Hierarchies of interacting contributors form a multidimensional web. Cause and effect, in the ordinary sense, is usually an artifact of oversimplified in vitro experimental systems with illusory relevance to life. The more robust paradigm, described herein, will unleash the power of science to understand the complex causality that characterizes life (1).
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ESSENTIAL TASKS |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Only when the modern tools of biology are employed within the context of this biologic time structure will we have the opportunity to begin genuinely to understand life. How can cancer research begin to operate within this new paradigm and begin the daunting task of temporo-spatial biologic integration? A different kind of thinking and different kinds of experiments are essential.
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NEW THINKING |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Current science rests upon the tacit and spoken assumption that biologic systems are time invariate. The origin of this assumption seems to be an overly simplistic application of Walter Cannon’s elegant idea of homeostasis. Cannon’s general description never claimed or meant to claim time invariance, but this oversimplification is the practical twenty-first century reality. This assumption stipulates that an identical input to the living system is supposed to result in identical internal effects and output, regardless of when this input occurs. If the system does not behave identically, this is blamed upon ‘biologic variability’. The essence of the wrong-headedness of current thinking is fundamental misunderstanding of the nature (topology) of ‘biologic variability’. It is assumed to be stochastic and have the random qualities and amorphous shape of noise. No thinking scientist would deny the existence of this kind of variability within life. This kind of variability is, however, responsible for much less than the 100%, that current thinking presupposes. A large part of biologic variability is, in fact, ordered non-linearly. How much of this ordered variability is long-term predictable, rhythmic across many cosmically anchored frequency ranges and how much of it is short-term predictable, chaotic and how these predictable rhythmic and chaotic domains interact are the kinds of questions that must be answered before life can be meaningfully understood.
Examples are essential to bring such ideas down to earth. The balances among host and cancer represent a typical non-linear complex system. The institution of blunt and primitive anticancer therapies can cure or can cripple patients already damaged by the cancer. The administration of fixed drug regimens to the same individual at different times within biologic rhythms can be superbly tolerated or lethal depending upon their timing. We have identified predictable circadian, menstrual and seasonal temporal topologies that can explain and predict potentially lethal biologic variability.
The fundamental processes altered by cancer, such as DNA synthesis, cell proliferation and apoptosis, are organized rhythmically within circadian, reproductive and annual cycles, in both normal tissues and cancerous ones (2). A fixed dose of drug that attacks one of these rhythmically organized fundamental processes will have predictably different biological effects depending upon when in the cycle it is given (3). The bone marrow toxicity and/or gut toxicity of thymidylate synthase targeted drugs, such as 5-FU, FUDR, 5-FU/leuovorin, tomudex, capecytibine, S1, UFT and Ftorafur, are predictably 6–8-fold different depending upon when in these cycles the drug is given (4–6). The ability of these drugs to control cancer also depends, at least 2–4-fold, upon their timing within these cycles (7–9).
The adverse effects of surgical wounding upon metastatic cancer spread are, likewise, dependent upon when in the menstrual cycle a breast cancer resection is performed or when in the circadian cycle tumor cells are inoculated (10). Women resected in the early luteal phase of the menstrual cycle have a 25% greater chance of cure than women, with otherwise identical cancers, resected in their follicular phases of their cycles (11–13). The frequencies of all premalignant changes and frank cancer of the uterine cervical epithelium are more than twice as great in pap smears obtained in summer than other seasons. The meaning of what is on the glass slide and the likelihood of cervical precancer and cancer regression or progression depend, to a large extent, upon when in the annual cycle a smear is obtained and upon when, in the year, a follow-up pap smear is obtained (14).
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ENHANCING ANTICANCER AGENT SELECTIVITY |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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The essence of the anticancer drug discovery and development process is the search for selectivity. The century-long history of cancer therapeutics is the history of disappointment in a series of supposed ‘silver bullets’. The concept of metabolic selectivity for cancer was adopted completely and uncritically from the successful discovery of such selectivity for the treatment of a range of bacterial diseases. The metabolic processes of bacteria and human cells have diverged enough so that a wide range of metabolic targets can be selectively attacked. Such divergence is not a property of mammalian cancer cells. The narrow divergence of cancer cells which occurs largely within the life cycle of the organism rather than within millennia is responsible for subtle differences of degree of metabolic activities, only. There are, for example, subtle cancer specific differences in the rate of DNA synthesis, cell proliferation, apoptosis or the amount of adhesion, motility or hormone sensitivity of specific cancers. There is, however, no obvious common overriding difference to be exploited for cure or control of all cancers, at genetic or biochemical levels.
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DRUG DELIVERY SYSTEMS (DDS) AND CANCER SELECTIVITY |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Thinking of the cancer holistically rather than as an isolated string of molecular genetic abnormalities can be useful in uncovering meaningful strategies for selective anticancer therapy. Unique blood flow and blood vessel characteristics, for example, characterize the majority of primary and metastatic cancers (15). These physiologic abnormalities include increased tumor vessel tortuosity, increased vascular stickiness, increased tumor vessel permeability to large molecules (EPR effect named by Hiroshi Maeda), decreased physiologic controls of blood flow, the absence of lymphatic drainage of tumors and tumor deposits, decreased oxygen tension and pH within most cancers and a frequent shift to anaerobic metabolism within cancers (16). These cancer-associated physiologic abnormalities are being targeted by the development of drug delivery systems whose physical and/or chemical characteristics manage to take advantage of these cancer-associated physiologic changes (17). The development of liposomal polymeric, miceller, antibody-based and other tumor-targeted systems have incrementally enhanced anticancer drug selectivity mainly by diminishing anticancer drug toxicity, but more lately by also enhancing cancer cell cytotoxicity (18,19). The divorce of the spatial aspect of anticancer drug delivery selectivity from its temporal context is not rational, sensible or desirable. Each of the physiologic characteristics of cancer that DDS propose to take advantage of have profound and unique circadian organization. Katsuyoshi Hori has already shown elegantly how the circadian organization of cancer and normal tissue blood flow may be taken advantage of therapeutically (20–22) and differentially manipulated pharmacologically (23). In addition to the circadian organization of these physiologic parameters relevant to drug delivery, all of the molecular processes regulating cancer cell proliferation are likewise organized within circadian time (24,25).
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THE TEMPORAL CONTROL OF DRUG DELIVERY |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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In 1991, a New York Academy of Sciences meeting in New York City explored the temporal organization of biologic processes (26). At this meeting, the underlying logic and reasoning for the development of biological cycle (time)-based drug delivery systems was laid out for endocrine, cardiovascular, pulmonary, anti-inflammatory and anticancer therapeutics. The experts attending this meeting made the case for the inappropriateness of divorcing drug delivery systems from biological time. This meeting was followed several years later by the assembly of the specifications for temporal patterning of anticancer drug delivery. The small book Circadian Cancer Therapy lays out the physiologic basis for and the temporal specifications of, circadian timed cancer therapy (27). Since the 1991 NYAS meeting and the publication of Circadian Cancer Therapy, additional randomized clinical trial-based information has been published indicating that the attempt to consider selective drug delivery systems in the absence of their optimal circadian timing is not sensible and can be utterly self-defeating. The Japan–US Chronobiology Study Group will integrate DDS and these essential temporal concepts (28).
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ESSENTIAL CLINICAL EXPERIMENTS |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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In order, both, to help patients with serious diseases better and to understand life and disease better, we must continue basic/translational investigation of the time structure of fundamental biologic processes and therapeutic interventions. Studies supported by the US Department of Veterans Affairs, the US Army and the US NIH/National Cancer Institute will continue under our direction. EORTC, under the leadership of Francis Lévi, has instituted a growing number of such multi-center randomized controlled clinical chronotherapy trials throughout Europe. In Japan, a Japan–US chronotherapy study group, headquartered at Tokyo’s National Cancer Center Hospital, has been initiated under the leadership of Yasuhiro Matsumura. These Asian, American and European chronobiology study groups will continue to gather empirical data demonstrating how to use timing, within biological cycles, to better understand and control human cancer. These groups will, at the same time, continue to add to the growing weight of evidence against the current linear biologic thinking.
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KEY EXPERIMENTS/CLOCK GENES AND CANCER |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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The essence of cancer includes loss of temporal control of fundamental biologic processes and physical translocation of cells (metastasis). Transformation invariably includes abnormality of the proliferation–apoptosis balance. It is impossible to imagine such an imbalance other than in terms of abnormal timing of one or both processes. The logic of this truism requires that abnormality of time keeping is an essential requirement for carcinogenesis. At least one of the many timing genes, i.e. clock and clock control genes, identified and cloned in the past decade must be abnormal or abnormally regulated in virtually all cancers. Experiments to document this logical necessity have not been initiated, to date.
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GENE EXPRESSION WITHIN BIOLOGICAL RHYTHMS |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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The complex, multi-frequency interactive balance between host and cancer is known to participate powerfully in biological rhythms. The difference between death and cure resides predictably within this time structure. For a decade it has been clear that study of the patterns of gene expression in host tissues and tumors across circadian and menstrual cycles are absolutely essential to understanding how the host–cancer balance and drug targets are organized in time and for learning how to use this understanding to cure more patients with cancer. Despite the best efforts of some of us, no such experiments have been initiated, nor are they planned.
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SUMMARY |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Time has run out for the idea that biologic variability is amorphous and, thereby, unpredictable. Learning the shape, in time, of all relevant aspects of biologic variability will allow us to understand life and cancer better and at the same time enhance the efficacy while concurrently diminishing the toxicities of all current and future cancer therapies. With this publication we launch a Japan–US commitment to these ideas.
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Acknowledgments |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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This work was supported in part by DVA Merit Grant 8358-0017, NCI R01CA 31635 Grant, US Army Idea Grant DAMD17-98-1-8016, New York State Breast Cancer Research Award, Robison Family Foundation Grants and Foundation for Promotion of Cancer Research Grant (Japan), each to the author.
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FOOTNOTES |
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+ For reprints and all correspondence: William J. M. Hrushesky, WJB Dorn VAMC, 6439 Garners Ferry Road, Columbia, SC 29209, USA. E-mail: William.Hrushesky@med.va.gov
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REFERENCES |
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TOPABSTRACTIDEAS ANCHORING BIO-MEDICAL...THE NON-LINEAR TIME STRUCTURE...ADVANTAGES OF NON-LINEAR...CHRONOBIOLOGY’S COSMIC...CONSEQUENCES OF COMPLEX, NON...ESSENTIAL TASKSNEW THINKINGENHANCING ANTICANCER AGENT...DRUG DELIVERY SYSTEMS (DDS)...THE TEMPORAL CONTROL OF...ESSENTIAL CLINICAL EXPERIMENTSKEY EXPERIMENTS/CLOCK GENES AND...GENE EXPRESSION WITHIN...SUMMARYAcknowledgmentsREFERENCES |
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Received July 31, 2000; accepted September 22, 2000.
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