, For Planetary Governance

Chronotherapy: Unlocking the Interrelation of Viruses and Circadian Clocks

Author: Dustin Breitling

Instead of a biopolitics that dismisses time as a means of discipline and control, the pandemic has spurred new research into the coevolution of humans and pathogens united by the circadian cycles that govern their effects. Better understanding the chronobiological mechanisms of control, infection, replication, and survival is a step towards a positive biopolitics for the pandemic age.

Colorized scanning electron micrograph of an apoptotic cell (blue) infected with SARS-COV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Image courtesy of NIAID

Within two months of the world being plunged into fear and terror over a novel strand of coronavirus, Anthony Fauci, the director of the US National Institute of Allergy and Infectious Diseases and the chief medical advisor to the president, made the astute observation that “we are on the virus’s time.” Here Fauci acknowledged an important point about what stays within our ability to control when a non-human force keeps us guessing about its intervals of infection, life cycle, and onset of symptoms.

Living in what seems like an interminable cycle of update-app-news-cases-deaths that ramps up anxiety, stress, job losses, and financial instability, we feel how our bodies and their most basic cycle, the circadian rhythm, has been thrown out of order. It has reminded us that even as the minutes, hours, days, and nights blur, our bodies are still intimately tied to an ancient habituating loop that extends throughout the animal kingdom.

This “habituating circuit” consists of “biological clocks” or “circadian clocks” whereby every tissue and organ in your body operates according to endogenous and exogenous rhythms. These clocks direct our bodily metabolism, ensuring our bodies run according to schedule, regulated by the timing of processes like eating, sleeping, and body temperature. It is these very clocks that compel us to consider the interplay between our bodily timers and the schedules of invaders.

 

The Fine-Grained Precision of Viral Time

Emerging research reveals that our circadian rhythm is vital for the replication of pathogens. The effectiveness of infection or immune response is subject to the particular minutes, hours, and times of day that work either to the advantage of the host or pathogen. A study carried out at the University of Cambridge in 2016 demonstrated the injection of herpes viruses into wild-type mice timed during different phases of the animals’ circadian clocks. The research showed that viral replication was ten times higher in mice infected at the start of their resting phase, or what for us humans would be our late evenings.

Similar observations have highlighted the link between the time of day when infection with respiratory and influenza viruses takes place and the progression of the illness. Moreover, emerging studies and data now suggest that the multiplication and replication of SARS-CoV-2 in human monocytes—the white blood cells tasked with fighting infection—also fluctuate according to the time of day.

With this more fine-grained resolution of understanding we see our bodies as composites of companions or collaborators, announcing our entrance into what philosopher Tobias Rees has characterized as the “Microbiocene.” Rees points to how organisms emerged from bacteria with viruses inserted into their genomes, a process at the origin of many immune systems. The ongoing mapping of our genetic makeup estimates around 8 percent of our genome is intimately linked with viruses.

Viruses were formative throughout the mammal kingdom: a symbiotic retrovirus enabled the emergence of a placenta over many generations and a key protein has proven critical for memory formation. Retroviruses are notable for reverse-engineering themselves into the genome of DNA in order to enable their replication through the genetic line and ensure they become a part of our evolutionary course.

Host and pathogen dynamics are based on the strategies and entanglements that emerge from hijacking and countering adverse effects. Yet a host does not merely play puppet to pathogens or parasites. The way the host produces strategies for counteracting infection makes artifacts of our internal organs, crafted to combat the ceaseless threat of manipulative pathogens or parasites. We are palimpsests of disease. Yet viruses and parasites are companions in evolutionary innovation that unlock new means of adapting to our world and open up new pathways for our development as a species. Fundamentally, evolution unfolds at the crossroads where external rhythms and internal biology meet.

Taking Fauci’s claim that we are on the virus’s time compels us to not only acknowledge the perilous yet fascinating course of evolution, but to better grasp the methods by which parasites, viruses, and bacteria enhance their chances of survival and assert control of their hosts. For viruses, the ability to change the biological processes of infected cells to ensure their replication and spread to various tissues is decisive. Stressing how our immune systems and their success against different pathogens is deeply time-dependent.

Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine. Image courtesy of NIAID

 

A History of Circadian Clocks

The development of knowledge concerning circadian clocks can be traced to the work of Jean Jacques d’Ortuous de Mairan, an eighteenth-century French scientist who observed the daily patterns of Mimosa pudica plants. De Marian observed the opening and closing of their leaves as they alternated during cycles of light and dark. He put his plants in constant darkness and monitored them, noticing that despite the lack of sunlight the leaves would still open and close, operating to the cadence of an internal clock. The machinery of the circadian clock was further uncovered through experiments with fruit flies, yet it was not until the twentieth century that the exact location of the circadian clock was found in humans. The suprachiasmatic nucleus is the master clock of the brain, known for regulating our sleep-wake cycles and consisting of over 20,000 neurons, housed behind our hypothalamus. The suprachiasmatic nucleus sends signals throughout the body and brain that are crucial in controlling daily changes in blood pressure, temperature, level of activity, and alertness, and also provides a signal so the pineal gland knows when to unleash the melatonin that helps induce sleep.

It is understood that circadian clocks in humans and non-humans evolved in tandem with the geological history of the earth, and have been fine-tuned by selection pressures imposed by cyclic factors in the environment. Circadian rhythms are hypothesized to have been essential for organisms to anticipate changes in environmental oxygen levels driven by photosynthetic bacteria and the solar cycle. Moreover, for humans, the autonomous circadian rhythm spans roughly twenty-four hours in length and ought to be synchronized to the daily rotational cycle of the earth.

Approximately 10 percent of the human genome is controlled by the circadian clock. Further, molecular evidence has emerged to show that the adaptive immune system is also under circadian control and that it is programmed to external cues linked directly to light as well as several other environmental signals such as temperature and feeding cycles. Yet circadian clocks are not only based in the brain. The discovery of “peripheral clocks” in various organs tissues throughout the body such as the liver, skin, lungs, and kidneys has reshaped the landscape for thinking about different parts of the body operating according to replication cycles. This underlines that when circadian clocks become desynchronized it can have a disruptive effect upon a whole host of processes such as neuronal signaling, secretion of hormones, sleep-wake cycles, body temperature regulation, inflammation, and DNA damage response.

Healing cells are more active during daytime. Image courtesy of Vshyukova / Science Photo Library

 

Time and Biopolitics

Working through the genealogy of diseases and medical practices organized by governing bodies and institutions in terms of how they play out temporally and spatially—as has been particularly clear during phases of quarantine—lies at the heart of biopolitics. Importantly, the emphasis on how time is bound up with regulative, administrative, and institutional practices can be characterized as a form of chronobiopolitics, where “people are bound to one another, engrouped, made to feel coherently collective, through particular orchestrations of time,” in the words of queer theorist Elizabeth Freeman. These “orchestrations of time” can be exercised through a variety of devices such as calendars, timetables, and clocks, which become important for shaping the modern subject as a product of classifying, quantifying, and categorizing, especially in hospitals, schools, and prisons where the need to discipline and enforce regularity is administered through temporal intervals. Arguably, we can further extend and complicate the notion of temporality that has underpinned Biopolitics, where through the incorporation of basic circadian cycles and their effects, we can emphasize that patterns and systems of governance are also profoundly biological.

This leads us to consider if we can weave in the role of the circadian rhythm to reevaluate how “time” and basic rhythm processes foreground a basic embodiment of governance? Here control is a fundamental principle for organisms and their capacity to maintain physiological processes, yet we also have to grasp control as it relates to pathogens, enabling a pathway to reevaluate how this is contextually based according to the ancient cycles of day and night.

Reconsidering a definition of governance from an elementary biological point of view opens us to the fabric of Real, where the bid to govern through an immune system or pathogen takeover cascades across numerous bodies and scales, from individuals to the supranational organizations. We can emphasize how understanding the dynamics between host and pathogen, as well as times of day that enhance or hinder infection, replication, and combating them, becomes a form of positive biopolitics. Here we can embrace the baseline layers of control that emerge from the biological realm, and the need for our bodies to persist in space and time, but can design ways to interact with pathogens and contact novel understandings of ourselves that reshape practices that relate to our internal machinery and its deep-time organization.

This scanning electron micrograph shows tupanviruses — a newly discovered type of giant virus that is typically more than a micron long. They may hold clues to the evolution of all viruses. Image courtesy of Microscopy Center of UFMG, Brazil

 

ChronoTherapy

What insights can we extract from the relationship between circadian rhythms and the timing of infections? A bridge between disease ecology and chronobiology opens up a new arena in which to study host-parasite-vector coevolution with broad consequences for applied bioscience. With our developments and advancements in circadian research, the introduction of a temporal dimension related to our metabolism, inflammation, and host-pathogen interactions, demonstrates that specifically targeting genes that cycle at specific times of day may work to our benefit. These benefits are examined through the fields of chronotherapy and chronopharmacology which serve as a form of positive biopolitics, tasked with aiming to chart out and align drug delivery with active periods of immunity. The principal goal of chronotherapy here intends to examine and administer medications at different times of the day in order to minimize negative responses and maximize therapeutic effects.

We can concretely highlight the role of Chronotherapy in the manner of how we could potentially reconceptualize our response to viruses by maximizing the benefits enjoyed by administration during a period of a day such as vaccinating in the morning (9-11 am.). Another point of discussion has been the design of drugs for the treatment of inflammatory diseases which specifically target the products of genes governed by clock control.

A “positive biopolitics” pushes us to engage with these developments and findings that potentially could have transformative implications in health policy as well as the temporal organization of medical services. Moreover, it reshapes our conceptions of time affording us the capacity to see the deeper evolutionary character of our bodies and the rhythms of life itself as a vital tool in guiding our fight against pathogens. This is further emphasized through the need to devise strategies to monitor and better grasp viral cycles and their (timed) impact on our bodies that will become more imperative than ever with increasing viral overspill projected for the coming decades, exacerbated by climate change. Disconcerting projections highlight how increasing temperatures and habitat disruption will trigger more species to migrate towards the poles, leading to further zoonotic transfer between our species and others. With an estimated 1.67 million unknown viruses thought to exist, and somewhere between 631,000 and 827,000 of these with the potential to infect humans, fundamental considerations of the ways in which we are subject to virus time will be essential. Ultimately, how we adjust our medical strategies to come further into tune with the infections cycle and immunity phases could be an essential key for understanding the interrelationship between bodies and pathogens.

Cover image: A transmission electron microscopic image of an isolate from the first U.S. case of the ‘Covid-19’ coronavirus. Courtesy of SCIENCE SOURCE

Dustin Breitling

Dustin Breitling is an independent scholar based in Prague and helps organize the Diffractions Collective.

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