The Creative Machine

No one has been able to define creativity, which is not surprising as it can existing in many different forms – just as there are many ‘art forms’. Creativity encompasses everything from inventing disruptive technologies to painting ‘Guernica’. 

A number of people have tried to categorize creativity e.g (K Lunke 2016, James C. Kaufman and Ronald Beghetto (2007)

However a ‘silo’ approach to creativity, suggesting that individuals can be creative in some ways, but not others, may be based on ‘cultural norms’.  Such an approach to creativity may present barriers to further development including the development of creative machine intelligence.

Here, I will explore whether different forms of creativity might align with each other.

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Biological semiconductors and quantum biology

INTRODUCTION

There are several evidenced examples in biology of processes which involve ultra-fast electron transfer, singlet and triplet spin mechanisms and quantum coherence.

These includes:

  1. Evidence of the solid state photo-CIDNP effect (via singlet and triplet states), ultra-fast electron transfer, and quantum coherence in photosynthesis.
  2. Evidence of the solid state photo-CIDNP effect (via singlet and triplet states) and ultra-fast electron transfer in flavoproteins.  In addition there are widely explored scientific theories of cryptochrome (a flavoprotein) triggering a quantum mechanical effect during ‘magnetoreception’.

There is also evidence of that the redox state of cysteine residues may support singlet and triplet states, and ultra-fast electron transfer in both flavoproteins and photosynthesis.  The coupling between circadian rhythms (providing periodicity) and redox could potentially influence the oxidative interface -consisting mainly of the redox regulation of redox-reactive cysteine residues on proteins. This may provide environmental support for quantum transport.

Consideration is also given to other environments where singlet and triplet states, ultra-fast electron transfer, and quantum coherence can be found – including at higher temperatures. Manifestations of quantum coherence in different solid state systems include semiconductor confined systems, magnetic systems, crystals and superconductors. Ultrafast electron transfer and charge separation is possible in semiconductors A Ayzner 2015, S Gélinas 2014, and work is currently being undertaken on semiconductor spintronic devices operating at room temperature. (N Thanh Tu 2016)

PJ Hore (2016) has pointed out that certain organic semiconductors (OLEDs) exhibit magnetoelectroluminescence or magnetoconductance, the mechanism of which shares essentially identical physics with radical pairs in biology. There are three main types of organic spintronic phenomena.  This includes a magnetic field effect in organic light emitting diodes, where spin mixing between singlet and triplet polaron pairs can be influenced by an external magnetic field leading to organic magnetoresistive effect.  E Ehrenfreund 2011F Geng 2016.   

J Vattay and S A Kaufmann (2015) have also suggested the existence of bio-conductor materials which neither metals nor insulators but new quantum critical materials which have unique material properties.  E Prati (2015) then used their work to explore room temperature solid state quantum devices at the end of chaos for long living quantum states.

The idea of biological semiconductors has been around for some years (e.g see A V Vannikov 1970). Several natural semiconductors have now been identified in biology.  Endogenous bioelectrical signals play critical roles in a near-infinite number of ubiquitous biological processes such as energy harvesting, rapid communications and inter/intra cellular synchronisation.  Specific examples include photosynthesis, vision, carbohydrate metabolism, neurophysiology, wound healing, tissue regeneration and embryonic development.  And several natural semiconductors have already been identified e.g melanin and peptides. Charge transport has been found in a variety of naturally-derived small molecule, semiconducting biological compounds – carotenoids (produced by plants and bacteria).  These include protection against oxidative species, pigmentation, and light havesting for photosynthesis.  The polyconjugated structure of this class of compounds suggests that the natural electronic activity of derivatives could be repurposed as an active semiconductor material for organic electron devices.   M Mukovich 2012.    And there are π-conjugated organic semiconducting materials. C Wang 2011.

It is of interest then that organic molecules that serve as chromophores (of which flavins such as cryptochrome, are examples) consist of extended conjugated π-systems, which allow electronic excitation by sunlight and provide photochemical reactivity. Eukaryotic riboflavin-binding proteins typically bind riboflavin between the aromatic residues of mostly tryptophan- and tyrosine-built triads of stacked aromatic rings…Ultrafast electron transfer mechanisms from an aromatic moiety to a photoexcited flavin are not only observed for riboflavin-binding proteins but for other flavoproteins, like for BLUF (blue light sensing using FAD) domains, cryptochromes, and DNA photolyases.  H Staudt 2011.

Hopping conduction is widely considered the dominant charge transport mechanism in disordered organic semiconductors. A V Nenashev 2015.  And in biology, evidence has been found that the existence of central aromatic acids can serve as stepping stones to support an electron hopping mechanism W Sun 2016, including in flavins.

It may be the case that levels of conductivity could change/adapt within biology.  This is explored in more depth towards the end of this article. Biology could draw on a complex system of interfaces between different types of conductors (from flavins to iron sulphur clusters which are ubiquitous in biology) and insulators, periodic oscillations (biological rhythms), redox systems, and generated magnetism (biological organisms also produce tiny electrical currents exist due to the chemical reactions that occur as part of the normal functions, even in the absence of external electric fields). There will also be responses to changes in the environment (e.g temperature and external magnetic fields).  

For example redox doping could increase the conductivity of a material – and in biology such redox doping could be provided by the biological redox state – including the redox state of cysteine residues.  It might also be the case, that in certain conditions, there could be a transition to superconducting (e.g  E H Halpern 1972.

‘RADICAL PAIRS’ MECHANISMS IN MAGNETORECEPTION AND PHOTOSYNTHESIS

In chemical reactions involving transient radical pairs (singlet and triplet states), quantum effects are proposed to induce a sensitivity to the intensity and/or orientation of external magnetic fields. The governing principle of these phenomena is the magnetic field dependent interconversion between quantum-coherent and often entangled states of electronic spin pairs.

When activated by light, it is theorised that cryptochromes undergo a redox cycle, in the course of which radical pairs are generated during photo-reduction as well as during light-independent re-oxidation. 

In biology a ‘radical pair’ is a short-lived reaction intermediate comprising 2 radicals formed in tandem whose unpaired electron spins may be either antiparallel (↑↓, a singlet state, S) or parallel (↑↑, a triplet state, T). C T Rogers 2008.  It is proposed that in magnetoreception the absorption of a photon raises a receptor molecule into an excited state and leads to a light-activated electron transfer from a donor to an acceptor, thus generating a spin-correlated pair. By interconversion, singlet states radical pairs with an antiparallel spin are transformed into triplet states with parallel spin and vice versa. The singlet/triplet ratio depends on, among other factors, the alignment of the receptor molecule in the external magnetic field and could thus mediate information on magnetic direction. R Wiltschko 2014. 

A well-studied precedent for magnetically sensitive radical pair chemistry is provided by the initial charge separation steps of bacterial photosynthetic energy conversion, which proceed via a series of radical ion pairs formed by sequential electron transfers along a chain of immobilized chlorophyll and quinone cofactors in a reaction center protein complex. Provided subsequent forward electron transfer is blocked, the recombination of the primary radical pair responds to magnetic fields in excess of ≈1 mT. In unblocked reaction centers, spin correlation can be transferred along the electron transport chain from the primary to the secondary radical pair, whose lifetime is also magnetically sensitive. Similar effects occur in plant photosystems. C T Rogers 2008. 

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Good Timing: The Synchronisation of Neural Networks in Computing and Implications for Neurology

A symbiotic relationship now exists between the study of neural networking in computing, and neurology.  Artificial neural networks were originally inspired by neuroscience, although major developments have been guided by insights into the mathematics of efficient optimization, rather than neuroscientific findings.  A H Marblestone 2016.  Now neurology is looking towards the development of neural networks to increase our understanding of how the brain works.  There is the possibility that  the two fields will increasingly merge – with particular recognition of the importance of bio-physics in the study of intelligence.

For a long time, the accepted model of memory formation was linear. Short term memories were thought to directly transform into long term memory in a classical, mechanistic fashion. But this model has been challenged.

The new model emerging is complex and non-linear.  The brain is starting to be seen as ‘more than the sum of its parts’ – analogous to a parallel computer (with many interconnected networks), artificial neural networks/deep learning, or a ‘network of networks (such as the Internet), with all the problems (cascading failures) and solutions (built in redundancy) that are associated with such a model.

Modern neuroscience is going through a renaissance of its own – moving away from mechanistic views of the brain, to focus on connectivity.  It recognises some networks may be particularly important for such connectivity e.g the default mode network – which is effected in various neurological conditions such as Alzheimer’s, as well as altered states of consciousness such as meditation and psychedelic drug use.
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Biological Clocks and Ageing

Intraterrestrial life extends down at least 5 km and animals are found even in the deepest oceans. The biosphere is, therefore, dominated by dark, largely “arrhythmic” habitats, and in terms of biomass, most of life on earth resides in places isolated from the direct effects of the sun…studies of species that live away from the sun […]

Is the Coupling of Circadian Rhythms and Metabolism/Redox Regulating Morphogenesis

Self Organisation Far from Equilibrium

New states can arise from far from equilibrium, possessing an extraordinary degree of order, whereby trillions of molecules coordinate their actions in space and time. Under certain circumstances, entropy producing processes are able to organise themselves in the presence of noise, in a way that so called dissipative structures are formed (Prigogine and Lefever 1975, and Nicolis and Prigogine 1977).  Also see J England 2015 on ‘dissipative adaptation in driven self-assembly’.

Dissipative processes are present in biology.  It is asked whether these could be contributing to morphogenesis.

Stochastic reaction-diffusion simulations have been successfully used in a number of biological applications. Formation of skin patterns and the biochemical processes in living cells (like gene regulatory networks), the cell cycle, circadian rhythms, signal transduction in E Coli chemotaxis, MAPK pathway, oscillations of Min proteins in cell division, and intracellular calcium dynamics are examples of processes mathematically modelled by reaction and reaction-diffusion systems. T Vejchodsky 2013, J Eliaš – ‎2014A Zakharov 2014T Hinze 2011. Read More…

The evolutionary importance of iron sulphur flavoproteins

Iron Sulphur Flavoproteins.

This posting explores how evolution may have brought together flavoproteins and iron-sulphur clusters (as co-factors) to optimise a range of functions – including in sequence. Iron-sulfur clusters rank with biological prosthetic groups, such as hemes and flavins in pervasive occurrence and multiplicity of function.

There has been the tendency in research to explore each of the functions of flavoproteins and iron sulphur clusters separately, but such functions can also combine to support a cycle.

It is proposed that adaptation of multiple functions into a cycle may have emerged through an adaptive evolutionary response – initially to the Great Oxidation Event, and then through endosymbiosis.  Perhaps this even offered the basis for the evolution of photosynthesis and respiration in an oxygen rich environment.

As electron transfer proteins they would enable long range electron transfer (which is used in photosynthesis, respiration, catalytic events). Electron transfer proteins contain redox-active prosthetic groups or “redox sites” where oxidation/reduction occurs. The most common redox sites contain metals such as hemes, iron-sulfur clusters, and copper centers but also include flavins, reducible disulfides, and quinones.  

Electron transfer (ET) is a very simple chemical process but closely governs the life on Earth. In nature, an immediate transfer of the electron(s) in photosynthetic reaction center converts light from the Sun to the forms of chemical energy and is stored in glucose or other types of organic compounds, ultimately supplying “food” for living creatures. In a class of blue-light receptor called cryptochrome found ubiquitously in plants and in animals, the process of ET is pivotal to generate the 24-hour life cycle of circadian rhythm and endogenously informs the body organism “time to sleep”. Furthermore, the ET reaction is also involved in repairing photo-damaged DNA and prevents some diseases like skin cancer. The role of ET in biology serves as an energy transmission and evolves the life using Sun power. Ting-fang He 2011. 

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Multi-model Oscillation Based Connectivity Theory Applied to the Integration of Bio-Sensory Data

1. Global Clock Synchronisation 

In computing many emerging sensor network applications require that the sensors in the network agree on the time. A global clock in a sensor system will help process and analyze the data correctly and predict future system behavior. For example, in the vehicle tracking application, each sensor may know the time when a vehicle is approaching. By matching the sensor location and sensing time, the sensor system may predict the vehicle moving direction and speed. Without a global agreement on time, the data from different sensors cannot be matched up. Other applications that need global clock synchronization include environment monitoring (for example, temperature), navigation guidance, and any other application that requires the coordination of locally sensed data and mobility.  Q Li 2004.

In these systems various approaches have been taken to temperature compensation  e.g Q Li 2004. S Chauhan 2012.   J M Castillo-Secilla 2013. 

A similar approach could potentially be taken to synchronising biosensors. A Prindle 2015T Danino 2009. J Hasty 2008,  J V Selinger 2003,

This posting considers whether a similar mechanism to global clock sychronisation could be connecting together biological sensors (using  the Transient Receptor Potential (TRP) superfamily of ion channels), and supporting temperature compensation.

Another posting on this site explores how this could also support the operational of neural networks. Read More…

Applying Universality to Systems Biology

Over recent years, the field of “systems biology” has been emerging.  It is throwing light on areas that have long been a mystery.  There are also vast back catalogues of biological research that need to be reviewed from the perspective of systems biology. Read More…

How Microbes Influence Evolution

Associations between microbes and health have been made by researchers for a number of decades, but the question has remained by what mechanism are microbes influencing human health?

A new field of chronobiomics is emerging that may provide an answer this question through researching the associations between microbes and biorhythms. The extent to which large microbial populations, are affected by and/or entrain biorhythms is still being explored, but evidence suggests strong links.

This could also have implication for those who are interested in the concept of the holobiont – which suggests that microbes could have a key role to play in evolution.

Microbes Can Influence Host Gene Expression. 

Recent research suggests that microbe have some influence on the circadian rhythms of their hosts.

The bacterial bioluminescence (from the bacteria ‘Vibrio fischeri’) regulates expression of a host cryptochrome gene in the squid-vibrio symbiosis. This finding that bacteria can directly influence the transcription of a gene encoding a protein implicated in the entrainment of circadian rhythms provided the first evidence for the role of bacterial symbionts in influencing, and perhaps driving, peripheral circadian rhythms in the host. In mammals, biological rhythms of the intestinal epithelium and the associated mucosal immune system regulate such diverse processes as lipid trafficking and the immune response to pathogens. EAC Heath-Heckman 2013.

C A Thaiss et al 2016 found that the intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis. And that the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.

Microbes can partially disable Hnf4a in mice and zebrafish and perhaps obstruct its protective role (throughout evolution, Hnf4a appears to protect against microbial contributions to inflammatory bowel diseases). When Hnf4a is fully disabled, microbes stimulate patterns of gene expression in animals that are associated with inflammatory bowel diseases. Similar effects in zebrafish and mice suggests that this is a common feature of host-microbe interactions that might have existed in our common (vertebrate) ancestors. J M Davidson et al 2017 

The integral liver transcription factor, hepatocyte nuclear factor 4 alpha (HNF4a) is a key target for circadian and glucocorticoid-mediated orchestration of liver gene expression. Thus, glucocorticoids, as well as body temperature, are likely to be key synchronizers of the liver clock, acting through transcriptional cascades involving mPer2 and other regulators. Key liver-specific proteins, such as the glucocorticoid-responsive HNF4a, likely play roles in local synchronization and circadian transcriptional programming. A B Reddy 2007.

In mice gut microbial colonization influences rhythmic signalling events in the ileal epithelium downstream of toll-like receptors (TLRs). This, in turn, regulates the organization of molecular clock activity and glucocorticoid production in the intestine.. A Mukherji 2013. Glucocorticoids in turn play a key role in circadian cell cycle rhythms. T Dickmeis 2007.

Nearly all aspects of digestion and detoxication – from gastric emptying time to fat processing and xenobiotic degradation by the liver – are under circadian control (Dallmann et al., 2014).

Microbes and Epigenetics.

Epigenetic control has been implicated in the modulation of biological timekeeping, and cellular metabolism and epigenetic state seem to be closely linked rhythms. L Aguilar-Arnal 2014, and S Masri 2013,.

Various research has also show how microbes may contribute to host epigenetic changes and the development of disease Robert M. Brucker 2013 Brucker and Bordenstein 2012, R Al Akeel 2013,and this may have implications for the effectiveness of treatments such as anti-biotics A Morgun 2015.

Most of the reported chromatin modifications induced by bacteria are histone acetylation/deacetylation and phosphorylation/dephosphorylation events generated through activation of host cell signaling cascades by bacterial components. As chromatin modifications may be transmitted to daughter cells during cell division, leading to heritable changes in gene function, it is possible that a bacterial infection could generate heritable marks after pathogen eradication. H Bierne – 2012, L Aguilar-Arnal 2014.

CLOCK:BMAL1 mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Recent research has demonstrated that chromatin remodeling is at the cross-roads of circadian rhythms and regulation of metabolism and aging. S Sahar 2012

A role for mammalian gut microbiota, as an epigenetic modifying factor, in the pathogenesis of metabolic syndrome and associated diseases has been identified.. Host genes involved in cell cycle progression, senescence, survival, inflammation and immunity are prime candidates as targets for such epigenetic control. Raid Al Akeel 2013

Circadian Rhythms, Redox, and the Metabolism

Biological clocks (of various types) have been found across many species, and may ultimately be found to be fundamental to all life. Increasingly it is also being found that they have a strong association with the metabolism/cellular redox oscillations.

Redox balance is key for molecules utilised in the context of anti-oxidation protection. A critical event of oxidative stress resets the circadian clock in other mammalian cell lines, resulting in a concurrent activation of a network of circadian genes that then continued onward to modulate an antioxidant, cell survival response. These results strongly suggest that the circadian clockwork is involved in complex cellular programmes that regulate endogenous reactive oxygen species (ROS) and also defend the organism against exogenous oxidative challenge.

Mechanistic links between the redox state and the intracellular transcriptional/post-translational feedback loops (TTFL) framework of circadian rhythms have begun to appear in a variety of organisms from bacteria to flies to mammals. Although a single model has yet to emerge, studies strongly suggest that redox state may be an oscillation that feeds back upon the TTFL, whereby a cell’s redox state may alter clock gene expression and the clock genes, in turn, regulate redox state. Lisa Wulund 2015,  A Stangherlin – 2013.  K Nishio 2015 N B Milev 2015.

Unravelling the exact relationship between redox and the TTFL could prove extremely difficult, but could potentially result improved understanding of various physiological processes from metabolic disorders to cancer and ageing (Milev and Reddy 2015, and M Putker and O’Neill 2016).

The Redox-Circadian Link: Implications for Immunity

Many aspects of antimicrobial pathway and innate immune response regulation involve the circadian clock, as was first discovered in Drosophila. In mice, the molecular clock regulates diurnal expression of proinflammatory genes in macrophages, thereby generating characteristic profiles of cytokine expression over the course of a day. Furthermore, leukocyte abundance in the circulation and recruitment to peripheral tissues underlies strong circadian fluctuation. The circadian clock also controls the expression of innate immune receptors. As a result, inflammatory responses, including susceptibility to sepsis, are strongly influenced by the time of day. The susceptibility of the host to pathogenic infection varies over the course of a day. For instance, the degree of the immune response to oral infection with Salmonella Typhimurium is more pronounced when the infection occurs during the active phase of the host – likely to anticipate a higher risk to acquire foreign microbial elements during the time of food intake. The time of day therefore also affects the ability of the host to clear infection. C A Thaiss. 2015.  Also see N Labrecque 2015.A M Curtis 2014,  C Scheiermann – ‎2013A Nakao – ‎2014

There has been a range of research on the interactions between gut microbes and immune homeostasis e.g Y Belkaid 2011 and 2014C L Maynard 2012, Hsin-Jung Wu 2012C M da Costa Maranduba 2015D K. Podolsky 2015B Sanchez 2015C Chevalier 2015A Mardinoglu 2015, D Pagliari 2015. Studies have suggested that microbial signalling plays a critical role in homeostatic maintenance of intestinal function along with the host circadian mechanism.  Jiffin K. Paulose 2016.

Accumulating evidence suggests that some intestinal microflora has protective, metabolic, trophic and immunological functions and is able to establish a “cross-talk” with the immune component of mucosal immunity. F Purchiaroni 2013

A regulatory mechanism links the circadian clock and glucocorticoid hormones to control both time of day variation and the magnitude of pulmonary inflammation and response to bacterial infection.  Gibbs -2014

Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses. D Ruane 2016

Recent studies suggest that catecholamines (CAs) and acetylcholine (ACh) play essential roles in the crosstalk between microbes and the immune system. Host cholinergic afferent fibers sense pathogen-associated molecular patterns and trigger efferent cholinergic and catecholaminergic pathways that alter immune cell proliferation, differentiation, and cytokine production. L Weinstein 2015.

Bacterial translocation from the mouse gut is increased during pregnancy and lactation, and bacterially loaded dendritic cells in the milk have been proposed to contribute to neonatal immune imprinting (Perez et al., 2007)…  Also  J M R Gomez 2008, Y Belkaid 2011K Aagaard 2014, and  A Ardeshir – 2014

Gut Microbes and Mammalian Disease

It has been found that circadian disorganization alters intestinal microbiota. R M Voigt 2014 

The gut microbiota and its disturbance also appear to be involved in the pathogenesis of diverse diseases including metabolic disorders, gastrointestinal diseases, cancer, etc. Kyu Yeon Hur 2015,  Claire L. Boulangé 2016. This includes chronic inflammatory diseases, such as Crohn’s Disease V Pascal et al 2017 and obesity, diabetes, multiple sclerosis and Lupus. SM Vieira – 2014 , Also see Q Mu 2015, and  Zhang 2014.

Gut microbes have been linked to age-associated inflammation and premature death in mice. Imbalances in the gut microbes in older mice cause the intestines to become leaky, allowing the release of bacterial products that trigger inflammation and impair immune function. N Thevaranjan et al 2017

Circadian Rhythms and Cancer

The relationship between microbes, circadian rhythms and the immune system might also explain strong associations between microbes and cancer.

Researchers have found that germ-free mice and mice treated with a heavy dose of antibiotics responded poorly to a variety of cancer therapies typically effective in rodents. These findings incited research and speculation about how gut microbes contribute to cancer cell death, even in tumors far from the gastrointestinal tract. The most logical link between the microbiome and cancer is the immune system.

Mostly because of its effects on metabolism, cellular proliferation, inflammation, and immunity, the microbiota regulates cancer at the level of predisposing conditions, initiation, genetic instability, susceptibility to host immune response, progression, comorbidity, and response to therapy. A Dzutsev 2017.

Cell differentiation, for example, that of stem cell populations, has been shown to be under circadian influence. S A Brown 2014 and circadian clocks have been implicated in the differentiation, apoptosis and activity of mouse pluripotent stem cells. Chao Lu 2016.

Like normal cells, cancer cells contain molecular clocks that generate circadian rhythms in gene expression and metabolic activity. Disruption of circadian rhythms can therefore be associated with abnormal cell divisions that occur in cancer and there are links between altered circadian clocks and tumorigenesis in metastatic colorectal cancer, osteosarcoma, pancreatic adenocarcinoma and breast cancer.

It has been suggested that just as there is a circadian regulation of the redox state of the cell which regulates the cell cycle, there is a relationship between circadian rhythms and apoptotic cell death. C Rodiguez et al (Edited by T Vanden Driessche 2000).

Indications that circadian rhythms can alter growth.

  1. Photomorphogenesis A functioning circadian clock enhances survival and biomass accumulation. Intriguingly, altered clock function contributes to the increased growth. Intuitively, given the plethora of processes regulated by the clock, one might expect that the mechanisms by which the circadian clock confers a growth advantage may be both many and complex.   C. Robertson McClung 2010. C. Robertson McClung 2006Maria L. Guerriero et al 2014. It has been found that oscillating gene expression determines competence for periodic Arabidopsis root branching. Genetic studies show that some oscillating transcriptional regulators are required for periodicity in one or both developmental processes. This molecular mechanism has characteristics that resemble molecular clock-driven activities in animal species. Moreno-Risueno 2010.  Nora Bujdoso 2013. 
  2. Brush Border Architecture Recent research has shown that the microbiota affects the biology of associated host epithelial tissues, including their circadian rhythms.  E A C Heath-Heckman 2016.
  3. Dendritic Spines: There is evidence or circadian rhythms in synaptic plasticity, in some cases driven by the central clock and in others by peripheral clocks. Circadian rhythms in brain temperature, hormone/neuromodulator concentrations and GABAergic signalling may adjust the gain of different forms of plasticity as a function of circadian time. These central influences likely work in concert with peripheral clocks that modulate the response to the central influence and also control cellular processes that impact on plasticity. M G Frank 2016.  It is known that the circadian plasticity of neurons requires a functional cytoskeleton and involves microtubules remodeling and actin microfilament organization. Ewelina Kijak 2017.
  4. Fibroblasts: Cultured mouse fibroblasts show a complex clock gating pattern that suggests multiple control points. .  S Brown 2014
  5. Skin, Hair and Teeth: Skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, and carcinogenesis. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. In addition to circadian fluctuation, CLOCK–regulated genes are also modulated in phase with the mouse hair growth cycle. Kevin Lin. 2009.  MV Plikus 2015. The circadian clock genes play a role in regulation of the hair growth cycle during synchronized hair follicle cycling, uncovering an unexpected connection between these two timing systems within skin. Mikhail Geyfman  Y Watabe 2013. A circadian clock is also present in tooth ameloblasts, where it controls antiphase rhythms of enamel matrix endocytosis and secretion, as well as ameloblast maturation (Lacruz et al., 2012Zheng et al., 2013S Brown 2014
  6. Somites: In vertebrates, somites give rise to skeletal muscle, cartilage, tendons, endothelial cells, and dermis. It is thought likely that oscillator networks constitute the core of the segmentation clock- which involves cyclic gene expression. R Kageyama – ‎2012. 
  7. The Heart: There is evidence that the circadian clock gene, dCry, plays an essential role in heart morphogenesiand function – in Drosophila. A Alex – ‎2015.
  8. The Liver: Circadian variations of glucocorticoids have been found to be responsible for both circadian rhythms in proliferation and the differentiation in rat liver cells under physiological conditions. Thérèse Vanden Driessche et al 2013
  9. Mammary Gland: Data suggests that circadian clock genes may play a role in mouse mammary gland development. Xiaoyu Qu 

Indications that microbes could alter growth:

  1. Recent experiments have established that eukaryotes have marked responses to the N-acyl L-homoserine lactone (AHL) signals used by Gram-negative bacteria for quorum sensing.  AHLs can significantly alter seedling growth in an acyl-chain length dependent manner. A G Palmer 2014.
  2. In Agrobacterium tumefaciens, the plant pathogen responsible for crown gall tumours, quorum-sensing outputs are responsive to both bacterial and host signals.
  3. In fungus, quorum sensing systems regulates morphogenesis, filamentation and pathogenesis S Majumdar 2015.
  4. Animals raised in the absence of live microbes referred to as germ-free (GF), revealed that the microbiota plays a critical role in secondary lymphoid structure development. This is particularly evident in the gastrointestinal tract Y Belkaid 2011

Associations between Cancers and BioRhythms

Biological clocks have been implicated in Colorectal Cancer (RC). T Karantanos 2014G Mazzoccoli 2014S Rios-Arrabal 2016S A Huisman 2014SA. Huisman 2016

It has been shown that pathological conditions in the lung can affect local circadian homeostasis and that genetic disruption of circadian machinery in the lung can impact inflammatory processes. In rodent studies that lung adenocarcinoma sends signals to the liver through an inflammatory response, which rewires the circadian mechanisms that manage metabolic pathways. As a result of this inflammation, the insulin signaling pathway is inhibited in the liver, leading to decreased glucose tolerance and reorganization of lipid metabolism. It seems that lung tumors take control of circadian metabolic function in the liver, potentially to support the heightened metabolic demands of cancer cells, and that this distal rewiring of metabolic tissues does not occur only in the liver, suggesting a systemic shake-up of metabolism.”

Masri (2016) examined the effects of lung adenocarcinoma on circadian function distally in the liver, using a mouse model. Lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. It was found that there were disruptions of the normal oscillations in glucose production, insulin signaling and lipid metabolism, likely mediated by altered signaling via the AKT, AMPK, and SREBP pathways. These effects were observed in the absence of any direct infiltration of the liver by malignant cells. The alterations in the circulating metabolites may be derived from the tumor cells themselves indicating that these effects on circadian rhythms in the liver may be in response to tumor derived metabolites. However, alterations to cytokine concentrations and inflammatory pathways were also observed, suggest that an immune response initiated by tumor development may play a role in mediating these effects. It was also not clear what was causing local changes to the circadian homeostasis in the liver. These results suggest that the impact of therapeutic timing on the metabolic function of uninvolved organs, especially the liver should be investigated. R A Cairns 2016.

Circadian clocks have been associated with breast cancer. V Blakeman 2016. . Studies on aggressive metastatic breast cancer (using a mouse model pinpointed a circadian rhythm gene, Arntl2, which codes for a protein that binds to and controls the activity of other genes within a cell. NH Ha – 016.

It has been found that leukemia stem cells(LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models.  Both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. These findings establish a role for the core circadian clock genes in acute myeloid leukemia. R V Puram 2016.

An overview of further studies associating circadian clocks with cancer is provided by A Salavatv 2015. 

The Influence of Fasting 

It has been demonstrated that the intestinal microbiota undergoes rhythmic fluctuations in taxonomic composition and, consequently, genomic coding capacity. As a result, different times of the day feature distinct microbial community configurations and microbiota functions…These compositional fluctuations are controlled by the circadian clock of the host, since they cease in the absence of a functional host molecular clock. Furthermore, the type of diet and the rhythmicity of food intake are major drivers of the oscillations in the intestinal microbial ecosystem. A C Thais 2015. 

Altered food intake, especially protein and insoluble fiber have a profound effect on the gut microbiota structure, function, and secretion of factors that modulate multiple inflammatory and metabolic pathways. L Fontana 2015.

Studies show that the gut microbiome is highly dynamic, exhibiting daily cyclical fluctuations in composition. Diet-induced obesity dampens the daily feeding/fasting rhythm and diminishes many of these cyclical fluctuations. Time Restricted Feeding (TRF), in which feeding is consolidated to the nocturnal phase, partially restores these cyclical fluctuations. Furthermore, TRF, which protects against obesity and metabolic diseases, affects bacteria shown to influence host metabolism. Cyclical changes in the gut microbiome from feeding/fasting rhythms contribute to the diversity of gut microflora and likely represent a mechanism by which the gut microbiome affects host metabolism. Thus, feeding pattern and time of harvest, in addition to diet, are important parameters when assessing the microbiome’s contribution to host metabolismA Zarrinpar 2014,  Patterson et al 2015 , M Hatori et al 2012 and Chaix, 2014S Gill 2015,  G Asher 2015. 

A number of studies on the impact of time restricted dieting on women found that frequency and circadian timing of eating may influence biomarkers of inflammation and insulin resistance associated with breast cancer risk (C R. Marinac 2015).

Fasting dramatically alters cysteine-residue redox status in D. melanogasterK E Menger 2015. 

The Brain

The importance of timing for the operation of the brain is explored in another posting on this site – click here

Although historically it has been thought that circadian rhythms were light dependent, new evidence suggests that feeding time is a dominant factor in determining the phase of peripheral circadian clocks (Oike et al 2014). Circadian rhythms have a profound influence on metabolic processes, as they prepare the body to optimise energy use and storage. Food-related signals confer temporal order to organs involved in metabolic regulation. Therefore food intake should be synchronised with the suprachiasmatic nucleus (SCN) to elaborate efficient responses to environmental challenges. Human studies suggest that a loss of synchrony between mealtime and the SCN promotes obesity and metabolic disturbances. Animal research using different paradigms has been performed to characterise the effects of timing of food intake on metabolic profiles (Moran-Ramos et al 2016).

This link between gut-microbiota and the brain may also have implications for behaviours. Studies have shown that the presence of microbes can influence forging behaviours. This in turn may be linked to circadian clocks – as timing (both from the perspective of the host and microbiota) of such foraging related activities as eating, defecatingmating, and nesting, etc, will be important.  

Stress may also have a role to play. Studies have shown that there is an intricate connection between host stress signalling, bacterial quorum sensing and pathogenesis, which suggests that stress responses, some of the most basic physiological functions in prokaryotic and eukaryotic cells, are central to inter-kingdom communication. DT Hughes 2008.

Microbial Endocrinology

To date, there is rapidly increasing evidence for host microbe interaction at virtually all levels of complexity, ranging from direct cell-to-cell communication to extensive systemic signalling, and involving various organs and organ systems, including the central nervous system. As such, the discovery that differential microbial composition is associated with alterations in behaviour and cognition has significantly contributed to establishing the microbiota brain axis as an extension of the well-accepted gut brain axis concept. Many efforts have been focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome to neurodevelopmental disorders such as autism. RM Stilling – ‎2014 –

In addition to the ‘Gut-Brain Axis theory, bacteria has been discovered in healthy brains across different species, including humans. proteobacteria represented the major bacterial component of the primate brain microbiome regardless of underlying immune status, which could be transferred into hosts leading to microbial persistence in the brain.  William G. Branton,2013 

The ability of bacterial pathogens to influence behavior has been recognized for decades, most notably bacteria that directly invade the nervous system. However, increasing evidence is mounting that microorganisms may directly interact with elements of the host’s neurophysiological system in a noninvasive manner that ultimately results in modification of host behavior. This ability of microorganisms contained within the microbiome to influence behavior through a noninfectious and possibly non-immune-mediated route may be due to their ability to produce and recognize neurochemicals that are exactly analogous in structure to those produced by the host nervous system. This form of interkingdom signaling, which is based on bidirectional neurochemical interactions between the host’s neurophysiological system and the microbiome, was introduced two decades ago and has been termed microbial endocrinology. Mark Lyte 2016. 

Mark Lyte (2013) has looked at evidence of whether diet can influence bacteria e.g to produce neuroendocrine hormones that interact with the enteric nervous system (ENS) or are absorb into portal circulation. He suggests the possibility that this could present a new mechanism by which nutrition could impact on the host and ultimately influence various aspects of behaviour, as well as food preferences and appetite. It is known that the neurochemical composition of food can influence the growth of particular bacteria, and perhaps different species of bacteria will commute a specific need to its host (via neuroendrocrine hormones). One hypothesis is that there is a feedback loop between the microbia and the brain, in determining food preferences.

The implications of the above findings are still open further research, but some have already speculated on possible interactions between microbes and the brain e.g see  H V Westerhoff 2014Cryan and Dinan, 2012Relman and Falkow, 2001.

  • In mice, indigenous bacteria from the gut microbiota have been found to regulate host serotonin biosynthesis. Research has demonstrates that microbes normally present in the gut stimulate host intestinal cells to produce serotonin. Although this study was limited to serotonin in the gut, the research team are now investigating how this mechanism might also be important for the developing brain. J M Yano 2014.
  • Gut-microbial products can affect chromatin plasticity within their host’s brain that in turn leads to changes in neuronal transcription and eventually alters host behaviour. RM Stilling – ‎2014 –
  • There is an association between the gut microbiota and the brain regions involved in the processing of sensory information from their bodies. The results suggest that signals generated by the brain can influence the composition of microbes residing in the intestine and that the chemicals in the gut can shape the human brain’s structure. J S Labus 2017.
  • Commensal gut bacteria impact on the host immune system and can influence disease processes in several organs, including the brain. Antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants.  C Benakis 2015. 

Recent work highlights that clock driven acetylation modulates a considerable number of mitochondrial proteins involved in multiple metabolic networks. S Ray and A Reddy 2016.

Recently findings have shown that more than 68% of ASD cases shared a common histone acetylation pattern at 5,000 gene loci, despite the wide range of genetic and environmental causes of ASD.  W Sun 2016.  Histone acetylation and other posttranslational modifications have been linked to clock function. Rhythms of histone acetylation contribute to the circadian expression pattern of some core circadian genes. Mitrochondrial dysfunction is common in people with autism and a range of other neurological conditions.

The Relationship is Not One Way: Quorum Sensing, Autoinducers and Growth

E A C Heath-Heckman (2016) has explored several other examples of interactions of both pathogenic and mutualistic associations with host and symbiont circadian rhythms. One important theme taken from these studies is the fact that mutualisms are profoundly affected by the circadian rhythms of the host, but that the microbial symbionts in these associations can, in turn, manipulate host rhythms. Symbiotic microbial colonization is required for circadian homeostasis of the host. In turn, a functional host circadian clock ensures periodic oscillations of its symbiotic microbial ecosystem. A C Thais 2015.  So the circadian interactions between host and microbiota are not solely restricted to microbial control of host clock function but rather constitute a bidirectional cross talk.

It is being found that bacterial signals can modulate mammalian cell-signal transduction, but then host hormones can cross signal with quorum sensing signals to modulate bacterial gene expression.   J A Thompson 2015,  B Lasarre 2013

In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the hosts circadian clock. In addition, least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility.J K Paulose 2016.  As a chelating agent, melatonin is a potent free radical scavenger and a regulator of redox active enzymes. It is secreted during darkness and plays a role in various physiological responses, including regulation of circadian rhythms, sleep, homeostasis, retinal neuromodulation, and vasomotor responses. It preserves mitrochrondial homeostasis, reduces free radical generation, and protected ATP synthesis.  M L Fanjul-Moles 2015.

The abundance of mouse gut bacteria, over a 24-hour cycle, particularly in females, is tied to rhythms in the internal clock and clock genes. Disruption of the host circadian clock by deletion of Bmal1, a gene encoding a core molecular clock component, abolished rhythmicity in the fecal microbiota composition in both genders.  Xue Liang et al 2015.

What Could be Mediating the Host-Microbe Interaction

Bacteria may be influencing clock gene expression (e.g cryptochrome) and neurochemicals such as serotonin.

Serotonin, together with histamine, dopamine, acetylcholinenoradrenaline and adrenaline are neurotransmitters that are found across biology including in plants, animals and microbiota. GABA is another common factor. M Lyte 2016.In mice, indigenous bacteria from the gut microbiota have been found to regulate host serotonin biosynthesis. Research has demonstrates that microbes normally present in the gut stimulate host intestinal cells to produce serotonin. J M Yano 2014.

mFeS-BCP ( bacterial cryptochromes and photolyases with iron sulphur cluster)) sequences have been found in hundreds of bacterial organisms including many human and plant pathogens such as Vibrio cholerae and Pseudomonas syringae. I Oberpichler 2011P Scheerer 2015.  Bacterial iron sulfur cluster proteins can function as regulators of gene transcription and the cluster can act as a sensor of the environment and enables the organism to adapt to the prevailing conditions, leading directly to changes in DNA binding affinity. FeS cluster biogenesis pathways are extremely well conserved, and are invariably essential for viability. Among eukaryotic pathogens, all endosymbiotic organelles studied to date appear to contain FeS cluster biogenesis machinery, and, in some cases, this seems to be the sole reason for retention of the organelle. A Teegan 2013.

Are We the Result of a Long Term Relationship with Our Microbes

It has been suggested that the evolution of cell to cell signalling in mammals relies more on late horizontal gene transfer from bacteria to animals than on vertical inheritance. This hypothesis has been driven by the observation that the enzyme that regulates vertebrate melatonin biosynthesis, arylalkylamine N-acetyl-transferase, is encoded in bacteria, yeast and vertebrates, but not in plants, worms or flies.  DT Hughs 2008.

It is speculated that this could potentially translate into an immune system (which is strongly associated with circadian rhythms) attacking microbes that are not attuned to the hosts circadian rhythms and so can cause dysfunction and disease.

In addition where the cells of the hosts body have themselves have fallen out of alignment with the standard rhythms of the host, the immune system may automatically attack them (on the assumption they are also unwanted microbes).

Entrainment/alignment of circadian rhythms might even be a primary mechanism in the process of symbiosis and endosymbiosis.

Please note that although this post reflects my interest in systems biology, I am not a scientist or medical professional.

This article merely joins up other peoples work into an overall system.  These works have been referenced so it is clear that others have provided the individual pieces of evidence that have been used to shape a specific systems approach.    

 

 

A Combined Clock and Compass

In animals with magnetoreception, there may be the possibility that cryptochrome (with its connection to both a navigation strategy, and circadian rhythms) may be supporting in an integrated sense of time and place through a system that combined together a clock and compass. Evidence of such a system has been indicated in various species and this is explored further in this posting. Read More…