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“Judge a man by his questions rather than by his answers.”
― Voltaire
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Project Proposal #1
Molecular signatures of synaptic functions related to cognition and memory:
This project is focused on molecular mechanisms of dopaminergic, serotonergic, and glutamatergic neurotransmission, including signal transduction, regulation of pre- and postsynaptic plasticity by posttranslational modifications and the formation of biomolecular condensates.
These processes play key roles in learning and memory. Methodological approaches comprise advanced cellular imaging, such as live cell super-resolution microscopy, optogenetics, and state-of-the-art techniques in cell biology, biochemistry, and molecular biology. Potential postdoc hosts are Stefan Herlitze, Denise Manahan-Vaughan, Melanie Mark, Andreas Reiner, Jörg Tatzelt, and Konstanze Winklhofer (all RUB).

The neuropsychological effects of psilocybin on genetic aging
Think @ Ruhr
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Socratic epistemological humility as a cognitive conditio sine qua non for scientific discoveries

The following parabel draws an analogy between perception and a fishing net with a wide mesh width which allows small fish to escape unnoticed. Per analogiam, our perceptual (empirical) system is very limited in its scope and many aspects of reality are occult to us (etymology of the Latin term occultus = hidden from the eye, invisible). This is the reason why we utilise sense-enhancing technologies like the microscope and the telescope. These apparati are essentially extension of our sensorium and they reveal new, previously unaccessible dimensions of reality (data at the micro and macro scale; cf. fractal scale invariance). Nihil est in intellectu, quod non prius fuerit in sensu. (Transl.: There is nothing in the mind/intellect which is not first in the senses.) This Aristotelian gnoseologic dictum (i.e., peripatetic axiom) forms the axiomatic basis of Lockean associationism which, in turn, forms the conceptual basis of behaviorism and contemporary machine learning approaches (i.e., multi-layered neural networks according to Bayesian/Hebbian principles of association).

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Sir Arthur Eddington's parabel of the ichthyologist

Let us suppose that an ichthyologist is exploring the life of the ocean.
He casts a net into the water and brings up a fishy assortment.

Surveying his catch, he proceeds in the usual manner of a scientist to systematise what it reveals.
He arrives at two generalisations:

1. No sea-creature is less than two inches long.

2. All sea-creatures have gills. These are both true of his catch, and he assumes tentatively that they will remain true however often he repeats it.

In applying this analogy, the catch stands for the body of knowledge which constitutes physical science, and the net for the sensory and intellectual equipment which we use in obtaining it. The casting of the net corresponds to observation; for knowledge which has not been or could not be obtained by observation is not admitted into physical science.

An onlooker may object that the first generalisation is wrong.

“There are plenty of sea-creatures under two inches long, only your net is not adapted to catch them.”

The icthyologist dismisses this objection contemptuously.

“Anything uncatchable by my net is ipso facto outside the scope of icthyological knowledge. In short, “what my net can’t catch isn’t fish.”

Or — to translate the analogy — “If you are not simply guessing, you are claiming a knowledge of the physical universe discovered in some other way than by the methods of physical science, and admittedly unverifiable by such methods. You are a metaphysician. Bah!”

Sir Arthur Stanley Eddington: The Philosophy of Physical Science (1938)

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A plethora of genetic and geroscience studies indicate that telomere length is a reliable biomarker of cellular aging [1,2], i.e., telomeres are regarded as a robust indicator of mitotic cell and possibly organismal longevity [3]. Attrition/uncapping of telomeres is associated with the degeneration of multiple systems such as various organ failures, depletion of the totipotent stem cell répertoire, tissue atrophy, impairments in injury responses and various (neuro)restorative processes, inter alia [4]. Furthermore, it has been proposed that telomeres function as a “psychobiomarker” as they are partially regulated by psychological factors [5,6].

Germann, C. B. (2020). The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging. Medical Hypotheses. https://doi.org/10.1016/j.mehy.2019.109406

Telomeres & Telomerase
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The ends of linear eukaryotic chromosomes are protected by telomeres, which serve to ensure proper chromosome replication and to prevent spurious recombination at chromosome ends. We predict that a single therapeutic intervention with the naturally occurring non-selective 5-HTR agonist psilocybin is sufficient to slow down or even reverse telomere attrition (as quantified by telomere length analysis; enzymatic telomerase activity should be monitored and analytically included). The molecular structure of psilocybin is closely related to serotonin (5-hydroxytryptamine) and accumulating empirical evidence indicates that psilocybin has significant therapeutic value in the treatment of trauma/PTSD, depression, anxiety disorders, and various addictions (perhaps due to its neurogenesis and synapto/neuroplasticity enhancing actions). Insights derived from this reseach domain may enable us to better understand how trauma is encoded in the neurocircuitry of the brain (Project #7) and how trauma can be effectively treated in order to alleviate human suffering. Perhaps most significantly: This line of research has the potential to substantially increases our still rudimentary understanding of the neurochemical basis of trauma and how depression and trauma effect basic (genetic/epigentic) molecular processes involved in organismal cell division and longevity. In the long run, insights derived from this radically interdisciplinary enquiry into the interactions between fungal and human signal transduction could be utilised to develop novel neurochemical interventions which enable much more effective treatments of depression and PTSD (as compared to dominant "BigPharma" SSRI prescription drugs which have to be used on a long-term basis and have been shown to have neurotoxic effects in vivo and vitro). Furthermore, this innovative research agenda may lead to new approaches how to senotherapeutically decelerate the normative aging process (and enhance quality of life during aging) in a systematic scientific manner.
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Psilocybin reduces depression
Kringelbach, M. L., Cruzat, J., Cabral, J., Knudsen, G. M., Carhart-Harris, R., Whybrow, P. C., Logothetis, N. K., & Deco, G. (2020). Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proceedings of the National Academy of Sciences, 117(17), 9566–9576. https://doi.org/10.1073/pnas.1921475117
Kraehenmann, R., Schmidt, A., Friston, K., Preller, K. H., Seifritz, E., & Vollenweider, F. X. (2016). The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical, 11, 53–60. https://doi.org/10.1016/j.nicl.2015.08.009
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X. (2015). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry, 78(8), 572–581. https://doi.org/10.1016/j.biopsych.2014.04.010
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Depression is associated with shorter telomeres
Ridout, K. K., Ridout, S. J., Price, L. H., Sen, S., & Tyrka, A. R. (2016). Depression and telomere length: A meta-analysis. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2015.11.052
Verhoeven, J. E., Penninx, B. W. J. H., & Milaneschi, Y. (2019). Unraveling the association between depression and telomere length using genomics. Psychoneuroendocrinology.
https://doi.org/10.1016/j.psyneuen.2018.11.029
Wang, X., Sundquist, K., Hedelius, A., Palmér, K., Memon, A. A., & Sundquist, J. (2017). Leukocyte telomere length and depression, anxiety and stress and adjustment disorders in primary health care patients. BMC Psychiatry. https://doi.org/10.1186/s12888-017-1308-0
Needham, B. L., Mezuk, B., Bareis, N., Lin, J., Blackburn, E. H., & Epel, E. S. (2015). Depression, anxiety and telomere length in young adults: Evidence from the National Health and Nutrition Examination Survey. Molecular Psychiatry. https://doi.org/10.1038/mp.2014.89

Abstract: We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). Our hypothesising follows the Popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. The ‘psilocybin-telomere hypothesis‘ is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). Another pertinent component of our argument is based on recent studies which demonstrate that “meditative states of consciousness” provide beneficial effects on genetic aging. Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). We postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). In order to substantiate the ‘psilocybin-telomere hypothesis’ potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity, hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT2A receptor agonism, neuroplasticity/synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4 serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary, and it has deep ramifications from a philosophy of science perspective as it connects the epistemic level (qualitative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the long term, multidisciplinary and innovative investigations of the ‘psilocybin-telomere hypothesis‘ could contribute to the improvement of senotherapeutic psychological interventions and the identification of novel geroprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve well-being and quality of life during the aging process.

Germann, C. B. (2020). The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging. Medical Hypotheses. https://doi.org/10.1016/j.mehy.2019.109406

More infos: https://psilocybin-research.com/psilocybin-and-genetic-ageing/

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Psilocybin patents
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Statistical methods

- Bayesian analysis
- Markov chain Monte Carlo
(MCMC) simulations
see: https://christopher-germann.de/markov-chain-monte-carlo-mcmc-simulations/

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Bioethics, Directed Evolution, Neurorights & Cognitive Liberty

Prof. Maxwell J. Mehlman “Improved Humans: Legal and Political Aspects of the New Genetics” Templeton Research Lecture

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Cobb, R. E., Chao, R., & Zhao, H. (2013). Directed evolution: Past, present, and future. AIChE Journal, 59(5), 1432–1440. https://doi.org/10.1002/aic.13995
Wang, Y., Xue, P., Cao, M., Yu, T., Lane, S. T., & Zhao, H. (2021). Directed Evolution: Methodologies and Applications. Chemical Reviews, 121(20), 12384–12444. https://doi.org/10.1021/acs.chemrev.1c00260
Sánchez, Á., Vila, J. C. C., Chang, C. Y., Diaz-Colunga, J., Estrela, S., & Rebolleda-Gomez, M. (2021). Directed Evolution of Microbial Communities. In Annual Review of Biophysics. https://doi.org/10.1146/annurev-biophys-101220-072829
Li, G., Dong, Y., & Reetz, M. T. (2019). Can Machine Learning Revolutionize Directed Evolution of Selective Enzymes? In Advanced Synthesis and Catalysis. https://doi.org/10.1002/adsc.201900149
Butt, H., Zaidi, S. S. e. A., Hassan, N., & Mahfouz, M. (2020). CRISPR-Based Directed Evolution for Crop Improvement. In Trends in Biotechnology. https://doi.org/10.1016/j.tibtech.2019.08.001
Tizei, P. A. G., Csibra, E., Torres, L., & Pinheiro, V. B. (2016). Selection platforms for directed evolution in synthetic biology. Biochemical Society Transactions. https://doi.org/10.1042/BST20160076
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Family Type Mechanism Potential
5-HT1 Gi/Go-protein coupled. Decreasing cellular levels of cAMP. Inhibitory
5-HT2 Gq/G11-protein coupled. Increasing cellular levels of IP3 and DAG. Excitatory
5-HT3 Na+ and K+ cation channel. Depolarizing plasma membrane. Excitatory
5-HT4 Gs-protein coupled. Increasing cellular levels of cAMP. Excitatory
5-HT5 Gi/Go-protein coupled. Decreasing cellular levels of cAMP. Inhibitory
5-HT6 Gs-protein coupled. Increasing cellular levels of cAMP. Excitatory
5-HT7 Gs-protein coupled. Increasing cellular levels of cAMP. Excitatory
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Recent advances in optogenetics have opened new routes to drug discovery, particularly in neuroscience. Physiological cellular assays probe functional phenotypes that connect genomic data to patient health. Optogenetic tools, and in particular tools for all-optical electrophysiology, now provide means to probe cellular disease models with unprecedented throughput and information content. These techniques promise to identify functional phenotypes associated with disease states and to identify compounds that improve cellular function regardless of whether the compound acts directly on a target or through a bypass mechanism. This review discusses opportunities and unresolved challenges in applying optogenetic techniques throughout the discovery pipeline, from target identification and validation, to target-based and phenotypic screens, to clinical trials.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495001/ https://www.qstatebio.com/

Optogenetics in neuroscience drug discovery
The impact of optogenetics will likely be greatest in drug discovery for neuroscience. On the
one hand, genetic studies are implicating an ever widening array of mutations, ranging from
rare large effect-size mutations in the epilepsies [2, 3] to common individually weak
mutations in psychiatric disease [4, 5]. On the other hand, the core functions of neurons are
electrical spiking and synaptic transmission. Due to the complex nonlinear interactions of
multiple ion channels within cells, and of multiple cell types within circuits, the
neurophysiological consequences of newly identified mutations can almost never be
predicted a priori, nor can one reliably predict how pharmacological modulation of a
particular target will affect brain function overall. Even as more targets are identified,
neuroscience drug discoverers are turning toward a cell- and circuit-centric phenotypic
approach [6, 7], rather than focusing on specific targets.

Key advantages:
(1) the ability to deliver temporally and spatially precise stimuli to elicit defined patterns
of molecular and cellular activity, (2) the rapid proliferation of fluorescent protein reporters
for a huge diversity of molecular and physiological signals, and (3) the ability to use genetic
techniques to target stimulus and readout to specified cell-types within a possibly complex
multicellular milieu. These capabilities give optogenetic assays throughput and information
content that transcend the limits of more traditional approaches

Serotonin transporter
Slice through the human serotonin transporter structure illustrating the SSRI binding sites. Citalopram is shown at the central site in purple and at the allosteric site in yellow. Jonathan A. Coleman, Evan M. Green, and Eric Gouaux, Oregon Health and Science University
https://www.frontiersin.org/articles/10.3389/fncel.2017.00117/full
SERT
https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0217377.g002

Serotonin Transporter Genotype Modulates the Gut Microbiota Composition in Young Rats, an Effect Augmented by Early Life Stress

https://www.frontiersin.org/articles/10.3389/fncel.2017.00222/full

SERT+/− rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations.

does psilocybin modulate microbionme
test: DNA was extracted from fecal samples using the PowerFecal DNA Isolation Kit (Mo Bio Laboratories, Inc., Carlsbad, CA, United States) following the manufacturer’s protocol. DNA concentration and purity (260/280 and 260/230 ratios) was quantified using NanoDrop 2000c (Thermo ScientificTM) and samples were thereafter stored at -20°C until further use.

The adverse early life conditions have been linked to increased sensitivity to anxiety- and depression-like behavior in subjects with lower expression of 5-HTT (Carola et al., 2008; van den Hove et al., 2011). However, to the best of our knowledge, the effect of the combination of these factors on the microbiota composition has yet not been investigated. Our study shows that the 5-HTT genotype, especially when combined with early life stress results in a state of microbiota dysbiosis. This dysbiosis is characterized by abundance distribution of members of the gut microbiota previously reported to be associated with a state of intestinal inflammation, including inflammation typically seen in cases of brain disorders such as autism, major depressive disorder and Parkinson’s disease. This is intriguing taking into account the role of 5-HTT in the gut. 5-HTT plays a key role in clearance of 5-HT by its rapid uptake to maintain optimal extracellular availability of 5-HT in the gut to facilitate its physiological actions and prevent receptor desensitization (Gill et al., 2013) In fact, several lines of evidence support downregulation of 5-HTT in inflammatory (Martel, 2006) or diarrheal disorders (Foley et al., 2007). In addition, recent studies have demonstrated 5-HTT downregulation via alterations in its gene expression in response to pro-inflammatory agents such as TNF and IFN-g. We and others have previously shown that opportunistic commensals (also known as pathobionts) flourish in an inflammatory gut environment [which is known to be associated with early life stress (Lennon et al., 2013) and 5-HTT genotype (Bischoff et al., 2009; Haub et al., 2010)] resulting in an imbalance in the microbiota community (Gaboriau-Routhiau et al., 2009; El Aidy et al., 2014). Thus, our data refer to a causal effect of 5-HTT genotype and/or early stress in the observed state of microbial dysbiosis.

Velando, A., Noguera, J. C., Aira, M., & Domínguez, J. (2021). Gut microbiome and telomere length in gull hatchlings. Biology Letters, 17(10). https://doi.org/10.1098/rsbl.2021.0398

Chakravarti, D., Hu, B., Mao, X., Rashid, A., Li, J., Li, J., Liao, W., Whitley, E. M., Dey, P., Hou, P., LaBella, K. A., Chang, A., Wang, G., Spring, D. J., Deng, P., Zhao, D., Liang, X., Lan, Z., Lin, Y., … DePinho, R. A. (2020). Telomere dysfunction activates YAP1 to drive tissue inflammation. Nature Communications, 11(1), 4766. https://doi.org/10.1038/s41467-020-18420-w

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Genetic screening to predict variations in psychological response to psychedelics

To date, there has been no peer-reviewed research identifying genes that can be used to predict how individuals will react to psychedelics.

"HTR2A TT (AA) carriers with higher 5-HTR2A receptor density, could be more susceptible to stronger hallucinogenic effects through increased receptor activity and may wish to consider a lower starting dose when undergoing potential psychedelic therapy,” states HaluGen.

https://www.halugen.com/test

"Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects"

Longitudinal studie: Long-term effects on executive functions (i.e., Stroop, syllogistic reasoning, inhibitory top-down processes, etc.).

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Reckweg, J., Mason, N. L., van Leeuwen, C., Toennes, S. W., Terwey, T. H., & Ramaekers, J. G. (2021). A Phase 1, Dose-Ranging Study to Assess Safety and Psychoactive Effects of a Vaporized 5-Methoxy-N, N-Dimethyltryptamine Formulation (GH001) in Healthy Volunteers. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2021.760671

Future research: Comparative effects of 5-MeO-DMT and psilocybin on telomeres (and telomerase activity) in order to systematically isolate the peretinent mechanisms of action in a rigorous experimental design, i.e., multi-factorial structure-activity relationships at various levels of analysis (viz., psychological, neuronal, molecular, (epi)genetic).

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