Toward a Logic of the Organism: A Process Philosophical Consideration

Mathematical models applied in contemporary theoretical and systems biology are based on some implicit ontological assumptions about the nature of organisms. This article aims to show that real organisms reveal a logic of internal causality transcending the tacit logic of biological modeling. Systems biology has focused on models consisting of static systems of differential equations operating with fixed control parameters that are measured or fitted to experimental data. However, the structure of real organisms is a highly dynamic process, the internal causality of which can only be captured by continuously changing systems of equations. In addition, in real physiological settings kinetic parameters can vary by orders of magnitude, i.e., organisms vary the value of internal quantities that in models are represented by fixed control parameters. Both the plasticity of organisms and the state dependence of kinetic parameters adds indeterminacy to the picture and asks for a new statistical perspective. This requirement could be met by the arising Biological Statistical Mechanics project, which promises to do more justice to the nature of real organisms than contemporary modeling. This article concludes that Biological Statistical Mechanics allows for a wider range of organismic ontologies than does the tacitly followed ontology of contemporary theoretical and systems biology, which are implicitly and explicitly based on systems theory.

Modern aspects of biological modeling of sexual development disorders

Введение. Изучение механизмов развития репродуктивных нарушений в условиях эксперимента на крысах является одним из важных направлений современной патофизиологии. Крыса имеет функционирующий эстральный цикл, трехнедельную гестацию и гемохориальный тип плацентации. На циклических изменениях в яичниках и эпителии влагалища крысы базируется биологическое моделирование эндокринной гинекологической патологии. В настоящее время интерес представляет разработка экспериментальной модели нарушения полового созревания в периоде детства. Нарушение полового созревания может приводить к различным патологическим изменениям в сфере репродуктивного здоровья в будущем, актуальность данной проблемы очевидна. Цель работы - изучение современных аспектов моделирования преждевременного полового созревания у девочек. Методика. Анализ современных отечественных и зарубежных работ, касающихся механизмов преждевременного полового созревания и исследований в области моделирования данной патологии в экспериментах на крысах. Результаты. Преждевременное половое созревание у девочек - нарушение, проявляющееся развитием одного или комплекса признаков половой зрелости до 7 летнего возраста. Детерминация полового развития связана с особенностью генетических и эпигенетических факторов. К последним традиционно относят характер питания, стресс как адаптационную реакцию, интегрированную с активацией гормонопоэза. Фактор питания связан с функционированием гормонов жировой ткани, включая лептин, грелин, эффектами инсулиноподобного фактора роста. В ряде экспериментальных исследований, связанных с воздействием факторов питания, стресса и световой дезадаптации на репродуктивную систему животного, доказано значимое влияние последней на нейромедиаторные системы мозга. Наименее изученными в механизме преждевременного полового созревания остаются вопросы нейроэндокринной регуляции гонадной оси системой KISS/KISS1R. Продолжение изучения ассоциации изменения профиля нейромедиаторов моноаминового ряда и динамики кисспептина в эксперименте на крысах способно расширить представление о механизмах половой дифференцировки мозга и транслировать полученные данные в клиническую практику, связанную с обследованием девочек с преждевременным половым созреванием. Заключение. В связи с малой распространенностью и ограниченностью представлений о патогенезе преждевременного полового созревания, данная проблема требует детального изучения. Необходимо дальнейшее изучение патогенетических основ данной патологии в условиях биологического моделирования на самках крыс раннего возраста. Introduction. Studying pathogenetic mechanisms responsible for development of reproductive disorders in rat models is an important direction of modern pathophysiology. The rat has a functioning estrous cycle, a three-week gestation, and a hemochorial placentation. Biological modeling of endocrine gynecological pathology is based on cyclic changes in the ovaries and in the epithelium of the rat vagina. Currently, the development of an experimental model of puberty disorders in childhood is of interest. Premature puberty can lead to various pathological changes in future reproductive health. The relevance of this problem is obvious. The aim of this work was to study modern aspects of modeling premature puberty in girls. Method. Modern domestic and foreign reviews on the mechanism of premature puberty and studies of modeling this pathology in experiments on rats were analyzed. Results. Premature puberty in girls is a disorder manifested by the development of one or all signs of puberty as early as before the age of 7 yrs. Sexual development is associated with characteristic roles of genetic and epigenetic factors. The latter traditionally include nutrition and stress as an adaptive reaction integrated with the activation of hormone synthesis. The nutrition factor is related with the functioning of adipose tissue hormones, including leptin, ghrelin, and the effects of insulin-like growth factor. A number of experimental studies on rats addressing effects of nutrition, stress, and light maladaptation on the reproductive system have demonstrated its significant effect on brain neurotransmitter systems. Regarding the mechanism of premature puberty, the least studied issue is the neuroendocrine regulation of the gonadal axis by the KISS/KISS1R system. Continuing study of the association between changes in the profile of monoamine neurotransmitters and the dynamics of kisspeptin in experiments on rats can expand understanding of sexual differentiation mechanisms in the brain. The obtained data can be translated into clinical practice for the management of premature puberty in girls. Conclusion. Due to the rare prevalence of premature puberty and insufficient data on its pathogenesis, this problem requires detailed study. It is necessary to further study the mechanism of this pathology by biological modeling on female rats at an early age.

Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non–Small-Cell Lung Cancer

PURPOSE KRAS-mutated ( KRASMUT) non–small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among KRASMUT NSCLC molecular subgroups. MATERIALS AND METHODS In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with KRASMUT NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers). RESULTS Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: KRAS MUT/ TP53 MUT, KRAS MUT/ CDKN2A/ B/ C MUT, KRAS MUT/ STK11 MUT, KRAS MUT/ KEAP1 MUT, KRAS MUT/ STK11 MUT/ KEAP1 MUT, KRAS MUT/ PIK3CA MUT, KRAS MUT/ ATM MUT, and KRAS MUT without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the KRAS MUT/ TP53 MUT, KRAS MUT/ PIK3CA MUT, and KRAS MUT alone subgroups and resistance in the KEAP1 MUT containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the KRAS MUT/ CDKN2A/ B/ C MUT, KRAS MUT/ STK11 MUT, and KRAS MUT/ ATM MUT subgroups. In an exploratory clinical cohort of 34 patients with advanced KRASMUT NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival ( r = 0.80, P < .001). CONCLUSION CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of KRASMUT NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.