Journal of Mind and Medical Sciences—A Journal of Bidirectional Emergence in Health and Disease

Abstract

Contemporary clinical medicine relies on the integration of clinical observation with physiological and pathological mechanisms to improve diagnosis, therapeutic decision-making, and patient outcomes. However, most current biomedical research interprets these mechanisms predominantly through the lens of upward emergence, according to which higher-order biological functions arise from the interaction of simpler lower-level components. Although indispensable for understanding visceral diseases, this perspective provides only partial access to biological complexity. Accumulating evidence from neuroscience, developmental biology, endocrinology, psychiatry, and regenerative medicine shows that higher-level systemic functions can also reorganize, modulate, or generate lower-level structures, a phenomenon known as downward emergence. Together, upward and downward emergence form a bidirectional framework that more accurately reflects the complex organizational pattern of biological systems. This editorial argues that clinical practice and biomedical research must explicitly acknowledge this bidirectional dynamic, as many diseases (including malignancy) cannot be fully understood through upward emergence alone. Downward emergent processes explain phenomena such as morphogenesis, regeneration, matrix remodeling, immunological reprogramming, endocrine-neurovegetative integration, and forms of pathological transformation that are difficult to interpret through classical reductionism. Viewing cancer as the pathological expression of a disturbed supracellular program provides a coherent explanation of its complex biology and highlights the possibility that malignant progression could be responsive to higher-order regulatory instructions. In this context, the Journal of Mind and Medical Sciences is undertaking a conceptual and editorial realignment, positioning itself as a journal of bidirectional emergence in health and disease. Rather than diminishing its clinical mission, this shift strengthens it by providing a more comprehensive framework for understanding physiological and pathological organization, one that integrates structure–function and function–structure relationships. As medicine moves toward increasingly integrative and mechanistic models of disease, adopting a bidirectional perspective becomes not only scientifically justified but also necessary for advancing diagnostic accuracy, therapeutic innovation, and the development of novel supracellular strategies for human health.

1. Introduction

Clinical medicine aims to maintain health, prevent disease, and optimize therapeutic outcomes by accurately identifying clinical manifestations, establishing a correct diagnosis and implementing evidence-based treatment [1]. However, effective clinical practice cannot rely solely on the descriptive observation of signs and symptoms, nor can it be reduced to the rigid application of standardized diagnostic and therapeutic protocols. Although guidelines represent essential frameworks of reference, they provide only minimal standards of care [2]. Therefore, real-world clinical decision-making must be adapted to the contextual (bio-psycho-social) particularities of each individual patient, reflecting the well-established principle that diseases do not exist independently of the people who experience them. This principle, formulated in the early decades of the 20th century as “there are no diseases, only patients”, has gained even greater relevance in contemporary practice with the expansion of personalized medicine [3].

While the individual particularities of each patient may contribute to the heterogeneity of disease expression in different subjects, the physiological and pathophysiological mechanisms underlying the disease constitute fundamental determinants of its onset, biological progression and prognosis [4]. These mechanisms are dynamic, interconnected, and often influenced by associated comorbidities, usually having specific and quantifiable parameters for each pathology (cardiomegaly, renal dysfunction, hepatic impairment, etc.) [5,6]. Consequently, a scientifically grounded medical approach must integrate clinical observation with a deep understanding of physiological and pathophysiological processes. Such integration allows clinicians to move beyond standardized diagnosis and treatment, in favor of understanding the dynamics of causal processes that shape both the manifestation of disease and the course of treatment and recovery [7,8]. It is not surprising that classifying diseases according to their pathophysiological mechanisms is substantially more informative and clinically relevant than relying on classifications derived solely from symptomatology [9].

Naturally, the current editorial landscape is dominated by journals that investigate health and disease in close correlation with the physiological and pathophysiological mechanisms that underlie them. This principle is the basis of translational medical research, commonly described in the literature as the continuous cycle “from bench to bedside and back again” [10]. In line with this vision, countries around the world have established programs designed to strengthen the mutual exchange of knowledge between laboratory research and clinical practice, promoting a dynamic interface in which discoveries, clinical observations, and therapeutic experience continuously inform and refine each other [11].

However, most contemporary studies and publications examine these mechanisms almost exclusively from an upward emergent perspective [12]. Such a perspective is important, but biologically incomplete [13,14]. Physiology and pathophysiology are dynamic phenomena, governed not only by the influence of lower levels on higher ones (upward emergence), but also by the reverse action, through which higher functions can reorganize, modulate, or remodel lower biological substrates (downward emergence) [15]. This duality/bidirectional emergence reflects the authentic logic of biological organization: structure generates function, and function, in turn, can reshape structure [16,17]. The phenomenon of downward emergence is well documented and widely recognized in neuroscience, developmental biology, endocrinology, psychiatry, and experimental medicine, and so it cannot be overlooked in the modern understanding of health and disease [18,19,20].

The Journal of Mind and Medical Sciences does not necessarily change its clinical scope by encouraging a bidirectional approach to the emergence of physiological processes and diseases, but rather anticipates a direction that clinical medicine and biomedical research will inevitably adopt. Clinicians already turn to pathophysiological mechanisms when standard guidelines and protocols prove insufficient, as doing so allows them to remain aligned with the inherent logic by which biological systems operate [21]. Thus, the inclusion of bidirectional emergence principles reinforces, rather than replaces, the clinical mission of the journal. In this way, the journal provides a more coherent and comprehensive foundation for diagnosis, therapeutic decision-making, and the development of new medical strategies, as illustrated in the final section of this editorial.

2. Discussion

Generally, contemporary medical research relies largely on a systematic and rigorous methodological framework, which involves regulations, standardization, statistical analysis, replicability, and transparency [22,23,24]. Such a structured approach provides a coherent protocol for scientific investigation, allowing researchers to formulate precise research questions and design studies with clearly defined objectives, appropriate methodologies, and explicit criteria for interpreting results. Methodological architecture is inherently aligned with biological investigations that are based on upward physiological emergence [25]. This compatibility explains the remarkable success of standardized research in elucidating cellular pathways, molecular interactions, and organ-specific functions, domains in which both the elementary components and their emergent properties remain quantifiable and therefore accessible to protocol-based investigations [26].

Although the progress of knowledge achieved through such a demanding procedure is substantial and measurable, it remains sensitive to intrinsic limitations: methodological constraints, regulatory boundaries, and predefined objectives that can restrict our ability to recognize unforeseen phenomena [27]. Furthermore, this methodological research provides a partial access to biological complexity, as it is conceptually aligned only with upward physiological emergence, thus providing limited access to processes governed in reverse by downward physiological emergence [28].

By contrast, the investigation of unexplained or paradoxical natural phenomena cannot always be carried out according to such a rigid methodological protocol. In medicine, such phenomena and observations have been the basis of accidental but remarkable discoveries, such as penicillin, insulin, warfarin, sildenafil, etc. [29,30,31,32]. In these cases, the researcher’s intuition, known in the literature as “gut feeling”, plays a decisive role in recognizing the latent scientific potential of unexpected discoveries [33,34]. Sometimes, the mechanisms behind these phenomena are easy to explain, facilitating their integration into existing conceptual frameworks. In other cases, however, unexpected or inexplicable observations are difficult to reproduce or understand within the scientific theories and knowledge at the dime of discovery. When this happens, these observations may require either new research perspectives, capable of redefining established models and explanatory boundaries, or a downward emergence approach, capable of identifying forms of biological organization that cannot be captured through the traditional lens of upward emergence.

Together, upward and downward emergences form a bidirectional framework that reflects the true organizational logic of biological systems. The upward emergence explains how structure gives rise to function; the downward emergence explains how function can reorganize or generate structure [35,36]. Their interaction defines the core of supracellular dynamics, providing a more complete and coherent perspective on physiology and disease. This integrated view reveals that biomedical science must expand beyond its exclusive reliance on reductionist methodologies. Understanding biological complexity requires approaches capable of capturing both the construction of function from structure and the generation of structure from function, which is a fundamental duality in biology and medicine [37].

2.1. Upward Emergence in Biology

In biology and medicine, upward emergence refers to situations in which simpler elements interact and organize into higher-level structures. The resulting physiological entity exhibits properties that cannot be fully investigated or understood through the isolated analysis of its basic components, because these properties arise from the collective, coordinated, and complementary contributions of the constituent elements [38].

At the cellular level, functions are relatively simple and well defined: metabolic regulation, ionic homeostasis, mitochondrial energy production, protein synthesis and degradation, maintenance of cytoskeletal architecture, etc. [39,40]. When cells assemble into tissues, new properties emerge (polarity, cohesion, coordinated spatial organization, cell–matrix interactions, paracrine communication, etc.), functional attributes that cannot be inferred directly from the biology of an isolated cell [41,42].

The subsequent organization of tissues into organs generates even more complex functions, such as blood filtration in the kidneys, electrical impulse generation in the heart, or information processing in the cerebral cortex. These emergent functions cannot be interpreted exclusively in cellular or tissue terms, as they result from the three-dimensional architecture, spatial distribution, vascular integration, and the neuro-hormonal control of the organ [43,44].

Furthermore, the integration of individual organs into larger apparatuses and systems generates an additional leap in biological complexity. Processes such as respiration, digestion, endocrine homeostasis or the immune response cannot be reduced to the isolated function of any single organ. Instead, they arise from the dynamic coordination of multiple organs and tissues, interconnected through layered physiological networks and regulatory signals that collectively sustain the systemic function [45,46,47].

The highest level of biological organization is the organism itself, a state in which human bio-psycho-social integrity cannot be explained by simply summing its component parts in isolation. Processes such as social interaction, emotional regulation, adaptive behavioral responses to the external environment, or global homeostatic self-regulation represent higher-order emergent functions [48,49,50]. These functions become possible only through the coherent integration and coordinated operation of all lower organizational levels: cells, tissues, organs, and systems.

In conclusion, upward emergence generates a hierarchy of increasing organizational complexity, with each new level depending on the properties of its lower parts, but also being inexplicable by them alone.

2.2. Downward Emergence in Biology

If upward emergence describes how simple elements cooperate to generate higher levels of organization, accompanied by emergent functions, downward emergence refers to situations in which the functions of complex systems initiate and guide the formation of new tissues, architectures, or biological forms. Unlike upward emergence, in which structure determines function, in downward emergence the systemic function precedes form, organizing molecular and cellular resources to produce new structures [51,52].

Downward emergence is essential for supracellular processes such as embryogenesis, regeneration, development, and adaptation [53,54]. In general terms, these processes integrate heterogeneous sources of information and structures (the cellular genome, the extracellular matrix, mechanical tension, endocrine signals, neurovegetative networks and environmental stimuli) to generate an operational framework that coordinates the behavior of lower-level components [55]. This coordination governs gene activation to initiate or stop proliferation, the reorganization of the extracellular matrix, the modulation of differentiation, the establishment of morphogenetic fields, the directionality of cell migration, and the dynamics of tissue repair [56,57]. All these processes converge toward a coherent structural biological finality.

In informational terms, supracellular processes operate as orchestration mechanisms based on distributed information vectors, which cannot be confined to a single cell or structural unit. They reflect the organism’s capacity to integrate information at the macro level, to process it, and to generate coherent instructions directed toward lower organizational levels, instructions that become operational in the generation of new structures [58]. As a result, the resulting biological architectures are not entirely pre-encoded within any single elementary component. Rather, they emerge from the systemic integration of continuous, variable, and dynamic information, which the organism transforms into directed flows of decentralized data [59].

An essential aspect of this dynamic is the dual role of micro-components. Structures such as the genome, the extracellular matrix, or the tissue microenvironment act simultaneously as information vectors (providing data necessary for the elaboration of downstream instructions) and as elements receptive to lower-level instructions (thus being directly involved in the generation of new biological architectures). In other words, the micro level contributes to both feeding the supracellular program with the information necessary for making functional decisions, and to implementing these decisions in new structures [60]. This feedback loop is indispensable, enabling processes such as tissue repair to occur in accordance with the extent and nature of the injury. However, it also represents a point of vulnerability: when regulatory mechanisms fail, the feedback may become self-sustaining, driving, for example, persistent proliferative signaling that can give rise to malignant transformation [61,62,63].

Embryogenesis is not a simple accumulation of cell divisions, but the result of a supracellular program by which global information establishes the time, place and direction in which new structures are formed [64,65]. Similarly, wound regeneration, scar tissue formation, bone remodeling in response to mechanical stress, muscle hypertrophy induced by exercise, or epithelial renewal all illustrate the ways in which systemic functions shape and reorganize biological structure [66,67,68,69].

In conclusion, the phenomenon of downward emergence complements the upward emergence described above. Together, they form the bidirectional dynamics of biological organization and constitute the foundation of supracellular processes that govern the development of the organism, the maintenance of its integrity, and the ability to heal.

2.3. Cancer as a Pathological Expression of Supracellular Downward Emergence

The illustrative power of concrete biological examples often surpasses the explanatory capacity of theoretical models. For this reason, the following section examines malignancy through the lens of supracellular downward emergence. From this perspective, it can reasonably be concluded that cancer therapy could become much easier to perform and more effective in the near future than infection control is today.

Infections are usually caused by unicellular (bacteria) or subcellular (virus) pathogens [70,71]. These individual biological entities are capable of rapidly multiplying, aggressively invading the host environment and, in extreme cases, severely disrupting the homeostasis of the organism, as in severe sepsis [72]. Controlling these pathogens can be difficult because they function autonomously and are evolutionarily equipped for rapid and independent survival/proliferation.

Malignancy is fundamentally distinguished from infectious pathology, because the proliferation of cancer cells (derived from the body’s own cells) is not analogous to the multiplication of (exogenous) pathogenic agents.

Under physiological conditions, the number, specialization, and functional activity of cells are directed by supracellular regulatory mechanisms, which coordinate cellular behaviors (proliferation, differentiation, secretion of hormones, enzymes, etc.) according to the needs of the body. Therefore, somatic cell mitoses have the status of physiological subunits within supracellular processes (embryogenesis, regeneration, development, adaptation, etc.) [73,74].

At the pathophysiological level, there are two theoretical scenarios that could explain the emergence of malignancy.

The first possibility would assume that a somatic cell functionally disconnects from the organism and begins to multiply autonomously, similar to a unicellular organism (a “rebellious” cell, uncontrollable by the body) [75,76]. However, this scenario is not feasible, since unicellular organisms never lead to cancer [77].

The second possibility assumes that the disconnection from the organism does not occur at the cellular level, but rather at the supracellular level. A supracellular process disconnected from the body’s needs would become dysfunctional, thus causing improper coordination of cell proliferation [78,79].

The scenario of a dysfunctional supracellular process is much more plausible, as it is able to explain not only exacerbated cell proliferation, but also the complex/supracellular pattern of cancer progression (reorganization of the extracellular matrix, recruitment of tumor-associated fibroblasts, angiogenesis, immunosuppression, metabolic remodeling—Warburg effect, generation of a chronic proinflammatory microenvironment, etc.) [80,81,82].

Furthermore, the supracellular perspective is able to explain phenomena that are difficult to interpret, such as spontaneous cancer regressions, the transformation of malignant tumors into benign structures, or a tumor microenvironment that is capable of normalizing tumor cells [83,84,85]. In such cases, the intervention of a key supracellular mechanism (operating as an informational vector) may either suppress proliferation or redirect the proliferative program towards benign phenotypes.

Table 1. Dual interpretation of malignancy.

Item	Upward Interpretation	Downward Interpretation
Cancer cell condition	The cause of malignancy	The effect/expression of malignancy
Interpretation of increased cell mitosis	Uncontrollable	Controllable, as cells are responsive to supracellular directives, even when inappropriate
Cause of malignancy	A cellular disease (genetic and epigenetic mutations)	A supracellular disease (inadequate supracellular control of proliferation)
Effect of malignancy	Uncontrolled mitosis/multiplication	Sustained supracellular coordination of cell proliferation, matrix formation, angiogenesis, immunosuppression, etc.
Role of the genome	The genome belongs to the cell and becomes the driver of uncontrolled multiplication	The genome is of the organism, generating supracellular instructions to cells, extracellular matrix, etc.
Analogy with other pathologies	Cancer cell multiplication cannot explain the complex biology of cancer	Gestational trophoblastic disease: trophoblastic invasion, with angiogenesis and immunosuppression. The cells lose their aggressive behavior after pregnancy.
Explanation of complex phenomena	Associated phenomena are addressed individually (angiogenesis, invasion, immunosuppression, etc.).	The phenomena are interrelated, being an integral expression of the deviated supracellular process.
Tumor heterogeneity	Result of mutation accumulation and clonal selection.	Manifestation of the flexibility and plasticity of a deregulated supracellular program.
The role of the tumor microenvironment	Secondary component that favors progression.	Integral part of supracellular process, supracellular remodeling.
The origin of angiogenesis, invasion, metastasis	Result of local hypoxia and distinct mutations in cells.	Behaviors emerging from dysregulation of supracellular control, including angiogenesis.
The vision of cancer	Local disease, with distant dissemination	Systemic disease, caused by dysregulation of a supracellular program (embryogenesis, regeneration, development or adaptation)
Therapeutic implications	Targeting cellular pathways.	Restoring normal supracellular control or reprogramming it towards a benign evolution program

summarizes the fundamental differences between the two approaches: upward emergence, which views cancer as the result of uncontrolled cell proliferation (driven primarily by genetic mutations and cell-cycle dysregulation), and downward emergence, which interprets cancer as the consequence of a dysregulated higher-level (supracellular) program.

Malignant melanoma exhibits remarkable biological behavior through phenotypic plasticity [86], migratory capacity [87], immunological resistance [88], and partial pluripotency [89]—features that are difficult to explain solely by the accumulation of cellular mutations. The specialized literature suggests that melanoma reactivates mechanisms specific to the embryogenesis program, including those of the neural crest and the trophoblast, reproducing both the embryonic migration characteristic of neural crest cells and the mechanisms of gestational-type immunosuppression [90,91]. The data presented in

Table 2. Melanoma.

Literature Data	Finding
Melanoma re-expresses embryonic genes and stem programs	Melanoma cells exhibit an “embryonic-stem phenotype”, re-expressing developmental programs and embryonic genes.
Melanoma pluripotency (differentiation into multiple tissue lineages)	Melanoma can mimic carcinoma, sarcoma, lymphoma, stromal tumors, osseocartilaginous tumors, etc., a phenomenon specific to embryonic stem cells.
Melanoma behaves as a deviated embryogenetic program	Melanoma combines features of embryoblast and trophoblast, suggesting a reactivated ancestral embryogenetic program.
Trophoblastic behavior: invasion, immune evasion, angiogenesis	Invasive capacity and immunosuppression are characteristics of trophoblasts; melanoma expresses trophoblastic factors.
Expression of trophoblast antigens (HLA-G, 5T4)	Melanoma expresses HLA-G and oncofetal antigen 5T4, which are physiologically used for gestational immunosuppression.
Gestational-type immunosuppression	Melanoma expresses HLA-G and activates CTLA-4/PD-1 pathways similar to pregnancy, generating immunological tolerance.
Melanoma is one of the most common cancers in pregnancy	Melanoma’s access to embryogenetic and gestational immunosuppression mechanisms.
Melanoma can become benign during pregnancy or in the newborn	Complete regressions of metastases in contexts where embryological high-order guidance becomes dominant.
Complete reprogramming in the embryonic microenvironment	The embryonic environment overrides the malignant phenotype, leading to reduced clonogenicity and tumorigenicity, with a return to the benign phenotype.
Blastocyst cloning using melanoma nucleus leads to embryonic stem cells	The nucleus from melanoma can support the formation of embryonic stem cells that differentiate normally.
Melanoma is derived from neural crest cells	Melanocytes originate from the neural crest; melanoma retains this embryological program.
Nodal signaling (embryonic morphogen) reactivated in melanoma	Nodal signaling, absent in normal skin, is reactivated and drives melanoma invasiveness; inhibition leads to reversion to the melanocytic phenotype.
Activation of the neural crest migration program (Wnt, NGF, Sox10, Rac1)	Melanoma reactivates embryological neural crest signals, including those that determine embryological migration.
Migration along neural crest routes in the embryo	Melanoma cells injected into zebrafish embryos become non-neoplastic and migrate along normal neural crest routes.
Zebrafish model: melanomas express neural crest identity at initiation	Animal models show the emergence of neural crest identity in melanoma initiation.
Evolutionary compatibility between the neural crest program and melanoma	Reprogramming to an embryonic program common to all vertebrates explains the systemic behavior of melanoma.

synthesize experimental, clinical, and molecular evidence, supporting the interpretation of melanoma as a reactivated, but inadequately coordinated, embryogenesis program.

Although the present article has mainly examined bidirectional emergence from a medical and physiological standpoint, numerous studies demonstrate that top-down emergence also operates in the domain of mental processes, influencing attention, emotion regulation, memory, and executive functions [92,93,94]. Given the conceptual breadth and methodological complexity of these interactions, the bidirectional dynamics between brain structures and mental functions will be addressed in detail in a subsequent manuscript.

3. Conclusions

As long as clinical reasoning and research methodology remain primarily conceptually focused on upward emergence, the component of physiological and pathophysiological organization generated by downward emergent mechanisms will continue to be underrepresented in biology and medicine. However, accumulating evidence from neuroscience, developmental biology, endocrinology, psychiatry, and regenerative medicine clearly demonstrates that many diseases manifest and evolve through downward emergent pathophysiological processes.

Accordingly, the perspectives, approaches, and arguments presented in this editorial suggest an imminent, profound, and inevitable conceptual transition in clinical medicine and biomedical research. This transition does not imply a possible competition between the two forms of emergence underlying biological systems, but rather a relationship of complementarity in which upward and downward emergence operate as convergent explanatory frameworks. Their integration provides a much more comprehensive and refined model of physiological and pathological organization, with significant potential to advance our understanding of health, disease, and therapeutic strategies.

A journal dedicated to clinical medicine and neuroscience cannot remain conceptually static when the disciplines it serves undergo structural conceptual renewal. As a result, the Journal of Mind and Medical Sciences is undertaking the mission of proactively redefining its scope, recognizing and thus supporting the methodological and theoretical transition towards a bidirectional emergence in contemporary medicine. The field is shifting, and the journal must shift with it.

Humanity has discovered the wheel, the automobile, spaceflight and, more recently, artificial intelligence. Despite these remarkable scientific advances, we continue to consider the cancer cell almost exclusively as a biological adversary. We forget that it is actually a cell of the body, profoundly modified functionally and structurally, but still receptive to microenvironmental signals and capable of executing the instructions it receives. Although we are using artificial intelligence to create increasingly sophisticated artificial systems, we have not yet applied this technological superintelligence to protect living systems through a deeper understanding and more effective control of malignancy.

The cancer cell, far from being completely autonomous, remains receptive to local, systemic, and potentially supracellular instructions, signals that we do not yet know how to formulate. A genuine paradigm shift may therefore require not only the destruction of cellular structure, but also the ability to communicate with these structures and processes to restore or divert the downward supracellular program.