Research Roadmap

I. Executive Summary #

The objectives laid out here represent a shift in the field of biology, aiming to fundamentally redefine our approach to biological interventions with a focus on aging. This program seeks to harness the untapped potential of bioelectric modulation, offering a holistic and dynamic methodology for inducing systemic biological changes. Our goal state is to enable precise and scalable manipulation of bioelectric patterns to guide organismal morphology and function.

The program is structured into three phases over a five-year timeline, encompassing proof-of-concept projects, experimental integration, and practical application. We aim to address the limitations of current biological and clinical interventions by implementing a paradigm shift from reductionist to holistic approaches, leveraging bioelectric modulation to achieve targeted interventions at cellular and organismal levels. Our interdisciplinary effort will bring together leading experts from various fields of biology, dynamical systems, and hardware development, to drive this vision forward.

In successfully realizing this vision, Aion promises to open new avenues in treating diseases like cancer, developmental disorders, and aging, while paving the way for innovative approaches in regenerative medicine and personalized therapies. By redefining our understanding of biology and intervention strategies, this initiative stands to make a significant impact on global health challenges, offering a new era of precision and adaptability in biological research and clinical practices.

II. Who is this Roadmap For? #

This roadmap describes a process that might make it possible to intervene in biological systems with far more certainty than what can be done with the existing approaches. The purpose of this roadmap is to lay out an actionable plan to coordinate people to build this technology and it is intended for the following readers:

1. End users who could imagine using the matured technology which could include people working in biopharma, biotechnology, chemical manufacturing, medical and fitness wearables, or beyond.
2. Builders who could be funded to create this technology, including people from academia, government research labs, start-ups, or established companies.
3. Individuals and groups that might be interested in providing philanthropic support of Aion Biosciences to push this forward.
4. Or anyone with an interest in the sciences who thinks there should be more ways to bring useful — or even science-fiction — things to the world.

This roadmap is a living document and needs input from the community. Please reach out to us if you are opinionated about these ideas or can think of ways to make it happen!

III. What Are We Trying to do? #

Central to this program is the exploration and application of bioelectric modulation techniques. The ultimate ambition of this program is the creation of a comprehensive tool for the precise control and modulation of bioelectric signals to direct the morphology and functionality of organisms.

1. Core Objective - Bioelectric Modulation for Biological Transformation: At the heart of the program is the aim to utilize bioelectric modulation as a novel means to induce significant changes in biological systems. Targeting the aging process, the program plans to innovate in the realm of bioelectric interventions to bring about systemic, beneficial biological alterations.
2. Structured Development in Three Phases Over Five Years:
   • Proof-of-Concept Phase: Bioelectric Pattern Mapping: In its initial stage, the program will focus on extensive research and targeted experimentation to fill existing knowledge gaps regarding bioelectric signals in cell cultures and small orgnaisms. This phase is dedicated to laying the groundwork by identifying crucial bioelectric patterns that can be manipulated to influence biological processes, especially those associated with aging.
   • Integration Phase: Progressing from theoretical understanding to practical application, this phase involves the execution of more informed experimental projects. These projects are designed to test and validate the effectiveness of bioelectric modulation in real-world biological contexts, establishing its potential in controlling aging processes and related biological functions.
   • Learning and Exploitation: Scaling Applications: This phase aims to consolidate all findings into a practical guide for bioelectric pattern manipulation. Here, concepts from basal cognitive theory and control theory will come into play to guide strategies for long term bioelectric pattern manipulation in large model species. Additionally, this stage will see the implementation of these techniques in broader applications, targeting age-related diseases and disorders, with the potential to significantly impact regenerative medicine and personalized treatment methods.
3. Implications and Future Directions:
   • The successful culmination of this initiative is expected to usher in new treatment methodologies for age-related conditions, including cancer and other developmental disorders. The program’s approach promises to enhance the scope of regenerative medicine and pave the way for more individualized therapeutic strategies.
4. Shift in Methodological Approach:
   • This initiative represents a strategic shift from conventional, narrowly focused biological intervention methods to a more comprehensive, system-wide approach. Emphasizing the manipulation of bioelectric signals, the program aims to bring about a new level of precision and adaptability in both research and clinical settings, challenging and expanding current understanding and practices in the field.

A. System Goals: Enabling CRUD Operations in Biological Systems via the Electrome #

In the research program, we are taking a novel approach to biological interventions by adopting a software-inspired framework known as CRUD operations. This concept, commonly used in information technology to manage data, is repurposed here to articulate our strategies for manipulating bioelectric patterns within biological systems. By viewing these patterns as dynamic data sets, we can apply the principles of Create, Read, Update, and Delete to initiate, monitor, alter, and remove specific bioelectric signals. This methodology not only represents an innovative cross-disciplinary fusion of ideas but also signifies a major leap in our capacity to understand and influence biological processes with unprecedented precision and control. It’s a transformative step that aligns the rigor and systematization of data management with the intricate complexities of biological systems, that will open new avenues in the field of regenerative medicine, disease treatment, and beyond.

CRUD Operations - Core Strategies in Bioelectric Pattern Manipulation:

• Create: This strategy involves formulating methods to orchestrate single cells or bioengineered constructs into sophisticated, functional assemblies. Central to this is the precise control of bioelectric patterns, guiding cellular behavior to achieve predefined objectives. These methodologies are expected to encompass a range of bioelectric modulation techniques, aiming to shape cellular development and organization for specific purposes like tissue engineering or disease modeling.
• Read: Here, we focus on pioneering technology for the real-time analysis of bioelectric patterns within various biological systems. This includes the creation of advanced diagnostic tools, building on existing resources such as multi-electrode arrays, patch clamps, and the integration of AI models for sophisticated pattern recognition. These technologies will enable a deeper understanding of bioelectric dynamics, crucial for both diagnostic and therapeutic applications.
• Update: This approach targets the modification of existing pathological bioelectric patterns. Specific applications include rectifying abnormal cellular activities in cancer or addressing dysfunctions in aging processes. By precisely adjusting these bioelectric signals, we aim to influence cellular behavior for therapeutic outcomes.
• Delete: This involves researching techniques to safely and effectively erase particular bioelectric signals. Given its ethical and technical complexities, this area demands careful consideration and innovation. We will explore strategies for selectively disrupting harmful bioelectric patterns, ensuring safety and ethical compliance.

B. Technical Benchmarks for the Project #

Key Technical Benchmarks:

• Chemical-Based Cellular Reprogramming: This benchmark focuses on reprogramming various cell types, such as fibroblasts, neurons, and bone cells, using bioelectric cues informed by chemical strategies. Unlike traditional methods relying on transcription factors, our approach utilizes chemical interventions, guided by real-time monitoring of intercellular signaling. The goal is to achieve a significant improvement in iPSC yield, marked by a standard deviation enhancement, by leveraging a tight feedback loop between bioelectric state monitoring and targeted chemical interventions.
• Advanced Electrome Mapping Technologies: The objective is to achieve comprehensive electrome mapping across organisms of diverse complexity, ranging from simple invertibrate models to more complex organisms like mice and primates. We aim to enhance existing technologies such as patch clamps, multi-electrode arrays and voltage fluorescent dye tracking to develop new approaches. We plan to explore other opportunities to innovate such as by integrating upconversion nanoparticle techniques for deeper tissue visualization and employing AI algorithms to infer deep bioelectric patterns from surface-level epithelial data.
• Targeted Phenotypic Alterations via Electrome Modulation: This benchmark involves inducing observable phenotypic changes in organisms through precise electrome modulation. We will explore two primary modulation mechanisms: (1) mRNA injections to modulate the capacity of specific signaling channels by altering ion channel and gap junction densities, and (2) the use of small molecules to regulate the opening or closing of these channels. Additionally, we will investigate non-invasive methods like external electromagnetic stimulation to induce exogenous bioelectric changes.

This coordinated approach, emphasizing interdisciplinary collaboration and integration with academia and industry, is crucial for advancing the understanding and application of bioelectric phenomena in biology. Such a framework not only accelerates research progress but also ensures that the knowledge gained is effectively translated into meaningful, real-world applications.

IV. Current Biological Interventions and Their Limitations #

Overview #

In the realm of biology and medicine, current interventions predominantly revolve around genetic and protein modification techniques. Proteins, the workhorses of the cell, are modified or mimicked to create therapeutic effects. In the clinical sphere, the dominant approach involves the use of small molecule drugs, engineered to interact with specific biological pathways. However, this prevailing paradigm, while having its merits, often fails to fully capture and address the systemic and interconnected nature of biological organisms.

The concept of targeting genes and proteins stems from a reductionist view of biology, where the focus is placed on individual components rather than the organism as a whole. This approach, while it has led to significant advancements, can overlook the broader context within which these components operate. For instance, a gene therapy targeting a specific genetic mutation may not account for the network of interactions that gene has within the cellular environment.

In clinical settings, the reliance on small molecule drugs is rooted in their ease of manufacture and the traditional pharmaceutical development model. These compounds typically interact with specific protein targets, aiming to modulate their activity to achieve a therapeutic effect. However, this approach often does not consider the multifaceted interactions that occur within biological systems. As a result, such interventions can be limited in their scope, failing to address the underlying complexity of many diseases.

Limitations and Challenges in Traditional Approaches #

Scientific Constraints: A major scientific hurdle has been the unpredictability of outcomes in biological interventions due to the complex nature of living systems. Gene therapy exemplifies this challenge, with patients exhibiting highly varied responses to similar treatments. This variability is often rooted in factors such as genetic diversity, different cellular environments, and unique epigenetic landscapes. Similarly, in cancer therapy, two patients with the same cancer type might have vastly different responses to the same pharmacological treatment, influenced by variations in tumor microenvironments, genetic mutations, or immune responses. These cases underscore the necessity for personalized medical approaches and a deeper understanding of biological complexities to achieve consistent and reliable therapeutic outcomes.

Technical Challenges: The field grapples with issues such as inefficiencies in critical processes like the generation of induced pluripotent stem cells (iPSCs), which limit their practical use in therapies. Additionally, advanced molecular analysis techniques like RNA sequencing and proteomics, although powerful, lack detailed time-series data. This shortfall impedes a comprehensive understanding of the dynamic biological processes at play, crucial for effective bioelectric intervention.

Clinical and Practical Challenges: The high costs associated with developing and implementing new therapies posed significant barriers to clinical application. These costs span research and development, clinical trials, and the manufacturing and distribution of therapies. Furthermore, patient-specific treatments, despite their effectiveness, presented challenges in scalability and universal applicability due to their resource-intensive nature.

Knowledge Gaps: A key gap in understanding was the precise mechanisms through which interventions impact systemic biological functions. This uncertainty raised concerns about the long-term effects and potential side effects of treatments, hindering confidence in their efficacy and safety.

This project was conceived to address these myriad challenges. By focusing on novel intervention methods grounded in bioelectric modulation, it promises not only to bridge these knowledge gaps but also to offer more predictable and effective therapeutic outcomes. This initiative represents a paradigm shift in the field, aiming to overcome the pre-existing constraints and unlock new possibilities in understanding and manipulating biological systems.

Implications for the Program #

Transforming Biological Intervention Approaches:

• This program marks a departure from traditional reductionist methods, embracing a holistic approach that centers on bioelectric modulation. This initiative recognizes that effective intervention in biological systems requires a comprehensive understanding that transcends the mere aggregation of individual components.
• Through the targeted manipulation of bioelectric signals, the initiative aims to transcend the constraints of traditional methodologies, promising a route that is not only more precise but also cost-effective and broadly applicable across various biological contexts.

Closing Existing Knowledge Gaps:

• A core objective of the program is to bridge the gaps in our current understanding by melding cutting-edge bioelectric research with tangible clinical applications. This fusion of research and practice is expected to lead to interventions that are both more predictable in their outcomes and scalable in their application.
• Concentrating on the systemic modulation of bioelectric signals, the initiative holds the potential to transform fundamental biological research and clinical practices alike. This could pave the way for novel therapeutic approaches and a more profound comprehension of the intricate mechanisms underpinning biological systems.

V. Technical Novelty and Success Potential of the Bioelectric Modulation Approach #

A. What is Technically New in this Approach? #

This program sets itself apart from conventional biological intervention methods through several novel technical advancements:

1. Advanced Control Through Bioelectric Modulation: The most significant innovation in our approach is the modulation of bioelectric cues for a more effective influence on downstream biological processes. Unlike traditional methods focused on gene and protein modification, our approach targets the bioelectric networks, which hold the key to a vast array of cellular activities and systemic responses.

Figure 1: Intercellular signaling dependent transcription.¹

Past research has highlighted the significant potential of bioelectric modulation in transforming organism phenotypes, evident in the reprogramming of cell fate and inducing whole-organism morphological changes. This transformative effect is primarily achieved through the manipulation of ion channels and gap junctions, which play a vital role in maintaining bioelectric homeostasis in cells and tissues. For instance:

Reprogramming Cell Fate: A study conducted by Chernet and Levin (2013) demonstrated the ability to convert melanoma cells into a benign state by altering their bioelectric status.² This was achieved through the modulation of ion channels, leading to a significant reduction in tumor growth and metastasis.

Morphological Changes in Organisms: In other groundbreaking work it has been shown that bioelectric modulation could lead to the induction of a two headed phenotype in planaria by altering the distribution of specific ion channels, depolarizing blastemas³. This study provided a clear example of how bioelectric cues could dictate complex tissue and organ regeneration. Other work in this same vein revealed how ion channel drug delivery via a wearable bioreactor could facilitate long-term limb regeneration and functional recovery in adult Xenopus laevis, further revealing how the use of bioelectric interventions could lead to drastic but effective outcomes⁴.

In a final example, Levin’s lab successfully induced the formation of ectopic eyes in Xenopus frog embryos through targeted bioelectric modulation. This was accomplished by manipulating the bioelectric gradients across the body of the tadpole, which guided the development of eye structures in non-native locations.⁵

These examples showcase the remarkable capacity of bioelectric modulation to induce significant changes at both the cellular and organismal levels, offering a new paradigm for understanding and manipulating biological processes.

2. Targeted Interventions Across Biological Scales:

Cellular Level: Precision Bioelectric Modulation: At the cellular scale, the technical novelty of this initiative lies in its precision in bioelectric modulation. While past studies have occasionally demonstrated the potential of such approaches in oncology, our initiative systematically applies this method across a broader spectrum of cellular functions. The unique aspect here is the targeted manipulation of ion channels and membrane potentials to control cellular behavior. Unlike traditional methods that focus on genetic alterations, this approach utilizes bioelectric cues to directly influence cell functions, offering a new dimension in cellular therapy and disease management.

Tissue Level: Advanced Bioelectric Signal Patterning: Moving to the tissue level, our initiative introduces advanced bioelectric signal patterning techniques. This method, inspired by isolated past successes, involves creating specific bioelectric landscapes to guide tissue development and repair. The innovation here is the application of controlled bioelectric gradients to direct cell-to-cell communication and organize tissue growth systematically. Such targeted bioelectric modulation at the tissue level opens up new possibilities in regenerative medicine, potentially revolutionizing how we approach tissue repair and regeneration.

Organismal Level: Systemic Bioelectric Interventions: At the organismal level, the initiative breaks new ground by exploring systemic bioelectric interventions. While there have been exceptional cases in the past, such as inducing morphological changes in model organisms, our approach seeks to consistently apply this strategy to understand and influence overall organism development. The technical innovation lies in the systemic modulation of bioelectric signals, aiming to unlock a deeper understanding of their role in organismal health and development. This approach is poised to offer insights into developmental biology and new therapeutic strategies for addressing systemic disorders.

3. Incorporation of Concepts from Control Theory, Dynamical Systems Theory and Causal Emergence:

Innovative Framework for Aging and Development: Our program integrates concepts from control theory and dynamical systems theory, viewing aging not just as a biological process, but as a dynamical system state attractor within the state space of bioelectric patterns. This perspective is rare in the field of aging and organism development, setting our approach apart from conventional methodologies.

Application of Dynamical Systems Theory: The initiative will utilize dynamical systems theory to develop intervention methodologies that are deeply informed by our understanding of bioelectric intervention points. This involves conceptualizing the aging process as a complex, dynamic system that can be influenced or redirected through precise bioelectric manipulations. By applying this theory, we aim to identify and target specific bioelectric state attractors that correspond to aging, devising strategies to shift these attractors towards more desirable states.

Control Theory in Bioelectric Modulation: Control theory will be instrumental in guiding our intervention strategies. By applying principles from control theory, we will develop methods to systematically modulate bioelectric signals across various biological scales. This approach allows us to maintain or alter bioelectric patterns in a controlled manner, effectively managing the dynamical system of aging and organismal development.

Integration of Causal Emergence: Furthermore, the initiative embraces the concept of causal emergence, where macro-scale bioelectric patterns can have more significant causal effects than the sum of micro-level interactions.⁶ This perspective allows us to focus on broader bioelectric patterns and their impact on biological processes, offering a novel approach to understanding and intervening in complex biological systems.

In summary, the technical novelty of the program lies in its integration of control theory, dynamical systems theory, and causal emergence into the study of aging and development. This interdisciplinary approach, while not entirely novel, is exceptionally uncommon and offers a fresh perspective on tackling biological challenges.

B. Why Has This Approach Not Been Realized Before? #

Challenges in Shifting Scientific Perspectives: The shift from a reductionist view, which emphasizes molecular or genetic components, to a focus on bioelectric fields as primary biological control mechanisms, presents significant scientific challenges. Historically, the reductionist approach has dominated due to its success in explicating complex biological phenomena into understandable parts. However, this perspective often overlooked the emergent properties and systemic interactions inherent in biological systems. The evolving understanding of bioelectric fields, emphasizing their role in overarching biological processes, challenges these traditional views. Pioneering studies have begun to highlight the influence of bioelectric patterns on cellular behavior, tissue development, and organismal morphology, supporting this paradigm shift. Nonetheless, integrating this new perspective into the broader scientific framework requires overcoming entrenched biases and advocating for a more holistic view of biology.

Necessity for Interdisciplinary Integration: Our program’s success hinges on an unprecedented level of interdisciplinary collaboration, merging fields like electrophysiology, developmental biology, computational modeling, information theory, dynamical systems theory and more. Historically, such integration has been challenging due to differing methodologies, terminologies, and research cultures. However, recent trends in scientific research emphasize the value of interdisciplinary approaches, driven by an increasing recognition that complex problems require diverse expertise. Funding agencies and academic institutions are now more supportive of interdisciplinary projects, facilitating collaborations that were once rare. This shift has been further accelerated by the development of collaborative platforms and digital tools that ease cross-disciplinary communication and data sharing. As a result, the barriers to interdisciplinary research are diminishing, paving the way for more integrated and comprehensive approaches like ours.

Technological and Theoretical Maturation: Recent advancements in technology and theory have been pivotal in enabling our approach to bioelectric manipulation. Technologically, we’ve seen significant progress in tools like high-resolution imaging, non-invasive bioelectric signal monitoring, and precise ion channel modulation techniques. These advancements allow for unprecedented observation and control of bioelectric phenomena in living systems. Theoretically, the development of integrative models that combine electrophysiological data with cellular and molecular biology has been crucial. These models help in deciphering the complex interactions within bioelectric networks. Furthermore, the growth of computational power and sophisticated algorithms has facilitated the simulation and prediction of bioelectric impacts on a larger scale. Together, these technological and theoretical advancements provide the necessary foundation for exploring and harnessing bioelectric fields in novel biological interventions. technological and theoretical advancements that enable this approach.

C. Why is This Approach the Optimal Path Forward? #

Unparalleled Precision and Control: This program’s emphasis on bioelectric modulation presents a new era of precision and control in biological interventions. This precision transcends the capabilities of traditional genetic or molecular methods, allowing for targeted interventions with minimal off-target effects. This means interventions can be fine-tuned to specific tissues or cellular processes without the broader systemic disruptions often seen with genetic modifications. Such precision significantly enhances the safety profile of treatments, reducing the risk of unintended consequences commonly associated with more invasive techniques. It also allows for iterative, real-time adjustments based on immediate bioelectric feedback, ensuring more effective and personalized interventions. This level of control is crucial, especially in delicate areas such as brain development or regenerative medicine, where even minor inaccuracies can lead to significant issues.

Systemic Understanding for Holistic Intervention: Targeting bioelectric patterns equips researchers with a more systemic understanding of biological mechanisms, fostering holistic interventions. This approach recognizes that biological processes are not just the sum of individual molecular events but are also shaped by the complex interactions of bioelectric fields across various systems. By manipulating these patterns, interventions can be designed to work in harmony with the body’s natural processes, enhancing their efficacy. This systemic perspective is particularly valuable in addressing multifactorial diseases like cancer or neurodegenerative disorders, where the interplay of various systems plays a critical role. Moreover, this approach paves the way for advancements in regenerative medicine, where understanding and guiding the body’s own healing mechanisms are key.

Bridging a Critical Gap in Biological Sciences: The focus on bioelectric phenomena addresses a crucial gap in our understanding of organismal function and development. Traditional biological research has often overlooked the role of bioelectric signals, yet recent evidence suggests they play a fundamental role in processes from embryonic development to wound healing. By exploring this relatively uncharted territory, the program has the potential to revolutionize our understanding of life sciences. This could lead to transformative breakthroughs in medical science, offering new treatments for diseases that have remained elusive to date. Furthermore, this research could redefine our basic understanding of how life operates at a cellular and systemic level, potentially leading to a new era of biological discovery and innovation.

In conclusion, the program represents a radical departure from traditional biological intervention methods. Its emphasis on bioelectric modulation, underpinned by recent scientific advancements and an increasing trend towards interdisciplinary collaboration, positions it as a promising new frontier in biological research and treatment. This initiative is poised to redefine our understanding and manipulation of biological systems, leading to a new era of precise, effective, and holistic interventions.

VI. Who cares? If we are successful, what difference will it make? #

A. Paradigm Shift in Biological Understanding and Intervention #

The success of our program would herald a monumental shift in our understanding and approach to biological systems, impacting both the academic and clinical realms:

1. Fundamental Change in Biological Perspective: The realization of our goals would be a catalyst for significant transformation in the field of biology. By moving away from traditional reductionist views, which focus on dissecting biological systems into smaller parts, to a more holistic, top-down approach, this initiative challenges the very foundation of biological understanding. Specifically, it would question the primacy of genetic determinism, the notion that genes alone dictate biological outcomes, and emphasize the importance of bioelectric phenomena in determining cell fate and organismal development. Such a shift could profoundly impact how we approach complex biological issues, including disease treatment, developmental biology, and regenerative medicine, potentially leading to groundbreaking advances in these fields.

2. Reassessing Biological Principles: A successful outcome from the program would necessitate reevaluating fundamental biological principles. This reassessment would have far-reaching implications, potentially redefining what we consider achievable in both research and clinical practice. For example, it could transform our approaches to cancer treatment, moving away from purely molecular interventions to bioelectrically centered therapies. In research, it might lead to new models for studying complex systems, embracing a more integrated perspective rather than isolated pathways. Clinically, it could introduce novel therapeutic modalities that are more effective and less invasive, by targeting systemic bioelectric patterns rather than just symptoms or specific molecular targets. This could open up new avenues in personalized medicine, offering treatments tailored not just to an individual’s genetic makeup, but also to their unique bioelectric profile.

In essence, the initiative stands to not only enrich our scientific understanding but also to fundamentally alter the landscape of biological research and clinical practice.

B. Addressing Global Health Challenges with Precision #

1. Transformative Approaches to Critical Health Issues:

• Cancer Treatment Paradigm: The program introduces a radical rethinking of cancer treatment, viewing the disease as a result of disrupted bioelectric signaling rather than just genetic mutations or molecular abnormalities. This perspective shifts the focus to recalibrating intercellular bioelectric communication, offering an innovative approach that targets the bioelectric environment of tumors. Unlike conventional treatments that often rely on chemotherapy or radiation, this method aims to correct the bioelectric anomalies causing tumor growth. This could result in treatments that are more targeted, potentially with fewer side effects, and that could halt or even reverse tumor progression by restoring normal cellular communication.
• Developmental Disorders: Utilizing insights from the initiative, there is potential to revolutionize the management of developmental disorders. This could lead to the early detection and correction of such disorders, potentially during prenatal development or early childhood. Disorders like autism spectrum disorder, congenital heart defects, or neural tube defects could be targeted through bioelectric modulation, offering a proactive approach to managing these conditions. By understanding and manipulating the bioelectric signals during critical developmental phases, the initiative could provide unprecedented means of preventing or mitigating these disorders.
• Heart Disease: The initiative’s exploration of bioelectric modulation also opens new possibilities for addressing heart disease. By understanding and manipulating the bioelectric signals that govern heart muscle function and vascular health, novel treatment strategies could emerge. For instance, bioelectric interventions might be used to normalize heart rhythms or promote vascular repair, offering new hope in the treatment of conditions like arrhythmias, ischemic heart disease, or hypertension. 2. Revolutionizing Aging Interventions: Our initiative posits aging as a result of declining bioelectric communication at the cellular and systemic levels, a concept that could radically alter our approach to aging interventions. By developing strategies to rejuvenate these bioelectric pathways, we could effectively ‘reset’ cellular and tissue states to more youthful configurations. Potential strategies include modulating ion channel activity to maintain cellular vitality, using electromagnetic fields to enhance tissue repair mechanisms, or employing bioelectric cues to improve systemic metabolic functions. Such interventions could significantly slow down aging processes, improve overall health in the elderly, and potentially extend human lifespan, presenting a groundbreaking shift in how we approach aging and age-related diseases.

C. Comprehensive Biological Control and Understanding #

1. Ultimate Goal of Complete Biological Manipulation: The program’s ultimate aim is to attain a comprehensive mastery over the physiology of large organisms, a goal that would usher in an era of unparalleled control and insight into complex biological systems. Achieving this level of control and understanding would have profound implications across the spectrum of biological research and medicine. In research, it could enable the exploration and modulation of biological systems with unprecedented detail and accuracy, leading to breakthroughs in understanding disease mechanisms, developmental processes, and organismal interactions. In medicine, this mastery could transform patient care, allowing for interventions tailored to individual physiological nuances. This could lead to highly effective treatments with minimal side effects, as therapies could be fine-tuned to the unique bioelectric profiles of each patient.

Gaining control over single-cell fate represents a potential revolution in various sectors, particularly regenerative medicine and personalized therapies. The capability to manipulate cellular states with exceptional precision would allow for the repair or replacement of damaged tissues, potentially curing diseases that are currently intractable. In personalized medicine, this could mean designing treatments based on individual cellular responses, offering more effective and targeted therapeutic strategies.

2. Development of the ‘Anatomical Compiler’: The initiative’s vision culminates in a significant stride towards the development of the ‘Anatomical Compiler’, a tool envisaged and termed by Michael Levin to engineer complex biological structures and functions. This technology would essentially function as a sophisticated platform for ‘programming’ biological systems, enabling researchers and clinicians to design and implement specific biological architectures and processes. The Anatomical Compiler could have wide-ranging applications, from creating tissue constructs for transplantation to designing novel biological systems for research. In regenerative medicine, it could be used to construct organs or tissues tailored to individual patients, greatly enhancing the success rates of transplantations. In research, it could facilitate the construction of complex biological models, providing deeper insights into developmental biology, disease pathology, and organismal biology. The Anatomical Compiler represents the pinnacle of bioengineering, merging biological understanding with technological innovation to redefine the boundaries of what is possible in biology and medicine.

D. Implications of Success #

1. Catalyst for Scientific and Clinical Innovation: The successful realization of the program could mark the dawn of a transformative era in both biology and medicine. This paradigm shift would move us from traditional, often fragmented methods of understanding and treating diseases to a more integrated and holistic bioelectric-based approach. Such a shift could significantly influence future scientific and clinical innovations. For instance, it could lead to the development of non-invasive, bioelectric-based therapies, offering more effective and less harmful alternatives to current treatments. Additionally, this new paradigm could inspire innovative diagnostic tools that leverage bioelectric signals to detect diseases at much earlier stages than currently possible.

The initiative is poised to pave the way for groundbreaking treatments and interventions, potentially resolving some of the most challenging health issues we face today. For example, this could include breakthroughs in treating neurodegenerative diseases like Alzheimer’s through bioelectric modulation in addition to previously mentioned examples, offering new hope where traditional pharmacological approaches have seen limited success. Similarly, in the realm of regenerative medicine, mastering bioelectric signals could lead to significant advancements in tissue regeneration and organ repair, addressing critical needs in organ transplantation and injury recovery.

2. Broadening the Horizons of Biological Science: By redefining the fundamental principles of biology, the initiative could be a driving force behind a new wave of scientific inquiry and innovation. This shift has the potential to inspire and equip future generations of scientists and clinicians with a new set of tools and concepts, enabling them to tackle complex biological challenges in ways previously unimaginable. The initiative could foster a new breed of interdisciplinary researchers, blending biology, physics, engineering, and computer science, leading to novel approaches in understanding and manipulating life processes.

The implications for clinicians are equally profound. With a deeper understanding of bioelectric phenomena, future clinicians could adopt more holistic and personalized treatment strategies, moving away from the one-size-fits-all approach prevalent in many current therapeutic practices. This could not only improve patient outcomes but also revolutionize the entire healthcare landscape, making it more responsive, effective, and patient-centered.

In summary, the success of the program promises not just advancements in current scientific and medical practices, but a fundamental evolution in how we approach, understand, and interact with biological systems, heralding a new age of discovery and innovation.

VII. What are the risks? #

A. Scalability of Bioelectric Modulation Techniques #

1. Challenges in Scaling Bioelectric Interventions: Scaling bioelectric modulation from controlled laboratory settings to clinical applications presents substantial challenges. One critical issue is ensuring that interventions that work effectively in small-scale models, such as cell cultures or simple organisms, retain their efficacy and safety when applied to more complex systems like humans. Bioelectric networks exhibit higher complexity in larger organisms, with more intricate interplays between various tissues and organs. This complexity increases the difficulty of accurately targeting and modulating specific bioelectric patterns without impacting adjacent systems. Additionally, systemic responses to bioelectric changes can vary significantly between different organism sizes and species, complicating the prediction and management of outcomes. Another challenge lies in the potential variability of bioelectric responses among individuals due to genetic, environmental, and lifestyle factors, necessitating highly personalized approaches. These issues underscore the need for extensive research and iterative development to adapt bioelectric interventions for broader, clinically relevant applications.

2. Technological Limitations: The current technological capabilities for bioelectric measurement and manipulation face several limitations that restrict large-scale application. The precision of bioelectric signal manipulation is still evolving, with existing tools often lacking the finesse required for complex biological systems. This is particularly evident in the depth of signal penetration and specificity, where influencing deeper tissues without affecting surface layers remains challenging. Monitoring technologies also face limitations in spatial and temporal resolution, making it difficult to capture the full spectrum of bioelectric activities in real-time across various tissues. Furthermore, the integration of bioelectric data with other physiological parameters is still in its infancy, which is crucial for a comprehensive understanding of organismal responses. The variability in bioelectric signals across different organisms and even within the same organism over time adds another layer of complexity. As such, there is a pressing need for technological advancements, including higher resolution imaging, more sensitive signal detection, and advanced computational models for data analysis and prediction. These improvements are essential for the successful translation of bioelectric interventions from experimental models to practical, scalable treatments.

B. Uncertainty in Biological Responses #

1. Predictability of Biological Outcomes: One of the inherent risks in our initiative is the unpredictability of how biological systems will respond to bioelectric modulation. Despite promising theory and preliminary research, the complexity and variability inherent in biological systems pose significant challenges. For instance, altering bioelectric signals in one tissue could inadvertently affect adjacent tissues or systems, leading to unanticipated physiological changes. There’s also the concern of individual variability – different organisms or even different individuals within the same species may respond in unique ways to identical bioelectric interventions. This unpredictability is compounded by the fact that bioelectric signals interact with a myriad of other physiological processes, from hormonal regulation to immune responses, making the outcomes of bioelectric modulation challenging to predict and control. Thorough, iterative testing and a deepened understanding of bioelectric systems are crucial for mitigating these risks and harnessing the full potential of bioelectric modulation.

2. Ethical and Safety Considerations: Bioelectric interventions, particularly those that impact fundamental physiological processes, bring forth significant ethical and safety considerations. The prospect of manipulating bioelectric patterns raises questions about the extent to which we should intervene in natural biological processes, especially in areas like brain development or regenerative medicine. The risk of unintended side effects, such as disrupting normal developmental processes or causing unforeseen health issues, is a major concern. Ethically, there is a need to balance the potential benefits of bioelectric interventions against the risks of manipulating complex and not fully understood biological systems. Ensuring informed consent, especially in clinical applications, and maintaining transparency about the potential risks and benefits are critical. Moreover, the long-term effects of bioelectric interventions are yet to be fully understood, necessitating a cautious and ethical approach to research and application in this field.

C. Integration with Existing Medical Practices #

1. Compatibility with Current Therapies and Practices: Integrating bioelectric modulation into existing medical practices involves significant challenges. The success of the program hinges not only on its scientific efficacy but also on how well it can be integrated into the current healthcare framework. This includes ensuring that bioelectric techniques are complementary to existing therapies, both in terms of efficacy and safety. Additionally, logistical aspects such as the integration of new bioelectric devices and protocols into clinical workflows, training healthcare professionals to use these new tools, and adapting healthcare infrastructures to accommodate these novel treatments are key challenges. There’s also the need to demonstrate that bioelectric interventions can be seamlessly combined with or serve as alternatives to traditional treatments, ensuring a holistic approach to patient care.

2. Acceptance in the Medical Community: Securing acceptance and trust within the medical community for bioelectric modulation techniques is crucial and challenging. Overcoming skepticism requires robust, evidence-based demonstrations of the efficacy and safety of these new methods. This includes conducting extensive clinical trials, publishing research findings in reputable medical journals, and actively engaging with medical professionals through conferences and workshops. Building a strong foundation of clinical evidence and fostering open dialogue with healthcare providers are essential steps in establishing the credibility and reliability of bioelectric interventions. Moreover, collaboration with respected medical institutions for pilot studies and trials can significantly aid in gaining the trust of the broader medical community.

3. Lack of an FDA Precedent: A significant risk in the program lies in the lack of FDA precedent for therapies developed through bioelectric modulation techniques. The FDA’s rigorous approval process necessitates stringent compliance with current good manufacturing practices (cGMP), and the introduction of therapies based on entirely new principles like bioelectric modulation could face substantial regulatory challenges. These challenges might include establishing new protocols, proving efficacy and safety beyond conventional approaches, and addressing any unique ethical concerns. While daunting, this obstacle is not insurmountable, as evidenced by the successful incorporation of other innovative medical technologies into clinical practice. The initiative would benefit from a proactive approach to regulatory engagement, including early consultations with the FDA, to navigate these uncharted waters. This approach could help in developing a framework for regulatory compliance that aligns with the innovative nature of bioelectric modulation, potentially setting a precedent for future therapies in this field.

XIII. How is the program structured? How long will it take and how much will it cost? #

This extensive research program spans three phases, envisioned to unfold over approximately 5 years as depicted in Figure 3. Each phase comprises a series of interconnected projects, designed to build upon each other, laying the groundwork for subsequent phases. The specific criteria each project must meet are detailed in their respective descriptions and summarized in the benchmark table.

In preparation for phase one, the selection of performers - be it academic researchers, government entities, startups, or others - will be conducted. This phase will involve establishing research agreements and recruiting qualified performers, some of whom may not currently be within Aion’s network. Timelines for each phase’s commencement will depend on these logistical arrangements. A key aspect of this program is fostering collaboration among researchers working on different projects, ensuring that all components synergize effectively to achieve the overarching objectives of the program.

A. PHASE 1: Proof-of-Concept Projects #

Phase 1 of our research program is dedicated to establishing foundational technologies and methodologies that will enable significant advancements in our understanding and manipulation of bioelectric phenomena. This phase includes three key projects:

i. Project 1A. Optimizing iPSC Generation with Integrated Computational and Chemical Methodologies

• This project is at the forefront of revolutionizing induced pluripotent stem cell (iPSC) production by harmonizing advanced computational models with cutting-edge chemical reprogramming techniques. The objectives are to enhance computational modeling, develop novel chemical reprogramming protocols, integrate electrophysiological data, and optimize and scale up the process. This project aims to significantly improve the yield and quality of iPSCs, setting a new benchmark in the field and laying a solid foundation for future advancements in stem cell research and regenerative medicine.

ii. Project 1B. Design and Preliminary Testing of Deep Tissue Read Hardware

• The goal of Project 1B is to develop novel technology capable of deep tissue physiological data acquisition, addressing the need for high penetration depth, resolution, non-invasiveness, safety, sensitivity, specificity, real-time data processing, and compatibility with existing medical infrastructure. The focus at this stage is on the design phase, emphasizing the creation of a prototype that meets the outlined criteria. Experimental demonstrations to validate the design concept are encouraged, aiming to establish a solid basis for the potential success and effectiveness of the developed technology.

iii. Project 1C. Advanced Computational Strategies for Electrome Data Management

• Project 1C addresses the computational challenges posed by the anticipated acquisition of extensive electrome data. The project’s objectives include developing methods for efficient data compression, integrating causal emergence theory for macro-scale data representation, and creating fast algorithms for quantifying effective information. By achieving these goals, this project will create a robust computational framework capable of managing the complexities of whole organism electrome data, which is crucial for advancing our understanding of bioelectric phenomena and supporting further research in this domain.

iv. Project 1D. Exogenous Interventions to Promote Effective Model Organism Changes

• Project 1D focuses on demonstrating that controlled exogenous electromagnetic fields can reliably induce specific biological changes in model organisms. Inspired by studies such as Michael Levin’s work on inducing a two-headed planaria phenotype via ion channel modulation, this project seeks to replicate and extend these findings using non-invasive, external electromagnetic interventions. The objectives include assessing and developing appropriate technologies for precise electromagnetic field application, ensuring safety and ethical compliance in experimental design, and utilizing computational models for predicting intervention outcomes. Successful implementation of this project could open new possibilities in the field of developmental biology and regenerative medicine, offering a novel method for controlled biological manipulation using external bioelectric cues.

Each project within Phase 1 is designed to tackle specific challenges and create opportunities for breakthroughs in bioelectric research, setting the stage for more advanced phases of our research roadmap.

i. Project 1A. Optimizing iPSC Generation with Integrated Computational and Chemical Methodologies #

This project aims to revolutionize the field of induced pluripotent stem cell (iPSC) production by integrating advanced computational feedback with innovative chemical reprogramming techniques. Key objectives and milestones are as follows:

1. Computational Modeling Enhancement:
   • Develop and refine a sophisticated computational model, possibly an adaptation of the BioElectric Tissue Simulation Engine (BETSE), to simulate and predict cellular responses during chemical reprogramming.
   • This model should be capable of real-time analysis and adjustment of reprogramming protocols based on live cell data.
2. Chemical Reprogramming Protocol Development:
   • Design and test a suite of chemical compounds for inducing iPSC generation, focusing on non-genetic, purely chemical methods.
   • These compounds should demonstrate efficacy across a range of fibroblast lines with minimal cytotoxicity.
3. Electrophysiological Data Integration:
   • Employ voltage fluorescent dye tracking to monitor bioelectric changes in cells during reprogramming, providing critical feedback to the computational model.
   • Integrate data from multi-electrode arrays (MEAs) for broader electrophysiological insights.
4. Optimization and Scale-up:
   • Achieve a target yield of iPSCs that represents a significant improvement over current benchmarks, aiming for an order of magnitude increase.
   • Scale up the optimized protocol for larger culture volumes, maintaining efficiency and cell quality.
5. Technological Adaptation and Flexibility:
   • Ensure that the methodologies developed are adaptable to various cell types and conditions, anticipating future expansions to other cell types like neurons and osteocytes.
   • Maintain flexibility in the approach, allowing for iterative improvements and modifications based on ongoing research findings.

This project is fundamental to the overarching goal of enhancing iPSC yield and quality through innovative and interdisciplinary approaches. The success of this project will lay the groundwork for further advancements in stem cell research and regenerative medicine.

ii. Project 1B. Design and preliminary testing of Deep Tissue Read Hardware #

This project is needed to create a novel technology to acquire deep tissue physiological data. The following design criteria must be considered:

1. Depth of Penetration and Resolution:
   • The hardware must be capable of penetrating deep into tissues without losing resolution or signal strength. This is crucial for accurately capturing bioelectric data from organs and tissues located deep within the body.
2. Non-Invasiveness and Safety:
   • The technology should be as non-invasive as possible to minimize discomfort and risk to subjects. This includes considerations for minimizing exposure to potentially harmful energies or substances.
   • Safety features must comply with medical device standards and regulations.
3. Sensitivity and Specificity:
   • High sensitivity is required to detect subtle bioelectric signals that are key indicators of physiological states.
   • The hardware should have the specificity to distinguish between different types of bioelectric activities, such as those from muscles, nerves, or other tissues.
4. Real-Time Data Acquisition and Processing:
   • The ability to acquire and process data in real-time is essential for immediate analysis and potential clinical applications.
   • Integration with advanced computational models for data interpretation and visualization.
5. Compatibility with Existing Medical Infrastructure:
   • Design should consider integration with current medical technologies and practices.
   • The hardware should be user-friendly for healthcare professionals, with minimal training required for operation.
6. Scalability and Adaptability:
   • The technology should be scalable for different sizes and types of organisms, including humans.
   • It must be adaptable to various research and clinical needs, possibly through modular design or adjustable settings.
7. Durability and Reliability:
   • The hardware must be durable and reliable for repeated use in various environments, from research laboratories to clinical settings.
   • Maintenance requirements should be minimal, with easy troubleshooting and repair options.
8. Ethical and Regulatory Compliance:
   • Design and testing phases must adhere to ethical guidelines, particularly in the context of human or animal use.
   • Compliance with regulatory bodies such as the FDA or EMA for potential clinical applications is essential.

The successful design and preliminary testing of deep tissue read hardware according to these criteria will significantly advance our capabilities in understanding and manipulating deep tissue physiological processes, paving the way for novel diagnostic and therapeutic tools.

This particular project for this stage of the program should be centered on design without fully testing performance of the building blocks. However, there must be a compelling case for why a given design will be able to meet the above criteria for success and experimental demos showing this is strongly encouraged if possible.

iii. Project 1C. Advanced Computational Strategies for Electrome Data Management #

In this project, we aim to address the computational challenges associated with the processing and interpretation of comprehensive electrome data sets. As we anticipate the acquisition of extensive whole organism electrome data – encompassing all ionic currents across cellular and organismal levels – we recognize the need for advanced computational solutions to effectively manage and utilize this wealth of information. This project will focus on two primary objectives:

1. Data Compression and Efficient Processing:
   • Objective: Develop methods to condense massive electrome data sets into more manageable sizes without significant loss of critical information.
   • Approach: Explore advanced data compression algorithms that can efficiently reduce the volume of electrome data. This may involve innovative techniques in signal processing, data summarization, and feature extraction.
   • Outcome: Achieve a balance between data comprehensiveness and computational manageability, enabling more effective use of electrome data within the broader goals of our project.
2. Integration of Causal Emergence for Macro-scale Data Representation:
   • Objective: Investigate the application of causal emergence theory as a framework for creating macro-scale representations of electrome data.
   • Approach: Develop algorithms that identify causally relevant patterns at larger scales, potentially simplifying the complexity of the data without losing its essential predictive and explanatory power.
   • Outcome: Facilitate a more intuitive understanding of the electrome data, highlighting key bioelectric interactions and phenomena that are crucial for our research objectives.
3. Development of Fast Algorithms for Quantifying Effective Information:
   • Objective: Create algorithms capable of rapidly quantifying the effective information contained within electrome datasets.
   • Approach: Design and test algorithms that can swiftly analyze electrome data to extract meaningful information, focusing on parameters that are most indicative of bioelectric states and dynamics.
   • Outcome: Provide a toolset for researchers to quickly assess and interpret large volumes of electrome data, aiding in decision-making and hypothesis testing. By undertaking these objectives, Project 1C aims to develop a robust computational framework capable of handling the complexities of whole organism electrome data. This framework will not only support our current research endeavors but also lay the groundwork for future advancements in the field of bioelectric research.

iv. Project 1D. Exogenous Interventions to Promote Effective Model Organism Changes #

This project will aim to demonstrate a viable proof-of-concept that controlled exogenous electromagnetic interventions can induce specific biological changes in model organisms, such as planaria. This project is inspired by studies, like those from Michael Levin’s lab, showing the induction of a two-headed planaria phenotype through ion channel modulation. Our goal is to replicate and expand upon such findings using entirely exogenous means, such as targeted electromagnetic waves, to achieve similar or more complex phenotypic changes. The key objectives and considerations for this project include:

1. Replication and Expansion of Previous Findings:
   • Investigate the feasibility of replicating results like the two-headed planaria phenotype using non-invasive, exogenous electromagnetic fields.
   • Explore the potential for inducing a wider range of controlled phenotypic changes in model organisms, expanding beyond the existing studies.
2. Technology Assessment and Development:
   • Evaluate existing technologies capable of delivering precise electromagnetic waves to target specific areas in model organisms.
   • Develop novel hardware, if necessary, to achieve the desired level of control and specificity in electromagnetic field application. This might involve creating devices that can accurately target small regions in organisms and modulate bioelectric signals in a controlled manner.
3. Safety and Ethical Considerations:
   • Ensure that the interventions are safe for the model organisms, minimizing any potential harm.
   • Adhere to ethical guidelines for the use of model organisms in research, especially when manipulating fundamental physiological processes.
4. Data Analysis and Computational Modeling:
   • Utilize advanced computational models to predict the outcomes of electromagnetic interventions and to guide the design of experiments.
   • Analyze data to understand the mechanisms by which electromagnetic fields influence bioelectric states and phenotypic outcomes.
5. Experimental Design and Validation:
   • Design experiments to test the efficacy of exogenous electromagnetic interventions in inducing desired changes in model organisms.
   • Validate the reproducibility and consistency of the results, ensuring that the interventions lead to the expected outcomes.
6. Interdisciplinary Collaboration:
   • Collaborate with experts in electrophysiology, developmental biology, and bioengineering to enhance the project’s success.
   • Engage with specialists in electromagnetic field technology for insights into optimizing hardware design and application. By achieving these objectives, this project will provide critical insights into the potential of exogenous electromagnetic interventions as a novel method for inducing controlled biological changes. This project not only contributes to our understanding of bioelectric phenomena but also opens up new avenues for research in developmental biology, regenerative medicine, and beyond.

B. PHASE 2: System Integration Projects #

Phase 2 of our research program is centered on the development and refinement of integrated systems, building upon the foundational successes of Phase 1. This phase aims to evolve our proof-of-concept results into minimal viable systems and then iteratively enhance these systems to meet and exceed the program’s performance goals. The focus here shifts from initial discovery and development to the integration and optimization of systems for broader applicability and impact. Key projects in this phase include:

i. Project 2A. Generalization of iPSC Findings and Precision Reprogramming from Bioelectric Modulation

• Building on Project 1A’s advancements, Project 2A extends iPSC generation techniques to a wider variety of cell types and explores precision in partial reprogramming. This project seeks to standardize bioelectric and chemical reprogramming across different cell types and develop targeted strategies for cellular age reversal. The integration of these techniques into broader cell types signifies a major step in customizable and versatile regenerative medicine applications.

ii. Project 2B. Invertebrate Model Lifespan Study

• This project integrates findings from Projects 1A, 1D, and 2A to conduct a comprehensive lifespan study in invertebrates like C. elegans. By applying bioelectric modulation and chemical reprogramming, Project 2B aims to uncover the effects of these interventions on aging processes, providing critical insights into lifespan extension and the mechanisms of aging at an organismal level.

iii. Project 2C. Rodent Model Deep Tissue Bioelectric Imaging

• Leveraging advancements from Projects 1B and 1C, Project 2C focuses on implementing deep tissue bioelectric imaging in rodent models. This project explores both non-invasive imaging techniques and the use of deep learning models for data extrapolation, aiming to achieve a comprehensive understanding of mammalian bioelectric phenomena. The success of this project is crucial for translating bioelectric research findings into mammalian and potentially human models.

iv. Project 2D. Advanced Bioelectric Data Integration and Application

• This project aims to transform the computational strategies developed in Project 1C into practical applications in biological research and medical fields. Project 2D focuses on integrating electrome data with ongoing biological research, developing predictive models for clinical use, implementing these insights in diagnostic and therapeutic technologies, and expanding the application to more complex organismal studies. This project is pivotal in bridging the gap between computational bioelectric data and real-world biological and clinical applications.

Together, these projects in Phase 2 represent a critical transition from foundational research to system-level integration and application. The emphasis is on refining and expanding the capabilities developed in Phase 1, ensuring that the research not only contributes to scientific knowledge but also leads to practical, impactful applications in medicine and biology.

i. Project 2A. Generalization of iPSC Findings and Precision Reprogramming from Bioelectric Modulation #

Project 2A aims to build upon the findings of Project 1A, extending the scope of iPSC generation to a broader range of cell types and implementing strategies for partial reprogramming through bioelectric interventions. This project is divided into two main objectives:

1. Generalization Across Cell Types:
   • Objective: Extend the chemical reprogramming methods developed in Project 1A to a wider array of cell types, including but not limited to fibroblasts, neurons, and bone cells.
   • Approach: Investigate the universal applicability of the reprogramming principles discovered in Project 1A, aiming to establish generalizable protocols that are effective across different cell types.
   • Outcome: Develop a set of standardized bioelectric and chemical reprogramming guidelines that are broadly effective, paving the way for versatile applications in various fields of biomedical research and regenerative medicine.
2. Precision in Partial Reprogramming:
   • Objective: Achieve targeted partial reprogramming of cells, focusing on age reversal at the cellular level through bioelectric modulation.
   • Approach: Select and utilize an appropriate aging clock or canonical biomarker to accurately measure biological age at the single-cell level. This will involve integrating cutting-edge bioelectric techniques with molecular markers of cellular aging.
   • Outcome: Establish a method for precisely controlling the degree of cellular reprogramming, enabling the reversal of aging markers without inducing full pluripotency. This could have significant implications in aging research, regenerative medicine, and therapeutic development.

Project 2A is critical in broadening the impact of iPSC technology and bioelectric modulation techniques. By achieving these objectives, the project not only contributes to the field of stem cell research but also enhances our understanding of cellular aging processes. The development of partial reprogramming strategies holds the promise of groundbreaking applications in age-related diseases and tissue regeneration.

ii. Project 2B. Invertebrate Model Lifespan Study #

Project 2B seeks to integrate and expand upon the insights gained from Projects 1A, 1D, and 2A, focusing on conducting a comprehensive lifespan study using invertebrate models, such as C. elegans. This project aims to explore the impact of bioelectric modulation and chemical reprogramming techniques on the aging process in these model organisms. The primary objectives and approaches of this project are as follows:

1. Selection of Invertebrate Model:
   • Objective: Identify and select an appropriate invertebrate model, such as C. elegans, known for its well-characterized genetics and lifespan, making it ideal for aging studies.
   • Approach: Assess various invertebrate models based on their suitability for bioelectric and chemical interventions, and their relevance to the research goals of lifespan extension and aging.
2. Integration of Previous Findings:
   • Objective: Utilize the methodologies developed in Projects 1A (iPSC generation), 1D (exogenous bioelectric interventions), and 2A (generalization across cell types and partial reprogramming) to design interventions aimed at lifespan extension.
   • Approach: Apply the optimized bioelectric modulation techniques and chemical reprogramming methods to invertebrate models to investigate their effects on aging and lifespan.
3. Lifespan Study Design and Implementation:
   • Objective: Conduct a detailed lifespan study to observe the effects of bioelectric and chemical interventions on aging processes in the chosen invertebrate model.
   • Approach: Design a comprehensive experimental setup that includes control and treated groups, with meticulous monitoring and recording of lifespan and aging-related biomarkers.
4. Data Analysis and Interpretation:
   • Objective: Analyze the data collected from the lifespan study to draw conclusions about the effectiveness of bioelectric and chemical interventions in modulating aging processes.
   • Approach: Employ advanced statistical methods and computational models to interpret the results, focusing on changes in lifespan, healthspan, and related biological markers.
5. Implications for Broader Research Goals:
   • Objective: Translate the findings of this study to broader research goals, potentially providing insights into human aging and age-related diseases.
   • Approach: Extrapolate the results to form hypotheses about similar interventions in more complex organisms, paving the way for future research. Project 2B is an essential component of our research program, bridging the gap between cellular-level interventions and organismal outcomes. By exploring the effects of bioelectric and chemical reprogramming on invertebrate lifespan, this project will contribute valuable knowledge to the fields of aging research, regenerative medicine, and bioelectric science.

iii. Project 2C. Rodent Model Deep Tissue Bioelectric Imaging #

Project 2C aims to leverage the advancements made in Projects 1B (Deep Tissue Read Hardware) and 1C (Advanced Computational Strategies for Electrome Data Management) to implement a minimum viable prototype (MVP) for deep tissue bioelectric imaging in rodent models. This project focuses on exploring and validating methods to capture and analyze the deep tissue electrome of rodents, a crucial step in understanding complex bioelectric phenomena in mammalian systems. The project will explore two potential approaches based on the outcomes of earlier projects:

1. Non-Invasive Deep Tissue Imaging:
   • Objective: Implement a non-invasive approach to deep tissue bioelectric imaging using advanced imaging technologies.
   • Approach: Build upon technologies such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or advanced ultrasound imaging to capture bioelectric patterns deep within rodent tissues.
   • Outcome: Develop a method that allows for the detailed visualization of bioelectric activity without the need for invasive procedures, providing insights into the electrome of complex biological systems.
2. Surface Data Projection Using Deep Learning:
   • Objective: Explore the feasibility of using surface-level electrical activity data to project bioelectric patterns deeper within the organism.
   • Approach: Utilize deep learning models to extrapolate surface bioelectric data, informed by existing knowledge of deeper organism structures, to estimate bioelectric patterns in deeper tissues.
   • Outcome: Develop a computational model capable of providing a comprehensive view of the electrome from minimally invasive data, potentially offering a novel method for studying deep tissue bioelectric phenomena.

Both approaches in Project 2C are designed to push the boundaries of current bioelectric imaging capabilities in mammalian models. The project will involve rigorous testing and validation of these methodologies in rodent models, setting the stage for potential applications in larger and more complex organisms. Success in this project would mark a significant advancement in our ability to understand and manipulate bioelectric signals in deep tissues, contributing to the broader goals of the research program in understanding complex bioelectric interactions and their implications in health and disease.

iv. Project 2D: Advanced Bioelectric Data Integration and Application #

Building on the foundation laid by Project 1C, the next phase will focus on advancing the integration and application of the computational strategies developed for electrome data management. This phase will aim to translate the computational framework into practical, impactful applications across various biological and medical fields. The key objectives for this follow-on phase include:

1. Advanced Integration of Electrome Data with Biological Research:
   • Objective: Seamlessly integrate the processed electrome data with ongoing biological research, particularly in areas such as developmental biology, regenerative medicine, and neuroscience.
   • Approach: Collaborate with researchers across these fields to apply the data in understanding complex biological processes, such as tissue regeneration and neural network formation.
   • Outcome: Enhance the understanding of bioelectric phenomena in biological systems, leading to novel insights and potential breakthroughs in various research areas.
2. Development of Predictive Models for Clinical Applications:
   • Objective: Utilize the electrome data to develop predictive models that can inform clinical decision-making, especially in personalized medicine.
   • Approach: Create algorithms that can predict disease progression, treatment outcomes, and patient responses based on bioelectric patterns.
   • Outcome: Facilitate the development of targeted, personalized treatment strategies, improving patient care and treatment efficacy.
3. Implementation in Diagnostic and Therapeutic Technologies:
   • Objective: Apply the electrome data and computational tools in the development of new diagnostic and therapeutic technologies.
   • Approach: Partner with biomedical technology companies to incorporate these insights into practical tools, such as non-invasive diagnostic devices or bioelectric therapy systems.
   • Outcome: Introduce novel technologies into the healthcare market that leverage bioelectric data for improved diagnosis and treatment of diseases.
4. Expansion to Complex Organismal Studies:
   • Objective: Expand the application of the computational framework to more complex organisms, bridging the gap between model organisms and human biology.
   • Approach: Conduct studies that apply the refined computational tools to larger and more complex organisms, assessing the scalability and translatability of the findings.
   • Outcome: Gain deeper insights into human bioelectric phenomena, paving the way for advanced biomedical research and applications. This follow-on phase will transform the computational achievements of Project 1C into tangible benefits for both scientific research and clinical practice. By integrating advanced computational strategies with practical applications, this phase aims to pioneer a new frontier in bioelectric research, significantly impacting our understanding and manipulation of biological systems at various scales.

C. PHASE 3: Advanced Integration and Application Projects #

Phase 3 of our research program is designed to advance the integration and application of our foundational research into more complex biological systems and practical medical applications. This phase involves three pivotal projects:

i. Project 3A. Dynamical Systems Model of Aging in the Electrome

• This project utilizes control theory and dynamical systems to develop a model that can guide biological systems towards a rejuvenated state. The focus is on creating a sophisticated model to represent aging within the electrome, developing strategies for electrome reorientation, and integrating insights from bioelectric perturbation studies. The aim is to test and refine these strategies through experimental validation, adhering to the highest ethical and regulatory standards. This project represents an innovative approach to manipulating the aging process within the electrome, potentially leading to significant breakthroughs in understanding and controlling aging at the bioelectric level.

ii. Project 3B. Hardware for Exogenous, Whole Organism Interventions

• Project 3B seeks to develop a device capable of performing CRUD operations on the electrome of whole organisms. This technology aims to externally manipulate and monitor bioelectric patterns, offering a novel degree of control over biological processes. The project includes developing hardware with full-spectrum CRUD capabilities, ensuring non-invasive and targeted intervention, integrating the hardware with advanced computational systems, and ensuring scalability and flexibility. Ethical and regulatory compliance is a paramount objective. This project is set to revolutionize bioelectric research, providing a tool for manipulating and monitoring the electrome with precision.

iii. Project 3C. Vertebrate Model Lifespan Studies

• Parallel to Projects 3A and 3B, this project aims to extend lifespan and improve aging-related phenotypes in vertebrate models. Integrating results from Projects 2A, 2B, and 2C, this project will apply electrome interventions to vertebrate models, assessing the impact on aging processes. The project’s goals include developing electrome interventions, conducting comprehensive lifespan studies, preparing for scaling to non-human primate models, and laying the groundwork for clinical translation. The successful completion of this project in vertebrate models would mark a significant milestone, potentially leading to applications in aging research and regenerative medicine.

Phase 3 represents the culmination of our research efforts, where advanced theoretical models and innovative technologies are applied to complex biological systems. The integration of these projects paves the way for significant advancements in understanding and manipulating bioelectric phenomena, with broad implications for aging research, regenerative medicine, and beyond. This phase is crucial for translating our research into practical applications that can extend healthy lifespans and combat age-related diseases.

i. Project 3A. Dynamical Systems Model of Aging in the Electrome #

Project 3A seeks to harness the principles of control theory and dynamical systems to analyze and manipulate the aging process within the electrome. This project will utilize the extensive electrome data and computational advancements from Project 2D, aiming to develop a model that can guide biological systems towards a rejuvenated, de-aged state. The key objectives and strategies for this project include:

1. Development of a Dynamical Systems Model:
   • Objective: Create a sophisticated model that represents the aging process within the electrome as a dynamical system.
   • Approach: Utilize control theory to understand how various bioelectric parameters evolve over time in the aging process and identify potential intervention points for redirecting these dynamics.
   • Outcome: A comprehensive model that accurately represents the dynamics of aging within the electrome, providing a basis for targeted interventions.
2. Targeted Electrome Reorientation:
   • Objective: Develop strategies to ’teach’ the electrome to orient towards a rejuvenated state over time.
   • Approach: Implement bioelectric modulation techniques that gradually guide the electrome towards a younger phenotype, borrowing strategies from studies demonstrating basal cognition and adaptive responses in biological systems.
   • Outcome: Effective methods for gradually inducing a de-aged state in biological systems, leveraging the inherent adaptive capabilities of these systems.
3. Integration with Bioelectric Perturbation Studies:
   • Objective: Utilize insights from bioelectric perturbation studies to inform our approach to reorienting the electrome.
   • Approach: Analyze existing research on how biological systems respond to various bioelectric stimuli and perturbations, particularly those related to aging and rejuvenation.
   • Outcome: Enhanced understanding of how to effectively manipulate the electrome to achieve desired morphological goals, particularly in the context of aging.
4. Experimental Validation and Refinement:
   • Objective: Test and refine the dynamical systems model and intervention strategies in controlled experimental settings.
   • Approach: Conduct experiments using model organisms to validate the model’s predictions and the efficacy of the bioelectric modulation strategies.
   • Outcome: A validated and refined approach to manipulating the aging process within the electrome, backed by empirical evidence.
5. Ethical and Regulatory Compliance:
   • Objective: Ensure that all aspects of the project adhere to ethical guidelines and regulatory standards, especially given the project’s focus on aging and rejuvenation.
   • Approach: Maintain ongoing communication with ethical boards and regulatory agencies, ensuring transparency and compliance throughout the project.
   • Outcome: A project that not only advances scientific understanding but also upholds the highest standards of ethical and regulatory responsibility.

Project 3A represents a pioneering effort to apply control theory and dynamical systems modeling to the field of bioelectric research, specifically targeting the aging process. By developing a model that can direct the electrome towards a de-aged state and testing these strategies in biological systems, this project has the potential to significantly advance our understanding and control of the aging process at the bioelectric level.

ii. Project 3B. Hardware for Exogenous, whole Organism Interventions that perform CRUD operations on a organisms electrome #

Project 3B, as an extension of the foundational work done in Project 1D and incorporating insights from all Phase 2 projects, aims to develop a sophisticated hardware device capable of executing CRUD (Create, Read, Update, Delete) operations on the electrome of whole organisms. This project involves the creation of a technology that can externally manipulate and monitor bioelectric patterns at a system-wide level, providing an unprecedented degree of control over biological processes. The key objectives and design criteria for this project are:

1. Full-Spectrum CRUD Capabilities:
   • Objective: Develop hardware that can perform all CRUD operations—creating, reading, updating, and deleting bioelectric signals within an organism.
   • Approach: Integrate advanced bioelectronic technologies capable of precise modulation and monitoring of bioelectric activities across various biological scales.
   • Outcome: A versatile device that can induce desired bioelectric changes, read existing bioelectric patterns, update or modulate these patterns, and even erase specific bioelectric signals when necessary.
2. Non-Invasive and Targeted Intervention:
   • Objective: Ensure that the hardware operates non-invasively, causing minimal discomfort or risk to the organism.
   • Approach: Utilize cutting-edge techniques such as focused electromagnetic fields or ultrasound, offering targeted intervention without the need for direct physical contact or invasive procedures.
   • Outcome: A safe and user-friendly system suitable for a wide range of research and clinical applications.
3. Integration with Advanced Computational Systems:
   • Objective: Seamlessly integrate the hardware with sophisticated computational systems for data analysis and real-time feedback.
   • Approach: Harness the computational frameworks developed in Phase 2 for processing complex electrome data, ensuring efficient and accurate operation of the CRUD hardware.
   • Outcome: A system that not only performs CRUD operations but also interprets the implications of these interventions in real-time, supported by powerful data processing capabilities.
4. Scalability and Flexibility:
   • Objective: Design the hardware to be adaptable to different organisms, from small model species to potentially larger, more complex systems.
   • Approach: Develop a modular and scalable design that can be customized for specific research or clinical needs.
   • Outcome: A flexible tool that can be applied to a broad spectrum of biological studies and interventions.
5. Ethical and Regulatory Considerations:
   • Objective: Adhere to the highest ethical standards and comply with regulatory requirements, particularly given the novel nature of the technology.
   • Approach: Engage with ethical boards and regulatory agencies from the early stages of development to ensure compliance and address potential ethical concerns.
   • Outcome: A technology that is not only innovative but also ethically responsible and regulatory compliant. Project 3B is poised to be a groundbreaking venture in the field of bioelectric research, offering a tool that can manipulate and monitor the electrome of whole organisms with precision and control. This project represents a significant leap forward in our ability to understand and influence biological systems, with potential applications spanning from fundamental research to advanced therapeutic interventions.

iii. Project 3C. Vertibrate Model Lifespan Studies #

Project 3C is a critical venture aimed at extending lifespan and improving aging-related phenotypes in vertebrate models, drawing upon the insights and methodologies developed in Projects 2A, 2B, and 2C. The primary goal is to conduct comprehensive lifespan studies using vertebrate models, applying targeted electrome interventions to modulate aging processes. Running parallel to Projects 3A and 3B, this project serves as a vital stepping stone towards scaling up interventions to non-human primate models, potentially leading to breakthroughs in aging research. Key objectives and strategies include:

1. Electrome Intervention Development:
   • Objective: Develop and apply bioelectric modulation strategies to positively influence aging processes in vertebrate models.
   • Approach: Leverage findings from Projects 2A (iPSC generalization), 2B (invertebrate lifespan study), and 2C (rodent deep tissue imaging) to design electrome interventions that target key aging mechanisms.
   • Outcome: Establish effective electrome modulation techniques that demonstrably improve aging-related phenotypes in vertebrate models.
2. Comprehensive Lifespan Studies:
   • Objective: Conduct in-depth lifespan studies in vertebrate models to assess the impact of electrome interventions.
   • Approach: Utilize a range of vertebrate models for lifespan studies, ensuring rigorous monitoring and documentation of aging markers and overall healthspan.
   • Outcome: Valuable data on the efficacy of bioelectric interventions in extending lifespan and improving healthspan in vertebrates.
3. Preparation for Scaling to Non-Human Primates:
   • Objective: Prepare for the application of successful interventions to non-human primate models.
   • Approach: Analyze the results from vertebrate studies to refine and adapt interventions for more complex organisms, ensuring ethical and scientific rigor in the process.
   • Outcome: A robust, ethically sound plan for scaling up interventions to non-human primate models, marking a significant advancement in the project.
4. Clinical Translation Preparation:
   • Objective: Lay the groundwork for the eventual translation of successful therapies into human clinical applications.
   • Approach: Collaborate with regulatory bodies, medical experts, and ethical committees to plan for the clinical translation of therapies, addressing all necessary regulatory and ethical considerations.
   • Outcome: A comprehensive strategy for introducing effective aging interventions to human clinical trials, paving the way for their potential use in human healthcare.
5. Integration with Projects 3A and 3B:
   • Objective: Ensure that findings and methodologies from this project contribute to and benefit from parallel projects.
   • Approach: Maintain a collaborative and integrated research approach, sharing insights and data across Projects 3A (Dynamical Systems Model of Aging in the Electrome) and 3B (Hardware for Exogenous Whole Organism Interventions).
   • Outcome: Enhanced synergy across projects, leading to more robust and comprehensive advancements in the field of bioelectric aging research.

The successful completion of Project 3C in vertebrate models would represent a major milestone in the overarching research program, setting the stage for groundbreaking applications in aging research and regenerative medicine. The transition from vertebrate models to non-human primates and eventually to human clinical applications signifies the project’s ultimate goal of extending healthy lifespan and combating aging-related diseases.

IX. Benchmarks for Each Phase of the Program #

The benchmarks listed below are crucial milestones for assessing the progress and success of each project within the program. These benchmarks are cross-referenced to multiple projects, indicating instances where projects may overlap or require collaborative efforts. It is important to note that these benchmarks are based on current assumptions and projections and may be subject to revisions as the program progresses and new insights are gained.

Benchmarks Overview: #

Table 1: Performance Criteria/Benchmarks for the Bioelectric Phenomena Research Program

X. Conclusions #

The research program laid out in this roadmap represents an effort to unravel and manipulate the complex bioelectric phenomena underlying biological processes, particularly aging. The integration of advanced computational models, innovative bioelectric modulation techniques, and the development of cutting-edge hardware for CRUD operations on an organism’s electrome, sets the stage for transformative breakthroughs in biomedical research.

The program is designed not to replace existing biological research tools but to complement and extend them into realms currently unexplored or underutilized. By focusing on dynamic systems models of aging, lifespan studies in invertebrate and vertebrate models, and the development of non-invasive bioelectric intervention technologies, we aim to gain deeper insights into the aging process and develop novel therapeutic strategies for age-related diseases.

As we move forward, continuous community engagement, feedback, and collaboration will be essential for refining our approach and achieving our ambitious goals. We invite researchers, clinicians, and technologists to join us in this exciting journey, contributing their expertise and insights to help bring these innovative concepts to fruition.

The format for this reseach roadmap was adapted from similar programs featured in Speculative Technologies’s library.

This roadmap is a living document. Please reach out to us if you are opinionated about these ideas, have a desire to get involved or think of ways to make it happen.

Thank you.

- Benjamin Anderson