What is the compelling question or challenge?
How do individual cells harness the laws of physics to form complex functional bodies? How is cellular information-processing & signaling machinery integrated toward building and repairing anatomy?
What do we know now about this Big Idea and what are the key research questions we need to address?
Free-living unicellular organisms manage exquisitely complex morphology, physiology, and behavior (even memory, problem-solving) – all of this is done in a single computationally and metabolically optimized cell. Somehow these individual cells join together into multicellular plants and animals and apply their information-processing skills toward the production and maintenance of complex anatomies. This is a radical expansion of the boundary of the “self”. In a metazoan animal, cells must cooperate to build a body during embryogenesis, recognize damage, and rebuild any missing structures (e.g., leg regeneration in salamanders), stopping when precisely the right form has been achieved. This process of embryogenesis and regeneration requires an understanding not only the hardware (cells created by cell proliferation and differentiation), but also the software (network cell dynamics that enable cells to recognize body patterning states) and to gauge when to repair and when to stop.
While the molecular pathways by which tissues are induced (i.e., differentiation) is well understood, and we are beginning to understand developmental outcomes at the systems-level, profound mysteries exist about the decision-making capacities of cells and cell collectives: how does life harness the basic properties of physics to enable cell collectives to scale their activity toward global goals? How does genetics relate to the biophysical processes that implement the pattern-editing throughout developmental and regenerative biology? The ocean of ignorance includes questions like: how do subcellular processes (gene-regulatory networks, cytoskeletal dynamics) underlie cells’ abilities to solve problems, form memories, and dynamically adjust to stressors and changing environments? What are the cognitive/computational limits of single cell organisms and somatic cells? How do these capacities scale up to the remarkably adaptive, plastic capabilities of self-repairing metazoan bodies? How does the cooperation of individual cells break down during cancer, where cells act individually and treat the body as the “environment”? Can this state be reversed (i.e., tumor reprogramming)? What are the limits of morphogenesis – can any shape be constructed (artificial living machines) if we know the code by which target morphology (the large-scale anatomy to which cells build and repair) is encoded? What is the relationship between the genome and the emergent pattern homeostasis that builds a functional body (how widely can the body be made to diverge from its genomic default)? What are the functional limits of anatomical plasticity and can the lessons learned from these models be translated into robotics?
These questions cannot be answered without understanding the information processing that enables the scaling of computational and biophysical properties from single cells to self-editing bodies. They are currently addressed piecemeal by a range of disciplines including game theory, evolutionary biology, cell/developmental biology, basal cognition, neurobiology, synthetic biology, and information theory. This diverse, highly-interdisciplinary area would benefit from a concerted effort to integrate it into a coherent field to make decisive progress on truly fundamental questions. This Big Question is an example of the frontier of modern science, in which former barriers between disciplines are transcended through deep consilience between experts in diverse disciplines. Key research directions include the biophysics of primitive cognition in body cells and their relationship to the pathways that regulate body morphogenesis, the development of top-down control strategies for growth and form (designer artificial living machines), and the investigation of the non-genetic bioelectrical and physiological software that is being shown to enable reprogramming of body-wide outcomes without genomic editing.
Why does it matter? What scientific discoveries, innovations, and desired societal outcomes might result from investment in this area?
This is a truly fundamental Question, and the ramifications of its Answer extend across many areas. Evolutionary and exobiology would be revolutionized by a better understanding of how complex self-regulating structures arise and change over time. Cognitive science would be closer to cracking its ultimate goal – the decoding of information in the brain into its mental content – by success in understanding how non-neural cellular networks store and process information about morphogenetic changes. Biomedical applications would include the repair of pattern-targeting birth defects, regenerative therapies in which the patient’s own cells rebuild damaged or aging organs, and cancer reprogramming (tumor normalization). Bioengineering would gain the ability to create artificial living machines, taking synthetic biology beyond metabolic reprogramming and cell soups toward functional ‘biobots’ with designed structures and functions and a myriad of applications, from biomedicine to space colonization. Information technology would benefit from bio-inspired self-repairing communication and control networks and the creation of new (highly general) artificial intelligence platforms built on fundamental cellular memory and computational processes, not on mimicking human brain architecture. Societal outcomes thus range from biomedical therapies that induce regenerative repair (avoiding the complexity barrier of manually constructing artificial hands, eyes, etc. and rejection barriers in transplantations) to new technologies that exploit discoveries about the Software of Life to enable unprecedented robustness and immunity to a wide range of existential and societal threats.
If we invest in this area, what would success look like?
Success will involve significant disruption of the current strategies for biological control (working exclusively bottom-up at the level of the molecular hardware), towards a kind of morphological compiler, where the user can specify the target morphology at the anatomical level (design the shape of a living structure as one does in CAD for engineered structures) and have the compiler convert this design into specific strategies that enable cells to build it. Success will lead to new conceptual insights which will change the classical text-book understanding of evolutionary developmental biology of functional (anatomical) novelty, multicellularity, and evolvability. Success will include the establishment of new study sections, funding streams, journals, and PhD programs with sufficient breadth to address educational, funding, and research needs in this emerging highly interdisciplinary field. Specific (practical) success outcomes will be visible as: new applications for regenerative medicine (organ rebuilding in situ/in the patient, cancer reprogramming/normalization, birth defect repair), appearance of novel synthetic living machines with desired structure and function, the propagation of insights into biological robustness into development of highly resilient communication networks, and robotics (machine learning platforms) based on novel (non-neural) cellular information processing modes.
Why is this the right time to invest in this area?
This is an ideal time because (1) disparate disciplines have produced conceptual advances that can now begin to be integrated toward a Unification – new mathematical formalisms in systems science and information theory for the first time make it possible to address not just the mechanisms of complex life but the cognitive and computational meaning that underlies the very nature of being alive. (2) technology is coming on-line in the fields of physics, cell biology, and computer science which is finally making it feasible to embark on the interrogation of cellular perception spaces, creation of biobots, and multiscale predictive models to achieve guided self-assembly. In addition, society is facing threats related to the exponential scaling of population, needs, environmental and public health challenges, etc. which may not be survivable without exploiting the central wisdom discovered by our biosphere after 3 billion years of evolution.
References
Friston, K., 2013. Life as we know it. Journal of the Royal Society, Interface / the Royal Society 10, 20130475.
Moore, D., Walker, S.I., Levin, M., 2017. Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem. Convergent Science Physical Oncology 3, 043001.
Pezzulo, G., Levin, M., 2015. Re-membering the body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs. Integr Biol (Camb) 7, 1487-1517.
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