Applying Systems Thinking to Regenerative Medicine Proceedings of a Workshop (2021) / Chapter Skim
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2 Introduction to Systems Thinking Concepts
2 Introduction to Systems Thinking Concepts
Pages 9-28
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(Bialek) • Underlying molecular structures and mechanisms need to be integrated into critical quality attributes and other measurements to move the field of cell therapy from empirical mechanistic modeling toward process development.
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The reductionist perspective focuses on identifying microscopic components, with the implicit assumption that they can be used to reconstruct macroscopic phenomena. Systems-level thinking focuses on the macroscopic phenomena with a recognition that, while these phenomena ultimately originate from microscopic events, these macroscopic phenomena cannot be easily recreated or predicted using molecular components alone.
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Example from Early Fruit Fly Development To illustrate these implications, Bialek described a biological process that is controlled by a genetic network and considered what can be predicted if all the relevant genes and their interactions have been identified. In the process, many of these genes encode transcription factors that regulate the expression of other genes in the network.
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12 APPLYING SYSTEMS THINKING TO REGENERATIVE MEDICINE FIGURE 2-1 Fruit fly early development: from maternal inputs to larva. SOURCES: William Bialek workshop presentation, October 22, 2020.
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Thus, creating a model of early fruit fly development with predictive power would require knowing what numbers to assign to all 50 or more parameters. Even in the well-studied case of fruit fly development, these numbers remain unknown.
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In the case of fruit flies, for instance, at just 3 hours into development there are fewer than 100 rows of cells along the length of the embryo, so that 1 percent precision means that every cell knows where it is, he said. A challenge in trying to "squeeze all of the information" out of these signaling molecules is that they are present at such low concentrations that any measurements of those concentrations will be noisy (variable due to a range of extrinsic or intrinsic factors)
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This work can be tested using fruit fly genetics by observing mutants in which some maternal inputs have been deleted, Bialek added. Mutants defective in maternal inputs produce distorted patterns of gap gene expression.
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One of the early observations in this work was the potential role of feedback control in the cell creation system. This insight led to an investigation into why it is so difficult to grow blood stem cells when different cell types are generated that are continuously influencing their growth and differentiation.
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In the context of a human stem cell–centric cell–cell communication network in which there are secreted factors in the system, this approach can be used to help elucidate which cells are secreting which factors, the directionality of these factors, and the overall function of the system when the factors are used to modulate the interaction networks. One example of research using an integrated systems approach involved the use of omics technologies to associate cell types within the hematopoietic system with certain molecules (Qiao et al., 2014)
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The aim of the stem cell–derived manufacturing of immunotherapies is to move toward a universal, homogenous, and scalable off-the-shelf product. This is a challenging endeavor, Zandstra said, because generating mature T cells from stem cells involves a long and complex differentiation process: from pluripotent stem cells, either in their normal or engineered state, to blood progenitor cells, to progenitor T cells, and eventually to more mature T cells.
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Cell population modeling of thymopoiesis to understand how cul ture parameters modulate cell T cell differentiation and kinetics; and 3. Cellular kinetic pharmacokinetic/pharmacodynamic modeling to investigate how culture-generated T cell populations interact with human (patho-)
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SYSTEMS DYNAMICS OF CELL-STATE TRANSITIONS: RELEVANCE FOR REGENERATIVE MEDICINE Huang presented an exploration of systems dynamics of cell-state transitions and their relevance for regenerative medicine, with a focus on singlecell transcriptomics. Cell Type Reprogramming as Cell-State Transition Cell type reprogramming is a core process of interest throughout the field of regenerative medicine, Huang said.
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Within this perspective, the manipulation is intended to trigger the cell-state transition. This requires defining the state of the cell, which is governed by the gene regulatory network which has evolved to generate cell states and cell types.
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Because of stochastic fluctuations, or non-genetic heterogeneity, these cells are all slightly different -- even within a clonal cell population. Single-cell transcriptomics allows for a precise view of individual cells, while big data and statistical data analysis allow for individual cells to be plotted in a reduced dimensional space, creating clusters of various cells in various states.
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This dispersion is reflected in single-cell analysis. The positions of individual cells in such analyses are governed by the underlying landscape which represents the constraints from the gene regulatory network.
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DISCUSSION Expanding Beyond Empirical Modeling Referring to an earlier remark by Zandstra that the systems component of mathematical modeling is becoming more than the mere application of empirical models, Zylberberg asked about the point at which the complexity becomes so great that key principles need to be extracted from datasets. This question is still being explored, Zandstra said, as researchers work to discover how to extract measurable parameters from global observations of cell states.
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He offered an example from the early research on pluripotent stem cells: the cells would be put in an undefined aggregate (an embryoid body) , and the variability in the types of differentiation that emerged were considered to be partially due to system noise.
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Referring to an example from his presentation, he described a situation where cardiomyocytes are desired but, in reality, a mixture of cell types would be needed due to the highly dynamic nature of cells. For example, in tumor therapy, in most cases one cannot simply kill tumor cells; it is necessary to account for other dynamics of tissues and tumors.
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Currently, there is too much reliance on purely computational approaches, Huang said, but theory could be helpful to counteract this reliance, especially to the extent that it may reveal instances where it is not necessary to collect the fullest possible detail in terms of measurement. Much of the session's discussion of systems had been related to cell engineering and decision making at the level of individual cells, Zylberberg noted.
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28 APPLYING SYSTEMS THINKING TO REGENERATIVE MEDICINE boundaries will be productive, Bialek said, not on a belief that a system's interactions do not cross those boundaries. In the history of biology, Bialek said, progress has often been related to the degree to which processes being studied have been able to be isolated.
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