Assignation of a letter to a stationary concentration of ADP.
Abstract
We are concerned with computer simulations of a ring of 20 coupled CSTRs with glycolytic oscillatory reaction. Each CSTR represents an artificial cell, and the ring can be regarded as an artificial blastula. The cells are coupled to two adjacent CSTRs via the mass exchange of reagents. The glycolytic oscillatory reaction is simulated using the two-variable core model. Our work is focused on the classification of stationary discrete nonuniform concentration patterns (discrete Turing patterns). The control parameters in simulations are autocatalytic and inhibition rate coefficients, as well as the transport rate coefficients. We performed the analysis of stability and bifurcations of stationary states to identify the stationary states. The inflow of reagents into each CSTR was used to initiate a particular pattern. We propose a method to assess the morphogenetic toxicity of any chemical from a database by switching between patterns or between patterns and oscillations. Moreover, we investigated nonuniform patterns that create discrete concentration waves inside the ring of 20 coupled cells, which can trigger gastrulation.
Keywords
- discrete turing patterns
- glycolysis
- 2D artificial blastula
- cheminformatics
- morphogenesis toxicity
1. Introduction
Chemoinformatics tools allow us to define information and parameters of various chemicals influencing more complex systems. The information and parameters are focused on chemical structure, experimental and physicochemical data, and toxicity. The toxicity data can concern living tissues, metabolic pathways [1], DNA [2, 3], RNA, [4, 5], gut microbia [6], or mitochondrial toxicity [7]. Chemoinformatics is also essential for the development of new drugs [8, 9, 10, 11] and for the assessment of their toxicity [12]. Since the databases of chemicals are extensive and count in millions of elements, the approach of using artificial intelligence [13], artificial neural networks [14], and machine learning seems to be the only method to deal with such a huge amount of collected information [15].
In this paper, we are concerned with the toxicity of chemicals causing morphogenetic malfunctions. The malfunctions can be seen as deformed organs, excessive or missing limbs, and fingers. The toxic factors can also terminate morphogenesis, causing the death of living organisms. On the other hand, the identification of toxic factors can be useful for slowing down the growth of cancer cell clusters. As an alternative to experiments with actual living cells, we created the 2D model of an artificial blastula, which mimics a multicellular living organism in its developmental stage (blastula). Within our model, toxicity and morphogenic malfunctions can be recorded as the formation and destruction of discrete nonuniform patterns and switching between them. These patterns were first introduced by A. Turing in his pioneering study [16]. They are partially responsible for yeast budding [17] and are expected to play a key role during fetal development and gastrulation [18], limb development [19], and fingers development [20]. While the stationary Turing pattern can occur under conditions of faster transport rate of inhibitor species, usually under the scheme “short-range activation and long-range inhibition” [21, 22], they can also occur for equal transport rates of both activator and inhibitor, provided that the overall kinetics is enhanced, and the system is properly perturbed [23, 24, 25, 26]. Turing patterns have been proven experimentally [27, 28, 29, 30, 31, 32], but for its occurrence, the activator molecule transport rate has to be slowed down by different agents. The occurrence of discrete Turing patterns has been shown experimentally and in models in various artificial systems using the Belousov-Zhabotinsky reaction and its modifications [33, 34, 35, 36, 37, 38].
Our recent research shows it is possible to make transitions between uniform oscillations and discrete nonuniform patterns [39]. This can be used for chemical computing as well as a type of chemical memory. Moreover, nonuniform patterns can also be used as the output of chemical classification. The network considered in this paper can be used as a classifier under different kinetic and transport parameters and under different network topology. The reaction parameters and coupling constants have to be optimized for each topology. Evolutionary algorithms are frequently used for parameter optimization. Once optimized, even a small network can classify schizophrenia [40] or color of points on the Japanese flag [41] with accuracy exceeding 90%.
In this chapter, we would like to show how the 2D blastula model can exhibit various discrete nonuniform patterns and how these patterns can be quenched by varying kinetic parameters, transport parameters, and the inflow of the substrate.
2. Methods
2.1 Theoretical setup
To model a small multicellular organism of unspecialized cells having only one layer of cells, a blastula, we chose a ring of N = 20 equivalent cells representing the cross section of a blastula. This theoretical setup, see Figure 1, follows the morphogenesis work of A. Turing [16]. The only difference in our case is that both activator and inhibitor are transported at the same rate, as proposed in work by Vastano et al. [23, 24]. Under such circumstances, both nonuniform patterns and uniform oscillations exist simultaneously. If initially, all cells are in the same state, uniform, fully synchronized oscillations appear. In order to obtain a nonuniform stationary pattern, the initial state should be nonhomogeneous. Alternatively, a nonuniform stationary pattern can be obtained by a nonhomogeneous perturbation of synchronized oscillations. This is schematically shown in Figure 1, where in Figure 1a the 2D blastula model operates in a regime of uniform oscillations, and it acts as 20 synchronized cells. After it is perturbed, it goes into a regime of a discrete nonuniform pattern (discrete Turing pattern) (see Figure 1b). Afterward, it can be switched into other discrete nonuniform patterns (see Results) by an additional perturbation, or it can be switched back to uniform oscillations, as shown in Figure 1c.
2.2 Model of glycolysis
Our 2D blastula model consists of 20 coupled cells in which chemical reactions occur. A separated cell can be modeled using the kinetic equation:
where vector
and the boundary condition is Z
In the case considered in our study, all species have the same transport rate coefficient in between all cells, and thus
where
2.3 Varying parameters to set up the 2D blastula model
Our 2D blastula model has to have carefully chosen parameters, so it can exhibit the coexistence of discrete patterns and nonuniform oscillations. The core model of glycolysis for one cell shows uniform oscillations, stable uniform stationary state, birhythmicity, and hard excitation [42] under fixed autocatalytic rate coefficient σ
2.4 Solution diagram
For the analysis of stability and location of bifurcations of stationary states and for simulations of the system, we used the program CONT [47, 48]. A solution diagram was obtained as the result of a one-parameter continuation. The solution diagram for ADP concentration in the first cell as a function of
3. Results
Our goal is to provide a method for assessing organism development toxicity. To create the method, we need to map all possible patterns inside the 2D blastula model. For the purpose of machine reading and loading the resulting discrete patterns, we are assigning a letter to certain ranges of stationary concentrations of ADP, Table 1.
Letter | Range of stationary concentration of ADP |
---|---|
A | [1, 12] |
B | (12, 28) |
C | [28, 36] |
D | (36, 47) |
E | [47, 100] |
A uniform stationary state has thus pattern C20 with its dimensionless stationary concentration of ADP = 30.6667.
The 2D blastula model can operate in a regime of uniform oscillations, uniform stationary state, and according to Figure 2 at least 12 discrete nonuniform patterns are possible for
The same analysis can be done for any chemical input we define as a metabolic pathway inside each cell. The guide for our analysis under constant
To assess all accessible discrete nonuniform patterns, we used initial conditions taken from the solution diagram in Figure 2, or in case any pattern occurs for different parameters than those used in Figure 2, we took the initial conditions from the whole parameter space we have analyzed.
The first set of discrete nonuniform patterns is presented in Figure 4. The patterns in Figure 4a and b show concentration profile E2A3E2A3E2A3E2A3. They occur for
The second set of discrete nonuniform patterns is specific. Figure 5 shows nine discrete patterns which coexist simultaneously for
4. Discussion
The coexistence of multiple patterns for the same set of parameters illustrated in Figure 5 allows for multiple morphogenetic results. Our analysis of the model has shown there is not a simple pattern with one minimum of concentration of ADP and one maximum of concentration of ADP, and with the wavenumber 1, which we would expect to start gastrulation. There are, however, three patterns with wavenumber 1, where we can observe certain concentration profiles with both maxima and minima.
This might be the pattern, which could start gastrulation as a result of a concentration profile in 10 cells altogether or all 20 cells. In these cases, we expect the gastrulation to start at D2 in between …CAD2AC… or it can start at A2 in between …DEA2ED… or finally it can occur at A2 in between …DEA2ED… We can notice the last two cases have the same structure. This might be either a mechanism to ensure that two patterns can lead to gastrulation or our universal 2D blastula model incorporating both gastrulation and limb development to multiple organisms with a tail and without a tail. Such organism would have only one axis of body symmetry. The concentration profiles show that a variety of perturbations can lead to the same pattern type, just rotated by a few cells. Since our model can also serve as a model for developing organism or may set prepatterns for future limb development creating multiple axes of body symmetry. The importance of growing legs on a position shifted by π/10, while all limbs have a constant position to each other, is insignificant. What could be a problem if the perturbation switches the pattern from wavenumber 4 to wavenumber 5 or vice versa. A chemical causing this is toxic toward morphogenetic development, because the organism will grow a tail when it is not supposed to or vice versa. If applied to a growing palm, a perturbing chemical will influence a number of digits.
For the purpose of a method of obtaining chemoinformatics toxicity information in living developing organisms, our 2D blastula model serves only as a skeleton hybrid/artificial organism since it only works with ATP and ADP and takes into account only the anaerobic part of glycolysis via kinetic parameters. For the purpose of modeling the pattern behavior of cancer cells [49] due to the Warburg effect [50], it can be extended toward the full model of anaerobic glycolysis using the model proposed by Hynne et al. [51, 52]. If we want to assess the pattern toxicity toward cells with a whole glycolytic reaction chain, including aerobic part of glycolysis [7], it is possible to incorporate artificial mitochondria [53, 54].
Our long-term goal is the creation of an array [55] of artificial cells [56], which could simulate behavior of blastula or even start a shape development, depending on the capabilities of the artificial cell.
5. Conclusions
We have performed an analysis of the stability and bifurcation of stationary states for the 2D model of blastula consisting of 20 coupled cells. The chemistry of each cell is described by the two-variable model of glycolysis (cf. Eq. (3)). The system shows a remarkable number of discrete Turing patterns and can be used to model different phenomena.
One of them is the application of coupled cells as a chemical memory unit. Different patterns can be used for different symbol coding. Figure 2 suggests a straightforward method of switching between discrete patterns. In order to optimize memory, an extensive study on the best strategy for switching between patterns is necessary.
The introduced model can also serve as an artificial living organism for studies on developmental toxicity. We have chosen a parameter plane of
Our analysis of pattern occurrence inside artificial 2D blastula should generalize the current cheminformatics methods to include toxicological databases toward the potential development of living organisms while not actually harming animals. It can also extend cheminformatics databases about toxicity toward cancer cells, since the model incorporates anaerobic glycolysis and, therefore, can describe the Warburg effect. The model currently works with ATP and ADP but can be extended toward all species taking part in glycolysis. It can also incorporate artificial mitochondria to work with aerobic glycolysis.
Acknowledgments
This publication is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 847413.
Scientific work published as part of an international co-financed project founded from the program of the Minister of Science and Higher Education entitled “PMW” in the years 2020–2024; agreement no. 5005/H2020-MSCA-COFUND/2019/2.
Data availability
All numerical data and the model are stored in the repository at: https://doi.org/10.18150/JKFBUW
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