Here we report a systematic method for constructing a large scale kinetic metabolic model and its initial application to the modeling of central metabolism of Methylobacterium extorquens AM1, a methylotrophic and envi...Here we report a systematic method for constructing a large scale kinetic metabolic model and its initial application to the modeling of central metabolism of Methylobacterium extorquens AM1, a methylotrophic and environmental important bacterium. Its central metabolic network includes formaldehyde metabolism, serine cycle, citric acid cycle, pentose phosphate pathway, gluconeogensis, PHB synthesis and acetyl-CoA conversion pathway, respiration and energy metabolism. Through a systematic and consistent procedure of finding a set of parameters in the physiological range we overcome an outstanding difficulty in large scale kinetic modeling: the requirement for a massive number of enzymatic reaction parameters. We are able to construct the kinetic model based on general biological considerations and incomplete experimental kinetic parameters. Our method consists of the following major steps: 1) using a generic enzymatic rate equation to reduce the number of enzymatic parameters to a minimum set while still preserving their characteristics; 2) using a set of steady state fluxes and metabolite concentrations in the physiological range as the expected output steady state fluxes and metabolite concentrations for the kinetic model to restrict the parametric space of enzymatic reactions; 3) choosing enzyme constants K's and K'eqs optimized for reactions under physiological concentrations, if their experimental values are unknown; 4) for models which do not cover the entire metabolic network of the organisms, designing a dynamical exchange for the coupling between the metabolism represented in the model and the rest not included.展开更多
Based on recent work, I will give a nontechnical brief review of a powerful quantitative concept in biology, adaptive landscape, ini- tially proposed by S. Wright over 70 years ago, reintroduced by one of the founders...Based on recent work, I will give a nontechnical brief review of a powerful quantitative concept in biology, adaptive landscape, ini- tially proposed by S. Wright over 70 years ago, reintroduced by one of the founders of molecular biology and by others in different bio- logical contexts, but apparently forgotten by modem biologists for many years. Nevertheless, this concept finds an increasingly important role in the development of systems biology and bionetwork dynamics modeling, from phage lambda genetic switch to endogenous net- work for cancer genesis and progression. It is an ideal quantification to describe the robustness and stability of bionetworks. Here, I will first introduce five landmark proposals in biology on this concept, to demonstrate an important common thread in theoretical biology. Then I will discuss a few recent results, focusing on the studies showing theoretical consistency of adaptive landscape. From the perspec- tive of a working scientist and of what is needed logically for a dynamical theory when confronting empirical data, the adaptive landscape is useful both metaphorically and quantitatively, and has captured an essential aspect of biological dynamical processes. Though at the theoretical level the adaptive landscape must exist and it can be used across hierarchical boundaries in biology, many associated issues are indeed vague in their initial formulations and their quantitative realizations are not easy, and are good research topics for quantitative biologists. I will discuss three types of open problems associated with the adaptive landscape in a broader perspective.展开更多
An innovative theoretical framework for stochastic dynamics based on the decomposition of a stochas- tic differential equation （SDE） into a dissipative component, a detailed-balance-breaking component, and a dual-ro...An innovative theoretical framework for stochastic dynamics based on the decomposition of a stochas- tic differential equation （SDE） into a dissipative component, a detailed-balance-breaking component, and a dual-role potential landscape has been developed, which has fruitful applications in physics, engineering, chemistry, and biology. It introduces the A-type stochastic interpretation of the SDE beyond the traditional Ito or Stratonovich interpretation or even the a-type interpretation for multi- dimensional systems. The potential landscape serves as a Hmniltonian-like function in nonequilibrimn processes without detailed balance, which extends this important concept from equilibrium statistical physics to the nonequilibrium region. A question on the uniqueness of the SDE decomposition was recently raised. Our review of both the mathematical and physical aspects shows that uniqueness is guaranteed. The demonstration leads to a better understanding of the robustness of the novel frame- work. In addition, we discuss related issues including the limitations of an approach to obtaining the potential function from a steady-state distribution.展开更多
A decade ago mainstream molecular biologists regarded it impossible or biologically ill-motivated to understand the dynamics of complex biological phenomena, such as cancer genesis and progression, from a network pers...A decade ago mainstream molecular biologists regarded it impossible or biologically ill-motivated to understand the dynamics of complex biological phenomena, such as cancer genesis and progression, from a network perspective. Indeed, there are numerical difficulties even for those who were determined to explore along this direction. Undeterred, seven years ago a group of Chinese scientists started a program aiming to obtain quantitative connections between tumors and network dynamics. Many interesting results have been obtained. In this paper we wish to test such idea from a different angle: the connection between a normal biological process and the network dynamics. We have taken early myelopoiesis as our biological model. A standard roadmap for the cell-fate diversification during hematopoiesis has already been well established experimentally, yet little was known for its underpinning dynamical mechanisms. Compounding this difficulty there were additional experimental challenges, such as the seemingly conflicting hematopoietic roadmaps and the cell-fate inter-conversion events. With early myeloid cell-fate determination in mind, we constructed a core molecular endogenous network from well-documented gene regulation and signal transduction knowledge. Turning the network into a set of dynamical equations, we found computationally several structurally robust states. Those states nicely correspond to known cell phenotypes. We also found the states connecting those stable states.They reveal the developmental routes—how one stable state would most likely turn into another stable state. Such interconnected network among stable states enabled a natural organization of cell-fates into a multi-stable state landscape. Accordingly, both the myeloid cell phenotypes and the standard roadmap were explained mechanistically in a straightforward manner. Furthermore,recent challenging observations were also explained naturally. Moreover, the landscape visually enables a prediction of a pool of additional cell states and developmental routes, including the non-sequential and cross-branch transitions, which are testable by future experiments. In summary, the endogenous network dynamics provide an integrated quantitative framework to understand the heterogeneity and lineage commitment in myeloid progenitors.展开更多
Experimental evidences and theoretical analyses have amply suggested that in cancer genesis and progression genetic information is very important but not the whole. Nevertheless, ＂cancer as a disease of the genome＂ ...Experimental evidences and theoretical analyses have amply suggested that in cancer genesis and progression genetic information is very important but not the whole. Nevertheless, ＂cancer as a disease of the genome＂ is still currently the dominant doctrine. With such a background and based on the fundamental properties of biological systems, a new endogenous molecular-cellular network theory for cancer was recently proposed by us. Similar proposals were also made by others. The new theory attempts to incorporate both genetic and environmental effects into one single framework, with the possibility to give a quantitative and dynamical description. It is asserted that the complex regulatory machinery behind biological processes may be modeled by a nonlinear stochastic dynamical system similar to a noise perturbed Morse-Smale system. Both qualitative and quantitative descriptions may be obtained. The dynamical variables are specified by a set of endogenous molecular-cellular agents and the structure of the dynamical system by the interactions among those biological agents. Here we review this theory from a pedagogical angle which emphasizes the role of modularization, hierarchy and autonomous regulation. We discuss how the core set of assumptions is exemplified in detail in one of the simple, important and well studied model organisms, Phage lambda. With this concrete and quantitative example in hand, we show that the application of the hypothesized theory in human cancer, such as hepatocellular carcinoma （HCC）, is plausible, and that it may provide a set of new insights on understanding cancer genesis and progression, and on strategies for cancer prevention, cure, and care.展开更多
This is a question which would certainly divide physicists in particular and scientists in general.Being aware of that,here I would like to take the successful career path of an excellent physicist as a positive examp...This is a question which would certainly divide physicists in particular and scientists in general.Being aware of that,here I would like to take the successful career path of an excellent physicist as a positive example,supplemented by my own humble and negligible experience.I do hope that a bit of such discussion would be useful in the current rash state of scientific research in China.展开更多
基金USA National Institutes of Health(Nos.K25-HG002894-05(P.A.)GM36296(L.W.L.and M.E.L.)
文摘Here we report a systematic method for constructing a large scale kinetic metabolic model and its initial application to the modeling of central metabolism of Methylobacterium extorquens AM1, a methylotrophic and environmental important bacterium. Its central metabolic network includes formaldehyde metabolism, serine cycle, citric acid cycle, pentose phosphate pathway, gluconeogensis, PHB synthesis and acetyl-CoA conversion pathway, respiration and energy metabolism. Through a systematic and consistent procedure of finding a set of parameters in the physiological range we overcome an outstanding difficulty in large scale kinetic modeling: the requirement for a massive number of enzymatic reaction parameters. We are able to construct the kinetic model based on general biological considerations and incomplete experimental kinetic parameters. Our method consists of the following major steps: 1) using a generic enzymatic rate equation to reduce the number of enzymatic parameters to a minimum set while still preserving their characteristics; 2) using a set of steady state fluxes and metabolite concentrations in the physiological range as the expected output steady state fluxes and metabolite concentrations for the kinetic model to restrict the parametric space of enzymatic reactions; 3) choosing enzyme constants K's and K'eqs optimized for reactions under physiological concentrations, if their experimental values are unknown; 4) for models which do not cover the entire metabolic network of the organisms, designing a dynamical exchange for the coupling between the metabolism represented in the model and the rest not included.
基金supported in part by a grant from USA National Institutes of Health (No. K25-HG002894-05)985 Project from Shanghai Jiao Tong University.
文摘Based on recent work, I will give a nontechnical brief review of a powerful quantitative concept in biology, adaptive landscape, ini- tially proposed by S. Wright over 70 years ago, reintroduced by one of the founders of molecular biology and by others in different bio- logical contexts, but apparently forgotten by modem biologists for many years. Nevertheless, this concept finds an increasingly important role in the development of systems biology and bionetwork dynamics modeling, from phage lambda genetic switch to endogenous net- work for cancer genesis and progression. It is an ideal quantification to describe the robustness and stability of bionetworks. Here, I will first introduce five landmark proposals in biology on this concept, to demonstrate an important common thread in theoretical biology. Then I will discuss a few recent results, focusing on the studies showing theoretical consistency of adaptive landscape. From the perspec- tive of a working scientist and of what is needed logically for a dynamical theory when confronting empirical data, the adaptive landscape is useful both metaphorically and quantitatively, and has captured an essential aspect of biological dynamical processes. Though at the theoretical level the adaptive landscape must exist and it can be used across hierarchical boundaries in biology, many associated issues are indeed vague in their initial formulations and their quantitative realizations are not easy, and are good research topics for quantitative biologists. I will discuss three types of open problems associated with the adaptive landscape in a broader perspective.
基金This work was supported in part by the National Natural Science Foundation of China （Grant Nos. NSFC91329301 and NSFC9152930016） and grants from the State Key Laboratory of Oncogenes and Related Genes （Grant No. 90-10-11）.
文摘An innovative theoretical framework for stochastic dynamics based on the decomposition of a stochas- tic differential equation （SDE） into a dissipative component, a detailed-balance-breaking component, and a dual-role potential landscape has been developed, which has fruitful applications in physics, engineering, chemistry, and biology. It introduces the A-type stochastic interpretation of the SDE beyond the traditional Ito or Stratonovich interpretation or even the a-type interpretation for multi- dimensional systems. The potential landscape serves as a Hmniltonian-like function in nonequilibrimn processes without detailed balance, which extends this important concept from equilibrium statistical physics to the nonequilibrium region. A question on the uniqueness of the SDE decomposition was recently raised. Our review of both the mathematical and physical aspects shows that uniqueness is guaranteed. The demonstration leads to a better understanding of the robustness of the novel frame- work. In addition, we discuss related issues including the limitations of an approach to obtaining the potential function from a steady-state distribution.
基金supported by the National Basic Research Program of China(2010CB529200)National Natural Science Foundation of China(91029738)
文摘A decade ago mainstream molecular biologists regarded it impossible or biologically ill-motivated to understand the dynamics of complex biological phenomena, such as cancer genesis and progression, from a network perspective. Indeed, there are numerical difficulties even for those who were determined to explore along this direction. Undeterred, seven years ago a group of Chinese scientists started a program aiming to obtain quantitative connections between tumors and network dynamics. Many interesting results have been obtained. In this paper we wish to test such idea from a different angle: the connection between a normal biological process and the network dynamics. We have taken early myelopoiesis as our biological model. A standard roadmap for the cell-fate diversification during hematopoiesis has already been well established experimentally, yet little was known for its underpinning dynamical mechanisms. Compounding this difficulty there were additional experimental challenges, such as the seemingly conflicting hematopoietic roadmaps and the cell-fate inter-conversion events. With early myeloid cell-fate determination in mind, we constructed a core molecular endogenous network from well-documented gene regulation and signal transduction knowledge. Turning the network into a set of dynamical equations, we found computationally several structurally robust states. Those states nicely correspond to known cell phenotypes. We also found the states connecting those stable states.They reveal the developmental routes—how one stable state would most likely turn into another stable state. Such interconnected network among stable states enabled a natural organization of cell-fates into a multi-stable state landscape. Accordingly, both the myeloid cell phenotypes and the standard roadmap were explained mechanistically in a straightforward manner. Furthermore,recent challenging observations were also explained naturally. Moreover, the landscape visually enables a prediction of a pool of additional cell states and developmental routes, including the non-sequential and cross-branch transitions, which are testable by future experiments. In summary, the endogenous network dynamics provide an integrated quantitative framework to understand the heterogeneity and lineage commitment in myeloid progenitors.
文摘Experimental evidences and theoretical analyses have amply suggested that in cancer genesis and progression genetic information is very important but not the whole. Nevertheless, ＂cancer as a disease of the genome＂ is still currently the dominant doctrine. With such a background and based on the fundamental properties of biological systems, a new endogenous molecular-cellular network theory for cancer was recently proposed by us. Similar proposals were also made by others. The new theory attempts to incorporate both genetic and environmental effects into one single framework, with the possibility to give a quantitative and dynamical description. It is asserted that the complex regulatory machinery behind biological processes may be modeled by a nonlinear stochastic dynamical system similar to a noise perturbed Morse-Smale system. Both qualitative and quantitative descriptions may be obtained. The dynamical variables are specified by a set of endogenous molecular-cellular agents and the structure of the dynamical system by the interactions among those biological agents. Here we review this theory from a pedagogical angle which emphasizes the role of modularization, hierarchy and autonomous regulation. We discuss how the core set of assumptions is exemplified in detail in one of the simple, important and well studied model organisms, Phage lambda. With this concrete and quantitative example in hand, we show that the application of the hypothesized theory in human cancer, such as hepatocellular carcinoma （HCC）, is plausible, and that it may provide a set of new insights on understanding cancer genesis and progression, and on strategies for cancer prevention, cure, and care.
文摘This is a question which would certainly divide physicists in particular and scientists in general.Being aware of that,here I would like to take the successful career path of an excellent physicist as a positive example,supplemented by my own humble and negligible experience.I do hope that a bit of such discussion would be useful in the current rash state of scientific research in China.
