课件1-系统生物学与合成生物学

-(Leroy Hood, 1999)
什么是系统生物学
系统生物学是在细胞、组织、器官和生物体水平上 研究结构和功能各异的生物分子及其相互作用， 并通过计算生物学定量阐明和预测生物功能、表 型和行为。系统生物学将在基因组测序基础上完 型和行为。系统生物学将在基因组测序基础上完 成DNA序列到生命的过程，这是逐步整合、优化 DNA序列到生命的过程，这是逐步整合、优化 的过程，系统生物学的发展预计需要一个世纪或 更长的时期，因此常把系统生物学称为21世纪的 更长的时期，因此常把系统生物学称为21世纪的 生物学。 -杨胜利 2004
– b：调控因子完全开启时Y的 调控因子完全开启时Y 生成速度 – a：Y的稀释降解速度
So where do we start?
dY/dt = b – aY dY/ dY/dt = 0 dY/
– 稳态时
Yst = b/a
– 稳定时浓度
So where do we start?
dY/dt = b – aY dY/ b=0
Are Biologists Ready?
50 %
Xo
S1
S2
S3
v
S4
S5
S6
X1
If we can’t understand this system how can we hope to understand:
So where do we start?
Transcription Factors Intracellular Signaling cis sites Genetic Regulatory Network mRNA Nucleus Receptors Ion Channels Ligands ELECTROPHYSIOLOGY Translation + processing Cytoplasm Extracellular space
Molecular Scale 1.0 - 10 nm Interaction data Kon, Koff, Kd 10 ns - 10 ms Interactions
Cellular Scale 10 - 100 nm Concentrations Diffusion rates 10 ms - 1000 s Fluid dynamics
System heterogeneity in size & timescale
Tissue Scale 0.01m - 1.0 m Metabolic input Metabolic output 1 s – 1 hr Process flow
Organism scale 0.01m – 4.0 m Behaviors Habitats 1 hr – 100 yrs Mechanics
Are Biologists Ready?
Xo S1 S2 S3 v S4 S5 S6 X1
Xo and X1 fixed, all reactions reversible, assume stable steady state.
Are Biologists Ready?
50 %
Xo
S1
S2
S3
– Y转录停止X，诱导剂移除 转录停止X
dY/dt = - aY dY/
– 如何解？ 如何解？
Y = Yst e-at Y = Yst /2, T1/2 = ln2/a
So where do we start?
dY/dt = b – aY dY/ 从出现诱导物开始，Y的 从出现诱导物开始， 浓度如何变化？ 浓度如何变化？
robustrobust-adaptation of chemotaxis
Tumbling frequency IPTG inducer
pUA4 pUA4 pUA4 pUA4
Adaption time
E. Coli cheR -/- population
Express CheR over a 100-fold range Adaption precision 1 mM L-aspartate
So where do we start?
Feedback loops
So where do we start?
So where do we start?
autoregulation
So where do we start?
X Y
– 转录因子X调控基因Y 转录因子X调控基因Y
dY/dt = b - aY dY/
生物学角度( 生物学角度(PULL): 拓展认知，定量分析
Systems Biology vs. traditional cell and molecular biology
采用高通量的实验技术方案. 采用高通量的实验技术方案. 加强的计算需求和数据库的运用. 加强的计算需求和数据库的运用. 传统生物学实验遵循“假说-验证”循环，在循环中收 传统生物学实验遵循“假说-验证”循环， 集实验数据. 集实验数据. 系统生物学起于数据采集， 系统生物学起于数据采集，在后实验的数据分析中推 出假说，并验证假说. 出假说，并验证假说. 系统生物学是数据与途径的整合
Adaptation precision = ratio of steady-state tumbling frequency of unstimulated to stimulated cells Summary of results Tumbling frequency 0.3 ± 0.06 (20-fold) Adaption time 3 ± 1 (3-fold) Adaption precision 1.04 ± 0.07
Ecosystem scale 1 km – 1000 km Environmental impact Nutrient flow 1 yr – 1000 yrs Network Dynamics
System Models
对一个系统建立可计算的模型成为可行性越来越高的方案. 对一个系统建立可计算的模型成为可行性越来越高的方案 建立模型必须清楚的知道系统的制约因素， 建立模型必须清楚的知道系统的制约因素，最终模型会成 为强大的预测工具. 为强大的预测工具
Genomics, Proteomics & Systems Biology
Genomics Proteomics
Systems Biology 1990 1995 2000 2005 2010 2015 2020
Why Systems Biology?
技术角度( 技术角度(PUSH): 高通量数据采集能力
S5
Hale Waihona Puke Baidu
S6
X1
Typical replies: 1. Nothing happens. 2. Nothing happens unless it is the rate-limiting step. 3. The rate v goes down, but that’s all. 4. S3 goes up. 5. S4 goes down. 6. Species downstream of v go down. 7. Steady State flow changes but species levels don’t. 8. Xo and X1 change
系统与合成生物学
系统生物学
– System Biology
合成生物学
– Synthetic Biology
授课计划
Systems Biology – backers & attackers
Though coined 40 years ago, a lot of people still ask, "What's that?" when the term systems biology comes up. "It is used in so many different contexts, nobody is really clear what you mean by it," says John Yates III, a professor at the Scripps Research Institute in La Jolla, Calif. "Systems biology is just so general that it could apply to many things. When you're naming a category, the underlying principle is that if you make a statement like, 'I'm doing systems biology,' do people know what you're talking about?'“……
v
S4
S5
S6
X1
What happens to the steady state? Xo and X1 fixed, all reactions reversible, assume stable steady state.
Are Biologists Ready?
50 %
Xo
S1
S2
S3
v
S4
Technologies to study systems at different levels
Genomics (HT-DNA sequencing) (HTMutation detection (SNP methods) Transcriptomics (Gene/Transcript measurement, SAGE, gene chips, microarrays) Proteomics (MS, 2D-PAGE, protein 2Dchips, Yeast-2-hybrid, X-ray, NMR) YeastXMetabolomics (NMR, X-ray, capillary Xelectrophoresis)
系统与合成生物学
System Biology, Synthetic Biology
马昱澍， 马昱澍，王玮
系统与合成生物学
王玮 讲师
– wadexp@ecust.edu.cn – 鲁华生物科技研究所 鲁华生物 生物科技研究所
马昱澍 副教授
– myushu@ecust.edu.cn – 鲁华生物科技研究所 鲁华生物科技研究所
Volume 17 | Issue 19 | 27 Oct. 6, 2003, The Scientist
What is “Systems Biology”?
The study of the mechanisms underlying complex biological processes as integrated systems of many interacting components. Systems biology involves (1) components. collection of large sets of experimental data (2) proposal of mathematical models that might account for at least some significant aspects of this data set, (3) accurate computer solution of the mathematical equations to obtain numerical predictions, and (4) assessment of the quality of the model by comparing numerical simulations with the experimental data.
Each system has methods for modeling
Pi Calculus
Petri Nets
Flux Balance Analysis
Differential Eqs
System heterogeneity in size & timescale
Atomic Scale 0.1 - 1.0 nm Coordinate data Dynamic data 0.1 - 10 ns Molecular dynamics