overview

  1. Cell systems Biology

Systems Biology seeks to understand a complex biological system by looking at relationships and interactions between various components of that system. Systems Biology allows us to think broadly about cell processes.

Why do we need systems biology? To understand how an organism works.

Systems Biology Framework

  1. define the components of the system
  2. Perturb and monitor the components
  3. Reconcile the responses with a model
  4. Design and perform new perturbation

Discovery of DNA: o 1800s o Friedrich Miescher isolated “nuclein” in cell’s nuclei o Albrecht Kossel discovers ”nuclein” consists of proteins and nucleic acids and isolates the nitrogen bases of nucleic acids

Connecting genotype to phenotype: o 1900s - Sir Archibald Garrod: studied human disorder alkaptonuria by looking at family trees of people with the disorder o 1940s – Beadle & Tatum: connecting genes to enzymes by studying bread mould (one gene-one enzyme hypothesis)

o DNA as the ”transforming principle” : o 1940s – Oswald Avery, Colin MacLeod, and Maclyn McCarty - showing that DNA, not protein, carry the genetic information by studying Streptococcus pneumoniae o 1950s – Alfred Hersey and Martha Chase – proved that DNA is the hereditary material by studying radiolabelled bacteriophage.

o DNA structure: o 1950s: o Erwin Chargaff - found that the ratios of adenine (A) to thymine (T) and guanine (G) to cytosine (C) in DNA are equal. o Rosalind Franklin and Maurice Wilkins – described the helix structure of DNA using X-ray crystallography. o Francis Crick and James Watson – described the 3-D, double helix model of DNA and suggested the mechanism for DNA replication Beadle & Tatum Experiment

Exam Q: example of 4 test tubes – explain what is happening in terms of genetic pathways and genetic mutations

o In its normal, or "wild", state, the mould Neurospora crassa can grow on a medium containing just sugar, a small amount of biotin, and inorganic salts. o When the mould is exposed to X-ray radiation, mutations arise in occasional cells. Some of the mutations affect the mould’s ability to form organic compounds from simpler building blocks. o For example, some lose the ability to assemble particular amino acids. o To thrive, those strains need to have the particular amino acids supplied in their nutrient medium or, sometimes, they can make do with precursor compounds that the cells can convert into the required amino acids. o By supplying a variety of compounds in the nutrient medium and seeing which allow various mutant strains to grow and which don't, Beadle and Tatum saw that they could deduce the sequence of biochemical reactions in cells that make necessary compounds like amino acids. o The scientists concluded that the function of a gene is to direct the formation of a particular enzyme, which regulates a chemical event. o A mutation can alter a gene so it no longer produces the normal enzyme, resulting in a physical symptom, like the need for nutritional supplements. Beadle and Tatum proposed that, in general, each gene directs the formation of one (and only one) enzyme.

Alfred Hersey and Martha Chase

o Martha Chase and Alfred Hershey radioactively-labeled either the protein or the nucleic acids (DNA, RNA) of a bacteria-infecting virus (a bacteriophage or “phage”) o let the phage infect bacteria o looked to see where the radioactivity ended up (after using that blender to shear off viral shells stuck to the bacteria ). o the radioactivity only got inside the bacteria where the nucleic acids were labeled, showing that genetic information is stored and transmitted through nucleic acids.

New techniques for studying genes:

o How to determine the sequence of the DNA piece (DNA sequencing) o How to produce DNA using bacterial cells (Gene cloning) o How to amplify desired DNA sequences (DNA amplification, PCR) o High-throughput methods

Central Dogma of Systems Biology

o Genomics - is the study of all of organism’s genes (the genome) o Transcriptomics - is the study RNA transcripts that are produced by the genome (transcriptome). o Proteomics - is the large-scale study of proteins produced in a system (proteome), o Metabolomics – is the large-scale study of small molecule chemicals (metabolites) produced by the system (metabolome) o Fluxomics – is the large scale study of the rates of all metabolic fluxes (fluxome) in the central metabolism of biological systems

“Network of Networks” principle o Systems biology looks at these networks across scales to integrate behaviours at different levels, to formulate hypotheses for biological function and to provide insights into dynamical biological changes at a given location and time o Integrated and interacting networks o Integration of information at different level