What is Systems Biology

What is Systems Biology

2 CBS, Department of Systems Biology

3 CBS, Department of Systems Biology

Data integration In the Big Data era Combine different types of data, describing different things or the same thing with different error City guide analogy: Road maps Arial pictures of buildings Google Maps Street-level pictures Restaurant reviews 4 CBS, Department of Systems Biology

Reduction vs Holistic Reductionism seeks to find individual factors that explain/cause a phenomenon Typically study one factor at a time Which cells -> which organelle -> which molecules -> which sites on these molecules -> which atoms and H-bonds involved? Holistic approach looks at many or all components of the system and the interplay between them E.g. map of whole city (as opposed to map of one road) Understanding cancer (requires understanding of many different biological processes) 5 CBS, Department of Systems Biology

Increasing Interest in Systems Biology PubMed Term Publications 0 5000 10000 15000 Bioinformatics Systems Biology Cell Cycle Yeast genome completed Nobel Prize for Cell Cycle Human genome completed 1995 2000 2005 2010 Year 6 CBS, Department of Systems Biology

Also, systems Biology is a top-down science Systems Biology Integration Normal Biology Reducitonist 7 CBS, Department of Systems Biology

Systems biology and emerging properties 8 CBS, Department of Systems Biology

Integration of whole x-ome to understand life in health and disease genome metabolome LIFE etceterome transcriptome lipidome proteome 9 CBS, Department of Systems Biology

10 CBS, Department of Systems Biology

From components to models

Transcriptional regulation of the Cell Cycle Simon et al. Cell 2001 12 CBS, Department of Systems Biology

13 CBS, Department of Systems Biology

14 CBS, Department of Systems Biology Tyson JJ, Novak B, J. Theor. Biol. 2001

Carbohydrate metabolic map 15 CBS, Department of Systems Biology

Mathematical abstraction of biochemistry 16 CBS, Department of Systems Biology

The hierarchy of models 17 CBS, Department of Systems Biology

The hierarchy of models 18 CBS, Department of Systems Biology

From components to models

One framework for Systems Biology (part 1) 1. The components. Discover all of the genes in the genome and the subset of genes, proteins, and other small molecules constituting the pathway of interest. If possible, define an initial model of the molecular interactions governing pathway function (how?). 2. Pathway perturbation. Perturb each pathway component through a series of genetic or environmental manipulations. Detect and quantify the corresponding global cellular response to each perturbation. 20 CBS, Department of Systems Biology

One framework for Systems Biology (part 2) 3. Model Reconciliation. Integrate the observed mrna and protein responses with the current, pathwayspecific model and with the global network of proteinprotein, protein-dna, and other known physical interactions. 4. Model verification/expansion. Formulate new hypotheses to explain observations not predicted by the model. Design additional perturbation experiments to test these and iteratively repeat steps (2), (3), and (4). 21 CBS, Department of Systems Biology

From model to experiment and back again 22 CBS, Department of Systems Biology

Systems Biology to address the knowledge/data problem Genome sequencing

The human genome sequencing project (HGP) - 2000 24 CBS, Department of Systems Biology

Sequencing costs over time Drop in costs is faster than Moore s Law (Computer power doubles every 2 years) 25 CBS, Department of Systems Biology

Sequencing capability: throughput per machine Kilobases per day per machine 1,000,000,000 100,000,000 10,000,000 1,000,000 100,0000 10,000 1,000 100 10 Manual slab gel 1977 - Sanger Chain-termination method 26 CBS, Department of Systems Biology ~3X coverage of a human genome Gel-based systems Automated slab gel Capillary sequencing First-generation capillary 1980 1985 1990 1995 2000 Year Human genome Massively parallel sequencing Microwell pyrosequencing Second-generation capillary sequencer 2005 Single molecule? Short-read sequencers 2010 Future

Right now, upstairs in DMAC Output: ~30 Gbp/day Human genome is 3.2 Gbp 27 CBS, Department of Systems Biology

Completely sequenced genomes by year http://www.genomesonline.org/cgi-bin/gold/index.cgi?page_requested=statistics 28 CBS, Department of Systems Biology

Bioinformatics And the wealth of information

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CTCCCCGCCACAACATACATCCCATGCCAGCCTGGGGACCCTCAAAGGTGCTTCATCATTAGGTTTGTGGCTGGGTCCTACTGAAGTAAGTCTTGGCACTCAGAGGGATAGGAATTG AATGAAGACATGAGATTCCTCTGCGGGAGGCCTCTCTAGGAAATCTGTGGACTCACACGTTTACTAATGTTGCTGCAGCCCCGCACCCACCTTGGCCTTGGGCAGCCATACTCTAGG GCTTTTGTAACCTCTCCATGTGAGGAACTCAAATTAGACCTGGGTTTGGAGGCGGTGCTCCGAGCTGGCCTTTGGGGGAGGTTTTGTGCGAGGCATTTCCCAAGTGCTGGCAGGATT GTGTCACAGACACAGAGTAAACTTTTGCTGGGCTCCAAGTGACCGCCCATAGTTTATTATAAAGGTGACTGCACCCTGCAGCCACCAGCACTGCCTGGCTCCACGTGCCTCCTGGTC TCAGTATGGCGCTGTCCTGGGTTCTTACAGTCCTGAGCCTCCTACCTCTGCTGGAAGCCCAGATCCCATTGTGTGCCAACCTAGTACCGGTGCCCATCACCAACGCCACCCTGGACC GGGTGAGTGCCTGGGCTAGCCCTGTCCTGAGCACATGGGCAGCTGCCTCCCTTCTCTGGGCTTCCCTTTACCTGCTGGCTGTGGTCGCACCCCCACTCCCAGCTCTGCCTTTTTCTC TTCTGGGTCCCCAGGGTGAAATTCTCACCAGCCCAGGGGACTCTGGAGGCACCCCCTGCCTCCAAACACAGAAGCCTCACTGCAGAGTCCTTCACGGAGGACGGTTCTGTGCTGGGC CTGGAGGGGCTGCCTGGGGGGCAATGACTGATCCTCAGGGTGAGCTCCTGCATGCGCACTGCCCACCAGGGGCCTCATCTCCCCATCTGCAAAATCAGGGAGAGATCTGCCTGAGTC TCCTCCCAGCTGACAGTCAAAGATTCAGCATCAAGCCCCCATCACCAGCTCCCCCCTTCTCCCCAGATCACTGGCAAGTGGTTTTATATCGCATCGGCCTTTCGAAACGAGGAGTAC AATAAGTCGGTTCAGGAGATCCAAGCAACCTTCTTTTACTTTACCCCCAACAAGACAGAGGACACGATCTTTCTCAGAGAGTACCAGACCCGGTGAGAGCCCCCATTCCAATGCACC CCCGATCTCAGCTGTCTGGCCAGAAGACCTGAGCAAGTCCCTCCTTCTTCCTGGCCTTGGCCTTCCCATGGGTGGAACCGGGAGGGTTGGCTTTAATCTCCACCAGAACTCTTGCCC CGGGACTGTGATGGGCGATTGGCCACTTCTCCTCGATAACATTACTGTTTTTCTTCCGCCTTCTGGTTGACTTTAGCCAGAACCAGTGCTTCTATAACTCCAGTTACCTGAATGTCC AGCGGGAGAATGGGACCGTCTCCAGATACGGTGAGGGCCAGCCCTCAGGCAGGAGGGTTCACCGTGGGAACAGGGCAGGCCAGCATAAGGTGGGGGCTGGATGTAGAGCCCTGGAGG CTTTGGGCACAGAGAAATAACCACTAACATTTTTGAGCTCTTACCACGTGCTCAGAAAAAATCCCTAAGAAGACACTGAGAGAATTAGATGAGGAAACATAAGAACAGAGACCTCAA ATAGTTTCCCCAAGGTCACACAGCTTATAATTAGAACTAGAATTGGAACTCCAGGCTGGCTTCAGATCTGCCTCTCTCTCACGCCCTCTTTAAGATCCTTTGCAAACCAATGGTAGA AGCCTGTATGTTGGAGAGGTGGTACCTTCAACTATGTCCCCCATCACCGCAGAGGTGGCACATGGCAGGGATCTGATGGAGCTGAACTGACATCATTTAGCATCCCGAGCCTCCTCT CTGGGCCTCATTTTCCTCCTCTGTAAAACGGGGAGAAAGGCCCTGACAGCCACAGTCTGTGTGAGGCTCCTGAGATCTCATGTACAGAAAGTGCTTGGCGTGGAGCTGGGCACGCAG CAGGGGCTGGGCACACGGTGGCCCAAAGGAGACCCGGGCCTTCACTGATGGGCTTTGTGGCCCCGGACACATTTCTCTTCCAGAGGGAGGCCGAGAACATGTTGCTCACCTGCGTTC CTTAGGGACACCCCTAGGACTCCTCACCTGTAAGACAGGCACCATTGTGCCATCCCATGTTCTCACCCAGAGGCTCTTAAGACCTTGATGTTTGGTTCCTACCTGGACGATGAGAAG AACTGGGGGCTGTCTTTCTATGGTAGGCATGCTTAGCAGCCCCAAACTCATGCCCCTCTCAGGCCTCACCCCCCATTCACCCACCCCTGGGCTGGCCCCTAGAACCCCAGCCCTCCC TGGCCTCCGCCGGGCCCCACCATGTCCCCAGTCAGTCTCCTTGCTCCCCCTGCAGCTGACAAGCCAGAGACGACCAAGGAGCAACTGGGAGAGTTCTACGAAGCTCTCGACTGCTTG TGCATTCCCAGGTCAGATGTCATGTACACCGACTGGAAAAAGGTAAACGCAAGGGATTGGACATTGCCCACCTTGTCCATGGCCCAACTTGGGCAGCCCCAGAGGCCCAGAGCAGGA AAGCTGCCAGGCAAGGCTGCACAGCTAGGCAGATCTTCTGCTTTTAGGCACCTGCCTCACTGTAGGGACAGCTGAGCTCTACAGAGGCCCAGGGGTGGTGGATGAGAGCCCAGGAGG GAGAAGTCCCTGTGAAACCAGGGAGGACCTGAAAGCTAACAGGAGGGAACAGCGTGAGCCACGGGGTTGGGGGATTGGCAATTGGAGGGGACGTAATGCGGGGAGTTACCACCTACA GACGCGTCCCAAACCCCAGGCTTTCACCCCAACCTCCACTCCCCGCTCATTTTTAATACCCGTGCAGTGGGGAATTGATACTGTGGTTTTCAATGTCACCCACACTGCAGCACGGCC ACAGTCACCATCCCGATTTTTGCTACAAATGAAAATTACTGTATAATGAGCTCCTTAACACTTTTCTTTAAACCTGTGTTTGGAAGACTTGTGTTGGTGTGGCCCTGTGCCCTAATA CCTGTGAAATCACAGCACCGATGAGCTGGTTCCAATTTTTAAAATATATACATGCAGTACTTCCATGACTATTCAAAGAAAAACAATTCCTTCCATTTGCCACCTGAGATGACCACC AGGGATGTGAACTACCTCCTGCCCCATCCCCAGCCCCAGGATCCTGGGACAGGGCTTATGAACGCAACCACTGTAGTCAGCTCACTTGATCCACAGCCTGGCACCTCCACTGTCTGG CTAGGGAGCCTCGAATGGGTCCCAAGGCCACCCTGCTCCTCAGTTACATCATCTGCATAGTAGTGGTGGTTGTGAGGAATTCAGGAGCTGCAGCATAAGGGCCCTGCAGGTACTATG TGCTCAGTAAATGCCAGTGGTTCTTAAGGGTCTGAGCTCCCATTGTAGAGGCAAGTAAGCTGAGGTTCAGAGAAGAAAATGACTTGCCCAAGATCACCCAGCTGGGAAGTGACAGTG CCAGGGTTGGAGCCCTGGTTGAGCTGGTTCCACAGGCCAGAGCTCATTCTGCCCTCTCCCCGGAAGACCTCCCACCCTGTCCCCATGCCTCTGCTTCTCCCTCACCCCAATTCCCCG CTGCCTTCTAGGATAAGTGTGAGCCACTGGAGAAGCAGCACGAGAAGGAGAGGAAACAGGAGGAGGGGGAATCCTAGCAGGACACAGCCTTGGATCAGGACAGAGACTTGGGGGCCA TCCTGCCCCTCCAACCCGACATGTGTACCTCAGCTTTTTCCCTCACTTGCATCAATAAAGCTTCGCATCGGCCTTTCGAAACGAGGAGTACAATAAGTCGGTTCAGGAGCCCTCAGG CAGGAGGGTTCACCGTGGGAACAGGGCAGGCCAGCATAAGGTGGGGGCTGGATGTAGAGCCCTGGAGGCTTTGGGCACAGAGGCCACCCTGGACCGGGTGAGTGCCTGGGCTAGCCC TGTCCTGAGCACATGGGCAGCTGCCTCCCTTCTCTGGGCTTCCCTTTACCTGCTGGCTGTGGTCGCACCCCCACTCCCAGCCCCCAACTCTCCCCGCCACAACATACATCCCATGCC 30 CBS, Department of Systems Biology CAGGAGGGTTCACCGTGGGAACAGGGCAGGCCAGCATAAGGTGGGGGCTGGATGTAGAGCCCTGGAGGCTTTGGGCACAGAGGCCACCCTGGACCGGGTGAGTGCCTGGGCTAGCCC

31 CBS, Department of Systems Biology Source: http://www.ncbi.nlm.nih.gov/genbank/genbankstats.html

32 CBS, Department of Systems Biology

Current state-of-the art: - 1024 Cores - 8 Tb RAM Fastest commercial computer 33 CBS, Department of Systems Biology