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

“ Organisms function in an integrated manner-our
senses, our muscles, our metabolism and our minds
work together seamlessly. But biologists have
historically studied organisms part by part and
celebrated the modern ability to study them molecule
by molecule, gene by gene. Systems biology is critical
science of future that seeks to understand the
integration of the pieces to form biological systems”
(David Baltimore, Nobel Laureate)
Biology

Biomolecules
RNA

Chemistry
Medicine

DNA

Cells

Networks
Proteins

Engineering

Computers
Mathematics
Variomics

Transcriptomics

Genomics
Phenomics

Proteomics
Metagenomics
Metatranscriptomics
biome, CHOmics, cellome, cellomics, chronomics, clinomics,
complexome, crystallomics, cytomics, cytoskeleton, degradomics,
diagnomicsTM, enzymome, epigenome, expressome, fluxome, foldome,
secretome, functome, functomics, genomics, glycomics, immunome,
transcriptomics, integromics, interactome, kinome, ligandomics,
lipoproteomics,
localizome,
phenomics,
metabolome,
pharmacometabonomics,
methylome,
microbiome,
morphome,
neurogenomics, nucleome, secretome, oncogenomics, operome,
transcriptomics,
ORFeome, parasitome, pathome, peptidome,
pharmacogenome, pharmacomethylomics, phenomics, phylome,
physiogenomics, postgenomics, predictome, promoterome, proteomics,
pseudogenome, secretome, regulome, resistome, ribonome, ribonomics,
riboproteomics, saccharomics, secretome, somatonome, systeome,
toxicomics, transcriptome, transcriptomics, translatome, secretome,
unknome, vaccinome, variomics.............
(http://www.genomicglossaries.com/content/omes.asp)
Any FOOD for thoughts………..
Complicated!!…….Why?
How can we make sense of this complexity?
Can we convey our understanding of this
complexity?
Molecular biologybiomolecule structure and
function is studied at the
molecular level
Systems biologyspecific interactions of
components
in
the
biological system are
studied
–
cells, tissues, organs, and
ecological webs
◦ Integrative
approach
in
which
scientists
study
pathways and networks, will
touch
all
areas
of
biology,
including
drug
discovery

Era of Molecular Biology (1953 –2001)

Era of Systems Biology (2001 – ??)
Genomics
Transcriptomics
Proteomics
Systems Biology
1990

1995

2000

2005

2010

2015

2020

(http://www.biomedcentral.com/bmcsystbiol/)
study
of
an
organism,
viewed
as
an integrated and interacting network of
genes, proteins and biochemical reactions which give
rise to life.
Looking at the whole system rather than at
components, such as sugar metabolism or a cell
nucleus
Completeness is a recent aspect
Mathematics/modelling-essential
Whole>Sum of parts: Give Rise Emerging properties
Properties ‘arise’ from components interaction
(Interactomics!!)


Details are now clearer…….
Top-down and bottom-up
approach

(Bruggeman and Westerhoff, 2006)
Challenged Vs. Control
B
O
T
T
O
M

T
O
P
D
O
W
N

U
P
Deductive: From known properties of
components, system functions deduced.
Properties emerge from interaction of the
components.

Inductive: From how the system reacts to
the perturbations. One infers which
components are critical and how the system
may function
Omics (the bottom-up approach) focuses on the identification and global measurement of molecular
components. Modeling (the top-down approach) attempts to form integrative (across scales) models of
animal physiology and disease, although with current technologies, such modeling focuses on relatively
specific questions at particular scales, e.g., at the pathway or organ levels. An intermediate
approach, with the potential to bridge the two, is to generate profiling data from high-throughput
assays for biological complexity, interacting active pathways, intercommunicating cell types and
different environments at multiple levels

(Butcher et al., 2004)
Basic Science/”Understanding Life”
Predicting Phenotype from
Genotype
Understanding/Predicting
Metabolism
Understanding Cellular Networks
Understanding Cell-Cell
Communication
Understanding
Pathogenicity/Toxicity
“Raising the Bar” for Biologists

“Making Biology a Predictive
Science”
100’s of completed genomes
1000’s of known reactions
10,000’s of known 3D structures
100,000’s of protein-ligand interactions
1,000,000’s of known proteins & enzymes
Decades of biological/chemical know-how
Computational & Mathematical resources

“The Push to Systems Biology”
Genomics
Proteomics
Metabolomics
Phenomics
Bioinformatics

Genometrics
Proteometrics
Metabometrics
Phenometrics
Biosimulation
Genomics (HT-DNA sequencing)
Mutation detection (SNP methods)
Transcriptomics
(Gene/Transcript
measurement, SAGE, gene chips, microarrays)
Proteomics (MS, 2D-PAGE, protein chips, Yeast-2hybrid, X-ray, NMR)
Metabolomics
(NMR,
X-ray,
capillary
electrophoresis)
study of organisms in terms of their
DNA sequences, or 'genomes'
Study of total set of transcripts in a
given organism, or to the specific
subset of transcripts present in a
particular cell type
(Soares and Valcárcel, 2006)
Large-scale
study
of
proteins, particularly their structures
and functions
Bioinformatics
Data

Research,
development,
or
application of computational tools
and approaches for expanding the
use
of
biological, medical, behavioural or
health data, including those to
acquire, store, organize, archive, ana
lyze, or visualize such data
systematic study of the unique
chemical fingerprints that specific
cellular processes leave behind" specifically, the study of their smallmolecule metabolite profiles.
( Bionaz and Loor, 2008)
Genome-wide reconstruction of the regulatory and metabolic
network in a sequenced organism….. Gives only static
information

(Weckwerth, 2011)
Sequencing capacity ↑
Number of sequenced genomes↑
Number of SNPs identified ↑
SNP typing capacity ↑
Microarray data ↑
Proteomics data ↑
Metabolomics data ↑
Data in databases ↑

Sequencing costs ↓
SNP genotyping costs ↓
Profiling costs ↓
Integromics
Information

Omics classes
Genomics

Transcriptomics

Proteomics

Metabolomics

Phenomics

Sequence

Pathways (Reactome)
Structure

APIaPIAPI
Data / DBMS

Expression

Pathways

Bioinformatics

Portal/Publication
Integromics approach in the Systems Roadmap

(Sauer et al., 2007)
Accessing information using ontologies and web databases that contain models
encoded in ML

The ML ensure that
models are encoded
in a consistent form
and allow simulation
packages to import
the models in a
standard format
CGH
The functional sequelae of SNPs and the consequences
of alterations in transcript levels can not be routinely
predicted in a comprehensive manner
The amount of protein does not necessarily correlate
with enzyme activity or protein function due to
multiple
posttranslational
modifications
and
compartmentation
Examination of whole cell or tissue extracts are not
necessarily indicative of the physical interactions
between moieties
Data management:
Clear indication of the source and context of the
data
Meaningful identifiers (everybody’s proud of their
clever system that nobody else uses)
Accessible data sources

Models / Methods to interpret the data
An honest assessment of the benefits and limits of
various modeling approaches
A realistic assessment of the near-term capabilities of
current modeling approaches.
The ability to understand the limits of the
data and models
Complexity of mammalian systems
"As the complexity of the variable increases, it
becomes more important to have a solid model
of what you think you can predict and to then
test it explicitly, rather than less important as
the machine learning enthusiasts would have it"
(Michael Bittner, Tgen)
Atomic Scale
0.1 - 1.0 nm
Coordinate data
Dynamic data
0.1 - 10 ns
Molecular dynamics

Molecular Scale
1.0 - 10 nm
Interaction data
10 ns - 10 ms
Interactions

Cellular Scale
10 - 100 nm
Concentrations
Diffusion rates
10 ms - 1000 s
Fluid dynamics
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

Ecosystem scale
1 km – 1000 km
Environmental impact
Nutrient flow
1 yr – 1000 yrs
Network Dynamics
If one scale (e.g., protein-protein
interactions) behaves deterministically and
with isolated components, then we can use
plug-n-play approaches
 If
it
behaves
chaotically
or
stochastically, then we cannot
 Most biological systems lie between this
deterministic order and chaos: Complex
systems









High level of biological organization.
Traits
broader
than
in
human
medicine:
Productivity,
product
quality,
disease
resistance, fertility, behaviour, welfare, footprint
Divergently selected lines that differ quantitatively in
specific traits.
Samples from tissues, blood or other body fluids
(milk) from a large number of animals with welldocumented
management,
and
performance
recordings are available


Understand underlying mechanisms of complex
traits, and genotype environment-phenotype
relationships



Fill the gap between genotype and phenotype:
‘Deep’ phenotyping.



“predictive biology”; Biomarkers for product
quality or health issues
Technology development
Nanotechnology and microfluidic devices
High thoroughput and inexpensive genome sequencing tech.
Improved computational approaches to modeling and

simulation

Advances in basic biological concept
elucidate a catalogue, or “periodic chart” of modules that

cells typically use to perform basic biological processes
Practical Applications: targeted prediction and control
P4 Medicine (predictive, preventive,
participatory medicine) : goals-

personalized

and

Stratification of diseases and patient populations for
specific diagnosis and more effective treatment
More rational drug design for improved efficacy and
decreased side effects
Use of genetic information to determine probable
health history and blood biomarker diagnostic tests.
“The blood will become a window into health and
disease”
Restoration of a disease-perturbed network to its
normal state by genetic or pharmacological
intervention
Understanding of genes and mechanisms involved in
estrous behavior, estrus regulation and milk or meat
production

Can unveil dynamic cellular networks that provide an
important framework for drug discovery and design. The
future of drug target discovery is going to be
understanding the dynamics of disease-perturbed
networks
Targeting bacterial protective pathways that are induced to
remediate reactive oxygen species damage, and in particular
manipulating
the
DNA
damage
repair
pathways, becomes, therefore, one potential approach to
potentiate the effect of antibiotics.
small molecules could be produced that would lead to the
creation of super-Cipro, super-Gentamicin, or super-Ampicillin
Insight into bacterial cell death pathways and protective
mechanisms induced by antibiotics. Network-based analyses
will lead to the development of novel, more effective
antibiotics, as well as ways to enhance existing antibacterial
drugs. These efforts will be critical in our ongoing fight
against antibiotic resistance
“Solving the puzzle of complex diseases, from
obesity to cancer, will require holistic
understanding of the interplay between factors
such
as
genetics,
diet,
infectious
agents, environment, behavior, and social
structures.”
(Elias Zerhouni, The NIH Roadmap, Science2003, 302:63- 64)
THANK
YOU
“Our brains are wired for narrative,
not statistical uncertainty.”
(Francis Bacon)

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Interactomics, Integromics to Systems Biology: Next Animal Biotechnology Frontier

  • 1.
  • 2.  “ Organisms function in an integrated manner-our senses, our muscles, our metabolism and our minds work together seamlessly. But biologists have historically studied organisms part by part and celebrated the modern ability to study them molecule by molecule, gene by gene. Systems biology is critical science of future that seeks to understand the integration of the pieces to form biological systems” (David Baltimore, Nobel Laureate)
  • 5. biome, CHOmics, cellome, cellomics, chronomics, clinomics, complexome, crystallomics, cytomics, cytoskeleton, degradomics, diagnomicsTM, enzymome, epigenome, expressome, fluxome, foldome, secretome, functome, functomics, genomics, glycomics, immunome, transcriptomics, integromics, interactome, kinome, ligandomics, lipoproteomics, localizome, phenomics, metabolome, pharmacometabonomics, methylome, microbiome, morphome, neurogenomics, nucleome, secretome, oncogenomics, operome, transcriptomics, ORFeome, parasitome, pathome, peptidome, pharmacogenome, pharmacomethylomics, phenomics, phylome, physiogenomics, postgenomics, predictome, promoterome, proteomics, pseudogenome, secretome, regulome, resistome, ribonome, ribonomics, riboproteomics, saccharomics, secretome, somatonome, systeome, toxicomics, transcriptome, transcriptomics, translatome, secretome, unknome, vaccinome, variomics............. (http://www.genomicglossaries.com/content/omes.asp)
  • 6. Any FOOD for thoughts………..
  • 7. Complicated!!…….Why? How can we make sense of this complexity? Can we convey our understanding of this complexity?
  • 8. Molecular biologybiomolecule structure and function is studied at the molecular level Systems biologyspecific interactions of components in the biological system are studied – cells, tissues, organs, and ecological webs ◦ Integrative approach in which scientists study pathways and networks, will touch all areas of biology, including drug discovery Era of Molecular Biology (1953 –2001) Era of Systems Biology (2001 – ??)
  • 10. study of an organism, viewed as an integrated and interacting network of genes, proteins and biochemical reactions which give rise to life. Looking at the whole system rather than at components, such as sugar metabolism or a cell nucleus Completeness is a recent aspect Mathematics/modelling-essential Whole>Sum of parts: Give Rise Emerging properties Properties ‘arise’ from components interaction (Interactomics!!)
  • 11.
  • 12.  Details are now clearer…….
  • 14. Challenged Vs. Control B O T T O M T O P D O W N U P Deductive: From known properties of components, system functions deduced. Properties emerge from interaction of the components. Inductive: From how the system reacts to the perturbations. One infers which components are critical and how the system may function
  • 15. Omics (the bottom-up approach) focuses on the identification and global measurement of molecular components. Modeling (the top-down approach) attempts to form integrative (across scales) models of animal physiology and disease, although with current technologies, such modeling focuses on relatively specific questions at particular scales, e.g., at the pathway or organ levels. An intermediate approach, with the potential to bridge the two, is to generate profiling data from high-throughput assays for biological complexity, interacting active pathways, intercommunicating cell types and different environments at multiple levels (Butcher et al., 2004)
  • 16. Basic Science/”Understanding Life” Predicting Phenotype from Genotype Understanding/Predicting Metabolism Understanding Cellular Networks Understanding Cell-Cell Communication Understanding Pathogenicity/Toxicity “Raising the Bar” for Biologists “Making Biology a Predictive Science”
  • 17. 100’s of completed genomes 1000’s of known reactions 10,000’s of known 3D structures 100,000’s of protein-ligand interactions 1,000,000’s of known proteins & enzymes Decades of biological/chemical know-how Computational & Mathematical resources “The Push to Systems Biology”
  • 19. Genomics (HT-DNA sequencing) Mutation detection (SNP methods) Transcriptomics (Gene/Transcript measurement, SAGE, gene chips, microarrays) Proteomics (MS, 2D-PAGE, protein chips, Yeast-2hybrid, X-ray, NMR) Metabolomics (NMR, X-ray, capillary electrophoresis)
  • 20. study of organisms in terms of their DNA sequences, or 'genomes'
  • 21.
  • 22. Study of total set of transcripts in a given organism, or to the specific subset of transcripts present in a particular cell type
  • 25.
  • 26.
  • 27. Bioinformatics Data Research, development, or application of computational tools and approaches for expanding the use of biological, medical, behavioural or health data, including those to acquire, store, organize, archive, ana lyze, or visualize such data
  • 28. systematic study of the unique chemical fingerprints that specific cellular processes leave behind" specifically, the study of their smallmolecule metabolite profiles.
  • 29. ( Bionaz and Loor, 2008)
  • 30. Genome-wide reconstruction of the regulatory and metabolic network in a sequenced organism….. Gives only static information (Weckwerth, 2011)
  • 31. Sequencing capacity ↑ Number of sequenced genomes↑ Number of SNPs identified ↑ SNP typing capacity ↑ Microarray data ↑ Proteomics data ↑ Metabolomics data ↑ Data in databases ↑ Sequencing costs ↓ SNP genotyping costs ↓ Profiling costs ↓
  • 33.
  • 35.
  • 36. Integromics approach in the Systems Roadmap (Sauer et al., 2007)
  • 37.
  • 38. Accessing information using ontologies and web databases that contain models encoded in ML The ML ensure that models are encoded in a consistent form and allow simulation packages to import the models in a standard format
  • 39. CGH
  • 40. The functional sequelae of SNPs and the consequences of alterations in transcript levels can not be routinely predicted in a comprehensive manner The amount of protein does not necessarily correlate with enzyme activity or protein function due to multiple posttranslational modifications and compartmentation Examination of whole cell or tissue extracts are not necessarily indicative of the physical interactions between moieties
  • 41. Data management: Clear indication of the source and context of the data Meaningful identifiers (everybody’s proud of their clever system that nobody else uses) Accessible data sources Models / Methods to interpret the data An honest assessment of the benefits and limits of various modeling approaches A realistic assessment of the near-term capabilities of current modeling approaches.
  • 42. The ability to understand the limits of the data and models Complexity of mammalian systems "As the complexity of the variable increases, it becomes more important to have a solid model of what you think you can predict and to then test it explicitly, rather than less important as the machine learning enthusiasts would have it" (Michael Bittner, Tgen)
  • 43. Atomic Scale 0.1 - 1.0 nm Coordinate data Dynamic data 0.1 - 10 ns Molecular dynamics Molecular Scale 1.0 - 10 nm Interaction data 10 ns - 10 ms Interactions Cellular Scale 10 - 100 nm Concentrations Diffusion rates 10 ms - 1000 s Fluid dynamics
  • 44. 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 Ecosystem scale 1 km – 1000 km Environmental impact Nutrient flow 1 yr – 1000 yrs Network Dynamics
  • 45. If one scale (e.g., protein-protein interactions) behaves deterministically and with isolated components, then we can use plug-n-play approaches  If it behaves chaotically or stochastically, then we cannot  Most biological systems lie between this deterministic order and chaos: Complex systems 
  • 46.     High level of biological organization. Traits broader than in human medicine: Productivity, product quality, disease resistance, fertility, behaviour, welfare, footprint Divergently selected lines that differ quantitatively in specific traits. Samples from tissues, blood or other body fluids (milk) from a large number of animals with welldocumented management, and performance recordings are available
  • 47.  Understand underlying mechanisms of complex traits, and genotype environment-phenotype relationships  Fill the gap between genotype and phenotype: ‘Deep’ phenotyping.  “predictive biology”; Biomarkers for product quality or health issues
  • 48. Technology development Nanotechnology and microfluidic devices High thoroughput and inexpensive genome sequencing tech. Improved computational approaches to modeling and simulation Advances in basic biological concept elucidate a catalogue, or “periodic chart” of modules that cells typically use to perform basic biological processes
  • 49. Practical Applications: targeted prediction and control P4 Medicine (predictive, preventive, participatory medicine) : goals- personalized and Stratification of diseases and patient populations for specific diagnosis and more effective treatment More rational drug design for improved efficacy and decreased side effects Use of genetic information to determine probable health history and blood biomarker diagnostic tests. “The blood will become a window into health and disease” Restoration of a disease-perturbed network to its normal state by genetic or pharmacological intervention
  • 50. Understanding of genes and mechanisms involved in estrous behavior, estrus regulation and milk or meat production Can unveil dynamic cellular networks that provide an important framework for drug discovery and design. The future of drug target discovery is going to be understanding the dynamics of disease-perturbed networks
  • 51. Targeting bacterial protective pathways that are induced to remediate reactive oxygen species damage, and in particular manipulating the DNA damage repair pathways, becomes, therefore, one potential approach to potentiate the effect of antibiotics. small molecules could be produced that would lead to the creation of super-Cipro, super-Gentamicin, or super-Ampicillin Insight into bacterial cell death pathways and protective mechanisms induced by antibiotics. Network-based analyses will lead to the development of novel, more effective antibiotics, as well as ways to enhance existing antibacterial drugs. These efforts will be critical in our ongoing fight against antibiotic resistance
  • 52. “Solving the puzzle of complex diseases, from obesity to cancer, will require holistic understanding of the interplay between factors such as genetics, diet, infectious agents, environment, behavior, and social structures.” (Elias Zerhouni, The NIH Roadmap, Science2003, 302:63- 64)
  • 53. THANK YOU “Our brains are wired for narrative, not statistical uncertainty.” (Francis Bacon)

Notas del editor

  1. An overview of the eukaryotic transcriptome through examples of its products. Transcription by RNA polymerase I of ribosomal RNA precursors is followed by removal of 5', 3' extensions and intervening sequences (blue thin lines) to generate ribosomal RNAs (blue rectangles), which are further modified by pseudouridynilation () and ribose methylation (CH3) at specific residues and assemble onto ribosomal subunits (blue circle and ellipse), which are then exported to the cytoplasm, where they mediate protein synthesis. Transcription by RNA polymerase II of mRNA precursors follows the processing pathway depicted in Figure. Exonic sequences can also be removed as part of an intron (green rectangle, in the example) to generate alternative mRNAs that can direct the synthesis of distinct protein isoforms. One class of transcripts that do not have extensive coding capacity (ncRNAs) are similarly generated and may play important cellular functions (in the example, by acting as a scaffold for the assembly of functionally connected protein factors, represented as polygons of various shapes). Some introns can generate additional transcripts with important functions in gene regulation. One example are snoRNAs, which assemble onto snoRNP RNP complexes and direct pseudouridynilation and ribose methylation of rRNA and other transcripts. Another example are precursors of miRNAs, which after cleavage by Drosha-type RNases in the nucleus and by Dicer-type enzymes in the cytoplasm, generate 20–28 dsmiRNAs that assemble onto RNP complexes that repress translation by binding to 3' UTRs of mRNAs and/or cause mRNA degradation, depending on the degree of complementarity with their target sequence. Other dsRNAs (e.g. siRNAs) can also trigger mRNA decay through the same mechanism. snoRNAs and miRNA precursors can also be generated from exonic sequences of dedicated transcripts. Small dsRNA fragments generated through bidirectional transcription—shRNAs (often from repetitive DNA—rasiRNAs) and cleavage can also induce transcriptional silencing through histone and DNA methylation.
  2. Integromics / Omics Matrix are established terms, it is not my creation.