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AS E T 30 years A Perspective Talk on Biology Biology and its complexity Our own efforts here at Colaba campus: A brief introspection CONCLUDING THOUGHTS Where is Biology headed?. Biologists. Want to understand organisms and living systems - PowerPoint PPT Presentation
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ASET 30 yearsA Perspective Talk on Biology
1. Biology and its complexity
2. Our own efforts here at Colaba campus: A brief introspection
CONCLUDING THOUGHTS Where is Biology headed?
Biologists
• Want to understand organisms and living systems
• Discover underlying mechanisms that govern how organisms work
• The knowledge is then used to develop or improve medical, industrial or agricultural processes.
• Comfortable with uncertainty and intrinsic noise in their systems
Combinatorial explosion that can deal with complexity
Assume each biological function depends on 2 genes(absurd, but still instructive)
Total number of possible ‘functions’ would be (assuming ~40K functional genes/cell)
0.5 x 40,000 x 39,999= 799,980,000
With more realistic assumptions about # of genes in each function, the figures are huge : at 100/function (~ 1.5 e302);
for all combinations (~ 2 e166713)Feytmans, Noble & Peitsch, Transactions in Computational Systems Biology, 2004
NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.
Unravelling complexityNeed to work in an integrative way at all levels:
organism organtissue
cellular sub-cellularpathwaysprotein
gene
There are feed-downs as well as upward between all these levels
Unravelling complexity
Top-Down or
Bottom-Up?
Middle-out!!
Noble D (2002) The Rise of Computational Biology. Nature Reviews Molecular Cell Biology, 3, 460-463
Sidney Brenner2001
Figure 1. The biocomplexity pyramid. A hierarchy of entities beginning with the gene and moving up to an entire organism is matched against a variety of corresponding technologies, thereby transforming biological information into knowledge.
Uncertainty Principle in Biology: The more we uncover the components, the less we seem to
understand the ‘whole” of the system!
ASET 30 yearsA Perspective Talk on Biology
1. Biology and its complexity
2. Our own efforts here at Colaba campus: A brief introspection
CONCLUDING THOUGHTS Where is Biology headed?
BIOLOGY as seen through various model organisms
MODEL ORGANISMS: Bakers yeastChlamydomonasDictyostelium Plasmodium Drosophila C. elegansZebra Fish Mouse Rat
Human (epidemiology) and cell lines
SEVERAL FOCUS AREAS :Developmental biologyMotor biologyParasitologyNeurobiologyGenome integrity and remodelingGenetics of phenotypesBiophysics – single molecule biologyMetabolism and organismal physiology
Malarial Parasite Biology: Immunity, properties of novel protective proteins & Neuro-inflammatory responses
Genotype - Phenotype problem in “budding yeast”
(QTL: Quantitative Trait Loci)Many genes cross-talk non-linearly
Chlamydomonas Life Cycle
Sirtuins
Intracellular signalingCommunication between organelles
Tissue specific functionsInteraction with other nutrient sensing pathways
Trans-tissue effectsSystemic changes
CELLULAR FUNCTIONS
Mediates molecular mechanisms linking nutrient sensing to development, growth, aging
and disease
ORGANISMAL PHYSIOLOGY
NAD-dependentdeacetylase
Interphase chromosome territories• Each chromosome occupies a distinct three-
dimensional space called the chromosome territory (CT)
• These chromosome territories are organized in a non-random manner
• These chromosome territories are known to intermingle (CT’s are not “hard-ball” entities)
• The CT’s relocate (across several microns) during chromosomal repairs
• Gene-rich CT’s seem to do this “feat” preferentially
• Inhibition of Chromosomal repairs lead to loss
of CT movements.
Bolzer, et al; 2005
Molecular Motors in Intracellular Transport Generate cargo in cell body
Recruit motors
Direct motor-cargo complex to start-point
Move processively
Release cargo at the correct destination
Take care of the free motors
Single molecule studies
of
Molecular motors
and
Motor complexes
Regulation of pre-synaptic vesicle transport by neuronal activity
• Generate cargo in the cell body • Recruit motors• Direct motor-cargo complex to axon • Move processively along axon • Release cargo at the correct destination • Take care of the free motors
Epidermis: A stratified epithelium
Questions
??
?
Mechanical stresses and geometry directed cytoskeletal dynamics
Mechanical stressesChemistry
GeometryCytoskeletal organisation
Cell dynamics
actomyosin
In wild type brains, the hem (green) and the antihem (red) flank the expanse of cortical neuroepithelium.
Medial neuroepithelium is the hippocampal primordium (dark blue) and lateral neuroepithelium is the neocortical primordium (grey).
In Lhx2 -/- embryos, both medial and lateral cortical primordium is lost and the hem and antihem expand.
SPACIAL PATTERNING OF MAMMALIAN BRAIN : Regional Functionalization Problem
2. Role of early environment in shaping adult responses to stress
and antidepressants: Molecular and cellular mechanisms
Neurobiology of Depression in mammals
Hippocampus
Medial Prefrontal Cortex
(2) Targets of rapid actionAntidepressant Treatments
(1) Animal models of depression
Cytochrome C – LEE / Photon Interaction
To the best of our knowledge this is the first attempt to study LEE interaction with whole Proteins
+
Heme with Iron
+
Soft electrons or photons interact with biomolecules leading to Biologically relevant changes such as DNA strand breaks!
e-
hν
ASET 30 yearsA Perspective Talk on Biology
1. Biology and its complexity
2. Our own efforts here at Colaba campus: A brief introspection
CONCLUDING THOUGHTS Where is Biology headed?
Rewiring signalling pathways. The pheromone and osmolarity response pathways in yeast use protein scaffolds (Ste5 and Pbs2) to avoid crosstalk through the shared component Ste11. By constructing a modified fusion protein of Pbs2 and Ste5, the authors constructed a rewired pathway in which cells produce osmolarity stress responses after pheromone induction
1. Complexity in Biology
2. Can this complexity be split into modules/units
3. If so, are engineering approaches implementable for
(A) Tuning existing Biology
(B) Generate new “Biology”
(C) etc.etc..
The Yeast system
• Scaffold proteins
• Mediating recruitment • Improve efficiency of signal
transfer.• Facilitate interactions among
different signal pathways• Control localization of signal
proteins within a cell.
MODULAR APPROACH DOES WORK:The Diverter story
Digital Cells MeetSynthetic Biology
• Model the circuit of its modules• Validate the circuit• Tinker with the circuit at module or inter-
module levels• Then…• Alter the gene to build a new protein
– SNPs will give you a ‘first approach’• See if the new protein is ‘well tolerated’
Reprogramming the Cell• The cell is a
molecular system where all parts also participate in an information system.
• We model that system, and then attempt to alter the ‘internal influences’ to create different functional outputs.
Strong applications are expected (just one example): Cell and Tissue Engineering
• Cell and Tissue Engineering allows us to repair or replace the function of natural tissue with bioengineered substitutes.
• Principles of engineering, chemistry, and biology are combined to create tissue substitutes from living cells and synthetic materials.
Tissue Engineered SkinNew Companies: Advanced Tissue Sciences, Inc.
Organogenesis
Figure 1. The biocomplexity pyramid. A hierarchy of entities beginning with the gene and moving up to an entire organism is matched against a variety of corresponding technologies, thereby transforming biological information into knowledge.
Uncertainty Principle in Biology: The more we learn about the components, the less we seem to
understand the ‘whole” of the system!However the exciting journey continues, forever!!
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