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!!