ASET 30 years
A 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 complexity
Need to work in an integrative way at all levels:
organism
organ
tissue
cellular
sub-cellular
pathways
protein
gene
There are feed-downs as well as upward between all these levels
Unravelling complexity
Top-Down or
Middle-out!!
Sidney Brenner
2001
Bottom-Up?
Noble D (2002) The Rise of Computational Biology.
Nature Reviews Molecular Cell Biology, 3, 460-463
Uncertainty Principle in Biology:
The more we uncover the components, the less we seem to
understand the ‘whole” of the system!
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.
ASET 30 years
A 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 yeast
Chlamydomonas
Dictyostelium
Plasmodium
Drosophila
C. elegans
Zebra Fish
Mouse
Rat
Human
(epidemiology)
and cell lines
SEVERAL FOCUS AREAS :
Developmental biology
Motor biology
Parasitology
Neurobiology
Genome integrity and remodeling
Genetics of phenotypes
Biophysics – single molecule biology
Metabolism and organismal physiology
Malarial
Parasite Biology:
Immunity,
properties of
novel protective
proteins
& Neuroinflammatory
responses
Genotype - Phenotype problem in “budding yeast”
QTL
(QTL: Quantitative Trait Loci)
Many genes cross-talk non-linearly
?
Phenotype
Chlamydomonas Life Cycle
Intracellular
signaling
Communication
between organelles
NAD-dependent
deacetylase
Tissue specific
functions
Interaction with other
nutrient sensing
pathways
Sirtuins
Trans-tissue effects
Systemic changes
Mediates molecular mechanisms linking
nutrient sensing to development, growth, aging
and disease
Interphase chromosome territories
•
Each chromosome occupies a distinct threedimensional space called the chromosome territory
(CT)
•
These chromosome territories are organized in a nonrandom 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 startpoint
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
Regulation at cellular level
?
?
Developmental regulation to achieve
spatial and temporal resolution
?
Structural components
Epidermal integrity and barrier function
Mechanical stresses and geometry directed cytoskeletal dynamics
actomyosin
Cytoskeletal
organisation
Cell dynamics
Geometry
Mechanical stresses
Chemistry
SPACIAL PATTERNING OF MAMMALIAN BRAIN : Regional Functionalization Problem
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.
Neurobiology of Depression in mammals
Hippocampus
2. Role of early environment in shaping
adult responses to stress
and antidepressants: Molecular and cellular
mechanisms
Medial Prefrontal Cortex
(1) Animal models
of depression
(2) Targets of rapid action
Antidepressant Treatments
Cytochrome C – LEE / Photon Interaction
Soft electrons or photons interact with biomolecules leading
to
Biologically relevant changes such as DNA strand breaks!
+
e-
+
hν
Heme with Iron
To the best of our knowledge this is the first attempt to study
LEE interaction with whole Proteins
ASET 30 years
A 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 Meet
Synthetic Biology
• Model the circuit of its modules
• Validate the circuit
• Tinker with the circuit at module or intermodule 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 Skin
New Companies: Advanced Tissue Sciences, Inc.
Organogenesis
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!!
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.