Transcript History of Biological Thought

A Quote…
There is no spirit-driven life force,
no throbbing, heaving,
pullulating, protoplasmic, mystic
jelly. Life is just bytes and bytes
and bytes of digital information.”
--Richard Dawkins
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History, Theory, and
Historical Contingency in
Biology
Jay Snoddy
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(or [email protected])
http://genome.ornl.gov/~v8v
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Ira and the Worm:
Similar Information in Genes and Gene Products
Complexity
Despite
of Form &
Deep
Function
Similarity
and Unity,
Deep
Diversity of
Population
Forms and
Variation
Function
within
Species
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Every biological
fact has a “here
and now” aspect
of how it
“works” and a
historical aspect
of how it got to
work that way.
Past
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Now
Now
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History…
 History of Biological Thought…
A history of “Applied bioinformatics”
“Through the Louvre on Roller Skates” view of some conceptual
views of biology, with an occasional homage to computation in
biology.
 History of Biological Information…
Pure Bioinformatics
Nothing in Biology makes any sense, except when viewed in the
light of evolution.
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A Computational/Conceptual Biology
Timeline
Mendel
“Quantitative”
Genetics
statistics in
populations
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Darwin (&
Malthus)
Population
growth;
intrinsic
rate of
increase, r:
Carrying
capacity, K
The Modern
Synthesis:
The NeoDarwinian
Synthesis
between
genetics and
evolution.
Populations
under
selection.
Molecular
Evolution:
Molecular
Biology,
Protein
Structure,
Biophysics;
Sequence
Analysis
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Applied bioinformatics history: A
beginning with Aristotle.
Observe
Diversity
What is out there?
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Applied bioinformatics history: A
beginning with Aristotle.
 Observe Diversity
 What is out there?
 Compare and
Classify Diversity
 Organized what is out there by
similarity….
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Applied bioinformatics history: A
beginning with Aristotle.
 Observe Diversity
 Compare and Classify Diversity
 Explain Origin of Complexity,
Diversity, Similarity
 How is biological form and function created in new
individual?
 Recognized two possibilities
 Preformed structures. (“Russian Dolls”)
 Information on the “possible” from parents
somehow transformed into the “actual”
observed phenotype:
Aristotle favored the latter as most likely…most like the current idea
that the possible of genotypic information somehow gets
transformed each generation into a phenotypic actual.
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Applied Bioinformatics:
Getting Data to Classify by
“Voyages of Discovery”
 Voyages of Discovery
build upon the maps
created by past Voyages
of Discovery…
 Examples
 Species Diversity Voyages of
Humboldt, Darwin, Alfred Russel
Wallace, Bates, etc.
 Other voyages have
ventured below level of
organisms (Anatomy,
Development,
Physiology, Cell
Biology, Biochemistry,
etc. )
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Malthus: Rate of Increase
 Elephant –19,000,000 in 750 years
 Staphulococcus aureus—enough to cover
the earth 7 feet deep in 48 hours
 Progeny is far in excess of what is actually
capable of living in an environment.
 r – Intrinsic Rate of Increase.
 K – Carrying capacity.
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HOMOLOGY
“The same organ in all its
varieties of form”
Serial Homology
Derived forms within
the same organism
Special Homology
Derived forms between
different species
Versus
Sir Richard Owen
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Analogy
Forms similar due to
same function
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Be careful here….importance of
“historical contingency”
 Owen was—for a time, at least a proponent of what
could be called “Rational Morphogenesis” The
similarity of shape indicated, in their view,
constraints and drivers that were the cause of
similarity. (simplistically put, leg bones are more
like crystals that grow from common rules, and they
are NOT similar due to common origin.)
 While there are some biophysical constraints and
drivers—esp. at more molecular level—it should be
clear that a lot of similarity is due to a common
origin and the historically-contingent events along
the lines of descent.
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MECHANISM of DARWINIAN NATURAL
SELECTION
 Variation exists in the population
 Competition for survival, dying before
leaving offspring often
 Survival of those most fit for the
environment (or genetic drift)
 Offspring are from the survivors
 Offspring tend to have the genes that
made their parents fit for the
environment.
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Darwin Finches: Geospiza fortis
Microevolution
happens
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CLADOGRAM ( partial) of VERTEBRATES: DESCENT WITH
MODIFICATION: Macroevolution happens
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Germ Plasm
Cell Biology,
and Genomics
Continuity of the
Germ Plasm;
Soma vs. Germ
Cells;
Differentiated
somatic cells
share same
genome
information (but
use it differently).
Weismann
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Modern Understanding: Source of
Genotypic information
DNA in chromosomes
 DNA coiled in chromosomes
 DNA passed in special cells (germ cells) from a generation to next.
 DNA helps direct a developmental program to create a new
individual (soma) during embryogenesis from the fused germ cells.
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Rediscovery of Mendelism
Adaptive landscape
Statistical Genetics
Mathematical biology
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THE MODERN SYNTHESIS
“Evolution is a change in the genetic composition of populations.
The study of the mechanisms of evolution falls within the province
of population genetics.”
--Theodosius Dobzhansky. 1951
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Hardy-Weinberg equilibrium:
 Assumes organisms are
 diploid
 sexually reproducing
 randomly mating
 And have




no drift (i.e. an "infinite" population)
no selection
no mutation
no migration (gene flow)
 Two allele case for a gene:

 allele A allele has frequency, p, The allele a  has a frequency, q
 p + q =1
AA homozygote is p2, the Aa heterozygote 2pq, the
aa homozygote is q2.
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Now add “fitness” functions and
adaptive landscapes…to these
population genetics equations….
 Adaptive Landscape : An adaptive landscape is a surface in
multidimensional space (analogous to a mountain range) that
represents the mean fitness of a population (not the fitness of a
genotype). An individual is represented as a point on the surface
(mountain) and a population is represented as a cloud of points.
“Adaptive landscape is probably the most common metaphor in
evolutionary genetic[s]” Futuyma (1998) Evolutionary Biology pg.
403
Evolution may be envisioned as the movement of a population of
points (individuals) on the w surface (adaptive landscape). The
points move up-slope until it arrives at the peak (mountain top).
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Evolution is a change in the gene
pool of a population over time.
Evolution is the cornerstone of modern biology. It unites all the fields of
biology under one theoretical umbrella.
It is not a difficult concept, but very few people -- the majority of biologists included -have a satisfactory grasp of it. One common mistake is believing that species can be
arranged on an evolutionary ladder from bacteria through "lower" animals, to
"higher" animals and, finally, up to man. Mistakes permeate popular science
expositions of evolutionary biology. Mistakes even filter into biology journals and
texts. For example, Lodish, et. al., in their cell biology text, proclaim, "It was Charles
Darwin's great insight that organisms are all related in a great chain of being..." In
fact, the idea of a great chain of being, which traces to Linnaeus, was overturned by
Darwin's idea of common descent.
 Misunderstandings about evolution are damaging to the study of evolution and
biology as a whole. People who have a general interest in science are likely to
dismiss evolution as a soft science after absorbing the pop science nonsense that
abounds. The impression of it being a soft science is reinforced when biologists in
unrelated fields speculate publicly about evolution.
http://www.talkorigins.org/faqs/faq-intro-to-biology.html
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Molecular evolution
 When looked at molecular
sequences in 1960 and 70s …
 Recognized that these changes
are result of
 Mutation
 Selection
 Primarily purifying selection or near-neutral
mutations
 Not primarily result of directional
selection!!!
 Genetic Drift
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Molecular
Evolution
Evolution of
Biological
Sequences;
Methods to
compare
sequences and
find patterns.
Gene
Duplication &
Divergence
Margaret Dayhoff
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Physiology and Cell-Cell
Communication
Networked
Molecular
Cell
Regulatory Regulators
Networks (e.g. hormones,
morphogens)
communicate
across cells;
intracellular
regulation;
signal
transduction
Bernard
Cell
Type
B
A cell type produces an
informational molecule (e.g.
hormone)
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Cell
Type
A
Another cell type is capable of
sensing this informational
molecule. It has a receptor
“lock” for the “key” produced
by the other cell.
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Cells as receiving/integrator of
different environmental signals.
Cell Membranes restrict
access to environmental
information;
Promote “modularity”
(information hiding)
Internal Methods
External Methods
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Receptors ( a type of
protein) sit in the
membrane and allow
only some external
information to be
received and transduced.
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Developmental
biology and
Evolution
Developmental
Biology
Emergence of
heterogeneous
phenotypes
from apparent
homogeneity;
complexity
from
homogenity
Driesch
 Long standing interest and problem, but not
really part of the first Modern
Synthesis…yet.
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KARL ERNST von BAER: (Not Haeckel!)
“The general features of a large group of animals
appear earlier in development than do the specialized
features of a smaller group…The early embryo is never
like a lower animal, but only like its early embryo.”
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CHARLES DARWIN
Studied Barnacle classification and development
ON THE ORIGIN OF SPECIES
1859
“Community of embryonic
structure reveals community
of descent.”
“Embryology rises greatly in interest, when we look
at the embryo as a picture, more or less obscured,
of the progenitor, either in its class or larval state,
of all the members of the same great class.”
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COMPLEXITY
How do Genomes build up phenotypic Complexity
during development?
Phenotypic complexity is
created during development
of an embryo;
Development 
a) [Gene
Regulation]/t
&b) [Cell communication]/t
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How Do we explain this emergence
of complexity?
 Over developmental time…
 Largely by a change in gene regulation and
cell-cell communication….
 The same genes in the body, but different
expression of those genes in different cells
and different types of cells..
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Change in Gene Regulation
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What is the important information encoded in the genome?
Control & Regulatory sites for OR
Gene Expression
Gene Product
Sequence
“Gene”
A
B
C
D
‘Regulatory Sites and proteins that
promote or prevent making RNA and
proteins
hnRNA
mRNA
protein: 1D,
2D, 3D
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Transcription
--Boolean operation
--Sums Regulatory Signals
--Combinatorial Complexity
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Think of logical gates!!!
 While there are subtleties (and things may
not work as well in very simple systems as
predicted)…
…repressors and activators of gene
expression can be thought of as acting as
AND, NOT, OR, NAND gates…
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The Sea Urchin Endo 16 gene
6 Modules
F
E
D
C
B
A
BP
Unique binding
sites within
each module
1st EXON
Binding sites that
define a specific
module
Circa 50 binding site motifs
Regulatory region
Coding region
Redrawn from Yuh et al., Science 279, 1998
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Change in Cell-Cell Communication
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Cell Differentiation—Stem Cells
Pluripotent
Restricted
Fate
From: Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding
of Phenotypic Variation and Evolutionary Adaptability
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Different cell types have different GRNS and use only a
fraction of the same genome information.
ON Genes
Inducible
Genes
Actively
inhibited
Genes
Off Genes
Cell Type 2
ON Genes
Inducible
Genes
Cell Type 1
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Actively
inhibited
Genes
Off Genes
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Cell Differentiation—Sensing
Environments via Receptors
Cell Type 1
What should I do?
A signal produced by other cells in a
region or position in body that is
received by the cell helps decide on
path.
From: Cells, Embryos, and Evolution: Toward a Cellular and Developmental Understanding
of Phenotypic Variation and Evolutionary Adaptability
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Different Cell Types: Different GRNs
A cell will have a
set of GRNs that
allow it to respond
to signals (in this
case, GRNs A, B,
C, D, E,)
A, B, C, D, E
A different cell
type (even in the
same lineage) can
have a different set
of GRNs that
allow it to respond
to different signals
D, E, F, X, Y
A Cartoon…
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Cascades of Different GRNs
A, B, C, D, E
A, C, D, E, G
B, C, D, E, F
D, E, F, X, Y
A Cartoon…
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How does biology build up phenotypic
complexity, diversity, and variability
over EVOLUTIONARY time?
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A Bioinformatics Timeline
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A Bioinformatics Timeline
Metazoa
circa 700 million years or so of
multicellular animal life…
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Key Genome Data & Idea
Similar gene products
lay down the radically
different body plans!
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Very Different Body Plans, yet remarkably similar protein-coding
`11
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Pure Bioinformatics
Phenotypic Complexity in Bilateria
not created with protein coding…
 Greater complexity of gene regulation (e.g. more
binding sites and more proteins that could
regulate expression of genes)
 Cellular compartmentalization and selective use
of genome information in different cells
“Gene”
hnRNA
Believe that non-Protein Coding,
regulatory sequences are most changed.
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mRNA
Protein
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Some things that may be needed to explain this apparent “sameness”…
Evolution is
a tinkerer,
not an
engineer
….and she
often tinkers
with networks
that create
emergent
phenotypic
complexity
from genotype
Gene
‘Small changes
Regulatory in the
Networks distribution in
time and space
of the same
structures are
sufficient to
affect deeply
form, functions,
and behavior”
e.g. F Jacob
Networked
Molecular
Cell
Regulatory Regulators
Networks communicate
across cells;
intracellular
regulation;
signal
transduction
(in both
physiology &
development)
e.g. C. Bernard
Models For
Morphogenesis
Complexity,
Networks
Some hope
that one can
model and
study the
emergence of
Phenotypic
complexity
and
heterogeneity
from apparent
homogeneity
e.g. Alan Turing, Erdos, Kaufman,
Barabasi, Von Neuman, Wolfram
Implication: Must Study Networks
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Bioinformation History: Three
areas of evolutionary change…
 Genomic
information
 Internal Gene
Regulatory networks
(selective use of genomic
information in cells)
 Environmental (external)
information…cell-cell
communication networks.
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END
Jay Snoddy
Oak Ridge National Laboratory
& The University of Tennessee
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Or [email protected]
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A View: Biological Theory is Important
Information & Evolutionary Adaptation
 ‘It is important for biologists to know some
physics…[in part because it is}..best examplar of
kinds of theories that can exist and of the ways that
can explain reality. But it is also important for
physical scientists moving into biology to
recognize that they are entering a strange territory
in which two unfamiliar concepts—information and
adaptation—are central.’
From Shaping Life:Genes, Embryos, and Evolution by John Maynard
Smith.
And historical contingency …and population.
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