the search for the hereditary molecule. scientific investigations consider all possible explanations...
TRANSCRIPT
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The Search for the Hereditary MoleculeThe Search for the
Hereditary Molecule
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Scientific Investigations
Consider all possible explanations
Test explanations with evidence
Scientific explanations are: Predictive Testable tentative
Phases: Rely on logic and crude data in initial probes Identify players with better data Identify the underlying mechanisms
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By 1920, the Chromosomal Theory of Inheritance and the chemical composition of chromosomes have been revealed
A. Chromosomal Theory of Inheritance revealed that genes are born on chromosomes
B. Chemical composition of chromosomes: only proteins and nucleic acids, not carbohydrates or lipids
C. therefore the hereditary molecule (genes) must be composed of proteins or nucleic acids
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The search is on: false starts point to protein
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A.P. Levene - The Tetramer Structure of DNA
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Nucleotides
SP
B
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Four kinds of DNA nucleotides
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The tetramer structure of DNA hypothesis
2. Tetramer structure of DNA hypothesis:
DNA {AdenineGuanineCytosineThymine
chemical analysis to measure the relative abundance of the four nucleotides
mistakenly concluded that the four nucleotides are equally abundant
interpretation
DNA is composed of subunits that possess 1 of each kind of subunit
named the subnunits nucleotide tetramers:
purified nucleotides
Conclusion
A T
GC
DNA has a simple tetramer structure. The structure of DNA is too simple to confer the abilities to reproduce or to store information, so protein must be the hereditary molecule
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Levene’s Problems?
• First (poor) techniques for measuring nucleotide composition
• Drew an important conclusion from tenuous data
• Was not suitably tentative about these conclusions
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The “Alphabet Analogy”
A reliance on logical argument alone:
1. the hereditary molecule must be capable of coding for vast amounts of information
2. If the hereditary molecule is a protein or NA (both polymers), then it is likely to be composed of subunits that are functionally analogous to letters of an alphabet, with the arrangement of the subunit “letters” spelling out different biological “words” (functions).
3. proteins have 20 subunits (amino acids), DNA only has 4 (nucleotides)
4. this suggested that proteins should be able to store more information ...in fact, it seemed preposterous that all the complexity of life could be spelled out with an alphabet of 4 letters
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Problems?
• The investigators underestimated the length of biological “words” (genes)
• Reliance on logic alone hindered demonstration that the explanation was false
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The trail is found: circumstantial evidence points to DNA
• Avery et al. (1944)
• Chargaff (1949)
• Hershey and Chase (1952)
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Griffiths & Transformation
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Griffiths 1928Discovery of Transformation
• Pneumonia bacteria
• Wanted to develop a vaccine
• Had two genetically different strains– Virulent (normal)– Non-virulent (mutant)
• Protocol...
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Griffiths 1928Discovery of Transformation
mousevirulent bacteria
injectedmouse died
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Griffiths 1928Discovery of Transformation
mousevirulent bacteria
injectedmouse died
mousenon-vir. bacteria
injectedmouse lived
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Griffiths 1928Discovery of Transformation
mousevirulent bacteria
injectedmouse died
mousenon-vir. bacteria
injectedmouse lived
mousedead vir bacteria
injectedmouse lived
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Griffiths 1928Discovery of Transformation
mousevirulent bacteria
injectedmouse died
mousenon-vir. bacteria
injectedmouse lived
mousedead vir bacteria
injectedmouse lived
mouselive non-vir. bacdead vir bacteria
mouse died
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Griffiths 1928Discovery of Transformation
mouselive non-vir. bacdead vir bacteria
mouse died
virulence genes
Non-virulent bacterium
virulent bacterium
transformation
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Avery Avery et alet al, 1944; , 1944; the transformation the transformation bioassay is appliedbioassay is applied
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Problems of Interpretation?
a) bacteria are very different from all other life forms, which suggested to researchers then that bacteria might have resulted from a completely different origin of life ...so they might have their own unique hereditary molecule. unwise to generalize to other organisms then
b) circumstantial evidence: the mechanisms by which it worked had not been revealed, only its probable identity
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Chargaff, 1949 Levene’s examination of the nucleotide composition of DNA
is repeated with refined methods
1. question: what is the nucleotide composition of DNA like and does it reveal whether DNA could be the hereditary molecule?
2. methods:
a) measured the nucleotide composition of DNA (repeating Levene’s work with more refined methods)
b) for many species, covering the whole spectrum of life (to contend with detractors of Avery’s work who were wary about the limited utility of bacterial studies)
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Chargaff, 1949 Levene’s examination of the nucleotide composition of DNA
was repeated with refined chromatographic methods
3. results:
a) each species has its own unique nucleotide composition, as you would expect for the hereditary molecule
b) Chargaff’s Rule: [A] = [T] and [C] = [ G] ...nobody understood why. This suggested that DNA had a structural similarity, and therefore a functional similarity (heredity?) in every species
4. problem of interpretation:
circumstantial evidence: the mechanisms by which it worked had not been revealed, only its probable identity
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Hershey & Chase, 1952 - a second bioassay
1. question: is the hereditary molecule protein or DNA?
2. background:
a) viruses inject their hereditary molecule into bacterial host cells, then from inside they take over the cell to reproduce
b) therefore, the viruses themselves separate their hereditary molecule from the rest of their bodies (ghosts)
ghostsghosts
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Hershey & Chase, 1952 - a viral bioassay
Protein ***DNA
ProteinDNA ***
virus injects hereditary molecule into host cell
shaker dislodges ghosts from hosts
centrifuge separatesghosts from hosts
virus injects hereditary molecule into host cell
shaker dislodges ghosts from hosts
centrifuge separatesghosts from hosts
radioactivity:***
***
***
ghosts
hosts
ghosts
hosts
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Hershey & Chase, 1952 - a viral bioassay
problem of interpretation:
circumstantial evidence: the mechanisms by which it worked had not been revealed, only its probable identity
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Watson and Crick, 1953The Structure of DNA
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A critical test of two perspectives:
• A long-standing view of life:
V I T A L IS MLife is composed of special processes that
cannot be studied or understood by man
• Understanding life as a mechanistic process:1. Life is the product of evolution2. Evolution is the product of reproduction3. Reproduction is the foundation of life
• Could the structure of the hereditary molecule reveal the mechanistic basis of life?
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The hereditary molecule’s structure was expected to reveal:
• The molecular basis of REPRODUCTION
• The molecular basis of MUTATION
• The molecular basis of INFO STORAGE
• The molecular basis by which STORED INFO IS TRNASFORMED TO BIOLOGICAL ACTIVTY
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Watson and Crick’s Approach
• They possessed clues about DNA’s 3D shape, dimensions, and nucleotide composition
• They would build hypothetical models, whose dimensions could be compared to the known dimensions of DNA
• They wanted to examine whether a structure whose dimensions fit would explain the molecular basis of the hereditary functions …the big prize
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Linus Pauling developed this method when he discoveredthe alpha helix secondary structure of proteins
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Electron Microscopy Imaging
• DNA is long and thin
• Diameter = 20 A°
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X-ray Diffraction
Clues about 3D shape: several important dimensions
of the molecule
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Rosiland Franklin
X-ray Diffraction Image of DNARosiland Franklin
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Chargaff’s Rule
Nucleotide composition of DNA:
[A] = [T] and [C] = [G]
Why?
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Nucleotides are organized into polynucleotide strands with bases deployed as side chains
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3D Molecular Modeling
• Build hypothetical structures
• Measure dimensions
• Compare with known dimensions of DNA
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First Consideration:How many colinear strands?
20 A°
too small
20 A°
maybe
20 A°
maybe
20 A°
too big
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First considered 3 stranded models
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First considered 3 stranded models
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Two stranded models:
• First, tried bases out • Next, tried bases in
didn’t work
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Two stranded models with bases facing in:
Measured base pairs:
purine - purine
pyrimidine - pyrimidine
purine - pyrimidine
< 20 A°
> 20 A°
= 20 A°
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Possible purine - pyrimidine pairs:
A - C
A - T
G - C
G - T
Chargaff’s Rule
Chargaff’s Rule
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Only A-T and G-C pairs form hydrogen bonds(A-C and G-T cannot because their partial charges are not oriented favorably)
C-G A-T
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A closer look at the C-G base pair
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A closer look at the A-T base pair
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The hereditary molecule’s structure was expected to reveal:
• The molecular basis of REPRODUCTION
• The molecular basis of MUTATION
• The molecular basis of INFO STORAGE
• The molecular basis by which STORED INFO IS TRNASFORMED TO BIOLOGICAL ACTIVTY
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The molecular basis of REPRODUCTION
DNA is double stranded
The two strands can UNZIP
Single strands can act as TEMPLATES to order the synthesis of a second strand
Addition of only COMPLEMENTARY nucleotides to a new elongating strand ensures that sequence information is
preserved in new strands
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REPLICATION
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QuickTime™ and aGraphics decompressor
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The molecular basis of MUTATION
Accidental addition of non-complementary nucleotides to a new elongating strand
or
Chemical modification of a nucleotide, rendering it non-complementary
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The molecular basis of INFORMATION STORAGE
Neighboring nucleotides with a nucleotide pair are complementary (contributing to ability to reproduce)
Neighboring nucleotides within a polynucleotide strand suffer no such limitation - any nucleotide can occupy such a site
Information is stored as specific nucleotide sequences within polynucleotide strands (or sequences of nucleotide pairs)
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The molecular basis of
TRANSFORMATION OF STORED INFORMATION TO
BIOLOGICAL ACTIVITY
Required elucidation of
transcription, translation, and the genetic code
…which about 15 years
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The Beginning