FROM THE DISCOVERY OF THE HELIX TO STRUCTURAL GENOMICS Challenges for the future Rien de Bie Bijvoet

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FROM THE DISCOVERY OF THE HELIX TO STRUCTURAL
GENOMICS Challenges for the futureRien de
BieBijvoet Center for Biomolecular
ResearchUtrecht, The Netherlands
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What is Life
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What is Life?

• Erwin Schrödinger (1944)
• Life can be thought of in terms of storing and
  passing on biological information.
• Chromosomes are information bearers.
• The huge amount of information is compressed in a
  heriditary code-script embedded in the
  molecular fabric of the chromosomes.
• To understand life, we have to identify these
  molecules and crack the code.
• Oswald Avery, Maclyn McCarthy and Colin MacLeod
  (1944)
• They showed in a beautiful series of experiments
  that DNA is the substance inducing transformation
  of pneumococcal types.
• This discovery leads directly to conclusion that
  the heriditary code-script is embedded in DNA.
• No Nobel was awarded for this pivotal discovery
  because one member of the Nobel committee fought
  consistently for many years against this
  conclusion.

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The paper



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The model
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The base pairs
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Maurice Wilkins
M.H.F. Wilkins, A.R. Stokes, H.R.
Wilson Molecular Structure of Deoxypentose
Nucleic Acids. Nature 171, 738 (1953)
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Rosalind Franklin
R.E. Franklin and R.G. Gosling Molecular
Configuration in Sodium Thymonucleate, Nature
171, 740 (1953)
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The Meselson-Stahl experiment
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Frederick Sanger (Nobel 1958)
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Severo Ochoa, Arthur Kornberg (Nobel 1959)
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Nobel laureates 1962
Wilkins, Perutz, Crick, Steinbeck, Watson, Kendrew
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Citations
DNA Publication never became a hot
paper Citations/year
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Perutz (Haemoglobin), Kendrew (Myoglobin)
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Myoglobine structure
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Location, Location, Location
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DNA folding-1
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DNA folding-2
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DNA replication
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From DNA to protein
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Exons and Introns (1977)Roberts and Sharp (Nobel
1993)
A precursor-RNA may often be matured to mRNAs
with alternative structures. An example where
alternative splicing has a dramatic consequence
is somatic sex determination in the fruit fly
Drosophila melanogaster. In this system, the
female-specific sxl-protein is a key regulator.
It controls a cascade of alternative RNA splicing
decisions that finally result in female flies.
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Building a complex
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Ribosome
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SequencingSanger, Gilbert (Nobel 1980)
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Venter, Clinton, Collins (2001)Draft sequence
from Celera and IHGSC
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Chromosome 20
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H. Influenza gene
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Structural Tools
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Richard Ernst (Nobel 1991)
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Kurt Wüthrich (Nobel 2002)
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Prion Structure
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Robotics
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Proteomics on 2D-gel
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DNA Repair
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DNA Repair-2
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Model of a part of the DNA repair proteinUvrC
with a SS/DS DNA
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Live Wire
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The histone code
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Tamm-Horsfall protein
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Carbohydrate chains
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John Maddox
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Acknowledgements

• This lecture is based on material obtained from
  various sources
• James D. Watson DNA, the secret of life (2003)
• James D. Watson The Double Helix (1968)
• John Maddox What remains to be discovered (1998)
• Brenda Maddox Rosalind Franklin The dark lady
  of DNA (2002)
• Tyler Wasson ed. Nobel Prize Winners (1987)
• John C. Kendrew The three-dimensional structure
  of a protein molecule. Scientific American
  196112, 96-110
• Nature, January 2003 The double Helix, 50 years
• New Scientist, March 2003 DNA, The next 50 years
• Nature Insight Proteomics (January 2003)
• http//www.nobel.se
• Members of the Bijvoet Center L.J. Braakman,
  J.P. Kamerling, R. Boelens