DNA in the chromosomes of the genome contains all the information to develop an organism and operate all its cell types.

1
The Elements of Molecular Biology
A principal goal is to understand cells and
organisms as molecular systems / machines. The
basic classes of molecules are

• DNA in the chromosomes of the genome contains all
  the information to develop an organism and
  operate all its cell types.
• RNA serves both short-term informational roles
  and structural roles.
• Proteins execute the functions of a cell and
  provides its structural integrity.
• Small metabolites (fats, sugars, etc.) provide
  energy, raw materials, and serve some limited
  structural roles.

2
Cells As Molecular Machines
3
Understanding Cells at the Molecular Level

• Determining the DNA sequences of the chromosomes
  of a species. Sequencing
• An accurate parts list of all the proteins and
  RNAs in the cell. Annotation
• A graph of all the interactions taking place
  between these agents. Pathways
• What is happening during each interaction. Fun
  ction
• Where each interaction is taking
  place. Subcellular Localization
• Simulating the system to predict behavior.
• Cellular Dynamics

4
Current State

• We can sequence the euchromatic portions of
  genomes.
• We can recognize 75 of the genes but not
  accurately unless they have been experimentally
  verified. We dont know much about alternate
  splicing.
• We can crudely observe expression of mRNAs and
  with even greater difficulty observe the more
  abundant proteins.
• Most accurate molecular biological information is
  still being verified one hypothesis at a time.
• We must either coordinate efforts or reduce
  experimental costs to the point where each
  investigator is greatly empowered.

5
Current Technologies

• Sequencing Randomly sample and sequence 600bp
  stretches from the ends of segments of a given
  length and assemble, followed by a directed
  finishing phase.
• Expression Assays High density arrays where
  each spot is a set of 18-50bp DNAs complementary
  to the RNA sequence to be measured, or geometric
  amplification from a pair of DNA probes
  complementary to the RNA sequence (quantitative
  PCR).
• Proteomics Mass spectrometers can measure the
  amount and atomic weight of ionized protein
  pieces (peptides) allowing complex mixtures to be
  analyzed.
• Light Microscopy With confocal microscopes and
  antibody, or RNA, or organo-metallic staining,
  phenomenon involving but a few particles are
  being observed.
• All of these technologies involve interesting
  problems in the interpretation of the data.
• Data Analysis vs. Data Mining

6
On Systems Biology

• The goal is to understand cells and organisms as
  molecular systems. An objective that can be
  reached in the next 10-25 years is the
  elucidation of the topology of the circuit
  diagram of a species cells.
• A graph whose nodes are proteins, RNAs, DNAs, and
  metabolites
• Edges or hyper edges describe relationships, e.g.
• Catalyzes A-gtB, Kinase (adds phosphate group),
  Complexes with, etc.
• Nodes carry attributes describing where and when
  the agent is present
• Believe that such knowledge will result in
  tremendous understanding in that it will
  generate many hypotheses that are true.
• Many circuits when modeled as stochastic diff.
  eq.s are so robust to their parameters that they
  have only a handful of operating ranges and the
  biologically relevent one(s) is readily evident.

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Apoptosis Programmed cell death
8
A Proposal based on Drosophila

• Goal Develop a comprehensive set of accurate
  genomics-based data and biological resources for
  the advancement of cellular biology. Make them
  openly and readily accessible and available to
  all.
• Sequence 10-20 species of Drosophila, 3-5 to a
  nearly-finished state and 10-15 to an assembled
  state.
• Understand the evolution of the genomes and
  accurately annotate the genes and regulatory
  signals using comparative informatics.
• Develop a comprehensive, experimentally verified
  annotation of all possible transcripts of the
  nearly-finished species. Capture each in a
  gate-way clone library.
• Build state of the art expression assays for
  these genomes and apply them in a number of
  surveys.
• Utilize mass spec. technology to begin
  systematically exploring complex formation and
  signalling cascades of Drosophila cells.

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Why Drosophila?

• Sufficiently interesting model development,
  differentiation, behavior
• Easy to stock lines and many experimental
  methods.
• Compact genome 20 Dros. Genomes 1 mammalian
  genome
• Excellent evolutionary and molecular model for
  humans
• Large community coordinated efforts are possible

10
Comparative Gene Finding
Require ab initio models to predict orthologs
consistent with the evolutionary ladder amongst
all strains.
Given a ladder of 5-10 Drosophila genomes we
should be able to accurately discern most protein
encoding genes, many RNA genes, and a host of
regulatory signals
11
The Role of Informatics

• We need to make computers easier to program
  i.e. we need to put scientific computing in the
  hands of the scientists.
• Our information management technologies are
  inadequate huge data sets, semi-structured,
  data contains errors, not integrated we need to
  model these and develop flexible data mining
  capabilities over them.
• There will be a continued need for new algorithms
  and tools as driven by new technologies and
  protocols.
• Physical simulations systems of various types
  will be needed docking, ligand binding,
  stochastic differential equations.
• Experimental design, driven by analysis and
  simulation, should be a part of our discipline
  and is an area where we can but are not
  contributing.