Transcript No Slide Title - Whitehead Institute for Biomedical Research

WHY DO BIOLOGISTS STUDY
BACTERIA, YEASTS, WORMS, FLIES,
AND MICE?
Harvey F. Lodish, Ph.D.
Member, Whitehead Institute for Biomedical Research
Professor of Biology and Professor of Bioengineering
Massachusetts Institute of Technology
Gene numbers and DNA Content of
Representative Types of Cells
All organisms from simple bacteria to complex plants and
animals undoubtedly evolved from a common single- celled
progenitor
The Central Dogma
The Basics of Molecular Biology
• DNA is a “code” comprised of a very long linear string of A,
T, G, and G “bases” divided into blocks called genes.
• Each gene “codes for” one protein and contains two
segments:
• One specifies the sequence of amino acids for each of the
thousands of proteins the organism can make.
• Another tells the cell when and in what amount each
protein is to be made.
• Proteins are the working “molecular machines” in cells and organisms.
• Proteins are strings of 20 different amino acids (“beads”) that are folded in
such a way that the protein can carry out is specific function.
We work and think at the level of
individual atoms and molecules
Proteins - The Working Molecules
of Cells and Organisms
• Enzymes (Catalyze chemical reactions)
• Antibodies (Bind foreign objects, such as bacteria)
• Binding (Hemoglobin in red blood cells)
• Transporters (Proteins in cell membranes that enable
sugars and other nutrients to cross)
• Structural (Form the internal cytoskeleton and the
extracellular matrix)
• Movement (Contractile fibers in muscle)
• Bind to DNA (Turn genes on or off)
• Hormones (send signals fro cell to cell)
Proteins are formed as linear strings
(polymers) of chemicals called amino acids
Each of the 20 different kinds of amino acids that
constitute proteins have the same basic structure, but
differ in the chemical properties of the “side chain” or
R group.
Nine of the 20 amino acids have side chains that
interact well with and dissolve in water.
They are said to be hydrophilic (water- loving)
Eight of the 20 amino acids have side chains that
interact with and dissolve in oil but not water.
They are said to be hydrophobic (water- repelling)
Proteins vary in size, shape, and function
(Hormone)
(Enzyme)
(Binds oxygen)
(Antibody)
(Enzyme)
Many proteins are enzymes, regularly changing
their shape as they facilitate specific chemical
reactions
Chromosomes, Genes, and DNA
DNA Content of Representative Types of Cells
The Central
Dogma
Each amino acid is first linked to a particular type of transfer RNA (tRNA) and is then
brought to the ribosome - the molecular machine that incorporates specific amino acids
one- at- a- time into the growing protein. By binding specifically to a 3-base codon in
the mRNA the tRNA insures that the correct amino acid is incorporated into each
position. The ribosome literally walks along the mRNA adding one amino acid for each
3- nucleotide codon in the messenger RNA
The ribosome, a molecular machine that binds to one
specific end of the messenger RNA, and then “walks”
along the mRNA 3 bases at a time adding amino acids
one- at- a- time to the growing protein chain.
QuickTime™ and a Animation decompressor are needed to see this picture.
The Human Genome
Of the ~30,000 genes (thus ~30,000 different encoded
proteins) in the human genome
42% have unknown functions
14% are involved in turning genes on or off within the cell nucleus
12% allow cells to communicate with other cells
10.2% are enzymes that facilitate specific chemical reactions
5.0% relate to the fibrous cytoskeleton that gives cells their shape and allows
cell movement
4.8% are proteins in cell membranes that allow various chemicals to cross
3.3% allow cells to bind to other cells forming tissues
2.9% are involved in controlling cell division, mainly tumor suppressors
0.9% are involved in functions of the immune system.
Gene numbers and DNA Content of
Representative Types of Cells
Bacteria are the smallest and simplest cells
Bacteria are the smallest and simplest cells
Most of the genes and proteins found in
bacterial cells are also found in human cells.
Gene numbers and DNA Content of
Representative Types of Cells
Yeasts are among the simplest eukaryotic cells
Eukaryotic cells, unlike prokaryotes, have a nucleus as well as
many other organelles, compartments that are separated from
the cytoplasm by a membrane.
The fission yeast
Schizosaccharomyces pombe
The cell cycle in yeast and humans uses the
same set of regulatory proteins
The process of cell division is very
similar in yeasts and mammals
QuickTime™ and a
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The division of yeast and human cells uses
the same set of motor proteins to move
chromosomes into the two daughters.
In metazoan animals groups of cells form into
tissues, and multiple tissues form organs
In metazoan animals, plasma membrane proteins
bind cells to each other and to collagens and other
components of the extracellular matrix
Gene numbers and DNA Content of
Representative Types of Cells
White- eye Drosophila mutant
The Eyeless gene is conserved during evolution and
codes for the “master gene control protein” that
initiates eye formation in both flies and man.
Normal
(wild- type)
Mutant in
Eyeless gene
Homeotic Drosophila mutant
FEATURES OF THE NEMATODE
Caenorhabditis elegans
• SMALL: ~ 250 µm
• SHORT GENERATION TIME
• TRANSPARENT
• SIMPLE GROWTH MEDIUM
• 959 CELLS
• SELF- FERTILIZING HERMAPHRODITE
• 300 NEURONS
• RAPID ISOLATION AND CLONING OF
MULTIPLE TYPES OF MUTANT ORGANISMS
The nematode Caenorhabditis elegans
QuickTime™ and a
MPEG-4 Video decompressor
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One can trace the
fate (lineage) of
each of the 929
cells in the worm
C. elegans
Watch a cell undergo apoptosis
(programmed cell death)
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Certain cells in the worm C. elegans are born only to die
(top; yellow arrows). Mutation of certain genes abolishes
this programmed cell death (bottom; yellow arrowheads)
Comparison of the
human and mouse genomes
• The proportion of mouse genes without any detectable
homolog in the human genome (and vice versa) is about
1%.
• Dozens of local gene family expansions have occurred in the
mouse genome, mainly related to immunity, reproduction,
and olfaction.
• These physiological systems have apparently been the focus
of extensive lineage- specific innovation in rodents.
Comparison of the human and mouse genomes
Both genomes contain ~30,000
protein- coding genes.
The mouse genome, 2.5 x 109
bp, is 14% smaller than the
human genome of 2.9 x 109 bp.
Over 90% of mouse and human
genomes can be partitioned into
conserved regions, indicating a
common evolutionary ancestor.
Breakdown of mouse proteins
according to evolutionary origin
Note that only a small fraction of genes are possibly rodent-specific (<1%) as compared with those
shared with other mammals (14%, not rodent-specific); shared with chordates (6%, not mammalianspecific); shared with metazoans (27%, not chordate-specific); shared with eukaryotes (29%, not
metazoan-specific); and shared with prokaryotes and other organisms (23%, not eukaryotic-specific).
Mouse Genome Sequencing Consortium (2002) Nature 420:520- 562.
Mouse (left) transgenic for human
growth hormone
Epo “gene knock- out” mice are normal except that
they have no adult- type red blood cells and die at
embryonic day 14.