WHY DO BIOLOGISTS STUDY BACTERIA, YEASTS, WORMS, FLIES, AND MICE? Harvey F. Lodish, Ph.D. Member, Whitehead Institute for Biomedical Research Professor

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 BioengineeringMassachusetts Institute of Technology

Gene numbers and DNA Content of Representative Types of Cells

Organism

PROKARYOTIC

Mycoplasma genitalum (Bacterium)

Helicobacter pylori (Bacterium)

Haemophilus influenza (Bacterium)

EUKARYOTIC

Saccharomyces cerevisiae (yeast)

Drosophila melanogaster (insect)

Caenorhabditis elegans (worm)

Homo sapiens (human)

Arabidopsis thaliana (plant)

Number of base pairs (millions)

0.58

1.67

1.83

12

165

97

2900

125

Number of encoded proteins

470

1590

1743

5885

13,601

19,099

30,000 TO 40,000

25,498

Number of chromosomes

1

1

1

17

4

6

23

10

All organisms from simple bacteria to complex plants and animals undoubtedly evolved from a common single- celled

progenitor

The Central Dogma

• 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.

The Basics of Molecular Biology

• 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

(Enzyme) (Enzyme)(Antibody)(Binds oxygen)

(Hormone)

Many proteins are enzymes, regularly changing their shape as they facilitate specific chemical

reactions

Chromosomes, Genes, and DNA

DNA Content of Representative Types of CellsOrganism

PROKARYOTIC




EUKARYOTIC







0.58

1.67

1.83

12

165

97

2900

125


470

1590

1743

5885

13,601

19,099

30,000 TO 40,000

25,498


1

1

1

17

4

6

23

10

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 aAnimation decompressorare needed to see this picture.

The Human GenomeOf 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.


Organism

PROKARYOTIC




EUKARYOTIC







0.58

1.67

1.83

12

165

97

2900

125


470

1590

1743

5885

13,601

19,099

30,000 TO 40,000

25,498


1

1

1

17

4

6

23

10

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.


Organism

PROKARYOTIC




EUKARYOTIC







0.58

1.67

1.83

12

165

97

2900

125


470

1590

1743

5885

13,601

19,099

30,000 TO 40,000

25,498


1

1

1

17

4

6

23

10

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 yeastSchizosaccharomyces 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 aMPEG-4 Video decompressor

are needed to see this picture.

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


Organism

PROKARYOTIC




EUKARYOTIC







0.58

1.67

1.83

12

165

97

2900

125


470

1590

1743

5885

13,601

19,099

30,000 TO 40,000

25,498


1

1

1

17

4

6

23

10

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 NEMATODECaenorhabditis elegans

• SMALL: ~ 250 µm

• TRANSPARENT

• 959 CELLS

• 300 NEURONS

• SHORT GENERATION TIME

• SIMPLE GROWTH MEDIUM

• SELF- FERTILIZING HERMAPHRODITE

• RAPID ISOLATION AND CLONING OF MULTIPLE TYPES OF MUTANT ORGANISMS

The nematode Caenorhabditis elegans



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)



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 mammalian-specific); 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.

Documents

WHY DO BIOLOGISTS STUDY BACTERIA, YEASTS, WORMS, FLIES, AND MICE? Harvey F. Lodish, Ph.D. Member, Whitehead Institute for Biomedical Research Professor