Download The Story of Molecular Biology and Its Creators

Chapter 1
The Beginnings of
Molecular Biology
The double helical, base-paired structure
of DNA is a scientist’s dream―simple,
elegant, and universal for all organisms.
[In the words of Watson] “The structure
was too pretty not to be true.”
Harrison Echols, Operators and Promoters: The Story
of Molecular Biology and Its Creators (2001), p. 8
1.1 Introduction
What is molecular biology?
The study of biological phenomena at the
molecular level, in particular the study of:
• the molecular structure of DNA and the
information it encodes;
• the biochemical basis of gene expression
and regulation.
Deoxyribonucleic acid (DNA)
•
•
•
•
Captivates Hollywood and the general public.
Excites scientists and science fiction writers.
Inspires artists.
Challenges society with emerging ethical
issues.
Three lines of research led to
the discovery that DNA is the
hereditary material
• The nature of genes.
• The behavior of chromosomes during
mitosis.
• The chemical composition of DNA.
DNA is the hereditary material: each
chromosome is a single molecule of
DNA, and genes are sequences of DNA.
Six important principles of scientific
discovery
1. Some great discoveries are not appreciated or
communicated to a wide audience until years
after the discoverers are dead and their
discoveries are “rediscovered.”
2. A combined approach of in vivo and in vitro
studies has led to significant advances.
Six important principles of scientific
discovery
3. The study of mutations is a driving force in
genetics and in modern molecular biology.
4. Major breakthroughs often follow technological
advances.
5. Progress in science may result from
competition, collaboration, and the tenacity and
creativity of individual investigators.
Six important principles of scientific
discovery
6. All research in biology during the last 150+
years has developed within the framework of
evolution.
1.2 Insights into the nature of
the heredity material
Heredity
• The transmission of characteristics from
parent to offspring by means of genes.
“The more deeply … we penetrate into the
phenomena of heredity, the more firmly are
we convinced that something of the kind
[germ-plasm or hereditary substance] does
exist, for it is impossible to explain the
observed phenomena by means of much
simpler assumptions. We are thus reminded
afresh that we have to deal not only with the
infinitely great, but also with the infinitely
small…”
August Weismann, Germ-Plasm: a Theory of Heredity
(1893)
Mendel’s laws of inheritance
• The law of segregation.
• The law of independent assortment.
• The law of dominance.
Mendel’s report was greeted by a disinterest
that lasted 36 years…
The law of segregation
• During the formation of gametes, the
paired hereditary determinants separate
(segregate) in such a way that each
gamete is equally likely to contain either
member of the pair.
The law of independent
assortment
• Segregation of the members of any pair of
hereditary determinants is independent of
the segregation of other pairs in the
formation of gametes.
The law of dominance
• For each physical trait, one member of any
pair of hereditary determinants is dominant
so that the physical trait that it specifies
appears in a 3:1 ratio.
• The alternative form is recessive.
Incomplete dominance
• A form of intermediate inheritance in which
one allele for a specific trait is not
completely dominant over the other allele.
• This results in a combined phenotype.
The chromosome theory of
inheritance
• A unifying theory stating that inheritance
patterns can be explained by assuming
the genes are located in specific sites on
chromosomes.
Meiosis explains Mendel’s law
of segregation
• Homologous chromosomes separate
during meiosis I.
• Alleles (alternative forms of a gene) are
segregated into different gametes during
meiosis II.
Meiosis explains Mendel’s law
of independent assortment
• Nonhomologous chromosomes assort
independently during meiosis I.
• Thus, genes for different traits assort
independently.
The transforming principle is DNA
• In vivo experiments
1928: Frederick Griffith described a transforming
principle that transmitted the ability of bacteria to
cause pneumonia in mice.
The transforming principle is DNA
• Griffith’s model of genetic transformation
was met with almost universal skepticism.
• He was so shy that he had trouble even
reading his papers in front of a small
audience.
The transforming principle is DNA
• In vitro experiments
1944: Oswald Avery, Colin MacLeod, and
Maclyn McCarty demonstrated that purified DNA
was sufficient to cause transformation.
Creativity in approach leads to the
one gene-one enzyme hypothesis
1941: George Beadle and Edward Tatum were the
first to demonstrate a link between a gene and a
step in a metabolic pathway catalyzed by an
enzyme.
Instead of working out the chemistry of
known genetic differences…
• Beadle and Tatum worked backwards.
• They selected mutants of the pink bread
mold, Neurospora crassa, in which known
chemical reactions were blocked.
The importance of technological
advances: the Hershey-Chase
experiment
•1952: Alfred Hershey and Martha Chase
demonstrated that the genetic material of a virus
that infects bacteria, bacteriophage T2, is DNA.
•Their findings suggested that DNA could be the
universal hereditary material.
1.3 A model for the structure of
DNA: the DNA double helix
•1953: James Watson and Francis Crick
proposed the double helix as a model for the
structure of DNA.
•Their discovery was based, in part, on Xray diffraction analysis performed by
Rosalind Franklin in Maurice Wilkin’s lab
Other scientific findings at the time provided
the context for the proposed structure of DNA
1. The proposed a-helical secondary structure of
proteins by Linus Pauling in 1951
2. The disproving of Phoebus Levene’s
tetranucleotide hypothesis by Erwin Chargaff
1.4 The central dogma of
molecular biology
The Central Dogma was summarized by
Francis Crick as follows:
“Once information has passed into protein it
cannot get out again”… Crick’s choice of the
word “dogma” was not a call for blind faith in
what was really a central hypothesis. According
to Horace Judson in his book The Eighth Day of
Creation, it was because Crick had it in his mind
that “a dogma was an idea for which there was
no reasonable evidence.” Crick told Judson “I
just didn’t know what dogma meant… Dogma
was just a catch phase.”
• Replication: The process of making an exact
copy of DNA from the original DNA.
• Transcription: The process of DNA being copied
to generate a single-stranded RNA identical in
sequence to one strand of the double-stranded
DNA.
• Translation: The process of the RNA nucleotide
sequence being converted into the amino acid
sequence of a protein.
• Reverse transcription: the process of a singlestranded DNA copy being generated from a
single-stranded RNA.
1.5 An evolutionary framework
for heredity
On the Origin of Species
• 1859: Darwin concluded that evolution
occurs when heritable variation leads to
differential success in reproduction.
• Darwin’s theory of evolution by natural
selection implied that all organisms are
related by common ancestry.
Last Universal Common
(Cellular) Ancestor (LUCA)
• A first simple life-form that existed on
Earth more than 4 billion years ago.
• All life evolved from LUCA.
Selectionist (neo-Darwinian)
theory
• Natural selection is the force that gradually
shapes the adaptation of organisms,
acting on individuals in populations and
affecting their ability to survive and
reproduce.
• Evolution is a change in the characteristics
of a population over time.
• Advantageous changes are passed on in
offspring by Darwinian (positive) selection
• Deleterious changes tend to disappear by
purifying (negative) selection
• Neutral changes may be fixed or may
disappear in a population over time.
The nearly neutral theory of
molecular evolution
• Late 1960s: Motoo Kimura proposed that
the main cause of evolutionary change at
the molecular level is random fixation of
selectively neutral or nearly neutral
mutations.
• How much genetic variation is adaptive
and maintained by natural selection and
how much is neutral and maintained by
genetic drift?
• Genetic drift: random changes in gene
frequencies of a population from
generation to generation.
The nearly neutral theory of
molecular evolution
• Positive selection of adaptive mutations is
not the dominant mode of selection.
• The dominant mode of selection is
purifying selection that eliminates
deleterious mutations while allowing
random fixation of nearly neutral
mutations.