A Brief History of
Genetics
1
Early Concepts of Heredity


Ancient Greeks –
believed in
“pangenesis”, in
which miniature
versions of body
parts were
transmitted during
sexual
reproduction;
Darwin despite his
evolutionary
theories believed in
a modified sort of
pangenesis, via
“gemmules”



1865 Gregor Mendel–
studied inheritance of
seven traits in pea
plants and first used the
terms dominant and
recessive.
Laws of independent
assortment and
segregation are based
on his work.
Proposed similar but
separate inheritable
characters, one from
each parent, later to be
called genes.
2
1869
Fredrich Miescher
 Successfully
isolated nuclein from
pus cells obtained from discarded
bandages.
 He noticed that nuclein was
acidic, contained a lot of
phophorus and nitrogen and was
found in the nucleus of cells.
 Nuclein eventually became known
as DNA
3
Theodor Boveri – 1888-1890
Investigated chromosomes
 Found that:

 Chromosomes are organized and
individual structures throughout the
process of cell division.
 Sperm and egg contribute the same
number of chromosomes.
4
1900 Gregor Mendel



Mendel’s work is rediscovered by
three scientists (one German, one
Dutch and one Austrian) Hugo de
Vries, Carl Correns, and Erich von
Tsernak
16 years after his death, and 34
years after publication, Mendel’s
work is finally recognized.
The first 20 years of the 20th
century build upon the rediscovered
experiments of Mendel
5
1902
Walter Sutton
The Boveri-Sutton Chromosome Theory:
suggested that chromosomes are
paired and may be the carriers of
heredity
 suggested that Mendel’s "factors"
are located on chromosomes

6
1909
Wilhelm Johannsen

First used the term gene not
knowing quite what it was, just
wanting a distinction from
Darwin’s “gemmules”.
“The word gene…is completely
free from any hypotheses, it
expresses only the evident fact
that in any case, many
characteristics of the organism
are specified in the gamete by
means of special conditions and
conditions and determine which
are presented in unique separate,
and thereby independent ways—in
short precisely what we wish to
call genes.”
7
1910
Thomas Hunt Morgan



Morgan proved that genes
are carried on
chromosomes.
He also demonstrated the
existence of sex-linked
genes.
His work eventually lead to
the to a fundamental
understanding of the
mechanisms of heredity
The Nobel Prize in
Physiology of Medicine
1933
8
T. H. Morgan’s Fruit Flies
1907-1930s



Morgan's experimental and
theoretical work inaugurated
research in genetics and
promoted a revolution in
biology.
Evidence he gathered from
embryology and cell theory
pointed the way toward a
synthesis of genetics with
evolutionary theory.
Morgan himself explored
aspects of these developments
in later work, including
Evolution and Genetics
published in 1925, and The
Theory of the Gene in 1926.
9
1928
Fred Griffith
Studied different strains of
Streptococcus pneumoniae, the
bacteria that causes pneumonia.
 This bacteria come in two strains: S
and R
 the S-form has a capsule and looks
smooth under the microscope. It is
virulent and kills infected mice
because the immune system cannot
break through the cell wall of the S
bacterium.

10
1928
Fred Griffith
The R-form of the bacterium
doesn't have a capsule and
appears rough.
 The immune system is able to
destroy the cell wall of the R
bacterium. This makes the R
form non-virulent. The mice
infected by this form of the
bacteria will survive.

11
Griffith's Experiments




Griffith injected mice with the S form of
bacteria and all the mice died from
pneumonia.
He injected mice with the R form of bacteria
and the mice survived the infection.
He then killed the S form by exposing them
to high temperatures. Mice injected with
these heat-killed bacteria survived with no ill
effects.
He mixed his heat-killed, disease-causing
bacteria with live, harmless ones and
injected the mixture into mice.
12
Griffith's Experiments
He was expecting the mice to survive
because both strains were harmless. But,
the mice died from pneumonia!!!
And he found living S cells in the mice!
Somehow the heat-killed S strain passed
their ability to cause disease to the live R
strain.
Griffith called this Transformation





one strain of bacteria had been changed
into another. Some factor was transferred
from heat-killed cell into the live cells. He
also found that the change was permanent.
He hypothesized that factor could be a
gene that could change the properties of
bacteria.
13
1928
Frederick Griffith
Transformation of Bacteria
14
1929
Phoebus Levene
 He
identified the deoxyribose
sugar in “thymus” nucleic acid
and the ribose sugar in
“yeast”nucleic acid
 Also identified the nitrogenous
bases: adenine, guanine,
cytosine and thymine in
“thymus” nucleic acid and
uracil in “yeast” nucleic acid.
15
What Could the Genetic Material Be?
Griffith had shown that “something” was
passing from one type of bacteria to another.
This “something” could be





Parts of the capsule
Proteins
Nucleic acids
Whatever “it” was, it had to be



Duplicated when the cell divided
Stable and resistant to heat
16
George Beadle and Edward Tatum
1941 (Nobel Prize 1958)
One gene-one enzyme hypothesis
17
1944
Avery, MacLeod and McCarty
Avery and his colleagues decided to expand on
Griffith’s experiments to try to identify the
“transforming” material.
18
Separated the Components

Ruptured heat killed S strain bacteria to release their contents.

Separated and purified the RNA, DNA, proteins and the
polysaccharide capsules from the bacteria into separate
factions.
Mixed each faction with live R bacterial cells and injected them into
mice.

 R-bacteria + RNA from S-bacteria = live mouse
 R-bacteria + proteins from S-bacteria = live mouse
 R-bacteria + polysaccharides from S-bacteria = live mouse
Only R cells were found in their blood.
19
Separated the Components

Ruptured heat killed S strain bacteria to
release their contents.
 Separated and purified the RNA, DNA,
proteins and the polysaccharide capsules
from the bacteria into separate factions.
 Mixed each faction with live R bacterial cells
and injected them into mice.
 R-bacteria + RNA from S-bacteria = live mouse
 R-bacteria + proteins from S-bacteria = live mouse
 R-bacteria + polysaccharides from S-bacteria = live
mouse
 Only R cells were found in their blood.
 R bacteria + DNA from S-bacteria = DEAD MOUSE!!!
 They concluded that DNA was the hereditary material



Despite the fact that the Transforming substance
had to be resistant to heat, and proteins are
inactivated by heat…
Most scientists thought that proteins were the
hereditary material because they were more
complex and varied than nucleic acids.
Scientists were generally skeptical, believing DNA
to be too simple a molecule to contain all the
genetic information for an organism.
21
1950
Erwin Chargaff
Discovered that in DNA, the
amount of Adenine is equal to
the amount of Thymine and the
amount of Guanine is equal to
the amount of Cytosine.
 Chargaff’s Rule:

A=T
G=C
22
1952
Alfred Hershey and
Martha Chase
23
1952
Alfred Hershey and Martha Chase
24
25
DNA
IS NOW
ACCEPTED AS THE
GENETIC MATERIAL!!!

And the race is on to determine
the structure of DNA
26
1951-1953
Rosalind Franklin

Franklin was responsible for
much of the research and
discovery work that led to the
understanding of the structure
of deoxyribonucleic acid, DNA.

Headed a X-Ray crystallography
unit at King’s College in London

Did extensive work to elucidate
structure of DNA

Franklin resisted model
building unlike Pauling and
Watson and Crick
1951-1953
Rosalind Franklin
Franklin made marked
advances in x-ray diffraction
techniques with DNA.
 She extracted finer DNA
fibers than ever before and
arranged them in parallel
bundles.
 She studied the DNA fibers'
reactions to humid
conditions.
 All of these allowed her to
discover crucial keys to
DNA's structure.

28
1951-1953
Rosalind Franklin
She recognized that two
states of the DNA molecule
existed (A and B) and defined
conditions for the transition.
 From early on, she realized
that any correct model must
have the phosphate groups on
the outside of the molecule.
 After the formation of the
Watson Crick model she
demonstrated that a double
helix was consistent with the
X-ray patterns of both the A
and B forms.

29
Linus Pauling
1953
Prominent American
biochemist who wrote ”The
Nature of the Chemical Bond”;
 Elucidated the structure of
amino acids and proteins, and
associated helical structures;
 Proposed a 3-chain helical
structure for DNA, but with
sugar-phosphate groups on
the inside;
 Evelynn Fox Keller (2000)
notes that had Pauling used
all available literature, his
model might have been
correct; Watson and Crick are
sure that he was on to it.

30
1953
James Watson and
Francis Crick
31
Watson and Crick’s
approach was to make
physical models to narrow
down the possibilities and
eventually create an
accurate picture of the
molecule.
 After Wilkins showed them
pictures of Franklin’s x-ray
diffraction work, Watson
and Crick took a huge
conceptual step. They
suggested that the DNA
molecule was made of two
chains of nucleotides, each
in a helix (as Franklin had
found) but one going up and
the other going down.

1953
James Watson and
Francis Crick
32
Crick had just learned of
Chargaff's findings about base
pairs. He added that to the
model, so that matching base
pairs interlocked in the middle of
the double helix to keep the
distance between the chains
constant. This was consistent
with Franklin’s measurements.
 The key to Watson and Crick's
discovery was the realization that
because of its size, shape and
chemical makeup, each base on
one side of the ladder could pair
by hydrogen bonds with only one
other base on the other
complementary side of ladder
going down.

1953
James Watson and
Francis Crick
33
Specifically, the large adenine molecule could
pair with only the smaller thymine and the
large guanine molecule could pair with only the
smaller cytosine.
The Nobel Prize in Physiology or Medicine 1962
"for their discoveries concerning the molecular structure of nucleic acids and its significance for
information transfer in living material“
34
1957
Arthur Kornberg
Discovers and isolates
DNA polymerase, which
becomes the first enzyme
used to make DNA in a
test tube.
 Also proves that the
strands are anti-parallel
and that replication
proceeds only in one
direction (5’to3’)

a template.
35
DNA Replication


The Watson-Crick model of DNA clearly provided a mechanism for
replication of DNA. Each strand could act as a template for the
formation of new strands.
Three models were suggested for the mechanism of replication:
36
1958
Meselson and Stahl
 Their
experiment
determined the
mechanism of
DNA replication
37
1957
Matthew Meselson and Edward Stahl
38
1957
Matthew Meselson and Edward Stahl

First, they grew bacteria for many generations in a growth
medium containing 15N. This is a heavy isotope of
nitrogen (in contrast to the normal isotope 14 N).

Over many generations, 15N would be incorporated into
all nitrogen-containing molecules of the cells, including
DNA. DNA isolated from these cells could be
distinguished from normal DNA because it would have a
higher density.

The bacteria grown in heavy nitrogen were then
transferred to growth medium containing 14 N for one
round of replication. This lighter isotope would
incorporate into any newly synthesized DNA.
39
1957
Matthew Meselson and Edward Stahl

If semi-conservative replication occurred, then
each DNA molecule after replication would
contain heavy nitrogen and light nitrogen, and
would therefore have a density intermediate
between the two.

Conservative replication would produce one DNA
molecule containing heavy nitrogen and one
molecule containing light nitrogen, so there
would be two different densities.

Dispersive replication would produce a single
intermediate density, just like semi-conservative.
40

After one generation:

Replication was therefore either semi-conservative or
dispersive. These possibilities could be distinguished after a
second round of replication.
After two rounds, semi-conservative replication would produce
two DNA molecules containing only light nitrogen, and two DNA
molecules containing one light strand and one heavy strand.
Therefore there would be two different densities: light and
intermediate.
Two rounds of dispersive replication would produce four DNA
molecules, each of which would contain mostly light nitrogen
and some heavy nitrogen.


41

When density of the DNA was measured after
two rounds, two densities were observed: light
and intermediate, indicating that DNA replication
is semi-conservative, and not dispersive or
conservative.
42
1957
Matthew Meselson and Edward Stahl
43
The 1970’s


This decade is when human beings began to systematically control, manipulate and
exploit DNA technology.
It marked the beginning of recombinant DNA technology, gene splicing and the first
biotechnology company, Genentech.

1970. Isolation of "reverse transcriptase," a restriction enzyme that cuts DNA
molecules at specific sites. This allows scientists to create clones and observe their
function.

1972 - creation of the first recombinant DNA molecule.
- The first successful DNA cloning experiment was performed in California.

1973 - Scientists successfully transferred DNA from one life form to another,
creating the first recombinant DNA organism.

1976 – Herberg Boyer and Robert Swanson found Genentech Inc., the first
biotechnology company dedicated to developing and marketing products based on
genetic engineering technology.

1977- a man-made gene was used to manufacture a human protein in bacteria for
the first time.

1978- successful production of human insulin using recombinant DNA technology
44
The 1980’s

A combination of the computer revolution
and more easily available enzymes led to the
creation of several new technologies like the
polymerase chain reaction (PCR) and
automated gene sequencers. These in turn
would make the job of mapping the entire
human genome possible
45
1990 to Now…
Human clones are created in Petri dishes,
genes are dissected, the infant field of gene
therapy begins and the first mammalian living
clone is created
 2001 – The complete map of the human
genome is published.

46