Branch of biology that studies biological systems at the molecular level
Molecular biology
is a branch of
biology
that seeks to understand the
molecular
basis of biological activity in and between
cells
, including
biomolecular
synthesis, modification, mechanisms, and interactions.
[1]
[2]
[3]
Though cells and other microscopic structures had been observed in living organisms as early as the 18th century, a detailed understanding of the mechanisms and interactions governing their behavior did not emerge until the 20th century, when technologies used in physics and chemistry had advanced sufficiently to permit their application in the biological sciences. The term 'molecular biology' was first used in 1945 by the English physicist
William Astbury
, who described it as an approach focused on discerning the underpinnings of biological phenomena?i.e. uncovering the physical and chemical structures and properties of biological molecules, as well as their interactions with other molecules and how these interactions explain observations of so-called classical biology, which instead studies biological processes at larger scales and higher levels of organization.
[4]
In 1953
Francis Crick
,
James Watson
,
Rosalind Franklin
, and their colleagues at the
Medical Research Council Unit, Cavendish Laboratory
, were the first to describe the
double helix
model for the chemical structure of
deoxyribonucleic acid
(DNA), which is often considered a landmark event for the nascent field because it provided a physico-chemical basis by which to understand the previously nebulous idea of nucleic acids as the primary substance of biological inheritance. They proposed this structure based on previous research done by Franklin, which was conveyed to them by
Maurice Wilkins
and
Max Perutz
.
[5]
Their work led to the discovery of DNA in other microorganisms, plants, and animals.
[6]
The field of molecular biology includes techniques which enable scientists to learn about molecular processes.
[7]
These techniques are used to efficiently target new drugs, diagnose disease, and better understand cell physiology.
[8]
Some clinical research and medical therapies arising from molecular biology are covered under
gene therapy
, whereas the use of molecular biology or
molecular cell biology
in medicine is now referred to as
molecular medicine
.
History of molecular biology
[
edit
]
Angle description in DNA structure
Diagrammatic representation of Watson and Crick's DNA structure
Molecular biology sits at the intersection of
biochemistry
and
genetics
; as these scientific disciplines emerged and evolved in the 20th century, it became clear that they both sought to determine the molecular mechanisms which underlie vital cellular functions.
[9]
Advances in molecular biology have been closely related to the development of new technologies and their optimization.
[10]
Molecular biology has been elucidated by the work of many scientists, and thus the history of the field depends on an understanding of these scientists and their experiments.
[
citation needed
]
The field of genetics arose from attempts to understand the set of rules underlying
reproduction
and
heredity
, and the nature of the hypothetical units of heredity known as
genes
.
Gregor Mendel
pioneered this work in 1866, when he first described the laws of inheritance he observed in his studies of mating crosses in pea plants.
[11]
One such law of genetic inheritance is the
law of segregation
, which states that diploid individuals with two
alleles
for a particular gene will pass one of these alleles to their offspring.
[12]
Because of his critical work, the study of genetic inheritance is commonly referred to as
Mendelian genetics
.
[13]
A major milestone in molecular biology was the discovery of the structure of
DNA
. This work began in 1869 by
Friedrich Miescher
, a Swiss biochemist who first proposed a structure called
nuclein
, which we now know to be (deoxyribonucleic acid), or DNA.
[14]
He discovered this unique substance by studying the components of pus-filled bandages, and noting the unique properties of the "phosphorus-containing substances".
[15]
Another notable contributor to the DNA model was
Phoebus Levene
, who proposed the "polynucleotide model" of DNA in 1919 as a result of his biochemical experiments on yeast.
[16]
In 1950,
Erwin Chargaff
expanded on the work of Levene and elucidated a few critical properties of nucleic acids: first, the sequence of nucleic acids varies across species.
[17]
Second, the total concentration of purines (adenine and guanine) is always equal to the total concentration of pyrimidines (cysteine and thymine).
[14]
This is now known as Chargaff's rule. In 1953,
James Watson
and
Francis Crick
published the double helical structure of DNA,
[18]
based on the
X-ray crystallography
work done by
Rosalind Franklin
which was conveyed to them by
Maurice Wilkins
and
Max Perutz
.
[5]
Watson and Crick described the structure of DNA and conjectured about the implications of this unique structure for possible mechanisms of DNA replication.
[18]
Watson and Crick were awarded the
Nobel Prize in Physiology or Medicine
in 1962, along with Wilkins, for proposing a model of the structure of DNA.
[6]
In 1961, it was demonstrated that when a
gene
encodes a
protein
, three sequential bases of a gene's DNA specify each successive amino acid of the protein.
[19]
Thus the
genetic code
is a triplet code, where each triplet (called a
codon
) specifies a particular amino acid. Furthermore, it was shown that the codons do not overlap with each other in the DNA sequence encoding a protein, and that each sequence is read from a fixed starting point.
During 1962?1964, through the use of conditional lethal mutants of a bacterial virus,
[20]
fundamental advances were made in our understanding of the functions and interactions of the proteins employed in the machinery of
DNA replication
,
DNA repair
,
DNA recombination
, and in the assembly of molecular structures.
[21]
Griffith's experiment
[
edit
]
Griffith's experiment
In 1928,
Frederick Griffith
, encountered a virulence property in
pneumococcus
bacteria, which was killing lab rats. According to Mendel, prevalent at that time, gene transfer could occur only from parent to daughter cells. Griffith advanced another theory, stating that gene transfer occurring in member of same generation is known as horizontal gene transfer (HGT). This phenomenon is now referred to as genetic transformation.
[22]
Griffith's experiment addressed the pneumococcus bacteria, which had two different strains, one virulent and smooth and one avirulent and rough. The smooth strain had glistering appearance owing to the presence of a type of specific polysaccharide ? a polymer of glucose and glucuronic acid capsule. Due to this polysaccharide layer of bacteria, a host's immune system cannot recognize the bacteria and it kills the host. The other, avirulent, rough strain lacks this polysaccharide capsule and has a dull, rough appearance.
[
citation needed
]
Presence or absence of capsule in the strain, is known to be genetically determined. Smooth and rough strains occur in several different type such as S-I, S-II, S-III, etc. and R-I, R-II, R-III, etc. respectively. All this subtypes of S and R bacteria differ with each other in antigen type they produce.
[6]
Avery?MacLeod?McCarty experiment
[
edit
]
The Avery?MacLeod?McCarty experiment was a landmark study conducted in 1944 that demonstrated that DNA, not protein as previously thought, carries genetic information in bacteria.
Oswald Avery
,
Colin Munro MacLeod
, and
Maclyn McCarty
used an extract from a
strain
of
pneumococcus
that could cause
pneumonia
in mice. They showed that
genetic transformation
in the bacteria could be accomplished by injecting them with purified DNA from the extract. They discovered that when they
digested
the DNA in the extract with
DNase
, transformation of harmless bacteria into virulent ones was lost. This provided strong evidence that DNA was the genetic material, challenging the prevailing belief that proteins were responsible. It laid the basis for the subsequent discovery of its structure by Watson and Crick.
Hershey?Chase experiment
[
edit
]
Hershey?Chase experiment
Confirmation that DNA is the genetic material which is cause of infection came from the
Hershey?Chase experiment
. They used
E.coli
and bacteriophage for the experiment. This experiment is also known as blender experiment, as kitchen blender was used as a major piece of apparatus.
Alfred Hershey
and
Martha Chase
demonstrated that the DNA injected by a phage particle into a bacterium contains all information required to synthesize progeny phage particles. They used radioactivity to tag the bacteriophage's protein coat with radioactive sulphur and DNA with radioactive phosphorus, into two different test tubes respectively. After mixing bacteriophage and
E.coli
into the test tube, the incubation period starts in which phage transforms the genetic material in the
E.coli
cells. Then the mixture is blended or agitated, which separates the phage from
E.coli
cells. The whole mixture is centrifuged and the pellet which contains
E.coli
cells was checked and the supernatant was discarded. The
E.coli
cells showed radioactive phosphorus, which indicated that the transformed material was DNA not the protein coat.
The transformed DNA gets attached to the DNA of
E.coli
and radioactivity is only seen onto the bacteriophage's DNA. This mutated DNA can be passed to the next generation and the theory of Transduction came into existence. Transduction is a process in which the bacterial DNA carry the fragment of bacteriophages and pass it on the next generation. This is also a type of horizontal gene transfer.
[6]
Meselson?Stahl experiment
[
edit
]
Meselson-Stahl experiment
The Meselson-Stahl experiment was a landmark experiment in molecular biology that provided evidence for the
semiconservative replication
of DNA. Conducted in 1958 by
Matthew Meselson
and
Franklin Stahl
, the experiment involved growing E. coli bacteria in a medium containing heavy isotope of nitrogen (
15
N) for several generations. This caused all the newly synthesized bacterial DNA to be incorporated with the heavy isotope.
After allowing the bacteria to replicate in a medium containing normal nitrogen (
14
N), samples were taken at various time points. These samples were then subjected to centrifugation in a density gradient, which separated the DNA molecules based on their density.
The results showed that after one generation of replication in the
14
N medium, the DNA formed a band of intermediate density between that of pure
15
N DNA and pure
14
N DNA. This supported the semiconservative DNA replication proposed by Watson and Crick, where each strand of the parental DNA molecule serves as a template for the synthesis of a new complementary strand, resulting in two daughter DNA molecules, each consisting of one parental and one newly synthesized strand.
The Meselson-Stahl experiment provided compelling evidence for the semiconservative replication of DNA, which is fundamental to the understanding of genetics and molecular biology.
Modern molecular biology
[
edit
]
In the early 2020s, molecular biology entered a golden age defined by both vertical and horizontal technical development. Vertically, novel technologies are allowing for real-time monitoring of biological processes at the atomic level.
[23]
Molecular biologists today have access to increasingly affordable sequencing data at increasingly higher depths, facilitating the development of novel genetic manipulation methods in new non-model organisms. Likewise, synthetic molecular biologists will drive the industrial production of small and macro molecules through the introduction of exogenous metabolic pathways in various prokaryotic and eukaryotic cell lines.
[24]
Horizontally, sequencing data is becoming more affordable and used in many different scientific fields. This will drive the development of industries in developing nations and increase accessibility to individual researchers. Likewise,
CRISPR-Cas9 gene editing
experiments can now be conceived and implemented by individuals for under $10,000 in novel organisms, which will drive the development of industrial and medical applications.
[25]
Relationship to other biological sciences
[
edit
]
Schematic relationship between
biochemistry
,
genetics
and molecular biology
The following list describes a viewpoint on the interdisciplinary relationships between molecular biology and other related fields.
[26]
While researchers practice techniques specific to molecular biology, it is common to combine these with methods from
genetics
and
biochemistry
. Much of molecular biology is quantitative, and recently a significant amount of work has been done using computer science techniques such as
bioinformatics
and
computational biology
.
Molecular genetics
, the study of gene structure and function, has been among the most prominent sub-fields of molecular biology since the early 2000s. Other branches of biology are informed by molecular biology, by either directly studying the interactions of molecules in their own right such as in
cell biology
and
developmental biology
, or indirectly, where molecular techniques are used to infer historical attributes of
populations
or
species
, as in fields in
evolutionary biology
such as
population genetics
and
phylogenetics
. There is also a long tradition of studying
biomolecules
"from the ground up", or molecularly, in
biophysics
.
[29]
Techniques of molecular biology
[
edit
]
DNA animation
Molecular cloning
[
edit
]
Transduction image
Molecular cloning is used to isolate and then transfer a DNA sequence of interest into a plasmid vector.
[30]
This recombinant DNA technology was first developed in the 1960s.
[31]
In this technique, a
DNA
sequence coding for a protein of interest is
cloned
using
polymerase chain reaction
(PCR), and/or
restriction enzymes
, into a
plasmid
(
expression vector
). The plasmid vector usually has at least 3 distinctive features: an origin of replication, a
multiple cloning site
(MCS), and a selective marker (usually
antibiotic resistance
). Additionally, upstream of the MCS are the
promoter regions
and the
transcription
start site, which regulate the expression of cloned gene.
This plasmid can be inserted into either bacterial or animal cells. Introducing DNA into bacterial cells can be done by
transformation
via uptake of naked DNA,
conjugation
via cell-cell contact or by
transduction
via viral vector. Introducing DNA into
eukaryotic
cells, such as animal cells, by physical or chemical means is called
transfection
. Several different transfection techniques are available, such as calcium phosphate transfection,
electroporation
,
microinjection
and
liposome transfection
. The plasmid may be integrated into the
genome
, resulting in a stable transfection, or may remain independent of the genome and expressed temporarily, called a transient transfection.
[32]
[33]
DNA coding for a protein of interest is now inside a cell, and the
protein
can now be expressed. A variety of systems, such as inducible promoters and specific cell-signaling factors, are available to help express the protein of interest at high levels. Large quantities of a protein can then be extracted from the bacterial or eukaryotic cell. The protein can be tested for enzymatic activity under a variety of situations, the protein may be crystallized so its
tertiary structure
can be studied, or, in the pharmaceutical industry, the activity of new drugs against the protein can be studied.
[34]
Polymerase chain reaction
[
edit
]
Polymerase chain reaction (PCR) is an extremely versatile technique for copying DNA. In brief, PCR allows a specific
DNA sequence
to be copied or modified in predetermined ways. The reaction is extremely powerful and under perfect conditions could amplify one DNA molecule to become 1.07 billion molecules in less than two hours. PCR has many applications, including the study of gene expression, the detection of pathogenic microorganisms, the detection of genetic mutations, and the introduction of mutations to DNA.
[35]
The PCR technique can be used to introduce
restriction enzyme sites
to ends of DNA molecules, or to mutate particular bases of DNA, the latter is a method referred to as
site-directed mutagenesis
. PCR can also be used to determine whether a particular DNA fragment is found in a
cDNA library
. PCR has many variations, like reverse transcription PCR (
RT-PCR
) for amplification of RNA, and, more recently,
quantitative PCR
which allow for quantitative measurement of DNA or RNA molecules.
[36]
[37]
Two percent
agarose gel
in
borate buffer cast
in a gel tray
Gel electrophoresis
[
edit
]
SDS-PAGE
Gel electrophoresis is a technique which separates molecules by their size using an agarose or polyacrylamide gel.
[38]
This technique is one of the principal tools of molecular biology. The basic principle is that DNA fragments can be separated by applying an electric current across the gel - because the DNA backbone contains negatively charged phosphate groups, the DNA will migrate through the agarose gel towards the positive end of the current.
[38]
Proteins can also be separated on the basis of size using an
SDS-PAGE
gel, or on the basis of size and their
electric charge
by using what is known as a
2D gel electrophoresis
.
[39]
Proteins stained on a PAGE gel using Coomassie blue dye
The Bradford protein assay
[
edit
]
The
Bradford assay
is a molecular biology technique which enables the fast, accurate quantitation of protein molecules utilizing the unique properties of a dye called
Coomassie Brilliant Blue
G-250.
[40]
Coomassie Blue undergoes a visible color shift from reddish-brown to bright blue upon binding to protein.
[40]
In its unstable, cationic state, Coomassie Blue has a background wavelength of 465 nm and gives off a reddish-brown color.
[41]
When Coomassie Blue binds to protein in an acidic solution, the background wavelength shifts to 595 nm and the dye gives off a bright blue color.
[41]
Proteins in the assay bind Coomassie blue in about 2 minutes, and the protein-dye complex is stable for about an hour, although it is recommended that absorbance readings are taken within 5 to 20 minutes of reaction initiation.
[40]
The concentration of protein in the Bradford assay can then be measured using a visible light
spectrophotometer
, and therefore does not require extensive equipment.
[41]
This method was developed in 1975 by
Marion M. Bradford
, and has enabled significantly faster, more accurate protein quantitation compared to previous methods: the Lowry procedure and the biuret assay.
[40]
Unlike the previous methods, the Bradford assay is not susceptible to interference by several non-protein molecules, including ethanol, sodium chloride, and magnesium chloride.
[40]
However, it is susceptible to influence by strong alkaline buffering agents, such as
sodium dodecyl sulfate
(SDS).
[40]
Macromolecule blotting and probing
[
edit
]
The terms
northern
,
western
and
eastern
blotting are derived from what initially was a molecular biology joke that played on the term
Southern blotting
, after the technique described by
Edwin Southern
for the hybridisation of blotted DNA. Patricia Thomas, developer of the RNA blot which then became known as the
northern blot
, actually did not use the term.
[42]
Southern blotting
[
edit
]
Named after its inventor, biologist
Edwin Southern
, the Southern blot is a method for probing for the presence of a specific DNA sequence within a DNA sample. DNA samples before or after
restriction enzyme
(restriction endonuclease) digestion are separated by gel electrophoresis and then transferred to a membrane by blotting via
capillary action
. The membrane is then exposed to a labeled DNA probe that has a complement base sequence to the sequence on the DNA of interest.
[43]
Southern blotting is less commonly used in laboratory science due to the capacity of other techniques, such as
PCR
, to detect specific DNA sequences from DNA samples. These blots are still used for some applications, however, such as measuring
transgene
copy number in
transgenic mice
or in the engineering of
gene knockout
embryonic stem cell lines
.
[29]
Northern blotting
[
edit
]
Northern blot diagram
The northern blot is used to study the presence of specific RNA molecules as relative comparison among a set of different samples of RNA. It is essentially a combination of
denaturing RNA gel electrophoresis
, and a
blot
. In this process RNA is separated based on size and is then transferred to a membrane that is then probed with a labeled
complement
of a sequence of interest. The results may be visualized through a variety of ways depending on the label used; however, most result in the revelation of bands representing the sizes of the RNA detected in sample. The intensity of these bands is related to the amount of the target RNA in the samples analyzed. The procedure is commonly used to study when and how much gene expression is occurring by measuring how much of that RNA is present in different samples, assuming that no post-transcriptional regulation occurs and that the levels of mRNA reflect proportional levels of the corresponding protein being produced. It is one of the most basic tools for determining at what time, and under what conditions, certain genes are expressed in living tissues.
[44]
[45]
Western blotting
[
edit
]
A western blot is a technique by which specific proteins can be detected from a mixture of proteins.
[46]
Western blots can be used to determine the size of isolated proteins, as well as to quantify their expression.
[47]
In
western blotting
, proteins are first separated by size, in a thin gel sandwiched between two glass plates in a technique known as
SDS-PAGE
. The proteins in the gel are then transferred to a
polyvinylidene fluoride
(PVDF), nitrocellulose, nylon, or other support membrane. This membrane can then be probed with solutions of
antibodies
. Antibodies that specifically bind to the protein of interest can then be visualized by a variety of techniques, including colored products,
chemiluminescence
, or
autoradiography
. Often, the antibodies are labeled with enzymes. When a
chemiluminescent
substrate
is exposed to the
enzyme
it allows detection. Using western blotting techniques allows not only detection but also quantitative analysis. Analogous methods to western blotting can be used to directly stain specific proteins in live
cells
or
tissue
sections.
[46]
[48]
Eastern blotting
[
edit
]
The eastern blotting technique is used to detect
post-translational modification
of proteins. Proteins blotted on to the PVDF or nitrocellulose membrane are probed for modifications using specific substrates.
[49]
Microarrays
[
edit
]
A DNA microarray being printed
Hybridization of target to probe
A DNA microarray is a collection of spots attached to a solid support such as a
microscope slide
where each spot contains one or more single-stranded DNA
oligonucleotide
fragments. Arrays make it possible to put down large quantities of very small (100 micrometre diameter) spots on a single slide. Each spot has a DNA fragment molecule that is complementary to a single
DNA sequence
. A variation of this technique allows the
gene expression
of an organism at a particular stage in development to be qualified (
expression profiling
). In this technique the RNA in a tissue is isolated and converted to labeled
complementary DNA
(cDNA). This cDNA is then hybridized to the fragments on the array and visualization of the hybridization can be done. Since multiple arrays can be made with exactly the same position of fragments, they are particularly useful for comparing the gene expression of two different tissues, such as a healthy and cancerous tissue. Also, one can measure what genes are expressed and how that expression changes with time or with other factors.
There are many different ways to fabricate microarrays; the most common are silicon chips, microscope slides with spots of ~100 micrometre diameter, custom arrays, and arrays with larger spots on porous membranes (macroarrays). There can be anywhere from 100 spots to more than 10,000 on a given array. Arrays can also be made with molecules other than DNA.
[50]
[51]
[52]
[53]
Allele-specific oligonucleotide
[
edit
]
Allele-specific oligonucleotide (ASO) is a technique that allows detection of single base mutations without the need for PCR or gel electrophoresis. Short (20?25 nucleotides in length), labeled probes are exposed to the non-fragmented target DNA, hybridization occurs with high specificity due to the short length of the probes and even a single base change will hinder hybridization. The target DNA is then washed and the labeled probes that did not hybridize are removed. The target DNA is then analyzed for the presence of the probe via radioactivity or fluorescence. In this experiment, as in most molecular biology techniques, a control must be used to ensure successful experimentation.
[54]
[55]
In molecular biology, procedures and technologies are continually being developed and older technologies abandoned. For example, before the advent of DNA
gel electrophoresis
(
agarose
or
polyacrylamide
), the size of DNA molecules was typically determined by rate
sedimentation
in
sucrose gradients
, a slow and labor-intensive technique requiring expensive instrumentation; prior to sucrose gradients,
viscometry
was used. Aside from their historical interest, it is often worth knowing about older technology, as it is occasionally useful to solve another new problem for which the newer technique is inappropriate.
[56]
See also
[
edit
]
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[
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