DNA is considered the molecule of life and is now easily identified as a double helix.
However, figuring out its structure and how DNA works was not an easy task. And just a
little over 60 years ago, it was still a complete mystery. Then in 1953 came Watson and Crick
who discovered how the 6 billion base pairs that make up our genetic material is stored
in the cell: that DNA was actually a helix made of two strands. This DNA was passed on
from generation to generation as a double helix. Specific DNA bases (which we call A:
adenine, T: thymine, G: guanine, or C: cytosine) are found on both strands and pair with each
other in a conserved way: A pairs with T and G pairs with C. Our DNA is made up of these
4 bases in a variety of different orders that code for all of life! This is an amazing fact:
these 4 bases are the sole building blocks for our 6 BILLION bases genetic code, which
defines our identity as humans and as individuals, our height, hair color, disease susceptibility,
and much, much more. Discovering the structure of DNA was a very important first step to
understanding how this "simple" molecule controls all of life.
However, one important question lingered: when a cell divides, the daughter cell will
have the same DNA sequence as the parental cell. So how does this happen? How does one
cell produce a second cell with the same exact DNA sequence? In other words, how does DNA
replicate? This is a fundamental question that is the
basis of life: we all come from a single cell that will produce an entire organism with
trillions of cells that all have the exact same DNA sequence. And we are able to have
children that share our DNA because our eggs and sperm carry our DNA sequence. Understanding
how DNA replicates and how all of our cells can carry the same DNA sequence is the basis
for understanding development, inheritance, heritability and life. Understanding how DNA
replicates is understanding a fundamental truth, like gravity, or how the sun emits
energy. In 1953 the question lingered: how does DNA
replicate? There were a few theories (3 actually). One
of them was conservative replication where a DNA molecules would get copied and make
a second DNA molecules. The second was dispersive where the DNA molecule would be cut at various
parts, each of which would get copied and reattached to produce two DNA molecules. And
the third was semi-conservative where the two strands of DNA would separate and each
one would serve as a template to copy a second strand, thus producing two DNA molecules.
But which one was it? Many scientists did not believe that two DNA strands could separate
because of how strong a DNA molecule is, so they were skeptical of the semi-conservative
model. However, other scientists were skeptical that there could be a way to simply copy a
whole DNA molecule and thus did not believe the conservative model. The only way to solve
this was to create an experiment to tell the new DNA strand apart from the old one.
So two scientists, Matthew Meselson and Franklin Stahl, had an idea to design an experiment
that would be known as the "most beautiful experiment in biology". Their findings are
published in their article titled "The replication of DNA in Escherichia coli" published in May
1958 in the Proceedings of National Academy of Sciences. These scientists used bacteria
to answer the question of DNA replication since it could be easily grown in the laboratory.
They grew the cells in the presence of a specific type of nitrogen, which is naturally found
in DNA that would make the DNA very heavy. They used centrifugation, which can separate
things according to their weight. Initially, all of the DNA in the cell was heavy and was
at the bottom of the tube. Then they started growing these cells in the absence of the
heavy nitrogen. So all of the new DNA made in subsequent cell divisions would be lighter.
After one cell division, the DNA was half as heavy: so half of the DNA molecule contained
heavy nitrogen and the other half didn't. This is not in line with the conservative
DNA replication model, which would predict that one molecule would be all light and the
other all heavy. However, this was still in line with the semi-conservative or the dispersive
model. After two cell divisions, the DNA molecule was now either half heavy and half light or
entirely light. So this is now not in line with the dispersive model. Instead, this experiment
agrees with the semi-conservative DNA replication model: every cell gets one old DNA strand
and one new one. By discovering that two strands of DNA can
separate and provide the template for the production of two NEW DNA strands, Meselson
and Stahl revolutionized genetics. Scientists were very skeptical that this was even possible
but Meselson and Stahl proved it with a beautifully designed experiment. They also went on to
show that heating DNA can also cause the DNA strands to separate. This simple concept is
the basis for an important technique we frequently use in the laboratory called polymerase chain
reaction, which is used in genetic testing, forensics, and paternity tests. Meselson and
Stahl identified the fundamental process by which our DNA gets passed on from cell to
cell. This is the basis for inheritance and an essential part of our development from
a single cell to a complete organism that maintains the same DNA sequence in all of
its cells. This exciting finding opened up many new doors
and research avenues. Because DNA is the command center of the cell, we could now study how
DNA gives orders for the cell to follow. What controls the ability of DNA to make protein?
How does one cell know that it's a heart cell and another cell know it's a liver cell if
they all have the same DNA? Now DNA was real. DNA wasn't just a static double helix, it
was a molecule that was animated, it could replicate and make more of itself, it could
instruct a cell to behave a certain way. All of the secrets of biology were ready to be
answered. Today, we now understand many of these questions. We know that the process
of DNA replication is VERY complex with many proteins coming together to make this happen
as well as proofreading and repair mechanisms that make sure the DNA is properly copied.
We know a great deal about what instructs a cell to become a heart cell vs. a liver
cell even though they have the same DNA sequence. In fact, we can even produce a heart cell
from a skin cell. We know what controls cell division and how we can stop or accelerate
it. We know what sorts of things can cause mutations, or change the DNA sequence, and
we have the tools to understand how that influences cell behavior and fate.
It's amazing now to look back at this very fundamental finding: that DNA replicates in
a semi-conservative manner, and see how it has revolutionized biology and our appreciation
for DNA.