Genes are made of DNA

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Today we are so familiar with the fact that DNA is the genetic material that it comes as quite a surprise to learn that this idea was considered ridiculous by most biologists until the 1940s and that experimental proof that human genes are made of DNA was not obtained until the 1970s. Why did it take so long to establish this fundamental fact of genetics?

At first, it was thought that genes might be made of protein

The first speculations about the chemical nature of genes were prompted by the discovery in the very early years of the twentieth century that genes are contained
in chromosomes. Cytochemistry, in which cells are examined under the microscope after staining with dyes that bind specifically to just one type of biochemical, showed that chromosomes are made of DNA and protein, in roughly equal amounts. One or the other must, therefore, be the genetic material.In deciding whether it was protein or DNA, biologists considered the properties of genes and how these properties might be provided for by the two types of compound. The most fundamental requirement of the genetic material is that it be able to exist in an almost
In deciding whether it was protein or DNA, biologists considered the properties of genes and how these properties might be provided for by the two types of compound. The most fundamental requirement of the genetic material is that it be able to exist in an almost
infinite variety of forms. Each cell contains a large number of genes, several thousand in the simplest bacteria, and tens of thousands in higher organisms. Each gene specifies a different biological characteristic, and each presumably has a different structure.
The genetic material must, therefore, have a great deal of chemical variability.This requirement appeared not to be satisfied by DNA,
This requirement appeared not to be satisfied by DNA because in the early part of the twentieth century it was thought that all DNA molecules were the same. On the other hand, it was known, correctly, that proteins are highly variable polymeric molecules, each
one made up of a different combination of 20 chemically distinct amino acids. There are many different proteins, distinct from one another by virtue of their different amino acid sequences. Proteins, therefore, possess the variability that would be required by the
genetic material. Not surprisingly, biologists during the first half of the twentieth century concluded that genes were made of protein and looked on the DNA component of chromosomes as much less important—perhaps a structural material, needed to hold
the protein “genes” together.

Two experiments suggested that genes might be made of DNA

The errors regarding DNA structure lingered on, but by the late 1930s, it had become accepted that DNA, like protein, has immense variability. The notion that
protein was the genetic material initially remained strong but was eventually overturned by the results of two experiments.
The first of these was carried out by Oswald Avery, Colin MacLeod, and Maclyn McCarty, of Columbia University, New York. They studied what researchers of the time were calling the transforming principle. They prepared an extract from dead cells of Streptococcus pneumoniae, a bacterium that causes pneumonia. Something in the extract was known to
transform a harmless strain of S. pneumoniae into one capable of causing the disease. This transforming principle must, therefore, contain genes that provide the bacteria with the biological characteristics they need to cause pneumonia. Avery and his colleagues
showed in 1944 that the active component of the extract, the transforming principle, is DNA (Figure 1).

gene 1
figure 1 Avery and his colleagues treated extracts containing the transforming principle with a protease enzyme, which specifically degrades protein, with a ribonuclease, which breaks down RNA, and with a deoxyribonuclease, which degrades DNA. The protease and the ribonuclease had no effect on the ability of the extract to transform harmless S. pneumoniae bacteria. The deoxyribonuclease, on the other hand, inactivated the transforming principle. The active component of the transforming principle must, therefore, be DNA.

The second experiment was performed in 1952 by Alfred Hershey and Martha Chase, at Cold Spring Harbor, New York. They showed that when a bacterium is infected with a virus, the DNA of the virus enters the cell, but most of the virus protein stays outside (Figure 2). This was a vital observation because, during the infection cycle, the genes of the infecting viruses are used to direct synthesis of new viruses, and this synthesis occurs within the bacterial cells. If it is the DNA of the infecting viruses that enters the cells, then it follows that the virus genes must be made of DNA. Hershey and Chase also showed that
the new viruses that are produced contain DNA, but only small amounts of protein, from the original infecting viruses. In other words, the new viruses inherit DNA but not protein from their parents.

gene 2
figure 2. The Hershey-Chase experiment showed that the genes of T2 bacteriophage, a type of virus that infects E. coli, are made of DNA. Hershey and Chase Knew that T2 bacteriophage was made of DNA and protein. We now know that the DNA contained a protein “head” which is attached to a “body” and “legs” also made of protein. Hershey and Chase added some T2 bacteriophage to a culture of E.coli bacteria, and then waited a few minutes to allow the viruses to inject their genes into the cells. They then agaitated the culture in a blender in order to detach the empty virus particles from the surfaces of the bacteria. The culture was then centrifuged, which collects the bacteria plus virus genes as a pellet at the bottom of the tube, but leaves the empty virus particles in suspension. Hershey and Chase found that the bacterial pellet contained most of the viral DNA, but only 20% of the viral protein. Hershey and Chase also allowed some of the bacteria to complete their infection cycles. The new viruses that were produced. inherited 50% of the DNA from the original T2 bacteriophages, but only 1% of the protein.

The double helix convinced biologists that genes are made of DNA

Although from our perspective the Avery and the Hershey–Chase experiments provided the key results to tell us that genes are made of DNA, biologists at the time were not so easily convinced. Both experiments had limitations that enabled skeptics to argue
that protein could still be the genetic material. For example, there were worries about the specificity of the deoxyribonuclease enzyme that Avery used to inactivate the transforming principle. This result, a central part of the evidence that the transforming
principle is DNA, would be invalid if the enzyme contained trace amounts of a contaminating protease and so was also able to degrade protein. The Hershey–Chase experiment is less open to criticism,
The Hershey–Chase experiment is less open to criticism, but Hershey and Chase did not believe that it proved that genes are made of DNA. In the paper describing their results, they state, “The chemical identification of the genetic part [of the virus] must wait, however, until some questions … have been answered.”Whether these two experiments actually proved that
Whether these two experiments actually proved that genes are made of DNA is not really important. They made biologists much more receptive to the notion that DNA might be the genetic material. This meant that when the double-helix structure of DNA was discovered by Watson and Crick in 1953, revealing how genes can replicate, the scientific world immediately accepted that genes really are made of DNA.

It was not proved that human genes are made of DNA until cloning was invented

If we wish to apply the most rigorous scientific principles, then we might argue that the Avery experiment shows that bacterial genes are made of DNA, and the Hershey–Chase experiment does the same for virus genes, but neither tells us anything about the genes
of higher organisms such as humans.
It was not until 1979 that an experiment was carried out that showed that human genes are made of DNA. David Goeddel, working for the biotechnology company Genentech, used DNA cloning to transfer the gene for somatotrophin, one of the human growth hormones, into Escherichia coli. The bacteria acquired the ability to make somatotrophin, showing that the DNA that had been transferred did indeed contain the human gene. The purpose of this experiment was to develop a means of using bacteria to produce the large amounts of somatotrophin needed for its clinical use in the treatment of growth defects, and it is
rightly looked on as one of the major breakthroughs in the development of the biotechnology industry. The fact that it also finally laid to rest the question about
the chemical nature of the genetic material, first asked some 75 years earlier, went unnoticed.

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