The post-World War I Spanish influenza pandemic influenced Frederick Griffith to study the epidemiology and pathology of bacterial pneumonia in order to attempt creating a successful vaccine. Hence, he carried out experiments, where he injected mice with strains of virulent and avirulent Streptococcus pneumoniae. The experiment he reported in 1928, gave the first description of the phenomenon of transformation, where one bacterial strain could change into the other strain, and this activity was linked to an unidentified element called the transforming factor or transforming principle. Oswald T. Avery, an American pneumococcal researcher, speculated that Griffith's experiment lacked appropriate control. However, subsequent, similar experiments carried out in Avery's laboratory confirmed Griffith's discovery. The experiments conducted later by Avery, MacLeod, and McCarty, and by Hershey and Chase proved that the transforming factor was DNA and elucidated its exact nature. Thereby, establishing the central role of DNA in inheritance. For his experiments, Griffith used two strains of Streptococcus pneumoniae that affected mice - type III S (smooth) and type II R (rough). The type III S form has a smooth appearance due to the presence of a polysaccharide layering over the peptidoglycan cell wall of the bacterial cell. This extra coating helps the cell in evading the phagocytosis carried out by the immune cells of the host; hence, allowing the strain to proliferate and become virulent. In contrast, the type II R form lacks this coating, and hence, has a rough appearance. The absence of the polysaccharide layer leads to its efficient elimination by the host's immune cells rendering the strain avirulent. While injecting the mice with these bacteria, Griffith devised four sets of inoculation that are as follows: When the mice were inoculated, the bacterial virulence was exhibited, causing pneumonia, and this eventually led to the death of the mice. On examining the blood of the deceased mice, progeny of the inoculated cells were obtained. When injected into the mice, the bacterial cells were successfully eliminated by the immune system, and hence, the mice lived. The blood showed no presence of the inoculated cells. When the virulent strain was rendered avirulent by heating and killing it (heat-killed), and then injected into the mice, the strain did not show virulence, and was eliminated by the host's immune system; hence, the mice survived. Their blood showed no presence of the inoculated cells. Injecting the mice with a combination of equal number of cells of type II R strain and heat-killed type III S strain, caused pneumonia which progressed till the mice died. The bacterial cells isolated from the blood of these mice showed the presence of live type III S bacterial cells. This indicated that the live R strain had assimilated and incorporated the virulent element from the heat-killed S strain in order to transform itself into the virulent S strain. Based on this observation, Griffith concluded that a transforming element from the heat-killed strain was accountable for the transformation of the avirulent strain into the virulent strain. Successive experiments carried out in 1944 by Oswald Avery, Colin MacLeod, and Maclyn McCarty, proved that the element taken up by the harmless strain was genetic in nature. Transformation is a stable genetic change brought about by the uptake of naked DNA, and the state of being able to take up exogenous DNA is called competence. They occur in two forms―natural and artificial. Only 1% of the bacterial species is capable of taking up DNA. Bacteria also exchange genetic material through a process called horizontal gene transfer, where bacterial cells conjugate and form a bridge via which the genetic material is transferred from one cell to another. A few bacterial species also release their DNA via exocytosis on their death, and this DNA is later taken up by the bacterial cells present in the vicinity. While transformation can occur between various bacterial species, it is most efficient when occurring between closely related species. These cells possess specific genes that code for natural competence allowing them to transport the DNA across the cellular membrane and into the cell. This transport involves the proteins associated with the type IV pili and type II secretion system as well as the DNA translocase complex at the cytoplasmic membrane. This mechanism differs slightly due to the difference in the structure of the cell membranes of the bacteria. Bacteria are broadly classified into two types based on this difference - Gram-negative and Gram-positive. The general outline is more or less similar. The presence of exogenous DNA is detected by the cell and natural competence is induced, then the foreign DNA binds to a DNA receptor on the surface of these competent cells. This receptor binding allows the activation of the DNA translocase system that allows the passing of DNA into the cell via the cell membrane. During this process, one strand of the DNA is degraded by the action of nucleases. The translocated single strand is then incorporated into the bacterial genome via the help of a RecA-dependent process. Gram-negative bacteria show the presence of an extra membrane, hence, for DNA to be taken up, a channel is formed on the outer membrane by secretins. The uptake of a DNA fragment is generally not specific to its sequence; however, in some bacterial species, it has been seen that the presence of certain DNA sequences facilitate and enhance efficient uptake of the genetic material. This concept and technique has seen varied applications in the field of molecular biology with respect to expression studies, gene knockout studies, and cloning experiments. It is also used in the production of genetically modified organisms.