The history of biology is filled with incidents in which research on one specific topic has contributed richly to another, apparently unrelated area. Such a case is the work of Frederick Griffith, an English physician whose attempts to prevent the disease pneumonia led to the identification of the material in cells that contains genetic information – the information that determines an organism's characteristic structure. In the 1920s, Griffith was studying the bacterium Streptococcus pneumoniae, or pneumococcus, one of the organisms that cause pneumonia in humans. He was trying to develop a vaccine against this devastating illness. He was working with two strains of the bacteria pneumococcus. A bacterial strain is a population of cells descended from a single parent cell; strains differ in one or more inherited characteristics. Griffith's strains were designated S and R because, when grown in the laboratory, one produced shiny, smooth (S) colonies or groups of bacteria, and the other produced colonies that look rough (R). When the S strain was injected into mice, the mice became diseased. When the R strain was injected, the mice did not become diseased. Bacteria of the S strain are virulent (able to cause disease) because they are surrounded by a protective jelly-like coating that prevents the mouse's immune defense mechanisms from destroying the bacteria before they can multiply. The R strain lacks this coating. With the hope of developing a vaccine against pneumonia, Griffith injected some mice with heat-killed S pneumococci. These heat-killed bacteria did not produce infection. Griffith assumed the mice would produce antibodies to the bacteria that would allow them to fight the virulent form if they were exposed to it. However, when Griffith inoculated other mice with a mixture of living R bacteria and heat-killed S bacteria, to his astonishment, the mice became ill with pneumonia. When he examined blood from these mice, he found it full of living bacteria – many with characteristics of the virulent S strain. Griffith concluded that, in the presence of the dead S pneumococci, some of the living R pneumococci had been transformed into virulent S-strain organisms. Did this transformation of the bacteria depend on something the mouse did to the bacteria? No. It was shown that simply putting living R and heat-killed S bacteria together in a test tube yielded the same transformation. Next it was discovered that a cell-free extract of heat-killed S cells also transformed R cells. (A cell-free extract contains all the contents of cells, but no intact cells.) This result demonstrated that some substance – called at the time a chemical transforming principle – from the extract of S pneumococci could cause a heritable change (a change that could be passed on to future generations) in the affected R cells. From these observations, some scientists concluded that this transforming material carried heritable information, and thus was the genetic material that scientists had been searching for. The identification of the transforming material was a crucial step in the history of biology, accomplished over a period of several years by Oswald Avery and his colleagues at what is now Rockefeller University. They treated samples of the transforming extract in a variety of ways to destroy different types of substances – proteins, nucleic acids, carbohydrates, and lipids – and tested the treated samples to see if they had retained transforming activity. The answer was always the same: If the DNA (deoxyribonucleic acid) in the extract was destroyed, transforming activity was lost; everything else could be eliminated without removing the transforming ability of the extract. As a final step, Avery, with Colin MacLeod and Maclyn McCarty, isolated virtually pure DNA from a sample of pneumococcal transforming extract and showed that it caused bacterial transformation. In retrospect, the work of Avery, MacLeod, and McCarty, published in 1944, was a milestone in establishing that DNA is the genetic material. However, at the time, it had little impact on scientists' view about the physical basis of inheritance. The genetic material had to encode all the information needed to specify an organism, and the chemical complexity and diversity of proteins were known to be impressive. So during the first half of the twentieth century, the hereditary material was generally assumed to be a protein. Nucleic acids, by contrast, were known to have only a few components and seemed too simple to carry such complex information.