In 1910 he was hired by the British government to work for the Ministry of Health under Arthur Eastwood. The government spent money sparingly in times of expected war, so the laboratories Griffith worked in were primitive. However, his creativity and inquisitive mind allowed him to excel in his scientific exploration. One of his friends claimed that "he could do more with a kerosene tin and a primus stove than most men could do with a palace."
The famous experiment was done when Griffith was trying to make a vaccine to prevent pneumonia infections in the "Spanish flu" influenza pandemic after World War I, by using two strains of the Streptococcus pneumoniae bacterium. The smooth strain (S strain) had a polysaccharide capsule and was virulent when injected, causing pneumonia and killing mice in a day or two. The capsule is a slimy layer on the cells' surface that allows the bacteria to resist the human immune system. The rough strain (R strain) did not cause pneumonia when injected into mice (it was avirulent), since it lacked a capsule. When the virulent S strain was heated to kill it, and then injected into mice, it produced no ill effects. However, when dead S strain mixed with live R strain was injected into the mouse, the R/S mouse died.
After isolating bacteria from the blood of the R/S mice, Griffith discovered that the previously avirulent R bacteria had acquired capsules. The bacteria isolated from the mice infected with the mixture of live R and heat-killed S were now all of the S strain, and maintained this phenotype over many generations. Griffith hypothesized that some "transforming principle" from the heat-killed S strain converted the R strain into the virulent S strain.
Griffith was killed at work in his laboratory in 1941, along with longtime friend and bacteriologist William M. Scott in London as a result of an air raid in the London Blitz. It wasn't until several years later that Griffith's "transforming principle" was identified as DNA by Oswald Theodore Avery, along with coworkers Colin MacLeod and Maclyn McCarty, in 1944.
He was the uncle of John Stanley Griffith, a winner of the Royal Society's Faraday Medal.