Fraenkel-Conrat H. and Williams R.C. (1955). Reconstitution of active tobacco mosaic virus from its inactive protein and nucleic acid components. PNAS USA 41: 690-698.
This week's citation classic is probably the coolest experiment you've never heard of. Fraenkel-Conrat and Williams literally took a virus apart, separated its components, then put it back together again. Granted TMV is a relatively simple virus, consisting of 2130 molecules of coat protein and one molecule of genomic RNA 6390 bases long. Nonetheless, this experiment caused quite a buzz in the scientific world.
Gunther Stent wrote to Sidney Brenner, "Frankel-Conrat seems to have done the biggest thing with TMV since Stanley crystalized it. He can add soluble TMV protein to soluble TMV RNA, aggregate the whole mess into rods of which 0.1% are infective!!! Naturally, you don't believe it--nor did I or anyone else, but unless he has made up the whole thing it seems that it must be true. You can't beat that for laughs, can you buddy?"
It was true.
First Fraenkel-Conrat and Williams treated TMV with a mild acid. This treatment eliminated the charges that held the virus together. Then they separated and purified the protein. In parallel, they treated TMV with a detergent to strip away the protein, and recovered the RNA. After these steps, the viruses were no longer infective. Then they mixed the whole mess together again, and lo and behold! Reconstituted viruses!
The following year, Fraenkel-Conrat hybridized the viruses by mixing protein from one strain with RNA from another. Not only did he get viable viruses, he also was able to show that progeny viruses always had the same type of protein coats as the parent strain that donated the RNA. Thus proof that RNA was the genetic material for these viruses.
Photo of Tobacco Mosaic Virus from NIH.