SCIENCE & TECHNOLOGY
ANNIVERSARY OF RNA DOUBLE-HELIX DISCOVERY Structure was created in the lab by carrying out the first nucleic acid hybridization reaction STU BORMAN, C&EN WASHINGTON find out whether RNA could form a double anniversary of the discovery helix. In the classic paper on the structure of the structure of the D N A of double-helical DNA, Watson and Crick had pointed out that RNA could not form a double helix by biologistsJames double helix like the one they had described D. Watson and Francis H. C. for DNA because the 2' hydroxyl on each Crick was grandly celebrated. Last month marked a less celebrated an- RNA nucleotide would interfere with such a structure. niversary: 50 years since the discovery of the RNA double helix. It was in theJuly 20, "So if RNA couldn't form that type of 1956 Journal'of'the American Chemical Societydouble helix, could it form any double he{78,3548) that Alexander Rich and David R. lix?" Rich says he speculated at the time. In 1954, Rich and Watson, then postdoctoral fellows at California Institute of Technology, tried to address this question by studying X-ray diffraction patterns of RNA fibers. "We published a couple of papers about
A
FEW YEARS BACK, THE 5OTH
X-RAY MAN Rich in his lab at NIH in 1956. "I am shown adjusting an X-ray fiber camera mounted on an X-ray generator," he says. "This was the type of camera that produced the first diffraction pattern of an RNA double helix." this, but they were inconclusive," Rich says. A hint of an RNA double helix was seen soon thereafter. In 1955, an enzyme that catalyzes the synthesis of polyribonucleo-
a:
Experts in Fluorochemical Analysis ON THE LAWN Rich (center) in 1954, when he was a Pauling postdoc at Caltech. At the time, he was working with Watson (left) to try to determine whether RNA could form a double helix. Also shown is Rich's wife, Jane. Davies of the National Institute of Mental Health, in Bethesda, Md., reported for the first time that RNA could form a double helix. Rich is now professor of biophysics at Massachusetts Institute of Technology, and Davies is chief of the molecular structure section in the laboratory of molecular biology at the National Institute of Diabetes & Digestive & Kidney Diseases, in Bethesda. In fact, it's a double anniversary. It's also 50 years since the discovery of the nucleic acid hybridization reaction—the reaction of two unstructured polynucleotides to form a double helix based on the specificity of hydrogen bonding between the monomer units. Where was that reported? It's the same work, reported in the same short paper. At the time the paper was published, Rich had been working for three years to
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ficity," Rich says. Therefore, chemists were very skeptical about his findings at the time, he says. "PolyA and polyU were each very large macromolecules, and they were highly negatively charged. Therefore, why would they combine? Because they were so long, polymer chemists felt they would probably be entangled and would never be able to sort themselves out." Rich himself was surprised about the RNA double-helix discovery. Within a couple ofweeks ofhaving sent his paper toJ ACS for review, Rich wrote about it to his postdoctoral mentor, Caltech chemistry professor Linus Pauling. In the letRNA TIE CLUB Crick (from left)p Rich, ter, Rich wrote that the hybridizachemist Leslie E. Orgel, and Watson relax in tion reaction was a most remarkable Crick's house, in Cambridge, England, in 1955 thing and that it was completely "Three of us are wearing RNA Tie Club ties," reproducible. The letter "is filled Rich says. "The RNA Tie Club was started by with astonishment," he says. physicist George Gamow, who was interested The discoveries of the RNA in RNA coding for protein synthesis. The club double helix and nucleic acid hyhad 20 members, one for each amino acid." bridization paved the way for the tides was discovered by enzvmolqgist Severo elucidation of many other phenomena, Ochoa of New York University, enabling including the polymerase chain reaction, researchers to make RNA polynucleotides antisense nucleic acids, and RNA intersuch as polyriboadenylic acid (polyA) and ference. The discoveries represented "a polyribouridylic acid (polyU). In March paradigm shift in the way people thought 1956, NYU biochemistry professor Robert about nucleic acids," Rich says. "They beC. Warner obtained polyA and polyU made gan to think of them as being more mobile that way, mixed them together, and studied and more reactive than they had thought the mixture spectroscopically. The study up to then." suggested that polyA and polyU were interPrior to the 1956 discoveries, Rich says, acting with each other in the mixture, but the interpretation wasn't clear. At about the same time, Rich, then at the National Institutes of \ Health, was also study- " ing RNA polynucleotides. "We discovered that polyA and polyU alone didn't have any he and colleagues "talked a lot particular structure," about RNA, but nobody, inRich says. "But when cluding myself, suggested, *Why we mixed the two to- Rich don't you mix together polyA and gether, to our astonish- ~~ ~ ~~~ ment, I could draw out afiber,and there was polyU?'' I think that speaks to the fact that a diffraction pattern of a double helix, quite it wasn't at all obvious that that could work. different from the DNA one." When I asked Francis Crick about this a few That was the discovery of the RNA dou- years ago, he said, Maybe it's because we all ble helix. It was also the discovery of nucleic felt it would require an enzyme.' Prior to the acid hybridization. But the reaction wasn't discovery, people had no idea that hybridcalled "hybridization" until later, because in ization could occur by itself." So what induced Rich to mix the two to1956 that term had not yet been coined. "There had never been another reaction gether? "Well, I tell you, I've asked my colbetween polymers in which two different leagues and searched through my memory, monomer units combined with great speci- and I don't actually know," Rich says. •
The discoveries represented "a paradigm shift in the way people thought about nucleic acids."
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