1989 Nobel Prize for Chemistry with Sidney

Thomas Cech shared the 1989 Nobel Prize for Chemistry with Sidney Altman (Enzymatic cleavage of RNA by RNA. Biosci. Rep. 10:317–337, 1990). That year we also published the lectures by the winners of the Physiology or Medicine prize: Harold E Varmus (Retroviruses and oncogenes I. Biosci. Rep. 10:413–430, 1990) and J Michael Bishop (Retroviruses and oncogenes II. Biosci. Rep. 10:473–491, 1990) and ever since James Sumner crystallized the enzyme urease some 80 years ago and showed it to be a protein, a finding that was followed by similar demonstrations with pepsin and other enzymes, it has been biochemical dogma that enzymes are proteins’. Not so any more. Cech’s work with a ciliated protozoan called Tetrahymena, and Altman’s studies with the bacterium Escherichia coli, changed all that. Cech was using Tetrahymena for a very good reason. The choice of organism, or particular type of cell, is often crucial to a cutting-edge break-through. Cech was interested in studying the transcription of ribosomal DNA (rDNA), that is, the copying of ribosomal genes into RNA. The reason for his choice of Tetrahymena was two-fold. First, the genes for ribosomal RNA (rRNA) are located not on the giant chromosomes of this organism that contain most of the DNA, but on small DNA molecules present in the nucleolus. Second, the ribosomal RNA genes are present not as single genes, but as some 10,000 amplified copies (as they are in other organisms). These factors make isolation of rDNA a somewhat simpler task. What Cech found was that in addition to producing high-molecular weight rRNA, the purified cell-free system that he was using formed also some lowmolecular weight rRNA. Cech decided—in an almost off-hand manner—to encourage one of his graduate students to examine the DNA sequences corresponding to this rRNA: ‘‘Driven more by curiosity than by any conviction that the results would be of central importance to our research goals . . .’’. What a difference between this approach and that of John Vane (‘‘I think I know how aspirin works’’) or James Black (‘‘I started . . . with a clear goal – I wanted to find a b-receptor antagonist’’) or Hartmut Michel (‘‘. . . I was convinced that it should be possible . . . to produce threedimensional crystals’’). It shows that great scientific discoveries arise by more than one route: all (all!) that is required, as Einstein pointed out, is an open mind. The graduate student (Art Zaug) followed Cech’s suggestion, and came up with a surprising result. A G (guanine) residue was present at the 5¢ end of the small RNA, whereas there was no corresponding residue (it would have been a C (cytosine) at the end of the corresponding DNA. Moreover the implication was that it had been added after any proteins of potential enzymatic activity had been removed. Could a covalent bond—between one nucleotide and another—be formed without the participation of an enzyme? The idea seemed so strange to Thomas Cech that he decided to do the crucial experiment on his own: ‘‘. . . it seemed incredibly naı̈ve and unrealistic to expect that simple mixing of a nucleotide with a phenol-extracted, proteinase-treated RNA could possibly result in formation of a covalent bond. I certainly didn’t want to be embarrassed in front of my graduate students and colleagues by the failure of such an experiment, so I did it very quietly’’. However, the experiment worked, and Cech had unequivocally shown that RNA possesses certain catalytic properties. Of such moments is great science made. Bioscience Reports, Vol. 24, Nos. 4/5, August/October 2004 ( 2005) DOI: 10.1007/s10540-005-2738-3