George Eugene Uhlenbeck (1900–1988)

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_N_AT_u_R_E_v_o_L_._3_36_z_zt_29_D_E_c_E_M_B_E_R_J9_s_s ______NEWS AND VIEWS ______7_1 7 derived (0. Uhlenbeck, University of Colorado, Boulder). Remarkably, only George Eugene Uhlenbeck (1900-1988) seven specific nucleotides of the ribozyme GEORGE UHLENBECK, who died on 31 Octo- discussed it with Pauli, who discouraged and six of the RNA substrate are absolutely ber, was primarily known as one of the him? Or did it consider that the subsequent required for activity. The simplicity of the originators of the notion of electron spin. work of these two candidates, although active site of these ribozymes makes This idea was the result of an intensive valuable, was not quite of Nobel class? them extremely attractive candidates for collaboration with S.A. Goudsmit, a colla- Neither argument sounds convincing. detailed structural analysis. boration encouraged and stimulated by Uhlenbeck's later work deals with Hepatitis delta virus (HDV), a circular Paul Ehrenfest, their professor at Leiden various topics. Together with Konopinsky, satellite RNA of hepatitis B virus, University. The idea of Uhlenbeck and he developed a somewhat different version increases the severity of viral hepatitis. Goudsmit was one of the two final touches of Fermi's theory of nuclear f)-decay, HDV RNA can undergo autocatalytic that were added during 1925 to the so- which revealed interesting insights, but cleavage and ligation in vitro in a manner called vector model of atomic structure, the was later abandoned. The main emphasis similar to plant viroid and satellite RNAs other being Pauli's exclusion principle. It of his work, however, is on statistical (D. Gottleib, Drexel University). How "' mechanics. With E. Beth, Uhlenbeck ever, the structure at the cleavage site ~ formulated the quantum mechanics of the does not resemble the hammerhead', § second virial coefficient (the second term in suggesting that there are undiscovered " a power expansion of the equation of state types of catalytic RNA structures waiting ~ for a non-ideal gas). And with B. Kahn to be defined. ~ who later, during the occupation of The Netherlands, fell victim to Nazi antisemitism Splicing reactions - he made considerable progress in the Whereas the processing reactions men theory of condensation. Uhlenbeck moved tioned above involve only cleavage of the to the United States before the outbreak of RNA substrates, splicing entails both World War II and during the war he cleavage and ligation. The essential headed the theoretical division of the similarities between three types of splic Massachusetts Institute of Technology ing reactions - group I intron self gave a clear-cut explanation of mysterious radiation laboratory, where he mainly splicing; group II intron self-splicing; and quantum numbers that arose in the analysis studied problems of noise. nuclear-pre-messenger RNA splicing of complex spectra. Two years later Pauli After the war he devoted more time to (c, d in the figure; see ref. 6) - were showed how the spin of the electron could teaching. A project to write a comprehen enumerated by T. Cech (University of be dealt with in non-relativistic quantum sive treatise on the foundations of statistical Colorado, Boulder). First, all are two mechanics; in the relativistic theory of mechanics was frustrated by the untimely step reactions, in which the 5' splice site is Dirac, the spin appears as a necessary con death of his collaborator T.H. Berlin, but cleaved in the first step and the 3' splice sequence of the formalism. And the notion he did publish two smaller volumes based site cleaved in the second. Second, all the of spin is not confined to the electron but is on lecture notes. He also wrote valuable cleavage-ligation reactions seem to occur a universal feature of particle physics. papers on the equation of state, brownian by transesterification mechanisms. Third, Why was this important work never motion and the kinetic theory of transport there are similarities in the conserved rewarded with a Nobel prize? Pauli received phenomena. Uhlenbeck was an outstand bases at the splice junctions, which when his for the exclusion principle in 1945; ing lecturer and his students, at Ann Arbor, mutated can lead to comparable effects. would it not have been logical to let a Nobel Utrecht and Rockefeller University will For example, 5' splice-site mutations can prize to Uhlenbeck and Goudsmit follow? remember him as a wise and benevolent result in activation of cryptic 5' splice sites Was the Nobel committee disturbed by counsellor. H.B.G. Casimir in group I introns and nuclear pre the fact that, completely unknown to H. B. G. Casimir, formerly Research Director of mRNAs. Conversely, mutation of the Uhlenbeck and Goudsmit, Ralph Kronig the Philips Company at Eindhoven, lives at De conserved guanosine at the 3' splice site had had the same idea before and had Zegge 7, 5591 IT Heeze, The Netherlands. abolishes 3' splice-site cleavage but not the first step of splicing for both group I as well as four small nuclear ribonucleo sity of California, San Francisco). These introns and nuclear pre-mRNAs. protein particles (snRNPs), termed U1, results implicate at least one other cis- or The various systems differ, however, U2, US and U4/U6. These pieces are trans-acting component in addition to with respect to the elements that determine assembled with the pre-mRNA into a yeast Ul snRNP in specifying the precise selection of the 5' splice site. For nuclear structure called the 'spliceosome' in which position of 5' splice-site cleavage. Selection pre-mRNAs, the intron sequences near the cleavage-ligation reactions occur. of the 3' splice site is potentially quite the 5' splice junction are required for The order of snRNP binding during complex, as at least two cis-acting ele determining the 5' splice site, whereas in assembly of the yeast spliceosome, repor ments (the branch point and 3' splice site) group I and group II introns, flanking ted by J. Abelson (California Institute of can play a role in the appropriate experi exon sequences have the principal role. Technology), turns out to be identical to mental conditions (A. Weiner, Yale Single-base substitutions in intron the mammalian pathway, although the University). The ability to reconstitute sequences flanking a nuclear pre-mRNA prerequisites may be subtly different. In snRNPs from their snRNA moieties and 5' splice site, for example, can decrease or yeast, for example, U1 snRNP binding protein components (our own work) abolish cleavage at that site (see refs 7 ,8), requires both the 5' splice site and branch should facilitate future studies on whereas the first six nucleotides of a group point, whereas in the mammalian system spliceosome assembly. II intron can be altered without affecting only the 5' splice site is required. In both The reaction pathways of group II the accuracy of 5' splice-site cleavage the mammalian and yeast systems, 5' intron self-splicing and nuclear pre (P. Perlman, Ohio State University). splice-site cleavage requires prior binding mRNA splicing are identical (d in the The most obvious difference between of UJ snRNP to the 5' splice site. But figure), strongly suggesting that the self-splicing and nuclear pre-mRNA splic aberrant splicing of 5' splice-site mutants collective RNA moieties of the snRNPs ing is that in the latter the catalyst must be is not completely corrected by compensa provide at least some (perhaps all) of the assembled from several parts. The pieces tory mutations in U 1 snRNA (M. Rosbash, catalytic function. Individual domains (splicing factors) include multiple proteins Brandeis University; C. Guthrie, Univer- of self-splicing group II introns, when