A Selected Chronological Bibliography of Biology and Medicine


Part 7B


1992 — 2021



Compiled by James Southworth Steen, Ph.D.

Delta State University


Dedicated to my loving family


This document celebrates those secondary authors and laboratory technicians without whom most of this great labor of discovery would have proved impossible.


Please forward any editorial comments to: James S. Steen, Ph.D., Professor Emeritus, DSU Box 3262, Cleveland, MS 38733. jsteen08@bellsouth.net



“One reason why medical history is not much taught in medical schools is that so much of it is an embarrassment.” Lewis Thomas (1244).


Edmond H. Fischer (US) and Edwin Gerhard Krebs (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism.


Eric Betzig (US) and Jay K. Trautman (US) produced a near-field super-resolution image of a biological sample for the first time (103). Note: Near-field scanning optical microscopy overcomes the diffraction limit by removing the lenses and thus eliminates the need for focusing. Instead, the light passes through a small aperture that is positioned close to the sample (in the near-field zone), such that light cannot substantially diffract. The lateral resolution, determined by the diameter of the aperture, is typically 20-120 nm.


Kenneth R. Ludwig (US), Kathleen R. Simmons (US), Barney J. Szabo (US), Isaac J. Winograd (US), Jurate M. Landwehr (US), Alan C. Riggs (US), and Ray J. Hoffman (US) were among the first to use mass spectrometric uranium series dating (MS/U-series) of calcite. The technique is typically applied to calcite or tooth materials intercalated into archaeological or paleoanthropological sites and works well for samples between 1,000 and 400,000 year s old (793).


Uwe Maskos (GB) and Edwin Mellor Southern (GB) described a novel linker for the synthesis of oligonucleotides on a glass support. Oligonucleotides synthesized on the support remain tethered to the support after ammonia treatment and are shown to take part in sequence specific hybridization reactions. These hybridizations were carried out with oligonucleotides synthesized on 'ballotini' solid sphere glass beads and microscope slides. The linker has a hexaethylene glycol spacer, bound to the glass via a glycidoxypropyl silane, terminating in a primary hydroxyl group that serves as starting point for automated or manual oligonucleotide synthesis (825).


Douglas C. Prasher (US), Virginia K. Eckenrode (US), Franklyn G. Pendergast (US), and Milton J. Cormier (US) described the cloning and sequencing of both cDNA and genomic clones of green fluorescent protein (GFP) from the cnidarian, Aequorea victoria. The gfp gene encoded by the lambda GFP2 genomic clone is comprised of at least three exons spread over 2.6 kb (1013).

Martin Chalfie (US), Yuan Tu (US), Ghia Euskirchen (US), William W. Ward (US), and Douglas C. Prather (US) showed that a complementary DNA for the Aequorea victoria green fluorescent protein (GFP) produces a fluorescent product when expressed in prokaryotic (Escherichia coli) or eukaryotic (Caenorhabditis elegans) cells. Because exogenous substrates and cofactors are not required for this fluorescence, GFP expression can be used to monitor gene expression and protein localization in living organisms (188).


Mark D. Adams (US), Mark Dubnick (US), Anthony R. Kerlavage (US), Ruben Moreno (US), Jenny M. Kelley (US), Teresa R. Utterback (US), James W. Nagle (US), Chris Fields (US), and John Craig Venter (US) partially sequenced 2,672 new, independent cDNA clones isolated from four human brain cDNA libraries to generate 2,375 expressed sequence tags to nuclear-encoded genes (13)


Kimiko Murakami-Murofushi (JP), Masaki Shioda (JP), Kazuhiko Kaji (JP), Shonen Yoshida (JP), and Hiromu A. Murofushi (JP) were the first to describe the parent compound, cyclic phosphatidic acid, which they found in myxoamoebae of a true slime mold, Physarum polycephalum (891).

Tetsuyuki Kobayashi (JP), Rieko Tanaka-Ishii (JP), Ryo Taguchi (JP), Hiroh Ikezawa (JP), and Kimiko Murakami-Murofushi (JP) found cyclic phosphatidic acid later in the human serum albumin fraction where it may have biological activities related to the inhibition of cell proliferation (675).


Gifford H. Miller (US), Peter B. Beaumont (ZA), Anthony J.T. Jull (CA), and Beverly J. Johnson (US) discovered that degradation of polypeptides, including hydrolysis to smaller peptide fragments and eventual release of free amino acids, decomposition, and racemization and epimerization occur at regular, predictable rates dependent on ambient temperature. This provided a method of dating materials of biological origin (858). The method is accurate from 500 to 300,000 years ago.

Gifford H. Miller (US), John W. Magee (AU), Beverly J. Johnson (US), Marilyn L. Fogel (US), Nigel A. Spooner (AU), Malcolm T. McCulloch (AU), and Linda K. Ayliffe (AU) used this dating technique to determine that the large flightless bird Genyornis newtoni became extinct in the late Pleistocene, some 50,00 years ago. They reasoned that extinction was the result of human impact (859).


Seunghyon Choe (Korean-US), Melanie J. Bennett (US), Gary Fujii (US), Paul M.G. Curmi (AU), Katherine A. Kantardjieff (US), R. John Collier (US), and David Eisenberg (US) solved the three dimensional structure of diphtheria toxin (210).


J. Fernando Bazan (US) determined the tertiary structure of interleukin-2 (IL-2) (86).


Yan Luo (US), Hiroshi Fujii (US), Thomas Gerster (CH), and Robert Gayle Roeder (US) demonstrated that coactivators can be ubiquitous, monitoring many genes in a variety of cells, or specific to one particular cell type. They introduced the concept of cell specificity after they demonstrated that the coactivator OCA-B, the first cell-specific coactivator, discovered by Roeder in 1992, is unique to immune system B cells



Paul S. Meltzer (US), Xin-Yuan Guan (US), Ann Burgess (US), and Jeffrey M. Trent (US) used microdissection and in vitro amplification of specific chromosomal regions, followed by labelling for fluorescent in situ hybridization (FISH) to normal metaphase chromosomes (Micro-FISH). These Micro-FISH probes could successfully determine the derivation of chromosome segments unidentifiable by standard chromosome banding analysis (854).


Anne Kallioniemi (FI), Olli P. Kallioniemi (FI), Damir Sudar (US), Denis Rutovitz (GB), Joe W. Gray (US), Frederic Waldman (US), and Dan Pinkel (US) introduced "comparative genome hybridization" (CGH). This is a form of reverse chromosome painting used to detect chromosome deletions and duplications from a patient's total genomic DNA rather than from his or her karyotype. The patient's DNA is labeled in one color and mixed with control DNA labeled in another color. Both are mixed and hybridized to normal metaphases and the ratio of the two colors determined along the length of each chromosome. Duplications are recognized by the predominance of the subject DNA color, whereas deletions are revealed by the predominance of the control DNA color. CGH has been useful both in screening for small constitutional chromosome aberrations in patients and in detecting aberrations in cancer cells (630).

Sabina Solinas-Toldo (DE), Stefan Lampel (DE), Stephan Stilgenbauer (DE), Jeremy E.  Nickolenko (DE), Axel Benner (DE), Hartmut Dohner (DE), Thomas Cremer (DE), Peter Lichter (DE) developed a protocol that allows comparative genomic hybridization (CGH) to chips consisting of glass slides with immobilized target DNAs arrayed in small spots. High-copy-number amplifications contained in tumor cells were rapidly scored by use of target DNAs as small as a cosmid. Low-copy-number gains and losses were identified reliably by their ratios by use of chromosome-specific DNA libraries or genomic fragments as small as 75 kb cloned in PI or PAC vectors as targets, thus greatly improving the resolution achievable by chromosomal CGH (1178).

Donald Pinkel (US), Richard Segraves (US), Damir Sudar (US), Steven Clark (US), Ian Poole (US), David Kowbel (US), Colin Collins (US), Wen-Lin Kuo (US), Chira Chen (US), Ye Zhai (US), Shanaz H. Dairkee (US), Britt-marie Ljung (US), Joe W. Gray (US), Donna G. Albertson (US) developed a high resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays (1002). Note: Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes.


Hĺkan Telenius (CA), Bruce A.J. Ponder (GB), Alan Tunnacliffe (GB), Adčle H. Pelmear (GB), Nigel P. Carter (GB), Malcolm Andrew Ferguson-Smith (GB), Annemarie Behmel (AT), Magnus Nordenskjöld (SE), and Roswitha Pfragner (AT) showed that flow sorting of aberrant chromosomes and chromosome painting can be used as a rapid aid to cytogenetic analysis, particularly in cases of difficult karyotypes, such as tumors. Furthermore, the DOP-PCR technique they described will have applications to other areas of genome analysis, such as cloning of new markers; its design will allow a general and representative amplification to occur from any starting DNA in any species (1240).


 Karin G. Au (US), Katherine Welsh (US), and Paul L. Modrich (US) revealed the events involved in the initiation of the E. coli methyl-directed mismatch repair pathway. Using purified Mut proteins, they found that MutL, MutS, and ATP activate the MutH- associated endonuclease, that activation was dependent on ATP hydrolysis, and that the incised d(GATC) sequence could lie either 3' or 5' to the mismatch on the unmethylated strand. From these results they concluded that “MutH activation represents the initiation stage of methyl-directed repair and that interaction of a mismatch and a d(GATC) site is provoked by MutS binding to a mispair, with subsequent ATP-dependent translocation of one or more Mut proteins along the helix leading to cleavage at a d(GATC) sequence on either side of the mismatch" (53).

Michelle Grilley (US), Jack Griffith (US), and Paul L. Modrich (US) suggested that the methyl-directed mismatch repair system is capable of bidirectional excision. To this end they described the nature of the excision tracts produced by the bidirectional repair system in E. coli (460).

Woei-horng Fang (US) and Paul L. Modrich (US) found that the human mismatch repair system not only displays a mismatch specificity similar to that of the bacterial reaction but also shares a bidirectional excision mechanism with properties that are essentially identical with those described for the bacterial pathway (332). This reaction is defective in tumors from patients with hereditary nonpolyposis colon cancer.


Hermann Bujard (DE) and Manfred Gossen (DE) developed the "Tet-Off" system for controlling expression of genes of interest in mammalian cells. Control elements of the tetracycline-resistance operon encoded in Tn10 of Escherichia coli were utilized to establish a highly efficient regulatory system in mammalian cells. By fusing the tet repressor with the activating domain of virion protein 16 of Herpes simplex virus, a tetracycline-controlled transactivator (tTA) was generated that is constitutively expressed in HeLa cells. This transactivator stimulates transcription from a minimal promoter sequence derived from the human cytomegalovirus promoter IE combined with tet operator sequences. Upon integration of a luciferase gene controlled by a tTA-dependent promoter into a tTA-producing HeLa cell line, high levels of luciferase expression were monitored. These activities are sensitive to tetracycline. Depending on the concentration of the antibiotic in the culture medium (0-1 microgram/ml), the luciferase activity can be regulated over up to five orders of magnitude. Thus, the system not only allows differential control of the activity of an individual gene in mammalian cells but also is suitable for creation of "on/off" situations for such genes in a reversible way (152).

Florence Paillard (US) described "Tet-on": a gene switch for the exogenous regulation of transgene expression (961).

The difference between "Tet-On" and "Tet-Off" is not whether the transactivator turns a gene on or off, as the name might suggest; rather, both proteins activate expression. The difference relates to their respective response to doxycycline (Dox, a more stable tetracycline analogue); "Tet-Off" activates expression in the absence of Dox, whereas "Tet-On" activates in the presence of Dox.


Nigel P. Carter (GB), Malcolm Andrew Ferguson-Smith (GB), Marian T. Perryman (GB), Hakan Telenius (GB), Adele H. Pelmear (GB), Margaret A. Leversha (GB), Mary T. Glancy (GB), Stephan L. Wood (GB), Kern Cook (GB), and Harold M. Dyson (GB) described a method, termed reverse chromosome painting, which allows the rapid analysis of the content and breakpoints of aberrant chromosomes. The method involves the sorting of small numbers of the aberrant chromosome from short term blood culture preparations or cell lines by using bivariate flow karyotype analysis. Reverse chromosome painting is useful for routine clinical cytogenetics when analyzing cases involving an insertion, a deletion, a translocation, and the origin of de novo unbalanced chromosome duplications (176).


Carlos J. Gimeno (US), Per O. Ljungdahl (US), Cora A. Styles (US), and Gerald R. Fink (US) rediscovered that yeast cells, and the colonies that they produced, can adopt a mode of growth different from the vegetative style familiar to yeast researches. Instead of forming ovoid buds that separate cleanly from the mother cell, under conditions of nutrient limitation, yeast cells grew as filaments in which the daughter cells remain adhered to the mother cell. They carefully described the physiological events that characterize the phenomenon and investigated the underlying molecular mechanisms (423). See, Guilliermond, 1920.


Brian J. Stevenson (US), Nelson Rhodes (US), Beverly Errede (US), and George F. Sprague, Jr. (US) recognized a protein kinase cascade in Saccharomyces cerevisiae that appears to be an essential feature of the pheromone response pathway and probably connects the receptor/G protein to an identified transcription factor, Ste12. STE12 is a gene that encodes a protein kinase activity essential for mating (1205).

Kang-Yell Choi (KR), Brett Satterberg (US), David M. Lyons (US), and Elaine A. Elion (US) produced results using Saccharomyces cerevisiae to substantiate a novel signal transduction component, Ste5 that physically links multiple kinases within a single cascade (211).


Yasumasa Ishida (JP), Yasutoshi Agata (JP), Keiichi Shibahara (JP), and Tasuku Honjo (JP) provided evidence to suggest that activation of the PD-1 gene (a member of the immunoglobulin gene superfamily) might be involved in the classical type of programmed cell death (588).


Pauline Johnson (GB-CA), Hanne L. Ostergaard (CA), Chris Wasden (US), and Ian S. Trowbridge (US) Johnson helped to established the function of CD45 as a critical protein tyrosine phosphatase in T cell activation (612)


Seth Lederman (US), Michael J. Yellin (US), Alexander Krichevsky (US), John Belko (US), Julie J. Le (US), and Leonard Chess (US) discovered 5c8 Ag, a novel, activation-induced surface T cell protein that is involved in mediating a contact dependent element of the helper effector function of CD4+ T lymphocytes (730). Note: CD4+ T lymphocytes provide contact-dependent stimuli to B cells that are critical for the generation of specific antibody responses in a process termed T helper function.


Robert H. Carter (US) and Douglas T. Fearon (US) noted that lymphocytes must proliferate and differentiate in response to low concentrations of a vast array of antigens. The requirements of broad specificity and sensitivity conflict because the former is met by low-affinity antigen receptors, which precludes achieving the latter with high-affinity receptors. They found that the B cell resolves its dilemma by having an accessory protein (CD19) that enables activation when few antigen receptors are occupied (177).


Daisuke Kitamura (DE), Akira Kudo (CH), Stefan Schaal (DE), Werner Muller (DE), Fritz Melchers (CH), and Klaus Rajewsky (DE) generated mice in which the lambda 5 gene is inactivated by targeted gene disruption in embryonic stem cells. In these mice, B cell development in the bone marrow is blocked at the pre-B cell stage. However, the blockade is leaky, allowing B cells to populate the peripheral immune system at a low rate. These cells are allelically excluded and able to respond to antigen (666).


Donald F. Hunt (US), Robert A. Henderson (US), Jeffrey Shabanowitz (US), Kazuyasu Sakaguchi (US), Hanspeter Michel (US), Noelle Sevilir (US), Andrea L. Cox (US), Ettore Appella (US), and Victor H. Engelhard (US) described the characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry (571).


Franz M. Karlhofer (US), Randall K. Ribaudo (US), and Wayne M. Yokoyama (US) described MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells (636).


Rie Watanabe-Fukunaga (JP), Camilynn I. Brannan (US), Neal G. Copeland (US), Nancy A. Jenkins (US), and Shigekazu Nagata (JP) explained a lymphoproliferation disorder in mice by defects in Fas antigen that mediates apoptosis (1323).


Murry R. Badger (AU) and G. Dean Price (AU) first suggested the function of the pyrenoid (found in many algae and the hornworts) to be analogous to that of the carboxysome in cyanobacteria, in being associated with carbon-concentrating mechanism activity (58).


Toshikazu Takeshita (JP), Kiyoshi Ohtani (JP), Hironobu Asao (JP), Satoru Kumaki (JP), Masataka Nakamura (JP), and Kazuo Sugamura (JP) produced results which suggested the possibility that p64 (a membrane molecule) associates with IL-2R beta and has an important role in formation of the functional IL-2R complex (1231).


Laura Velazquez (FR), Marc Fellous (FR), George R. Stark (FR), and Sandra Pellegrini (FR) showed that tyrosine kinase 2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes (1295).


Richard O. Williams (GB), Marc Feldmann (GB), and Ravinder Nath Maini (GB) showed that anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis (1348). Note: This research was in response to the considerable evidence implicating tumor necrosis factor (TNF-a) in the pathogenesis of rheumatoid arthritis.


Joseph G. Naglich (US), James E. Metherall (US), David W. Russell (US), Leon Eidels (US) determined that the receptor for diphtheria toxin is a membrane bound growth factor precursor that the toxin exploits as a receptor (902).


Simon McQueen-Mason (GB), Lian-Chao Li (US), Daniel M. Durachko (US), and Daniel J. Cosgrove (US) discovered the expansin gene family, which produces expansins; proteins that allow plant cell walls to grow while maintaining their rigidity (752; 846).


Harry F. Noller, Jr. (US), Vernita Hoffarth (US), and Ludwika Zimniak (US) confirmed that the ability to catalyze the formation of a covalent bond between adjacent amino acids—the peptidyl bond—lies in rRNA and not in proteins associated with the ribosome (933).

Poul Nissen (DK), Jeffrey L. Hansen (US), Nenad Ban (Crotian-US-CH), Peter B. Moore (US), and Thomas A. Steitz (US) used the atomic structures of the large ribosomal subunit from Haloarcula marismortui (Archaea) and its complexes with two substrate analogs, to establish that the ribosome is a ribozyme and explored the catalytic properties of its all-RNA active site (929).


Swapan K. Datta (PH), Karabi Datta (PH), Nouchine Soltanifar (CH), Günter Donn (DE), and Ingo Potrykus (CH) produced herbicide resistant rice plants through polyethylene glycol (PEG) mediated transformation of protoplasts (265).


Edward F. DeLong (US), Jed A. Fuhrman (US), Kirk McCallum (US), Alison A. Davis (US), Tohru Ueda (JP), Yuko Suga (JP), and Tatsuhiko Matsuguchi (JP) discovered numerous crenarchaeal ribosomal RNA (rRNA) genes in low-temperature marine and terrestrial environments. This destroyed the notion that all Crenarchaeota (a major subdivision of the Archaea) were from high-temperature geothermal environments (277; 378; 1283).


Susan K. McLaughlin (US), Peter J. McKinnon (US), and Robert F. Margolskee (US) discovered gustducin, a taste cell expressed G protein (844). Note: Their subsequent work has demonstrated that gustducin is critical to the transduction of compounds that humans consider bitter or sweet.


Siegfried Burggraf (DE), Gary J. Olsen (US), Karl O. Stetter (DE), Carl R. Woese (US), Gertrud Huber (DE), Elisabeth Drobner (DE), Harald Huber (DE), Robert Huber (DE), Thomas Wilharm (DE), Antonio Trincone (IT), Helmut König (DE), Reinhard Rachel (DE), Ingrid Rockinger (DE), and Hans Fricke (DE) discovered and characterized Aquifex pyrophilus as a deeply branching, eubacterial (Bacteria) hyperthermophile whose optimum environment is marine and near 85˚C, where it uses small amounts of oxygen to oxidize hydrogen (154; 568; 569).


Stephen George Oliver (GB), Quirina J.M. van der Aart (NL), Maria Luisa Agostoni-Carbone (IT), Michel Aigle (FR), Lilia Alberghina (IT), Despina Alexandraki (GR), G. Antoine (FR), R. Anwar (GB), Juan P. Garcia Ballesta (ES), P. Benit (FR), G. Berben (BE), E. Bergantino (IT), N. Biteau (IT), A. Bolle (BE), Monique Bolotin-Fukuhara (FR), Jean-Marie Buhler (FR), C. Carcano (IT), Giovanna Carignani (Italy), H. Cederberg (DE), R. Chanet (FR), Roland Contreras (BE), M. Crouzet (FR), Bertrand Daignan-Fornier (FR), E. Defoor (BE), M. Delgado (ES), J. Demolder (BE), C. Doira (FR), Edu Dubois (BE), Bernard Dujon (FR), A. Dusterhof (DE), D. Erdmann (DE), M. Esteban (ES), F. Fabre (FR), Cecile Fairhead (FR), G. Faye (FR), Horst Feldmann (DE), W. Fiers (BE), M.C. Francingues-Gaillard (FR), L. Franco (ES), L. Frontali (IT), Hiroshi Fukuhara (FR), L.J. Fuller (GB), P. Galland (GR), M.E. Gent (GB), D. Gigot (BE), V. Giliquet (BE), Nicolas Glansdorff (BE), Andre Goffeau (BE), M. Grenson (BE), P. Grisanti (IT), Les A. Grivell (NL), M. de Haan (NL), M. Haasemann (DE), D. Hatat (FR), J. Hoenicka (ES), J. Hegemann (DE), G.J. Herbert (FR), Francois Hilger (BE), S. Hohmann (DE), Cornelis P. Hollenberg (DE), K. Huse (DE), F. Iorra (FR), K.J. Indge (GB), K. Isono (Japan), Claude Jacq (FR), Michel Jacquet (FR), C.M. James (GB), Jean-Claude Jauniaux (BE), Y. Jia (FR), Antonio Jimenez (ES), A. Kelly (GB), U. Kleinhans (DE), P. Kreisl (DE), G. Lanfranchi (IT), C. Lewis (GB), C.G. van der Linden (NL), Giovanna Lucchini (IT), K. Lutzenkirchen (DE), M.J. Maat (NL), Laurent Mallet (FR), G. Mannhaupt (DE), E. Martegani (IT), A. Mathieu (FR), C.T.C. Maurer (NL), M. Muzi-Falconi (IT), David McConnell (GB), Andrew McKee (GB), Francine Messenguy (BE), H.W. Mewes (DE), F. Molemans (BE), M.A. Montague (GB), L. Navas (ES), Carol S. Newlon (US), D. Noone (GB), C. Pallier (FR), L. Panzeri (IT), B.M. Pearson (GB), J. Perea (FR), Peter Philippsen (DE), Andre Pierard (BE), Rudi J. Planta (NL), Paolo Plevani (IT), B. Poetsch (DE), F. Pohl (DE), Benedicte Purnelle (BE), Massoud Ramezani-Rad (DE), Soren W. Rasmussen (DK), A. Raynal (FR), M. Remacha (ES), P. Richterich (DE), A.B. Roberts (GB), F. Rodriguez (IT), E. Sanz (ES), I. Schaaff-Gerstenschlager (DE), B. Scherens (BE), B. Schweitzer (DE), Y. Shu (FR), J. Skala (BE), Piotr P. Slonimski (FR), Frederic Sor (FR), C. Soustelle (FR), R. Spiegelberg (DE), L.I. Stateva (GB), H. Yde Steensma (NL), S. Steiner (DE), A. Thierry (FR), Georges Thireos (GR), M. Tzermia (GR), L. Antonio Urrestarazu (BE), G. Valle (Italy), I. Vetter (DE), J.C. van Vliet-Reedij (NL), M. Voet (BE), Guido Volckaert (BE), P. Vreken (NL), H. Wang (GB), J.R. Warmington (GB), Dietter von Wettstein (DK), B.L. Wicksteed (GB), C. Wilson (IT), H. Wurst (DE), G. Xu (DE), A. Yoshikawa (JP), F.K. Zimmermann (DE), and John G. Sgouros (DE) determined the entire DNA sequence of chromosome III of the yeast Saccharomyces cerevisiae. This was the first complete sequence analysis of an entire chromosome from any organism (949).


Michael J. Dawson (GB), John E. Farthing (GB), Peter S. Marshall (GB), Robert F. Middleton (GB), Melanie J. O’Neill (GB), Alan Shuttleworth (GB), Chari Stylli (GB), Robert Murray Tait (GB), Pam M. Taylor (GB), Howard G. Wildman (GB), Antony D. Buss (GB), David Langley (GB), Michael V. Hayes (GB), Philip J. Sidebottom (GB), Rona M. Highcock (GB), Stephen J. Lane (GB), Panayiotis A. Procopiou (GB), Nigel S. Watson (GB), James D. Bergstrom (GB), Marc M. Kurtz (GB), Deborah J. Rew (GB), Allison M. Amend (GB), John D. Karkas (GB), Richard G. Bostedor (GB), Vinay S. Bansal (GB), Christiana Dufresne (GB), Frank L. Van Middlesworth (GB), Otto D. Hensens (GB), Jerrold M. Liesch (GB), Deborah L. Zink (GB), Kenneth E. Wilson (GB), Janet C. Onishi (GB), James A. Milligan (GB), Gerald F. Bills (GB), Louis Kaplan (GB), Mary Nallin-Omstead (GB), Rosalind G. Jenkins (GB), Leeyuan Huang (GB), Maria S. Meinz (GB), L. Quinn (GB), Richard W. Burg (GB), Yu-Lin Kong (GB), Sagrario Mochales (GB), Marina Mojena (GB), Isabel Martin (GB), Fernando Pelaez (GB), Maria T. Diez (GB), and Albert W. Alberts (GB) announced the discovery of a new class of natural products they found in two different fungi. Each research group gave the family a different name—squalestatins and zaragozic acids respectively (97; 270; 1148).

Allan Baxter (GB), Belinda J. Fitzgerald (GB), Julie L. Hutson (GB), Alun D. McCarthy (GB), Joanne M. Motteram (GB), Barry C. Ross (GB), Meenu Sapra (GB), Michael A. Snowden (GB), Nigel S. Watson (GB), Robert J. Williams (GB), and Carolyn Wright (GB) discovered that zaragozic acid A (squalestatin S1) has a very high affinity for squalene synthase and could lower serum cholesterol levels in the marmoset (85).

Kyriacos Costa Nicolaou (CY-US), Alan Nadin (US), James E. Leresche (US), Susan La Greca (US), Tatsuo Tsuri (US), Eddy W. Yue (US), Zhen Yang (US), Yoshimitsu Naniwa (US), and Francesco De Riccardis (US) carried out the total synthesis of zaragozic acid A, a potent reducer of serum cholesterol (918; 919; 925; 926).


Xing-Wang Deng (CN-US), Minami Matsui (JP), Ning Wei (US), Daniel S. Wagner (US), Angela M. Chu (US), Kenneth A. Feldmann (US), Peter H. Quail (US), and Brian P. Dilkes (US) pioneered the development of T-DNA-tagged Arabidopsis mutant populations (279; 286). Note: This resource led to many important discoveries such as cloning of the first Arabidopsis homeotic gene (AG), important in flower development, and the first photomorphogenetic gene (COP1).


Francois Rousset (FR), Didier Bouchon (FR), Bernard Pintureau (FR), Pierre Juchault (FR), and Michel Solignac (FR) found that the pill bug, Armadillidium vulgare, frequently associates with bacteria of the genus Wolbachia as a symbiont. These bacterial symbionts convert all hosts to females if they are not already females. The bacterium is passed from one generation of pill bug to the next by the transovarian route (1076).


Duncan A. Veal (AU), Joseph E. Trimble (AU), and Andrew J. Beattie (AU) discovered that bull ants, Myrmecia gulosa, possess a gland on the dorsal aspect of the thorax, which contains potent antibiotics (1294).


Hugh S. Mason (US), Dominic M. Lam (US), and Charles J. Arntzen (US) genetically transformed tobacco plants with the gene encoding hepatitis B surface antigen (HBsAg) and concluded that transgenic plants hold promise as low-cost vaccine production systems (826).

Tariq A. Haq (US), Hugh S. Mason (US), John D. Clements (US), and Charles J. Arntzen (US) orally immunized mice with potato tubers transgenic for Escherichia coli heat-labile enterotoxin (LT-B) (509).

Carol O. Tacket (US), Hugh S. Mason (US), Genevieve Losonsky (US), John D. Clements (US), Myron M. Levine (US), and Charles J. Arntzen (US) demonstrated immunogenicity in humans for a recombinant bacterial antigen delivered orally in a transgenic potato (1228).


Gregory M. Preston (US), Tiziana Piazza Carroll (US), William B. Guggino (US), and Peter Agre (US) developed a striking assay for a water channel gene. They prepared synthetic mRNA from the previously unknown cDNA, injected it into Xenopus laevis oocytes, and then watched them swell and rupture (1015).


A new species of the cholera bacteria (O139) was discovered in Bangladesh. It has since been detected in 11 countries raising the possibility of future pandemics (212).


Steven D. Norton (US), Linda Zuckerman (US), Kevin B. Urdahl (US), Rachel Shefner (US), Jim Miller (US), and Marc K. Jenkins (US) discovered the first co-stimulating pathway (CD28/B7) for T cell activation (936).


Richard J. Armitage (US), William C. Fanslow (US), Laura Strockbine (US), Timothy A. Sato (US), Ky N. Clifford (US), Brian M. Macduff (US), Dirk M. Anderson (US), Steven D. Gimpel (US), Terri Davis-Smith (US), Charles R. Maliszewski (US), Edward A. Clark (US), Craig A. Smith (US), Kenneth H. Grabstein (US), David Cosman (US), and Melanie K. Spriggs (US) reported the cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interIeukin-4 (40).


Melanie K. Spriggs (US), Richard J. Armitage (US), Laura D. Strockbine (US), Ky N. Clifford (US), Brian M. Macduff (US), Timothy A. Sato (US), Charles R. Maliszewski (US), and William Christian Fanslow (US) identified and cloned a cDNA encoding a murine ligand for the CD40 molecule (mCD40-L) and showed that it has biological activity in vitro. The predicted amino acid sequence indicates that this human ligand for CD40 (hCD40-L) is a 261 amino acid type II membrane protein that exhibits 78% amino acid identity with its murine counterpart. Cells transfected with hCD40-L caused the proliferation of human tonsil B cells in the absence of costimuli and, in the presence of interleukin 4, induced immunoglobulin E secretion from purified human B cells (1187).


Randolph J. Noelle (US), Meenakshi Roy (US), David M. Shepherd (US), Ivan Stamenkovic (US), Jeffrey A. Ledbetter (US), and Alejandro Aruffo (US) showed that triggering via CD40 is essential for the activation of resting B cells by helper T cells (Th). The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated Th. The 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation (930).


Tsutomu Ogata (GB), Peter Goodfellow (GB), Christine Petit (GB), Mabrouki Aya (GB), and Nobutake Matsuo (GB) proposed that in humans a growth gene(s) is present in the distal part of the pseudoautosomal region of the X chromosomal (945).


Walter Rosenthal (US), Anita Seibold (US), Anaid Antaramian (US), Michčle Lonergan (CA), Marie-Francoise Arthus (CA), Geoffrey N. Hendy (CA), Mariel Birnbaumer (US), and Daniel G. Bichet (CA) discovered the gene for a form of congenital X-linked nephrogenic diabetes insipidus (NDI) —it encoded arginine vasopressin receptor 2 (AVPR2), normally expressed on the plasma membrane of collecting ducts (1071).


Jeff M. Hall (US), Lori S. Friedman (US), C. Guenther (US), Ming K. Lee (US), James L. Weber (US), Donald M. Black (GB), and Mary-Claire King (US) found linkage of early-onset familial breast and ovarian cancer to 11 markers on chromosome 17q12-q21 which defines an 8-cM region which is very likely to include the disease gene BRCA-1 (495).


Douglas R. Lowy (US), John T. Schiller (US), Reinhard Kirnbauer (AT), Frank P. Booy (GB), Naiqian Cheng (US), Janet Taub (US), Heather L. Greenstone (US), Richard B.S. Roden (US), Matthias Dürst (DE), Lutz Gissmann (DE), Francoise K.R. Breitburd (FR), Nancy L. Hubbert (US), Bernadete Nonnemacher (BR), Trin-Dinh-Desmarquet Carole (FR), and Gérard Orth (FR) devised a blueprint for several safe and effective vaccines that promise to slash the incidence of cervical cancer and mortality, the fourth most common cancer among women worldwide, as well as other malignancies and disorders that arise from human papillomaviruses (132; 661; 662).


Wilfred Niels Arnold (US) presented evidence that Vincent van Gogh, the great Dutch painter, suffered from acute intermittent porphyria. This disease makes sufferers more sensitive to the neurotoxicity of absinthe (the active ingredient of absinthe is alpha-thujone) (41).


David C. Bellinger (US), Karen M. Stiles (US), Herbert L. Needleman (US) reported that among children exposed to lead early in life, serum lead levels at 24 months of age were significantly associated with decreased cognitive performance on measures of intelligence and educational achievement at 10 years old. Each 0.48 μmol/L (10 μg/dL) increase in serum lead at 24 months of age was associated with a 5.8 point decline in a measure of intelligence quotient and an 8.9 point decline in educational achievement score during cognitive testing at 10 years of age (90).


Michael M. Davis (US), Philip M. McCabe (US), Neil Schneiderman (US), Theodore W. Jarrell (US), Christopher G. Gentile (US). Alan H. Teich (US), Ray W. Winters (US), and David R. Liskowsky (US) determined that the neural pathways involved in fear conditioning include sensory pathways transmitting the signal to the amygdala where specific internal connections ultimately project to motor systems. The amygdala is involved in fear conditioning regardless of the sensory modality of the conditioned stimulus and independent of which motor response is used (268; 836).


Marc Alan Pfeffer (US), Eugene Braunwald (US), Lemuel A. Moyé (US), Lofty Basta (US), Edward J. Brown, Jr. (US), Thomas E. Cuddy (US), Barry R. Davis (US), Edward M. Geltman (US), Steven Goldman (US), Greg C. Flaker (US), Marc Klein (US), Gervasio A. Lamas (US), Milton Packer (US), Jacques Rouleau (US), Jean L. Rouleau (US), John Rutherford (US), John H. Wertheimer (US), and C. Morton Hawkins (US) found that treating patients with captopril after acute myocardial infarction (MI) with asymptomatic left ventricular dysfunction reduces mortality from cardiovascular causes (i.e., atherosclerotic heart disease, progressive heart failure). The captopril group experienced lower rates of hospitalization due to heart failure and recurrent (MI) (990).


Andrew E. Czeizel (HU) and István Dudás (HU) found that periconceptional vitamin use decreases the incidence of a first occurrence of neural tube defects (258).


Olivier J. Goulet (FR), Yann Revillon (FR), Nicole Brousse (FR), Dominique Jan (FR), Danielle Canion (FR), Caroline Rambaud (FR), Nadine Cerf-Bensussan (FR), Christianne Buisson (FR), Philippe Hubert (FR), Sophie de Potter (FR), Jean-Francois Mougenot (FR), Alain Fischer (FR), and Claude Ricour (FR) performed the first successful small bowel transplantation in humans (442).


Mehernoor F. Watcha (US) and Paul F. White (US) reported that newer anesthetic drugs (e.g. propofol) appear to have contributed to a recent decline in the incidence of postoperative emesis. Factors associated with an increased risk of postoperative emesis include: age, gender (menses), obesity, previous history of motion sickness or postoperative vomiting, anxiety, gastroparesis, and type and duration of the surgical procedure (e.g., laparoscopy, strabismus, middle ear procedures). Anesthesiologists have control over many factors that influence postoperative emesis (e.g., preanesthetic medication, anesthetic drugs and techniques, and postoperative pain management). Patients at high risk for postoperative emesis should receive special considerations with respect to the prophylactic use of antiemetic drugs. Potent nonopioid analgesics (e.g., ketorolac) can be used to control pain while avoiding some of the opioid-related side effects. Gentle handling in the immediate postoperative period is also essential. If emesis does occur, aggressive intravenous hydration and pain management are important along with antiemetic drugs. If one antiemetic does not appear to be effective, another drug with a different site of action should be considered. New antiserotonin drugs, should reduce the incidence of recurrent (intractable) emesis (1324).


John M. Epley (US) described the Canalith Repositioning Procedure (CRP) and its rationale, and reported the results in 30 patients who exhibited the classic nystagmus of benign paroxysmal positional vertigo (BPPV) with Hallpike maneuvers. CRP obtained timely resolution of the nystagmus and positional vertigo in 100%. These results also support an alternative theory that the densities that impart gravity-sensitivity to a semicircular canal in BPPV are free in the canal, rather than attached to the cupula. CRP offers significant advantages over invasive and other noninvasive treatment modalities in current use (320).


Gary S. Hoffman (US), Gail S. Kerr (US), Randi Y. Leavitt (US), Claire W. Hallahan (US), Robert S. Lebovics (US), William D. Travis (US), Menachem Rottem (US), and Anthony S. Fauci (US) noted that the course of Wegener granulomatosis has been dramatically improved by daily treatment with cyclophosphamide and glucocorticoids. Nonetheless, disease- and treatment-related morbidity is often profound. A long-term follow-up of patients with Wegener granulomatosis has led to increasing concerns about toxicity resulting from prolonged cyclophosphamide therapy and has encouraged investigation of other therapeutic regimens (546).


Marie-José Ramond (FR), Thierry Poynard (FR), Bernard Rueff (FR), Philippe Mathurin (FR), Christian Théodore (FR), Jean-Claude Chaput (FR), and Jean-Pierre Benhamou (FR) found that compared to placebo, treating patients with severe alcoholic hepatitis with 28 days of prednisolone significantly improved the short-term survival up to 6 months.

There remains significant controversy surrounding the use of glucocorticoids in managing severe alcoholic hepatitis, as numerous other trials have demonstrated no mortality benefit, but significantly higher risk of infection with glucocorticoid therapy (1035).


Michael R. Ransom (US) and C. Arden Pope, III (US) took advantage of an industrial quirk to more directly document the health effects of air contaminants in an area of Utah where particulate air pollution was historically dominated by emissions from a steel mill. Owing to a labor dispute, that mill was shut for 13 months, thus providing a “control” period to which pre- and post-closure public health measures could be compared. A significant and robust association was found between PM10 levels and absence rates in local schools, which persisted at levels below current air quality standards. The relative simplicity of this study and its intuitively reasonable findings had major influence on subsequent air pollution policies (1037).


The CDC introduced “Public Health Focus: Effectiveness of Disease and Injury Prevention” published monthly in the MMWR (1).


Tsu-Ming Han (US) and Bruce N. Runnegar (AU-US) found fossils of the multicellular Grypania spiralis (probably an alga) in the 2.1 Ga Negaunee Iron Formation in Michigan, U.S.A (505). Malcom R. Walter (US), Du Rulin (US), and Robert Joseph Horodyski (US) had previously discovered multicellular fossil (c.1.4 Ga) in old Greyson Shale, lower Belt Supergroup, in Montana, US, and from the similarly aged Gaoyuzhuang Formation, upper Changcheng Group, in the Jixian section, Northern China. The organism was identified as Grypania spiralis, a coiled ribbon-like creature. It was judged to most likely have been a multicellular eukaryotic alga (1312). Shale is rock formed by condensation of layers of clay or mud, along with phytoplankton and other debris, sedimented at the bottoms of lakes or ocean basins.



"Humans are here today because our particular line never fractured—never once at any of the billion points that could have erased us from history." Stephen Jay Gould (US) (441)


"Living organisms preserve their internal order by taking from their surroundings free energy, in the form of nutrients or sunlight, and returning to their surroundings an equal amount of energy as heat and entropy." Albert Lester Lehninger (US), David L. Nelson (US), and Michael M. Cox (US) (740). This concept was first articulated by Ludwig Boltzmann (DE) (122), then refined by Erwin Schrödinger (DE) (1115).


“Very difficult decisions will have to be made if we are to have a sustainable human society in a sustainable environment. Many of those decisions will require extensive knowledge of biology. We have reached the point in history, therefore, when biological knowledge is the sine qua non for a viable human future.” John Alexander Moore (US) (870).


“To discover nature’s true order, the mind must be purified of all its internal obstacles, purged of its habitual tendencies to produce rational or imaginary wish fulfillments in advance of empirical investigation.” Richard TheodoreTarnas (CH) (1234).


"In science and elsewhere there are two types of truth: (1) The truth everybody already knows, and (2) the truth that is not yet discovered…The second type of truth is different. At first it looks too bizarre to be true, and it may be as dangerous as fire. If you are not clever it may destroy you." Benno Müller-Hill (DE) (888).


"I have recently been reassured that this formulation of sodium ion-coupled glucose transport in the intestine was the basis for the development by others of the simple glucose-sodium chloride solution taken by mouth that is used world-wide to treat victims of life-threatening diarrhea as in cholera. A practical development based on my little piece of basic research has saved thousands upon thousands of lives." Robert Kellogg Crane (973). See, Crane, 1961


All is Fair in Love and Warts


 “He proclaimed she had given him warts

 Of the most ignominious sorts

 Said that her papilloma

 Had entered his soma

 And the issue was clearer than quartz


 She denies having given him warts

 Says that "His allegation distorts.

 It's incredibly plain

 That they differ by strain

 As shown in my doctor's reports.


And despite his assertion of torts

On the issue of giving him warts,

She was quickly acquitted

Of having transmitted

(And upheld in the lowest of courts).” Robert D. Siegel, November 16, 1993


Kary Banks Mullis (US) for his invention of the polymerase chain reaction (PCR) method and Michael Smith (GB-CA) for his fundamental contributions to the establishment of oligonucleotide-based, site-directed mutagenesis and its development for protein studies shared the Nobel Prize in Chemistry.


Richard John Roberts (GB) and Phillip Allen Sharp (GB-US) were awarded the Nobel Prize in Physiology or Medicine for their independent discoveries of split genes.


Elias James Corey (US) and Yong-Jin Wu (US) carried out the total synthesis of paeoniflorigenin and paeoniflorin (239).


Kai Chen (CN-US) and Frances Hamilton Arnold (US) applied directed evolution to engineer a version of the enzyme subtilisin E that was active in a highly unnatural environment, namely in the organic solvent dimethylformamide (DMF). They carried out the work using four sequential rounds of mutagenesis of the enzyme's gene, expressed by bacteria, through error-prone polymerase chain reaction. After each round they screened the enzymes for their ability to hydrolyze the milk protein casein in the presence of DMF by growing the bacteria on agar plates containing casein and DMF. The bacteria secreted the enzyme and, if it were functional, it would hydrolyze the casein and produce a visible halo. They selected the bacteria that had the biggest halos and isolated their DNA for further rounds of mutagenesis. Using this method, she designed an enzyme that had 256 times more activity in DMF than the original (195). Note: Barry G. Hall (US), in 1978, was the first person to use directed evolution for optimizing enzyme activity.


Emmanuel Delhaise (AU), Peter R. Ryan (AU), and Peter J. Randall (AU) showed that aluminum tolerance in plants is accomplished by organic acid (e.g. malate or citrate) secretion from roots. The secreted organic acids chelate aluminum extracellularly, inhibiting aluminum uptake and thus avoiding subsequent toxicity to plants (276).


Bertil Pettersson (SE), Mathias Uhlen (SE), and Pĺl Nyren (SE) described the principle of "pyrosequencing" by combining the solid phase sequencing method using streptavidin coated magnetic beads with recombinant DNA polymerase lacking 3´to 5´exonuclease activity (proof-reading) and luminescence detection using the firefly luciferase enzyme (986).

Marcel Margulies (US), Michael Egholm (US), William E. Altman (US), Said Attiya (US), Joel S. Bader (US), Lisa A. Bemben (US), Jan Berka (US), Michael S. Braverman (US), Yi-Ju Chen (US), Zhoutao Chen (US), Scott B. Dewell (US), Lei Du (US), Joseph M. Fierro (US), Xavier V. Gomes (US), Brian C. Godwin (US), Wen He (US),Scott Helgesen (US), Chun Heen Ho (US), Gerard P. Irzyk (US), Szilveszter C. Jando (US), Maria L. I. Alenquer (US), Thomas P. Jarvie (US), Kshama B. Jirage (US), Jong-Bum Kim (US), James R. Knight (US), Janna R. Lanza (US), John H. Leamon (US), Steven M. Lefkowitz (US), Ming Lei (US), Jing Li (US), Kenton L. Lohman (US), Hong Lu (US), Vinod B. Makhijani (US), Keith E. McDade (US), Michael P. McKenna (US), Eugene W. Myers (US), Elizabeth Nickerson (US), John R. Nobile (US), Ramona Plant (US), Bernard P. Puc (US), Michael T. Ronan (US), George T. Roth (US), Gary J. Sarkis (US), Jan Fredrik Simons (US), John W. Simpson (US), Maithreyan Srinivasan (US), Karrie R. Tartaro (US), Alexander Tomasz (US), Kari A. Vogt (US) , Greg A. Volkmer (US), Shally H. Wang (US), Yong Wang (US), Michael P. Weiner (US), Pengguang Yu (US), Richard F. Begley (US), and Jonathan M. Rothberg (US) described a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, they have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. They showed the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine (820).


Nikolai Lisitsyn (RU-US), Natalya Lisitsyn (RU-US), and Michael Wigler (US) developed a system in which subtractive and kinetic enrichment was used to purify restriction endonuclease fragments present in one population of DNA fragments but not in another. Application of this method to DNA populations of reduced complexity ("representations") resulted in the isolation of probes to viral genomes present as single copies in human DNA, and probes that detect polymorphisms between two individuals (771).


Michael R.K. "Dickon" Alley (US), Janine Maddock (US), and Lucy Shapiro (US) were able to show that chemoreceptor proteins occupy specific areas within the bacterial cell (27; 803).

Christine Jacobs (US), Ibrahim J. Domian (US), Janine R.Maddock (US), and Lucy Shapiro (US) discovered that the master CtrA response regulator functions in Caulobacter to repress replication initiation in different phases of the cell cycle. Here, they identify an essential histidine kinase, CckA, that is responsible for CtrA activation by phosphorylation. Although CckA is present throughout the cell cycle, it moves to a cell pole in S phase, and upon cell division it disperses (600).

Lucy Shapiro (US), Michael T. Laub (US), Harley H. McAdams (US), Tamara Feldblyum (US), Claire M. Fraser (US), Swaine L. Chen (US), Christine Jacobs (US), Nora Ausmees (US), and Stuart J. Cordwell (US) were the first to show that bacterial DNA replication occurs in a spatially organized way and that cell division is dependent on this spatial organization. They discovered the genetic basis of cell cycle progression and consequently the identification of three regulatory proteins, DnaA, GcrA, and CtrA, which controlled complex temporal and spatial behaviors affecting large numbers of genes (599; 721; 722).

Patrick H. Viollier (US), Martin Thanbichler (US), Patrick T. McGrath (US), Lisandra West (US), Maliwan Meewan (US), Harley H. McAdams (US), and Lucy Shapiro (US) using time-lapse microscopy and fluorescent tags, were able to demonstrate that chromosomal regions are duplicated in both an orderly and a location-specific manner, involving "a much higher degree of spatial organization than previously thought" (1303).

Erin D. Goley (US), Luis R. Comolli (US), Katherine E. Fero (US), Kenneth H. Downing (US), Lucy Shapiro (US), Andrea Möll (DE), Susan Schlimpert (DE), Ariane Briegel (DE), Grant J. Jensen (DE), Martin Thanbichler (DE), Sebastian Poggio (US), Constantin N. Takacs (US), Waldemar Vollmer (US), and Christine Jacobs-Wagner (US) describe a novel protein, called DipM for Division Involved Protein with LysM domains, that is required for cell division in Caulobacter crescentus. DipM localizes to the mid-cell during cell division, where it is necessary for the hydrolysis of the septal peptidoglycan to remodel the cell wall. DipM is essential for reorganizing the cell wall at the division site, for envelope invagination and cell separation in Caulobacter (429; 867; 1006). Note: LysM is a protein domain which binds peptidoglycan

Jason Hocking (US), Richa Priyadarshini (US), Constantin N. Takacs (US), Teresa Costa (US), Natalie A. Dye (US), Lucy Shapiro (US), Waldemar Vollmer (US), and Christine Jacobs-Wagner (US) showed that spatial distributions of specific cell wall proteins in Caulobacter crescentus are sensitive to small external osmotic upshifts. An essential cell elongation-specific transpeptidase, switches its localization from a dispersed, patchy pattern to an accumulation at the FtsZ ring location. This osmolality-dependent relocation to the division apparatus is initiated within less than a minute (545).


Edward J. Weinman (US), Deborah Steplock (US), Shirish Shenolikar (US), and Yu Wang (US) discovered, purified, and characterized a molecule called sodium-hydrogen exchanger regulatory factor (NHERF) that binds to adrenergic receptors to begin the internal fight-or-flight signaling process (1333; 1334). Note: Prior to this finding G-protein was the only molecule known to have this binding property. This is an entirely new signaling model for the cell's internal machinery.


Hua Gu (DE), Yong-Rui Zou (DE), and Klaus Rajewsky (DE) employed a method based on the Cre-loxP recombination system of bacteriophage P1 to generate a mouse strain in which the JH segments and the intron enhancer in the IgH locus are deleted. By analysis of immunoglobulin isotype switch recombination in heterozygous mutant B cells activated by lipopolysaccharide plus interleukin-4, they showed that, on the mutant chromosome, switch recombination at the mu gene switch region is strongly suppressed, whereas the switch region of the gamma 1 gene is efficiently rearranged (482).


Leu-Fen H. Lin (US), Daniel H. Doherty (US), Jack D. Lile (US), Susan Bektesh (US), and Frank Collins (US) were the first to isolate glial cell line-derived neurotrophic factor (GDNF). It functions as a survival and differentiation factor for midbrain dopaminergic neurons (764).


Mary Sym (US), JoAnne Engebrecht (US), and G. Shirleen Roeder (US) proposed that ZIP1 is a novel meiosis-specific gene, which acts as a molecular zipper to bring homologous chromosomes in close apposition in Saccharomyces cerevisiae (1225).


Michel Rohmer (FR), M’hamed Knani (FR), Pascale Simonin (FR), Bertrand Sutter (FR), and Hermann Sahm (FR) described the glyceraldehyde-3-phosphate (GAP)-pyruvate pathway to the production of isopentyl diphosphate (IPP). The IPP is synthesized by the condensation of pyruvate and glyceraldehyde-3-phosphate, via 1-deoxyxylulose-5-phosphate (DXP) as the first intermediate (1068). The isoprenoids are composed of repeating five-carbon, isopentenyl diphosphate (IPP) subunits.  Eubacterial hopanoids and plastid-associated isoprenoids of algae and higher plants are produced via this pathway.


Sydney Brenner (GB), Greg Elgar (GB), Richard Sandford (GB), Alexander D. Macrae (GB), Byrappa Venkatesh (SG), and Samuel Aparicio (GB) characterized the small genome (400 Mb) of the tetraodontoid fish, Fugu rubripes. A random sequencing approach supported by gene probing shows that the haploid genome contains 400 Mb of DNA, of which more that 90% is unique. This genome is 7.5 times smaller than the human genome and because it has a similar gene repertoire it is the best model genome for the discovery of human genes(133).


Kazimierz Tye Tycowski (US), Mei-Di Shu (US), and Joan Elaine Argetsinger Steitz (US) discovered that introns, which were thought to be inert, code for snRNAs that target the modification of other cellular RNAs during their maturation (1280-1282).

Shobha Vasudevan (US), YingchunTong (US), and Joan Elaine Argetsinger Steitz (US) proposed that translation regulation by microRNPs oscillates between repression and activation during the cell cycle (1293).


Craig M. Thompson (US), Anthony J. Koleske (US), David M. Chao (US), and Richard A. Young (US) defined the Saccharomyces cerevisiae Mediator complex in detail and provided evidence for its role in the regulation of transcription (1245). Note: The Mediator complex appears in all eukaryotes. It is a protein complex physically associated with RNA polymerase II during transcription.


Edward M. Brown (US), Gerardo Gamba (MX), Daniela Riccardi (US), Michael Lombardi (US), Robert Butters (US), Olga Kifor (US), Adam Sun (US), Matthias A. Hediger (US), Jonathan Lytton (US), and Steven C. Hebert (US) reported the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor (139).


Kazutoshi Mori (JP-US), Peter Walter (US), Wenzhen Ma (JP-US), Mary-Jane Gething (US), Joseph F. Sambrook (US), Tetsushi Kawahara (JP), Hiderou Yoshida (JP), Hideki Yanagi (JP), Takashi Yura (JP), Kyosuke Haze (JP), Toshie Matsui (JP), Akira Yamamoto (JP), Tetsuya Okada (JP), Yoshimi Sato (JP), Satomi Nadanaka (JP), Tetsuya Okada (JP), and Katsuya Okawa (JP) Jeffery S. Cox (US), Caroline E. Shamu (US), Carmela Sidrauski (US), Tania N. Gonzalez (US), Silke Dörfler (US), Alexei V. Korennykh (US), Pascal F. Egea (US), Andrei A. Korostelev (US), Janet Finer-Moore (US), Chao Zhang (US), Kevan M. Shokat (US), Robert M. Stroud (US), Brooke M. Gardner (US), David Pincus (US), Katja Gotthardt (US), and Ciara M. Gallagher (US) discovered the unfolded protein response, an intracellular quality-control system that detects harmful misfolded proteins in the endoplasmic reticulum and signals the nucleus to carry out corrective measures (245; 246; 393; 431; 521; 641; 689; 875; 876; 1095; 1149; 1381).


Carol Beadling (US), Kirk W. Johnson (US), and Kendall A. Smith (US) isolated interleukin 2-induced immediate-early genes (87).


Frauke Melchior (US), Bryce M. Paschal (US), Janice Evans (US), and Larry Gerace (US) found in HeLa cells that a GTPase named Ran, promotes nuclear uptake of proteins sporting a nuclear localization sequence (NLS) (851).

Mary Shannon Moore (US) and Günter Klaus-Joachim Blobel (DE-US) made a similar finding in Xenopus oocytes (871).

Stephen A. Adam (US), Larry Gerace (US), Ermoné J.H. Adam (US), Dirk Görlich (DE), Siegfried Prehn (DE), Ronald A. Laskey (GB), Enno Hartmann (DE), Aurelian Radu (US), Günter Klaus-Joachim Blobel (DE-US), and Mary Shannon Moore (US) revealed the importin proteins responsible for transporting molecules into the nucleus (10; 11; 437; 1029).


Ramsay Fuleihan (US), Narayanaswamy Ramesh (US), Richard Loh (US), Haifa Jabara (US), Fred S. Rosen (US), Talal Chatila (US), Shu Man Fu (US), Ivan Stamenkovic (US), and Raif S. Geha (US) obtained results suggesting that defective expression of the CD40 ligand underlies the failure of isotype switching in X chromosome-linked immunoglobulin deficiency disease (381).


Paritosh Ghosh (US), Tse-Hua Tan (US), Nancy R. Rice (US), Antonio Sica (US), and Howard A. Young (US) found that the interleukin 2 CD28-responsive complex contains at least three members of the NF-kB family: c-Rel, p50, and p65 (412).


Steven E. Macatonia (US), Chyi-Song Hsieh (US), Kenneth M. Murphy (US), and Anna O'Garra (US) discovered that dendritic cells and macrophages are required for T-helper 1(Th1) development of CD4+ T cells. They also determined that interleukin 12 (IL-12) substitution for macrophages to stimulate IFN-gamma production is IFN-gamma-dependent (801).


Dale I. Godfrey (US), Jacqueline Kennedy (US), Takashi Suda (US), and Albert Zlotnik (US) subdivided mouse CD4-CD8-CD3- triple-negative (TN) thymocytes into four subsets based upon expression of CD44 and CD25, including CD44+CD25-, CD44+CD25+, CD44-CD25+ and CD44-CD25-. The repopulation potential of these subsets in 2-deoxyguanosine-treated fetal thymic lobes supports the following maturation sequence: CD44+CD25- -->CD44+CD25+ -->CD44-CD25+ -->CD44-CD25- (425)


Yoichi Shinkai (US), Shigeo Koyasu (US), Kei-ichi Nakayama (US), Kenneth M. Murphy (US), Dennis Y. Loh (US), Ellis L. Reinherz (US), and Frederick W. Alt (US) found that introduction of TCR alpha transgene, TCR beta transgene, or both into RAG-2-/-mice differentially rescues T cell development (1145).


Satoshi Tsukada (US), Douglas C. Saffran (US), David J. Rawlings (US), Ornella Parolini (US), R.Cutler Allen (US), Ivana Klisak (US), Robert S. Sparkes (US), Hiromi Kubagawa (US), Thuluvancheri Mohandas (US), Shirley Quan (US), John W. Belmont (US), Max D. Cooper (US), Mary Ellen Conley (US), and Owen N. Witte (US) described a novel cytoplasmic tyrosine kinase, termed BPK (B cell progenitor kinase), which is expressed in all stages of the B lineage and in myeloid cells. BPK was evaluated as a candidate for human X-linked agammaglobulinemia (XLA), an inherited immunodeficiency characterized by a severe deficit of B and plasma cells and profound hypogammaglobulinemia (1271).

David Vetrie (GB), Igor Vorechovsky (SE), Paschalis Sideras (SE), Jill Holland (GB), Angela Davies (GB), Frances Flinter (GB), Lennart Hammarstrom (SE), Christine Kinnon (GB), Roland Levinsky (GB), Martin Bobrow (GB), C. I. Edvard Smith (SE), and David R. Bentley (GB) isolated a novel gene which maps to the XLA locus, is expressed in B cells, and shows mutations in families with the disorder. The gene is a member of the src family of proto-oncogenes which encode protein-tyrosine kinases. This was among the first evidence that mutations in a src-related gene are involved in human genetic disease (1298).


James L. Ferrara (US), Sunil Abdhyankar (US), and Dwight Gary Gilliland (US) were the first to use the phrase “cytokine storm,” which appeared in their article on graft-versus-host disease (346). Note: The use of this phrase in infectious disease research began in early 2000 in reports on cytomegalovirus (73), Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (580), group A streptococcus (106), influenza virus (1380), variola virus (604), and severe acute respiratory syndrome coronavirus (SARS-CoV) (567). The phrase appears to have first been applied in the context of avian H5N1 influenza virus infection in 2005 (1387).


Shixin Qin (GB), Stephen P. Cobbold (GB), Heather Pope (GB), James Elliott (GB), Dimitris Kioussis (GB), Joanna Davies (GB), and Hermann Waldmann (GB) were the first to show that CD4+ T cells from transplantation tolerant mice disabled naďve lymphocytes so that they too could not reject the graft. The naďve lymphocytes that had been so disabled also became tolerant and, in turn, developed the capacity to specifically disable other naďve lymphocytes. This process of "infectious" tolerance explains why no further immunosuppression is needed to maintain long-term transplantation tolerance (1026).

Shimon Sakaguchi (JP), Noriko Sakaguchi (JP), Masanao Asano (JP), Misako Itoh (JP), and Masaaki Toda (JP) presented results indicating that CD4+CD25+ T cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ T cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases (46; 1088).

Joanna D. Davies (GB), Louise Y.W. Leong (GB), Andrew L. Mellor (GB), Stephen P. Cobbold (GB), and Hermann Waldmann (GB) were the first to demonstrate that dominant tolerance maintained by Treg cells to one set of antigens in a tissue could spread to prevent immune attack directed to other antigens in the same tissue (267).

Fabienne Van de Keere (US), Susumu Tonegawa (US), Danyvid Olivares-Villagomez (US) Yijie Wang (US), and Juan J. Lafaille (US) showed that CD4+ T cell populations contain a regulatory subset that can prevent the development of experimental autoimmune encephalomyelitis in a transgenic mouse model (948; 1286).

Benedict Seddon (GB) and Don Mason (GB) were the first to provide evidence that target organ specificity of Treg cells provides protection against organ-specific autoimmunity (1124).

Luis Graca (GB), Stephen P. Cobbold (GB), and Hermann Waldmann (GB) were the first to provide a clear demonstration that Treg cells can be found in the tolerant tissues, opening testable hypotheses on acquired immunological privilege (447).

Chun-Yen Lin (), Luis Graca (GB), Stephen P. Cobbold (GB), and Hermann Waldmann (GB) provided data linking tolerance to chronic viruses with transplantation tolerance and possibly tumor tolerance. This finding indicated that Tregcell-mediated suppression at the level of effector function rather than proliferation seems to be the same thing that happens in the induction of virus tolerance (761).


Viktor Steimle (CH), Luc A. Otten (CH), Madeleine Zufferey (CH), and Bernard Mach (CH) identified a splicing mutation that results in a 24 amino acid deletion in CIITA, resulting in loss of function of the transactivator. Hence, the CIITA gene is essential for MHC class II gene expression and has been shown to be responsible for hereditary MHC class II deficiency (1195). Note: Hereditary major histocompatibility complex (MHC) class II deficiency (or Bare Lymphocyte Syndrome) is a form of severe primary immunodeficiency with a total lack of MHC class II expression. 


Denise Gay (US), Thomas Saunders (US), Sally Camper (US), and Martin Weigert (US) generated data suggesting that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. They suggested that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance (403).


Susan L. Tiegs (US), David M. Russell (US), and David Nemazee (US) showed that transgenic bone marrow B cells encountering membrane-bound Kb or Kk proteins modify their receptors by expressing the V(D)J recombinase activator genes and assembling endogenously encoded immunoglobulin light chain variable genes. This (auto)antigen-directed change in the specificity of newly generated lymphocytes is termed receptor editing (1250).


Demetrius Moskophidis (CH), Franziska Lechner (CH), Hanspeter Pircher (CH), and Rolf Martin Zinkernagel (CH) found that some strains of non-cytopathic lymphocytic choriomeningitis virus (LCMV) persist after acute infection because they induce most of the specific antiviral CD8+ cytotoxic T cells so completely that they all disappear within a few days and therefore neither eliminate the virus nor cause lethal immunopathology (882).


Masayuki Noguchi (US), Huafang Yi (US), Howard M. Rosenblatt (US), Alexandra H. Filipovich (US), Stephen Adelstein (US), William S. Modi (US), O. Wesley McBride (US), and Warren J. Leonard (US) localized the IL-2R gamma gene to human chromosome Xql3. Genetic linkage analysis indicates that the IL-2R gamma gene and the locus for X-linked severe combined immunodeficiency (XSCID) appear to be at the same position. These data establish that XSCID is associated with mutations of the IL-2R gamma gene product (932). Note: The interleukin-2 (IL-2) receptor gamma chain (IL-2R gamma) is a component of high and intermediate affinity IL-2 receptors that is required to achieve full ligand binding affinity and internalization.


Julia M. Turner (GB) found that IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A. These observations suggest that cyclins D2 and D3 may monitor the interleukin 2-receptor (IL-2R) signal but that their induction does not guarantee entry into S phase (1278).


Chyi-Song Hsieh (US), Steven E. Macatonia (US), Catherine S. Tripp (US), Stanley F. Wolf (US), Anne O'Garra (US), and Kenneth M. Murphy (US) showed the development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages (564). Note: this regulatory pathway may have evolved to enable innate immune cells, through interactions with microbial pathogens, to direct development of specific immunity toward the appropriate TH phenotype.


Warren J. Strittmatter (US), Ann M. Saunders (US), Donald Schmechel (US), Margaret Pericak-Vance (US), Jan Enghild (US), Guy S. Salvesen (US), and Allen D. Roses (US) found that apolipoprotein E (a serum transporter of cholesterol) is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease (1209).


William R. Jacobs, Jr. (US), Raúl G. Barletta (US), Rupa A. Udani (US), John Chan (US), Gary Kalkut (US), Gabriel Sosne (US), Tobias Kieser (GB), Gary J. Sarkis (US), Graham F. Hatfull (GB-US), and Barry R. Bloom (US) developed luciferase reporter phages with which they could assess drug susceptibility based on the efficient production of photons by viable mycobacteria infected with specific reporter phages expressing the firefly luciferase gene. Cells killed by a drug would not emit light (601).


Galina A. Dubinina (RU), Natalia V. Leshcheva (RU), and Margarita Yu Grabovich (RU) reported that the colorless sulfur bacterium Thiodendron is actually a symbiotic association of spirochetes and sulfidogens (298; 299).


Friedrich Widdel (DE), Sylvia Schnell (DE), Silke Heising (DE), Armin Ehrenreich (DE), Bernhard Assmus (DE), and Bernhard Schink (DE) discovered that ferrous ions can serve as the electron donors for certain purple nonsulfur phototrophs (1346). Note: This provides an explanation for the banded iron oxide geological formations, which were deposited when the earth's atmosphere was anoxic: anoxic phototrophs very likely did it.


Guofeng You (US), Craig P. Smith (US), Yoshikatsu Kana (US), Wen-Sen Lee (US), Matthias Stelzner (US), and Matthias A. Hediger (US) successfully promoted the expression of a clone of the first urea transporter, now named UT-A2 (1384).


Vincent Brichard (BE), Aline van Pel (BE), Thomas Wölfel (DE), Catherine Wölfel (DE), Etienne De Plaen (BE), Bernard Lethé  (BE), Pierre G. Coulie (BE), and Thierry Boon (BE) identified a tyrosine kinase gene coding for a melanoma antigen which offers a potential target for T-cell mediated immunotherapy (134).


Marc Stadler (DE), Timm Anke (DE), Johannes Dasenbrock (DE), and Wolfgang A. Steglich (DE) described a new hirsutane derivative, phellodonic acid (1); isolated from fermentations of Phellodon melaleucus strain 87113. Its structure was elucidated by spectroscopic methods. The compound exhibits antibiotic activities towards bacteria and fungi. It is the first bioactive metabolite from cultures of a species belonging to the family Thelephoraceae (1189).


Esther R. Angert (US), Kendall D. Clements (NZ), and Norman Richard Pace, Jr. (US) isolated the largest (600 microns by 80 microns) bacterium to be described so far. It is the morphologically peculiar microorganism Epulopiscium fishelsoni that inhabits the intestinal tract of Acanthurus nigrofuscus, a brown surgeonfish (family Acanthuridae), from the Red Sea. Similar microorganisms have been found in surgeonfish species from the Great Barrier Reef. They are considered to be specific symbionts of surgeonfish, although the nature of the symbiosis is unclear (34).

Esther R. Angert, (US), Austin E. Brooks (US), and Norman Richard Pace, Jr. (US) presented ribosomal RNA (rRNA) phylogenetic evidence placing this organism nearest the cellulolytic Clostridia (33).


Vincent Falanga (US) and Robert S. Kirsner (US) were the first to obtain vigorous growth and multiplication of isolated single euploid animal cells. They did this by reducing the oxygen tension from the usual 20% down to 2% (331).


René H. Medema (NL) and Johannes L. Bos (NL) found that Ras proteins are present in structurally altered forms that enable them to release a flux of mitogenic signals into cells, without ongoing stimulation by their normal upstream regulators (847).

Douglas Hanahan (US) and Robert Allan Weinberg (US) suspect that growth-signaling pathways suffer deregulation in all human tumors (506).


Thomas Söllner, Sidney W. Whiteheart (US), Michael Brunner (US), Hediye Erdjument-Bromage (US), Scott Geromanos (US), Paul Tempst (US), and James Edward Rothman (US) reported that the existence of numerous SNARE-related proteins, each apparently specific for a single kind of vesicle or target membrane, indicates that NSF and SNAPs may be universal components of a vesicle fusion apparatus common to both constitutive and regulated fusion (including neurotransmitter release), in which the SNAREs may help to ensure vesicle-to-target specificity. Note: N-ethylmaleimide-sensitive fusion protein = NSF; soluble NSF attachment proteins = SNAPs; SNAP receptors = SNAREs (1179).


Lee W. Janson (US) and D. Lansing Taylor (US) proposed that amoeboid motion could be explained by contraction of the cortical gel in mid-regions and near the rear of an advancing amoeba (605).


Julie R. Pear (US), Rick A. Sanders (US), Kristin R. Summerfelt (US), Belinda Martineau (US), and William Hiatt (US) produced the first genetically engineered vegetables to reach the market. They were tomatoes in which the action of polygalacturonase (PG), a pectinase contributing to normal ripening, was blocked by the insertion of an antisense gene (976).


Kenichi Higo (JP), Yusuke Saito (JP), and Hiromi Higo (JP) created transgenic tobacco plants capable of producing epidermal growth factor; a mitogen (541).


Cynthia J. Kenyon (US), Jean Chang (US), Erin Gensch (US), Adam Rudner (US), Ramon Tabtiang (US), Kui Lin (CN), Jennie B. Dorman (US), and Aylin Rodan (US) found mutants of the hermaphroditic nematode Caenorhabditis elegans with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, which live more than twice as long as wild-type. These mutants are active and fully fertile and have normal metabolic rates. The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3(HNF-3)/forkhead family of transcriptional regulators (648; 763).

Honor Hsin (US) and Cynthia J. Kenyon (US) demonstrated that signals from the reproductive system influence the lifespan of the nematode Caenorhabditis elegans. This study demonstrates an inherent relationship between the reproductive state of this animal and its lifespan, and may have implications for the co-evolution of reproductive capability and longevity (565).


Rosalind C. Lee (US), Rhonda L. Feinbaum (US), and Victor R. Ambros (US) made a comparison of the lin-4 genomic sequence from four species and site-directed mutagenesis of potential open reading frames. They found that lin-4 does not encode a protein. Two small lin-4 transcripts of approximately 22 and 61 nt were identified in Caenorhabditis elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin-4 regulates lin-14 translation via an antisense RNA-RNA interaction (734; 735). Note: lin-4 is essential for the normal temporal control of diverse postembryonic developmental events in C. elegans.

Amy E. Pasquinelli (US), Brenda J. Reinhart (US), Frank J. Slack (US), Betsy Maller (US), Mitzi I. Kurodo (US), Mark Q. Martindale (US), Ashok Srinivasan (US), Mark Fishman (US), David C. Hayward (US), Eldon E. Ball (US), Bernard Degnan (US), Peter Müller (US), John Finnerty (US), Michael Levine (US), Patrick Leahy (US), Eric Davidson (US), and Gary B. Ruvkun (US), discovered a second tiny regulatory RNA in worms of exactly the same size as the lin-4 RNA and in the same genetic pathway. Similar to the lin-4 RNA, this let-7 RNA dampens activity of its target gene through its 3' UTR. Furthermore, its sequence too resides within a larger molecule that folds up on itself to form a double-stranded hairpin structure (972).

Brenda J. Reinhart (US), Frank J. Slack (US), Michael Basson (US), Amy E.  Pasquinelli (US), Jill C. Bettinger (US), Ann E. Rougvie (US), H. Robert Horvitz (US), and Gary B. Ruvkun (US) found that many other creatures including humans, fruit flies, chickens, frogs, zebrafish, mollusks, and sea urchins, carry their own versions of let-7, which could also fold into hairpins. The apparent binding site for let-7 RNA in its target was conserved in some of these organisms as well. Moreover, let-7 RNA appeared and disappeared at similar points during development in many of the animals (1049).

Phillip D. Zamore (US), Thomas Tuschl (US), Phillip A. Sharp (US), and David P. Bartel (US) examined the molecular mechanism underlying RNAi. We find that RNAi is ATP dependent yet uncoupled from mRNA translation. During the RNAi reaction, both strands of the dsRNA are processed to RNA segments 21-23 nucleotides in length. Processing of the dsRNA to the small RNA fragments does not require the targeted mRNA. The mRNA is cleaved only within the region of identity with the dsRNA. Cleavage occurs at sites 21-23 nucleotides apart, the same interval observed for the dsRNA itself, suggesting that the 21-23 nucleotide fragments from the dsRNA are guiding mRNA cleavage (1391).

Note: Double-stranded RNA (dsRNA) directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi).

Note: In 2001, Victor R. Ambros's group (US), as well as those of David Bartel (US) and Thomas Tuschl (DE) discovered almost 100 of these small regulatory RNAs in flies, humans, and worms.

In 2001, the Mello, Ruvkun, and Fire groups collaborated to show that efficient liberation of the lin-4 and let-7 RNAs from the hairpin molecules relies on the C. elegans version of Dicer, an enzyme that Gregory Hannon (US) discovered and named for its ability to chop dsRNA into uniformly sized, small RNAs that direct mRNA destruction during RNAi. These results and others, including similar ones generated by Philip Zamore (US), cemented the connection between miRNAs and RNAi, thus providing one biological 'reason' for the RNAi machinery.

The human genome contains more than 500 and perhaps as many as 1000 miRNAs that could collectively control a third of all of our protein-producing genes. These regulatory molecules have been implicated in a wide range of normal and pathological activities. They play roles not only in embryonic development, but in blood-cell specialization, cancer, muscle function, heart disease, viral infections, and possibly neurological signaling and stem-cell behavior. Researchers are exploring the possibility of using miRNAs 'signatures' for diagnosis and prognosis and are considering manipulating their quantities for therapeutic purposes.

Frank Ratcliff (GB), Bryan D. Harrison (GB), David C. Baulcombe (GB), Andrew J. Hamilton (GB), Tamas Dalmay (GB), Stephen Rudd (GB), Susan Angell (GB), Olivier Voinnet (GB), and Louise Chappell (GB) established that small RNAs silence genes in plants as well, thus catalyzing discoveries of many such RNAs in a wide range of living things. Their findings led to the identification of the biochemical machinery that unifies numerous processes by which small RNAs govern gene activity (261; 499; 500; 1041). See, Fire 1991 and 1998


Claude Lévi (FR) introduced the use of reproductive characters for the higher classification of Demosponges (744; 745). He is commemorated by Acarnus claudei Van Soest et al., 1991; Acarnus levii Vacelet, 1960; Diacarnus levii Kelly-Borges & Vacelet, 1995; Levinella Borojevic & Boury-Esnault, 1986; Levinellidae Borojevic & Boury-Esnault, 1986; Microciona levii Sarŕ & Siribelli, 1960; Paresperella levii Uriz, 1989; Tethya levii Sarŕ, 1988; Lekanesphaera levii Argano & Ponticelli, 1981; and Seguenzia levii B.A. Marshall, 1991.


James C. Smith (GB) discovered mesoderm-inducing factors in Xenopus embryos (1169).


John A. Eisman (AU), Paul J. Kelly (AU), Nigel A. Morrison (AU), Nicholas A. Pocock (AU), Rosanna Yeoman (AU), Joan Birmingham (AU), and Philip N. Sambrook (AU) found that the vitamin D receptor is associated with variability in susceptibility to osteoporosis (314).


Peter Agre (US), Gregory M. Preston (US), Barbara L. Smith (US), Jin Sup Jung (US), Surabhi Raina (US), Chulso Moon (US), William B. Guggino (US), and Sřren Nielsen (DK) discovered the aquaporin membrane water channels thus answering a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders (16).


The landmark national collaborative study called the DCCT (Diabetes Control and Complications Trial) was published. The DCCT conclusively demonstrated the value of tight glucose control in type 1 diabetes. The study clearly revealed that better control leads to better outcomes (214).


David M. Danks (AU) located the gene for Huntington’s disease on the short arm of chromosome number 4 (262).


Harry T. Orr (US), Ming-yi Chung (US), Sandro Banfi (US), Thomas J. Kwiatkowski Jr. (US), Antonio Servadio (US), Arthur L. Beaudet (US), Alanna E. McCall (US), Lisa A. Duvick (US), Laura P. W. Ranum (US), and Huda Y. Zoghbi (US) determined that spinocerebellar ataxia type 1 was caused by an expansion of the glutamine-coding CAG trinucleotide repeat in this gene (953).

Sandro Banfi (US), Antonio Servadio (US), Ming-yi Chung (US), Thomas J. Kwiatkowski Jr. (US), Alanna E. McCall (US), Lisa A. Duvick (US), Ying Shen (US), Elizabeth J. Roth (US), Harry T. Orr (US), and Huda Y. Zoghbi (US) identified ATXN1 as the gene responsible for spinocerebellar ataxia type 1 (SCA1) (65).

Christopher J. Cummings (US), Michael A. Mancini (US), Barbara Antalffy (US), Donald B. DeFranco (US), Harry T. Orr (US), and Huda Y. Zoghbi (US) demonstrated that the misfolding, aggregation, and degradation of the protein product of this gene, ataxin-1, plays a role in the disorder, a finding relevant to other, more common neurodegenerative diseases such as Alzheimer's (255).


Huntington's Disease Collaborative Research Group (US), Huntington G. Willard (US), Russell G. Snell (GB), John C. MacMillan (GB), Jeremy P. Cheadle (GB), Iain Fenton (GB), Lazarus P. Lazarou (GB), Peter Davies (GB), Marcy E. MacDonald (US), James F. Gusella (US), Peter S. Harper (GB), Duncan J. Shaw (GB), Anne Norremolle (DK), Olaf Riess (DK), Jörg T. Epplen (DK), Kristen Fenger (DK), Liz Hasholt (DK), and Sven A. Sorensen (DK) found that near the middle of the gene associated with Huntington’s disease the trinucleotide CAG is repeated 9-34 times in the normal allele and 30-70 times in the disease allele (469; 935; 1172; 1347). The Danish group determined that the normal allele produces a protein called Huntingtin.


Akitada Ichinose (JP) and Earl Warren Davie (US) reported the complete amino acid sequences of all the known blood coagulation factors and the DNA sequences coding for the genes for all the clotting factors (577).


Elaine Tuomanen (US) found that the agent of whooping cough, Bordetella pertussis, fools the body’s defense mechanisms by producing a chemical signal which interferes with the ability of patrolling white blood cells to recognize the address at their destination (1276). See, Tuomanen, 1988.  Note: This chemical might be useful as a highly selective anti-inflammatory agent to treat inflammation in the brain, joints, eyes and other sites where the surrounding tissues must be protected from the immune system as well as from invaders.


Alan T. Hudson (GB) reported that atovaquone, a member of the hydroxynaphthoquinone family, is an outstanding antimalarial drug (570).


Yael Katz-Levy (IL), Susan L. Kirshner (IL), Michael Sela (IL), and Edna Mozes (IL) synthesized two immunodominant myasthenogenic T cell epitopes (p195–212 and p259–271) derived from an alpha-subunit of the nicotinic acetylcholine receptor (AchR) (639).

Miri Paas-Rozner (IL), Molly Dayan (IL), Yoav Paas (FR), Jean-Pierre Changeux (FR), Itzhak Wirguin (IL), Michael Sela (IL), and Edna Mozes (IL) found that when administered orally, the dual analog (p195–212 and p259–271) could treat experimental allergic myasthenia gravis (EAMG) induced in mice by immunization with the multideterminant native Torpedo AChR (TACHR)  (957). Note: Torpedo is a genus of electric ray fishes.


Maria Victoria Valero (CO), Luis Roberto Amador (CO), Claudia Galindo (CO), Jorge Figueroa (CO), Mary Stella Bello (CO), Luis Angel Murillo (CO), Ana Lucia Mora (CO), Gloria Patarroyo (CO), Claudia Lucia Rocha (CO), Mauricio Rojas (CO), John Jairo Aponte (CO), Luis Eduardo Sarmlento (CO), Diana M. Lozada (CO), Carlos Gustavo Coronell (CO), Norella M. Ortega (CO), Jaiver E. Rosas (CO), Manuel Elkin Patarroyo (CO), and Pedro Luis Alonso (ES) reported on the first successful large scale malaria vaccine trial in South America  (1285).


Richard J. Cristiano (US), Louis C. Smith (US), Mark A. Kay (US), William R. Brinkley (US), Savio L.C. Woo (US), Steven Rothenberg (US), Charles N. Landen (US), Dwight A. Bellinger (US), Francis Leland (US), Carol Toman (US), Milton Finegold (US), Arthur R. Thompson (US), Marjorie S. Read (US), and Kenneth M. Brinkhous (US) announced that gene therapy in dogs with hemophilia B has provided short-term relief from bleeding, an important first step toward a permanent cure  (251; 252; 644).


Jeffrey B. Ulmer (US), John J. Donnelly (US), Suezanne E. Parker (US), Gary H. Rhodes (US), Philip L. Felgner (US), Varavani J. Dwarki (US), Stanisiaw H. Gromkowski (US), R. Randall Deck (US), Corrille M. DeWitt (US), Arthur Friedman (US), Linda A. Hawe (US), Karen R. Leander (US), Douglas Martinez (US), Helen C. Perry (US), John W. Shiver (US), Donna L. Montgomery (US), and Margaret A. Liu (US) were among the first to successfully vaccinate animals with plasmid DNA encoding a specific gene, in their case influenza A nucleoprotein. They generated nucleoprotein-specific cytotoxic T lymphocytes and protection from a subsequent challenge with a heterologous strain of influenza A virus  (1284). Note: This technology is now being used to generate immunity to a host of antigens, from malaria to cancer.


Seamas C. Donnelly (GB), Robert M. Strieter (GB), Steven L. Kunkel (GB), Alfred Walz (GB), Colin R. Robertson (GB), David C. Carter (GB), Ian S. Grant (GB), Antony J. Pollok (GB), and Christopher Haslett (GB) provided evidence of a relation between the presence of interleukin-8 in early bronchioalveolar lavage (BAL) samples and the development of acute respiratory distress syndrome (ARDS). The early appearance of interleukin-8 in BAL of patients at risk of ARDS may be an important prognostic indicator for the development of the disorder and reinforces the likely importance of neutrophils and the effects of their accumulation and activation in the pathogenesis of many cases of ARDS  (289).

Rolf Rossaint (DE), Konrad J. Falke (DE), Frank Lopez (DE), Klaus Slama (DE), Ulrich Pison (DE), and Warren N. Zapol (DE) found that inhalation of nitric oxide by patients with severe adult respiratory distress syndrome (ARDS) reduces the pulmonary-artery pressure and increases arterial oxygenation by improving the matching of ventilation with perfusion, without producing systemic vasodilation  (1073).

Gordon R. Bernard (US), Antonio Artigas (ES), Kenneth L. Brigham (US), Jean Carlet (FR), Konrad J. Falke (DE), Leonard Hudson (US), Maurice Lamy (FR), Jean Roger LeGall (FR), Alan Morris (US), Roger Spragg (US), and The Consensus Committee clarified and sharpened definitions, mechanisms, and relevant outcomes as they pertained to adult acute respiratory distress syndrome (ARDS). They also set up a mechanism for clinical trial coordination  (100).

Alan H. Morris (US), C. Jane Wallace (US), Ronald L. Menlove (US), Terry P. Clemmer (US), James F. Orme, Jr. (US), Lindell K. Weaver (US), Nathan C. Dean (US), Frank Thomas (US), Thomas D. East (US), Nathan L. Pace (US), Mary R. Suchyta (US), Eduardo Beck (ES), Michela Bombino (ES), Dean F. Sittig (US), Stephen Böhm (US), Barbara Hoffmann (US), Hayo Becks (US), Samuel Butler (US), James E. Pearl (US), and Brad Rasmusson (US) performed controlled trials comparing extracorporal gas exchange (and thereby resting the injured lung) with mechanical ventilatory support (which may increase lung inflammation). They showed that survival was not significantly different in 19 patients subjected to mechanical ventilation and 21 patients undergoing extracorporal support for severe ARDS (880).

G. Umberto Meduri (US), A. Stacey Headley (US), Emmel Golden (US), Stephanie J. Carson (US), Reba A. Umberger (US), Tiffany Kelso (US), and Elizabeth A. Tolley (US) determined that prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and multiple organ dysfunction syndrome (MODS) scores and reduced mortality  (848).


Sheena Kinmond (GB), Thomas C. Aitchison (GB), Barbara M. Holland (GB), John G. Jones (GB), Tiffany L. Turner (GB), and Charles A.J. Wardrop (GB) found that among preterm infants randomized to delayed cord clamping for 30 seconds after birth required less cardiorespiratory intervention, less supplemental oxygen and fewer blood transfusions compared to controls (659).


Robert S. Kirsner (US), Vincent Falanga (US), and William H. Eaglstein (US) described the ability of skin allografts to release growth factors as well as to act as pharmacologic agents  (664).

Alberto Bolgiani (AR) and Fortunato Benaim (AR) reported that skin allografts provided by tissue banks were routinely used in burn centers as a temporary cover for serious burn wounds  (121; 128).


Georg Gosztonyi (DE) Bernhard Dietzschold (US), Moujahed Kao (DE), Charles E. Rupprecht (US), and Hilary Koprowski (US) determined that during rabies viral antigens are almost exclusively found on neurons  (438).


The IFNB Multiple Sclerosis Study Group reported that interferon beta-1b (IFNB) is the only treatment that has substantially altered the natural history of multiple sclerosis (MS) in a properly controlled clinical trial (474).


Joan Goverman (US), Andrea Woods (US), Lisa Larson (US), Leslie P. Weiner (US), Leroy Hood (US), and Dennis M. Zaller (US) constructed a transgenic mouse model that mimics the human autoimmune disease multiple sclerosis in its spontaneous induction and pathology. This model system affords a unique opportunity to dissect the genetic and environmental variables that may contribute to the development of spontaneous autoimmune disease (443).

Juan J. Lafaille (US), Kumiko Nagashima (US), Motoya Katsuki (JP), and Susumu Tonegawa (US) produced data indicating that experimental autoimmune encephalomyelitis (EAE) can be mediated by CD4+ anti-myelin basic protein T cells in the absence of any other lymphocytes and that nontransgenic lymphocytes that are present in transgenic T/R+ but absent in T/R- mice have a protective effect. The data also suggested that spontaneous EAE may be triggered by an in situ activation of CD4+ anti-MBP cells in the nervous system (708).


Richard H.T. Edwards (GB), Henry Gibson (GB), John E. Clague (GB), and Timothy Helliwell (GB) reported that the symptoms of chronic fatigue syndrome or myalgic encephalitis (ME) were shown to be due to general fatigue rather than a myalgic disorder (312).


Thandavarayan Ramamurthy (IN), Surabhi Garg (IN), Rakhi Sharma (IN), Sujit K. Bhattacharya (IN), Gopinath Balakrish Nair (IN), Toshio Shimada (JP), Tae Takeda (JP), Tadahiro Karasawa (JP), Hisao Kurazano (JP), Amit Pal (PK), and Yoshifumi Takeda (JP) reported emergence of a novel strain of Vibrio cholerae with epidemic potential in southern and eastern India