A Selected Chronological Bibliography of
Biology and Medicine
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
Please forward any editorial comments to: James S. Steen, Ph.D., Professor Emeritus,
DSU Box 3262, Cleveland, MS 38733. email@example.com
reason why medical history is not much taught in medical schools is that so
much of it is an embarrassment.” Lewis Thomas (1244).
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.
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).
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).
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).
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).
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).
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).
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).
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
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).
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).
Fernando Bazan (US) determined the tertiary structure of interleukin-2 (IL-2) (86).
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
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).
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).
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).
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
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).
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).
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.
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
Paillard (US) described "Tet-on":
a gene switch for the exogenous regulation of transgene expression (961).
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.
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).
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.
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).
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).
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).
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)
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
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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
Soltanifar (CH), Günter Donn (DE), and Ingo Potrykus (CH) produced herbicide resistant rice plants through
polyethylene glycol (PEG) mediated transformation of protoplasts (265).
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).
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.
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).
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).
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).
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
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).
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).
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).
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
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).
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
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).
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
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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)
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).
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).
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
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).
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,
All is Fair in Love and Warts
proclaimed she had given him warts
most ignominious sorts
that her papilloma
entered his soma
the issue was clearer than quartz
denies having given him warts
that "His allegation distorts.
they differ by strain
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
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.
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.
James Corey (US) and Yong-Jin Wu (US) carried out the total synthesis of
paeoniflorigenin and paeoniflorin (239).
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.
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).
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).
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
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).
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).
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).
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).
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).
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
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).
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.
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).
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).
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
Michel Rohmer (FR), M’hamed Knani (FR),
Pascale Simonin (FR), Bertrand Sutter (FR), and Hermann Sahm (FR) described the
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.
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).
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).
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).
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.
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).
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).
Beadling (US), Kirk W. Johnson (US), and Kendall A. Smith (US) isolated
interleukin 2-induced immediate-early genes (87).
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).
Shannon Moore (US) and Günter Klaus-Joachim Blobel (DE-US) made a similar
finding in Xenopus oocytes (871).
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).
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).
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).
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).
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+
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).
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).
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).
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).
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).
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).
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).
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).
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).
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
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).
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.
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).
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).
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).
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).
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.
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).
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).
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.
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).
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).
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).
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).
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).
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).
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
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).
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).
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).
Higo (JP), Yusuke Saito (JP), and Hiromi Higo (JP) created transgenic tobacco
plants capable of producing epidermal growth factor; a mitogen (541).
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).
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).
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).
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
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.
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
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.
C. Smith (GB) discovered mesoderm-inducing factors in Xenopus embryos (1169).
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).
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).
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).
M. Danks (AU) located the gene for Huntington’s disease on the short arm of
chromosome number 4 (262).
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).
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).
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).
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
and the DNA sequences coding for the genes for all the clotting
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.
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)
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.
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).
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).
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.
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).
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).
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
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).
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).
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).
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).
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
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).
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
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).
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