A Selected Chronological Bibliography of Biology and Medicine
by James Southworth Steen, Ph.D.
to my loving family
document celebrates those secondary authors and laboratory technicians without
whom most of this great labor of discovery would have proved impossible.
forward any editorial comments to: James S. Steen, Ph.D., Professor Emeritus, email@example.com
why medical history is not much taught in medical schools is that so much of it
is an embarrassment.” Lewis Thomas (1451).
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.
Betzig (US) and Jay K. Trautman (US) produced a near-field super-resolution
image of a biological sample for the first time (123). 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.
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 of calcite
(MS/U-series). 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 years old (909).
(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 (950).
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 GFP-2 genomic clone is comprised of at least
three exons spread over 2.6 kb (1179).
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 (224).
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 (16).
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 (1037).
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 (782).
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 (996). The method
is accurate from 500 to 300,000 years ago.
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 (997).
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 (247).
Bazan (US) determined the tertiary structure of interleukin-2 (IL-2) (103).
(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 (912).
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 (987).
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 (730).
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 (1375).
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 (1168). 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 (1446).
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" (65).
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 (542).
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 (390). Note: 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 way (181).
Paillard (US) described "Tet-on":
a gene switch for the exogenous regulation of transgene expression (1119).
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 (208).
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 (500). 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 (1403).
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 (248).
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 (686).
(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 (710)
(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
(840). 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
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 (209).
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 (772).
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 (666).
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 (738).
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 (1544).
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 (72).
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 (1435).
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 (1507).
Williams (GB), Marc Feldmann (GB), and Ravinder Nath Maini (GB) showed that
anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced
arthritis (1575). Note:
This research was in response to the considerable evidence
implicating tumor necrosis factor (TNF-a) in the
pathogenesis of rheumatoid arthritis.
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 (1050).
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 (866; 978).
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 (1085).
(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 (1081).
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 (317).
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 (329; 445; 1493).
McLaughlin (US), Peter J. McKinnon (US), and Robert F. Margolskee (US)
discovered gustducin, a taste cell expressed G protein (976). 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 (183; 662; 663).
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 (1106).
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 (331; 339). 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 (1260).
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 (1506).
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 (951).
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) (595).
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 (1431).
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 (1182).
species of the cholera bacteria (O139) was discovered in Bangladesh. It has
since been detected in 11 countries raising the possibility of future pandemics
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 (1090).
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 (48).
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 (1387).
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 (1082).
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 (1101).
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 (1254).
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 (580).
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 (159; 767; 768).
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) (49).
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 (108).
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 (320; 966).
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
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) (1156).
E. Czeizel (HU) and István Dudás (HU) found that periconceptional vitamin use
decreases the incidence of a first occurrence of neural tube defects (307).
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 (521).
Gagner (CA), Andre Lacroix (CA), and Edouard Bolté (CA) reported the successful
use of a laparoscopic approach to adrenalectomy in three patients for Cushing's
disease/syndrome and a right-sided phaeochromocytoma (level 4 evidence). They
concluded that laparoscopic adrenalectomy is safe, effective, and associated
with a rapid recovery and low complication rate. Venous thromboprophylaxis was
strongly recommended to avoid potential post-operative morbidity (457).
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
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 (1545).
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 (377).
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 (636).
Moore (US), David V. Feliciano (US), Richard J. Andrassy (US), Allan H. McArdle
(US), Frank McL. Booth (US), Tina B. Morgenstein-Wagner (US), John M. Kellum,
Jr. (US), Richard E. Welling (US), and Ernest E. Moore (US) showed that in
high-risk surgical patients early nutrition reduces post-operative septic
complications and where possible the GI tract should be preferred as a route of
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.
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 (1206).
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 (1208).
introduced “Public Health Focus:
Effectiveness of Disease and Injury Prevention” published monthly in the MMWR (1).
(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 (591). 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 (1530). 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) (520)
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) (850). This concept was first
articulated by Ludwig Boltzmann (DE) (149), then refined by Erwin
Schrödinger (DE) (1303).
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) (1012).
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) (1034).
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 (1134). See, Crane, 1961
All is Fair in Love and Warts
“He proclaimed she had
given him warts
Of the most ignominious
Said that her papilloma
Had entered his soma
And the issue was clearer
She denies having given him
Says that, his allegation
It's incredibly plain
That they differ by strain
As shown in my doctor's
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
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.
Roberts (GB) and Phillip Allen Sharp (GB-US) were awarded the Nobel Prize in
Physiology or Medicine for their independent discoveries of split genes.
David C. Schwatz (US), Xiao Jun Li (US), Luis I. Hernandez (US),
Satyadarshan P. Ramnarain (US), Edward J. Huff (US), and Yu-ker Wang (US) developed
a method for creating a “visual physical map” along large DNA molecules
(similar in principle to a restriction enzyme map), by which one can correlate
DNA sequence with physical location (1305). Note: Optical mapping is
useful for completing large genome projects (chromosome sized-contigs) and
other applications, such as the identification of rearrangements in genomes. It
can be used to assist in genome assembly, compare genomic structures, and
correct genome assembly errors. It can also be used for comparing strain
differences, for instance in medical microbiology applications. A major advantage
of this method is that it avoids cloning or PCR artifacts and analyzes a single
molecule at a time.
Corey (US) and Yong-Jin Wu (US) carried out the total synthesis of
paeoniflorigenin and paeoniflorin (282).
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 (232). Note: Barry G. Hall
(US), in 1978, was the first person to use directed evolution for optimizing
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 (328).
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 (1152).
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 (884).
"Dickon" Alley (US), Janine Maddock (US), and Lucy Shapiro (US) were
able to show that chemoreceptor proteins occupy specific areas within the
bacterial cell (34; 923).
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 (699).
(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 (698; 831; 832).
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" (1520).
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 (508; 1008; 1172). 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 (634).
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 (1559; 1560). 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
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 (563).
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 (877).
(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 (1428).
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
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(160).
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 (1490-1492).
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 (1505).
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 (1452). Note: The Mediator complex
appears in all eukaryotes. It is a protein complex physically associated with
RNA polymerase II during transcription.
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 (168).
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 (289; 290; 465; 510; 609; 743; 797; 1018; 1019; 1281; 1338; 1612).
(US), Kirk W. Johnson (US), and Kendall A. Smith (US) isolated interleukin
2-induced immediate-early genes (104).
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) (984).
Moore (US) and Günter Klaus-Joachim Blobel (DE-US) made a similar finding in Xenopus
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 (13; 14; 516; 1197).
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 (448).
(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 (487).
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
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+
(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 (1335).
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 (1477).
(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 (1514).
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 (405). Note: The use of this
phrase in infectious disease research began in early 2000 in reports on
cytomegalovirus (88), Epstein-Barr
virus-associated hemophagocytic lymphohistiocytosis (678), group A streptococcus (128), influenza virus (1611), variola virus (703), and severe acute respiratory
syndrome coronavirus (SARS-CoV) (661). The phrase appears to have
first been applied in the context of avian H5N1 influenza virus
infection in 2005 (1618).
(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 (1194).
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 (56; 1271).
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 (319).
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 (1105; 1498).
Seddon (GB) and Don Mason (GB) were the first to provide evidence that target
organ specificity of Treg cells provides protection against organ-specific
(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 (526).
(), 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
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 (1395). 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.
(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 (477).
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 (1457).
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 (1026).
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 (1084). 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 (1487).
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 (658). 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 (1409).
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 (700).
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 (353; 354).
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 (1573). 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.
(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 (1615).
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 (161).
(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 (1389).
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 (42).
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 (41).
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% (389).
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
Hanahan (US) and Robert Allan Weinberg (US) suspect that growth-signaling
pathways suffer deregulation in all human tumors (592).
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 (1376).
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 (704).
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 (1139).
(JP), Yusuke Saito (JP), and Hiromi Higo (JP) created transgenic tobacco plants
capable of producing epidermal growth factor; a mitogen (630).
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 (751; 876).
(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
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 (844; 845). 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 (1133).
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 (1224).
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 (1622).
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.
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 (312; 585; 586; 1212). See,
Fire 1991 and 1998
(FR) introduced the use of reproductive characters for the higher
classification of Demosponges (854; 855). 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.
Smith (GB) discovered mesoderm-inducing factors in Xenopus embryos (1364).
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 (370).
(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 (20).
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 (252).
Danks (AU) located the gene for Huntington’s disease on the short arm of chromosome