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RIP's - The poisons that heal - National Institute
N A T I 0 N A L I N S T I T U T E S 0 F H E A L T H
National Institute of General Medical Sciences
Research Reports
September 1993
Editor: Doris Brody
(301) 496-7301
Research Reports, a feature service by the Office of Research
Reports of the National Institute of General Medical Sciences, is
designed to let you know what some of our grantees are doing.
This issue contains a list of a number of recent NIGMS grant
awards and the following stories:
RIP'S: The Poisons that Heal
RIP's are highly toxic plant products with cell-killing and
antiviral actions. Scientists are interested in harnessing
their effects for medical and agricultural uses. Now that
researchers understand how RIP's function, these goals are
closer to being realized.
RIP'S: The Poisons that Heal
"Plants could kill themselves many times over, but they
don't," says Maureen Bonness, Ph.D., of the University of Texas
at Austin. Her comment refers to the presence in plants of
RIP's (ribosome inactivating proteins), the aptly named molecules
that can kill cells of a plant's enemies. RIP's work by
disrupting ribosomes, which oversee and orchestrate the
production of proteins. Clearly, if the powerful cell-poisoning
potential of RIP's could be directed at unwanted cells, such as
cancer cells and virus-infected cells, RIP's could become
valuable therapeutic agents.
RIP's are found in the roots, leaves, and seeds of plants as
different as mistletoe, carnations, barley, and corn. They
defend the plants against both tiny enemies (viruses) and larger
ones (animals). "RIP's," says Dr. Bonness, "have an uncanny
ability to enter virus-infected cells and kill them selectively."
They are just one component of the diverse defensive
armamentarium of plants, which, unlike animals, cannot run away
from their attackers.
Scientists have been studying RIP's for almost a quarter of
a century. The first RIP to be studied was one made by an herb,
pokeweed (Phytolacca americans). Pokeweed plants have edible
shoots much like asparagus, but their tantalizingly juicy purple
berries and their roots are poisonous to people and animals.
In 1987, researchers discovered exactly how RIP's bring
protein production to a standstill. With surgical precision,
RIP's clip away a single base in the RNA of the cell's ribosomes.
This minor but specific excision causes a devastating structural
change in the ribosome.
Early studies of pokeweed RIP's raised the interesting
possibility that pokeweed plants might be protected from the
toxicity of their own RIP'S. But Dr. Bonness, working in the
laboratory of NIGMS grantee Tom Mabry, Ph.D., demonstrated that
pokeweed ribosomes are just as susceptible to pokeweed RIP's as
are other ribosomes.
Dr. Bonness prepared RIP-free pokeweed ribosomes that were
actively producing proteins. When she added pokeweed RIP to the
ribosomes, protein synthesis stopped. Despite an extensive
search, she found no evidence for a factor in the cell that was
repressing RIP actions under normal circumstances.
Thus, Dr. Bonness concluded that poison and target can
coexist in the same cell, because RIP's are stored in the walls
of pokeweed cells, far from the ribosomes they destroy. Only
when an infectious virus disrupts the wall of a leaf cell are the
RIP molecules liberated. Then, as the virus attempts to co-opt
the cell's machinery, the pokeweed RIP's find the pokeweed
ribosomes, clip the bases, and thereby halt the production of
infectious virus particles.
Scientists predict that the practical uses of RIP's will be
many and varied. Agriculture researchers are attempting to
combat costly viral diseases by transferring the genes for RIP's
into a number of crop plants that do not seem to have their own.
Medical researchers are interested in RIP's for several
reasons. One is that RIP's have the unusual ability to prevent
viral infections-in animal cells as well as in the cells of
plants. For example, both pokeweed RIP and the RIP from Chinese
cucumbers, which is called Compound Q, block production of the
human immunodeficiency virus by animal cells in laboratory
experiments. (Compound Q is a traditional Chinese medicine that
is taken by some AIDS patients, but that has not been approved
for treating AIDS.)
RIP's are also interesting because they kill cells by
halting protein production. Might they be the "magic bullets"
that will selectively kill cancer cells, cells of the immune
system that make transplantation difficult or that cause
autoimmune diseases, and cells in grafted tissues that react
against the transplant recipient?
For RIP's to kill cells successfully and selectively, they
must locate the cells of interest, be internalized, and retain
their base-removing activity. Several strategies are under
development for achieving localization and selective killing.
Pokeweed RIP and the RIP from castor bean seeds, which is called
ricin, have been attached to antibodies that carry them to target
cells in the immune system that are recognized by the antibody.
These RIP-antibody "immunotoxins" do kill their targets.
Scientists are also exploring techniques for incorporating RIP's
into sacs, like empty red blood cells, that can then fuse with
target cells.
The RIP's now under study may represent just the tip of the
RIP iceberg. Dr. Mabry has pointed out that nature tends to
reuse successful devices, and it is therefore likely that similar
potent defensive substances will be found in a range of other
types of cells. Earlier this year, for example, scientists
concluded that the toxins that contaminated hamburgers in a fast-
food chain and fresh-pressed cider were most likely bacterial
RIP'S.
Ruth Levy Guyer
Recent NIGMS Grant Awards
This sampling of titles from the more than 3,000 grant
awards NIGMS makes each year is designed to give you an idea of
the basic research the Institute supports. A computer printout
of all current (new and continuing) NIGMS grants at your
institution is available from us, if you request it. Among the
awards that were made in late 1992 are the following:
Bowman Gray School of Medicine
H. Alexander Claiborne, Jr.: "Mechanisms Involved in Flavin-
linked Oxygen Metabolism"
Health Science Center at Syracuse
David R. Mitchell: "Molecular and Genetic Analysis of Flagellar
Dyneins"
Iowa State University of Science and Technology
Jack Horowitz: "Transfer Ribonucleic Acid Structure and Function"
Kansas State University
Michael R. Kanost: "Serine Proteinase Inhibitors in Insects"
Medical College of Wisconsin
Kalpana Chakraburty: "Regulation of Ribosomal Reactions"
Michigan state University
John R. Stille: "Selective Intramolecular Carbon-Carbon Bond
Formation"
New York University
Gloria M. Coruzzi: "Regulation of Amino Acid Biosynthesis Genes
in Plants"
Ohio State University
Berl R. Oakley: "Molecular Biology of Microtubule-Interacting
Proteins"
Pennsylvania State University--University Park
Kenneth A. Johnson: "Mechanism and Fidelity of DNA Replication"
Rice University
John S. Olson: "Functional Properties of Hemoglobins and
Myoglobins"
Sloan-Kettering Institute for Cancer Research
Stewart H. Shuman: "Vaccinia Virus DNA Topoisomerase I"
State University of New York, Stony Brook
Charles H. Lang: "Mechanisms of Insulin Resistance in sepsis"
Syracuse University
Joan Maddox Belote: "Molecular Study of a Sex Transformer Gene in
Drosophilall
Texas A & M University, College Station
Frank M. Raushel: "Isotopic Probes of Enzymatic Reaction
Mechanisms"
University of California, Irvine
Francisco J. Ayala: "Evolutionary Genetics of a Model System"
University of California, Santa Barbara
Jacob N. Israelachvili: "Structure and Interactions of Model
Biomembranes"
University of Chicago
William D. Wulff: "Synthetic Applications of Carbene Complexes"
University of Colorado at Boulder
Susan K. Dutcher: "Genetic Analysis of Basal Body Function"
University of Florida
Philip J. Laipis: "Genetic Analysis of Mammalian Mitochondrial
Inheritance"
University of Houston
William R. Widger: "Genomic Organization of Photosynthetic Genes"
University of Iowa
Chi-Lien Cheng: "Transcriptional Control of Arabidopsis Nitrate
Reductasell
University of Maryland, Baltimore
Daniel N. Darlington: "Death and Shock from Adrenal
Insufficiency"
University of Michigan
C.H. Williams, Jr.: "Structure and Mechanism of Flavoenzymes"
University of Minnesota
Lawrence Que, Jr.: "Non-Heme Iron Oxygen Activation in Enzymes
and Models"
University of Mississippi medical center
Mona T. Norcum: "Structure of Aminoacyl-tRNA Synthetase
Complexes"
University of Missouri, Columbia
John F. Cannon: "Type 1 Protein Phosphatase of S. cerevisiaell
University of Nebraska, Lincoln
Carolyn M. Price: "Telomere Structure in Euplotes crassus"
University of Notre Dame
Robert W. Scheidt: "X-Ray and Chemical Studies of
Metalloporphyrins"
University of Pittsburgh
Robert A. Branch: "Mechanisms of Amphotericin B Nephrotoxicity"
University of Rhode Island
Ching-Shih Chen: "Metabolic Stereoisomeric Inversion of Chiral
Drugs"
University of Southern California
Roger F. Duncan: "Heat Stress Effects on Protein Synthesis"
University of Tennessee at Memphis
Lawrence M. Pfeffer: "Interferon Action on Cell Structure and
Proliferation"
University of Texas at Austin Stephen F. Martin: "Design and
Synthesis of Novel Pseudopeptides"
University of Vermont & State Agricultural College
Douglas J. Taatjes: "Subcompartmentation of Golgi Apparatus
Glycosylation"
University of Wisconsin, Madison
Patricia J. Kiley: "Regulation of Gene Expression by Oxygen"
Vanderbilt University
Roger J. Colbran: "Regulation of Calmodulin-Dependent Protein
Kinase III'
Virginia Commonweadth University
Mark S. Rosenkrantz: "Control of Citrate Synthase Expression in
Yeast"
Washington State University
Bruce A. McFadden: "Biochemistry of Membrane and Catalytic
Proteins"
Washington University
Elliot L. Elson: "Biophysical Studies of Cytoskeletal Function"
Yale University
Nancy Maizels: "Molecular Mechanisms of Isotype Switch
Recombination"
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