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Genetically
Engineered
Mice
Handbook
Research Methods for Mutant Mice Series
Series Editor
John P. Sundberg
Systematic Approach to Evaluation of Mouse Mutations

John P. Sundberg and Dawnalyn Boggess
Systematic Evaluation of the Mouse Eye:

Anatomy, Pathology, and Biomethods
Richard S. Smith, Simon W. M. John,
Patsy M. Nishina, and John P. Sundberg
Genetically Engineered Mice Handbook

John P. Sundberg and Tsutomu Ichiki
Genetically
Engineered
Mice
Handbook
edited by
John P. Sundberg
Tsutomu Ichiki
Boca Raton London New York
A CRC title, part of the Taylor & Francis imprint, a member of the
Taylor & Francis Group, the academic division of T&F Informa plc.
Published in 2006 by
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2006 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8493-2220-0 (Hardcover)
International Standard Book Number-13: 978-0-8493-2220-4 (Hardcover)
Library of Congress Card Number 2005041899
This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
have been made to publish reliable data and information, but the author and the publisher cannot assume
responsibility for the validity of all materials or for the consequences of their use.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only
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Library of Congress Cataloging-in-Publication Data
Genetically engineered mice handbook / edited by John P. Sundberg and Tsutomu Ichiki.
p. cm. -- (Research methods for mutant mice series)
Includes bibliographical references and index.
ISBN 0-8493-2220-0 (alk. paper)
1. Transgenic mice--Handbooks, manuals, etc. I. Sundberg, John P. II. Ichiki, Tsutomu. III. Series.
QH470.M52G463 2005
616'.027333--dc22 2005041899
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We wish to thank our wives, Beth A. Sundberg and Noriko Ichiki,
for their support and encouragement in conception to completion of this book.
Preface
The laboratory mouse has unquestionably become the animal model of choice in
biomedical research. Three decades ago this was not obvious unless one counted
the numbers of models by species. Mice were always first, rats second, and
domestic companion animals third. Transgenic technology followed by targeted
mutagenesis and many variations thereof, collectively known as genetic engineer-
ing, rapidly brought the mouse to the head of the line as the premier model
organism. The problem that arose was a severe lack of expertise in what became
known as phenotyping. This is a modern term for detailed clinical and pathologic
evaluation of the patient, in this case, the mouse. To address this need, several
of us organized a meeting at the National Institutes of Health (NIH) in Bethesda,
Maryland, titled Pathology of Genetically Engineered Mice. This large open
meeting was followed by a series of similar meetings held in Stockholm, Sweden
and then Kumamoto, Japan on alternate years. The topic spread from being
focused on pathology of mice with spontaneous or genetically engineered muta-
tions, primarily, if not exclusively, single gene mutations, to a broader topic
initially on large scale phenotyping to an overview approach of the entire field.
This book, Genetically Engineered Mice Handbook, is an extension of the meeting
in Japan and attempts to bring the technology together into a centralized resource
as an aid to those entering the field.
The first meeting at NIH resulted in a book titled Pathology of Genetically
Engineered Mice. Much of the information revolves around traditional technology
that is still accurate and useful today. An obvious change is the predominance in
this current book of information focusing on publicly accessible databases. The
database approach merges the value of a hard-copy book with the plasticity of
web-based information resources, which, if maintained, will be regularly updated
and expanded. Knowing where to start and how to use these is the key. Complaints
on the pathology book focus on lack of coverage of some organ systems and its
being static and therefore not having information on new models. The current
book provides information on how to access databases that have this information
in a constantly expanding and updated format. Mouse pathology Websites are
now publically accessible. While in the past finding and working with an expert
on a particular organ system in mice was ideal, now groups of experts work
together to generate these websites, discuss and argue the data, and provide a
resource easily accessible. While this does not eliminate the need for a trained
pathologist to interpret the histopathology of a disease, these Websites provide
reference materials for those lacking expertise in particular anatomic structures.
The lack of adequate numbers of veterinarians trained in mouse clinical
medicine and pathology resulted in development of many imaging devices as
well as test apparatuses. Downsizing imaging tools used in human medicine has
now become commonplace. Many centers, particularly the mutagenesis centers,
developed testing systems for various organ systems, which, over time, have been
developed to high levels of accuracy. Technicians with relatively little training
can now perform many of these tasks.
Husbandry and microbiological monitoring are critical aspects of dealing
with any animal model system. These too have evolved to such a high level of
sophistication that specific microflora are needed to optimize experimental results
or else the presence of some agents can severely and negatively affect the outcome
of experiments. Examples of these approaches are provided.
The technology to generate mutant mice remains the same but also changes
very quickly. Spontaneous mutations remain the gold standard as we learn that
manipulation of the genome often results in unexpected findings that are artifacts
and not true representations of real life. The chemical mutagenesis approach, a
method of choice in decades past, became a major focus during the last 5 years.
Large scale ethylnitrosourea (ENU) chemical mutagenesis programs on several
continents were very active and generated many novel mutant mice or allelic
mutations of spontaneous mutant mice already characterized. The value of this
approach from a cost benefit perspective was questioned in recent years resulting
in the downsizing and closing of such projects in the United States and Germany.
Newer approaches are to generate repositories of embryonic stem cells (ES cells)
that carry null mutations with reporter constructs.
Genetic engineering methods have evolved into production line science. High
throughput phenotype screening programs have evolved to meet this demand to
some degree. Ultimately, scientists trained in clinical medicine, particularly in
pathology, are key to defining the real value of these mutant mice as models for
specific human diseases. Dramatic breakthroughs continue to emerge from studies
with these mouse models on the basic genetics, and to some degree the mecha-
nisms of disease. Now these models need to be used aggressively as preclinical
models to have a more direct impact on human patients. All of this is happening
and we can expect more exciting discoveries in the coming years.
Editors
John P. Sundberg, D.V.M., Ph.D. is a senior staff
scientist at The Jackson Laboratory in Bar Harbor,
Maine. Dr. Sundberg graduated summa cum laude
from the University of Vermont in 1973, and received
his doctor of veterinary medicine degree in 1978 from
Purdue University. After working in private practice
he received his Ph.D. in 1981 in virology from the
University of Connecticut where he also did a resi-
dency in anatomic pathology, passing the specialty
board examination in 1982. He worked as an assistant
professor and staff pathologist at the University of
Illinois College of Veterinary Medicine from
1981–1986 after which he joined The Jackson Labo-
ratory as a staff scientist and diagnostic pathologist. He served as head of pathol-
ogy there from 1989-2000. In 1998 he became a senior staff scientist.
He currently is a principal investigator studying genetically-based skin dis-
eases in laboratory mice as models for genetic diseases in humans. He is also
involved in setting up large scale drug efficacy trials at The Jackson Laboratory’s
West Sacramento, California facility for the mouse dermatology models he devel-
oped. His basic genetic research focuses on autoimmune (alopecia areata), pro-
liferative (psoriasis-like), and hair follicle developmental studies. He has pub-
lished nearly 300 scientific papers and more than 100 book chapters. This is his
sixth book on the biology, pathology, and management of laboratory mice.
Tsutomu Ichiki, Ph.D. is a general manager of Safety

Assessment Lab at Dainippon Ink and Chemicals, Inc.
in Sakura, Chiba, Japan. Dr. Ichiki graduated in 1979
from Kyusyu University in Fukuoka with a bachelor
of science degree in animal husbandry and obtained
his masters degree in 1981 from Kyusyu University.
Dr. Ichiki completed his residency in pathology,
and earned his Ph.D., from Fukuoka University School
of Medicine. Dr. Ichiki was a manager of the Pathology
Division at Panapharm Laboratories Co., Ltd. from
1985 to 2000. In 2000 he joined the staff scientist of
Transgenic Inc. In 2001 he served a sabbatical as vis-
iting investigator of The Jackson Laboratory until 2003.
Dr. Ichiki is a diplomate of Japanese Society of Toxicologic Pathology. He
is a member of the Society of Toxicologic Pathology in United States, and a
member of Planning and Managing Panel of the Long-range Research Initiative
in the Japan Chemical Industry Association.
Dr. Ichiki’s research interests focus on laboratory animals — especially on
mice and rats — for the health effects of various chemicals.
Contributors
Kimi Araki, Ph.D., Institute of James R. Fahey, Ph.D., D.V.M.,
Molecular Embryology and Genetics, American College of Veterinary
Kumamoto University School of Microbiologists, The Jackson
Medicine, Kumamoto, Japan. Laboratory, Bar Harbor, Maine,
United States.
Jonathan B. L. Bard, Ph.D.,
Department of Biomedical Martin D. Fray, Ph.D., Mammalian
Sciences, Edinburgh University, Genetics Unit, Medical Research
Edinburgh, United Kingdom. Council, Harwell, United Kingdom.
Carol J. Bult, Ph.D., The Jackson Jabier Gallego Llamas, M.Sc.,

Laboratory, Bar Harbor, Maine, Institut de Genetique et de Biologie
United States. Moleculaire et Cellulaire,
CNRS/INSERM/Universite Louis
Hsueh-Ping Chu, Ph.D., Institute of Pasteur, CU de Strasbourg, France.
Molecular Biology, Academia
Sinica, Nankang, Taipei, Taiwan and Peter H. Glenister, Mammalian
Graduate Institute of Biochemistry, Genetics Unit, Medical Research
National Yang-Ming University, Council, Harwell, United Kingdom.
Taipei, Taiwan.
Carroll-Ann W. Goldsmith, Sc.D.,
Bon-chu Chung, Ph.D., Institute of The Jackson Laboratory, Bar
Molecular Biology, Academia Harbor, Maine, United States.
Sinica, Nankang, Taipei, Taiwan.
Noomen Ben El Hadj, Ph.D., Institute
Pascal Dollé, M.D., Ph.D., Institut de of Molecular Biology, Academia
Genetique et de Biologie Sinica, Nankang, Taipei, Taiwan.
Moleculaire et Cellulaire,
CNRS/INSERM/Universite Louis Meng-Chun Hu, Ph.D., Graduate
Pasteur, CU de Strasbourg, France. Institute of Physiology, National
Taiwan University College of
David Einhorn, B.S.E., L.L.B., The Medicine, Taipei, Taiwan.
Jackson Laboratory, Bar Harbor,
Maine, United States. Tsutomu Ichiki, Ph.D., Japanese
Society of Toxicologic Pathology,
Janan T. Eppig, Ph.D., The Jackson Safety Assessment Laboratory,
Laboratory, Bar Harbor, Maine, Dainippon Ink and Chemicals, Inc.,
United States. Chiba, Japan.
Kimiko Inoue, Ph.D., Bioresource Tsutomu Mizoshita, M.D., Ph.D.,
Center, RIKEN, Tsukuba, Ibaraki, Division of Oncological Pathology,
Japan. Aichi Cancer Center Research
Institute, Nagoya, Japan.
Kikuji Itoh, Ph.D., Laboratory of
Veterinary Public Health, Graduate Naomi Nakagata, Ph.D., Center for
School of Agricultural and Life Animal Resources and
Sciences, The University of Tokyo, Development, Kumamoto
Tokyo, Japan. University, Kumamoto, Japan.
Takehito Kaneko, Ph.D., Division of Seiko Narushima, Ph.D., Food

Reproductive Engineering, Center Functionality Research Institute,
for Animal Resources and Meiji Dairies Corporation,
Development (CARD), Kumamoto Kanagawa, Japan.
University, Kumamoto, Japan.
Karen Niederreither, Ph.D.,
Departments of Medicine and
Shuichi Kani, Ph.D., Department of
Molecular and Cellular Biology,
Genome Sciences, Kobe University
Center for Cardiovascular
Graduate School of Medicine,
Development, Baylor College of
Kobe, Japan.
Medicine, Houston, Texas,
Hideki Katoh, Ph.D., Institute for United States.
Experimental Animals, Hamamatsu
H. Nishida, Center for Animal
University School of Medicine,
Resources and Development
Hamamatsu, Japan and ICLAS
(CARD) and Graduate School of
Monitoring Center, Central Institute
Molecular and Genomic Pharmacy,
for Experimental Animals,
Kumamoto University, Kumamoto,
Kanagawa, Japan.
Japan.
Isabelle Le Roux, Ph.D., Institut de Y. Ogino, Ph.D., Center for Animal
Génétique et de Biologie Resources and Development
Moléculaire et Cellulaire, (CARD) and Graduate School of
CNRS/INSERM/Universite Louis Molecular and Genomic Pharmacy,
Pasteur, CU de Strasbourg, France. Kumamoto University, Kumamoto,
Japan.
Hiromi Miki, Bioresource Center,
RIKEN, Ibaraki, Japan. Narumi Ogonuki, Bioresource Center,
RIKEN, Ibaraki, Japan.
Yasuhiro Minami, M.D., Ph.D.,
Department of Genome Sciences, Atsuo Ogura, Ph.D., D.V.M.,
Kobe University Graduate School of Bioresource Center, RIKEN,
Medicine, Kobe, Japan. Ibaraki, Japan.
T. Ohba, M.D., Ph.D., Center for Paul Schofield, M.A., D.Phil.,
Animal Resources and University of Cambridge,
Development (CARD) and Department of Anatomy,
Graduate School of Molecular and Cambridge, United Kingdom.
Genomic Pharmacy, Kumamoto
University, Kumamoto, Japan. John P. Sundberg, D.V.M., Ph.D.,
American College of Veterinary
S. Ohta, Ph.D., Center for Animal Pathologists, The Jackson
Resources and Development Laboratory, Bar Harbor, Maine,
(CARD) and Graduate School of United States.
Medical Sciences, Kumamoto
University, Kumamoto, Japan. K. Suzuki, Ph.D., Center for Animal
Resources and Development
Isao Oishi, Ph.D., Department of (CARD) and Graduate School of
Genome Sciences, Kobe University Molecular and Genomic Pharmacy,
Graduate School of Medicine, Kumamoto University, Kumamoto,
Kobe, Japan. Japan.
Vanessa Ribes, M.Sc., Institut de Makoto Mark Taketo, M.D., Ph.D.,

Génétique et de Biologie Department of Pharmacology,
Moléculaire et Cellulaire, Graduate School of Medicine,
CNRS/INSERM/Universite Louis Kyoto University, Kyoto, Japan.
Pasteur, CU de Strasbourg, France.
Masae Tatematsu, M.D., Ph.D.,
Martin Ringwald, Ph.D., The Jackson Division of Oncological Pathology,
Laboratory, Bar Harbor, Maine, Aichi Cancer Center Research
United States. Institute, Nagoya, Japan.
Stephen F. Rockwood, B.S., The Tetsuya Tsukamoto, M.D., Ph.D.,

Jackson Laboratory, Bar Harbor, Division of Oncological Pathology,
Maine, United States. Aichi Cancer Center Research
Institute, Nagoya, Japan.
Björn Rozell, D.D.S., Ph.D., D.V.M.,
Clinical Research Center, Julien Vermot, Ph.D., Institut de
Department of Laboratory Génétique et de Biologie
Medicine, Karolinska Institutet, Moléculaire et Cellulaire,
Karolinska University Hospital, CNRS/INSERM/Université Louis
Stockholm, Sweden. Pasteur, CU de Strasbourg, France.
Y. Satoh, Ph.D., Center for Animal Y. Wada, Ph.D., Department of

Resources and Development Urology Graduate School of
(CARD) and Graduate School of Medical and Kumamoto University
Medical Sciences, Kumamoto School of Medicine, Kumamoto,
University, Kumamoto, Japan. Japan.
Teruhiko Wakayama, Ph.D., G. Yamada, Ph.D., Center for Animal
Laboratory for Genomic Resources and Development
Reprogramming, Center for (CARD) and Graduate School of
Developmental Biology, RIKEN Molecular and Genomic Pharmacy,
Kobe, Kobe, Japan. Kumamoto University, Kumamoto,
Japan.
Leo Chi-Kuang Wang, Ph.D.,
Institute of Molecular Biology, Yukiko Yamazaki, Ph.D., Center for
Academia Sinica, Nankang, Taipei, Genetic Resource Information,
Taiwan. National Institute of Genetics,
Mishima, Japan.
Jerrold M. Ward, D.V.M., Ph.D.,
American College of Veterinary Akinori Yoda, Ph.D., Department of
Pathologists, National Institutes of Genome Sciences, Kobe University
Health, Maryland, United States. Graduate School of Medicine,
Kobe, Japan.
Y. Xu, Ph.D., Center for Animal
Resources and Development Y. Zhang, Ph.D., College of
(CARD), and Graduate School of Bioengineering, Fujian University,
Molecular and Genomic Pharmacy, Fuzhou, Fujian, China.
Kumamoto University, Kumamoto,
Japan.
Table of Contents
Chapter 1 Genetically Engineered Mice: Past, Present, and Future ...............1
John P. Sundberg, Tsutomu Ichiki, Jerrold M. Ward, and
Björn Rozell
Chapter 2 Sharing Reseach Tools: The Laboratory Mouse...........................11

David Einhorn
Chapter 3 Managing Success: Mutant Mouse Repositories..........................27

Stephen F. Rockwood, Martin D. Fray, and Naomi Nakagata
Chapter 4 Mouse Genome Informatics: Database Access to Integrated

Phenotype Data ..............................................................................39
Carroll-Ann W. Goldsmith, Martin Ringwald,
John P. Sundberg, Carol J. Bult, and Janan T. Eppig
Chapter 5 Genetic Resouce Databases in Japan............................................57

Yukiko Yamazaki
Chapter 6 Computational Pathology: Challenges in the Informatics of

Phenotype Description in Mutant Mice........................................61
Paul N. Schofield, Jonathan B. L. Bard, Björn Rozell, and
John P. Sundberg
Chapter 7 Biological Methods for Archiving and Maintaining

Mutant Laboratory Mice ...............................................................83
Martin D. Fray, Peter H. Glenister, Steven Rockwood,
Takehito Kaneko, and Naomi Nakagata
Chapter 8 Mouse Genetic Resources without Germ Cells:

Somatic Cell Nuclear Transfer and ES Technology...................113
Teruhiko Wakayama
Chapter 9 The Present Status of Somatic Cell Cloning ..............................125
Atsuo Ogura, Kimiko Inoue, Narumi Ogonuki, and
Hiromi Miki
Chapter 10 Exchangeable Gene Trapping .....................................................131

Kimi Araki
Chapter 11 Genetic Monitoring of Mice .......................................................143

Hideki Katoh
Chapter 12 Microbiological Monitoring of Laboratory Mice .......................157

James R. Fahey
Chapter 13 Effect of Intestinal Flora on Phenotype......................................165

Seiko Narushima and Kikuji Itoh
Chapter 14 Helicobacter pylori and Stomach Cancer...................................173

Masae Tatematsu, Tetsuya Tsukamoto, and Tsutomu Mizoshita
Chapter 15 Professional Use of Mutant Laboratory Mice in Research ........185

John P. Sundberg and Carol J. Bult
Chapter 16 Phenotyping Postpartum Mutant Laboratory Mice and

Determining Their Value for Human Diseaes ............................211
Chapter 17 Common Diseases Found in Inbred Strains

of Laboratory Mice .....................................................................223
Chapter 18 Colon Cancer and Polyposis Models..........................................233

Makoto Mark Taketo
Chapter 19 Phenotypic Analysis of Mice with Steroid Deficiency...............253

Noomen Ben El Hadj, Meng-Chun Hu, Hsueh-Ping Chu,
Leo Chi-Kuang Wang, and Bon-chu Chung
Chapter 20 External Genitalia Development: A Model System to
Study Organogenesis ...................................................................263
K. Suzuki, H. Nishida, S. Ohta, Y. Satoh, Y. Xu, Y. Zhang,
Y. Wada, Y. Ogino, N. Nakagata, T. Ohba, and G. Yamada
Chapter 21 Genetic Approaches to Investigate Retinoic Acid Functions in

Mouse Development....................................................................279
Pascal Dollé, Karen Niederreither, Julien Vermot, Vanessa
Ribes, Jabier Gallego Llamas, and Isabelle Le Roux
Chapter 22 Mouse Models for Developmental Biology:

Functional Analysis of Ror and Wnt Signaling..........................295
Isao Oishi, Akinori Yoda, Shuichi Kani, and Yasuhiro Minami
Index .................................................................................................................303
1 Genetically Engineered
Mice: Past, Present,
and Future
John P. Sundberg, Tsutomu Ichiki,
Jerrold M. Ward, and Björn Rozell
TABLE OF CONTENTS
Generation of Mutant Mice ..................................................................................1

Gene Mapping.......................................................................................................3
Maintenance and Archiving ..................................................................................3
Phenotyping Approaches.......................................................................................4
Summary ...............................................................................................................5
References .............................................................................................................5
Mutant mice have changed from curiosities in the nineteenth century, being pri-
marily of concern to mouse fanciers,1 to become the premier animal model for
human diseases, mammalian genetics, and biomedical research in the twenty-first
century. Archives of spontaneously occurring mutations, a valued resource for over
fifty years, are being supplemented and supplanted by genetically engineered mice
(GEMs) created by transgenesis, targeted mutagenesis, inducible mutagenesis,
gene trap, and chemical mutagenesis methods at an overwhelming rate. Evaluation
of these mice to determine clinical and physiological deviations from normal for
a particular inbred strain (i.e., phenotyping) has become a major undertaking in
the evaluation of these new strains. Current methods to create, archive, distribute,
and phenotype mice were the focus of a meeting, “Pathology of Genetically
Engineered Mice: Large Scale Phenotyping of Mutant Mice,” held in October
2003 in Kumamoto, Japan. Leaders in the field presented the current strategies,
which are summarized in this book. An overview of the field is given here.
GENERATION OF MUTANT MICE

Transgenesis, the process of introducing novel genes or overexpressing known
genes into the mouse genome, has been the basis for the genetics revolution
1
2 Genetically Engineered Mice Handbook
since the first successes in the early 1980s.2 Another important development, the
blastocyst-derived embryonic stem cells,3,4 later led to the technique of targeted
mutagenesis, whereby known genes could be inactivated using homologous
recombination of genes containing molecular tags (LacZ or neomycin cassettes) to
interfere with transcription of specific exons producing so-called gene “knock-outs”
or “hypomorphs” for those genes not totally inactivated.5,6 Many of these targeted
mutations resulted in phenotypes similar to human diseases, but equal numbers
had no phenotype or were embryonic or neonatal lethals. Stressing the system
under investigation sometimes revealed differences from the background strains.7
Inasmuch as embryonic or perinatal lethality are fairly common consequences of
targeted mutagenesis, alternate gene constructs were developed to study these
genes in adult animals.
Conditional mutagenesis or the so-called “gene switch” approaches were
subsequently developed using Cre-recombinase together with LoxP or Frt sites.
Furthermore, inducible systems, based on tetracycline (tet-on/off), or progester-
one antagonists, led to even greater refinements whereby genes could be activated
or inactivated by adding exogenous systems.8,9 In this manner, effects of gene
inactivation could be studied either throughout the organism in selected organs,
or even in part of an organ. The neomycin (Neo) gene often leads to a suppression
of the mutant allele, resulting in a phenotype not different from normal. Thus,
making a construct where the Neo cassette is flanked by LoxP sequences enables
local and restricted excision of the Neo gene in skin, thereby activating the
targeted allele, thus enabling the creation of mouse models of a selected number
of human genetic diseases.10–13
As a complement to the technique of targeted mutagenesis, gene trap methods
provide another tool to approach the problem of identifying novel genes within
the genome. Genetic constructs with marker sequences are used to immediately
map mutant gene loci once an interesting phenotype is produced.14,15 Different
modalities of the gene trap technique are available.16 Because many more genes
are coded for in the human and mouse genome than are currently known
(www.celera.com), other approaches were needed to augment the mutations
derived by targeted mutagenesis or that occurred spontaneously. Spontaneous
mutations occur at a frequency 1/100000 offspring, however, this is not enough
to achieve a saturation of mutations throughout the genome. To increase the
frequency of mutations, chemical mutagenesis, specifically using ethylnitrosourea
(ENU), randomly produces single base pair changes, and increases the mutation
rate 100-fold. These old protocols are now used in large-scale mutagenesis
projects, potentially providing a wealth of novel mutant mice that can subse-
quently have the mutant locus mapped and defined.17–24 A new version of this
technique uses ethylmethanesulfonate on embryonic stem cells25 with similar
results. Back-crossing the chimeric mice to C57BL/6 immediately provides a
rapid tool to map the mutant gene locus.
Contrary to the techniques employing homologous recombination (gene-driven
approach), the discovery of the chemically induced mutations are phenotype
driven (vide infra). This requires a setup whereby mutations affecting different
Genetically Engineered Mice 3
organ systems can be specifically detected by screening assays. Furthermore,

although dominant mutations are easily detected in a variety of screens, recessive
mutations require special breeding protocols, thus slowing down the process.
However, in some screens, such as the one at MRC Harwell, sperm freezing was
adopted as the method of choice to preserve identified mutants. An advantage of
this procedure is that sperm can be used in an in vitro fertilization (IVF) procedure
to obtain a large colony suitable for mapping the mutation, thereby circumventing
slow and costly breeding.26–33
Both dominant and recessive mutations must also be mapped. Because some
of the recessive mutations discovered already resemble phenotypic copies of
mutant mice previously described, these can be tested by breeding (allelism
testing) to see if the new alleles are noncomplementary and therefore allelic with
the well-characterized mutant mouse.34,35 When novel phenotypes are found, the
mutated locus must first be mapped using standard genetic techniques (vide infra),
before positionally cloning the affected gene.36
GENE MAPPING
Finding abnormal mice, at least those with dominant mutations, is often relatively
simple. Figuring out what the defects are and whether the lesions resemble those
found in human or domestic animal diseases is described below. Mapping the
mutant gene locus is relatively easy for single gene mutations. A variety of
methods and approaches is available. In mice, unlike humans, it is possible to
set up breedings between inbred strains carrying the mutated gene and different
strains carrying two copies of the wild-type gene. Recessive mutations will be
expressed in the second, F2 generation, from such an intercross. The mouse
genome can then be rapidly screened using simple sequence length polymorphism
(SSLP) and single nucleotide polymorphism (SNP) technologies with molecular
markers at regular intervals (15–20 cM).36,37 A shift in genes from 50 percent of
both inbred strains to the strain that originally carried the mutated gene indicates
linkage. The gene can be localized by refining this approach with additional
markers (saturation mapping) within the suspected interval. The gene can be
identified by sequencing through known genes in that interval, or positional
cloning of the gene, then creating targeted mutations of the gene or rescuing it
by transgenesis with the known gene or BAC clones containing the interval.36,38
The availability of anchored full-length mouse cDNA clones and other genetic
tools is of great help in determining candidate genes for positional cloning.
MAINTENANCE AND ARCHIVING

Production of all these mutant mice and the normal inbred strains that they occur
on naturally or are created on has become a daunting task. Live mouse archives
were pioneered by Drs. Elizabeth Russell and George Snell at The Jackson
Laboratory in the 1940s.39 Dr. Russell began moving the mutated genes onto a
standard inbred background, the C57BL/6J mouse, to create congenic lines.

Intercrossing various mutations all maintained on a single inbred background
enabled scientists to investigate the interaction of the two genes in question
without worrying about the effects of background modifier genes.36 This approach
and creation of repositories to house these mice at The Jackson Laboratory,
National Institutes of Health, Oak Ridge National Laboratory, Harwell, The
Institut Pasteur, and other institutions around the world were adequate until the
early 1990s when transgenic technology became relatively common.
Commercial repositories charge high prices, often have follow-through agree-
ments, and long waiting periods; therefore this was not acceptable to the academic
or commercial scientific community. The first public repository was the Induced
Mutant Resource at The Jackson Laboratory in 1992.40,41 Several commercial
vendors soon followed as well as other public repositories around the world
including the joint European effort, European Mouse Mutant Archive (EMMA).
A nodal system in Europe and North America has now been developed to share
technology and the burden of housing all these mice, and also to reduce redun-
dancy on those rarely used.
Alternatives to live colonies were necessary whereby mice could still be
obtained years later. Building on technology developed for domestic species,
cryopreservation of mouse embryos has become the de facto standard for
archiving potentially important lines. More current work focuses on cryopreser-
vation of sperm and their use for in vitro fertilization. An added benefit is the
use of this technology for rapidly expanding colonies, rapidly setting up large
breedings for gene mapping, and transporting lines in a pathogen-free environ-
ment between institutions.26–33,42–46
PHENOTYPING APPROACHES
Classic approaches to phenotyping utilize basic medical techniques, and these are
discussed in detail in several chapters in this book. Physical examination of the
normal and mutated mice may reveal obvious changes. Collection of blood, serum,
plasma, urine, and other body fluids can be analyzed using equipment modified
from human clinical pathology laboratories.47 Blood values for commonly used
strains are published.48,49 The Mouse Phenome Project (www.jax.org/phenome)
was created to actively obtain a wide variety of data on individual mouse strains
from researchers around the world and put them online.50 This is a major effort
to make these types of data on major inbred strains of mice freely available to the
biomedical research community.
Careful, systematic, and detailed necropsies of mutant and control mice at
defined ages with histopathology remain a standard for defining lesions. Com-
parative pathology between human and domestic animals provides insight into
whether the mutant mice are potential models for specific diseases or unique tools
to dissect the function of a gene or organ. Numerous textbooks were published
recently providing overviews on these methods and the types of lesions commonly
found in aging and mutant mice.51–54 Many Web sites are online and are constantly
being updated with similar information. How to access and use these are described
in detail in other chapters in this book. Approaches to setting up such phenotyping
programs are also now available.55
Very specialized equipment was developed for each organ system. Much
effort is being put into tools to better define neurological abnormalities in mice.52
The SHIRPA protocol was developed to provide a panel of clinical evaluations
and analytical tests to determine if mice had neurological abnormalities.56 These
are being adapted by many of the ENU programs worldwide as well as by startup
companies providing phenotyping services. Specialty books on various organ
systems are also being published.57–59
Because anatomic and clinical pathologists with mouse expertise are relatively
few and far between, there has been downscaling of traditional diagnostic equip-
ment with intense development of very sophisticated equipment to provide rapid,
high-throughput, low-labor information. X-ray machines, originally designed for
scanning electronic boards, work extremely well with mammography film to
provide flat-plate images of mice (www.faxitron.com).60 CAT scans, Pet scans,
MRIs, and other methods are now available to provide real-time, three-dimensional
images of mouse organs or to test physiologic parameters (www.scanco.ch,
www.imtekinc.com, www.optiscan.com, www.colinst.com). New technologies are
constantly under development.61–65
SUMMARY
The laboratory mouse is a domestic animal. Veterinarians, physicians, and bio-
medical researchers can now use both traditional technology and microanalytical
tools to evaluate mutant or experimentally manipulated mice to answer fundamental
medical and biological questions. The area is reviewed here to provide key refer-
ences and Web sites from which specific information and resources can be found.
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2 Sharing Research Tools:
The Laboratory Mouse
David Einhorn
TABLE OF CONTENTS
1980.....................................................................................................................12
Cold Spring Harbor.............................................................................................13
The “Harvard Mouse”.........................................................................................14
Cre-Lox ...............................................................................................................14
NIH and the Memoranda of Understanding (MOU) .........................................15
NIH Policy ..........................................................................................................16
Issues Raised in NIH Sharing Policy .................................................................18
Definition of Research Tools ..................................................................18
Reach-Through Rights ............................................................................18
Patenting Mice ........................................................................................20
Sharing Mice within Academia ..........................................................................20
Jackson Mouse Repository .................................................................................21
The Research Exemption ....................................................................................22
References ...........................................................................................................24
This chapter examines the historic change in perception of the laboratory mouse
from that of a research tool, freely exchanged among scientists, to its being
considered intellectual property. This transformation was triggered by the con-
fluence of three milestones: (1) the U.S. Supreme Court decision allowing
patenting of genetically altered life; (2) passage of the Bayh–Dole Act; and
(3) development of technologies to genetically engineer mice. Three examples
are discussed that illuminate the tension between the scientific sharing ethic and
the demands of commercialization: (1) the P53 knock-out mouse, (2) the “Harvard
Mouse” Patent, and (3) the Cre-lox technology. We consider how the National
Institutes of Health (NIH) dealt with this tension and review its policy statement,
“Sharing Biomedical Research Resource: Principles and Guidelines for Recipi-
ents of NIH Research Grants and Contracts.” “Reach-through” and other prob-
lematic provisions in licenses and material transfer agreements are addressed. As
a model, The Jackson Laboratory’s approach to facilitating the availability and
distribution of mouse strains is considered. From the overall perspective on how
11
the patent system may inhibit research in academia, we also consider a recent
judicial decision regarding the “experimental use” exemption.
The remarkable advances in molecular biology over the past quarter century
have been a challenge to the traditional ethic in academia of encouraging the free
flow of ideas and information. Universities and nonprofit research institutions
(hereafter “Academia”) have always viewed themselves as fundamentally differ-
ent from for-profit companies (hereafter “For-Profits”), inasmuch as the raison
d’être of Academia is research and education and not the pursuit of lucre on
behalf of shareholders. However, the tremendous advances in biology, and the
commercial opportunities created in the new industry of biotechnology, have
presented a challenge to the tradition of openness and freedom of exchange in
Academia, because efforts to protect and exploit intellectual property developed
in Academia through patenting or licensing inevitably involve some secrecy and
restriction of availability.1
The Jackson Laboratory (hereafter “Jackson”) is a nonprofit research institu-
tion situated on an idyllic island in the state of Maine. As well as being a
preeminent mammalian genetics research and educational institution, Jackson has
been for many years and continues to be the most important source in the world
for strains of laboratory research mice. For 75 years, Jackson has been identifying
and characterizing spontaneous mutant mice in its colonies, importing spontane-
ous mutant mice from scientists worldwide, creating congenic strains carrying
these mutations, developing inbred and other mouse lines, and in the past decade
serving as an international repository of strains of genetically engineered mice
(also called induced mutant mice) developed by scientists from virtually every
major research institution in the world. The laboratory mouse, and more recently
the genetically altered mouse, is generally understood to be the single most
important research tool for studying human disease. It is therefore not surprising
that genetically altered mice have been the trigger points of public debate over
research access and commercialization, with Jackson a principal player in the
drama. To understand this debate we need to take a short historical journey.
1980
The year 1980 was significant in this story. First, it was the year the U.S. Supreme
Court decided Diamond v. Chakrabarty.2 Before that landmark decision, there
was a widely accepted legal assumption that living organisms were unpatentable,
because they were considered products of Mother Nature and not of man. In
Chakrabarty, the Supreme Court (in a sharply divided 5–4 decision) ruled that a
living genetically engineered microorganism was patentable subject matter, and
that the litmus test of patentability was not between living and nonliving matter,
but between products of Nature and “anything under the sun made by man.”
That same year of 1980, the U.S. Congress passed the Bayh–Dole Act.3 Prior
to Bayh–Dole, the federal government owned, but rarely patented or commer-
cialized, inventions that arose from federally funded research in Academia. Out
Sharing Research Tools 13
of realization that the federal government was not suited to further develop
technologies, Bayh–Dole allowed Academia to retain ownership of inventions
developed with federal funds, the expectation being that the turnover of ownership
would spur the commercialization of inventions that would in turn benefit the
public with new drugs and therapies.
The third event at the start of the 1980s was the development of recombinant
DNA technology, which involves the altering of the genetic information of cells
by combining the DNA of different organisms. In the case of the mouse, this
allows for the creation of transgenic mice. The term “transgenic mouse” tech-
nically means a mouse that has a foreign gene introduced randomly into all of
its cells, but it has commonly been used to describe any genetically altered
mouse. This technology has been succeeded by the ability to target specific genes
to “knock-in” or “knock-out” activity of these genes in mice as well as many
other technologies, such as the so-called “gene switch” systems where genes
can be turned on or off in specific anatomic sites. These new technologies have
made the laboratory mouse an even more powerful research tool for studying
human diseases.
COLD SPRING HARBOR

The first major manifestation of the tension between sharing and commercializa-
tion erupted into the public arena at a meeting of 300 scientists at the Cold Spring
Harbor Meeting on Mouse Molecular Genetics, where Nobel laureate Dr. Harold
Varmus [then a researcher at the University of California, San Francisco, and
later Director of the National Institutes of Health (hereafter NIH)] moderated a
heated discussion over the P53 knock-out mouse. This mouse, with the tumor
suppressor gene P53 inactivated, had been developed with federal funds by Baylor
University and licensed to a private biotechnology company. The company then
attempted to license the mice on what was considered by many scientists to be
terms and conditions that were too costly and restrictive: title to the mice was
reserved, annual payments were required, and there were restrictions on internal
breeding. These terms had never before been encountered by researchers when
trying to obtain a mouse. What concerned Dr. Varmus and others was that scien-
tists receiving funding grants from the federal government should be able to
readily obtain federally funded research tools, such as the P53 mouse, and not
be thwarted by unreasonable restrictions.
The following year a workshop was held at the National Academy of Sciences
entitled “Sharing Laboratory Resources: Genetically Altered Mice” and a report
was issued finding that severe proprietary restrictions on the distribution and breed-
ing of genetically altered mice would impede the progress of biomedical research.
In response to these events, Jackson—first with the help of private healthcare
foundations and then with funding from the NIH—established the Induced Mutant
Resource (IMR) to import and provide a repository for the cryopreservation, main-
tenance, and distribution of transgenic, targeted, and chemically induced mutant
mice, with the assurance by Jackson that these new models would be made available
to the whole research community with as few restrictions as possible.
THE “HARVARD MOUSE”

The next controversy involved the “Harvard Mouse”. Harvard University filed
and was able to obtain the first patent on a mammal, a mouse with a human
oncogene that made the mouse more likely to develop cancer. Claim I of the
patent is very broad: “A transgenic non-human mammal all of whose germ cells
and somatic cells contain a recombinant activated oncogene sequence introduced
into said mammal, or an ancestor of said mammal, at an embryonic stage.”4 The
funding of the research effort that produced the mouse was provided by the
Dupont Company, and Harvard gave Dupont an exclusive license to the patent.
The issue of whether an advanced mammal should be subject to a patent is a
philosophic and moral question which for many years has been the subject of
heated debate in Europe, and last year the Supreme Court of Canada ruled that
advanced life forms such as mammals were not patentable subject matter under
Canadian law. In the United States, the “Harvard Mouse” patent did not engender
the same degree of philosophical debate, perhaps because Chakrabarty had been
seen as putting that issue to rest.5 In contrast to Europe and Canada, in the United
States the “Harvard Mouse” has instead been controversial, like the P53 mouse,
because the licensing terms requested by Dupont were considered onerous and
were resisted by Academia. Dupont’s initial terms included limited internal breed-
ing; no use of the mice in corporate-sponsored research; reservation of title; an
annual report of research results; and a royalty on mice, products, or processes
resulting from the use of the mice (initially a royalty not to exceed 7.5% and, in
a subsequent license iteration, an unspecified amount of royalty). In addition,
Dupont has taken the position that the breadth of the patent includes not just
transgenic mice expressing any oncogene, but also mice with targeted mutations,
such as the P53 knock-out mouse, and Dupont licenses all of these mice under
its trademark, Oncomouse®.
CRE-LOX
While the resistance by Academia to the license terms for Oncomouse® was still
unresolved, another technology, Cre-lox, was developed and patented by Dupont.6
Cre-lox proved to be a very powerful and ubiquitously used technology because
it allowed a researcher to knock out genes on a tissue-specific basis. This tech-
nology involves flanking the gene of interest with Lox sites, and when Cre is
introduced with a tissue-specific promoter, it deletes the flanked DNA. Cre-lox
allows researchers to knock out genes in selective tissues when otherwise knock-
ing out all expression would be embryonically lethal. Later developments allowed
a researcher to turn gene expression on and off at will. Dupont’s terms for a
license to use and share mice made with Cre-lox included an advance view of
Sharing Research Tools 15
any publications resulting from using the technology and unspecified royalties
on any products resulting from the use of mice containing Cre or Lox.
NIH AND THE MEMORANDA OF

UNDERSTANDING (MOU)
A sharing crisis emerged as researchers were inhibited by the Cre-lox patent and
licensing terms from exchanging their new Cre-lox mouse models with research-
ers in other institutions or from having the mice distributed to the research
community through Jackson. Because of the licensing terms under the Harvard
Patent, there were also inhibitory concerns over the use and sharing of mice
genetically altered to develop cancer. In the context of negotiations with Jackson
over Cre-lox, Dupont belatedly informed Jackson that it considered a number of
the cancer mouse strains that Jackson had been distributing to be subject to the
Harvard Patent. As the national mouse repository, the sole source of most genet-
ically altered mice strains, and as a leading voice for the unfettered availability
of the mouse as a research tool, Jackson (perhaps inevitably) now found itself a
principal player in this drama.
It was apparent to Jackson that this issue concerned not only Jackson but was
an important public policy concern that affected the entire biomedical research
community, so Jackson sought the assistance of the NIH and Dr. Varmus (who
had since become head of the NIH). Jackson worked with the NIH in addressing
this impasse, and Dr. Varmus made a personal appeal to Dupont on behalf of the
research community. Even though these technologies were reportedly not
developed with any federal funds, they had become the poster-child examples of
the difficulties involved in sharing and obtaining research tools, and Dr. Varmus
used his bully pulpit to convince Dupont that it should reconsider its licensing
policy. The result was a Memorandum of Understanding (MOU) in 1998 between
the NIH and Dupont covering the use of Cre-lox,7 followed the next year by
another MOU dealing with research conducted under the Harvard Patent.8
These MOUs allow use of the patent rights for noncommercial biomedical
research without any rights to fees or royalties, rights to review publications, and,
most significantly, any rights to developments made using the respective patent
rights. Transfers of any materials covered by the patent rights may be made by
one nonprofit to another nonprofit institution using a Material Transfer Agreement
(hereafter MTA) subject essentially to the same terms set forth in the MOUs
between the NIH and Dupont. If a nonprofit institution wishes to transfer such
materials to a for-profit company, it may do so using a license or an MTA, but
it must also notify the for-profit of the existence of Dupont’s patent rights, notify
Dupont of the identity of the for-profit and the material to be transferred, and
further notify the for-profit that use of the material will require a license and a
fee from Dupont. What is unprecedented about the MOUs is that NIH negotiated
terms for using Cre-lox technology and the “Harvard Mouse,” not only for
intramural federal government scientists, but also for extramural nonprofit
recipient institutions of federal grants. The MOUs provide that Dupont shall under
separate license agreements make the patent rights available to nonprofit grantees
“... in accordance with the terms and conditions …” of the MOUs. The MOUs
were and remain a unique example of a resolution by government, Academia,
and a company addressing the tension between availability of, and proprietary
rights to, research tools.9
NIH POLICY
No doubt prompted by the issues surfaced by the P53 Mouse, “Harvard Mouse”,
and Cre-lox controversies, Dr. Varmus requested that a Working Group of the
Advisory Committee to the Director look into concerns over the dissemination
and use of unique research tools, the competing interests of the owners and users
of these tools, and how the NIH might provide a policy response. The Report of
the Working Group found that patent and licensing restrictions could stifle the
broad dissemination of research tools and thereby frustrate basic research and
the development of products for the benefit of public health. The Report found,
on the other hand, that reasonable restrictions might be necessary to protect
intellectual property rights and preserve incentives for further research and com-
mercial development. The challenge, of course, was to balance these competing
interests. After submission for public comment of a draft policy, the NIH adopted
a final document entitled “Sharing Biomedical Research Resources: Principles
and Guidelines for Recipients of NIH Research Grants and Contracts” (hereafter
“NIH Sharing Policy”),10 setting forth four basic principles.
1. Ensure Academic Freedom and Publication: The NIH Sharing Policy

pronounces as a matter of first principle that academic freedom to
conduct research and publish are “… at the heart of the scientific
enterprise,” and that NIH grantees must ensure that interactions with
the private sector do not involve veto rights over publication or excessive
publication delay beyond that necessary to permit the filing of patent
applications or to protect from disclosure of confidential information.
2. Ensure Appropriate Implementation of Bayh–Dole: Recipients of fed-
eral funding must ensure that there is compliance with the statutory
goals of Bayh–Dole to promote utilization, commercialization, and
public availability of inventions. The NIH Sharing Policy finds that
patenting and licensing are not the only or necessarily appropriate
means of achieving these goals. If there is no further private investment
needed to develop and utilize a research tool, then the goals of
Bayh–Dole can be met by a combination of dissemination approaches,
such as publication, deposit in a repository, or widespread nonexclusive
licensing. “Restrictive licensing of such an invention, such as to a for-
profit sponsor for exclusive internal use, is antithetical to the goals of
the Bayh–Dole Act,” because by definition, limiting the use to one
Exploring the Variety of Random
Documents with Different Content
CHAPTER XVI.
THE KING OF FRANCE INVITES MELANCTHON TO
RESTORE UNITY AND TRUTH.
(End of 1534 to August 1535.)
While the work of the Reformation appeared exposed to great

dangers in a small city of the Alps, it had in the eyes of the optimists
chances of success in two of the greatest countries of Europe—
France and Italy. The two finest geniuses of the reform, Melancthon
and Calvin, had been summoned to those two countries respectively.
Luther, their superior by the movements of his heart and the
simplicity of his faith, was inferior to them as a theologian, and they
probably surpassed him in their capacity to comprehend in their
thoughts all nations and all churches.
The first half of the sixteenth century was the epoch of a great
transformation to the people of Europe; there had been nothing like
it since the introduction of Christianity. During the middle ages, the
pope was the guardian of Christendom, and the people were infants,
who, not having attained the necessary age, could not act for
themselves. The pontificial hierarchy opened or shut the gates of
heaven, laid down what every man ought to believe and do,
dominated in the councils of princes, and exercised a powerful
influence over all public institutions. But a wardship is always
provisional. When a man attains his majority, he enters into the
enjoyment of his property and rights, and having to render an
account to none but God, he walks without guardians by the light
which his conscience gives him. There is also a time of majority for
nations, and Christian society attained that age in the sixteenth
century. From that moment it ceased to receive blindly all that the
priests taught; it entered into a higher and more independent
sphere. The teaching of man vanished away; the teaching of God
began again. Once more those words were heard in Christendom
which Paul of Tarsus had uttered in the first century: ‘I speak as to
wise men; judge ye what I say.’[669] But it must be carefully observed
that it was by throwing open the Bible to their generation that the
reformers realized this sentence. If they had not restored a heavenly
torch to man, if they had left him to himself in the thick shadows of
the night, he would have remained blind, uneasy, restless, and
unsatisfied. The holy emancipation of the sixteenth century invited
those who listened to it to draw freely from the divine Word all that
was necessary to scatter the darkness of their reason and fill up the
void in their hearts. Elevating them above the goods of the body,
above even arts, literature, science, and philosophy, it offered to
their soul eternal treasures—God himself. The Gospel, then restored
to the world, gave an unaccustomed force to the moral law, and
thus conferred on the people who received it two boons,—order and
liberty,—which the Vatican has never possessed within its precincts.
Alarm And Joy. All men, however, did not understand that
the majority which each must necessarily
attain individually is at the same time essential to them collectively,
and that the Church in particular must inevitably attain it. There
were many, among those who were interested in the prosperity of
nations, who felt alarm at the abolition of the papal guardianship.
They saw that this stupendous act would work immense changes in
the sphere of the mind; that society as a whole, literature, social life,
politics, the relations of foreign countries with one another, would be
made new. This prospect, which was a subject of joy to the greater
number, excited the liveliest apprehensions in others. Those
especially who had not learnt that man, as a moral being, can only
be led by free convictions, imagined that all society would run wild
and be lost if that power was suppressed which had so long
intimidated and restrained it by the fear of excommunications and
the stake. These men, alarmed at the sight of the free and living
waters of reform and wishing at any cost to save the nations of
Europe from the deluge which appeared to threaten them, thought it
their duty to confine them still more, to restore, strengthen and raise
the imperilled dikes, and thus keep the stagnant waters in the foul
canals where they had stood for ages.
Notwithstanding his liberal tendencies with regard to literature and
the arts, Francis I. was not exempt from these fears, and gave a
helping hand to a restoration,—often a cruel restoration of the
Romish jurisdiction. Henry VIII., of little interest as an individual,
though great as a king, and who was truly the father, predecessor,
and fore-runner of Elizabeth and her reign, even while striving
ineffectually to preserve the catholic doctrines in his realm,
separated it decisively from the papacy, and by so doing laid the
foundations of the liberty and greatness of England. Francis I., on
the other hand, maintained the papal supremacy in his dominions,
and labored to restore it in the countries where it had been
abolished. In 1534 and 1535 we see him making great exertions to
that end, and finding numerous helpers to back him up.
The idea of restoring unity in the Christian Church of the West, not
only engrossed the attention of those who were actuated by
despotic views, but also of noble-minded and liberal men. ‘By what
means can we succeed?’ they asked. The violent answered, ‘By
force;’ but the wise represented that Christian unity could not be
brought about by the sword. Those who were occupied with this
great question determined to examine whether they could not solve
it by means of mutual concessions; and they set about their task
with different motives and in different tempers. They formed three
categories.
There existed at that time in all parts of Europe men of wit and
learning, children of the Renaissance, who disliked the superstitions
and abuses of Rome, as well as the bold doctrines and severe
precepts of the Reformation. They wanted a religion, but it must be
an easy one, and more in conformity (as they held) with reason.
Between Luther and the pope, they saw Erasmus, and that elegant
and judicious writer was their apostle: hence the Elector of Saxony
called them Erasmians.[670] They thought that by melting popery and
protestantism together they might realize their dreams.
In like manner, too, there were persons to be found of greater or
less eminence in whom the desire prevailed to maintain Europe in
that papal wardship which had lasted through all the middle ages:
they feared the most terrible convulsions if that supreme authority
should come to an end. At their head in France was the king. Francis
I. had also a more interested object: he desired, from political
motives, to unite protestants and catholics, because he had need of
Rome in Italy to recover his preponderance there, and of the
protestants in Germany to humble Charles V. To this class also
belonged, to a greater or less extent, William du Bellay, the king’s
councillor and right hand in diplomacy. So far as concerns doctrine,
both were on the side of Erasmus; but, in an ecclesiastical point of
view, while the prince inclined to a moderate papal dominion, the
minister would have preferred a still more liberal system.
The Moderate Finally, there were, particularly in Germany,
Evangelicals. a few evangelical Christians who consented
to accept the episcopalian form, and even the primacy of a bishop,
in the hope of obtaining the transformation of the doctrine and
manners of the universal Church. Melancthon at Wittemberg, Bucer
at Strasburg, and Professor Sturm at Paris, were the most eminent
men of this school. Melancthon went farther than his colleagues. He
believed that the great revolution then going on was salutary and
even necessary; but he would have liked to see it limited and
directed. Former ages had elaborated certain results which ought, in
his opinion, to be handed down to ages to come; and he imagined
that if the pope could be induced to receive the Gospel, that despot
of old times might still be useful to the Church. Another and a still
more urgent interest animated these pious men: it was necessary to
rescue the victims of fanaticism, to extinguish the burning piles. The
bloody and solemn executions which had taken place in Paris on the
21st of January, 1535, in presence of the king and court, had excited
an indescribable horror everywhere. One might have imagined that
those noble-hearted men foresaw the miseries of France, the battle-
fields running with blood, and the night of St. Bartholomew with its
murders ushered in by the death-knell from the steeple of St.
Germain l’Auxerrois; that they saw pass before them those armies of
fugitives whom the revocation of the Edict of Nantes scattered over
the wide world.
One common feature characterized all three classes. Those who
composed them were in general of an accommodating disposition,
an easy manner, ready to sacrifice some part of what they thought
true, in order to attain their end. But there were in Europe, on the
side of Rome many inflexible papists, and on the side of the
Reformation many determined protestants, who set truth above
unity, and were resolved to do everything ‘so that the talent which
God had entrusted to them might not be lost through their
cowardice, or taken from them on account of their ingratitude.’[671]
Effects Of The The famous placards posted up in the
Placards. capital and all over France on that October
night of 1534 had carried trouble into the hearts of the
peacemakers. They had seen, as they imagined, the torch suddenly
applied to the house in which they were quietly laboring to reconcile
Rome and the Reformation. ‘Such a seditious act agitates the whole
kingdom, and exposes us to the greatest dangers,’[672] wrote Sturm
from Paris to Melancthon. ‘The authors of those placards are men of
a fanatical turn, rebels who circulate pernicious sentiments, and who
deserve chastisement,’ wrote Melancthon to the Bishop of Paris. But
at the same time the most energetic of the German protestants,
revolted by the cruelty of Francis I., refused to join in union with a
prince who burnt their brethren. The King of France had formed the
plan of a congress, destined to restore peace to Christendom; but an
imprudent hand had applied the match to the mine, and the friends
of peace were struck with terror and confusion. From that moment
there was nothing heard but recriminations, reproaches, and
altercations.
Francis I. saw clearly that, if his project was on the brink of failing,
the fault was due mainly to his own violence; he therefore undertook
to set straight the affairs he had so imprudently damaged. On the
1st February, 1535, he wrote to the evangelical princes of the
empire, assuring them that there was no similarity between the
German protestants and the French heretics, his victims. The
contriver of the strappadoes of the 21st January, assumed a lofty
tone, as if he were innocence itself. ‘I am insulted in Germany,’ he
said, ‘in every place of assembly, and even at public banquets. It is
said that people dressed like Turks can walk freely about the streets
of Paris, but that no one dares appear there in German costume.
People say that the Germans are looked upon here as heretics, and
are arrested, tortured, and put to death. We think it our duty to
reply to these calumnies. Just when we were on the point of coming
to an understanding with you, certain mad-men endeavored to upset
our work. I prefer to bury in darkness the paradoxes they have put
forth; I am loth to set them before you, most illustrious princes, and
thus display them in the sight of the world.[673] I think it sufficient to
say that even you would have devoted them to execration. I wished
to prevent the pestilence from spreading over France, but not a
single German was sent to prison.[674] The men of your nation,
princes and nobles, continue to be graciously received at my court;
and as for the German students, merchants, and artisans who work
in my kingdom, I treat them like my other subjects, and, I may say,
like my own children.’ The letter produced some little effect, and
there was a reaction on the other side of the Rhine. Melancthon
resumed his schemes of reunion.
But a new change then occurred: suddenly, and with greater
violence than ever, new difficulties arose, which threatened to make
shipwreck of the whole business. Francis I. had caused the
conciliatory opinions of Melancthon, Hedio, and Bucer to be
circulated in Germany.[675] Some unwise and by no means upright
adherents of catholicism mutilated and abridged those opinions,[676]
and then proclaimed with an air of triumph that the heretics, with
Melancthon at their head, were about to return into the bosom of
the Church!... Excessive was the irritation of the evangelical flocks,
and loud cries arose from every quarter against the temporizers and
their weakness. They called to mind that truth is not a merchandise
which can be cheapened; but a chain, of which if but one link be
broken, all the rest is useless. ‘Melancthon is of opinion,’ said some,
‘that a single pontiff, residing at Rome, would be very useful to
maintain harmony of faith between the different nations of
Christendom. Bucer adds that we must not overthrow all that exists
in popery, but restore in the protestant churches many of the
practices observed by the ancients. The men who speak thus are
deserters and turncoats. They betray our cause, they commit a
crime.’[677] If such protestants as these were heard among the
Lutherans, doctors such as Farel and Calvin spoke out still more
plainly against all attempts at a union with popery. ‘It is wrong,’
wrote Calvin afterwards to some English friends, ‘to preserve such
paltry rubbish, the sad relics of papal superstition, every recollection
of which we ought to strive to extirpate.’[678] The thought that
Francis I. was at the head of these negotiations filled the Swiss
theologians in particular with ineffable disgust. ‘What good can be
expected of that prince,’ said Bullinger, ‘that impure, profane,
ambitious man?[679] He is dissembling: Christ and truth are of no
account in his projects. His only thought is how to gain possession of
Naples and Milan. What does this or that matter, so that he makes
himself master of Italy?’ These honest Swiss were not wanting in
common sense. Alarmed at the trap that was preparing for Reform,
Bullinger, Blaarer, Zwyck, and other reformed divines wrote to Bucer:
‘It is of no use your contriving a reunion with the pope; thousands of
protestants would rather forfeit their lives than follow you.’
At the same time the Sorbonne and its followers raised their voices
still higher against all assimilation with Lutheran doctrines. The
storm swelled on both sides, and burst upon the moderate party.
Poor Bucer, driven in different directions, succumbed under the
weight of his sorrow. ‘Would to God,’ he exclaimed, ‘that, like the
French martyrs, I were delivered from this life to stand before the
face of Jesus Christ!’[680]
Hope Of Union Lost. Every hope of union seemed lost. The ship
which the politic King of France had
launched, and to which the hand of the pious Melancthon had
fastened the banners of peace, had been carried upon the breakers;
all attempts to get her out to sea again appeared useless; there was
neither water enough to float her, nor wind enough to move her. She
was about to be abandoned, when a sudden breeze extricated her
from the shallows, and launched her once more upon the wide
ocean.
Clement VII. having died of chagrin, occasioned by the prospect of a
future in which he could see nothing but deception and sorrow,[681]
the King of France considered himself thenceforward liberated from
the promises made to Catherine’s uncle. Ere long the choice of the
Sacred College gave him still greater liberty. Alexander Farnese, who,
under the title of Paul III., succeeded Clement, was a man of the
world; he had studied at Florence in the famous gardens of Lorenzo
de’ Medici, and from his youth had lived an irregular life. On one
occasion, being imprisoned by his mother’s orders in the castle of St.
Angelo, he took advantage of the moment when the attention of his
jailers was attracted by the procession of Corpus Christi to escape
through a window by means of a rope. Although he had two
illegitimate children, a son and a daughter, he was made cardinal,
and from that hour kept his eyes steadily fixed upon the triple
crown. He obtained it at last, at the age of sixty-seven, and declared
that in religious matters he would follow very different principles
from those of his predecessors. This man, who had so much need of
reformation for himself and his family, was engrossed wholly with
reforming the Church. We shall find not only a king of France, but a
pope of Rome also, making advances to Melancthon. Leo X.
bequeathed schism to Christendom. Paul III. undertook to restore
unity, and thus hoped to acquire a greater glory than that of the
Medicis. He promised the ambassadors of Charles V. to call a council,
and four days after his election declared his intentions in full
consistory. ‘I desire a reform,’ he said; ‘before we attempt to change
the universal Church, we must first sweep out the court of Rome;’
and he nominated a congregation to draw up a plan of reform.
Proud of his skill, he thought that everything would be easy to him,
and already triumphed in imagination over the Germans, who were,
in his opinion, so boorish, and the Swiss, who were so barbarous.
Francis I., satisfied with this disposition of the pope, was not
unaware, besides, that he had private means of communicating with
him. The first secretary of his Holiness was Ambrosio, an influential
man and by no means averse to presents. A person who had need
of his services having given him sixty silver basins with as many
ewers, ‘How is it,’ said a man one day, ‘that with all these basins to
wash in, his hands are never clean?’[682]
Popery In France. But the work of union was not to be so
easy as the conjunction of two such stars
as Farnese and Valois seemed to promise. While the Romish Church
was being toned down at Rome, popery became stricter in France.
The fanatical party that was to acquire a horrible celebrity by the
crimes of the Bartholomew massacre and of the League, was
beginning to take shape round the dauphin, the future Henry II.
That youth of eighteen, who had not long returned from Madrid, was
far from being lively, talkative, and independent, like a young
Frenchman, but gloomy and silent, and appeared to live only to obey
women. There were two at his side, admirably calculated to give him
a papistical direction: first, his wife, Catherine de Medicis, and next
his mistress, Diana of Poitiers, a widow, still beautiful in spite of her
age, and who would not (as it has been said) have spoken to a
heretic for an empire. The mistress and the wife, who were on the
best of terms, and all of the dauphin’s party, endeavored to thwart
the king’s plans. The most influential members of that faction were
continually repeating to him that the protestants of Germany were
quite as fanatical and seditious as those of France. At the same time,
the emperor’s agents, animated by the same intentions, told the
German protestants that Francis I. was an infidel in alliance with the
Turks. The obstacles opposed in France and Germany to the
reconciliation of Christendom were such that its realization appeared
a matter of difficulty.
But in the midst of these intrigues the moderate party held firm. The
Du Bellays belonged to one of the oldest families in France; their
nobility could be traced back to the reign of Lothaire,[683] and their
mother, Margaret de la Tour-Landry, reckoned among her ancestors
a man who had occupied himself with laying down the rules of a
good education. After a life of busy warfare, the Chevalier de la
Tour-Landry, seignior of Bourmont and Claremont, who lived in the
fourteenth century, wrote two works on education: one for his sons,
the other for his daughters, copies of which became numerous. The
treatise intended for the girls was printed in 1514, perhaps by the
direction of the parents of the Du Bellays. ‘Out of the great affection
I bear to my children,’ wrote the old cavalier, ‘whom I love as a
father ought to love them, my heart will be filled with perfect joy if
they grow up good and honorable, loving and serving God.’[684]
William and John particularly seemed to have responded to this
prayer. William, the elder, was not void of Christian sentiments. ‘I
desire,’ he said, ‘that nothing may happen injurious to the cause of
the Gospel and the glory of Christ;’[685] but he was specially one of
the most distinguished generals and diplomatists of his epoch. He
knew, says Brantome, the most private secrets of the emperor and
of all the princes of Europe, so that people supposed him to have a
familiar spirit. Although maimed in his limbs—the consequence of his
campaigns—he was a man of indefatigable activity. His brother John,
Bishop of Paris, who was also ‘another master-mind,’ professed like
him an enlightened catholicism; and hence it happened that on the
accession of Henry II. he was deprived of his rank by the intrigues of
the papist party, and driven from France. Still, to show that he
remained a catholic, he took up his residence in Rome.
Melancthon’s In 1535 the moderate catholic party, at the
Position. head of which were these two brothers,
seeing the chances of success at Rome as well as at Paris, resolved
to take a more decided step, and to invite Melancthon to France.
The proposal was made to Francis I., and supported by all the
members of the party. They knew that Melancthon was called ‘the
master of Germany,’ and thought that if he came to France he would
conciliate all parties by the culture of his mind, by his learning,
wisdom, piety, and gentleness. One man, if he appears at the right
moment, is sometimes sufficient to give a new direction to an entire
epoch, to a whole nation. ‘Ah, sire,’ said Barnabas Voré de la Fosse,
a learned and zealous French nobleman, who knew Germany well,
and had tasted of the Gospel, ‘if you knew Melancthon, his
uprightness, learning, and modesty! I am his disciple, and fear not
to tell it you. Of all those who in our days have the reputation of
learning, and who deserve it, he is the foremost.’[686]
These advances were not useless: Francis I. thought the priests very
arrogant and noisy. His despotism made him incline to the side of
the pope; but his love of letters, and his disgust at the monks,
attracted him the other way. Just now he thought it possible to
satisfy both these inclinations at once. Fully occupied with the effect
of the moment, and inattentive to consequences, he passed rapidly
from one extreme to another. At Marseilles he had thrown himself
into the arms of Clement VII., now he made up his mind to hold out
his hand to Melancthon. ‘Well!’ said the king, ‘since he differs so
much from our rebels, let him come: I shall be enchanted to hear
him.’ This gave great delight to the peacemakers. ‘God has seen the
affliction of his children and heard their cries,’ exclaimed Sturm.[687]
Francis I. ordered De la Fosse to proceed to Germany to urge
Melancthon in person.
A king of France inviting a reformer to come and explain his views
was something very new. The two principal obstacles which impeded
the Reformation seemed now to be removed. The first was the
character of the reformers in France, the exclusive firmness of their
doctrines, and the strictness of their morality. Melancthon, the mild,
the wise, the tolerant, the learned scholar, was to attempt the task.
The second obstacle was the fickleness and opposition of Francis I.;
but it was this prince who made the advances. There are hours of
grace in the history of the human race, and one of those hours
seemed to have arrived. ‘God, who rules the tempests,’ exclaimed
Sturm, ‘is showing us a harbor of refuge.’[688]
Efforts Of The The friends of the Gospel and of light set
Mediators. earnestly to work. It was necessary to
persuade Melancthon, the Elector, and the protestants of Germany,
which might be a task of some difficulty. But the mediators did not
shrink from before obstacles; they raised powerful batteries; they
stretched the strings of their bow, and made a great effort to carry
the fortress. Sturm, in particular, spared no exertions. The free
courses he was giving at the Royal College, his lectures on Cicero,
his logic, which, instead of preparing his disciples (among whom was
Peter Ramus) for barren disputes, developed and adorned their
minds—nothing could stop him. Sturm was not only an enlightened
man, a humanist, appreciating the Beautiful in the productions of
genius, but he had a deep feeling of the divine grandeur of the
Gospel. Men of letters in those times, especially in Italy, were often
negative in regard to the things of God, light in their conduct,
without moral force, and consequently incapable of exercising a
salutary influence over their contemporaries. Such was not Sturm:
and while those beaux-esprits, those wits were making a useless
display of their brilliant intelligence in drawing-rooms, that eminent
man exhibited a Christian faith and life: he busied himself in the
cultivation of all that is most exalted, and during his long career,
never ceased from enlightening his contemporaries.[689] ‘The future
of French protestantism is in your hands,’ he wrote to Bucer;
‘Melancthon’s answer and yours will decide whether the evangelicals
are to enjoy liberty, or undergo the most cruel persecutions. When I
see Francis I. meditating the revival of the Church, I recognize God,
who inclines the hearts of princes. I do not doubt his sincerity; I see
no hidden designs, no political motives; although a German by birth,
I do not share my fellow-countrymen’s suspicions about him. The
king, I am convinced, wishes to do all he can to reform the Church,
and to give liberty of conscience to the French.’[690] Such was, then,
the hope of the most generous spirits—such the aim of their labors.
Sturm, wishing to do everything in his power to give France that
liberty and reformation, wrote personally to Melancthon. He was the
man to be gained, and the professor set his heart upon gaining him.
‘How delighted I am at the thought that you will come to France!’ he
said. ‘The king talks much about you; he praises your integrity,
learning, and modesty; he ranks you above all the scholars of our
time, and has declared that he is your disciple.[691] I shed tears when
I think of the devouring flames that have consumed so many noble
lives; but when I learn that the king invites you to advise with him
as to the means of extinguishing those fires, then I feel that God is
turning his eyes with love upon the souls who are threatened with
unutterable calamities. What a strange thing! France appeals to you
at the very time when our cause is so fiercely attacked. The king,
who is of a good disposition at bottom, perceives so many defects in
the old cause, and such imprudence in those who adhere to the
truth, that he applies to you to find a remedy for these evils. O
Melancthon! to see your face will be our salvation. Come into the
midst of our violent tempests, and show us the haven. A refusal
from you would keep our brethren suspended above the flames.
Trouble yourself neither about emperors nor kings: those who invite
you are men who are fighting against death. But they are not alone:
the voice of Christ, nay, the voice of God himself calls you.’[692] The
letter is dated from Paris, 4th March, 1535.
The Holy Scriptures, which were read wherever the Reform had
penetrated, had revived in men’s hearts feelings of real unity and
Christian charity. Such cries of distress could not fail to touch the
protestants of Germany; Bucer, who had also been invited, made
preparations for his departure. ‘The French, Germans, Italians,
Spaniards, and other nations, who are they?’[693] he asked. ‘All our
brethren in Jesus Christ. It is not this nation or that nation only, but
all nations that the Father has given to the Son. I am ready,’ he
wrote to Melancthon; ‘prepare for your departure.’
Importance Of What could Melancthon do? that was the
France. great question. Many persons, even in
Germany, had hoped that France would put herself at the head of
the great revival of the Church. Had not her kings, and especially
Louis XII., often resisted Rome? Had not the university of Paris been
the rival of the Vatican? Was it not a Frenchman who, cross in hand,
had roused the West to march to the conquest of Jerusalem? Many
believed that if France were transformed, all Christendom would be
transformed with her. To a certain point, Melancthon had shared
these ideas, but he was less eager than Bucer. The outspoken
language of the placards had shocked him; but the burning piles
erected in Paris had afterwards revolted him; he feared that the
king’s plans were a mere trick, and his reform a phantom.
Nevertheless, after reflecting upon the matter, he concluded that the
conquest of such a mighty nation was a thing of supreme
importance. His adhesion to the regenerating movement then
accomplishing might decide its success, just as his hostility might
destroy it. He must do something more than open his arms to
France, he must go to meet her.
Melancthon understood the position and set to work. First, he wrote
to the Bishop of Paris, in order to gain him over to the proposed
union, by representing to him that the episcopal order ought to be
maintained. The German doctor did not doubt that even under that
form, the increasing consciousness of truth and justice, the living
force of the Gospel, which was seen opening and increasing
everywhere, would gain over to the Reformation the fellow-
countrymen of St. Bernard and St. Louis. ‘France is, so to speak, the
head of the Christian world,’ he wrote to the Bishop of Paris.[694] ‘The
example of the most eminent people may exercise a great influence
over others. If France is resolved to defend energetically the existing
vices of the Church, good men of all countries will see their fondest
desires vanish. But I have better hopes; the French nation
possesses, I know, a remarkable zeal for piety.[695] All men turn their
eyes to us; all conjure us, not only by their words, but by their tears,
to prevent sound learning from being stifled, and Christ’s glory from
being buried.’
On the same day, 9th of May, 1535, Melancthon wrote to Sturm: ‘I
will not suffer myself to be prevented either by domestic ties or the
fear of danger. There is no human grandeur which I can prefer to
the glory of Christ. Only one thought checks me: I doubt of my
ability to do any good; I fear it will be impossible to obtain from the
king what I consider necessary to the glory of the Lord and the
peace of France.[696] If you can dispel these apprehensions, I shall
hasten to France, and no prison shall affright me. We must seek only
for what is fitting for the Church and France. You know that
kingdom. Speak. If you think I should do well to undertake the
journey, I will start.’
Melancthon’s letter to the Bishop of Paris was not without effect.
That prelate had just been made a cardinal; but the new dignity in
nowise diminished his desire for the restoration of truth and unity in
the Church; on the contrary, it gave him more power to realize the
great project. The Reformation was approaching. Delighted with the
sentiments expressed to him by the master of Germany, he
communicated his letter to such as might feel an interest in it, and
among others, no doubt, to the king. ‘There is not one of our friends
here,’ he said, ‘to whom Melancthon’s mode of seeing things is not
agreeable. As for myself, it is pleasant far beyond what I can
express.’[697] It was the same with his brother William. While the new
cardinal especially desired a union with Melancthon in the hope of
obtaining a wise and pious reform, the councillor of Francis I.
desired, while leaving to the pope his spiritual authority, to make
France politically independent of Rome. The two brothers united in
entreating the king to send for Luther’s friend. De la Fosse joined
them, and all the friends of peace, in conjuring the king to give the
German doctor some proof of his good-will. ‘He will come if you
write to him,’ they said.
Letter Of The King. Francis I. made up his mind, and instead of
addressing the sovereign whose subject
Melancthon was, the proud king of France wrote to the plain doctor
of Wittemberg. This was not quite regular; had the monarch written
to the elector, such a step might have produced very beneficial
results; not so much because the susceptibility of the latter prince
would not have been wounded, as because the reasons which
Francis, with Du Bellay’s help, might have given him, would perhaps
have convinced a ruler so friendly to the Gospel and to peace as
John Frederick. It is sometimes useful to observe the rules of
diplomacy. This is the letter from the King of France to the learned
doctor, dated 23d of June, 1535.
‘Francis, by the grace of God King of the French, to our dear

Philip Melancthon, greeting:
‘I have long since been informed by William du Bellay, my
chamberlain and councillor, of the zeal with which you are
endeavoring to appease the dissensions to which the Christian
doctrine has given rise. I now learn from the letter which you
have written to him, and from Voré de la Fosse, that you are
much inclined to come to us, to confer with some of our most
distinguished doctors on the means of restoring in the Church
that divine harmony which is the first of all my desires.[698] Come
then, either in an official character, or in your own name; you
will be very acceptable to me, and you will learn, in either case,
the interest I feel in the glory of your Germany and the peace of
the universe.’
These declarations from the King of France forwarded the

enterprise; before taking such a step, he must have been very clear
in his intentions. We may well ask, however, if the letter was sincere.
In history, as in nature, there are striking contrasts. While these
things were passing in the upper regions of society, scenes were
occurring in the lower regions which ran counter to those fine
projects of princes and scholars. The Swiss divines maintained that
the whole affair was a comedy in which the king and his ministers
played the chief parts. That may be questionable, but the interlude
was a blood-stained tragedy. In the very month when Francis I.
wrote to Melancthon, a poor husbandman of La Bresse, John
Cornon, was arrested while at work in the fields, and taken to
Macon. The judges, who expected to see an idiot appear before
them, were astonished when they heard that poor peasant proving
to them, in his simple patois, the truth of his faith, and displaying an
extensive knowledge of Holy Scripture. As the pious husbandman
remained unshaken in his attachment to the all-sufficient grace of
Jesus Christ, he was condemned to death, dragged on a hurdle to
the place of execution, and there burnt alive.[699]
In the following month of July, Dennis Brion, a humble barber of
Sancerre, near Paris, and a reputed heretic, was taken in his shop.
He had often expounded the Scriptures, not only to those who
visited him, but also to a number of persons who assembled to hear
him. Nothing annoyed the priests so much as these meetings, where
simple Christians, speaking in succession, bore testimony to the light
and consolation they had found in the Bible. Brion was condemned,
as the husbandman of La Bresse had been, and his death was made
a great show. It was the time of the grands jours at Angers; and
there he was burnt alive, in the midst of an immense concourse of
people from every quarter.[700] It is probable that those executions
were not the result of any new orders, but a mere sequel to the
cruelties of the 21st of January, the influence of which had only then
reached the provinces.
These two executions, however, made the necessity of laboring to
restore peace and unity still more keenly felt. Those engaged in the
task saw but one means: to admit on one side the evangelical
doctrine, and on the other the episcopal form with a bishop primus
inter pares. Western Christendom would thus have a protestant body
with a Roman dress. The Church of the Reformation (it was said)
holds to doctrine before all things, and the Church of Rome to its
government; let us unite the two elements. The Wittemberg doctors
hoped that the substance would prevail over the form; the Roman
doctors that the form would prevail over the substance; but many on
both sides honestly believed that the proposed combination would
succeed and be perpetual.
Du Bellay Goes To At the same time as De la Fosse started for
Rome. Wittemberg, the new cardinal, Du Bellay,
departed for Rome: two French embassies were to be
simultaneously in the two rival cities. The ostensible object of the
cardinal’s journey was not the great matter which the king had at
heart, but to thank the pope for the dignity conferred upon him; still
it was the intention and the charge of the Bishop of Paris to do all in
his power to induce the catholic Church to come to an understanding
with the protestants. Before quitting France, he wrote to
Melancthon: ‘There is nothing I desire more earnestly than to put an
end to the divisions which are shaking the Church of Christ. My dear
Melancthon, do all you can to bring about this happy pacification.[701]
If you come here, you will have all good men with you, and
especially the king, who is not only in name, but in reality, most
Christian. When you have conferred with him thoroughly, which will
be soon, I trust, there is nothing that we may not hope for. God
grant that at Rome, whither I am going with all speed, I may obtain,
in behalf of the work I meditate, all the success that I desire.’[702]
The cardinal’s journey was of great importance. The party to which
he belonged, which desired one sole Catholic Church, in which
evangelical doctrines and Romish forms should be skilfully combined,
was acquiring favor in the metropolis of catholicism. The new pope
raised to the cardinalate Contarini and several other prelates who
were known for their evangelical sentiments and the purity of their
lives. He left them entire liberty; he permitted them to contradict
him in the consistory, and even encouraged them to do so. The hope
of a reform grew greater day by day in Italy.[703] It thus happened
that Cardinal du Bellay found himself in a very favorable atmosphere
at Rome: he would be backed by the influence of France, and to a
certain point by the imperial influence also, for no one desired more
strongly than Charles V. an arrangement between catholics and
protestants. The Bishop of Paris, an enlightened and skilful
diplomatist and pious man, had a noble appearance, and displayed
in every act the mark of a great soul.[704] He thus won men’s hearts,
and might, in concert with Melancthon, be the chosen instrument to
establish the so much desired unity in the Church.
Du Bellay To While he was on his way to confer with the
Melancthon. pope and cardinals, others were canvassing
Melancthon and the protestants. De la Fosse left for Wittemberg,
bearing the king’s letter, and William du Bellay, an intelligent
statesman, who was determined to spare no pains to bring the great
scheme to a successful issue, wrote to the German doctor, explaining
motives and removing objections. In his eyes the cause in question
was the greatest of all: it was the cause of religion and of France.
‘Let us beware,’ wrote the councillor of Francis I. to Melancthon, ‘let
us beware of irritating the king, whose favor you will confess is
necessary to us. If, after he has written to you with his own hand,
after you have almost given your consent, after he has sent you a
deputation, in whose company you could make the journey without
danger,—if you finally refuse to come to France, I much fear that the
monarch will not look upon it with a favorable eye. It is necessary
both to France and religion that you comply with the king’s request.
[705]
Fear not the influence of the wicked, who cannot endure to be
deprived of anything in order that the glory of Jesus Christ should be
increased.[706] The king is skilful, prudent, yielding, and allows
himself to be convinced by sound reasons. If you have an interview
with him, if you talk with him, if you set your motives before him,
you will inflame him with an admirable zeal for your cause.[707] Do
not think you will have to dissemble or give way.... No; the king will
praise your courage in such serious matters more than he would
praise your weakness. I therefore exhort and conjure you in Christ’s
name not to miss the opportunity of doing the noblest of all the
works which it is possible to perform among men.’
As we read these important letters, these touching solicitations, and
the firm opinions of the councillor of Francis I., we are tempted to
inquire what is their date. Is it in reality only five months after the
strappadoes? One circumstance explains the startling contrast.
France might say: ‘I feel two natures in me.’ Which of them shall
prevail? That is the question. Will it be the intelligence, frankness,
love of liberty, and presentiment of the moral responsibility of man,
which are often found in the French people; or the incredulity,
superstition, sensuality, cruelty, and despotism, of which Catherine
de Medicis, her husband, and her sons were the types? Shall we see
a people, eager for liberty, submitting in religious things to the yoke
of a Church which never allows any independence to individual
thought? Strange to say, the solution of this important question
seemed to depend upon a reformer. Should Melancthon come to
France, he would, in the opinion of the Du Bellays and the best
intellects of the age, inaugurate with God’s help in that illustrious
country the reign of the Gospel and liberty, and put an end to the
usurpations of Rome.
If the great enterprise at which some of the greatest and most
powerful personages were then working succeeded, if the tendency
of Catherine and her sons (continued unfortunately by the
Bourbons) were overcome, France was saved. It was a solemn
opportunity. Never, perhaps, had that great nation been nearer the
most important transformation.
In addition to the appeals of Du Bellay, no means were spared to
persuade Germany. Sturm wrote another letter to the Wittemberg
doctor, telling him that the king was not very far from sharing the
religious ideas of the protestants, and that, if his views were laid
clearly and fearlessly before him, the reformer would find that the
sovereign agreed with him on many important points. And more
than this, Claude Baduel, who, after studying at Wittemberg, was in
succession professor at Paris, rector at Nismes, and pastor at
Geneva, was intrusted by the Queen of Navarre with a mission to
Melancthon. Francis I., wishing to pass from words to deeds,
published an amnesty on the 16th July, 1535, in which he declared
that ‘the anger of our Lord being appeased, persons accused or
suspected should not be molested, that all prisoners should be set at
liberty, their confiscated goods restored, and the fugitives permitted
to re-enter the kingdom, provided they lived as good catholic
Christians.’[708]
As Francis I. did not wish to alarm the court of Rome, and desired to
prevent it from interfering and seeking to disturb and thwart his
plans, he called Cardinal du Bellay to him a short time before his
departure, and said: ‘You will give the Holy Father to understand
that I am sending your brother to the protestants of Germany to get
what he can from them; at the very least to prevail on them to
acknowledge the power of the pope as head of the Church universal.
With regard to faith, religion, ceremonies, institutions, and doctrines,
he will preserve such as it will be proper to preserve,—at least, what
may reasonably be tolerated, while waiting the decision of the
council.... Matters being thus arranged, our Holy Father will then be
able earnestly and joyfully to summon a council to meet at Rome,
and his authority will remain sure and flourishing; for, if the enemies
of the Holy See once draw in their horns in Germany, they will do
the same in France, Italy, England, Scotland, and Denmark.’[709]
The opinions of Francis I. come out clearly in these instructions. The
only thing he cared about was the preservation of the pope’s
temporal power. As for religion, ceremonies, and doctrines, he would
try to come to an understanding,—he would get what he could; but
the protestants must pull in their horns,—must renounce their
independent bearing. The king declared himself satisfied, provided
the people of Europe continued to walk beneath the Caudine forks of
Romish power.
Conference With It was not long before the king showed
The Reformers. what were his real intentions, and towards
what kind of reconciliation a council would have to labor, if one
should ever be assembled, which was very doubtful. On the 20th
July, the Bishop of Senlis, his confessor, requested the Sorbonne to
nominate ten or twelve of its theologians to confer with the
reformers. If a bombshell had fallen in the midst of the Faculty, it
could not have caused greater alarm. ‘What an unprecedented
proposal!’ exclaimed the doctors; ‘is it a jest or an insult?’ For two
days they remained in deliberation. ‘We will nominate deputies,’ said
the assembly, ‘but for the purpose of remonstrating with the king.’
‘Sire,’ boldly said these delegates, ‘your proposal is quite useless and
supremely dangerous. Useless, for the heretics will hear of nothing
but Holy Scripture; dangerous, for the catholics, who are weak in
faith, may be perverted by the objections of the heretic.... Let the
Germans communicate to us the articles on which they have need of
instruction, we will give it them willingly; but there can be no
discussion with heretics. If we meet them, it can only be as their
judges. It is a divine and a human law to cut off the corrupted
members from the body. If such is the duty of the State against
assassins, much more is it their duty against schismatics who
destroy souls by their rebellion.’[710]
These different movements did not take place in secret; they were
talked about all over the city, and far beyond it. Enlightened minds
were much amused by the fear which the doctors of the Sorbonne
had of speaking. There was no lack of remarks on that subject. ‘We
must not chatter and babble overmuch about the Gospel; but it is
absurd that, when anybody inquires into our faith, we should say
nothing in defence of it. Let us discourse about the mysteries of God
peaceably and mildly: to be silent is a supineness and cowardice
worthy of the sneers of unbelievers.’[711] When Marot the poet heard
of the answer of the Sorbonne, he said:—
Je ne dis pas que Mélancthon

Ne déclare au roi son advis;
Mais de disputer vis-à-vis ...
Nos maîtres n’y veulent entendre.
The politicians were not silent. The prospect of an agreement with

the protestants deeply moved the chiefs of the Roman party, who
resolved to do all in their power to oppose the attempt.
Montmorency, the grand master, the Cardinal de Tournon, the Bishop
of Soissons, de Chateaubriand, and others exerted all their influence
to prevent Melancthon from coming to France, Cardinal du Bellay
from succeeding at Rome, and catholics and protestants from
shaking hands together under the auspices of Francis I.
This fanatical party, which was to make common cause with the
Jesuits, already forestalled them in cunning. ‘One morning,’, say
Roman-catholic historians,[712] ‘Cardinal de Tournon appeared at the
king’s levée, reading a book magnificently bound.’ ‘Cardinal, what a
handsome book you have there!’ said the king. ‘Sire,’ replied De
Tournon, ‘it is the work of an illustrious martyr, Saint Irenæus, who
presided over the Church of Lyons in the second century. I was
reading the passage which says that John the Evangelist, being
about to enter some public baths, and learning that the heretic
Cerinthus was inside, hastily retired, exclaiming: “Let us fly, my
children, lest we be swallowed up with the enemies of the Lord.”
That is what the apostles thought of heretics; and yet you, Sire, the
eldest son of the Church, intend inviting to your court the most
celebrated disciple of that arch-heretic Luther.’ De Tournon added
that an alliance with the Lutherans would not only cause Milan to be
lost to France, but would throw all the catholic powers into the arms
of the emperor.[713] Francis I., though persisting in his scheme, saw
that he could not force those to speak who had made up their minds
to be silent; and wishing to give De Tournon some little satisfaction
he let the Faculty know that he would not ask them to confer with
the reformers. The king intended to hear both parties; he sought to
place himself between the two stormy seas, like a quiet channel,
which communicates with both oceans, and in which it was possible
to manœuvre undisturbed by tempests.
Is A Mixed Congress The refusal of the Sorbonne, at that time
Possible? more papistical than the pope himself, does
not imply that a conference between protestant and catholic
theologians was impossible; for six years later such a conference
really did take place at Ratisbon, and nearly succeeded. A
committee, half protestant, half Romanist, in which Melancthon and
Bucer sat, and in which the pious Cardinal Contarini took part as
papal legate, admitted the evangelical faith in all essential points,
and declared in particular that man is justified not by his own merits,
but by faith alone in the merits of Christ, pointing out, however, as
the protestants had always done, that the faith which justifies must
work by love. That meeting of Ratisbon came to nothing: it could
come to nothing. A gleam of light shone forth, but a breath from
Rome extinguished the torch, and Contarini submitted in silence. The
conference, however, remains in history as a solemn homage, paid
by the most believing members of the Roman-catholic Church to the
Christian doctrines of the Reformation.[714]
CHAPTER XVII.
WILL THE ATTEMPT TO ESTABLISH UNITY AND
TRUTH SUCCEED?
(August to November 1535.)
Individuality And Was the union desired by so many eminent

Community. men to be for good or for evil? On this
question different opinions may be, and have been, entertained.
Certain minds like to isolate themselves, and look with mistrust and
disdain upon human associations. It is true that man exists first as
an individual, and that before all things he must be himself; but he
does not exist alone: he is a member of a body, and this forms the
second part of his existence. Human life is both a monologue and a
dialogue. Before the era of Christianity, these two essential modes of
being had but an imperfect existence: on the one hand, social
institutions absorbed the individual, and on the other, each nation
was encamped apart. Christianity aggrandized individuality by calling
men to unite with God, and at the same time it proclaimed the great
unity of the human race, and undertook to make into one family all
the families of the earth, by giving the same heavenly Father to all.
It imparts a fresh intensity to individuality by teaching man that a
single soul is in God’s eyes of more value than the whole universe;
but this, far from doing society an injury, becomes the source of
great prosperity to it. The more an individual is developed in a
Christian sense, the more useful a member he becomes of the
nation and of the human race. Individuality and community are the
two poles of life; and it is necessary to maintain both, in order that
humanity may fulfil its mission in revolving ages. The mischief lies in
giving an unjust pre-eminence to either of the two elements. Romish
unity, which encroaches upon individuality, is an obstacle to real
Christian civilization; while an extreme individuality, which isolates
man, is full of peril both to society and to the individual himself. It
would therefore be unreasonable to condemn or to approve
absolutely the eminent men who in 1535 endeavored to restore
unity to the Church. The question is to know whether, by
reconstructing catholicity, they intended or not to sacrifice individual
liberty. If they desired a real Christian union, their work was good; if,
on the contrary, they aimed at restoring unity with a hierarchical
object, with a despotic spirit, their work was bad.
There was another question on which men were not more agreed.
Would the great undertaking succeed? France continued to ask for
Melancthon; would Germany reply to her advances? We must briefly
glance at the events which had taken place in the empire since the
agreement between the catholics and protestants concluded, as we
have seen, in July, 1532.[715] These events may help us to solve the
question.
It had been stipulated in the religious peace that all Germans should
show to one another a sincere and Christian friendship. In the treaty
of Cadan (29th June, 1534), Ferdinand, who had been recognized as
King of the Romans, had undertaken, both for himself and for
Charles V., to protect the protestants against the proceedings of the
imperial court. Somewhat later, the city of Münster, in Westphalia,
had become the theatre of the extravagances of fanaticism. John
Bockhold, a tailor of Leyden, setting himself up for a prophet, had
made himself master of the city, and been proclaimed king of Zion.
He had also established a community of goods, and attempted, like
other sectarians, to restore polygamy. He used to parade the city,
wearing a golden crown; to sit in judgment in the market-place, and
would often cut off the head of a condemned person. A pulpit was
erected at the side of the throne, and after the sermon the whole
congregation would sometimes begin to dance. The Landgrave,
Philip of Hesse, one of the leaders of the protestant cause, marched
against these madmen, took Münster on the 24th June, 1535, and
put an end to the pretended kingdom of Zion.[716] These
extravagances did not injure the protestant cause, which was not
confounded with a brutal communism, reeking with cruelty and
debauchery; besides, it was the protestants, and not the catholics,
who had put them down. But from that hour, the evangelicals felt
more strongly than ever the necessity of resisting the sectarian
spirit: this they had done at Wittemberg as early as 1522. At last it
appeared clearer every day that the free and Christian general
council, which they had so often demanded, would be granted them.
All the events, which we have indicated, seemed to have prepared
protestant Germany to accept the proposals of France.
An Important Voré de la Fosse, bearing letters from
Mission. Francis I., William du Bellay, and other
friends of the union, was going to Germany to try and bring it to a
successful issue. De la Fosse was not such a distinguished
ambassador as those who figured at London and at Rome, and the
power to which he was accredited was a professor in a petty town of
Saxony. But Germany called this professor her ‘master,’ and De la
Fosse considered his mission a more important one than any that
had been confided to dukes and cardinals. Christendom was
weakened by being severed into two parts; he was going to re-
establish unity, and revive and purify the old member by the life of
the new one. The Christian Church thus strengthened would be
made capable of the greatest conquests. On the success of the steps
that were about to be taken depended, in the opinion of De la Fosse
and his friends, the destiny of the world.
The envoy of Francis I. arrived at Wittemberg on the 4th of August,
1535, and immediately paid Melancthon a visit, at which he
delivered the letters intrusted to him, and warmly explained the
motives which ought to induce the reformer to proceed to France.
De la Fosse’s candor, his love for the Gospel, and his zeal gained the
heart of Luther’s friend. By degrees a sincere friendship grew up
between them; and when Melancthon afterwards wanted to justify
himself in the eyes of the French, he appealed to the testimony of
the ‘very good and very excellent Voré.’[717] But if the messenger
pleased him, the message filled his heart with trouble: the perusal of
the letters from the king, Du Bellay, and Sturm brought the doubts
of this man of peace to a climax. He saw powerful reasons for going
to France and equally powerful reasons for staying in Germany. To
use the expression of a reformer, there were two batteries firing
upon him by turns from opposite quarters, now driving him to the
right, now to the left. What would Charles V. say, if a German should
go to the court of his great adversary? Besides, what was to be
expected from the Sorbonne, the clergy, and the court? Contempt....
He would not go. On the other hand, Melancthon had before him a
letter from the king, pressing him to come to Paris. An influential
nation might be gained to the Gospel, and carry all the West along
with it. When the Lord calls, must we allow ourselves to be stopped
by fear?... He hesitated no longer: he would depart. Voré de la Fosse
was delighted. But erelong other thoughts sprang up to torment the
doctor’s imagination. What was there not to be feared from a prince
who had sworn, standing before the stake at which he was burning
his subjects, that to stop heresy he would, if necessary, cut off his
own arm and cast it into the fire?... In that terrible day of the
strappadoes, a deep gulf had opened in the midst of the church.
Was it his business to throw himself, Curtius-like, into the abyss, in
order that the gulf should close over him?... Melancthon would
willingly leave to the young Roman the glory of devoting himself to
the infernal gods.
De la Fosse visited the illustrious professor daily, and employed
every means to induce him to cross the Rhine.[718] ‘We will do
whatever you desire,’ he said. ‘Do you wish for royal letters to secure
to you full liberty of going to France and returning? You shall have
them. Do you ask for hostages as guarantees for your return? You
shall have them also. Do you want an armed guard of honor to
escort you and bring you back? It shall be given you.[719] We will
spare nothing. On your interview with the king depends not only the
fate of France, but (so to speak) of the whole world.[720] Hearken to
the friends of the Gospel who dwell in Paris. Threatening waves
surround us, they say by my mouth; furious tempests assail us; but
the moment you come, we shall find ourselves, as it were,
miraculously transported into the safest of havens.[721] If, on the
contrary, you despise the king’s invitation, all hope is lost for us. The
fires now slumbering will instantly shoot forth their flames, and there
will be a cruel return of the most frightful tortures.[722] It is not only
Sturm, Du Bellay, and other friends like them who invite you, but all
the pious Christians of France. They are silent, no doubt—those
whom the cruellest of punishments have laid among the dead, and
even those who, immured in dungeons, are separated from us by
doors of iron; but, if their voices cannot reach you, listen at least to
one mighty voice, the voice of God himself, the voice of Jesus
Christ.’[723]
Melancthon A Man When Melancthon heard this appeal, he
Of God. was agitated and overpowered.[724] What an
immense task! These Frenchmen are placing the world on his
shoulders! Can such a poor Atlas as he is bear it? How must he
decide? What must he do? In a short time his perplexity was again
increased. The French gentleman had hardly left the room when his
wife, Catherine daughter of the Burgomaster of Wittemberg, her
relations, her young children, and some of his best friends
surrounded him and entreated him not to leave them. They were
convinced that, if Melancthon once set foot in that city ‘which killeth
the prophets,’ they would never see him again. They described the
traps laid for him; they reminded him that no safe-conduct had been
given him; they shed tears, they clung to him, and yet he did not
give way.
Melancthon was a man of God, and prayed his heavenly Father to
show him the road he ought to take; he thoroughly weighed the
arguments for and against his going. ‘The thought of myself and of
mine,’ he said, ‘the remoteness of the place to which I am invited,
and fear of the dangers that await me ought not to stop me.[725]
Nothing should be more sacred to me than the glory of the Son of
God, the deliverance of so many pious men, and the peace of the
Church troubled by such great tempests. Upon that all my thoughts
ought to be concentred; but this is what disturbs me: I fear to act
imprudently in a matter of such great importance, and to make the
disease still more incurable through my precipitancy. Will not the
French, while giving way on some trivial points which they must
necessarily renounce, retain the most important articles in which
falsehood and impiety are especially found?[726] Alas! such patchwork
would produce more harm than good.’
There was much truth in these fears; but De la Fosse, returning to
his friend, sought to banish his apprehensions, and assured him that
the disposition of Francis I. was excellent at bottom. ‘Yes,’ replied
Luther’s friend, ‘but is he in a position to act upon it?’[727] He
expected nothing from a conference with fanatical doctors. Besides,
the Sorbonne refused all discussion. ‘The king,’ he said, ‘is not the
Church. A council alone has power to reform it; and therefore the
prince ought to set his heart upon hastening its convocation. All
other means of succoring afflicted Christendom are useless and
dangerous.’
De la Fosse turned Melancthon’s objection against him. ‘At least we
must prepare the way for the council,’ he said; ‘and it is just on that
account that the King of France wishes to converse with you.’ Then,
desiring to strike home, the envoy of Francis I. continued: ‘The king
never had anything more at heart than to heal the wounds of the
Church: he has never shown so much care, anxiety, and zeal.[728] If
you comply with his wishes, you will be received with more joy in
France than any stranger before you. Will you withhold from the
afflicted Church the hand that can save her? Let nothing in the
world, I conjure you, turn you aside from so pure and sacred an
enterprise.’[729] De la Fosse was agitated. The idea of returning to
Paris without Melancthon—that is to say, without the salvation he
expected—was insupportable. ‘Depart,’ he exclaimed, ‘if you do not
come to France!... I shall never return there.’[730]
Melancthon’s Melancthon was touched by these
Character. supplications. He thought he heard (as they
had told him) the voice of God himself. ‘Well, then,’ he said, ‘I will
go. My friends in France have entertained great expectations and
apply to me to fulfil them: I will not disappoint their hopes.’
Melancthon was resolved to maintain the essential truths of
Christianity, and hoped to see them accepted by the catholic world.
Francis I. and his friends had not rejected Luther’s fundamental
article,—justification solely by faith in the merits of Christ, by a living
faith, which produces holiness and works. According to the most
eminent and most Christian orator of the Roman Church, Melancthon
combined learning, gentleness, and elegance of style, with singular
moderation, so that he was regarded as the only man fitted to
succeed in literature to the reputation of Erasmus.[731] But he was
more than that: his convictions were not to be shaken; he knew
where he was, and, far from seeking all his life for his religion—as
Bossuet asserts—he had found it and admirably explained it in his
Theological Commonplaces.[732] Still he constantly said to his friends:
‘We must contend only for what is great and necessary.’[733]
Melancthon, who was full of meekness, was always ready to do what
might be agreeable to others. Sincere, open, and exceedingly fond
of children, he liked to play with them and tell them little tales. But
with all this amiability he had a horror of ambiguous language,
especially in matters of faith; and although a man of extreme
gentleness, he felt strongly, his anguish could be very bitter, and
when his soul was stirred, he would break out with sudden
impetuosity, which, however, he would soon repress. His error, in the
present case, was in believing that the pope could be received
without receiving his doctrines: every true Roman-catholic could
have told him that this was impossible. At all events De la Fosse had
decided him. For the triumph of unity and truth, this simple-hearted
bashful man was resolved to brave the dangers of France and the
bitter reproaches of Germany. ‘I will go,’ he said to the envoy of
Francis I. It was the language of a Christian ready to sacrifice
himself. In history we sometimes meet with characters who enlarge
our ideas of moral greatness: Melancthon was one of them.
But would his prince allow him to go? The prejudices of Germany
against France, besides numerous political and religious
considerations, might influence the elector. These were difficulties

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Genetically Engineered Food Methods and Detection K.

Safety of Genetically Engineered Foods Approaches to

Genetically Engineered Food Methods and Detection 2,

How to Create Rooms of Radiance Creative Stamping for

An Ethical Approach to Practitioner Research Dealing

Fame and Infamy Essays for Christopher Pelling on

Cajal and de Castro s Neurohistological Methods 1st

Movie Greats A Critical Study of Classic Cinema Philip

Systematic Approach to Evaluation of Mouse Mutations

Systematic Evaluation of the Mouse Eye:

Genetically Engineered Mice Handbook

Boca Raton London New York

© 2006 by Taylor & Francis Group, LLC

Library of Congress Cataloging-in-Publication Data

Visit the Taylor & Francis Web site at

Tsutomu Ichiki, Ph.D. is a general manager of Safety

Carol J. Bult, Ph.D., The Jackson Jabier Gallego Llamas, M.Sc.,

Takehito Kaneko, Ph.D., Division of Seiko Narushima, Ph.D., Food

Vanessa Ribes, M.Sc., Institut de Makoto Mark Taketo, M.D., Ph.D.,

Stephen F. Rockwood, B.S., The Tetsuya Tsukamoto, M.D., Ph.D.,

Y. Satoh, Ph.D., Center for Animal Y. Wada, Ph.D., Department of

Chapter 2 Sharing Reseach Tools: The Laboratory Mouse...........................11

Chapter 3 Managing Success: Mutant Mouse Repositories..........................27

Chapter 4 Mouse Genome Informatics: Database Access to Integrated

Chapter 5 Genetic Resouce Databases in Japan............................................57

Chapter 6 Computational Pathology: Challenges in the Informatics of

Chapter 7 Biological Methods for Archiving and Maintaining

Chapter 8 Mouse Genetic Resources without Germ Cells:

Chapter 10 Exchangeable Gene Trapping .....................................................131

Chapter 11 Genetic Monitoring of Mice .......................................................143

Chapter 12 Microbiological Monitoring of Laboratory Mice .......................157

Chapter 13 Effect of Intestinal Flora on Phenotype......................................165

Chapter 14 Helicobacter pylori and Stomach Cancer...................................173

Chapter 15 Professional Use of Mutant Laboratory Mice in Research ........185

Chapter 16 Phenotyping Postpartum Mutant Laboratory Mice and

Chapter 17 Common Diseases Found in Inbred Strains

Chapter 18 Colon Cancer and Polyposis Models..........................................233

Chapter 19 Phenotypic Analysis of Mice with Steroid Deficiency...............253

Chapter 21 Genetic Approaches to Investigate Retinoic Acid Functions in

Chapter 22 Mouse Models for Developmental Biology:

Generation of Mutant Mice ..................................................................................1

GENERATION OF MUTANT MICE

organ systems can be specifically detected by screening assays. Furthermore,

MAINTENANCE AND ARCHIVING

standard inbred background, the C57BL/6J mouse, to create congenic lines.

COLD SPRING HARBOR

THE “HARVARD MOUSE”

NIH AND THE MEMORANDA OF

1. Ensure Academic Freedom and Publication: The NIH Sharing Policy

While the work of the Reformation appeared exposed to great

‘Francis, by the grace of God King of the French, to our dear

These declarations from the King of France forwarded the

Je ne dis pas que Mélancthon

The politicians were not silent. The prospect of an agreement with

Individuality And Was the union desired by so many eminent

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