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Phage Therapy Current Research and Applications 1st
Edition Andrzej Gorski Digital Instant Download
Author(s): Andrzej Gorski; Ryszard Miedzybrodzki; Jan Borysowski
ISBN(s): 9781908230744, 1908230746
Edition: 1
File Details: PDF, 7.01 MB
Year: 2014
Language: english
 Phage Therapy
Current Research and Applications

Edited by
Jan Borysowski
Ryszard Międzybrodzki
Andrzej Górski

Caister Academic Press

Phage Therapy
Current Research and Applications

Edited by

Jan Borysowski

Department of Clinical Immunology

The Medical University of Warsaw
Warsaw
Poland

Ryszard Międzybrodzki and Andrzej Górski

Department of Clinical Immunology

The Medical University of Warsaw
Warsaw
and
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy
Polish Academy of Sciences
Wrocław
Poland

Caister Academic Press

Copyright © 2014

Caister Academic Press

Norfolk, UK

www.caister.com

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN (hardback): 978-1-908230-40-9

ISBN (ebook): 978-1-908230-74-4

Description or mention of instrumentation, software, or other products in this book does

not imply endorsement by the author or publisher. The author and publisher do not assume
responsibility for the validity of any products or procedures mentioned or described in this
book or for the consequences of their use.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted, in any form or by any means, electronic, mechanical, photocopying,
recording or otherwise, without the prior permission of the publisher. No claim to original
U.S. Government works.

Cover design adapted from various images. Top-left image: Enterococcus faecalis EF1 phage
(courtesy of A. Gozdek and D. Izak, Institute of Biochemistry and Biophysics, Polish Academy
of Sciences, Warsaw, Poland). Top-right image: Stenotrophomonas maltophilia Steno11/8c
phage taken with electron microscope (courtesy of J. Kassner, University of Wrocław, and B.
Weber-Dąbrowska). Bottom-left image: plaques of Enterococcus faecalis Ent23 phage (courtesy
of R. Międzybrodzki). Bottom-right image: Enterococcus faecalis EF56 phage (courtesy of A.
Gozdek and D. Izak, Institute of Biochemistry and Biophysics, Polish Academy of Sciences,
Warsaw, Poland). The top-left and bottom-right images were taken in the Laboratory of
Electron Microscopy at the Nencki Institute of Experimental Biology, Warsaw, Poland, using
JEM 1400 ( JEOL Co., Japan, 2008) transmission electron microscope.
 Contents

Contributorsv
Forewordxi

Introduction xiii
Jan Borysowski, Ryszard Międzybrodzki and Andrzej Górski

Part I Characteristics of Phages as Antibacterial Agents 1

1 General Characteristics of Bacteriophages 3
Hans-Wolfgang Ackermann and Grzegorz Węgrzyn

2 The First Step to Bacteriophage Therapy: How to Choose the

Correct Phage 23
Małgorzata Łobocka, Monika S. Hejnowicz, Urszula Gągała,
Beata Weber-Dąbrowska, Grzegorz Węgrzyn and Michał Dadlez

3 Bacteriophages as Drugs: The Pharmacology of Phage Therapy 69

Stephen T. Abedon

4 Fighting Bacteriophage Infection: Mechanisms of Bacterial Resistance 101

Anneleen Cornelissen, Rob Lavigne and Sylvain Moineau

5 Non-bactericidal Effects of Phages in Mammals 141

Krystyna Dąbrowska, Ryszard Międzybrodzki, Paulina Miernikiewicz,
Grzegorz Figura and Andrzej Górski

Part II Applications of Phages and Phage-derived Enzymes as Antibacterials 157

6 Overview of Therapeutic Applications of Bacteriophages 159
David Kelly, Olivia McAuliffe, R. Paul Ross, Jim O’Mahony and Aidan Coffey

7 Considerations for Using Bacteriophages in Plant Pathosystems 189

Jeffrey B. Jones, Aleksa Obradović and Botond Balogh

8 Bacteriophage Therapy in Animal Production 201

William E. Huff and Geraldine R. Huff
iv | Contents

9 The Use of Phages as Biocontrol Agents in Foods 215

Jan Borysowski and Andrzej Górski

10 Phage Therapy: Experiments Using Animal Infection Models 237

Shigenobu Matsuzaki, Jumpei Uchiyama, Iyo Takemura-Uchiyama and
Masanori Daibata

11 Clinical Phage Therapy 257

Elizabeth Kutter, Jan Borysowski, Ryszard Międzybrodzki, Andrzej Górski,
Beata Weber-Dąbrowska, Mzia Kutateladze, Zemphira Alavidze,
Marina Goderdzishvili and Revaz Adamia†

12 Reintroducing Phage Therapy in Modern Medicine: The Regulatory

and Intellectual Property Hurdles 289
Daniel De Vos, Gilbert Verbeken, Carl Ceulemans, Isabelle Huys and
Jean-Paul Pirnay

13 The Use of Bacteriophages and Bacteriophage-derived Enzymes

for Clinically Relevant Biofilm Control 309
Sanna Sillankorva and Joana Azeredo

14 Using What Phage Have Evolved to Kill Pathogenic Bacteria 331

Vincent A. Fischetti

15 Genetically Engineered Phage as Antimicrobials and Biodetectors 343

Salim Manoharadas and Udo Bläsi

16 Engineered Filamentous Bacteriophages as Targeted Anti-bacterial

Drug-carrying Nanomedicines 357
Lilach Vaks and Itai Benhar

Index 373
 Contributors

Stephen T. Abedon Botond Balogh

Department of Microbiology Nichino America Inc.
The Ohio State University Apollo Beach, FL
Columbus, OH USA
USA
[email protected]
[email protected]
Itai Benhar
Hans-Wolfgang Ackermann Department of Molecular Microbiology and
Department of Microbiology Biotechnology
Laval University Tel-Aviv University
Quebec, QC Ramat Aviv
Canada Israel
[email protected] [email protected]

Revaz Adamia† Udo Bläsi

Eliava Institute of Bacteriophages, Microbiology and Department of Microbiology, Immunobiology and
Virology Genetics
Tbilisi University of Vienna
Georgia Vienna
Austria
[email protected]
[email protected]
Zemphira Alavidze
Eliava Institute of Bacteriophages, Microbiology and Jan Borysowski
Virology Department of Clinical Immunology
Tbilisi The Medical University of Warsaw
Georgia Warsaw
Poland
[email protected]
[email protected]
Joana Azeredo
Institute for Biotechnology and Bioengineering Carl Ceulemans
University of Minho Department of Philosophy
Braga Royal Military Academy
Portugal Brussels
Belgium
[email protected]
[email protected]
vi | Contributors

Aidan Coffey Grzegorz Figura

Department of Biological Sciences Ludwik Hirszfeld Institute of Immunology and
Cork Institute of Technology Experimental Therapy
Bishopstown Polish Academy of Sciences
Ireland Wrocław
Poland
[email protected]
[email protected]
Anneleen Cornelissen
Laboratory of Gene Technology Vincent A. Fischetti
Katholieke Universiteit Leuven Laboratory of Bacterial Pathogenesis
Leuven Rockefeller University
Belgium New York, NY
USA
[email protected]
[email protected]
Krystyna Dąbrowska
Ludwik Hirszfeld Institute of Immunology and Urszula Gągała
Experimental Therapy Autonomous Department of Microbial Biology
Polish Academy of Sciences Warsaw University of Life Sciences
Wrocław Warsaw
Poland Poland
[email protected] [email protected]

Michał Dadlez Marina Goderdzishvili

Institute of Biochemistry and Biophysics Eliava Institute of Bacteriophages, Microbiology and
Polish Academy of Sciences Virology
Warsaw Tbilisi
Poland Georgia
[email protected] [email protected]

Masanori Daibata Andrzej Górski

Department of Microbiology and Infection Ludwik Hirszfeld Institute of Immunology and
Kochi University Medical School Experimental Therapy
Kochi Polish Academy of Sciences
Japan Wrocław;
Department of Clinical Immunology
[email protected]
The Medical University of Warsaw
Warsaw
Daniel De Vos Poland
Laboratory for Molecular and Cellular Technology
Burn Wound Centre [email protected]
Queen Astrid Military Hospital
Brussels Monika S. Hejnowicz
Belgium Institute of Biochemistry and Biophysics
Polish Academy of Sciences
[email protected]
Warsaw
Poland
[email protected]
 Contributors | vii

Geraldine R. Huff Mzia Kutateladze

USDA–ARS Poultry Production and Product Safety Eliava Institute of Bacteriophages, Microbiology and
Research Unit Virology
University of Arkansas Tbilisi
Fayetteville, AR Georgia
USA
[email protected]
[email protected]
Elizabeth Kutter
William E. Huff The Evergreen Phage Biology Laboratory
USDA–ARS Poultry Production and Product Safety Evergreen State College
Research Unit Olympia, WA
University of Arkansas USA
Fayetteville, AR
[email protected]
USA
[email protected] Rob Lavigne
Laboratory of Gene Technology
Isabelle Huys Katholieke Universiteit Leuven
Centre for Intellectual Property Rights and Centre for Leuven
Pharmaceutical Care and Pharmacoeconomy Belgium
Katholieke Universiteit Leuven
[email protected]
Leuven
Belgium
Małgorzata Łobocka
[email protected] Institute of Biochemistry and Biophysics
Polish Academy of Sciences;
Jeffrey B. Jones Autonomous Department of Microbial Biology
Plant Pathology Department Warsaw University of Life Sciences
University of Florida Warsaw
Gainesville, FL Poland
USA
[email protected]
[email protected] [email protected]

David Kelly Olivia McAuliffe

Department of Biological Sciences Teagasc Food Research Centre
Cork Institute of Technology Fermoy
Bishopstown Ireland
Ireland
[email protected]
[email protected]
Salim Manoharadas
Marlena Klak Department of Microbiology, Immunobiology and
Ludwik Hirszfeld Institute of Immunology and Genetics
Experimental Therapy University of Vienna
Polish Academy of Sciences Vienna
Wrocław Austria
Poland
[email protected]
[email protected]
viii | Contributors

Shigenobu Matsuzaki Jean-Paul Pirnay

Department of Microbiology and Infection Laboratory for Molecular and Cellular Technology
Kochi University Medical School Burn Wound Centre
Kochi Queen Astrid Military Hospital
Japan Brussels
Belgium
[email protected]
[email protected]
Ryszard Międzybrodzki
Ludwik Hirszfeld Institute of Immunology and R. Paul Ross
Experimental Therapy Teagasc Food Research Centre
Polish Academy of Sciences Fermoy
Wrocław; Ireland
Department of Clinical Immunology
[email protected]
The Medical University of Warsaw
Warsaw
Poland Sanna Sillankorva
Institute for Biotechnology and Bioengineering
[email protected] University of Minho
Braga
Paulina Miernikiewicz Portugal
Ludwik Hirszfeld Institute of Immunology and
[email protected]
Experimental Therapy
Polish Academy of Sciences
Wrocław Iyo Takemura-Uchiyama
Poland Department of Microbiology and Infection
Kochi University Medical School
[email protected] Kochi
Japan
Sylvain Moineau
[email protected]
Groupe de recherche en écologie buccale (GREB)
Faculté de médecine dentaire;
Félix d’Hérelle Reference Center for Bacterial Viruses; Jumpei Uchiyama
Département de biochimie, de microbiologie et de Department of Microbiology and Infection
bio-informatique Kochi University Medical School
Université Laval Kochi
Québec city, QC Japan
Canada jumpeiu@ kochi-u.ac.jp
[email protected]
Lilach Vaks
Aleksa Obradović Department of Molecular Microbiology and
Plant Pathology Department Biotechnology
University of Belgrade Tel-Aviv University
Belgrade-Zemun Ramat Aviv
Serbia Israel

[email protected] [email protected]

Jim O’Mahony
Department of Biological Sciences
Cork Institute of Technology
Bishopstown
Ireland
[email protected]
 Contributors | ix

Gilbert Verbeken Grzegorz Węgrzyn

Laboratory for Molecular and Cellular Technology Department of Molecular Biology
Burn Wound Centre University of Gdańsk
Queen Astrid Military Hospital Gdańsk
Brussels Poland
Belgium
[email protected]
[email protected]

Beata Weber-Dąbrowska
Laboratory of Bacteriophages
Ludwik Hirszfeld Institute of Immunology and
Experimental Therapy
Polish Academy of Sciences
Wrocław
Poland
[email protected]
 Current books of interest

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Biofuels: From Microbes to Molecules 2014
Human Pathogenic Fungi: Molecular Biology and Pathogenic Mechanisms 2014
Applied RNAi: From Fundamental Research to Therapeutic Applications 2014
Halophiles: Genetics and Genomes 2014
Molecular Diagnostics: Current Research and Applications 2014
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Campylobacter Ecology and Evolution 2014
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Full details at www.caister.com

 Foreword

This book represents a number of impressive that such clinical studies are relatively expensive
efforts aimed at developing phage applications and the pharmaceutical industry is reluctant to
for the service of the mankind. In many ways it invest in any antibacterial therapies. This hesi-
is ironic that we are still struggling to find accept- tancy is due to the relatively low rate of economic
ance for such phage applications, as their capacity return of such therapies, especially when they are
to serve as antibacterial agents was discovered compared with the remuneration associated with
over three decades before the discovery of the therapies developed for chronic diseases, such as
widely employed antibiotics. Even now, with the heart disease and cancer. As noted in this book,
failure of antibiotics to treat numerous bacterial this is particularly unfortunate situation, given the
infectious agents (including three that the Cent- clear need for development, expedited regulatory
ers for Disease Control has recently classified review, and clinical clearance for phage therapy.
at the highest threat level: Clostridium difficile, Another important problem for clinical phage
Neisseria gonorrhoeae, and carbapenem-resistant therapy is unfavourable pharmacokinetics of
Enterobacteriaceae), applications of phage therapy phage preparations. In particular, as shown by
that could alleviate these problems are still not our group as early as 1973, a major factor which
clinically available. determines short half-life of phages in blood is
Some barriers to clinical applications of phage rapid clearance of phage particles by cells of the
therapy arose shortly after the initial discovery of reticulo-endothelial system of the spleen and the
phage. One of the problems has been the lack of liver (Geier et al., 1973). To address this problem,
carefully designed clinical studies to determine in another study (Merril et al., 1996) we devel-
the efficacy of phage therapy. This problem was oped a serial-passage technique which enabled
well illustrated soon after the discovery of phage us to obtain phage particles with substantially
in the prescient 1924 fictional book, Arrowsmith, prolonged half-life; predictably, such particles also
written by Sinclair Lewis and his silent collabo- displayed higher antibacterial activity in vivo com-
rator, the microbiologist, Paul de Kruif (Lewis, pared to parental phages. This is but one example
1924). In this story, Arrowsmith, a research physi- of present efforts to overcome main obstacles to
cian, attempts to use phage in a carefully designed further development of clinical phage therapy in
clinical study to treat a plague epidemic on a Western medicine (Merril et al., 2003).
fictional island (St. Hubert) in the Virgin Islands. In addition to the need for new antibacterial
However, when Arrowsmith’s wife dies of the agents to treat antibiotic resistant infections,
plague on the island he decides to treat everyone, we just are beginning to realize the importance
destroying the information that could have been of maintaining a diverse natural microbiome,
provided by the non-treated control population. which is often adversely affected by the use of the
Now, nine decades later, we are still struggling broad-spectrum antibiotics used to treat infec-
with a scarcity of required controlled clinical trials tious diseases. The employment of highly specific
of phage preparations. The current difficulty is phage strains as therapeutic anti-bacterial agents
xii | Foreword

would be less disruptive to the microbiome than vaccines following the discovery that many vac-
the broad spectrum antibiotics and they should cines were contaminated by phage (Merril et al.,
be preferred once they are further developed. 1971; Merril, 1975). At that time the FDA decided
Also as addressed in this book, it will be impor- that the risk of interrupting the vaccine program
tant to improve methods for rapidly determining was outweighed by the risks posed by phage con-
which phage strains to use in each specific clinical tamination, and an Executive Order was issued to
infection, to fully realize the capacities of phage permit the use of phage-contaminated vaccines. A
therapy. number of the authors in this book have addressed
Given the current economic environment, it similar concerns and while we cannot be certain
may be necessary for clinicians and researchers that the right decision will always be made, it
who are attempting to develop phage therapy should be apparent that we must continue to
to explore the alternate means to support their gather experimental data and vigorously explore
efforts. One such mechanism might be to develop the potentials for phage therapy. So far, the ther-
self-governing organizations that are capable of apy has proven to be safe and relatively free of side
cooperatively pooling resources, as described in effects. Importantly, in 2009 FDA broadened the
numerous publications by the 2009 Economics rules of “expanded access” to investigational drugs
Nobel Laureate, Elinor Ostrom, without the need which may provide seriously ill patients with a
for additional industrial or governmental grants. lifeline where none had existed before (Federal
These are some of the issues that the regulatory Register 2009, 74, No 155) and similar approach
agencies, such as the FDA will have to address, by is being developed in Europe by EMA (“compas-
carefully balancing “risk benefit ratios”. The FDA sionate use”). Those actions should pave the way
has faced such a problem in the past, as illustrated towards the broader application of phage therapy
by their decision to permit the continued use of in the coming years.

Carl R. Merril
National Institutes of Health, USA

References
Geier, M.R., Trigg, M.E., and Merril, C.R. (1973). Fate of Merril, C.R. (1975). Phage in Human Vaccines. Science
bacteriophage lambda in non-immune germ-free mice. 188, 8.
Nature 246, 221–223. Merril, C.R., Biswas, B., Carlton, R., Jensen, N.C., Creed,
Lewis, S. (1924). Arrowsmith (The Designer Publishing G.J., Zullo, S., and Adhya, S. (1996). Long-circulating
Company, Inc., New York). bacteriophage as antibacterial agents. Proc. Natl. Acad.
Merril, C.R., Friedman, T.B., Attallah, A., Geier, M.R., Sci. U.S.A. 93, 3188–3192.
Krell, K., and Yarkin, R. (1972). Isolation of bacterio- Merril, C.R., Scholl, D., and Adhya, S.L. (2003). The pros-
phages from commercial sera. In Vitro 8, 91–93. pect for bacteriophage therapy in Western medicine.
Nat. Rev. Drug Discov. 2, 489–497.
 Introduction
Jan Borysowski, Ryszard Międzybrodzki and Andrzej Górski

We live in the era marred by the increasing drama in bacterial cells, virulent bacteriophages are
of antibiotic resistance. According to the World unique antibacterial agents and their very high
Economic Forum the greatest risk to human bactericidal potential makes them the major
health comes in the form of antibiotic – resistant therapeutic modality in phage therapy (Górski
bacteria. “We live in a bacterial world where we et al., 2009). Phages were first administered to
will never be able to stay ahead of the mutation humans for therapeutic purposes in 1919. Since
curve. A test of our resilience is how far behind the then, many thousands of patients with bacterial
curve we will allow ourselves to fall” (Spellberg, infections have been treated with bacteriophages,
2013). The World Health Organization’s Director as reflected by the vast literature on phage therapy
General warned that the world risked entering (Sulakvelidze and Kutter, 2005). Unfortunately,
“post antibiotic” age unless new antibacterial the majority of earlier studies which showed high
drugs become available quickly, a threat aggra- efficacy and safety of bacteriophages have serious
vated by a worrying trend of the emergence of methodological shortcomings and do not meet
bacterial strains resistant to vaccines which under- current rigorous standards for clinical trials. How-
mines the hope that this approach may offer a ever, the first small randomized controlled trials of
reliable weapon against resistant bacteria (Hunter, phage therapy conducted in the last decade seem
2012). Furthermore, the UK chief medical officer to preliminarily confirm the safety and efficacy of
believes that antimicrobial resistance is a threat as phages (Rhoads et al., 2009; Wright et al., 2009;
grave as climate change (Torjesen, 2013). Worse Sarker et al., 2012). Very encouraging results
still, mounting antibiotic-resistance of bacteria is were also obtained in many high-quality studies
accompanied by inadequate investment of phar- performed on animal models of clinically relevant
maceutical industry in search for new antibiotics infections (Matsuzaki et al., 2003; Capparelli et
due to their relatively low profitability, especially al., 2010). Thus at the current state of research
as compared with drugs used in the treatment therapy using virulent phages appears to be a
of chronic diseases. Of particular concern is a realistic means of treatment of bacterial infections
shortage of new classes of antibiotics which are including those caused by antibiotic-resistant bac-
essential to combat multidrug-resistant bacteria. teria (Międzybrodzki et al., 2012).
This has created an urgent need to develop non- The main objective of this book is to present
antibiotic antibacterial agents (Stanton, 2013). virulent phages as antibacterial agents and their
Currently the most promising non-antibiotic anti- main therapeutic applications. In addition, the
bacterials are virulent bacteriophages (phages), book discusses other phage-based and phage-
viruses that specifically kill bacterial cells. In view derived antibacterials including lysins (lytic
of a combination of several features, especially enzymes of bacteriophage origin), genetically-
a new mode of action, a capacity to kill bacteria engineered phages, and filamentous phages used
regardless of their antibiotic resistance, a narrow as delivery vehicles for other antimicrobial com-
antibacterial range, and an ability to replicate pounds; while the safety and the efficacy of these
xiv | Borysowski et al.

products have not been evaluated in clinical trials Part II of the book is devoted to applications
as yet, they also hold promise for future therapeu- of bacteriophages and enzymes of bacteriophage
tic use, as discussed in relevant chapters. origin to combat bacteria. This part starts with
The book is composed of two major parts. Part an overview of different phage-based and phage-
I which includes Chapters 1–5 provides compre- derived antibacterials, including virulent phages,
hensive characteristics of virulent bacteriophages phage lysins, genetically-engineered phages, and
as antibacterial agents, their interactions with filamentous phages used as delivery vehicles,
bacterial cells, as well as the effects of phages on along with their possible applications (Chapter
eukaryotic cells which can occur following the 6). Main applications of virulent phages are
administration of phage preparations to patients. discussed comprehensively in Chapters 7–12.
This part of the book starts with general character- One of these applications is the use of phages to
istics of phages including but not limited to their eliminate plant pathogens (Chapter 7). Although
structure and the interactions between phages and several studies have shown potential of phages
bacterial cells (Chapter 1). Chapter 2 discusses to control different plant pathogens both in the
main stages of the complex process of develop- rhizosphere and the phyllosphere, a number of
ing bacteriophage preparations for therapeutic factors, both environmental and bacteria-related
use. These stages include isolation of phages from can contribute to inadequate efficacy of phage
environmental samples, preliminary grouping of preparations. The main objectives of Chapter 7
phage isolates based on electron microscopy and are to discuss main factors that determine the
analysis of phage DNA and proteins, selection outcome of phage treatment of plant diseases
of therapeutic phages, and purification of phage as well as methods to improve phage efficacy.
lysates. Included in this chapter are also insightful Phage therapy can be used also to prevent and
considerations about selection of correct bacterial treat bacterial infections in animal production
strains for therapeutic phage propagation, which (Chapter 8). Based upon a comprehensive discus-
may involve modification of propagation host sion of the results of experimental studies of the
to prevent contamination of phage preparations efficacy of the use of bacteriophages in different
with other phages, plasmids, or bacterial toxins. production animals, the authors indicate possi-
Chapter 3 is an interesting attempt to character- ble applications of phage therapy in commercial
ize phages as a unique “class” of drugs, as well as cattle, poultry, swine, and aquaculture systems.
to formulate basic principles of phage therapy These applications of phage therapy gain special
using terms of classic pharmacology. It includes importance in view of current tendency to restrict
a discussion of different issues relevant to both the use of antibiotics in production animals to
the pharmacokinetics and pharmacodynamics of curb the development of antibiotic resistance
phage preparations. Chapter 4 focuses on differ- both in the US and the European Union. Chapter
ent mechanisms of bacterial resistance to phages, 9 documents major advances in the use of phages
which is one of the major factors that may account as biocontrol agents against foodborne pathogens.
for failures of phage therapy. In addition, this In order to prevent foodborne infections, bacte-
chapter discusses strategies employed by phages riophages can be added directly to foods (at all
to overcome bacterial resistance. Chapter 5 pre- stages of food production) or can be applied onto
sents non-bactericidal effects of phages. While food contact surfaces; many studies have shown
phages can infect only prokaryotic cells, they can relatively high efficacy of phages in controlling the
also interact with some populations of eukaryotic growth of major foodborne pathogens especially
cells, including immune cells. Interestingly, there Listeria monocytogenes, Escherichia coli, Salmonella
are also some data to show that bacteriophages enterica, Campylobacter jejuni, and Staphylococcus
may interfere with infections by pathogenic aureus in a variety of foods. Recent clearance by
viruses. We believe that knowledge of these gener- FDA of four bacteriophage preparations for food
ally less known effects of phages, especially their applications indicates that bacteriophages are
immunomodulatory activity and immunogenic- gradually gaining acceptance as novel biocontrol
ity, is necessary for rational use of phage therapy. agents. Chapter 11 discusses the most important
 Introduction | xv

and at the same time the most controversial safety or efficacy of lysins have been completed
application of phage therapy – the treatment of so far, very promising results of in vitro experi-
bacterial infections in humans. This chapter ments and studies performed on animals models
focuses on recent randomized controlled trials of of infections indicate high potential of lysins
phage preparations and clinical experiences of the as antibacterials. Chapter 15 presents different
only two major worldwide centres of phage ther- possibilities for genetic engineering of phages to
apy, Phage Therapy Unit at the Ludwik Hirszfeld modify their basic features as antibacterial agents;
Institute of Immunology and Experimental Ther- as discussed in this chapter, genetically modified
apy, Wrocław, Poland, and the Eliava Institute, bacteriophages could find diverse applications
Tbilisi, Georgia. This chapter is complemented as antibacterial agents (e.g. augmentation of
by a discussion of the results of phage therapy antibacterial effects of antibiotics or reduction
performed on preclinical (largely murine) models of biofilms). Chapter 16 presents an interesting
of clinically relevant infections (Chapter 10), and application of filamentous (and to a lesser extent
of main regulatory paths that may enable phage of tailed) phage particles as delivery vehicles for
preparations to be officially approved for clinical other antibacterial agents such as antibiotics
use, as well as intellectual property rights relevant or compounds used in photodynamic therapy.
to the development of phage preparations (Chap- Discussed in the chapter are both methods for
ter 12). The latter chapter is particularly important conjugating antimicrobials to phage particles and
due to unique (as compared to antibiotics and the results of in vitro studies to evaluate the effi-
other antibacterial agents) biological nature of cacy of this approach.
bacteriophages which results in phage therapy not This book has its roots in Poland, a country
being covered by any existing regulatory pathway. with a special history and tradition of phage
A lack of suitable regulatory framework is consid- therapy. The first published reports of the therapy
ered one of the most important hurdles to further in Poland date back to the 1920s. For about 30
development of clinical phage therapy. years phage therapy in Poland has been performed
The last four chapters of the book (Chapters and supervised by the Ludwik Hirszfeld Institute
13–16) present modified bacteriophages and of Immunology and Experimental Therapy of
enzymes of bacteriophage origin as antibacterial the Polish Academy of Sciences in Wrocław. The
agents. Chapter 13 focuses on the use of phages editors of the book have been engaged in research
to control the growth of biofilms. While the into bacteriophages and phage therapy of patients
majority of experimental studies discussed in this thus having practical expertise with the subjects
chapter involve the use of unmodified virulent addressed in the book, which we wish to dedicate
bacteriophages to control the growth of biofilms to the founder of the Institute and one of the
in vitro, there are also reports on successful use of pioneers of phage therapy who believed that “a
genetically-engineered phages and phage lysins conflict between the invisible and the impercepti-
to reduce biofilms. Outlined in this chapter are ble may one day be used for protection of human
also prospects for clinical use of phages to control health and life” (Hirszfeld, 1948). We hope that
biofilms, as well as specific bacteriophage prepa- publication of this book will serve this purpose.
rations which could be used in the treatment of
infections involving biofilms. Chapter 14 presents References
general characteristics and potential prophylactic Capparelli, R., Nocerino, N., Iannaccone, M., Ercolini,
D., Parlato, M., Chiara, M., and Iannelli, D. (2010).
and therapeutic applications of lysins. A unique Bacteriophage therapy of Salmonella enterica: a fresh
combination of several features, including a new appraisal of bacteriophage therapy. J. Infect. Dis. 201,
(as compared to antibiotics) mode of action based 52–61.
on peptidoglycan cleavage, narrow antibacterial Górski, A., Międzybrodzki, R., Borysowski, J., Weber-
Dabrowska, B., Lobocka, M., Fortuna, W., Letkiewicz,
range, and a low probability of the development S., Zimecki, M., and Filby, G. (2009). Bacteriophage
of bacterial resistance makes lysins novel anti- therapy for the treatment of infections. Curr. Opin.
bacterial agents which are a major alternative to Investig. Drugs 10, 766–774.
virulent phages. While no clinical trials of the
xvi | Borysowski et al.

Hirszfeld, L. (1948). The battle of the invisible with the Sarker, S.A., McCallin, S., Barretto, C., Berger, B., Pittet,
imperceptible. Wroc. Tow. Nauk. 3, 3–18. A.C., Sultana, S., Krause, L., Huq, S., Bibiloni, R.,
Hunter, P. (2012). Where next for antibiotics? The Bruttin, A., et al. (2012). Oral T4-like phage cocktail
immune system and the nature of pathogenicity are application to healthy adult volunteers from Bangla-
providing vital clues in the fight against antibiotic- desh. Virology 434, 222–232.
resistant bacteria. EMBO Reports 13, 680–683. Spellberg, B. (2013). The future of antibiotics and resist-
Matsuzaki, S., Yasuda, M., Nishikawa, H., Kuroda, M., ance. New Eng. J. Med. 368, 299–302.
Ujihara, T., Shuin, T., Shen, Y., Jin, Z., Fujimoto, S., Stanton, T.B. (2013). A call for antibiotic alternatives
Nasimuzzaman, M.D., et al. (2003). Experimental research. Trends Microbiol. 21, 111–113.
protection of mice against lethal Staphylococcus aureus Sulakvelidze, A., and Kutter, E. (2005). Bacteriophage
infection by novel bacteriophage φMR11. J. Infect. Dis. therapy in humans. In Bacteriophages: Biology and
187, 613–624. Applications, Kutter, E., and Sulakvelidze, A., eds
Międzybrodzki, R., Borysowski, J., Weber-Dąbrowska, (CRC Press, Boca Raton, Florida), pp. 381–436.
B., Fortuna, W., Letkiewicz, S., Szufnarowski, K., Torjesen, I. (2013). Antimicrobial resistance presents an
Pawełczyk, Z., Rogóż, P., Kłak, M., Wojtasik, E., et al. “apocalyptic” threat similar to that of climate change,
(2012). Clinical aspects of phage therapy. Adv. Virus CMO warns. Brit. Med. J. 346, f1597.
Res. 83, 73–121. Wright, A., Hawkins, C.H., Anggård, E.E., and Harper,
Rhoads, D.D., Wolcott, R.D., Kuskowski, M.A., Wolcott, D.R. (2009). A controlled clinical trial of a therapeu-
B.M., Ward, L.S., and Sulakvelidze, A. (2009). Bacteri- tic bacteriophage preparation in chronic otitis due to
ophage therapy of venous leg ulcers in humans: results antibiotic-resistant Pseudomonas aeruginosa; a prelimi-
of a phase I safety trial. J. Wound Care 18, 237–238, nary report of efficacy. Clin. Otolaryngol. 34, 349–357.
240–243.
 Part I

Characteristics of Phages as
Antibacterial Agents
General Characteristics of
Bacteriophages
Hans-Wolfgang Ackermann and Grzegorz Węgrzyn
1

Abstract lysogenic bacteria, but unable to reproduce on

Bacteriophages are the most numerous biological their own. They may be morphologically defective
entities in the biosphere and the largest virus group and consist only of a phage tail. Killer-particles,
known. Tailed phages constitute approximately exemplified by Bacillus subtilis phage PBSX, are
96% of known phages. Bacteriophage research is defective lysogenic myoviruses with very small
an extremely dynamic branch of microbiology. heads and long thick tails. The heads contain
This review starts with the discovery of bacterio- bacterial DNA. The particles kill bacteria and are
phages and covers basic phage techniques, ecology unable to replicate. ‘GTA’ or ‘gene transfer ele-
and incidence, aspects of phage physiology and ments’ (Solioz et al., 1977; Lang et al., 2012) are
replication, host range, classification, morphol- phage-like particles that transfer only host DNA
ogy, physico-chemical properties, genomics, and (see ‘Transduction and conversion’, below). Simi-
selected practical aspects of phage research. It larly, plasmids and episomes are not phages, but
concludes with a section on electron microscopy extrachromosomal genetic elements that may be
for rapid phage identification. parts of the life cycle of certain phages. Plasmids
consist typically of circular dsDNA and inhabit
the cytoplasm of bacteria and some eukaryotes.
Introduction The term ‘episome’ designates both plasmids
Bacteriophages or ‘phages’ are viruses of bacteria. and prophages (see ‘Lysogeny’, below) that can
‘Bacteriophage,’ derived from the Greek word integrate into the host chromosome and replicate
φαγειν, to eat, literally means ‘eater of bacteria.’ The with it.
term excludes archaeal viruses, although archaea By 2012, nearly 6300 prokaryote viruses, of
were formerly considered as bacteria and some which only 88 were archaeal viruses, had been
of their viruses have the morphology of typical examined in the electron microscope (Ackermann
tailed phages of the Myoviridae and Siphoviridae and Prangishvili, 2012). Phages thus appear, at
families. These viruses all occur in the Crenar- least on paper, as the largest viral group in exist-
chaeota phylum of Archaea (Ackermann, 2007; ence. New phages are described at the rate of about
Prangishvili, 2006; Abedon and Murray, 2013) 150 per year. This corresponds to an enormous
and their existence suggests very ancient links number of publications. The phage bibliography
between bacteria and archaea. A ‘bacteriophage’ is of Raettig (1967) lists 11,405 publications for the
a viable virus that infects bacteria. This excludes years 1917 to 1965. The bibliography of H.-W.A.,
defective phages, e.g. particulate bacteriocins, now published on the internet (www.phage.
the ‘killer particles’ of Bacillus, gene transfer ele- ulaval.ca), comprises over 33,000 phage publica-
ments, and the many morphologically defective tions for 1965–2010 and is certainly incomplete.
entities that are regularly seen in bacterial lysates. The total volume of phage literature is probably
Particulate bacteriocins are phage-like particles about 45,000 publications. For brevity, this chap-
able to kill bacteria, harboured and produced by ter relies heavily on two excellent, very complete
Other documents randomly have
different content
The Project Gutenberg eBook of Panama and the Canal
in Picture and Prose

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Title: Panama and the Canal in Picture and Prose

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*** START OF THE PROJECT GUTENBERG EBOOK PANAMA AND THE CANAL IN
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Please see the Transcriber’s Notes at the
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The cover image has been created for this
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 Note: From its Atlantic end at Colon, the Canal runs for 10 miles due south; then its general
course is to the eastward into the Pacific. This is quite contrary to the popular conception of
its general direction and is due to the fact that the Isthmus, at the Canal, bends to the
eastward, so that the Pacific Ocean at this point is south and east of the Atlantic, as shown by
the small insert map at lower left hand corner of the main map above.

Larger map (1 MB)

PANAMA
And the Canal
IN PICTURE AND PROSE
A complete story of Panama, as well as the history, purpose
and promise of its world-famous canal—the most
gigantic engineering undertaking since
the dawn of time

Approved by leading officials connected with the great enterprise

By WILLIS J. ABBOT
Author of The Story of Our Navy, American Merchant Ships and Sailors, Etc.

Water-colors by
E. J. READ and GORDON GRANT

Profusely illustrated by over 600 unique and attractive photographs taken

expressly for this book by our special staff
 Published in English and Spanish by
S Y N D I C AT E P U B L I S H I N G C O M PA N Y
LONDON NEW YORK TORONTO
HAVANA BUENOS AIRES
1913

Copyright 1913, by F. E. Wright

 CONTENTS

PAGE

INTRODUCTION 5

CHAPTER I. THE FRONT DOOR TO PANAMA 9

Antilla, a New Sugar Port—The Island of Jamaica—Kingston, The Colonial Capital—
Women as Burden Bearers—Characteristics of the Native Jamaican—Life of the Negro
Woman.

CHAPTER II. CRISTOBAL-COLON; AND THE PANAMA RAILROAD 23

The Approach to Colon—The Architecture and Population of Colon—Railroad Building
in a Swamp—The French Come to Colon—The Beautiful Roosevelt Avenue—Colon
Streets in the Early Days—The Varied Population of Colon—San Blas Indians and Their
Cayucas—The Ghastly Story of the Chinese—Cost and Charges of the Panama
Railroad.

CHAPTER III. NOMBRE DE DIOS, PORTO BELLO AND SAN LORENZO 45

The Harbor of Porto Bello—The First Appearance of Balboa—Early Indian Life in
Panama—The Futile Indian Uprising—The First Sight of the Pacific—The Beginning of
Balboa’s Downfall—The Traitor in Balboa’s Camp—The Character of Vasco Nunez de
Balboa—Panama a Link in Philippine Trade—Flush Times in Porto Bello—The Piratical
Raid of Sir Francis Drake—The Futile Attack on the Treasure Train—The Appearance of
Morgan the Buccaneer—The Pillage of Porto Bello.

CHAPTER IV. SAN LORENZO AND PANAMA 75

The Waterway to San Lorenzo—Approach to San Lorenzo Castle—A Rip Van Winkle of
a Fortress—The Assault of the Buccaneers—The End of Porto Bello and San Lorenzo.

CHAPTER V. THE SACK OF OLD PANAMA 87

The Advance of the Buccaneers—The Banquet before Panama—The Buccaneers
Triumphant in Battle—The Pirates’ Orgy of Plunder—How Morgan Plundered His
Pirates—The Scene of Morgan’s Great Exploit.

CHAPTER VI. REVOLUTIONS AND THE FRENCH RÉGIME 101

The Scottish Settlement in Panama—Disasters Beset the Scotch Colonists—The
Repeated Revolutions of Panama—Early Projectors of a Panama Canal—Sea Level or
Lock Canal—A Relic of the French Days—Some of the Finished Work of the French—
The Financial Aberrations of De Lesseps—Yellow Fever’s Toll of French Lives—The
Value of the French Work.
CHAPTER VII. THE UNITED STATES BEGINS WORK 123
Why Panama Wanted Independence—Our Share in the Revolution—A Revolution
Without a Single Battle—Treaty Rights of the United States—Illustrations of the
Magnitude of the Canal Work—The Passage of the Canal Locks—Spectacular Features
of Gatun Lake—The Abandonment of Canal Towns—The Pacific Terminus of the Canal
—The Forts at the Pacific Entrance.

CHAPTER VIII. THE FORMATIVE PERIOD 147

The Beginning of Work under Wallace—The Absentee Commissioners and the Red
Tape—The Successful War with Yellow Fever—The Change from Wallace to Stevens—
The Varying Estimates of the Canal Cost—The Resignation of Engineer Stevens.

CHAPTER IX. COL. GOETHALS AT THE THROTTLE 161

What the Colonel Meant by Orders—The Colonel’s Sunday Morning Court—The
Autocratic Power of Col. Goethals—The Panama Work Shows Governmental Efficiency.

CHAPTER X. GATUN DAM AND LOCKS 171

Atlantic Beginning of the Canal—The Plan of the Gatun Dam—How the Chagres
Current was Blocked—The Spillway, The Nerve Center of Gatun Lake—The Uses of the
Electric Power of Gatun—The Colossal Concrete Work at Gatun—The Motive Power of
the Lock Gates.

CHAPTER XI. GATUN LAKE AND THE CHAGRES RIVER 187

The Native Affection for the Chagres—The Indispensable Native Cayuca—Keeping the
Record of the Chagres—Cruces in Its Day of Greatness—Animal Life on the Chagres
River—A Typical Foreign Laborer on The Zone.

CHAPTER XII. THE CULEBRA CUT 201

The Great Problem of the Slides—The Physical Characteristics of the Slide—Some
Peculiar Features of the Slides—The Explosive Experience of Miguel—The Gorgeous
Coloring of Culebra—The Perilous Passage of Culebra Cut—The almost Human Work
of the Steam Shovel—The Work of the Steam Shovellers—The almost Indispensable
Track Shifter—The Industrious Ants of Panama—The End of the Canal at Balboa.

CHAPTER XIII. THE CITY OF PANAMA 224

The First Appearance of Panama City—The Popular Panama Lottery—Panama’s Cost
of Living is High—Scenes in the Panama Market—The Prevalent Temper of the
Panamanians—Why Americans are not Popular—American Sentiment on the Isthmus
—The Public Buildings of Panama—The Stout Walls of Panama City—Scenes of the
Mardi Gras Carnival—Cock-Fighting and the Liquor Trade—In the Ancient Chiriqui
Prison—The Many Churches of Panama—Panama Clubs and Open Air Life.

CHAPTER XIV. THE SANITATION OF THE ZONE 253

Beginning the Warfare on Mosquitoes—Methods of the Anti-Mosquito Crusade—Some
Humors of the Mosquito War—How the Streams are Sterilized—Results of the War on
Mosquitoes—The Two Great Canal Commission Hospitals—The System of Free Medical
Treatment—The Pleasant Village of Taboga—The Sanitarium and Leper Colony.
CHAPTER XV. THE REPUBLIC OF PANAMA 273
The Doubtful Soil of Panama—The Simple Study of Native Life—The Building of the
Bridegroom’s House—Labor and Land Titles in Panama—Agriculture and Temperature
in Panama—Rubber and Cocoanuts Offer Possibilities—The Sport of Shooting
Alligators—A Colossal Agricultural Enterprise—The Banana as an Empire Builder—Why
the American Flag is Rare—Getting the Bananas to Market—David and the Cattle
Country—Gold from the Indian Tombs—Efforts for a System of Industrial Education.

CHAPTER XVI. THE INDIANS OF PANAMA 305

Marriage Customs of the Indians—The Many Tribes of Panama Indians—
Characteristics of the San Blas Tribe—An Exclusive Aboriginal People—Family Quarters
of the San Blas—Customs of the Chocos and Guaymies—Peculiarities of the Darien
Indians.

CHAPTER XVII. SOCIAL LIFE ON THE CANAL ZONE 320

The Population of the Canal Zone—The Temptations to Matrimony on the Zone—The
Gold and Silver Employees—The Object Lesson of the Canal Zone—Why It is not at all
“Socialistic”—In a Typical Canal Zone Dwelling—Some Features of Zone Housekeeping
—Prices of Food at the Commissary—The Complicated Social Life of the Zone—Church
Work and the Y. M. C. A.

CHAPTER XVIII. LABOR AND THE GOVERNMENT OF THE ZONE 341

The Colossal Business of the Commissary—The Task of Feeding Forty Nationalities—
The Stern Suppression of the Social Class—Evil Effect of the Abolition of the Canteen
—Some Figures Concerning the Commissary Service—The International Agreement on
the Commissary—The Police System of the Zone—The School System of the Zone—
Agricultural Possibilities on the Zone—Future Possibilities of the Canal Zone.

CHAPTER XIX. FORTIFICATIONS, TOLLS, COMMERCE AND QUARANTINE 363

Why Fortify the Canal at All?—The Suez Canal no Parallel—Some Details of the
Fortifications—The Mobile Force on the Zone—The Sufficiency of Fortifications
Planned—Effect of the Canal on Trade Routes—The Railroad Fight on the Canal—The
Canal and the Flag—The First Immediate Advantage of the Canal—The Much-mooted
Question of Tolls—Our Trade with Pacific-Latin America—Time Saved by Panama
Canal Route—The Possible Commerce of the Canal—Some Phases of Our Foreign
Trade—The Need of Our Own Ships and Banks—What Our Merchant Marine is—The
Grave Question of Quarantine.

CHAPTER XX. DIPLOMACY AND POLITICS OF THE CANAL 399

Our Reckoning with Colombia—Our Commercial Interests in South America—Mutual
Interests of the United States and Great Britain—What the Canal has and will Cost—
New Work for the Interstate Commerce Commission—The Moral Lesson of the
Panama Canal.
LIST OF COLORED ILLUSTRATIONS

1 Map of Panama Canal and Canal Zone Facing title page

FACING PAGE
2 Duke Street, Kingston, Jamaica 16
3 Going to Market 40
4 A Native Village 72
5 Old French Canal at Mount Hope 104
6 Ancon Hill from the Harbor of Panama 128
7 The Washing Place at Taboga 152
8 A Native Bakery 176
9 The River and Village of Chagres 192
10 The Culebra Cut 216
11 Avenida B, Panama City 232
12 Panama Bay from Ancon Hospital 256
13 A Typical Native Hut 280
14 Vendor of Fruit and Pottery 304
15 Old Landing at Taboga 336
16 Swimming Pool at Panama 368
17 Santa Ana Plaza, Panama 392
 LIST OF BLACK AND WHITE
ILLUSTRATIONS

PAGE
1 The Sentinel Tree 5
2 Scene on Otoque Island, Panama Bay 6
3 The Rank, Lush Growth of the Jungle 7
4 Ruins of Old Panama 8
5 Tree Growing out of a Chimney in Jamaica 9
6 Cane River Falls 10
7 The Road to Market 11
8 Sports on Shipboard 12
9 The “Oruba” 12
10 Bog Walk, Jamaica 13
11 Government Buildings, Kingston 14
12 King Street, Kingston, Jamaica 15
13 Jamaica, Where Motoring is Good 16
14 Women on the Way to Market 17
15 A Yard and its Tenants 18
16 Coaling Steamships 19
17 Market Women and their Donkeys 20
18 One Way of Carrying Bananas 21
19 “Gwine to de Big Job” 22
20 Toro Point Light 23
21 Toro Point Breakwater 24
22 The New Cristobal Docks 24
23 “Palms Which Blend With the Sea” 25
24 Colon in 1884 26
25 Fire-Fighting Force at Cristobal 27
26 The New Washington Hotel 28
27 The Only Stone Church in Colon 28
28 Nature of Country near Colon 29
29 Panama Pottery Sellers 30
30 Hindoo Laborers on the Canal 30
31 San Blas Boats at Early Dawn 31
32 San Blas Indian Boys 31
33 San Blas Lugger Putting Out to Sea 31
34 The Atlantic Fleet Visits the Isthmus 32
35 Roosevelt Avenue, Cristobal, About to Lose its Beauty 33
36 The De Lesseps Palace 34
37 The National Game—Cock-Fighting 34
38 How the Jungle Works 35
39 “Bottle Alley” 36
40 D Street, Colon, Paved 37
41 Bachelor Quarters at Toro Point 38
42 A Colon Water Carrier 39
43 An Open Sewer in a Colon Street 39
44 By a Coclé Brook 40
45 The Mangroves Marching on Stilt-like Roots 40
46 A Picturesque Inlet of the Caribbean 41
47 Childish Beauty Without Art 42
48 A Corner of Mount Hope Cemetery 42
49 The Soulful Eyes of the Tropics 43
50 Market Day at David 43
51 Scene on Almirante Bay 44
52 Modern Porto Bello from Across the Bay 45
53 Typical Native Hut in Porto Bello District 46
54 Entrance to Porto Bello Harbor, from Spanish Fort 47
55 Bullock Cart on the Savanna Road 47
56 Modern Indian, Darien Region 48
57 Native Family in Chorrera 49
58 Seventeenth Century Ruin at Porto Bello 50
59 Street in Modern Porto Bello 51
60 Ancient Trail from Porto Bello 52
61 Spanish Fort at Entrance to Porto Bello Harbor 53
62 A Group of Cholo Indians 54
63 Natives Grinding Rice in a Mortar Owned by All 55
64 Family Travel on the Panama Trail 56
65 Deserted Native Hut 57
66 What They Still Call a Road in Panama 58
67 Outdoor Life of the Natives 59
68 Native Hut and Open-Air Kitchen 60
69 Cocoanut Grove on the Caribbean Coast 61
70 Canal Commission Stone Crusher, Porto Bello 61
71 Native Huts near Porto Bello 62
72 An Indian Family of the Darien 62
73 Ruined Spanish Fort at Porto Bello 63
74 San Blas Luggers at Anchor 64
75 The Teeth of the Tropics 64
76 Native Bridge in the Darien 65
77 Choco Indian Girls 66
78 Indian Huts near Porto Bello 67
79 Country Back of Porto Bello 68
80 Native Women of the Savannas Bearing Burdens 68
81 Camina Reale, or Royal Road near Porto Bello 69
 82 A Lady of the Savanna 70
83 Native Children, Panama Province 70
84 Bull-Rider and Native Car at Bouquette, Chiriqui 71
85 The Indians Call Her a Witch 72
86 A Cuna Cuna Family near Porto Bello 72
87 A Trail near Porto Bello 73
88 A Cholo Mother and Daughter 73
89 A Group of Cuepa Trees 74
90 Mouth of the Chagres River 75
91 Mouth of the Chagres from the Fort 76
92 The Sally-Port at San Lorenzo 77
93 Church at Chagres 78
94 Old Spanish Magazine 79
95 Spanish Ruins, Porto Bello 79
96 Our Guide at San Lorenzo 80
97 The Author at San Lorenzo 80
98 Looking Up the Chagres from San Lorenzo 81
99 The True Native Social Center 82
100 Tropical Foliage on the Caribbean 83
101 On the Upper Chagres 84
102 Native Panama Woman 84
103 A Character of Colon 85
104 Woman of the Chagres Region 85
105 Near a Convent at Old Panama 87
106 Casa Reale or King’s House 88
107 The Ruined Tower of San Augustine 89
108 Wayside Shrine on the Savanna Road 90
109 Arched Bridge at Old Panama, Almost 400 Years Old 91
110 Foliage on the Canal Zone 92
111 The Chagres Above San Lorenzo 93
112 In the Crypt of Old San Augustine 94
113 A Woman of Old Panama 94
114 Wash Day at Taboga 95
115 A Street in Cruces 96
116 Breaking Waves at Old Panama 96
117 Old Bell at Remedios, 1682 97
118 The Beetling Cliffs of the Upper Chagres 97
119 The Roots Reach Down Seeking for Soil 98
120 Bluff near Toro Point 99
121 “Whether the Tree or the Wall is Stouter is a Problem” 100
122 San Pablo Lock in French Days 101
123 Part of the Sea Wall at Panama 102
124 The Pelicans in the Bay of Panama 103
125 The Road from Panama to La Boca 104
126 The City Park of Colon 105
127 Children in a Native Hut 105
128 The Water Front of Panama 106
129 The Water Gate of Panama 106
130 Entrance to Mount Hope Cemetery 107
131 Cathedral Plaza, Panama 108
132 Avenida Centrale 109
133 Ancon Hill at Sunset 110
134 Abandoned French Machinery on the Canal 110
135 Overwhelmed by the Jungle 111
136 A Lottery Ticket Seller 112
137 Machinery Seemingly as Hopeless as this was Recovered, Cleaned and set to
Work 112
138 The Power of the Jungle 113
139 La Folie Dingler 114
140 Near the Pacific Entrance to the Canal 114
141 Where the French Did Their Best Work 115
142 An Old Spanish Church 116
143 Juncture of French and American Canals 116
144 Part of the Toll of Life 117
145 The Ancon Hospital Grounds 118
146 A Sunken Railroad 118
147 A Zone Working Village 119
148 Negro Quarters, French Town of Empire 120
149 Filth that would Drive a Berkshire from his Sty 121
150 Canal Valley near Pedro Miguel 122
151 Panama Soldiers Going to Church 123
152 The Official Umpire, Cocle 124
153 The Man and the Machine 125
154 Landing Pigs for Market 126
155 The Trail near Culebra 126
156 In the Banana Country, on the Coast near Bocas del Toro 127
157 The Best Residence Section, Colon 128
158 The Old Fire Cistern, Panama 129
159 The Two Presidents: Roosevelt and Amador 130
160 Cholo Chief and His Third Wife 131
161 Native House and Group at Puerta Pinas 131
162 What They Call a Street in Taboga 132
163 Hindoo Merchants on the Zone 132
164 Chamé Beach, Pacific Coast 133
165 French Dry Dock, Cristobal 133
166 What the Work Expended on the Canal Might Have Done 134
167 A Graphic Comparison 134
168 What the Panama Concrete Would Do 135
169 Proportions of Some of the Canal Work 135
170 The “Spoil” from Culebra Cut Would Do This 135
171 In a Typical Lock 135
172 Lock at Pedro Miguel Under Construction 137
173 Range Tower at Pacific Entrance 138
174 Bird’s Eye View of Pedro Miguel Locks 138
175 The Vegetable Martyrs 139
176 Native Street at Taboga 140
177 Gamboa Bridge with Chagres at Flood 141
178 The Y. M. C. A. Club House at Gatun 141
179 Working in Culebra Cut 142
180 Miraflores Lock in March, 1913 143
181 Naos, Perico and Flamenco Islands to be Fortified 143
182 Beginning of New Balboa Docks 144
183 The Old Pacific Mail Docks at Balboa 144
184 The Pacific Gateway 145
185 Completed Canal at Corozal 146
186 Tunnel for the Obispo Diversion Canal 147
187 The Two Colonels 148
188 A Walk at Ancon 149
189 In the Hospital Grounds 149
190 French Cottages on the Water Front, Cristobal 150
191 Pay Day for the Black Labor 151
192 In Wallace’s Time 152
193 The Fumigation Brigade 153
194 Typical Screened Houses 154
195 A Street After Paving 154
196 Stockade for Petty Canal Zone Offenders 155
197 Hospital Buildings, United Fruit Co. 155
198 Beginning the New Docks, Cristobal 156
199 A Back Street in Colon 157
200 Steam Shovel at Work 158
201 The Balboa Road 158
202 A Drill Barge at Work 159
203 Pacific Entrance to the Canal 160
204 Col. Goethals at His Desk 161
205 Railway Station at Gatun 162
206 President Taft Arrives 162
207 Col. Goethals Reviewing the Marines at Camp Elliott 163
208 President Taft and “the Colonel” 164
209 Big Guns for Canal Defence 164
210 Col. Goethals Encourages the National Game 165
211 Old French Ladder Dredges Still Used 166
212 The Colonel’s Daily Stroll 166
213 A Side Drill Crew at Work 167
214 The Colonel’s Fireworks 168
215 A Heavy Blast Under Water 168
216 The Colonel’s Daily Meal 169
217 “The Goethals’ Own” in Action 169
218 Bas Obispo End of Culebra Cut 170
219 Entrance to Gatun Locks 171
220 I. Colon: These Pictures in Order form a Panorama of the Colon Water Front 172
221 II. Colon: Part of the Residential District on the Water Front 173
222 III. Colon: Panama Railroad and Royal Mail Docks 172
223 IV. Colon: The De Lesseps House in the Distance shows Location of New Docks 173
224 South Approach Wall, Gatun Locks 174
225 Gatun Locks Opening into the Lake 174
226 Gatun Lake Seen from the Dam 175
227 Bird’s Eye View of Gatun Dam 175
228 Construction Work on Gatun Dam 176
229 Pumping Mud into the Core of Gatun Dam 176
230 Gatun Upper Lock 177
231 Gatun Center Light 177
232 Emergency Gates 177
233 Spillway Under Construction 178
234 Partly Completed Spillway, 1913 179
235 The Giant Penstocks of the Spillway 180
236 The Spillway at High Water 180
237 Lock Gates Approaching Completion 181
238 The Water Knocking at Gatun Gates 182
239 Wall of Gatun Lock Showing Arched Construction 182
240 Traveling Cranes at Work 183
241 Building a Monolith 183
242 A Culvert in the Lock Wall 184
243 Diagram of Lock-Gate Machinery 184
244 Towing Locomotive Climbing to Upper Lock 184
245 The Heavy Wheel Shown is the “Bull Wheel” 185
246 The Tangled Maze of Steel Skeletons that are a Lock in the Making 186
247 The Chagres, Showing Observer’s Car 187
248 Fluviograph at Bohio, now Submerged 188
249 Automatic Fluviograph on Gatun Lake 188
250 The Village of Bohio, now Submerged 189
251 Steps Leading to Fluviograph Station at Alhajuela 190
252 A Light House in the Jungle 190
253 The Riverside Market at Matachin 191
254 Railroad Bridge Over the Chagres at Gamboa 192
255 A Quiet Beach on the Chagres 192
256 Poling Up the Rapids 193
257 Construction Work on the Spillway 193
258 Water Gates in Lock Wall 194
259 The Lake Above Gatun 194
260 How They Gather at the River 195
261 Washerwomen’s Shelters by the River 196
262 A Ferry on the Upper Chagres 196
263 The Much Prized Iguana 197
264 Cruces—A Little Town with a Long History 198
265 A Native Charcoal Burner 198
266 The Natives’ Afternoon Tea 199
267 Piers of the Abandoned Panama Railway 200
268 Working on Three Levels 201
269 The Original Culebra Slide 202
270 Slide on West Bank of the Canal near Culebra 203
271 Attacking the Cucaracha Slide 204
272 Diagram of Culebra Cut Slides 205
273 A Rock Slide near Empire 205
274 The Author at Culebra Cut 206
275 Cutting at Base of Contractors Hill 206
276 A Rock Slide at Las Cascades 207
277 Slicing Off the Chief Engineer’s Office 208
278 How Tourists see the Cut 208
279 Jamaicans Operating a Compressed Air Drill 209
280 Handling Rock in Ancon Quarry 209
281 In the Cucaracha Slide 210
282 Brow of Gold Hill, Culebra Cut 211
283 A Dirt-Spreader at Work 212
284 “Every Bite Recorded at Headquarters” 212
285 A Lidgerwood Unloader at Work 213
286 The Track Shifter in Action 213
287 One of the Colonel’s Troubles 214
288 The Sliced-off Hill at Ancon 214
289 A Lock-Chamber from Above 215
290 When the Obispo Broke in 215
291 Ungainly Monsters of Steel Working with Human Skill 216
292 Building an Upper Tier of Locks 217
293 Traveling Cranes that Bear the Brunt of Burden Carrying 217
294 The Floor of a Lock 218
295 Excavating with a Monitor as Californians Dig Gold 218
296 A Steam Shovel in Operation 219
297 Bird’s Eye View of the Miraflores Locks 220
298 The Rock-Break that Admitted the Bas Obispo 220
299 An Ant’s Nest on the Savanna 221
300 A Termite Ant’s Nest 221
301 Deep Sea Dredge at Balboa 222
302 Proportions of the Locks 222
303 The Great Fill at Balboa Where the Culebra Spoil is Dumped 223
304 Panama Bay from Ancon Hill 224
305 Santa Ana Plaza 225
306 Panama from the Sea Wall; Cathedral Towers in Distance 226
307 The Bull Ring; Bull Fights are now Prohibited 227
308 The Panama Water Front 227
309 The Lottery Office in the Bishop’s Palace 228
310 San Domingo Church and the Flat Arch 228
311 Chiriqui Cattle at the Abattoir 229
312 The President’s House; A Fine Type of Panama Residence 229
313 The Fish Market 230
314 San Blas Boats at the Market Place 230
315 The Vegetable Market 230
316 The Market on the Curb 231
317 Where the Flies get Busy 231
318 Cayucas on Market Day 231
319 Panama from the Bay; Ancon Hill in the Background 232
320 Pottery Vendors near the Panama City Market 233
321 From a Panama Balcony 234
322 The First Communion 235
323 Marriage is an Affair of Some Pomp 235
324 The Manly Art in the Tropics 236
325 A Group of National Police 236
326 Taboga, the Pleasure Place of Panama 237
327 Santa Ana Church, 1764 237
328 The Panama National Institute 238
329 The Municipal Building 239
330 The National Palace and Theater 239
331 Salient Angle of Landward Wall 240
332 Boys Skating on Sea Wall 240
333 Vaults in the Panama Cemetery 241
334 Ruins of San Domingo Church 242
335 Some Carnival Floats 243
336 The Ancient Cathedral 244
337 The Police Station, Panama 245
338 Church of Our Lady of Mercy (La Merced) 245
339 Young America on Panama Beach 246
340 Ready to Control the Pacific 246
341 The Flowery Chiriqui Prison 247
342 The Market for Shell Fish 248
343 The Cathedral and Plaza 249
344 In a Panama Park 250
345 Salvation Army in Panama 250
346 Costume de Rigueur for February 250
347 Bust of Lieut. Napoleon B. Wyse 251
348 On Panama’s Bathing Beach 252
349 Quarantine Station at Pacific Entrance to Canal 252
350 Col. W. C. Gorgas 253
351 What Col. Gorgas Had to Correct 254
352 Administration Building, Housing the Sanitary Department 254
353 Dredging a Colon Street 255
354 The War on Mosquitoes. I 256
355 The War on Mosquitoes. II 256
356 The War on Mosquitoes. III 257
357 The War on Mosquitoes. IV 257
358 Sanitary Work in a Village 258
359 The Mosquito Chloroformer’s Outfit 259
360 The Mosquito Chloroformer at Work 259
361 Ancon Hospital as Received from the French 260
362 The Canal Commission Hospital at Colon Built by the French 261
363 French Village of Empire after Cleaning up by Americans 262
364 The Bay of Taboga from the Sanitarium 262
365 The Little Pango Boats Come to Meet You 263
366 Old Church at Taboga 263
367 The Rio Grande Reservoir 263
368 In Picturesque Taboga 264
369 In the Grounds of Ancon Hospital 265
370 The Sanitarium at Taboga Inherited from the French 266
371 A Fête Day at Taboga 266
372 Feather Palm at Ancon 267
373 Taboga from the Bathing Beach 267
374 Taboga is Furthermore the Coney Island of Panama 268
375 Burden Bearers on the Savanna 269
376 Hotel at Bouquette, Chiriqui 270
377 A Bit of Ancon Hospital Grounds 270
378 The Chief Industry of the Natives is Fishing 271
379 Nurses’ Quarters at Ancon 271
380 The Leper Settlement on Panama Bay 272
381 The Gorge of Salamanca 273
382 Native Family in Chorrera 274
383 A Street in Penemone 275
384 The Hotel at David 275
385 View of Bocas del Toro 276
386 Vista on the Rio Grande 276
387 At the Cattle Port of Aguadulce 277
388 The Royal Road near Panama 277
389 The Meeting Place of the Cayucas 278
390 Banana Market at Matachin 279
391 In the Chiriqui Country 280
392 Banana Plant; Note Size of Man 280
393 Construction of Roof of a Native House 281
394 A Native Living Room and Stairway 281
395 Rubber Plantation near Cocle 282
396 Bolivar Park at Bocas del Toro 282
397 A Ford near Ancon 283
398 Old Banana Trees 284
399 Pineapples in the Field 284
400 Waiting for the Boat 285
401 Country House of a Cacao Planter at Choria 285
402 Started for Market 286
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