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Advances in Stem Cell Biology
Series Editor
Alexander Birbrair
Advances in Stem Cell Biology
iPSCs for Studying
Infectious Diseases,
Volume 8

Edited by
Alexander Birbrair
Academic Press is an imprint of Elsevier
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This book and the individual contributions contained in it are protected under copyright
by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
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editors, assume any liability for any injury and/or damage to persons or property as a
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 This book is dedicated to my mother, Marina Sobolevsky, of blessed memory, who passed
away during the creation of this volume. Professor of Mathematics at the State University
of Ceará (UECE), she was loved by her colleagues and students, whom she inspired by her
unique manner of teaching. All success in my career and personal life I owe to her.

My father Lev Birbrair and my beloved mom Marina Sobolevsky of blessed memory (July 28, 1959eJune 3, 2020)
Contributors
Serkan Belkaya
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent
University, Çankaya, Ankara, Turkey
David C. Bloom
Department of Molecular Genetics & Microbiology, University of Florida College of
Medicine, Gainesville, FL, United States
Guglielmo Bove
Schaller Research Group, Center of Infectious Diseases, Department of Virology,
Heidelberg University Hospital, Heidelberg, Germany
Adriana Bozzi
Instituto René Rachou, FIOCRUZ, Belo Horizonte, Brazil; Departamento de
Ciências Biológicas, Universidade Estadual de Santa Cruz, UESC, Ilhéus, Brazil
Kevin M. Coombs
University of Manitoba, Department of Medical Microbiology and Infectious
Diseases, Winnipeg, MB, Canada; Manitoba Centre for Proteomics & Systems
Biology, Winnipeg, MB, Canada; Children’s Hospital Research Institute of
Manitoba, Winnipeg, MB, Canada
Viet Loan Dao Thi
Schaller Research Group, Center of Infectious Diseases, Department of Virology,
Heidelberg University Hospital, Heidelberg, Germany
Matthew J. Demers
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of
Pittsburgh School of Medicine, Pittsburgh, PA, United States
Leonardo D’Aiuto
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of
Pittsburgh School of Medicine, Pittsburgh, PA, United States
Jessica L. Forbester
Division of Infection and Immunity/Systems Immunity University Research
Institute, Cardiff University, Cardiff, United Kingdom; MRC Weatherall Institute of
Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United
Kingdom
Eric C. Freundt
Department of Biology, The University of Tampa, Tampa, FL, United States
Sandra K. Halonen
Department of Microbiology and Immunology, Montana State University,
Bozeman, MT, United States

xiii
xiv Contributors

Brandon J. Kim
University of Alabama, Department of Biological Sciences, Tuscaloosa, AL,
United States
Paul R. Kinchington
Department of Ophthalmology, University of Pittsburgh School of Medicine,
Pittsburgh, PA, United States; Department of Molecular Microbiology and
Genetics, University of Pittsburgh, Pittsburgh, PA, United States
Thomas E. Lane
Department of Neurobiology & Behavior, University of California, Irvine, Irvine,
CA, United States
Jeanne F. Loring
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA,
United States
Laura L. McIntyre
Department of Molecular Biology & Biochemistry, University of California, Irvine,
Irvine, CA, United States
James McNulty
Department of Chemistry and Chemical Biology, McMaster University, Hamilton,
ON, Canada
Ann-Kathrin Mehnert
Schaller Research Group, Center of Infectious Diseases, Department of Virology,
Heidelberg University Hospital, Heidelberg, Germany
Vishwajit L. Nimgaonkar
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of
Pittsburgh School of Medicine, Pittsburgh, PA, United States
Warren C. Plaisted
Genomics Institute of the Novartis Research Foundation, San Diego, CA, United
States
Pavan Rajanahalli
Department of Biology, The University of Tampa, Tampa, FL, United States
Duncan R. Smith
Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom,
Thailand
David A. Stevens
California Institute for Medical Research, San Jose, CA, United States; Division of
Infectious Diseases and Geographic Medicine, Stanford University School of
Medicine, Stanford, CA, United States
 Contributors xv

Craig M. Walsh
Department of Molecular Biology & Biochemistry, University of California, Irvine,
Irvine, CA, United States
Maribeth A. Wesesky
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of
Pittsburgh School of Medicine, Pittsburgh, PA, United States
Ali Zahedi-Amiri
University of Manitoba, Department of Medical Microbiology and Infectious
Diseases, Winnipeg, MB, Canada; Manitoba Centre for Proteomics & Systems
Biology, Winnipeg, MB, Canada
Wenxiao Zheng
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of
Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of
Psychiatry, The Second Xiangya Hospital, Xiangya School of Medicine, Central
South University, Changsha, China
About the editor

Alexander Birbrair

Dr. Alexander Birbrair received his bachelor’s biomedical degree from Santa Cruz
State University in Brazil. He completed his PhD in Neuroscience, in the field of
stem cell biology, at the Wake Forest School of Medicine under the mentorship of
Osvaldo Delbono. Then, he joined as a postdoc in stem cell biology at Paul
Frenette’s laboratory at Albert Einstein School of Medicine in New York. In
2016, he was appointed faculty at Federal University of Minas Gerais in Brazil,
where he started his own lab. His laboratory is interested in understanding how
the cellular components of different tissues function and control disease progression.
His group explores the roles of specific cell populations in the tissue microenviron-
ment by using state-of-the-art techniques. His research is funded by the Serrapilheira
Institute, CNPq, CAPES, and FAPEMIG. In 2018, Alexander was elected affiliate
member of the Brazilian Academy of Sciences (ABC), and in 2019, he was elected
member of the Global Young Academy (GYA). He is the Founding Editor and
Editor-in-Chief of Current Tissue Microenvironment Reports and Associate Editor
of Molecular Biotechnology. Alexander also serves in the editorial board of several
other international journals: Stem Cell Reviews and Reports, Stem Cell Research,
Stem Cells and Development, and Histology and Histopathology.

xvii
Preface

This book’s initial title was “iPSCs: Recent Advances.” Nevertheless, because of the
ongoing strong interest in this theme, we were capable of collecting more chapters
than would fit in one single volume, covering induced pluripotent stem cells (iPSCs)
biology from different perspectives. Therefore, the book was subdivided into
several volumes.
This volume “iPSCs for Studying Infectious Diseases” offers contributions by
known scientists and clinicians in the multidisciplinary areas of biological and
medical research. The chapters bring up-to-date comprehensive overviews of current
advances in the field. This book describes the use of iPSCs to model several
infectious diseases in vitro, enabling us to study the cellular and molecular
mechanisms involved in different infectious pathologies. Further insights into these
mechanisms will have important implications for our understanding of infectious
disease appearance, development, and progression. The authors focus on the modern
state-of-the-art methodologies and the leading-edge concepts in the field of stem cell
biology. In recent years, remarkable progress has been made in the obtention of
iPSCs and their differentiation into several cell types, tissues, and organs using
state-of-the-art techniques. These advantages facilitated identification of key targets
and definition of the molecular basis of several disorders. Thus, the present book is
an attempt to describe the most recent developments in the area of iPSCs biology,
which is one of the rising hot topics in the field of molecular and cellular biology
today. Here, we present a selected collection of detailed chapters on what we
know so far about the use of iPSCs for modeling multiple infectious diseases. Eleven
chapters written by experts in the field summarize the present knowledge about
iPSCs for studying infectious diseases.
Duncan R. Smith from Mahidol University gives a historical perspective on the
application of iPSCs in virology. Thomas E. Lane and colleagues from University of
California discuss the use of iPSCs in coronavirus-induced neurologic disease. Ali
Zahedi-Amiri and Kevin M. Coombs from University of Manitoba describe iPSCs
for modeling influenza infection. Leonardo D’Aiuto and colleagues from University
of Pittsburgh compile our understanding of iPSCs for modeling of herpes simplex
virus 1 infections. Serkan Belkaya from Bilkent University updates us with what
we know about iPSCs for modeling coxsackievirus infection. Eric C. Freundt and
Pavan Rajanahalli from The University of Tampa summarize current knowledge
on iPSCs to model Theiler’s murine encephalomyelitis virus infection. Viet Loan
Dao Thi and colleagues from Heidelberg University address the importance of iPSCs
for modeling of hepatotropic pathogen infection. Sandra K. Halonen from Montana
State University talks about the use of human iPSCs to study the neuropathogenesis
of Toxoplasma gondii. Adriana Bozzi and David A Stevens from Stanford University
focus on iPSCs for modeling Chagas disease. Brandon J Kim from the University of
Alabama presents the use of iPSCs to study hostepathogen interactions with

xix
xx Preface

Streptococcus agalactiae and Neisseria meningitidis. Finally, Jessica L Forbester from

the University of Oxford updates us on the use of iPSCs for modeling of Salmonella
infection.
It is hoped that the articles published in this book will become a source of
reference and inspiration for future research ideas. I would like to express my
deep gratitude to my wife Veranika Ushakova, and Ms. Billie Jean Fernandez and
Ms. Elisabeth Brown from Elsevier, who helped at every step of the execution of
this project.
Alexander Birbrair
Editor
 CHAPTER

The application of iPSCs to

questions in virology: a
historical perspective 1
Duncan R. Smith
Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand

Chapter outline
A brief history of virology ............................................................................................ 2
Viruses as obligate parasites....................................................................................... 2
The advent of cell biology ........................................................................................... 3
Stem cells, embryonic stem cells, and induced pluripotent stem cells ........................... 5
Current applications of iPSCs to virology...................................................................... 6
The family Caliciviridae .............................................................................................. 9
The family Coronaviridae........................................................................................... 10
The family Flaviviridae .............................................................................................. 11
The family Hepadnaviridae ........................................................................................ 13
The family Hepeviridae ............................................................................................. 13
The family Herpesviridae........................................................................................... 13
The family Orthomyxoviridae...................................................................................... 15
The family Paramyxoviridae....................................................................................... 15
The family Picornaviridae.......................................................................................... 16
The family Polyomaviridae......................................................................................... 16
The family Retroviridae ............................................................................................. 17
The family Togaviridae .............................................................................................. 17
Future directions....................................................................................................... 18
Acknowledgment....................................................................................................... 18
References ............................................................................................................... 18

Abstract
Viruses are obligate parasites in that they can only replicate within a living host
cell. Thus the science of virology is largely dependent upon the requirement to be
able to grow and propagate such host cells. While it is relatively simple to be able
to grow and maintain suitable host cells for viruses that infect prokaryotic cells, the
situation is more complicated when eukaryotic host cells are required for viral
propagation. Studies on eukaryotic viruses are thus often a compromise between
the ease of propagation of the host cell and the fidelity of the propagated cells to
the bona fide host cell. Until recently the choice was largely between primary cells

iPSCs for Studying Infectious Diseases, Volume 8. https://doi.org/10.1016/B978-0-12-823808-0.00008-0 1

Copyright © 2021 Elsevier Inc. All rights reserved.
2 CHAPTER 1 The application of iPSCs to questions

(high fidelity, low ease of propagation) or immortalized and transformed cells (low
fidelity, high ease of propagation). More recently, the discovery of induced
pluripotent stem cells (iPSCs), which have high fidelity and relatively high ease of
propagation, has introduced a third option. This chapter will present the historical
context of the application of iPSCs to questions in virology and describe how these
cells are currently being used.

Keywords: Caliciviridae; Cell culture; Coronaviridae; Flaviviridae; Hepadnaviridae; Hepeviridae;

Herpesviridae; Induced pluripotent stem cells; Orthomyxoviridae; Paramyxoviridae; Picornaviridae;
Polyomaviridae; Retroviridae; Togaviridae; Virology.

A brief history of virology

The field of microbiology has existed for nearly 350 years and is considered to have
formally started in 1676 when the Dutch scientist Antionie van Leeuwenhoek first
observed microbial life using handmade microscopes. The field of virology as a
distinct subfield of microbiology has had a much shorter history. The roots of
virology lie in the work of Dimitri Ivanovsky (1846e1920), who, in 1892, demon-
strated the presence of a causal agent of tobacco mosaic disease that was smaller
than any previously described infectious particle. From this point on, viruses were
largely defined as an infectious agent that would pass through a filter that retained
bacteria and required living cells rather than culture medium for propagation. The
physical nature of the infectious agent remained largely unknown until Kausche,
Pfankuck, and Ruska observed discrete particles of tobacco mosaic virus using an
electron microscope in 1939 (Kausche et al., 1939). Even in the absence of an
understanding of the nature of viruses, a number of viruses had been identified as
disease agents before 1931 including foot and mouth disease virus by Leoffler
and Frosch in 1898, yellow fever virus by Walter Reed in 1900, and rabies virus
by Remlinger and colleagues in 1903. Even more strikingly, vaccines had been
developed for a number of diseases that we now know are viral in origin including
the use of cowpox virus for vaccination against smallpox by Jenner in 1796 and a
vaccination against rabies developed by Pasteur in 1885 (see Fig. 1.1).

Viruses as obligate parasites

One of the defining moments in virology was when Milton Rivers proposed that
viruses are obligate parasites (Rivers, 1927). Although initially controversial, the
proposal accounted for the fact that successful virus amplification had previously
only been achieved in embryonated eggs or laboratory animals. Maitland and Mait-
land demonstrated propagation of vaccinia virus in minced chicken kidney in a
mixture of chicken serum and Tyrode’s solution (Maitland and Maitland, 1928),
although they believed that this did not constitute a cell culture system. However,
Rivers, Haagen, and Muckenfuss showed the requirement for live cells using a
 The advent of cell biology 3

FIGURE 1.1 A brief history of virology.

The figure shows some of the key points on the path to defining virology as a distinct area
of study.

similar system (Rivers et al., 1929). Li and Rivers subsequently established

that the virus could grow in minced chicken embryo tissue in Tyrode’s solution (a
chemically defined medium), removing the need for a plasma component (Li and
Rivers, 1930).

The advent of cell biology

The use of minced animal tissues in defined media dominated much of virology in
the 1940s and 1950. Importantly, Enders, Weller, and Robbins showed that polio-
virus could be grown in cultured cells that were not nerve cells (Weller et al.,
1949), and this was instrumental in developing the first polio vaccines, with the orig-
inal injectable Salk inactivated vaccine (Salk et al., 1955) and the oral live attenuated
Sabin vaccine (Sabin et al., 1960) to protect against poliomyelitis being produced in
minced rhesus macaque monkey kidney cells. However, as eloquently stated by Tom
Curtis, “By 1960, scientists and vaccine manufacturers knew that monkey kidneys
were sewers of simian viruses” (Curtis, 2004). In particular, it is estimated that
millions around the world were exposed to polio vaccines contaminated with Simian
virus 40 (SV40). Questions over the safety of polio vaccines led to a shift of produc-
tion to African green money kidneys cells and finally to a vaccine produced in
the well-characterized Vero cell line (Montagnon, 1989). The polio vaccine story
highlighted the problem of using primary cellsdthe possible presence of endoge-
nous viruses. A second major drawback of using primary cells is their relatively
limited useful life span. Primary cells are not able to replicate indefinitely, and after
a period in culture, the cells become senescent and eventually die and thus must be
continually replaced with newly sourced tissues. The concept of a defined life span
for cells was first promoted by Leonard Hayflick based on his work with normal
4 CHAPTER 1 The application of iPSCs to questions

human diploid cells. Hayflick proposed that normal somatic cells had an inherent
replication capacity of 40 þ 10 cells divisions, after which the cells become senes-
cent and die (Hayflick, 1965). This intrinsic replication capacity is now termed the
“Hayflick limit,” and in 2009, Blackburn, Greider, and Szostak shared the Nobel
Prize in Physiology or Medicine for their work on telomeres and telomerase, an
enzyme linked with the biological counting mechanism of cellular replication (Var-
ela and Blasco, 2010).
The Hayflick limit was proposed to explain the behavior of normal diploid cells,
as there were already cell lines that did not conform to this limit. The first bona fide
cell line capable of continuous culture was the mouse strain L, generated by W.R.
Earle in 1940 from mouse subcutaneous areolar and adipose tissue (Earle et al.,
1943). A clone from this strain (L929) generated in 1948 from the 95th subculture
was subsequently the first cloned cell line developed (Sanford et al., 1948). In the
following years, a number of immortalized or transformed cell lines capable of
continuous growth were produced, including HeLa (Scherer et al., 1953), CHO
(Tjio and Puck, 1958), MDCK (the isolation of this line was not published by Madin
and Darby, but it was subsequently used (Green, 1962) and characterized (Gaush
et al., 1966) by others), and WI-38 (Hayflick, 1965), the last of which was developed
by Hayflick himself.
Currently there are a large number of cell lines capable of continuous growth. A
main central repository for cell lines, the American Type Culture collection (ATCC),
maintains over 4000 cell lines. These cells are easy to propagate and expand and
have thus driven virus research for the last 60 or more years. Cell lines are either
immortalized or immortalized and transformed. Immortalized cells generally have
achieved stable telomeres through the expression of telomerase activity (Bodnar
et al., 1998), while transformed cells additionally have undergone neoplastic trans-
formation. In this regard, as these cells have acquired properties not normally
possessed by the corresponding primary cell, immortalized and transformed cells
cannot be considered as “normal” cells. In particular, transformed cells often express
proteins not normally found in the original cell type and conversely can fail to
express proteins that are normally expressed (Pan et al., 2009).
The ability of a virus to productively infect a particular cell depends upon the
susceptibility of the cell, as well as the permissiveness of the cell. Susceptibility
indicates that a particular virus can enter into a cell, while permissiveness indicates
that viral replication, packaging, and cellular egress can occur. In this regard, the
deranged protein expression found in immortalized and transformed cells can lead
to the derivation of susceptible and permissive cell lines from tissues that are not
normally target tissues of infection. Conversely, cell lines derived from a known
viral target tissue might be refractory to infection. Much of virology is therefore
dependent upon less than satisfactory model systems in which virus/cell line pair-
ings are based on utility, rather than being a reflection of true tropism. That said,
it should be noted that a similar criticism applies to studies on human pathogenic
viruses conducted in animals, in which the pathology may only poorly reflect the
pathogenesis seen in humans (Ruiz et al., 2017).
 Stem cells, embryonic stem cells, and induced pluripotent stem cells 5

Stem cells, embryonic stem cells, and induced pluripotent

stem cells
A stem cell has the capacity to self-renew and to give rise to all of the differentiated
cell types of the organism. This concept is almost as old as the field of virology. In
his book Anthropogenie, published in 1874, Ernst Haeckel (1834e1919) proposed
that a fertilized egg be called a “stammzelle” (or stem cell) (Haeckel, 1874). Around
the same time, the field of hematopoiesis (the generation of the cells of the blood)
was revolutionized after Paul Erlich (1845e1915) developed the methods to specif-
ically stain different blood cell types (for a review of Erlich’s contributions to
histochemistry, see (Buchwalow et al., 2015)). In particular, this work triggered a
debate as to whether red and white blood cells had a common precursor. On the
side of those who believed in a single precursor, Pappenheim (Pappenheim, 1896)
used the term “stem cell” to describe the postulated precursor. In the following years,
a number of studies pointed toward the existence of a blood stem cell. For example,
Florence Sabin working with irradiated animals provided strong evidence of blood
stem cells, but did not identify the cells specifically (Sabin et al., 1932). In 1963, Till
and McCulloch published a study (Becker et al., 1963) that showed that one type of
cell in the blood was capable of differentiating into three distinct lineages (erythro-
cytic, granulocytic, and megakaryocytic). While not directly using the term “stem
cell,” the first identification of stem cells is commonly credited to them. However,
hematopoietic stem cells are not totipotent (capable of differentiating into all cell
types including extraembryonic tissues) or pluripotent (capable of differentiating
into cells of the three germ layers), but they are multipotent (capable of differenti-
ating into a number of related cell types). The first pluripotent stem cells were iso-
lated and cultured by Evans and Kaufmann from mouse blastocysts (Evans and
Kaufman, 1981), and the first human pluripotent stem cells were produced from
human blastocysts in 1998 by James Thompson (Thomson et al., 1998). Human
embryonic stem cells are produced from potentially viable human embryos, and
as such their production and use remain controversial (Lo and Parham, 2009).
In 2006, Takahashi and Yamanaka provided a solution to the problems associated
with the use of embryonic stem cells. Working with 24 genes identified as being
important to embryonic cell function, they showed that the presence of four of these
genes was sufficient to reprogram a mouse somatic cell to an embryonic stem
cell-like phenotype (Takahashi and Yamanaka, 2006). These four factors, called
the Yamanaka factors, consisted of Oct3/4, Sox2, Klf4, and c-Myc. These first-
generation cells, however, were not fully pluripotent in that they could neither pro-
duce functional chimeras nor contribute to the germ line (Takahashi and Yamanaka,
2006). Improved methodologies published the following year by three groups
(Maherali et al., 2007; Okita et al., 2007; Wernig et al., 2007) were able to generate
fully pluripotent cells, termed induced pluripotent stem cells (iPSC), which were
functionally identical to embryonic stem cells. In the same year, human iPSCs
generated from somatic cells (fibroblasts) were reported from Yamanaka’s group
6 CHAPTER 1 The application of iPSCs to questions

using the same factors (Takahashi et al., 2007), as well as by the group of James
Thompson using Oct4, Sox2, Nanog, and Lin28 (Yu et al., 2007). There is consider-
able research ongoing in developing iPSCs using different factors, cell types, and
protocols, as well as the development of protocols to differentiate iPSCs into
different cell types (Liu et al., 2020). However, crucially, the development and wide-
spread use of iPSCs put these cells into the hands of virologists who, for the first
time, were able to look at the cellular events ongoing during virus infection in a
cell line that could be differentiated into a bona fide cell type (See Fig. 1.2).

Current applications of iPSCs to virology

A search of the relevant literature undertaken in late March 2020 identified more
than 100 studies that used iPSCs to address questions in virology (Table 1.1). Not
included in the analysis were studies that used viruses such as a lentivirus (Takenaka
et al., 2010) or Sendai virus (Simara et al., 2014) to generate iPSCs, or those that use
a virus as a tool to investigate non-infection-related questions (Naaman et al., 2018).
Collectively, the studies investigated 25 different viruses in 18 genera belonging
to 12 virus families and utilized a number of different cell types (Fig. 1.3). More than
half of the studies investigated only three viruses, namely Zika virus (ZIKV),

FIGURE 1.2 The application of iPSCs to questions in virology.

The figure shows the overall route through which iPSCs are reprogrammed from somatic
cells and can be used in virology.
 Current applications of iPSCs to virology 7

Table 1.1 Studies in virology utilizing iPSCs, ordered alphabetically by virus

family.
Family Genus Virus References
Caliciviridae Norovirus Norwalk virus Sato et al. (2019)
Coronaviridae Betacoronavirus Mouse hepatitis Mangale et al. (2017)
virus (murine
coronavirus)
Flaviviridae Flavivirus Dengue virus Desole et al. (2019);
Lang et al. (2016);
Manh et al. (2018);
Muffat et al. (2018)
Murray Valley Fortuna et al. (2018)
encephalitis virus
Usutu virus Salinas et al. (2017)
West Nile virus Desole et al. (2019);
Fortuna et al. (2018);
Huang et al. (2019)
Zika virus Desole et al. (2019);
Muffat et al. (2018);
Abreu et al. (2018);
Alimonti et al. (2018);
Caires-Junior et al.
(2018); Fong et al.
(2017); Gabriel et al.
(2017); Garcez et al.
(2017); Goodfellow
et al. (2018); Lanko
et al. (2017); Ledur
et al. (2020); Liu et al.
(2019); Mesci et al.
(2018); Qian et al.
(2016); Rolfe et al.
(2016); Rosa-
Fernandes et al.
(2019); Salinas et al.
(2017a,b); Simonin
et al. (2019); Souza
et al. (2016); Tan et al.
(2019); Tang et al.
(2016); Tricot et al.
(2018); Wells et al.
(2016); Xu et al.
(2016); Zhang et al.
(2016); Zhou et al.
(2017); Anfasa et al.
(2017)
Continued
8 CHAPTER 1 The application of iPSCs to questions

Table 1.1 Studies in virology utilizing iPSCs, ordered alphabetically by virus

family.dcont’d
Family Genus Virus References
Related, Fitzroy River virus Fortuna et al. (2018)
unclassified
Bamaga virus Fortuna et al. (2018)
Hepacivirus Hepatitis C virus Carpentier et al.
(2014); Irudayam et al.
(2015); Ito et al.
(2017); Kishta et al.
(2016); Moriguchi
(2015); Moriguchi
et al. (2010); Sakurai
et al. (2017a,b);
Sa-Ngiamsuntorn
et al. (2016, 2017);
Schobel et al. (2018);
Schwartz et al. (2012);
Si-Tayeb et al. (2012);
Sourisseau et al.
(2013); Wu and Dao
Thi (2019); Wu et al.
(2012, 2014); Yoshida
et al. (2011)
Hepadnaviridae Orthohepadnavirus Hepatitis B virus Chang et al. (2016);
Kaneko et al. (2016);
Miyakawa et al.
(2015); Nie et al.
(2018); Sakurai et al.
(2017a,b); Shlomai
et al. (2014); Xia et al.
(2017); Xiong et al.
(2019); Yuan et al.
(2018)
Hepeviridae Orthohepadnavirus Hepatitis E virus Helsen et al. (2016);
Todt et al. (2018);
Wu et al. (2018);
Zhou et al. (2017)
Herpesviridae Cytomegalovirus Cytomegalovirus Brown et al. (2019);
Poole et al. (2019)
Simplexvirus Herpes simplex D’Aiuto et al. (2019);
virus D’Aiuto et al. (2018);
D’Aiuto et al. (2015);
D’Aiuto et al. (2017);
Lafaille et al. (2015);
McClain et al. (2015);
McNulty et al. (2016);
Zimmer et al. (2018)
Varicellovirus Varicella zoster McClain et al. (2015);
virus McNulty et al. (2016);
Baird et al. (2013);
Lee et al. (2012)
 The family Caliciviridae 9

Table 1.1 Studies in virology utilizing iPSCs, ordered alphabetically by virus

family.dcont’d
Family Genus Virus References
Orthomyxoviridae Influenza virus A Influenza A virus Ciancanelli et al.
(2015); Lim et al.
(2019); Zahedi-Amiri
et al. (2019)
Paramyxoviridae Morbillivirus Measles Hubner et al. (2017)
morbillivirus
Orthoavulavirus Newcastle disease Shittu et al. (2016);
virus Susta et al. (2016)
Picornaviridae Cardiovirus Theiler’s murine Benner et al. (2016)
encephalomyelitis
virus
Enterovirus Coxsackievirus B3 Hubner et al. (2017);
Lin et al. (2016);
Sharma et al. (2014)
Enterovirus D68 Hixon et al. (2019)
Polyomaviridae Alphapolyomavirus Merkel cell Cheng et al. (2017)
polyomavirus
Retroviridae Lentivirus Human Alvarez-Carbonell
immunodeficiency et al. (2019); Kang
virus et al. (2015); Liao et al.
(2015); Ni et al. (2011,
2014); Ye et al. (2014)
Togaviridae Alphavirus Chikungunya virus Ferreira et al. (2019)
Rubivirus Rubella virus Hubner et al. (2017)

Hepatitis C virus (HCV), and Hepatitis B virus (HBV). The family Flaviviridae
accounted for over half of all studies, and ZIKV alone was the subject of a quarter
of all studies.

The family Caliciviridae

The family Caliciviridae consists of 11 genera, Bavovirus, Lagovirus, Minovirus,
Nacovirus, Nebovirus, Norovirus, Recovirus, Salovirus, Sapovirus, Valovirus, and
Vesivirus (Vinje et al., 2019). The viruses in this family are nonenveloped with a
single-stranded, positive sense RNA genome. In terms of human health, the genus
Norovirus is the most important. This genus contains a single virus species, Norwalk
virus, but noroviruses are genetically very diverse with multiple genogroups and
genotypes (Atmar, 2010). Noroviruses are transmitted primarily by the fecaleoral
route and can cause both endemic and epidemic gastroenteritis. Noroviruses have
traditionally been very difficult to culture, and it was only recently that a
10 CHAPTER 1 The application of iPSCs to questions

FIGURE 1.3 The utilization of iPSCs.

iPSCs and cells differentiated from them have been used in studies on a number of
different viruses.

methodology was established to culture noroviruses using stem-cell-derived epithe-

lial cell cultures, with the stem cells being obtained from intestinal crypts from tis-
sues obtained at biopsy or surgery (Ettayebi et al., 2016). To overcome the
limitations of a culture system requiring adult stem cells, Sato and colleagues suc-
cessfully derived intestinal epithelial cells from iPSCs (Sato et al., 2019). It is likely
that iPSCs will result in rapid advances in our understanding of noroviruses given
this significant advance.

The family Coronaviridae

The family Coronaviridae has two subfamilies, the Letovirinae and the Orthocorona-
virinae. The subfamily Orthocoronavirinae contains four genera, Alphacoronavirus,
Betacoronavirus, Deltacoronavirus, and Gammacoronavirus (ICTV Master Species
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enforcements, who do not arrive. The disproportion of work actually
in hand, to the men and women who do that work, is most
distressing.
There are great questions of missionary policy to settle. A strong
force of missionaries, adequately superintended by men who are
acquainted with the work they superintend, is the least that can be
asked in our missions. A close and detailed oversight of all mission
interests, working out a far-sighted policy, which changes only by
light that comes by actual experience in mission work, is of the
greatest value. It is clear this superintendency can not be
accomplished by periodical visits of some official whose whole life
has been spent in the home field. A secretary or a Mission Board is
of little account in determining the internal management in any far-
distant field. An occasional visit by some such official may do
incidental good in acquainting the missionaries with the condition in
the home Church, and in bringing to the people at home fresh facts
from the field. But for administrative purposes on the field such visits
are of little or no value.
The Methodist Episcopal Missions in Southern Asia have been
most highly favored in thirteen years of the missionary episcopacy,
with Bishop Thoburn to fill the office of superintendent and leader.
His administration is sure to become more and more monumental as
time reveals its scope and character. It is now clear that no other
episcopal supervision hitherto provided by Methodism is equal to this
missionary episcopacy for the far-distant mission fields.
The success of this policy and of Bishop Thoburn in that office
determines the question of the future policy of the Church in the
administration of the mission field of Southern Asia. The General
Conference of 1900 by a decisive vote increased the missionary
episcopal force in this field, and by an equally decisive vote elected
Dr. E. W. Parker and Dr. F. W. Warne to the missionary episcopacy,
and in co-ordinate authority with Bishop Thoburn.
The election of Dr. Parker as bishop was a general recognition of
his long and pre-eminently successful missionary career. The
election of Dr. Warne to a like office was in response to a like choice
of India, for this younger, but very efficient missionary, whose
pastorate and presiding eldership in the city of Calcutta had been of
such a character as to make him well qualified for the larger office to
which he has been called. But one year has passed since their
election, and a great change has come. Bishop Warne has been
eminently acceptable in his new office, and he has traveled widely
throughout the great field where Methodism has its foothold in the
southlands of Asia. But Bishop Parker’s stalwart form has yielded,
after a prolonged battle with an obscure disease which laid its hand
upon him within a few months after his election. His death demands
a reverent pause, while we drink in renewed inspiration from
reflection on his noble Christian manhood and really pre-eminent
service as a missionary.
Bishop Parker had labored over forty-two years as a missionary
to India, and it is a safe statement that in this more than twoscore
years he did more work than any missionary in India of any Church,
or perhaps in any land, in the same time. The work which he did in
laying broad foundations, winning men to Christ, calling into being
valuable mission agencies, and as a masterful, statesman-like
administration in the Church, has classified him, from two separate
and distinct sources, as “the most successful missionary in India.”
Every element of his noble Christian manhood and eminent ability
measured up to the requirements of this exceptional estimate of the
missionary and his work.
He has now ascended to his heavenly reward, to be forever with
the Lord and to share in his glory. The cablegram that reached us in
America was brief, but laden with a great sorrow and a greater
triumph, “Parker translated!” We will no more have his counsels, his
inspiring presence, the grasp of his strong hand, or hear his manly
voice in Indian Conferences. For this loss we weep. He was
“translated.” In this glad triumph we are filled with joy. Death is
abolished to such a saintly follower of his Lord passing from mortal
vision.
Bishop Parker was ready for other worlds. His recent testimony
was triumphant, in keeping with the godly life he lived. It was fitting
that the good bishop should take his departure from amidst the
glorious Indian hills he had loved so long. His last days were spent in
Naini Tal, amid the most varied mountain scenery in India. Here lies
the lake of wonderful clearness, stretching for a mile in length, filling
the basin. Around the lake is the mall, or broad road. From this road
others branch off, some circular and others zigzagging up the
mountains, which rise a thousand and more feet above the lake,
their sides clad from base to top with, evergreen, pines, and oak.
Here residences, churches, and schools nestle among the trees
wherever space can be found. Here tired missionaries go in May and
June to rest from the fiery heat of the plains below, and to gird
themselves anew with strength as they look upon God’s mountains.
From the northern ridge they look upon the whole mountain
amphitheater with its glorious lake “shimmering” in the sunlight, high-
rimmed with its border of living green, while to the north, stretching
hundreds of miles to east and west, rise the perpetually snow-
covered Himalaya mountains. The picture, one of nature’s wonders,
has few equals for inspiring beauty and grandeur combined. As the
man looks through the rare, clear, mountain air, on peaks and range
resting in quiet strength and majesty, he almost feels as if he was in
sight of the eternal hills where God is.
Amid such scenes, with his brave wife by his side, companion of
his missionary labors about him, and a host of God-fearing
Christians all over India, among whom were a multitude of the dusky
natives, waiting in sorrow because they “should see his face no
more,” the bishop was “translated.” As his Lord on the Mount of
Olivet took one look upon his disciples, and then a cloud received
him and he ascended on high, so his servant was translated from the
hills of Naini Tal; was caught up amid the clouds to be forever with
his Lord.
So the workmen fall. Others labor on, but they are
overburdened. They must be re-enforced. The young native Church
must be shepherded. Thousands of others will join the flock.
Just here we missionaries have our greatest fear. We are the
Church’s representatives. God is with us, and the doors are all open.
We have done all that men and women can do. Will the Church at
home sustain us in the great and glorious task that is appointed to
us? This is our only fear. So loyal and true are many of the hearts at
home to the cause of missions, that it seems unkind to speak of any
lack. Yet, while we love every generous impulse of those who give
money and time to that which, as missionaries, we give our lives and
our loved ones, we love our cause so much the more that we must
be true to its urgent needs and its perils for the want of a little money.
That our advance is retarded over a vast area, that many of our
institutions are imperiled, that native preachers are being dropped for
the lack of the small salary they require, and that we are being
compelled to ask of our Board to give up a section of our India
Church because missionary appropriations are cut down, is but an
outline of our care at this time. To the home Church we look for relief.
This relief can come only in one way. Our people at home, in the
most wonderful prosperity America ever knew, are not increasing
their gifts to missions with their growth in wealth. Some are, but most
are not. The aggregate of all moneys given by the Methodist
Episcopal Church for preaching the gospel in heathen lands is only
about twenty-two cents per member. This is all that is given to
declare Christ to the Christless nations! Our people are giving about
forty times as much for their own religious instruction and for the
gospel in Christianized lands. This proportion is distressing to the
missionary who stands among millions of people who have been
waiting nineteen centuries, and have never yet heard that a Savior
had been born into the world.
The writer is convinced that the measurable failure to give to the
cause of missions as our people are able to give, is due to the failure
to get the information to them in an effective way. It is not the writer’s
intention to locate the responsibility or discuss a policy of raising
missionary funds, but clearly a virtual standstill in receipts under
present conditions is defeat for the missionary cause.
One fact is certain, our present methods of raising funds leaves
the majority of our people without feeling the immediate and
imperative need of this cause, or inspiring them with the certainty of
gaining a great result by the investment of money in missions. We
are in the second year of the “Thank-offering” movement, and more
than eleven million dollars have been pledged toward the “Thank-
offering,” and certainly not nearly one hundred thousand dollars of
this amount has gone to missions. Not one dollar in a hundred!
One chief reason why this disparity exists is because all other
causes have employed special agencies to reach every nook and
corner of the Church, and the cause of missions is being operated at
long range and on general principles, often as only one of the
“benevolences,” and must necessarily fail to advance to any
considerable extent under present conditions and absolute
restrictions.
But there are hopeful indications. Some officials and some
pastors begin to see the situation and to inquire what can be done to
relieve the straits. A number of loyal souls are tenderly giving their
most cherished treasures to the cause of missions. In a year’s
campaign at home I have come in heart-touch with so many such
that I would gladly believe there is a multitude who cherish the cause
of missions as supreme, as it really is.
The Mission Conference in Burma, little company that it is, is
being re-enforced by a promising band of six missionaries, long
overdue it is true, but now gladly and gratefully received. Nearly all of
these are being sent by the sacrifice of people who give largely of
that which is a sacrifice to give. One missionary family is being sent
out and sustained for a part of this year by more than fifteen hundred
dollars given by the preachers of the Kansas and the St. Louis
Conferences. This very large giving of men of very small resources
to a special object that touched their hearts has put new courage into
all our little Burma Mission. In this giving they have helped put true-
hearted missionaries in the field, and I believe permanently enlarged
their sympathy for missions, if indeed they have not also indicated an
improved policy of raising mission funds.
The Woman’s Foreign Missionary Society, through some of its
young lady Auxiliaries, is doing most generous things for the re-
enforcements to Burma.
Burma has waited long for even small re-enforcements, and
needs yet many other things before it is fairly launched as a mission.
But with the re-enforcements we have now in immediate prospect,
we are so encouraged we can return to our field and take up the
work with renewed courage and hope, knowing of the increased
number of friends of missions who support us with money and
prayerful sympathy.
A hope I often cherished in times of great weariness and
discouragement seems in part being realized. Many times in
Rangoon, when wearied to exhaustion with the work of two or three
men, I have gone up to the Sway Dagon Pagoda, and, looking upon
its gilded mass and the Burmans chanting their meaningless
laudations, I have longed for heralds enough to bring these people
the gospel instead of Buddhism, and to replace the pagodas of the
land with Christian Churches; longed for re-enforcements that came
not. Then I turned into the northeast corner of the pagoda area and
looked upon the graves of the British officers who fell in the war of
1852 while storming that pagoda. Then down the slope up which that
band of Anglo-Saxons charged, to the graves of soldiers who were
buried where they fell. My blood warmed with the thought that these
men gave their lives without a word of complaint for their queen
whom they loved, and the flag which they raised over this far-distant
land, to the immense benefit of the land of Burma. Then I
remembered that the world-wide empire of which this is a part had
been secured and maintained by men who, as these, had laid down
their lives for the flag they loved.
From this scene and its suggestions I turned away, encouraged
to hold my post till re-enforcements would come up for the preaching
of the gospel of the Son of God, who sent me to Burma. Here was a
very human kind of encouragement. Looking up the shining pagoda
shaft I saw a sprout of the peepul-tree, the sacred tree of Buddhism,
which grows anywhere on any surface where its spores can find
lodgment; which when neglected has torn to fragments hundreds of
pagodas, here springing from the great pagoda two hundred feet
from the ground. It had found an opening through the gold leaf, or
perhaps had been buried in the mortar with which its surface had
been plastered, and had sent its roots deep into the brick mass of
the pagoda; while its green branches grew in a thriving cluster over
the gilded sides. What did it matter that this tree was two hundred
feet from the ground, and had no moisture save what its roots could
extract from the dry bricks and its leaves draw out of the air! This
peepul-tree can thrive anywhere!
Beautiful symbolism! The gilded colossal pagoda represents the
lifeless system of hoary Buddhism. The growing young tree
represents the religion of Jesus Christ, filled with the life of the Son
of God. It will crumble Buddhism back to dust, as that tree, if
fostered, will destroy the pagoda, Buddhism’s most ornate symbol.
Looking on this scene, my heart took new courage, as under
Divinely-given cheer, to labor on for the salvation of the Buddhists
and other people of Burma.
When describing the pagoda and its surrounding, at Adams,
New York, I dwelt at some length on the graves of the English
soldiers there, and spoke of their courage and self-sacrifice. There
was a large congregation present, nearly all of whom were strangers
to me. At the close of the service I saw a little man start from the rear
of the church and make his way down the side aisle, then across the
church, and as he came he quickened his step; and grasping my
hand he exclaimed with trembling voice: “I tried to come to church
this morning, having heard a man from Burma was to speak; but I
could not get here. I live nine miles back in the Adirondacks, and I
drove in to-night to hear you. I am so glad those graves of the
English soldiers are cared for; I was in the regiment that stormed that
pagoda hill in 1852.” He wrung my hand and shed tears of gladness
because I came from Burma and brought him a voice from the land
of the stirring scenes of his soldier life of forty-eight years ago.
There will be a day when every pagoda will crumble down, every
mosque and Hindu temple fall into decay, and Christian churches
stand in their places, and Burma, as all other parts of this needy
world, will be fully redeemed. In a brighter world there will be a time
of rejoicing over the gospel triumphs, and all who in person or by
proxy aided in the gospel victories in all the world, shall strike glad
hands, like the old soldier, and say, “I was there and helped in the
glorious work.”
 CHAPTER XVII
Benefits of British Rule in Southern Asia

T HE missionary is one of the most interested students of

government that can be found. Good or bad government affects
his work vitally. Not only does good government give him protection
from violence, but it gives settled peace to the people among whom
he preaches, and thus provides the best conditions for the success
of his calling. He can not wait for good government where it is not;
but where he has the benefits of a settled state of society that is
protected by wholesome laws promptly executed, he is one of the
first men to recognize the priceless benefits of such government.
Then he looks to the effect of government on the general conditions
of the people. His views of government are not narrow. He looks
ahead to the final effect on the mass of the people of the
Government under which he lives. From every standpoint the
missionaries whose fields lie under the British flag are best situated
of all men of like calling in foreign lands. It therefore comes to pass
that all missionaries, of whatever nationality, living in Southern Asia
are almost a unit in praise of the Government. This Government,
which has for more than forty years given protection to life, calling,
and property of its nearly three hundred million diverse peoples, and
that in unbroken peace, deserves the highest approval of all fair-
minded men.
Life is as well protected in Southern Asia as it is in almost any
land. The highest in the land and the meanest coolie are alike
protected before the law. Where any man thinks he can insult or
assault with even a little lordliness there is recourse to the law, and
that within reach of the lowliest and the poorest, and he can get
evenhanded justice for any injury, and that quickly. Perhaps in no
land is the man of high and the man of low degree dealt with with
more evenhanded and prompt justice than in Southern Asia. There
are many social distinctions made in Asia, most of all in Southern
Asia, peculiar to the land, and the Government adds its official
distinctions and social ranks. But when it comes to the law and its
administration in protection against all oppression and injustices,
these social conditions have no place. It appears to be true that in a
Briton’s mind there are two places where men of all stations have
equal rights—before a court, and at the sacramental altar in the
church. Every man is protected in the exercise of his religious faith,
and must not be molested by any. To revile another’s religion is to
bring down the swift penalty of the law.
It is possible for missionaries and other travelers to come and go
anywhere in the Indian Empire without a thought as to their personal
safety, as that is assured. Even unattended ladies make long
journeys, and with only native carriers, sometimes travel in
unfrequented regions and in the darkness; but so far as I can learn,
there has not for many years been an insult offered to one of them.
Some of our own workers live and travel in remote regions, even on
the extreme borders of the empire, and sometimes these are lone
women; but we do not hear of even serious inconveniences to them
on account of their isolation. This is due chiefly to the Government,
which protects life, persons, and calling.
It is, therefore, not surprising that the missionaries are among
the most devoted supporters of the British Government in Southern
Asia. It is likely they would support any Government under which
they would find themselves called to work. They would teach their
converts loyalty and obedience to law. But it is a great gain to be
able to say to all the peoples of the Indian Empire that the
Government under which they find themselves is one of the very
best the world has produced. And if it were necessary to say it, they
could truthfully add, better than any possible Government by native
rulers, better for themselves, and better for all people in the land. It is
a great pleasure to American missionaries to acknowledge the good
government of India, for in it they find many of the best principles in
which they believe. So far as I can learn, this just tribute from the
American missionaries is well nigh universal among them, and the
older they are and the longer they have lived in any part of this great
empire, the more confirmed they are in their views.
Of all the institutions of the Government that are most to be
commended, the courts are perhaps the most notable. There are
several features of these courts which are specially commendable.
They are prompt to a degree. Long, vexatious delays over
technicalities of law are most unusual. It is not infrequent that a
serious breach of law is brought to account very soon, and finally
settled. Certain it is that money and influence and the “tricks of
lawyers” can not long delay final decision on any case. Then there is
no crowding to the wall the poor man without influence or money to
aid him. The poorest can sue as a pauper, and have his case heard
in regular order with the rich man of high station. He can get as
certain justice, based on evidence. Cases are on record in recent
years to illustrate how the socially high and even the official class
have been rebuked and punished at the plaint of the lowliest in the
land. They would be well worth recording if their publication would
not be understood as too personal. It is this absolutely even-handed
justice that has called out the comment of the native of India, “The
English judge is not afraid of the face of man.” No partiality is shown
for race or condition.
The system of Government seems to be well worthy of study.
There is the viceroy, and associated with him, but not limiting his
powers, a Council representing the entire Empire. There are
lieutenant-governors over provinces. Then there are chief
commissioners over portions of the country that are not regarded of
sufficient importance to have lieutenant-governors. Under both these
officials the next officers in rank are commissioners over divisions,
and these in turn have deputy commissioners under them who
administer districts. Below the deputy commissioners there are
several lesser officers, usually over townships, but having a wide
range of duties. From viceroy down to deputy commissioners the
officers have certain executive, or executive and judicial powers
combined. The higher officers have also authority to some extent in
military affairs.
 The army is made up of British troops and native soldiers, with a
great preponderance of the latter. There are also many belonging to
the military police. The same division is made in the civil police. The
police department is perhaps the most difficult branch of
Government to keep efficient and free from scandal, but there are
many worthy men in the police service.
In addition to the regular administrative officers mentioned there
are departmental officers, such as an engineering corps, which has
the care of all public works. There is the growing educational
department and a medical department including care of prisons,
hospitals, and a great forestry department, that conserves the
valuable forests of the empire. There is also a department of marine
with full official equipment.
There is a civil service system operating throughout all these
departments of government, including even the most subordinate
clerkships. The higher officials are usually brought out from some
part of Britain, and have been taken into Government employ after
the severest examinations. Their promotions are given by grade and
service, allowing also for special promotions for distinctive service.
Having been so placed that I have had to do with a wide range of
these officials, in most departments of the service, it becomes a
great pleasure to me to record the character of their official conduct
as I have found it in personal dealing. In the first place, they almost
without exception are men of courteous, gentlemanly manners. This
alone goes far to smooth the way in official transactions. Then I have
found them generally men who are very fair and even generous in
dealings where public interests, missionary matters, or property have
been dealt with. This is partly due to the system of aid given
especially to schools with which both the Government and the
missionary have to do, and partly due to fair dealing on general
principles, which I am led to believe from an experience all over the
province of Burma for a period of ten years, and from inquiries from
others of longer experience, is a British characteristic. This is
especially true of the better cultivated men. The snobbery of the
uneducated Briton is equal to that of the American of the same class.
In the whole range of my experience I have never met with other
than manly treatment from officials but twice, and then these were
not of the higher ranks, and one of them can not be said to be a
Briton. If an officer might be disposed to be unfair, he knows that
there is a superior above him that is ready to correct any abuse. But
the whole system of Indian service is well worth study, for it is not a
creation of a day, but the best fruit of England’s extensive colonial
experiences. In this matter it is well worth study, especially on the
part of America, which has now to enter upon the rule of large and
distant possessions. It is also to be noted that the wonder of
England’s Government is that she has been able to allow of a
diversity of Governments in her several possessions suited largely to
local conditions, so that no two of her colonies are entirely alike, and
yet she has been able to give protection, justice, and the largest
measure of liberty to each country that the people are able to utilize
for their own good. In these respects it is only fair to say her system
of Government over remote and diverse peoples is the best yet seen
on this globe.

Burmese Festival Cart

 There is also a striking feature of the Government of
municipalities in India. Municipalities have not wholly self-
government, yet they are so ordered that the popular will has a
representation, even when it retards the actual progress of the city,
as it not infrequently does. The municipalities are governed by
commissioners, about half of whom are elected by the people, and
the other half are appointed by Government. The latter are not
Government officers, however. They may be as democratic in their
votes as any member of the municipal committee. But these
commissioners are representative of the different native races, as
well as the Europeans in the city. In a city like Rangoon there are
several great race divisions that are recognized on the municipal
committee, both elective and appointive. In the election of these
commissioners appears one of the most extreme examples of the
democratic principles that the writer knows of anywhere. Perhaps it
has no parallel. In the case of the ballot, it is allowed freely to all
Europeans and Americans on exactly the same conditions. They, as
aliens, never having become British subjects, and never intending to
do so, have the ballot the same as an Englishman. This broad
democracy has greatly surprised many Americans when I have told
them of it. The alien has a right to hold the office of city
commissioner, if elected, the peer of the native-born Briton. This is
the broadest democracy found anywhere within the defined limits of
franchise.
The Government has a vast system of railroads in India
amounting to sixteen thousand miles, with many other extensions
and new lines in prospect. These roads now reach nearly all the
districts which could sustain them. They are sometimes built for
military purposes, but they are mostly directed for the carrying of
traffic in times of peace. The province of Burma, one of the later
provinces to be thoroughly developed, is having railroads to all its
principal sections, and some of these roads are being projected to
the very borders. That to Kunlon is extended to the borders of China.
They also talk of a line from Rangoon through Western China, and
there is every likelihood of connections direct with Bengal. So the old
world moves under the impetus of Western enterprise. The
telegraphs attend the railway, and exist even far outside of railway
lines to all parts of the empire and to foreign lands. Let it be
remembered that probably none of these improvements would have
been thought of in the country had not it been taken in hand by an
enlightened and enterprising people from the West.
Great systems of canals have been constructed, and more than
thirty million acres of land are irrigated, and famine in this area is
forever forestalled. Larger plans are being suggested by the recent
famine. The famine relief works constructed many tanks on land too
high for irrigation from running streams.
Good pavements in cities and good roads have been made in
the land universally. These roads are nearly all metaled and kept in
good order.
Public buildings of the most substantial and imposing kind are
built in all capital cities. The Government wisely erects buildings in
keeping with its own governmental ideas, and with its declared
intention of remaining in the land to work out its plans. The public
parks and gardens are on an elaborate scale, and are enjoyed by
everybody. The memorials to great men of India and the great men
who have made India British territory are placed in all public
gardens. Great men and great deeds are set before the world as
they should be, that the world may emulate them. The latest design
is to build a memorial to Queen Victoria in the city of Calcutta, to
which many of the rajahs of India are subscribing. The building is to
cost perhaps more than five million dollars, and while it is a great
memorial to Queen Victoria, it is to be a museum of great men of
India as well. There will be other memorials established in other
cities of the Indian Empire also. The taxes of the Government are
reasonable. They are mostly placed directly on the earning power of
the individual, or tax upon land assessed in proportion to the amount
of grain it produces, There is also a tax on houses in villages outside
municipalities. The land tax is very just. If the land produces regular
good crops, it is taxed accordingly. If there is a failure of crops, the
tax is reduced or remitted. As land needs rest, it is allowed a tax at
fallow rates, which is very light indeed. The income tax is collected
chiefly in cities, but of all Government employees, beginning with the
viceroy. This tax is two per cent per month. This is to be paid out of
the monthly salary. But it is said this tax only reaches one out of
three hundred and fifty of the native-born inhabitants of India.
The Government claims to own the land, very much as the
American Government owns the public lands. But, of course, the
greater part of this land comes into the ownership of the people, and
is transferable as elsewhere in the world. In the comparatively rich
province of Burma, where there has been until recently much of the
very best land of the tropical world lying idle, grown into grass and
forests—land that never was cultivated, the land is given out freely to
would-be cultivators. They only have to show that they are prepared
to cultivate it. They have to pay nothing but for its survey. When it is
cultivated they get a title to it, and then they can sell it as the actual
owners. If it is grass land, the cultivators are allowed one year
exemption from tax. If forest land, ten years are allowed exemption.
A more liberal plan could not be devised than this. It is just here that
England’s policy in the country is shown. If a Burman asks for a
piece of land, and a European, any Englishman indeed, asks for the
same piece of land, the Burman will surely get it. One becomes more
and more convinced that the policy of Government in India is to
govern for the best interests of the Government. There is another
great plan of Government to aid agriculture. The people of all parts
of the Indian Empire are chiefly agricultural. They are like all Asiatics,
great borrowers of money. They generally mortgage the crop by the
time it springs out of the soil. The native money-lender demands as
much as three per cent a month; but here the Government comes
forward, and agrees to loan the agriculturalist money at six per cent
a year, and allow him to repay it in partial payments. This is
eminently fair, and any man can get it who can show that he can
repay it, and can give two personal securities. This seems a very
liberal proposition.
The Government has also devised a great school system to aid
in popular education. The schools of Southern Asia have been
almost entirely in the hands of the various religions of the land. The
Government has undertaken to work out a plan by which a very large
part of this education can be put under popular control, and yet be
allowed to remain under the direction of the various religious
communities that conduct schools. Of course, under the old order
there was but a small part of the community allowed to go to school,
and the teaching was of an inferior kind. Government would promote
education and give a fixed standard. To do this they had to put the
secular instruction of all schools under the Government, and allow
the religious instruction to be carried out according to the ideas of
every society concerned. So that we witness Mohammedan,
Christian, Hindu, and Buddhist schools, all drawing aid from
Government, and all passing the same Government examinations in
secular subjects, but each imparting its own religious instructions. To
aid in this educational scheme, the Government will give grants in
putting up buildings, in paying accredited teachers, and in giving
grants to current expenses on passes secured in Government
examinations. In addition, the Government has built up certain
schools entirely under its control, where no religion is taught.
In all this it will be seen that the Government, in keeping with its
declared purpose and position, is neutral in the matter of religion. It
ought to be clear to all who will see it, that the Christian Church
should avail itself of all this educational plan that is possible, so as to
mold the minds of all the young in Christian principles. Nearly all
mission schools are identified with this educational system, but there
is opportunity for much more of the same kind of work.
There is another great and merciful arm of Government to be
mentioned. In every municipality, and even in large villages, there is
hospital treatment for all who need medical or surgical aid. All this is
freely given to every applicant.
All cities and large towns have great hospitals where medicines
and food and shelter in bad cases are given freely to men of all
races and creeds. No disease is turned away, and no sick man
denied attention. This charitable effort of Government is far-reaching
in its beneficence. It is not so valuable as it might be, because it has
a prejudice of the populace to deal with. But the amount of suffering
that is relieved by Government in all the empire is enormous.
In cases of epidemics there is a Government order to fight the
disease in an organized way. If it is smallpox, which is very
prevalent, public vaccination is enforced. Cholera epidemics are
taken in hand vigorously, water purified, and quarantine established,
until the pestilence is put under control.
The last four years has called out all the agencies of a great
Government to battle with the Bubonic plague and the famine. It is
now more than four years since the plague began its ravages in
India, and a little over three years since the famine began its course
of devastation. Both of these dire visitations were grappled with from
the start, and the battle is still being waged.
A competent board of physicians and a large force of skilled
nurses were quickly organized, and they have been unremitting in
their efforts, and many of these have fallen victims to their difficult
and dangerous duty. A system of inspection was at once established
on all railroads and steamship lines throughout India and along its
coasts. Every traveler, irrespective of race or rank, has been
examined by medical experts. Yet in spite of this precaution the
deadly scourge has insidiously worked its way almost throughout the
empire. But still the Government grapples with the pestilence. One
can feel something of its terrors when it is noted that ninety-four per
cent of all who are seized by the plague die. Six hundred thousand
have died of the plague in five years. The greatest hostility has been
shown at times by the native population, in opposing the most
necessary plague regulations.
With plague almost all over the empire, the Government had at
the same time to undertake a most extensive plan for relieving a
famine that was ever undertaken by any Government in human
history. The famine had only one immediate cause—the lack of rain.
The greater rains over almost all India occur between June and
September. For years on overlapping territory the rains failed, or
were deficient. The world knows the story. One-fourth of the nearly
three hundred millions of this population of the empire were in the
terrors of famine, with its slow starvation of man and beast, with its
attendant cholera, plague, and other diseases. It is worthy of cordial
recognition and perpetual memory that this gigantic specter was met
by a Christian Government. It was not a Mohammedan or Hindu
people which fought back this monster calamity, but a Government
and a people whose sympathies were Christian. The Christians
hurried to the relief of those of non-Christian belief and alien people,
and hardly thought of their race or religion. They only knew they
were starving communities of fellow-beings, and they put forth
supreme efforts to relieve their hunger and other ills due to the
famine. Yes, this was done by a Christian Government, aided by
private Christian beneficence of distant lands, while their own co-
religionists, having money in many cases, owning nearly all the grain
in the empire, enough to have fed all the hungry at every stage of the
famine, gave practically nothing for famine relief! They held their
feasts, organized their tiger hunts, looked on the dance of the impure
nautch-girl, and reveled while their people starved and died, or owed
their life to a foreign race of the Christian faith.
The Government of India spent $92,650,000 on famine relief
during 1899 and 1900. The relief works were open nearly two years
before that, and help on a large scale continues still. This is the most
gigantic effort of all human history to meet a great national calamity.
Strange that these noble and statesman-like efforts should have
been belittled by any, much less by some who should have known
better.
The census of 1901 has been gathered, and these columns of
figures tell their sad story of suffering and death in the famine
districts. Of India’s two hundred and eighty-six millions of ten years
ago, sixty-six millions were residents in native-protected States. The
census of 1901 shows that British India increased its population by
ten millions, while the peoples of the native States decreased three
millions. British territory increased its population by four and one-half
per cent, and the-native States decreased by four and one-half per
cent.
A close inspection of the figures shows the decrease to be
largely due to the famine. What would have been the death-rate but
for the English Government’s immense relief?
The missionaries worked hand in hand with the British officers,
and I have never heard that either has ever spoken except in words
of praise of the other’s labors. This proves that good Governments
and faithful missionaries are invaluable to each other.
A crowning proof of the good government of Britain in India, is in
the fact that her population does not migrate to any adjacent State
where there is limited or unlimited native rule. But from all such
States there is a steady stream of immigration pouring into British
territory. None of India’s peoples migrate in any numbers to any
Oriental or Occidental country, but from every Oriental land there are
immigrants to sojourn or to settle in India under the justice,
protection, and peace of British rule.
The tropical world is fast coming under Western domination.
These lands must be lifted by new blood from the North and West,
and must serve the needs of our race. While this process is going
on, the world can afford to be happy over the fact that so large a part
of the tropical countries is under British rule.
 Transcriber’s Notes
Punctuation, hyphenation, and spelling were made
consistent when a predominant preference was found in the
original book; otherwise they were not changed.
Simple typographical errors were corrected; unbalanced
quotation marks were remedied when the change was
obvious, and otherwise left unbalanced.
Illustrations in this eBook have been positioned between
paragraphs and outside quotations. In versions of this eBook
that support hyperlinks, the page references in the List of
Illustrations lead to the corresponding illustrations.
The first illustration is the cover. The illustration on the
Title Page is a photograph of a woman leaning against a
cocoanut tree (it is the leftmost part of the illustration on page
45 of this eBook). The four captionless illustrations are
identical decorative tailpieces.