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Systems Biomedicine Concepts and Perspectives 1st
Edition Edison T. Liu Digital Instant Download
Author(s): Edison T. Liu, Douglas A. Lauffenburger
ISBN(s): 9780123725509, 012372550X
Edition: 1
File Details: PDF, 13.31 MB
Year: 2009
Language: english
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10 11 12 13 14 15   10 9 8 7 6 5 4 3 2 1
 Overview
Douglas Lauffenburger

Systems biology is different things to differ- predictive understanding of how phenotypic

ent people. One definition, from Lee Hood’s behavior of cells, tissues, organs, and organ-
Institute for Systems Biology [Ideker et al., isms is dependent on molecular component
2001], is: “Systems Biology does not investigate characteristics, scientists and engineers must
individual genes or proteins one at a time, as incorporate multiple interacting components
has been the highly successful mode of biology and quantitative information concerning their
for the past 30 years. Rather, it investigates the properties into their studies. Moreover, this pre-
behavior and relationships of all the elements dictive understanding can most effectively be
in a particular biological system while it is raised beyond the confines of mere intuition by
functioning.” A second, from the US National constructing computational models of the com-
Institute of General Medical Sciences [NIH, ponents and interactions, both for hypothesis
2006], is: “Systems biology is a new interdis- generation and hypothesis testing.
ciplinary science that derives from biology, A third dimension of biological complexity
mathematics, computer science, physics, engi- must also be considered for purposes of this
neering, and other disciplines… Most biologi- particular book, which is aimed at systems biol-
cal systems are too complex for even the most ogy applications to human medical concerns.
powerful computational models to capture all This dimension represents the need to move
the system properties. A useful model, however, from analysis of molecular processes in sim-
should be able to accurately conceptualize the plified cell culture experimental systems, up
system under study and provide reliable predic- to tissue and organ physiological contexts, to
tive values. To accomplish this, a certain level organisms (patients) and populations thereof.
of abstraction may be required that focuses on Although genomics by itself is currently striv-
the system behaviors of interest while neglect- ing to connect gene sequence and expression
ing some of the other details.” These two defini- information directly to human pathophysiol-
tions clearly recognize complementary aspects ogy, there is no question that the most powerful
of biological system complexity: the first approach to this connection will be via com-
emphasizes the number of components under putational models that move information from
consideration, while the second features the genome to proteome to molecular networks
quantitative predictive capability and concep- governing cell functions, then propagate these
tual abstraction of system components, proper- models to larger length-scales and time-scales
ties and interactions. From where we sit, both of for eventual prediction of organism pathophysi-
these aspects are important, for biological sys- ology in terms of molecular properties. The
tem complexity is multi-dimensional. To gain notion of these three dimensions of biological

VII
VIII Overview

(a) (b) Time

Mechanistic complexity
Sequence Expression Localization Dynamics Populations

Biological complexity
Cells Tissues Organisms Populations
Dynamics
Systems complexity
Single gene Genomic complement Cells
Sequence

em ic
ol e
e

t
pl m
en
m On
ul

m no
ec

co Ge
systems complexity is schematically illustrated technologies and experimental approaches that
in the figure (originally developed by Peter is changing the conduct of biological research.
Sorger for the MIT Computational & Systems The availability of whole genome sequences
Biology Initiative). provides the complete catalog of genetic knowl-
In this book, then, systems biomedicine can be edge of an entire organism. Multiplex sensors
described as an emerging approach to biomedi- such as expression arrays and multi-channel
cal science that seeks to integratively infer, anno- flow cytometry, and high throughput screening
tate, and quantify multi-variate complexity of the maneuvers generate precise and comprehen-
molecular and cellular processes of living systems, sive data. Contemporary and developing com-
with ultimate aim of constructing formal algorith- putational capabilities are sufficiently powerful
mic models for prediction of process outcomes to envision capability for computing model-
from component input. Systems approaches are based inferences and/or predictions even as
characterized by several key attributes: the magnitude of systems (in terms of number
of components and their interactions) and asso-
1. A pursuit of quantitative and precise data;
ciated data-sets continue increase. The differ-
2. The comprehensiveness and completeness of
ence between systems and reductionist biology
the datasets used;
is in the objectivity with which we can analyze
3. A focus on interconnectivity and networks of
complex data and the resolution afforded by the
the component parts;
completeness of the datasets.
4. A willingness to define, measure, and
Furthermore, systems biology does not
manipulate biological complexity;
remain constant from year to year. Obsolescence
5. An interest to computationally (and
occurs in a matter of months. For this reason,
therefore quantitatively) predict outcomes.
this book has been written and assembled as
Certainly it can be said that all of biological a series of linked essays that convey strategies
research historically could be characterized by and processes. The arguments are bolstered by
these descriptors. Any scientific endeavor seeks commissioned chapters on specific topics dis-
to measure and systematize observations (quan- cussed in depth. These should be considered
tification) and, in finding underlying order as examples to clarify points and to stress con-
(model), would allow scientists to predict out- cepts rather than as an encyclopedia of past
come. However, there is an ongoing evolution of knowledge. There will be more departures from
 Overview IX

an expected book on systems biology. Our dis- narrative should be heard, starting with Chapter
cussion will extend from model systems to 1 (by Liu) which offers a conceptual introduc-
human biology and pharmacology. We will tion to systems biomedicine.
focus on applications of systems approaches The first section of the book lays experi-
to medical problems and thus the title Systems mental groundwork. It begins with summa-
Biomedicine. Some would demand that true ries of experimental technologies in genomics
systems approaches require precise mathemati- (Chapter 2, by Liu) and proteomics (Chapter 3,
cal models; however, in this book, because of by Hanash), to set a foundation for the observa-
the experimental complexity in human sys- tions and measurements which motivate, popu-
tems, we wish to broaden the inclusion criteria late, and test associated computational models.
for systems biology to qualitative systems and Chapters 4 (by Lauffenburger and Liu along
hypothesis generators. with associated colleagues) and 5 (by Lim)
Our attempt to describe systems medicine is describe molecular networks regulating cell
our final experiment. Often, the most rational functional responses to environmental inputs,
experimental strategy is to identify the simplest, which form a basis for a wide variety of envi-
most definable model system to study and then sioned models. These are followed by presenta-
to construct a computational model around tions of two particular manifestations of these
data output from such systems; ergo, the use of networks – cell/matrix adhesion networks
phage, microbial systems, and yeast. However, (Chapter 6, by Geiger and colleagues) and net-
such systems strategies can now be applied to works regulating stem cell behavior (Chapter 7,
more complex mammalian systems and even by Ng and colleagues).
to study human disease. The experimental sys- The second section of the book focuses on
tems approaches to studying a human problem mathematical and computational methods for
will, by necessity, be different and potentially modeling of these kinds of molecular networks
less complete than attacking a question using and consequent cell behaviors. Chapter 8 (by
prokaryotes simply because the possible solu- Subramaniam and Maurya) starts by outlining
tion space is orders of magnitude greater. fundamental challenges for network modeling,
Nevertheless, productive strategies have been followed by three chapters describing differ-
tried and the outcomes have proven useful even ent modeling approaches. Chapter 9 (by Janes,
in drug development. Woolf, and Peirce) focuses on “high level”
We are attempting to organize this book in approaches, which emphasize relational and
a manner reflecting important distinguishing logical operations of molecular and cellular
characteristics of systems strategies in experi- processes, whereas Chapters 10 (by Doyle and
mental biology and medicine: comprehensive Petzold and associates) and 11 (by Loew and
(even though not exhaustive) and quantitative associates) focus on “low level” approaches in
measurement, using quantitative data to con- which details of physico-chemical mechanism
struct a model of the system, and defining com- are incorporated. This section is rounded out by
plexity as an experimental dependent variable. Chapter 12 (by Sauro and Bergmann) discussing
Finally, we explore the applications of these modeling software.
principles to biomedical problems. Finally, the third section offers some early
Rather than an assembly of independent attempts at application of systems biology per-
entries or chapters, we have composed this book spectives to particular biomedical science areas
as a narrative. Whereas we cannot project how and pharmaceutical industry challenges. With
this book will ultimately benefit our readers, respect to physiological areas, Chapter 13 (by
we suggest that it is best read in sequence as a Hunter and Cooling) directs systems modeling
 Overview

toward cardiac pathophysiology, Chapter 14 insistence on dedicated test of model predic-

(by Asthagiri and Giurumescu) to develop- tions. Most importantly, the number of “success
mental regulation, and Chapter 15 (by Young stories” in which new insights and useful pre-
and colleagues) to immune system operation. dictive understanding even of relatively small
Important practical focus provides a climax to and constrained systems are demonstrated
this book, with Chapter 16 (by Liu and Qiang) should at least slowly but surely increase. We
on pharmacological treatment of disease, confidently anticipate that these successes will
Chapter 17 (by Gaynor and associates at Eli motivate wider and stronger commitment of
Lilly) on predictive systems analysis for cancer resources, in academia and in biotech/pharma
drug discovery, and Chapter 18 (by Harrington industry, for applying the systems biology per-
and Hodgson) on the applications of systems spective to the larger promise of rationally
concepts to clinical trials. informed therapeutics design.
We close by noting that in each of these three
sections the field is only in its infancy. There
will be continuing acceleration of advance in
experimental methods for gaining increasingly
Reference
complete, accurate, and intensive information Ideker, T., Galitski, T., Hood, L., 2001. A new approach
of molecular and cellular processes nearing to decoding life: systems biology. Annual Review of
Genomics and Human Genetics 2, 343–372.
genome-wide coverage in measurement and
NIGMS Systems Biology Center RFA. (2006). http://grants.
manipulation. This progress will motivate more nih.gov/grants/guide/RFA-files/RFA-GM-07-004.html
diverse, sophisticated, and rigorous computa-
tional modeling algorithms, along with stronger
 S e c t i o n I

Foundations of systems
biology
 C H A P T E R

1
Foundations for Systems Biomedicine:
an Introduction
Edison T. Liu
Genome Institute of Singapore, Singapore

o u t l i n e

Introduction 3 Circadian Cycles as a Relevant Model for

Systems Biomedicine 9
Experimental Strategies in Systems Biology 6
Conclusion 11
Systems Biomedicine 7

Introduction amount of blood in the chambers of the heart, cal-

culated the output of the heart by multiplying the
Quantitative biology, mathematical biology volume by the number of heart beats per day, and
and mathematical modeling have all been part of noted that the output differed wildly from the
biological investigations in one form or another volume of blood in an individual at any one time.
since the beginnings of investigative biology and With this information, he developed a model of
medicine. Carl Linnaeus’ creation of the binary circulating blood that could explain the blood
nomenclature (Systema Naturae, Carolus Linnaeus, volume discrepancies with supporting evidence
1735) marked the origin of biologic taxonomy from the anatomic presence of valves in veins.
and provided the basis for phylogenic analysis. The mathematical tradition in biology therefore,
William Harvey (An Anatomical Disquisition on the runs long and deep.
Motion of the Heart and Blood in Animals, William However, systems biology, as we conceive
Harvey, 1847) described the quantification of the of it, differs in scale and formalism from the

Systems Biomedicine  © 2010, Elsevier Inc.

 1. Foundations for Systems Biomedicine: an Introduction

earlier quantitative traditions. As with any new in complex organisms, and the later generations
field, there are many opinions as to what systems of William Harveys had rendered pulmonary
biology is. For the purposes of this book, systems and cardiac physiology into equations. To a
biology can be described as a discipline that seeks large extent, this approach has been remarkably
to quantify and annotate complexity in biological successful, and has brought us many of the
systems in order to construct algorithmic models medical advances in cardiopulmonary medicine
with which to predict outcomes from compo- and surgery. The cardiac diagnostics from angi-
nent input. Systems biomedicine is an extension ography, to echocardiography, to telemetry in
of these strategies into the study of biomedical which patient physiologic output is monitored
problems. We believe that this demarcation is rel- and automated alerts generated, represent a cul-
evant, given the challenges of the complexity of mination of such research in cardiac function. In
the human organism and the human impact of a sense, physiology was the systems science in
the results of these investigations. medicine. However, these organ-level models
This definition of systems biomedicine high- do not parse with molecular realities, because
lights the difference between quantitative data their unit of measure is in average blood flow,
acquisition and systems biology. The scale of for example, and not in the flow dynamics of
data acquisition in biology today is unparal- the red corpuscle. Therefore, in the past, quan-
leled in history. Analog and descriptive data titative physiologic models could not be unified
such as cellular images are now digitalized and with cellular models and, by scale, to molecular
converted to discrete data points. Genomic- and models. Moreover, the need that assumptions
proteomic-scale information is registered in the be greatly simplified in order to arrive at com-
gigabyte scale per experiment. This reality also putationally tractable models also limited the
demands formal mathematical and algorith- relevance of many physiologic models.
mic conversion of experimental data in biology Now, however, medicine is becoming amena-
in order for them to be simply understood by ble to complexity analysis. The understanding of
the investigator. The interposition of comput- the cell and molecular biology of human disease
ers and their algorithms as an essential part of has dramatically advanced in the past 25 years.
biological research immediately places, at least Whereas the pathophysiology of most human
a rudimentary, mathematical formalism around diseases was previously limited to the analysis
all experiments performed in this fashion. of organ failure, most diseases now have a cel-
Although measuring outcomes is standard lular and molecular explanation. It is precisely
in day-to-day biological experiments, these ear- this reduction to common units of measure—to
lier quantitative approaches do not scale. While the cell and the molecules within the cell—that
detailed biochemical kinetics can be calculated allows systems analyses to be applied across the
for a single biochemical reaction, most com- entire human condition. Therefore, the pump
monly, we have tended to resort to descriptive dynamics of the heart after myocardial infarc-
generalizations when we ascend to physiological tion can be resolved at the same level as pancre-
scales. With current technologies that can acquire atic beta-cell function in diabetes mellitus. There
precise, comprehensive and quantitative data, is convergence.
biological complexity can now be quantitatively The current systems biology now includes two
analyzed. The challenge, however, is to iden- important new characteristics that distinguish
tify the optimal mathematical approaches most it from historical physiology and mathematical
suited for this scale and complexity of analysis. biology. First, there is a focus on complexity; sec-
Physiologists and pharmacologists have ondly, the fundamental unit of study resides in
always sought to quantify inputs and outputs the DNA (and, by association, protein) sequence.

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 INTRODUCTION 

That the unit of measure can be the nucleotide Geneticists have already defined phenotypic
now provides the lingua franca that permits the interactions between genes or alleles as epistasis
direct translation of experimental results from (Phillips, 2008). In many cases, new properties
biochemistry to cell biology, to physiology and emerge: two white flowers that when crossed give
to population genetics. Moreover, the ultra-high- a purple flower, or two genes that when individu-
throughput and multiplex genomic technologies ally mutated give no phenotype, but show a lethal
allow for the digitalization of experimental data outcome when both are mutated. The mathemati-
of such precision and comprehensiveness that the cal representation of epistasis can be:
true complexity of a biological system can actually
be measured and dissected. In all aspects—bio- (1.1)
logical and mathematical—the greatest advance
has been the availability of computational capa- where W is the observed phenotype, x and y
bilities that can match the systems complexity. are the individual effects of each allele at loci x
This reliance on these genomic and computa- and y,  is the deviation that is due to epistasis.
tional technologies and datasets that can be trans- Systems biology, however, examines the sum of
muted across species has broadened significantly all epistatic relationships and hopes to uncover
the applicability of systems approaches to very the hierarchy. This, indeed, has been the direc-
complex systems such as human medicine. tion of this line of genetic research. Tong et al.
Other thinkers have expounded on the new (2004) crossed mutations in 132 “query” genes
possibilities in integrating mathematics with into a set of 4700 viable yeast gene deletion
biology. In an excellent essay, Joel E. Cohen mutants to develop a genetic interaction map
(2004) noted that “mathematics is not only biolo- containing more than 4000 functional gene
gy’s next microscope, but in fact is better”. He interactions. Classical genetics converges on
observed that, in biology, enormous complexity systems biology.
of up to 100 million species is built on just a few Kitano (2007) noted the importance of con-
basic elements of carbon, nitrogen, hydrogen trol theory in describing biological systems, and
and oxygen. By contrast, the entire periodic table described the primacy of “robustness” in the
generates only several thousand kinds of miner- design of biological systems. He differentiated
als in the earth’s crust. Thus the entire basis of robustness from homeostasis, in that homeosta-
biology is a complexity that produces ensemble sis seeks to return the system to the original state,
or emergent properties of much greater func- whereas robustness will accommodate migra-
tion than the component parts. Cohen argued tion to another state to achieve survivability. One
that mathematics can also benefit from attacking characteristic of evolvable systems described by
biological problems as it did in working through the Highly Optimized Theory (HOT) states that
problems in physics. Calculus was developed such systems are robust against common per-
in part to help solve the problems of celestial turbations, but are fragile against unusual ones
motion and of optics. Similarly, the multilayered (Carlson and Doyle, 2000). A common example
complexity, interlocking control loops, distrib- is the World Wide Web, which, despite being
uted switch mechanisms and the differential use robust because of its high interconnectivity, has
of the same components over developmental been brought down by specific attacks at hubs
time challenges mathematical and computational of activity. Thus systems robustness is a mat-
solutions. It is likely that new mathematics will ter of “trade-offs.” Mathematical descriptions of
be required to deal with these ensemble proper- robustness have been attempted.
ties and with the heterogeneity of the biological Kitano (2007) provides a representation of
input that feeds into the organismic output. robustness in the following equation, but also

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 1. Foundations for Systems Biomedicine: an Introduction

acknowledges that new mathematics may be the construction of a complete functional biolog-
necessary to accommodate these systems con- ical network map for Halobacterium salinarum,
cepts in biology: an Archaea species that thrives in conditions of
high salinity. The final network map describes
“Robustness (R) of the system (s) with regard to
the regulatory functional relationships among
function (a) against a set of perturbations (P):
80% of its genes. The predictive power of
this model was evident in its ability to predict
(1.2)
the transcriptional responses to challenge with
novel environmental conditions or disruption of
The function  is the probability for perturbation transcription factors. The predictive capability
‘p’ to take place. P is the entire perturbation space, of this genome-wide, whole-organism predic-
and D (p) is an evaluation function under perturba-
tion (p).” tive model was significant. In order to achieve
this, Bonneau and colleagues accomplished the
following in order to achieve their goal:
Experimental strategies in
1. The 2.6  Mb Halobacterium salinarum genome
systems biology was sequenced and functions were assigned
to each gene using protein sequence and
Systems approaches are characterized by sev- structural similarities (know all the components).
eral key attributes: 2. Cells were perturbed by varying
concentrations of environmental factors
1. The measurement of quantitative and
and / or gene knockouts (perturbation
comprehensive data of an experimental
analysis).
system.
3. The transcriptional changes of all genes
2. Assessment of the relationships between the
using microarrays were determined after
component parts.
each perturbation (genomic readout for
3. Perturbation of the system to detect response
perturbation analysis).
dynamics.
4. Diverse data (mRNA levels, evolutionary
4. Intersection of orthogonal data to arrive at
conservation in protein structure, metabolic
higher-order logic. (Orthogonal data are
pathways, and cis-regulatory motifs) were
defined as datasets derived from different
integrated to identify subsets of genes that
systems, perhaps addressing the same
are co-regulated in certain environment (data
question in which the intersection of the two
integration).
datasets can further resolve a problem: for
5. A dynamic network model was constructed
example, the set of genes with binding sites
for the of influence environmental and
of a transcription factor and the set of genes
transcription factor changes on the expression
that are expressed with overexpression of
of co-regulated genes (model building).
the same transcription factor [see Chapter 4]).
6. The resulting network was explored
5. Derivation of a model of the system that can
using software visualization tools within
be mathematical or qualitative.
an integrator that enables software
6. Correct prediction of output based on the
interoperability and database integration.
model.
This allowed for manual exploration and
The most complete analyses that engage all generation of hypotheses used to plan
these attributes have been made in lower organ- additional iterations of the systems analysis
isms. Bonneau and colleagues (2007) reported (model testing).

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 Systems biomedicine 

Similar strategies have been applied to the 2001). Together with the advent of expression
eukaryotic model system, yeast, with less pre- arrays in 1996 (Shalon, 1996) and their stable
dictive success (Luscombe, 2004; Tong, 2004; Yu, use by 2000, these technologies launched the
2008). Nevertheless, the strategy still requires next phase of growth for systems approaches
the integration of heterogeneous datasets, such to complex organisms like mammals. Network
as transcription factor binding sites, transcrip- analyses have been conducted primarily where
tional profiles and protein–protein interactions the system is cell-based, such as immunol-
(Fig. 1.1). ogy (Kitano, 2006) or cancer (Segal et al., 2005),
or where the tissue is homogeneous such as
the heart (Olson, 2006) or liver (Schadt, 2008).
Interestingly, computer scientists have looked
Systems biomedicine to the natural immune system to develop analo-
gous artificial immune systems for computer
Systems biomedicine is the analysis of medi- system security (Forrest and Beauchemin, 2007).
cal problems using systems approaches; there- There is much to be learned from biological sys-
fore pertinence to the human condition is a tems that have had the benefit of more than a
prerequisite. Given the complexity of mamma- billion years of evolutionary history.
lian systems, are we ready to study the ensemble The experimental systems approaches to
properties of the human model, and are we suf- studying a human problem will, by necessity,
ficiently clever to use these approaches to under- be different and potentially less complete than
stand and to treat human disease? Before 2001, those appropriate for attacking a question using
perhaps, it would have been difficult to answer prokaryotes. Such reconstruction of a regulatory
affirmatively. If access to the complete human network has been difficult in higher organisms,
genome is a prerequisite for a systems analysis, owing to the dramatically increased complex-
only after the sequencing of the human genome ity of the contributing subsystems. Thus the
could this goal be conceived (Lander et al., possible solution space is orders of magnitude

Expression
Protein
profiles after
interaction map
perturbation

Literature
Complete annotation of
genome protein and gene
sequence interactions

Cis-regulatory Metabolic
Network model
elements pathways

Evolutionary Genotyping
evidence associations

Feedback / hypothesis verification

Prediction

Figure 1.1 Input Information that can be Used to Construct a Network Model.

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 1. Foundations for Systems Biomedicine: an Introduction

greater than that for lower organisms. Gene following 6 stimulation conditions assessing 6
numbers increase in higher eukaryotes, but this signaling molecules. These states could sepa-
is not the confounding factor: splice variants, rate acute myeloid leukemia cells into signaling
transcription factors binding at great distances classes that corresponded to cytogenetic and
from the transcriptional start sites, gene dupli- clinical parameters (Irish, 2004).
cation, post-transcriptional regulation by micro- It has been said that biology asks six kinds
RNAs and other non-coding RNA species, and of question (Cohen, 2004): How is it built? How
complex post-translational modifications that does it work? How did it begin? What is it for?
change binding affinities all radically augment The remaining two questions are more in the
the complexity of the components. domain of medicine: What goes wrong? How
Despite these challenges, network models of is it fixed? So, systems biomedicine focuses, not
subsystems have been described, for example only on human biology, but also human dis-
for the class of receptor tyrosine kinases (RTKs) ease. Efforts to examine perturbations in gene
(Amit et al., 2007a, 2007b; Katz, 2007). In these and protein networks for clues to disease etiol-
analyses, signaling hubs for the RTKs, such as ogy have been pursued and will be described in
RAF and the phosphoinositide 3 kinase PI3K– subsequent chapters in this book. Most efforts
AKT nodes, are noted to be frequent points of are in the bench-to-bedside direction, but one
attack by oncogenic viruses, in addition to being approach that starts commonly from the patient
sites of de-novo mutations in primary cancers. and is validated at the bench is in human and
Such hubs, independently identified by both population genetics of disease genes.
viruses and cancer mutations, also are effective Human variations in the form of single nucle-
targets for anticancer therapeutics. otide polymorphisms (SNPs) are used to identify
Exploiting kinase networks, Sachs et al. genetic loci statistically associated with disease
(2005) pursued an interesting alternative strat- when compared with control populations. When
egy. Using multicolor / multiparameter flow assessed on a genome-wide basis, this has been
cytometry in which up to 11 different features a powerful, unbiased means of uncovering dis-
can be determined when labeled with different ease-associated genes. When expression arrays
fluorophores, they quantitatively assessed the are coupled with genetic markers, expression
combinatorial presence of specific phosphor- quantitative trait loci (eQTL) can be assigned.
proteins indicative of activated kinases. Because In eQTL analysis, each transcript on the array is
flow cytometry assesses the biochemical state of considered to be a quantitative phenotype and
individual cells, a large number of observations is correlated with the SNP configuration at each
can be accumulated that would otherwise be an locus in the genome (Cheung et al., 2005; Sieberts
average of the population. In this manner, Sachs and Schadt, 2007). cis-eQTL represent those SNPs
and colleagues were able to construct a Bayesian adjacent to the measured gene of which the con-
network from these data. Bayesian network figuration is correlated with transcript levels,
models disclose the dependent effect of each whereas trans-eQTLs are those associated with
biomolecule on the others, and therefore can SNPs that are distant from the transcribed gene.
infer causal relationships. Examining signaling eQTLs in humans have been used as proof of
in T cells, they could construct a network map the genetic basis of gene expression in humans
that faithfully portrayed known and experimen- (Cheung et al., 2008; Spielman et al., 2007). When
tally validated kinase–substrate relationships. viewed on a genome-wide basis, a transcriptional
In a similar fashion, they mapped the signaling network of regulatory “influence” can be dis-
profiles of acute myeloid leukemia cells after cerned by statistical association between individ-
cytokine challenge and found 36 node states, ual SNPs and expression of genes anywhere in

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 Circadian cycles as a relevant model for systems biomedicine 

the genome. Schadt and his colleagues at Rosetta REV-ERB accumulates to threshold levels,
Pharmaceuticals have shown that combining it represses BMAL1/CLOCK. This secondary
genotypic data and expression data can increase regulatory loop is not essential for the establish-
precision of the discovery for disease-associated ment of the circadian cycle, but it appears to be
genes (Drake et al., 2005; Zhu et al., 2007). involved in stabilizing the regulatory frame-
work. The oscillator function can be explained
by a time delay in PER/CRY feedback inhibi-
Circadian cycles as a tion of BMAL/CLOCK establishing a composite
relevant model for systems negative network motif with asymmetric tim-
ing. This oscillator is also affected by enzyme-
biomedicine families such as casein kinase 1 (CSNK1 and
CSNK1) that regulate the degradation of criti-
An excellent example of a systems model cal components like the PER protein (Fig. 1.2).
that has medical importance is that of oscil- (Takahashi et al., 2008).
lators as regulators of the circadian rhythm. Peripheral tissues also exhibit autonomous
Oscillators are machines that cycle functions circadian rhythms but are subservient to and
over time and are characterized by an auto- are entrained by the SCN. The SCN coordinates
matic periodicity (see Chapter 4), and the best the peripheral clocks through humoral and neu-
examples of biological oscillators are found in ral signals that are not well understood, and
studies of circadian rhythm. The guiding motif by indirect means such as body temperature,
for all living creatures is the ability to replicate, wakefulness and food intake. Thus the entire
which imparts a cycling of functions. Over evo- circadian system is a hierarchy of subnetworks
lutionary time, there appeared to be an adaptive that extend from the molecular and biochemical
advantage to entrain such physiologic processes level to the physiological level.
to an external clock defined by the day–night Components of the circadian clock are deeply
cycle. In order to do this, most organisms have involved in human physiology and disease. The
found biochemical mechanisms to maintain this most obvious association is with sleep disor-
cycling, and mechanisms to sense the environ- ders. Familial advanced sleep-phase syndrome
ment in order to modulate this periodicity. (FASPS) is an autosomal dominant circadian
The master circadian regulator in mammals rhythm disorder characterized by an abnormal
is in the suprachiasmatic nucleus (SCN) in the phasing of the circadian cycle relative to the
brain. The molecular mechanism underpinning desired sleep–wake schedule. Here sleep onset
this oscillator has been elucidated. The basic and awakening times are 3–4 hours ahead of the
helix–loop–helix containing transcription factor desired times. Through linkage analysis, indi-
CLOCK interacts with BMAL1 to activate tran- viduals with the syndrome were found to har-
scription of the Per and Cry genes. The Period bor a missense mutation, S662G, in the human
(PER) and Cryptochrome (CRY) protein prod- PER2 gene. This S662G mutation disrupts a
ucts heterodimerize and undergo negative feed- phosphorylation site within a casein kinase 1
back to inhibit their own transcription, and that (CSNK1)-binding domain of PER2, resulting
of BMAL1. The PER–CRY repressor complex in the increased turnover of nuclear PER2. As
is degraded during the night, and Clock-Bmal1 evidence that FASPS has heterogeneous genetic
are de-repressed and can then induce transcrip- origins, a mutation in a casein kinase isoform,
tion. There is a secondary feedback loop that CSNK1, was also found in FASPS.
involves the induction of a nuclear hormone Such sleep disorders are rare; however,
receptor, REV-ERB, by BMAL1/CLOCK. When there is the cumulative evidence that molecular

I. FOUNDATIONS OF SYSTEMS BIOLOGY

10 1. Foundations for Systems Biomedicine: an Introduction

Protein PER–CRY
CSNK1ε/δ
degradation
FBXL3

PER CRY
RORα BMAL–CLOCK

Clock-
BMAL1 CLOCK
controlled
genes
REV-ERBα

REV-ERBα

Figure 1.2 Schematic Representation of the Control Network for Circadian Cycling.
The core organization of the regulatory module is comprised of two interlocking negative-feedback network motifs with
asymmetric timing. BMAL1, brain and muscle Arnt (aryl hydrocarbon receptor nuclear translocator)-like protein-1; CLOCK,
Circadian Locomotor Output Cycles Kaput gene; CSNK1/, casein kinase 1  and ; CRY, Cryptochrome; FBXL3, an E3
ubiquitin ligase; PER, Period; REV-ERB: a retinoid-acid-related orphan nuclear hormone receptor; ROR, a retinoid-acid-
related orphan nuclear hormone receptor.

components of the circadian oscillator may be body weight and sensitivity to insulin shock.
involved in many common disorders. Gene pro- Fibroblasts from these Bmal1 knockout mice
filing experiments demonstrated that up to 10% also cannot undergo adipocyte differentiation
of the testable transcriptome shows circadian (Shimba et al., 2005). Clinically, a link between
periodicity, and that the attributes of these clock- circadian cycles and metabolism has been
regulated genes are highly enriched for metabolic observed. Epidemiologic studies in shift work-
functions. Recall that the nuclear hormone recep- ers have shown an increase in body mass index,
tors, ROR and REV-ERB, are integral parts of and in the rates of incidence of metabolic disor-
the oscillator loop. Extending this analysis fur- ders and cardiovascular events (Ellingsen et al.,
ther, Yang and colleagues (2006) examined the 2007). It is also well understood that the specific
detailed gene expression the 49 nuclear receptors sensitivity to exogenous insulin exhibited by dia-
in mice, and found that 28 display tissue-specific betic patients changes over the time of day. Thus
circadian rhythms. Given the function of nuclear the circadian clock mechanisms are inextricably
receptors in metabolic regulation, their circadian linked to metabolic functions, and may repre-
control provides one explanation for the diurnal sent an adaptive evolutionary response to maxi-
behavior of glucose and lipid metabolism. mizing energy utilization that is dependent on a
Studies in animal models also continue to consistent environmental change—the planetary
uncover associations between clock genes and reality of the day / night cycle (Green et al., 2008).
metabolic phenotypes: homozygous Clock- An intriguing side observation that now has
mutant mice are hyperphagic, obese and exhibit significant ramifications for cancer therapeutics
a metabolic syndrome with hyperlipidemia, fatty is that liver detoxifying genes also show signifi-
liver, high circulating glucose concentrations and cant circadian oscillations and have been shown
low circulating insulin concentrations (Turek to be regulated by clock mechanisms. Doses of
et al., 2005). Bmal1/ knockout mice not only the chemotherapeutic agent, cyclophosphamide,
have abnormal sleep patterns, but also show low given at different times of the circadian cycle can

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 Conclusion 11

result in differences in mortality rates—from 20% experimental access. Clearly, the human genome
to 100% (Gorbacheva et al., 2005). Exploring this and proteome is more complex than those of
phenomenon further, the investigators found that yeast and bacteria, and human genetic studies
Clock and Bmal1 knockout mice are sensitive to are more complex than those in mice. Moreover,
the toxic effects of cyclophosphamide, but Cry1 the complexity of a multicellular and multi-
and Cry2 double-knockout mice are resistant. organ system has yet to be configured into the
This resistance was not caused by pharmacoki- equation. To date, the comparative extent of that
netic differences, but appeared to be correlated complexity remains not quite known; therefore,
with cellular insensitivity of B lymphocytes to how much more data and how much more com-
the lymphotoxic effects of this drug. These exper- puting will be necessary to achieve the same
iments validate the clinical observations that tim- coverage as that described for Halobacterium
ing of chemotherapeutic administration has an salinarum is unclear, but will undoubtedly be
effect on drug toxicity and drug effectiveness more than the ratio of the size of our genome to
(reviewed by Takahashi et al., 2008). that of this microbe. However, the approaches
The growing body of knowledge of the mecha- and the opportunities are the same.
nisms around circadian clocks and their impact Of course, in the final analysis, systems bio-
on health has provided opportunities for the medicine, by directly benefiting human health,
development of drugs targeting these molecules. will be a significant endeavor. So any increment
Many of the clock-associated genes are amenable in improvement in prediction will help medicine
to the action of drugs or represent biochemical and benefit society. The challenges, however,
classes amenable to small-molecule modulation: are logistical, computational and organizational.
the melatonin receptors are G-protein-coupled Logistical because first, for obvious ethical rea-
receptors; GSK3 is a kinase that modifies PER, sons, experimentation in human systems is
and REV-ERB casein kinase 1 is another class slower and more ponderous; secondly, human
of kinases; REV-ERB and ROR are nuclear hor- variation will make initial estimates less general-
mone receptors (the ligand for REV-ERB has izable; and thirdly, the further division into organ
been identified as heme). All these targets have systems linked by circulation and endocrine fac-
candidate small-molecule modifiers. This has led tors will increase the number of studies needed
companies to explore the use of cell-based screens in order to complete the human organism. The
to identify molecules that would disrupt or alter computational challenges have been alluded to,
the circadian clock. Cell systems with luciferase and are most critical: massive amounts of data
reporter genes controlled by clock-dependent reg- requiring integration and iterative analysis of
ulatory elements can be used to screen libraries of high computational complexity. The new tech-
small molecules. The readout would be disruption nologies in sequencing, genotyping, proteomics
of the periodicity (reviewed by Liu et al., 2007). and imaging are generating a hyper-exponen-
Thus, starting from a simple oscillator, explana- tial growth in data acquisition that is quickly
tions of human physiology and identification of outstripping the capabilities of most biological
targets for therapy can be explored. laboratories and departments. The physical sci-
ences have pioneered the use of supercomputers
with the capability of handling this challenge.
Conclusion However, the porting of the all biological, genetic
and genomic algorithms to these new plat-
How is systems biomedicine different from forms and their continued development will be
other forms of systems studies? In my opin- a prodigious task. Lastly, the simple fact is that
ion, the differences are only ones of scale and our data standards do not routinely allow for

I. FOUNDATIONS OF SYSTEMS BIOLOGY

12 1. Foundations for Systems Biomedicine: an Introduction

cross-platform comparisons. Manual curation is platforms is too often bypassed as lacking sci-
still required for most high-level systems integra- entific content. By discounting participation in
tion. There is a need for integration of heteroge- collaborative projects and focusing exclusively
neous data (e.g. protein–protein interaction, RNA on individual effort, University promotion proc-
expression information, biochemical pathways, esses historically encourage faculty insularity.
genomic data and literature-based connections) Graduate student training, restrained by clas-
and for visualization tools that will enable the sical departmental boundaries and focused on
presentation of large-scale data that are interpret- individual faculty projects, is not responsive to
able to bench biologists. the educational requirements for success in inte-
Finally, the organizational challenges, although grative and systems biology. Systems biology is
man- made and therefore surmountable by man, deeply cross-disciplinary.
are also daunting (Liu et al., 2005). These organi- Daunting as these challenges are, the stakes
zational challenges are rooted in the sometimes are high. I believe that systems approaches in
contradictory requirements of systems biology biology will become as common as molecular
research and the operational intentions of our technologies are in current biological investi-
academic and funding institutions. gations. Molecular biology, which was a new
In systems research, scientists with very dif- creature in the 1970s and early 1980s and which
ferent skills (biology, mathematics, engineering, spawned biotechnology companies and insti-
medicine) must be working closely together tutes and departments with “molecular biol-
and have proximity with one another in what ogy” in their title, is now commonplace and
might almost be scientific collectives (Liu, integrated into the fabric of biological teachings.
2009). Traditionally, bioinformatics resided in Current medical investigations are all molecu-
a computer science or biostatistics department, lar medicine. The same will be true of systems
biology in a biochemistry department and a approaches.
genomics center that was functionally disso- Systems Biomedicine, indeed, is here to stay.
ciated from the previous two. However, the
scale of this interaction requires coordinated
resources from the funding agencies, much References
akin to the supercomputing program of the US Amit, I., Citri, A., Shay, T., et al., 2007a. A module of nega-
National Science Foundation. This unfortunate tive feedback regulators defines growth factor signaling.
disconnect would benefit from some concep- Nat. Genet. 39, 503–512.
Amit, I., Wides, R., Yarden, Y., 2007b. Evolvable signaling
tual realignment. Regarding data presentation, networks of receptor tyrosine kinases: relevance of rob-
there is a need to provide more natural inter- ustness to malignancy and to cancer therapy. Mol. Syst.
faces between humans and computers to serv- Biol. 3, 151.
ice the non-expert user. There will be a demand Bonneau, R., Facciotti, M.T., Reiss, D.J., et al., 2007. A predic-
tive model for transcriptional control of physiology in a
for simplified interfaces specifically designed
free living cell. Cell 131, 1354–1365.
for biologists. This does not detract from the Carlson, J.M., Doyle, J., 2000. Highly optimized tolerance:
important need to train the next generation of robustness and design in complex systems. Phys. Rev.
biologists who are mathematically and compu- Lett. 84, 2529–2532.
tationally literate, and the next generation of Cheung, V.G., Spielman, R.S., Ewens, K.G., Weber, T.M.,
Morley, M., Burdick, J.T., 2005. Mapping determinants
mathematicians, computer scientists and engi-
of human gene expression by regional and genome-
neers who are steeped in the nuances of biology. wide association. Nature 437, 1365–1369.
Grants management is often at odds with col- Cheung, V.G., Bruzel, A., Burdick, J.T., Morley, M., Devlin,
lective efforts. Funding for critical technology J.L., Spielman, R.S., 2008. Monozygotic twins reveal

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 references 13

germline contribution to allelic expression differences. Olson, E.N., 2006. Gene regulatory networks in the evo-
Am. J. Hum. Genet. 82, 1357–1360. lution and development of the heart. Science 313,
Cohen, J.E., 2004. Mathematics is biology’s next microscope, 1922–1927.
only better; biology is mathematics’ next physics, only Phillips, P.C., 2008. Epistasis—the essential role of gene inter-
better. PLoS Biol. 2, e439. actions in the structure and evolution of genetic systems.
Drake, T.A., Schadt, E.E., Davis, R.C., Lusis, A.J., 2005. Nat. Rev. Genet. 9, 855–867.
Integrating genetic and gene expression data to study the Sachs, K., Perez, O., Pe’er, D., Lauffenburger, D.A., Nolan,
metabolic syndrome and diabetes in mice. Am. J. Ther. G.P., 2005. Causal protein-signaling networks derived
12, 503–511. from multiparameter single-cell data. Science 308,
Ellingsen, T., Bener, A., Gehani, A.A., 2007. Study of shift 523–529.
work and risk of coronary events. J. R. Soc. Health 127, Schadt, E.E., Molony, C., Chudin, E., et al., 2008. Mapping
265–267. the genetic architecture of gene expression in human
Forrest, S., Beauchemin, C., 2007. Computer immunology. liver. PLoS Biol. 6, e107.
Immunolog. Rev. 216, 176–197. Segal, E., Friedman, N., Kaminski, N., Regev, A., Koller, D.,
Green, C.B., Takahashi, J.S., Bass, J., 2008. The meter of 2005. From signatures to models: understanding cancer
metabolism. Cell 134, 728–742. using microarrays. Nat. Genet. 37 (Suppl), S38–S45.
Gorbacheva, V.Y., Kondratov, R.V., Zhang, R., et al., 2005. Shalon, D., Smith, S.J., Brown, P.O., 1996. A DNA microar-
Circadian sensitivity to the chemotherapeutic agent ray system for analyzing complex DNA samples using
cyclophosphamide depends on the functional status two-color fluorescent probe hybridization. Genome Res.
of the CLOCK/BMAL1 transactivation complex. Proc. 6, 639–645.
Natl. Acad. Sci. USA 102, 3407–3412. Shimba, S., Ishii, N., Ohta, Y., et al., 2005. Brain and muscle
Irish, J.M., Hovland, R., Krutzik, P.O., et al., 2004. Single cell Arnt-like protein-1 (BMAL1), a component of the molec-
profiling of potentiated phospho-protein networks in ular clock, regulates adipogenesis. Proc. Natl. Acad. Sci.
cancer cells. Cell 118, 217–228. USA 102, 12071–12076.
Katz, M., Amit, I., Citri, A., et al., 2007. A reciprocal tensin- Sieberts, S.K., Schadt, E.E., 2007. Moving toward a system
3-cten switch mediates EGF-driven mammary cell genetics view of disease. Mamm. Genome 18, 389–401.
migration. Nat. Cell Biol. 9, 961–969. Spielman, R.S., Bastone, L.A., Burdick, J.T., Morley, M.,
Kitano, H., 2006. The B-cell interactome. Available from http:// Ewens, W.J., Cheung, V.G., 2007. Common genetic vari-
amdec-bioinfo.cu-genome.org/html/BCellInteractome. ants account for differences in gene expression among
html#Publication ethnic groups. Nat. Genet. 39, 226–231.
Kitano, H., 2007. Towards a theory of biological robustness. Takahashi, J.S., Hong, H.K., Ko, C.H., McDearmon, E.L.,
Mol. Syst. Biol. 3, 137. 2008. The genetics of mammalian circadian order and
Kitano, H., Oda, K., 2006. Robustness trade-offs and host- disorder: implications for physiology and disease. Nat.
microbial symbiosis in the immune system. Mol. Syst. Rev. Genet. 9, 764–775.
Biol. 2, 2006–2022. Tong, A.H., Lesage, G., Bader, G.D., et al., 2004. Global map-
Lander, E.S., Linton, L.M., Birren, B., et al., 2001. For the ping of the yeast genetic interaction network. Science
international human genome sequencing consortium. 303, 808–813.
Initial sequencing and analysis of the human genome. Turek, F.W., Joshu, C., Kohsaka, A., et al., 2005. Obesity and
Nature 409, 860–921. metabolic syndrome in circadian Clock mutant mice.
Liu, E.T., 2005. Systems biology, integrative biology, predic- Science 308, 1043–1045.
tive biology. Cell 121, 505–506. Yang, X., Downes, M., Yu, R.T., et al., 2006. Nuclear receptor
Liu, E.T., 2009. Integrative biology—a strategy for systems expression links the circadian clock to metabolism. Cell
biomedicine. Nat. Rev. Genet. 10, 64–68. 126, 801–810.
Liu, A.C., Lewis, W.G., Kay, S.A., 2007. Mammalian circa- Yu, H., Braun, P., Yildirim, M.A., Lemmens, I., et al., 2008.
dian signaling networks and therapeutic targets. Nat. High-quality binary protein interaction map of the yeast
Chem. Biol. 3, 630–639. interactome network. Science 322, 104–110.
Luscombe, N.M., Babu, M.M., Yu, H., Snyder, M., Zhu, J., Wiener, M.C., Zhang, C., et al., 2007. Increasing the
Teichmann, S.A., Gerstein, M., 2004. Genomic analysis power to detect causal associations by combining geno-
of regulatory network dynamics reveals large topologi- typic and expression data in segregating populations.
cal changes. Nature 431, 308–312. PLoS Comput. Biol. 3, e69.

I. FOUNDATIONS OF SYSTEMS BIOLOGY

 C H A P T E R

2
Genomic Technologies for Systems
Biology
Edison T. Liu1, Sanket Goel1, Kartiki Desai1 and Mathijs
Voorhoeve2
1
Genome Institute of Singapore, Singapore
2
Duke-National University of Singapore Graduate Medical School, Singapore

o u t l i n e

Summary 16 Interaction Analysis: Two-hybrid

Definitions 16 Screens 33
Introduction 16 Gene-based Perturbation Studies:
Transgenic Knockouts 34
DNA Sequencing: High-throughput
Forward Genetics 34
Sequencing Technologies 17
Reverse Genetics 35
Roche 454 Life Sciences: GS FLX Titanium 17
RNA Interference Approaches
Illumina: Genome Analyzer 20
in Systems Biology 35
Applied Biosystems: SOLiD Sequencing 22
Applications of Sequencing in Systems
Biology: The Transcriptome and
Transcriptional Regulation 24
Expression Arrays 26
ChIP-on-chip Arrays 28

Systems Biomedicine 15 © 2010, Elsevier Inc.

16 2. Genomic Technologies for Systems Biology

Summary enabled the use of short tags in genome re-

sequencing and made possible the identifi-
The term “genome-to-systems” used in sys- cation of peptide fragments from proteomic
tems biology is a reflection on how important interrogations. The term “genome-to-systems”
genomic strategies are to the systems analysis reflects the primary use of genomic informa-
of biological processes. The technical funda- tion in systems analysis of biological proc-
mentals of all genomic technologies are based esses. This is then coupled with characteristic
on the principles of base-pair hybridization and systems approaches: the precise designation of
DNA polymerization. From these basic steps each component under study, the comprehen-
comes the tool set of genome-to-systems work: sive measurement of all components involved
quantitative polymerase chain reaction, expres- in a process, and the computation of complex
sion and genomic arrays, DNA sequencing and information. Certainly, quantitative approaches
nucleic-acid-based disruption of gene expres- have been used in the past, solely with protein
sion. Each tool provides one or more aspects or biochemical components, but the complex-
of systems biological information: quantitative ity of these systems was low, studying a limited
assessment, precise component determination number of components with the goal of ren-
and comprehensive coverage. We will describe dering a mathematical model of a biochemical
each technology and explore their applications reaction. As such, early systems models were
in systems biosciences. models of biochemical kinetics.
Knowledge of the genome and, in particular,
the annotation of the transcriptome of model
organisms including the human, has enabled
Definitions
the construction of genome-wide probes by
ChIP Chromatin immunoprecipitation in-silico (computationally-based) means, and
dsRNA Double-stranded RNA. precise gene assignment for genome-wide
Hypomorph A genetic mutation that results in transcript analysis. The ability to assess the
partial loss of function. expression of all known gene transcripts in
miRNA MicroRNA. a quantitative fashion formed the basis for
RISC RNA-induced silencing complex. genome-wide systems analyses of biological
RNAi RNA interference. processes. Thus transcriptional profiles were
RT-PCR Reverse transcriptase polymerase chain the first to be used in such a manner. This was
reaction. followed by assessment of transcription factor
SAGE Serial analysis of gene expression. binding and of the influence of epigenetic mod-
shRNA Short hairpin RNA. ifications on gene expression. The final call for
siRNA Short interfering RNA. precision in transcript ascertainment has led to
the development of transcriptome re-sequencing
and genome-scale mutational maps. Other gene-
based technologies used for systems studies
Introduction include two-hybrid screens for protein interac-
tion mapping and gene silencing approaches
The sequencing of entire genomes and their (short interfering RNA [siRNA], short hair-
annotation have been the critical enabling fac- pin RNA [shRNA]) for perturbation analysis.
tors for all of systems biology. This information Table 2.1 summarizes these technologies that
permitted the in-silico preparation of probes to contribute to the pursuit of genome-to-systems
assess both genomic and expression changes, strategies.

I. FOUNDATIONS OF SYSTEMS BIOLOGY

Another Random Scribd Document
with Unrelated Content
attendance four months. Subsequently he took up telegraphy,
working for the American Union Telegraph Company about one year,
and for the Western Union Telegraph Company three years. On
January 8, 1884, Mr. Covert married Mary J., daughter of Albert
Merriam, of Wellsburg, N. Y. In the fall of 1885 he built the first store
in Armenia township, and here he carried on mercantile business
two years. In the meantime he circulated petitions and worked for
the establishment of a mail route from Troy to Fall Brook, and
succeeded in getting it as far as Covert's, five miles from Troy, the
name of which postofnce is "Covert," established in July, 1886; Mr.
Covert was appointed postmaster, July 8, 1886; and in October,
1887, he rented his store to Field Brothers, and May 11, 1891, he
resigned the office of postmaster in favor of O. D. Field, who is now
acting as postmaster. Mr. Covert has been successful in business as
far as he has been able to attend to it, but he has been in poor
health ever since he was wounded, and has been unable to perform
manual labor. Prior to his enlistment in the army, his occupation
 HISTORY OF BRADFORD COUNTY. 749 was farming, but he
has had to give up all business on account of his impaired health,
and he is at present living on the old homestead in Armenia
township. Mr. Covert is a member of the G. A. B., and in politics he is
a Eepublican. EDWAED M. COWELL, physician, East Smithfield, was
born in East Smithfield township, this county, January 29, 1864, a
son of Dr. Selden S. and Sarah A. (McCracken) Cowell, natives of
Bradford county, born in Asylum, the former of whom is still in the
practice at Scranton, Pa. Our subject's grandmother was a cousin of
. President John Q. Adams, and grandfather Cowell was a pioneer
settler in Wysox. Dr. Edward M. Cowell is an- only son ; he has one
sister, who is the wife of Wilson F. Voorhis, of East Smithfield. The
subject of this memoir was educated at the Collegiate Institute,
Towanda, and Hiram College, Ohio, three years; was graduated at
the Chicago Homoeopathic Medical College" in the spring of 1885,
and commenced practicing in East Smithfield the fall of that year. He
was married, September 16, 1885, to Lillian H., daughter of Charles
and Lydia (Dunn) Huntington, of Athens, Pa., born January 19, 1866,
and there have been born to them three children, only one of whom
is now living, Margaret E., born July 20, 1890. The Co wells are a
race of physicians ; the Doctor's father had four brothers who were
of the same profession, and each of them have two and three
children who are physicians ; for several generations back there
have been members of the family who have followed this profession.
The Cowells are of Welsh extraction, and the Doctor's mothers family
are of ScotchIrish descent. Dr. Cowell enjoys an extensive and
lucrative practice, and a wide circle of friends. He is a Democrat in
politics, and takes an interest in the affairs of the township and
county; Mrs. Cowell is a member of the Presbyterian Church.
GEOEGE H. COX, florist, Towanda, was born in Warwickshire,
England, and is a son of George H. and Mary (Walker) Cox. He was
reared and educated in his native place, where he served a three
years' apprenticeship at the gardener's and florist's business. In
1870 he came to America, locating in Canada for a time, and, after
traveling considerably to see the country, he settled in 1877 in
Sayre, this county, where he was engaged in business up to 1884,
when he removed to Towanda and established himself in business.
He has here since remained, has built up a successful trade, and is
the only florist in Towanda, his place of business being on rJorth
Main street, where he has three spacious green-houses, two of
which are 50 x 20 feet in size, the other being 40x20. Mr. Cox was
married, in 1870, to Elizabeth, daughter of William and Margaret
(McLaughlin) McMurray, of County Armagh, Ireland, and has three
children, George H.,Emilie P. and Charles A. Mr. Cox is a member of
the Episcopal Church, and in politics is Independent. EEY. DAVID
CEAFT is a lineal descendant of Lieut. Griffin Craft, who, with his
family, was an immigrant in the first company that came to Boston in
July, 1630, and settled in Eoxbury, now Boston, on a piece of land
which has been in the possession of his descendants, and in the
Craft name until now. David Craft was born
 750 HISTORY OF BRADFORD COUNTY. in Carmel, Putnam
Co., N. Y., October 3, 1832. He is a graduate of Lafayette College ;
studied theology at Princeton, N. J.; taught in the Susquehanna
Collegiate Institute at Towanda, in 1857 and '58 ; was licensed to
preach by the Susquehanna Presbytery, March, 1860, and in the
following September began preaching at Wyalusing. In August,
1862, the congregation having granted him leave of absence, he
accepted the appointment of chaplain of the One Hundred and
Forty-first Regiment, P. V. I., but resigned the following spring on
account of continued ill health, and resumed work in Wyalusing,
which he continued until January, 1891. In 1866, Mr. Craft published
his " Wyalusing," which included a history of his church and of the
early settlement of the town. This was received with so much favor
that the Bradford County Historical Society prevailed upon him to
undertake the history of the county, which was begun with great
reluctance, and published in 1877. In 1879 he delivered the historical
address at each of the celebrations of the one hundreth anniversary
of the "Sullivan expedition against the Western Indians," held at
Elmira, Waterloo, Geneseo and Aurora, in the State of New York.
These were combined in a continuous narrative, and published by
the Seneca County Iiistorical Society in 1880; rewritten and enriched
with numerous geographical and biographical notes, was published
by the State of New York in 1885. This has received the unqualified
approbation of eminent military men and historians, such as Gen. W.
T. Sherman, Sidney Howard Gay, W. C. Bryant and others. In 1887
he published the history of the One Hundred and Fortyfirst
Regiment, which, by common consent, ranks among the very best of
regimental histories. In 1891 he wrote the early history of the city of
Scranton, published by H. W. Crew, of Washington, D. C. Besides
these he has been an almost constant contributor to the press of
articles of a historical and literary character. In the midst of these
active literary labors, Mr. Craft has had charge of a large and
laborious field, where he has done most acceptable and successful
work as a pastor. He has been also active in promoting educational
and moral society, frequently called to speak at teachers'
associations, temperance meetings, etc. In 1889, after passing
through the subordinate offices, he was unanimously elected grand
master of the I. O. O. F., of Pennsylvania, where he had the
oversight of one thousand subordinate societies numbering about
one hundred thousand members. On April, 1891, he accepted a call
to the pastorate of the First Presbyterian Church in Lawrenceville,
Pa., where he now resides. On June 11, 1861, Mr. Craft married Jane
Elizabeth, daughter of the late Dr. G. F. and Abigail Horton, and two
children — one son and one daughter, both unmarried — have been
born to them. MACKAY CRAIG, merchant, Bentley Creek, was born
April 6, 1832, in County Down, Ireland, a son of Joseph (a hotel
keeper) and Jane (Walker) Craig, natives of the same county and of
Scotch-Irish ancestry. The family immigrated to America when the
subject of these lines was an infant, and settled near Burdett
Schuyler Co.,N. Y., where the father engaged in teaching school, and
after three years they came to Ridgebury township, this county,
where they engaged in
 HISTOKT OF BRADFORD COUNTY. 751 farming ; the family
consisted of four sons and one daughter. Mackay Craig was reared
on the farm and carried on farming for himself until the spring of
1870, when he embarked in mercantile business at Bentley Creek. In
the spring of 1874 he formed a partnership with E. M. Tuton under
the firm name of Craig & Tuton, who have had one of the most
extensive trades in the township ; they carry a large stock of general
merchandise, and are also dealers in agricultural implements. Mr.
Craig was married, March 25, 1871, to Jane, daughter of Hosea and
Letitia (Wilson) Kennedy, farmers, of Springfield township ; she had
two brothers, Orr and Alexander, in the Civil War,- both of whom saw
much hard service, and were made prisoners. Mr. Craig's brother
John was also a soldier in that war. To Mr. and Mrs. Craig have been
born three children, one son and two daughters : Hosea and Letitia
(twins), born March 25, 1872 (Hosea is a clerk in his father's store,
and Letitia is the wife of Jud S. Thompson, who is also a clerk in the
same store), and Ethlyn L. born May 30, 1875, died Nov. 4, 1876.
Mr. Craig is a Republican in politics, and has held several offices of
public trust in his township. SAMUEL W. CRAIG, farmer, P. 0. Bentley
Creek, was born April 10, 1838, on the farm where he now resides,
in Ridgebury township, this county, a son of Joseph and Jane
(Walker) Craig, of Scotch-Irish ancestry. The family removed to
America in 1832. Our subject is a brother of Mackay Craig, a
merchant, of Bentley Creek, and is the youngest in a family of four
sons and one daughter ; his father was killed by an accident at the
age of forty-one years, and the mother died aged seventy-two years.
His brother, John, was a soldier in the Civil War. Mr. Craig was reared
a farmer, and has continued to follow that occupation, being now the
owner of a fine farm of 200 acres, including the old homestead,
where he carries on dairying and sheep raising. The farm is nicely
located on one of the finest elevations in the township. He was
united in marriage, October 3, 1867, with Laura, daughter of Hiram
and Jane (Furman) Mason, of Columbia, who were among the
earliest settlers of the township of South Creek; she was born
February 8, 1848. Her grandfather Mason came from Ireland when
only fourteen years of age, and settled in Delaware county, N. Y. ;
her father is an extensive farmer and dairymaD, now aged eighty-
three years; her mother died at the age of seventy-six years. To Mr.
and Mrs. Craig have been born one son and one daughter : Edwin
M., born February 13, 1870, and Jennie, born November 3, 1872. Mr.
Craig is a Republican in politics, and has been auditor, school
director and judge of elections ; also held several other offices of
public trust. He is one of the enterprising and reliable men of the
township. CHARLES H. CRANDAL, farmer, P. O. Stevensville, was
born in Pike township, this county, May 21, 1837, a son of Dr.
Edward and Mary E. (Bosworth) Crandal, latter of whom is a
daughter of Salmon and Sarah (Olmstead) Bosworth. Salmon
Bosworth and his brother, Josiah, were the first of the name to
locate in Bradford county, and in 1798 they settled on the farm
where Charles H. Crandal now lives, coming from Connecticut. Dr.
Edward Crandal was a native of New
 752 HISTORY OF BRADFORD COUNTY. York, born of New
England origin. In his family were ten children of whom, Charles H.,
the fifth in order of birth, was educated in the common school, Saint
Timothy's Hall, Md., and Kenyon College, at Gambier, Ohio. He began
for himself at the age of twenty-one on his father's farm, but on
August 10, 1862, he enlisted at LeRaysville, and was mustered in at
Harrisburg in Company B, One Hundred and Forty -first Eegiment P.
V..L, took part in the battle of Mobile and in several skirmishes ; was
then detailed as a Hospital nurse, acting in that position in the
Patent Office and Lincoln's Hospitals, and the Washington and
McClellan Hospital, at Nicetown, near Philadelphia. In October, 1863,
he was ordered to join his regiment, and was afterward transferred
to the First Mississippi United States Colored Troops as second-
lieutenant, where he remained until the close of the war, being
mustered out as captain Fifty-first U. S. C. I., June 16, 1866, at
Baton Eouge, La ; then went to Alton, 111., where he was engaged
in the manufacture of a washing fluid until December, 1866, when
he returned home, and has since carried on farming. In 1871 he
purchased his present home of his mother, which contains 100 acres
of fertile and well cultivated land. Mr. Crandal was married June 29,
1871, to Mrs. Benjamin B. Babcock, daughter of Dr. Hiram and
Elizabeth H. (Eastabrook) Knapp, of Orwell, the former a native of
New York, and the latter of Connecticut. In their family there were
ten children, of whom Armenia is the sixth, and of them two where
physicians. Mr. and Mrs. Crandal have one child, Rowland J., born
April 5, 1874. They are members of the Protestant Episcopal Church.
In politics he is a Republican, has held the office of justice of the
peace six vears ; has also been constable in Pike township. GEORGE
A.CRANDALL, farmer, P.O. Troy, was born in Cortland county, N. Y.,
November 14, 1829, a son of Allen and Sarah (Chase) Crandall,
natives of Cortland and Delaware counties, N. Y., respective^', who
settled in Columbia township, this county, in 1835, where his father
purchased a tract of three hundred acres, cleared a part of it, but
later sold it and removed to Alba, where he died in 1876 ; his widow
still survives at the age of eighty-two ; he was a carpenter by trade,
which he followed as an occupation most of his life ; his children
were : George, Burdette (deceased), DeWitt C, Ann (Mrs. James
Reynolds, deceased), Henry, Minnie (Mrs. Edward Lewis), Wallace,
Charles L. and Mary (Mrs. J. W. Gould). Our subject was reared in
Bradford county from six years of age, where, with the exception of
two years, he has since resided ; in early life he followed the
carpenter's trade, but his principal occupation has been farming; he
has been a resident of Troy township upward of twenty years, and
owns 170 acres of land. He married, in 1854, Mary E., daughter of
Loomis and Emaline (Howland) Newberry, of Springfield township,
this county. Mr. Crandall is a well-known and respected citizen of
Troy township ; in politics he is a Republican. GILBERT B.
CRANDALL, carpenter, P. O. Sugar Run, was born October 27, 1836,
and is a son of Daniel D. and Melissa (Todd) Crandall, the former a
native of Connecticut, born of New England parentage, the latter a
native of Pennsylvania, of Irish lineage." He
 HISTORY OF BRADFORD COUNTY. 753 began life for
himself at the age of twenty-four, farming and lumbering in Wilmot
township, continuing in same until August 11, 1862, when he
enlisted at Towanda in Company H, Fifty-Seventh Eegiment P. V. I.
While in the service he was in the following engagements:
Fredericksburg, Chancellorsville, Gettysburg, Wilderness,
Spottsylvania, Cold Harbor, Petersburg, the Weldon Eaid, Deep
Bottom, and several minor engagements; he received a slight wound
in the foot at Fredericksburg, and was discharged June 10, 1865,
when he returned and began farming in Wilmot township, which he
continued five years, and then learned the carpenter's trade, at
which he has since been engaged in various parts of this State. Mr.
Crandall was married September 7, 1865, to Susan M., daughter of
George Quick, of Wilmot. Mrs. Crandall died April 6, 1874, leaving
one child, Stella; another daughter, Josephine, had died in 1872. Mr.
Crandall was re-married, January 30, 1877, this time to Isabell B.,
daughter of William and Irene Gamble, of Bradford county, Pa., and
they have one child, Cyrene M., born June 14, 1881. Mr. Crandall is a
member of the G. A. E. at Wyalusing, and in politics is a Eepublican.
ASHBEL L. CB ANMEE, retired, Monroeton, was born in Monroe
township, this county, January 6, 1809, and is a son of Samuel and
Sarah (Hubbell) Cranmer. His father, who was a native of New
Jersey, a son of Noadiah and Catherine Cranmer, settled in Monroe
township about 1790, cleared and improved a farm which is now
owned by subject, and died there in 1845 in his seventy-ninth year.
He was twice married, first time to Hannah Miller, by whom he" had
six children who grew to maturity: Josiah, Elizabeth (Mrs. John E.
Brown), Jedediah, John, Noadiah and Samuel; his second wife was
Sarah Hubbell, by whom he had two children who grew to maturity:
Ashbel L. and Enoch H. The subject of these lines was reared on the
old homestead, where he resided until 1863, since which time he
has occupied his present residence in Monroeton. For twenty years,
from 1853 to 1873, Mr. Cranmer was engaged in mercantile business
in Monroeton. He was also for some years extensively engaged in
lumbering and contracting; erected the covered bridge known as the
Eockwell bridge at Monroeton, in 1851, and the canal acqueduct
above Towanda, in 1852. On November 18, 1834, he married Mary
H., daughter of Joseph and Mary (Mason) Griggs, of Monroe
township, and has had five children: Albert, Bernard, Elma (Mrs.
Elias Park), Way land S. and Julia (Mrs. Hiram Sweet). Mr. Cranmer
has always been a Democrat, and served as commissioner of
Bradford county, one term; was a member of the boa.rd that erected
the present court-house at Towanda; from 18-10 until 1850 was a
justice of the peace. CHESTEE W. CEANMEE, farmer, Smithfield
township, P. O. East Smithfield, was born, October 22, 1835, in the
house where he now lives, a son of Calvin and Almira (Hartman)
Cranmer. The father came to Smithfield township when a young
man, with his parents from Monroe, this count}7. His mother came
when a child seven years of age, with her uncle, Samuel Morse, who
was of the third family in the township. Mr. Cranmer's grandfather
was a Eevolutionary soldier, and a brave and valiant hero. He was
united in mar 
 754 HISTORY OF BRADFORD COUNTY. riage, August 29,
1855, with Flotilda, daughter of Judson and Nancy (Foster) Gerould.
Her grandfather, Geronld, was the fourth settler in the township,
who came here in the spring of 1802 ; she was born October 26,
1835, the eldest of eleven. The Geroulds trace their genealogy back
to Jacques (or James) Gerould, who was a French Huguenot, of the
Province of Languedoc, and who, at the revocation of the " Edict of
Nantes," which occurred in 1685, came to this country and settled at
Medfield, Mass. He was a physician, and died October 25, 1760.
There have been born to Mr. and Mrs. Cranmer six children, five of
whom are living, as follows : Orvil C, born September 3, 1856.
married to Eosna Soper; N. Adella, born September 16, 1858,
married to Henry Gates, of Milan; Clarissa E., born June 29, 1868,
married to Daniel Truesdale, of Springfield ; Hattie C, born October
29, 1869, and Francis B., born July 2, 1875. Mr. Cranmer has a fine
farm of about ninety acres, which he manages successfully; he is a
natural artist, and has some very fine specimens of his work in wood
and pencil. He was for a number of years a designer and carver for a
large furniture manufacturing firm at Chicago and Minneapolis. He is
a Democrat, and has held several offices of public trust. HUGH
CEAWFOED, proprietor of a saw and feed mill, Canton, is a native of
Ohio township, Allegheny Co., Pa., born November 28, 1840, a son
of William and Harriet '(Steward) Crawford, natives of Carlisle and
Allegheny county, Pa., respectively. The father, who was a farmer,
died in Ohio township in 1876 in his eighty-fourth year ; the mother
died in 1874 in her seventy-third year. Hugh Crawford is one of a
family of twelve children — ten sons and two daughters— of whom
ten are living. He was reared in Allegheny county, receiving his
education in the common schools, and afterward worked two years
making brick for Moore Bros., at Dixmont, Pa., for the asylum that
was being built there. On April 28, 1861, he enlisted in Company H,
Eighth Pennsylvania Eeserve, and re-enlisted September 21, 1861,"
in Company B. Fourth Pennsylvania Cavalry. He participated in the
following: The Peninsular campaign, the battles of Antietam,
Cbancellorsville, Gettysburg, "Wilderness, Spottsylvania Court House,
Petersburg and in a number of minor engagements ; he was run
over by a wagon July 11, 1864, and was mustered out in front of
Petersburg, October 28, 1864. He returned home and worked in a
sawmill one year, and then, in 1866, went to Tioga county, Pa.,
whence, after remaining one year, he returned to Allegheny City, and
was there one year when he removed with his family to Tioga
county, Pa.; he went to Nevada where for a time he worked in
timber, and then with his brother ran freight teams from Battle
Mountain to Austin, 104 miles, and from there to Carson City, 116
miles. They continued in the freight business about eighteen
months; then returned to Tioga county, and purchased a one-half
interest in a water-power sawmill, which they changed to a steam-
power mill. At the end of six years he sold and went to Fall Brook,
where he operated the Fall Brook Coal Company's mill two years;
then moved to Canton, this county, October 7, 1886, and built the
mill he now owns. He is extensively engaged in timber land, and
carries on a grocery business as well.
 HISTORY OJ? BRADFORD COUNTY. 755 In 1S65 Mr.
Crawford was married, in Troy, to Lucy, daughter of William and
Elizabeth (Kiff) Mcintosh, natives of Delaware county, N. Y.; she is
the fifteenth in order of birth of a family of sixteen children, and was
born in Tioga county, Pa., in August, 1848. To Mr. and Mrs. Crawford
were born seven children, viz.: William J., married to Meda Andrus ;
Byron H., married to Ada Watts ; Harriet J.; James ; Minnie
(deceased); Lena B. and Charles. Mrs. Crawford is a member of the
Methodist Episcopal Church. He is a member of the G-. A. B.,
Ingham Post, No. 91, and Union Veteran Legion, No. 48. Politically
he is a Eepublican, and he served nine years as school director in
Tioga couDty, Pa., during eight of which he was president of the
board. HARRISON CBUM, P. O. Athens, was born in Spencer, Tioga
Co., N. Y., January 3, 1820, a son of William and Lucinda (Hubbard)
Crum, former of whom was a farmer living near Lake Champlain,
and was an eye witness to the last naval battle between Great
Britain and the United States, and with others was fired at by the
British. In their family there were ten children (five of whom are
living), of whom Harrison is the sixth in order of birth ; Peter lives at
Spencer, N Y.; James in Windham; Delila was married to James
Underwood, deceased ; Amanda was married to David Watkins ;
William died at the age of seventy-five in Illinois ; Lois died about
the year 1835 ; Charlotte died about 1880; Emily died in 1884;
McDonough died in 1887 at Candor, N. Y. Harrison Crum was reared
in his native place, receiving his schooling in an old log school-
house, which he attended in the winters until he was fifteen ; at
sixteen he commenced business for himself on a farm, working
thereon four years, and for twenty \Tears thereafter he was
employed in carpentering and lumbering. In 1863 he purchased the
farm he now occupies, which contains sixty-four acres, and the
comfortable surroundings amply attest to the perseverance and
industry of Mr. Crum, who, in his declining years, is now enjoying the
fruits of his labor. He was married, in 1846, to Elizabeth Snyder,
daughter of David and Hannah (Haner) Snyder, of Columbia county,
N. Y., and they have four children ; Avista, married to John
Rifenburg, of Athens ; Lueyette, married to Frank Rogers, also of
Athens; Cassandra, married to Horace Rogers, of Nebraska, and G.
W., married to Hattie Allen, and, in his father's declining years, is
assisting in conducting the farm. The family worship at the Baptist
Church, and in politics Mr. Crum is a Republican. GEORGE CUFFMAN,
farmer, of South Creek township, P. 0. Fassett, was born in Dryden,
Tompkins Co., N. Y., December 16, 1819, a son of Asa Cuffman, a
native of Germany. Asa Cuffman came to this country about 1813,
locating in Dryden, Tompkins Co., N. Y.; where he owned and
cultivated a small farm, living there the remainder of his life ; he
died in 1875, at the age of sixty-two years ; his family consisted of
six children, all of whom grew to maturity, four are now living.
George Cuffman the youngest of the family was reared and
educated in Dryden, Tompkins Co., N. Y., he has followed farming as
an occupation; starting at the age of nineteen for himself. When
twenty-one years old he married, January 9, 1841, Susan, daughter
of John Benjamin; they have had two children born to them, one of
 756 HISTORY OF BRADFORD COUNTY. whom is now living,
Thomas T., married to Mary Ameigh, and has five children. In 1862
George Cuffman entered the army as a private in Company G, One
Hundred and Seventy-first P. V. I.; served nine months, was
honorably discharged, and now receives a pension of §12.00 per
month; he resides on a welL-cultivated little farm of twenty acres,
having completed a new and beautiful residence ; when he first
came to this county, in 1869, he settled near Troy, removing later to
his present residence. Mr. Cuffman is a member of the G. A. R.,
Pettingill Post; politically he is a Republican. RTJLANDUS CULP,
farmer, P. O. Bentley Creek, was born November 27, 1824, in Elmira,
N. Y., a son of Samuel and Polly (Miller) Culp, former of whom was
born of German ancestry, in Tioga county, 1ST. Y, and latter on Long
Island, N. Y. Samuel Culp was a farmer and lumberman. He reared a
family of six children (of whom the subject of this sketch is the
second), and died in 1884, at the age of eighty-three years, the
mother having passed away in 1878 when aged eighty-one. Mr.
Gulp's great-grandfather, Col. John Hendy, was a colonel in the
Revolutionary War in Gen. Sullivan's army, and was through
Pennsylvania and New York States; he was one of the first settlers of
Chemung county, N. Y., having located in 1781, at the place where
Elmira now stands. Rulandus Culp was on the Erie and Chemung
Canal from the time he was fourteen years of age until about the
year 1857, when he settled in Springfield township on the farm
where he now resides. He owns 220 acres of as fine prime land as
there is in the township, and is one of the most successful and
prosperous farmers, dairying being his principal business. On
December 25, 1848, Mr. Culp was united in marriage with Maru J.,
daughter of Joseph and Nancy (Gibson) Mayhood, of Springfield.
She was born June 2, 1824, in County Down, Ireland, and her
parents came to America, about 1840, settling on the farm where
Mr. and Mrs. Culp now reside; the father died aged eighty-six, and
the mother at the age of seventy-three. Mrs. Culp had one brother,
John Mayhood, in the Civil War, serving during the entire struggle. To
Mr. and Mrs. Culp have been born six children viz. : Georgia, born
July 25, 1850 ; Emma, born September 25, 1854 ; Joseph R., born
July 25, 1857, married to Carrie Aber ; J. Thompson, born August 2,
1860, married to Jennie Gonzales ; Jennie, born November 21, 1804
; Grant, born March 4, 1869 Mr. Culp is a strong Prohibitionist. Mrs.
Culp is a consistent member of the Baptist Church, as are also her
children: Georgia, Jennie and Joseph R. LAFAYETTE J. CULVER,
farmer and stock-grower, of Sheshequin township. P. O. Sheshequin,
is a native of the same, having been born May 23, 1831, a son of
Daniel B. and Josephine (Horton) Culver. Timothy Culver, paternal
grandfather of our subject, among the first settlers of Bradford
county, participated in the Revolutionary War. The maternal
grandmother, who was a sister of Dr. Jayne, of Philadelphia, was
born on the Delaware river. Daniel B. Culver, father of Lafayette J.,
was born in Sheshequin township in April, 1806, and died in the
same township August 5, 1856, and his wife passed away in the
following September, aged forty-nine years, both dying of typhoid
 HISTORY OF BRADFORD COUNTY. 757 fever. Their family
numbered seven children, of whom the following is a brief record :
William died in infancy ; Lafayette J. is the subject proper of this
memoir; Hiram enlisted in the service of his country in the Civil War,
and gave his life for his country at the battle of the Wilderness;
James resides in Buffalo ; Oran is in this count}7; Emily (the only
daughter) is married to L. H.Kilmer, of Sheshequin; Mahlon died
when young. Lafayette J. Culver was educated in the public schools,
and commenced work when very young, having to assist his father,
with whom he carried on farming, until the latter's decease. He then
purchased the old homestead, which he cultivated seventeen years,
when he sold the farm, moved to North Towanda and was connected
with the flouring mill there, one year, although a resident two years;
and thence went to Wysox, remaining six years. In 1881 he was
commissioned by the Government Department of Agriculture, LeDuc,
to raise the cane for the experiments in sugar-making at
Washington, D. C, and remained there one year. Mr. Culver then
purchased and moved to the farm he now occupies — the old Gore
homestead — one of the first to be reclaimed from the wilderness in
the county. The house on it was built by Judge Gore nearly seventy-
five years ago, and is nailed together with nails forged by
blacksmiths. The farm had fallen sadly into deca}T when Mr. Culver
took possession ; but he repaired it, built new barns, put up fresh
fences, and it is now one of the finest properties in the county,
located in the lower portion of the valley and abutting mountains,
replete with old historical associations, all combining to make it a
most pleasant and desirable home. The farm consists of 400 acres,
seventy-five of which are bottom land, only a small portion of it
being unfit for cultivation. Here he grows about five tons of tobacco
annually, and raises Oxford-Down sheep and Percheron horses. Mr.
Culver was united in marriage January 21, 1857, with Mary
Patterson, a daughter of Abraham and Caroline (Ashman) Patterson.
Her ancestry on her father's side was Scotch-Irish, on her mother's,
German, and her paternal ancestor settled at Paterson, N. J., the
place taking its name from him. Her maternal grandfather ran away
from college in Hamburg, Germany, at the age of eighteen, enlisted
with the Hessians on purpose to get to- America, to help fight for
our independence, and as soon as he arrived here he deserted and
joined Washington's army, with which he fought until the close of
the war. Mrs. Culver's father's family consisted of six children, born
in Orange county, N. Y., viz.: William, of South Waverly; Nancy Ellen,
who married Lorenzo Dow Post, and died in Sheshequin; Henry C.
(deceased); J. S., of the Exchange Hotel, Athens; Eliza, wife of E. J.
Newell, of Sheshequin, and Mary (Mrs. Culver). To Mr. and Mrs.
Culver, have been born, two children, viz.: Josephine, married to P.
C. Gore, of Sheshequin, and Carrie Ellen, who was married to Victor
E. Piollet, but was left a widow within a few months. Mr. Culver was
the first man to be drafted into military service in Sheshequin, but
was rejected on account of physical disability. Politically he is a
Republican, and was elected to the Legislature, in 1888, by a vote of
4,000 majority; he has held all the 43
 ?58 HISTORY OF BRADFORD COUNTY. township offices. He
is a member of the I. O. O. E. and of the State Encampment, and
has passed all the chairs. JOHN M. CURRIER, farmer and stockman,
"Warren Centre, was born in Warren township, his natal day being
June 29, 1839 ; he is a son of John M. and Anna (Underwood)
Currier, natives of Vermont and Massachusetts, respectively," and of
the rugged Scotch extraction. His father, who was a farmer, came to
this county in 1815, being one of the earliest settlers in "Warren
township, and cleared his land and here made his permanent home;
he died in 1861 ; his widow died in 1873 ; they had twelve children
of whom John M.is the seventh in the order of birth. Our subject
commenced life on his own account as a farmer, and has labored
patiently in his chosen vineyard until the present time, being now
the owner of 105 broad acres, all in a high state of cultivation, with
ample and elegant farm buildings, and well stocked. Mr. Currier was
married in Chenango county, New York, November 1, 1858, to
Catherine Sleeper, daughter of Josephus and Maria (Bowen) Sleeper,
natives of Vermont and Rhode Island, respectively; they had eight
children, of whom Catherine was the eldest; she was reared in her
native place and attended school at Greene village, N. Y. To Mr. and
Mrs. Currier have been born children as follows: Anna (Mrs. George
A. Bowen), of Herriok township, who has four children ; Geo. E ;
Olive S. and Maria R. (twins) (Olive S. married Fred E. Pitcher and
has one child ; Maria R. married James N. Clapp, of Tioga county, N.
Y., and has one child) ; and Grace L. with her parents. The family
worship at the Regular Baptist Church, in which Mr. Currier holds the
offices of trustee and collector ; in politics he is a Republican and
has held the offices of assessor and commissioner. "When he
purchased the elegant farm he now owns there were but t\vent}'-
three acres cleared and a little log house was all the improvement —
but little, indeed, to indicate its present wealth and elegance. The
family is one of the most highly respected in the county. S. 0.
DAGGETT, proprietor of the "Stimson House," Athens, is a native of
Daggett's Mills, Tioga Co., Pa., and was born September 15, 1846 ;
his parents are Louis and Ellen S. ("Wells) Daggett, residing in Tioga,
the former a native of Tioga county, N. Y., and the latter of Yates
county, same State ; the father has been engaged in the mercantile,
lumbering and hotel business. Subject's great-grandfathers, Daggett
and "Wells, were soldiers in the Revolutionary "War. S. 0. Daggett is
the elder of two living children, and his brother, "W. L. Daggett, is
the proprietor of the "Bush House," Bellefonte, Pa. Our subject
completed his education in Mansfield State Normal School, and when
about seventeen years of age, engaged in the mercantile business in
Tioga, and also in the lumbering trade. In 1870 he engaged in the
hotel business with his father, in Lawrenceville, and was there six
years; in 1878 in a hotel in Tioga, also with the "Brooklyn House" a
short time, and then the "Park Hotel" (a summer resort), over two
years; went to Horseheads and ran the"Rayant House " two years,
and from there to "Wellsboro in control of the "Wilcox House" six
years ; then to Blossburg, at the head of the " Seymore House "
about a year, and thence to Athens, March 2, 1890, and took charge
of the
 HISTORY OF BRADFORD COUNTY. 759 "Stimson House."
He was first married, in 1878, in Havana, N. Y., to Miss Ell, daughter
of Ebeau and Helen (Miller) Boynton, natives of Schuyler county, N.
Y., and this county, respectively. She was the elder of their two
children, and was born in Reading, Schuyler Co., N. Y., December 23,
1860, and died October 2, 1885 ; they had two daughters : Georgia
and Leah. Mr. Daggett married again, at Watkins, N. Y., in March,
1880, his second wife being Miss Jessie, daughter of S. V. and Mary
(Jeroe) Brown. She is a member of the Presbyterian Church. He is a
member of the Masonic fraternity, Ossice Lodge, No. 317, Tioga
Chapter and Teodotin Commandery, and is a Republican. JACOB
DANIELS, locomotive engineer, Sayre, is a native of Rhein, Germany,
born October 27, 1835, and is a son of Jacob and Maria (Hilbert)
Daniels, natives of Germany ; the father, who was a farmer, died in
his native home in 1838, in his thirty-seventh year; the mother died
in 1837, in her thirty-fifth year. Jacob who is the second in the family
of three children was reared in his native place until the age of
eighteen, when he emigrated to New York City and- from there
moved to St. Clair, Schuylkill Co., Pa., where he worked in the coal
mines about three years, and then found employment on the Little
Schuylkill Railroad for a short time, he then went to firing for the
Catawissa Railroad, and was on that line about three years when he
was promoted to engineer, continuing in that employ until 1871,
when he went on the Lehigh Valley Railroad as engineer, and has
been in this employ ever since. He was married in Pottsville in 1855
to Miss Maria, daughter of Fredrick and Hannah Henninger, natives
of Pennsylvania and who was the fifth in a family of thirteen
children; she was born in Catawissa Valley, October 10, 1837, and
died December 1, 1889; she was a consistent member of the
Episcopal Church. To Mr. and Mrs. Daniels were born seven children,
as follows: Jacob F., a locomotive engineer, married to Ella Stevens;
Hattie, wife of Eugene Finch, of Binghamton,' N. Y.; William H., a
locomotive engineer, married to Ella Miller; Charles, a locomotive
engineer; George B., deceased; Jesse, a fireman, and Robert F.,
deceased. Mr. Daniels is a member of the Presbyterian Church: of
the Brotherhood of Locomotive Engineers, Sayre Division, No. 380,
and of the Knights of Honor, A. O. U. M. and Red Men; in politics he
is a Democrat. WILLIAM H. DANIELS, locomotive engineer, Sayre, is
a native of Williamsport, and was born in November. I860, a son of
Jacob and Maria (Henninger) Daniels, the former of whom was a
native of Germany and the latter of Pennsylvania. William is the third
in order of birth, in a family of seven children ; was reared in
Williamsport until eleven years of age, and then came with the
family to Waverly ; received a public-school education, and in 1876
went on the Lehigh Valley Railroad as brakeman, and October 26,
1881, was changed to fireman, and was promoted to engineer,
October 19, 1886, and has held that position since. He married, in
Sayre, August 5, 1886, Miss Ella J., daughter of James and Rebecca
(Albright) Miller, natives of Pennsylvania; her father was a locomotive
engineer, and is now in the employ of the same road, at the round-
house in Elmira ; she is the
 760 HISTORY OF BRADFORD COUNTY. eldest in a family of
three children, and was born in Mauch Chunk, January 28, 1865. To
Mr. and Mrs. Daniels was born a daughter, Mabel ; they are members
of the Episcopal Church. He is a member of the Brotherhood of
Locomotive Engineers, Sayre Division, No. 380, and No. 1817, and is
a Democrat in politics. CHARLES VIRGIL DARE, M. D., Troy, was born
in Bridgeton, Cumberland Co., N J., August 26, 1822, a son of John
and Rachel (Watson) Dare, and is of Scotch descent. He was reared
in his native State, educated in the common schools of his day, and
after serving an apprenticeship at the drug business and for a time
being one of the proprietors of a drug store in Salem, 1ST. J., he, in
1850, began the study of medicine with Dr. A. E. Small, of
Philadelphia, and in the spring of 1854 was graduated from the
Homeopathic Medical College of Pennsylvania. Same year he began
the practice of his profession at Millville, N. J., and in" December,
1854, he removed to Chester, Pa., remaining there until 1859, when
he located in Troy, where he has since resided. He was in active
practice up to September, 1864, when he enlisted in Company H,
One Hundred and Eleventh N. Y. V. I. and in February, 1865, was
promoted to assistant-surgeon of the regiment, in which capacity he
served until his discharge in June, 1865. On his return home he
resumed the practice of his profession in which, he still continues.
On December 2, 1845, he married Harriet Osborne, daughter of
Nathan and Sarah (Rose) Sheppard, of Cedarville, N. J., by whom he
had six children, four of whom grew to maturity : Laura V. (Mrs.
John L. French), Kate S. (Mrs. E. F. Lummis), Charles W. and Mary S.
Dr. Dare is a member of the Presbyterian Church and an ex-honorary
member of the Hahnemann Homeopathic Medical Society, of
Pennsylvania; in politics he is a Republican. His only son, Charles W.
Dare, was born November 9, 1856, at Chester, Pa., and received an
academical education, and for fifteen years has been engaged as a
clerk in the drug business ; was graduated from the Philadelphia
College of Pharmacy in 1882. Politically he is a Republican. JABEZ
G-. DAUGHERTY, proprietor of "Daugherty's Hotel," Wysox, was born
in Belvedere, N. J., February 28, 1835, son of Ignatius and Sarah
(Sidell) Daugherty, natives of New Jersey and of Holland origin. His
father, who was a miller by trade, reared a family of eleven children
of whom J. G. is the third. Our subject acquired a common-school
education, and at twenty-one engaged in the milling business in
Susquehanna county, where he remained one year, and then boated
on the North Branch Canal two years ; then again carried on the
milling business five years in Susquehanna county,- and one year in
Monroeton. In 1865 he purchased the VanBrunt mill at Wysox,
where he did a general milling business eight years ; then sold out
to R. S. Barnes, of Rome, and engaged in the hotel business in
Dushore, where he remained one year. He then located in his
present place of business, where he has since remained. Mr.
Daugherty was married March 6, 1859, to Miss Samantha, daughter
of John and Martha (Sickler) Smith, of Wysox, and they have had
born to them four children : Lillie R, born December 1, 1859,
married to George Sill, a farmer, Orwell; George McClellan, born
August 22, 1863 (was named
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