Lets begin our journey into systems biology by comparing complex
diseasesto a ring squad. While working as a postdoc at the California
Institute of Technology, I had the opportunity to know a talented biolo-
gist and a well-read Russian who convinced me to read Tolstoy’s War and
Peace. One thrilling highlight of that masterpiece nds the protagonist,
Pierre, in front of a ring squad in Moscow. Tolstoy describes the wild
thoughts ringing in Pierre’s mind as he faces the guns, wondering how
he had come to this point. “Who was it that had really sentenced him to
death?” As Pierre looks into the nervous eyes of the young soldiers, he
realizes that they are not to blame, for “not one of them had wished to or,
evidently, could have done it.
So, who was responsible? In all the chaos of the scene and his imminent
death, Pierre has a moment of clarity. He realizes that it was no one. Rather
(and I have added italics for emphasis), “It was a system—a concurrence of
circumstances. A system of some sort was killing him—Pierre—depriving
him of life, of everything, annihilating him.
As I read this passage, I could not help but think about the many patients
with complex and untreatable diseases that feel virtually the same way as
Pierre. What is it that has really sentenced them to death? When they read
the newspapers or watch television, they see headline aer headline about
“the cancer gene” or “the Alzheimer gene,” but if these genes truly exist,
then why have cures to these diseases eluded us?
I take my answer from Pierre: Such diseases do not depend on any one
gene, but on a “concurrence of circumstances”—a system. A Science com-
mentary on complex diseases emphasizes this point:
e most common diseases are the toughest to crack. Heart disease,
cancer, diabetes, psychiatric illness: all of these are “complex” or
xii Preface
multifactorial” diseases, meaning that they cannot be ascribed
to mutations in a single gene or to a single environmental factor.
Rather, they arise from the combined action of many genes, envi-
ronmental factors, and risk-conferring behaviors. One of the great-
est challenges facing biomedical researchers today is to sort out
how these contributing factors interact in a way that translates into
eective strategies for disease diagnosis, prevention, and therapy.
(From Kiberstis, P. and Roberts, L. Science. 2002, 296(5568): 685.
Reprinted with permission from AAAS.)
Put simply, our ability to tackle complex diseases is limited by our abil-
ity tounderstand biological systems. We need ways to explain organismal
behaviors in terms of cellular components and their interactions. Even
a small number of components can interact in nonintuitive ways; thus,
systems-level research requires mathematical and computational strategies.
We are at the cusp of a revolution in understanding the systems-level
mechanisms that underlie human disease. However, before the revolution
can achieve its full potential, we rst must grasp the systems-level behav-
ior of molecules, pathways, and single cells. Vast progress has been made
toward this goal in the past 30 years, but much exciting research remains
to be completed before the power of these systems-level investigations can
be turned to the elucidation and eradication of human disease.
is book seeks to empower you, the student, by aiding you to develop
the tools, techniques, and mindset to directly engage in primary research
yourself. Whether you are interested in microbes, organs, whole organ-
isms, diseases, synthetic biology, or just about any eld that investigates
living systems, the intuition that you will develop through the examples
and problems in this book will critically contribute to your success at ask-
ing and answering important scientic questions.
is book focuses on the use of computational approaches to model,
simulate, and thereby better understand complex molecular and cellular
systems, research that is oen called “systems biology.” is eld has grown
rapidly: ere is now an Institute for Systems Biology in Seattle, a new
Department of Systems Biology in various institutions (notably Harvard
Medical School and Stanford University), a Nature/EMBO (European
Molecular Biology Organization) journal, Molecular Systems Biology, and
an International Conference on Systems Biology that draws over 1,000 peo-
ple each year. e eld has drawn together researchers from nearly every
scientic domain. For example, students from biology, bioengineering,

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