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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2796_Библиотеки_им_академика_М_И_Перельмана
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“Systems Medicine is a masterpiece. Written in a conversational style, it invites us to think
about health and disease in a profoundly simple new way. From the secrets of aging to the
enigma of autoimmune diseases, Uri Alon uses physiological circuits and the principles that
underlie them to illuminate how our bodies work, why specic diseases occur, and what
strategies might be used to treat them. Whether you’re a curious mind, a biology enthusiast, or just someone excited to understand the magnicent orchestra of life, this book has
something extraordinary to oer. To my mind, it’s nothing short of revolutionary.”
—Steven Strogatz, Cornell University, USA, author of Nonlinear Dynamics and Chaos
“Uri Alon has once again opened our eyes to a new frontier of quantitative thinking, this
time applied to medicine. Systems Medicine is a masterpiece of clear interdisciplinary
exposition, suitable for interested students and researchers with minimal mathematical
or physiological background. Its inspiring narrative, accompanied by engaging exercises,
explains how the recent application of dynamical systems methods to diabetes, stress, ageing, and autoimmune disorders resolves long-standing puzzles in medicine. is book is
destined to be as inuential as his earlier Systems Biology, along with potentially important
impacts on human health.”
—Nigel Goldenfeld, University of California San Diego, USA
“is unique book will benet an unusually broad range of students, scientists, and medical professionals. If you have a background in math, physics, or engineering, you will learn
key concepts in physiology and medicine presented in the familiar language of dynamical
systems. If your background is in biomedical sciences, you will learn how to build and
employ powerful mathematical models to unveil hidden patterns behind disease vulnerabilities. Either way, Uri Alon will masterfully guide you to new insights into the underlying logic of physiological systems and their susceptibility to diseases.”
—Ruslan Medzhitov, Yale University, USA
“is book will be as inuential and transformative as Alon’s Systems Biology. Its quantitative approach provides new insight into the mechanisms that underline common diseases.
It should be of interest to students and researchers in medicine, biology, and engineering.
It will introduce quantitative analysis to medical students, interesting medical problems to
engineers, and catalyze a new synthesis of “systems medicine”. Alon is a pioneer and leading expert in systems biology. He is now pioneering a new eld with this book.”
—Liqun Luo, Stanford University, USA
“is book is a paradigm-shiing journey elegantly guiding readers to perceive health and
disease through a new lens. By weaving together multiple disciplines, from mathematics to
biology and medicine, Alon paints a vivid picture of how our understanding of biological
networks and their dynamics can revolutionize medical approaches. Using simple concepts coupled with real-world examples, the book oers a comprehensive exploration of
physiological circuits and exemplies the practical applications of Systems Medicine. With
insightful clarity, Alon distills intricate scientic concepts into digestible insights, making
this book accessible to both seasoned researchers and curious minds new to the eld.”
—Galit Lahav, Harvard University, USA
Systems Medicine
Why do we get certain diseases, whereas other diseases do not exist?
In this book, Alon, one of the founders of systems biology, builds a foundation for systems
medicine.
Starting from basic laws, the book derives why physiological circuits are built the way they
are. e circuits have fragilities that explain specic diseases and oer new strategies to
treat them.
By the end, the reader will be able to use simple and powerful mathematical models to
describe physiological circuits. The book explores, in three parts, hormone circuits,
immune circuits, and aging and age-related disease. It culminates in a periodic table
of diseases.
Alon writes in a style accessible to a broad range of readers - undergraduates, graduates, or researchers from computational or biological backgrounds. e level of math
is friendly and the math can even be bypassed altogether. For instructors and readers
who want to go deeper, the book includes dozens of exercises that have been rigorously
tested in the classroom.
ABOUT THE AUTHOR
Uri Alon is the Abisch-Frenkel Professor of Systems Biology at the Weizmann Institute of
Science, Israel. https://www.weizmann.ac.il/mcb/UriAlon/homepage
Chapman & Hall/CRC
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Computational Biology Series
About the Series
is series aims to capture new developments in computational biology, as well as
high-quality work summarizing or contributing to more established topics. Publishing a
broad range of reference works, textbooks, and handbooks, the series is designed to appeal
to students, researchers, and professionals in all areas of computational biology, i ncluding
genomics, proteomics, and cancer computational biology, as well as interdisciplinary
researchers involved in associated elds, such as bioinformatics and systems biology.
Computational Genomics with R
Altuna Akalin, Bora Uyar, Vedran Franke, and Jonathan Ronen
An Introduction to Computational Systems Biology: Systems-level Modelling of
Cellular Networks
Karthik Raman
Virus Bioinformatics
Dmitrij Frishman and Manuela Marz
Multivariate Data Integration Using R: Methods and Applications with the
mixOmics Package
Kim-Anh LeCao and Zoe Marie Welham
Bioinformatics
A Practical Guide to NCBI Databases and Sequence Alignments
Hamid D. Ismail
Data Integration, Manipulation and Visualization of Phylogenetic Trees
Guangchuang Yu
Bioinformatics Methods
From Omics to Next Generation Sequencing
Shili Lin, Denise Scholtens, and Sujay Datta
Systems Medicine
Physiological Circuits and the Dynamics of Disease
Uri Alon
For more information about this series please visit: https://www.routledge.com/
Chapman—HallCRC-Computational-Biology-Series/book-series/CRCCBS
Systems Medicine
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Physiological Circuits and the
DynamicsofDisease
Uri Alon
Weizmann Institute of Science, Israel
Designed cover image: Nigel Orme
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First edition published 2024
by CRC Press
2385 NW Executive Center Drive, Suite 320, Boca Raton, FL 33431
and by CRC Press
4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN
CRC Press is an imprint of Taylor & Francis Group, LLC
© 2024 Uri Alon
Reasonable eorts have been made to publish reliable data and information, but the author and publisher cannot
assume responsibility for the validity of all materials or the consequences of their use. e authors and p ublishers
have attempted to trace the copyright holders of all material reproduced in this publication and apologize to
copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been
acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or
utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including
photocopying, microlming, and recording, or in any information storage or retrieval system, without written
permission from the publishers.
For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the
Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are
not available on CCC please contact mpkbookspermissions@tandf.co.uk
Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for
identication and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Alon, Uri, 1969- author.
Title: Systems medicine : physiological circuits and the dynamics of
disease / Uri Alon.
Description: Boca Raton : CRC Press, 2024. | Includes bibliographical
references and index. | Contents: e insulin-glucose circuit –
Dynamical compensation, mutant resistance, and type-2 diabetes –
e stress hormone axis as a two-gland oscillator – Autoimmune diseases
as a fragility of mutant surveillance – Inammation and brosis as a
bistable system – Basic facts of aging – Aging and saturated repair –
Age-related diseases – Periodic table of diseases – Epilogue:
Simplicity in systems medicine.
Identiers: LCCN 2023014141 (print) | LCCN 2023014142 (ebook) |
ISBN 9781032412283 (hardback) | ISBN 9781032411859 (paperback) |
ISBN 9781003356929 (ebook)
Subjects: LCSH: Biological systems–Mathematical models. |
Human physiology–Mathematical models. | Systems biology.
Classication: LCC QH324.2 .A467 2024 (print) | LCC QH324.2 (ebook) |
DDC 570.285–dc23/eng/20230630
LC record available at https://lccn.loc.gov/2023014141
LC ebook record available at https://lccn.loc.gov/2023014142
ISBN: 978-1-032-41228-3 (hbk)
ISBN: 978-1-032-41185-9 (pbk)
ISBN: 978-1-003-35692-9 (ebk)
DOI: 10.1201/9781003356929
Typeset in Minion
by codeMantra
Contents
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IntroductIon 1
ABOUT MATH AND BIOLOGICAL TERMS 2
OUR FIRST FEEDBACK LOOP 3
BACKGROUND READING 4
Part I Hormone Circuits
chaPter 1 ◾ The Insulin-Glucose Circuit 7
GLUCOSE CONCENTRATION AND DYNAMICS IS TIGHTLY CONTROLLED 7
GLUCOSE CONCENTRATION IS CONTROLLED BY INSULIN 8
DIABETES IS A MALFUNCTION IN THIS SYSTEM 10
MATHEMATICAL MODEL FOR THE GLUCOSE-INSULIN CIRCUIT 11
A GRAPHICAL TOOL TO UNDERSTAND THE CIRCUIT,
THEPHASEPORTRAIT 14
INSULIN SENSITIVITY VARIES WIDELY BETWEEN PEOPLE 16
THE MINIMAL MODEL FAILS TO EXPLAIN HOW PEOPLE WITH INSULIN
RESISTANCE MAINTAIN NORMAL GLUCOSE LEVELS 17
SUMMARY AND OUTLOOK 18
EXERCISES 19
NOTE 23
REFERENCES 23
vi ◾ Contents
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chaPter 2 ◾ Dynamical Compensation, Mutant Resistance,
andType-2Diabetes
THE MINIMAL MODEL CANNOT EXPLAIN THE ROBUSTNESS OF
GLUCOSE LEVELS TO VARIATIONS IN INSULIN SENSITIVITY
A SLOW FEEDBACK LOOP ON BETA CELL MASS PROVIDES
COMPENSATION
Law 1: All Cells Come from Cells 28
ORGAN SIZE CONTROL IN BETA CELLS IS PROVIDED BY FEEDBACK
FROM GLUCOSE
THE CELL MASS FEEDBACK CIRCUIT MAINTAINS HOMEOSTASIS DESPITE
PARAMETER VARIATIONS
THE SAME CIRCUIT APPEARS IN MANY HORMONE SYSTEMS –
ACIRCUIT MOTIF
THE CIRCUIT ALSO MAKES THE DYNAMICS ROBUST 33
PREDIABETES IS DUE TO AN UPPER LIMIT TO BETA-CELL COMPENSATION 35
Law 2: Biological Processes Saturate
TYPE-2 DIABETES IS LINKED WITH INSTABILITY DUE TO A U-SHAPED
REMOVAL CURVE
THE CIRCUIT IS FRAGILE TO INVASION BY MUTANTS THAT MISREAD
THE SIGNAL
Law 3: Cells Mutate 40
BIPHASIC (U-SHAPED) RESPONSE CURVES CAN PROTECT AGAINST
MUTANT TAKEOVER
SUMMARY 42
EXERCISES 42
NOTE 45
FURTHER READING 46
REFERENCES 46
26
29
31
32
37
39
41
24
25
36
chaPter 2.5 ◾ Three Laws of Physiology 47
chaPter 3 ◾ The Stress Hormone Axis as a Two-Gland Oscillator 48
INTRODUCTION 48
THE HPA AXIS RESPONDS TO PHYSICAL AND PSYCHOLOGICAL STRESS 48
THE CLASSIC MODEL FOR THE HPA AXIS EXPLAINS RESPONSES ON THE
TIMESCALE OF HOURS, BUT NOT ON THE TIMESCALE OF MONTHS 51
THE HPA AXIS SHOWS A FEEDBACK LOOP IN WHICH TWO GLANDS
CONTROL EACH OTHER’S SIZE 53
THE PITUITARY AND ADRENAL GLANDS FORM A NEGATIVE FEEDBACK
LOOP THAT CAN OSCILLATE WITH A SEASONAL TIMESCALE 55
Contents ◾ vii
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DAMPED OSCILLATIONS IN STEROID WITHDRAWAL OVER MONTHS 57
RECOVERY FROM PROLONGED STRESS TAKES WEEKS AND SHOWS AN
ENDORPHIN UNDERSHOOT 58
SEASONALITY IN HORMONES 60
LARGE-SCALE MEDICAL RECORDS SHOW HORMONE SEASONALITY
WITH ANTIPHASE AND SPRING SHIFT 62
BIPOLAR DISORDER HAS A TIMESCALE OF WEEKS-MONTHS, AND THIS
TIMESCALE CAN BE GENERATED BY GLAND SIZE FLUCTUATIONS 64
BIPOLAR DISORDER IS A STRESS-RELATED DISEASE 65
THE HPA CIRCUIT SUGGESTS DRUG TARGETS TO LOWER CORTISOL 69
SUMMARY 70
EXERCISES 71
NOTES 74
REFERENCES 74
chaPter 3.5 ◾ The Thyroid and Its Discontents 76
THE HPT AXIS IS DESIGNED TO KEEP A STEADY LEVEL OF THYROID
HORMONE T4 76
STRUCTURE-FUNCTION RELATION IN THE HPT CIRCUIT 79
HOW IS THYROID HORMONE PRODUCED? 79
HYPERTHYROIDISM AND HYPOTHYROIDISM 80
HASHIMOTO’S DISEASE, A CASE OF SELF-ATTACK 81
TSH SHOWS A DELAY AFTER HASHIMOTO’S DISEASE IS TREATED 82
SUBCLINICAL HASHIMOTO’S IS DUE TO DYNAMICAL COMPENSATION 83
HYPERTHYROIDISM DUE TO TOXIC NODULES: ACASE OF A HYPER-
SENSING MUTANT 84
WHY ARE THERE AUTOIMMUNE DISEASES OF HORMONE GLANDS? 85
EXERCISES 85
FURTHER READING 86
Part II Immune Circuits
chaPter 4 ◾ Autoimmune Diseases as a Fragility of Mutant Surveillance 89
INTRODUCTION 89
TYPE-1 DIABETES IS A DISEASE IN WHICH THE IMMUNE SYSTEM KILLS
BETA CELLS 90
MANY ENDOCRINE ORGANS HAVE ORGAN-SPECIFIC AUTOIMMUNE
DISEASE 91
EXECUTIVE SUMMARY OF T-CELL BIOLOGY 91
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