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Science Policy Reports

P. Janmey · D. Fletcher · S. Gerecht

R. Levine · P. Mallick · O. McCarty
L. Munn · C. Reinhart-King Editors

Physical Sciences
and Engineering
Advances in
Life Sciences
and Oncology
A WTEC Global Assessment
Science Policy Reports
The series Science Policy Reports presents the endorsed results of important studies
in basic and applied areas of science and technology. They include, to give just a
few examples: panel reports exploring the practical and economic feasibility of a
new technology; R&D studies of development opportunties for particular materials,
devices or other inventions; reports by responsible bodies on technology
standardization in developing branches of industry.
Sponsored typically by large organizations - government agencies, watchdogs,
funding bodies, standards institutes, international consortia - the studies selected
for Science Policy Reports will disseminate carefully compiled information,
detailed data and in-depth analysis to a wide audience. They will bring out
implications of scientific discoveries and technologies in societal, cultural,
environmental, political and/or commercial contexts and will enable interested
parties to take advantage of new opportunities and exploit on-going development
processes to the full.

More information about this series at http://www.springer.com/series/8882

Paul Janmey • Daniel Fletcher
Sharon Gerecht • Ross Levine
Parag Mallick • Owen McCarty
Lance Munn • Cynthia Reinhart-King
Editors

Physical Sciences and

Engineering Advances in
Life Sciences and Oncology
A WTEC Global Assessment
Editors
Paul Janmey Daniel Fletcher
Institute for Medicine and Engineering Bioengineering
University of Pennsylvania University of California
Philadelphia, PA, USA Berkeley, CA, USA

Sharon Gerecht Ross Levine

JH Physical Sciences-Oncology Center, Human Oncology & Pathogenesis Program
Institute for NanoBioTechnology, Memorial Sloan-Kettering Cancer Center
Department of Chemical and New York, NY, USA
Biomolecular Engineering
John Hopkins University Owen McCarty
Baltimore, MD, USA Department of Biomedical Engineering
Oregon Health & Science University
Parag Mallick Portland, OR, USA
Cancer Institute
School of Medicine Cynthia Reinhart-King
Stanford University Department of Biomedical Engineering
Stanford, CA, USA Cornell Univesity
Ithaca, NY, USA
Lance Munn
Radiation Oncology Edwin L. Steele Lab
for Tumor Biology
Harvard Medical School
Charlestown, MA, USA

Copyright 2014 by WTEC. This document was sponsored by the National Cancer Institute
(NCI) Office of Physical Sciences – Oncology (OPSO) at the National Institutes of Health
(NIH), the National Institute of Biomedical Imaging and Bioengineering (NIBIB) at the NIH,
and the National Science Foundation (NSF) under a cooperative agreement (ENG 0844639)
with the World Technology Evaluation Center, Inc. (WTEC). The U.S. Government retains a
nonexclusive and nontransferable license to exercise all exclusive rights provided by
copyright. Any opinions, findings, and conclusions or recommendations expressed in this
material are those of the authors and do not necessarily reflect the views of the United States
Government, the authors’ parent institutions, or WTEC. A list of available WTEC reports and
information on obtaining them is provided on the inside back cover of this report.

ISSN 2213-1965 ISSN 2213-1973 (electronic)

Science Policy Reports
ISBN 978-3-319-17929-2 ISBN 978-3-319-17930-8 (eBook)
DOI 10.1007/978-3-319-17930-8

Library of Congress Control Number: 2015956024

Springer Cham Heidelberg New York Dordrecht London

© US Government 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.

springer.com)
World Technology
Evaluation Center, Inc. (WTEC)

R.D. Shelton, President

Frank Huband, Senior Vice President and General Counsel
Geoffrey M. Holdridge, Executive Vice President
Patricia Foland, Vice President for International Operations
Hemant Sarin, International Policy Fellow
Sarah Michaud, Report Editor
Grant Lewison, Advance Contractor
Hassan Ali, Advance Contractor
Haydon Rochester, Jr., Copy Editor

vii
Acknowledgments

We at WTEC wish to thank all the panelists for their valuable insights and their
dedicated work in conducting this international assessment of physical sciences and
engineering advances in life sciences and oncology (APHELION) research and
development and to thank all the site visit hosts for so generously sharing their time,
expertise, and facilities with us. For their sponsorship of this important study, our
sincere thanks go to the National Cancer Institute at the National Institutes of Health
(NIH), the National Science Foundation, and the National Institute of Biomedical
Imaging and Bioengineering at the NIH.

WTEC, Lancaster, PA, USA R.D. Shelton

ix
WTEC Mission

WTEC provides assessments of international research and development in selected

technologies under awards from the National Science Foundation (NSF), the Office
of Naval Research, and other agencies. Formerly part of Loyola University
Maryland, WTEC is now a separate nonprofit research institute. Sponsors interested
in international technology assessments and related studies can provide support for
the program through NSF or directly through separate grants or GSA task orders to
WTEC.
WTEC’s mission is to inform US scientists, engineers, and policy makers of
global trends in science and technology. WTEC assessments cover basic research,
advanced development, and applications. Panels of typically six technical experts
conduct WTEC assessments. Panelists are leading authorities in their field, techni-
cally active, and knowledgeable about US and foreign research programs. As part of
the assessment process, panels visit and carry out extensive discussions with foreign
scientists and engineers in their labs.
The WTEC staff helps select topics, recruits expert panelists, arranges study vis-
its to foreign laboratories, organizes workshop presentations, and, finally, edits and
publishes the final reports. Dr. R.D. Shelton is the WTEC point of contact: 717
299–7130, [email protected].

xi
Foreword

This study covers some of the applications of physical sciences and engineering to
oncology and to biology generally. It provides an international perspective of the
subject, through extensive visits to some of the leading labs abroad by a team of
American peer reviewers. The results provide a unique snapshot of the status and
trends in this field and help identify opportunities for further progress.
The main purpose of this foreword is to acknowledge the contributions of those
who helped make the study a success. Most of all, we are deeply indebted to our
foreign hosts who generously shared their research results with us and provided
many constructive discussions. How many? Well, we visited 63 sites in Europe,
Asia, and Israel and met with more than 200 host scientists. This does not count
many others who presented at several workshops organized in Asia. The details are
in Appendices B, C, and D. That is a lot of hospitality and a lot of travel by our
indefatigable panelists.
The panel was ably led by Paul Janmey, who cheerfully managed to get everyone
to provide their findings on time, despite their having a few other things to do. We
much appreciate his hard work and that of the other panelists: Dan Fletcher, Sharon
Gerecht, Ross Levine, Parag Mallick, Owen McCarty, Lance Munn, and Cynthia
Reinhart-King. Our NCI sponsors were also closely engaged in the study, including
attending many of the site visits abroad. Tito Fojo and Denis Wirtz provided sage
advice when it was most needed. We continue to be impressed by the quality and
insight of these scientists and the high regard with which they are held by members
of the worldwide oncology community. It is their expertise that makes this report
credible. Short bios are in Appendix A.
It takes resources to conduct a study like this. The study was planned by Jerry
S.H. Lee, Larry Nagahara, and Nastaran Kuhn at the National Cancer Institute,
which provided most of the funding. Program officers at the National Science
Foundation (Kesh Narayanan, Mike Roco, Semahat Demir, Kaiming Ye, and Clark
Cooper) and at the National Institute for Biomedical Imaging and Biotechnology
(Chris Kelley) also contributed to the study.

xiii
xiv Foreword

Prof. Janmey has prepared an executive summary that reflects consensus conclu-
sions by the whole panel. In his Introduction chapter, he provides the background
and scope of the study. In particular, he details the process used, including sites
visited abroad, and provides an overview of the chapters to follow, which use an
analytical organization of the topics covered geographically in the site reports.
Two earlier versions of this report have been posted at:
• http://www.wtec.org/aphelion/AphelionEuropeanReport09.23.12.pdf
• http://www.wtec.org/aphelion/AphelionFinalReport-web.pdf

WTEC, Lancaster, PA, USA R.D. Shelton

February 11, 2015
Executive Summary

The mission of publically funded investments in health-related scientific work,

including the billions of dollars invested in cancer research, is to determine the ori-
gins of diseases and thereby develop diagnostic methods and countermeasures to
prevent, reverse, or control their devastating consequences. Cancer research in the
United States and throughout the world has been dominated by programs in cell
biology, genetics, biochemistry, and animal models of cancer, which have led to
important scientific advances and improvements in the diagnosis and treatment of
many cancers. However, in contrast to the enormous advances in the prevention,
treatment, and cure of infectious disease, cardiovascular disease, and other major
causes of death throughout the world, the diagnosis of cancer is as devastating a
reality today as it was decades ago. The more we learn about cancer biology, the
more it has become apparent that the relationship between a specific gene mutation
and disease is often staggeringly complex, the interaction of cancer cells with their
local environment is an essential but largely obscure aspect of the disease, and tra-
ditional methods of cancer biology research might not be sufficient to produce the
results required for effective clinical improvements. In particular, concepts and
methods of physical science in cancer biology research have until very recently
been largely focused on engagement of physicists and engineers in design of instru-
mentation for diagnosis and therapy, rather than directly on issues related to how
malignant cells arise, develop, and spread to produce clinical symptoms.
To address these issues, the National Cancer Institute (NCI) held a series of three
Physical Sciences in Oncology Workshops and Think Tanks between February and
October 2008 (http://physics.cancer.gov/workshops/). The aim of these meetings
was to explore the opportunities to advance cancer research by integrating physi-
cists and physical science approaches with the more traditional research effort in
cancer biology. The ideas and discussions at these meetings helped guide an initia-
tive within the NCI to establish an Office of Physical Sciences Oncology (OPSO).
OPSO facilitates the development and implementation of physical science-based
initiatives supporting cancer research for NCI and integrates such efforts in other
divisions of the National Institutes of Health (NIH) and throughout the research
community.

xv
xvi Executive Summary

The focus of this effort is to go beyond involving physicists and engineers in the
development of new instrumentation or methods and to engage the methods and
concepts of physics to foster discoveries and new fields of study related to cancer
research. Broadly speaking, the goal is to study cancer as a physical process. The
National Science Foundation (NSF) has traditionally been involved in funding
research in engineering and the physical sciences. Such efforts can have an impor-
tant impact in biomedical research while maintaining a fundamentally basic research
perspective. Recently, NSF and NCI have collaborated on a funding opportunity
titled Physical and Engineering Sciences in Oncology (PESO) Awards that dovetails
with the efforts of OPSO. The main mission of OPSO is to fund physical sciences-
oncology research in various centers throughout the United States. As a result, 12
leading institutions were selected in 2009 to build a collaborative network of
Physical Science-Oncology Centers (PS-OCs) (http://physics.cancer.gov/centers/).
PS-OCs are now reaching the fruition of their initial assignments. To compare
the missions of this and other initiatives with related research efforts abroad, NCI,
in cosponsorship with NSF, commissioned the World Technology Evaluation Center
Inc. (WTEC) to undertake an international Assessment of Physical Sciences and
Engineering Advances in Life Sciences and Oncology (APHELION).
On 18 January 2012, the sponsors/chair meeting of the WTEC APHELION study
was held at NSF headquarters. The main goals of the sponsors’ meeting were to
provide an overview of the plans for the study, to solicit interest and participation of
other US Government agencies, and to coordinate the study design with WTEC.
On 1 February 2012, the kickoff meeting of the WTEC APHELION study was
held at NIH’s Bethesda, MD, campus where the scientific panel and advisors met
with the sponsors.
The initial phase of APHELION determined the status and trends of applying
physical sciences and engineering principles to oncology research and development
in leading laboratories and organizations in Europe via an on-site peer review pro-
cess. The study group visited laboratories in France, Italy, Israel, Germany, the
Netherlands, Spain, Sweden, and Switzerland, typically meeting with representa-
tives of multiple institutions at each stop. Assessments of the activities in the phys-
ics/biomedicine interface at European sites are provided in Appendix B. This project
was completed in 2012, and details of this stage of the study are available at http://
www.wtec.org/aphelion.
On 12 June 2012, panel members presented a workshop at the Cloisters building
lecture room on the NIH campus to report the findings of the study group’s visit to
European laboratories and to discuss these findings with the sponsors and the pub-
lic. Details and documents presented at this workshop are available at www.tvworld-
wide.com/events/nih/120612/.
The second phase of APHELION was initiated in June 2013 with visits to labo-
ratories in Asia working at the interface of physics and biomedical sciences. These
visits involved sites in Singapore, China, Taiwan, Hong Kong, and Japan. A third
phase of the project included visits from a subset of the committee to laboratories in
England and Scotland in October 2013. Reports on the activities at sites visited in
Asia and the United Kingdom are in Appendices C and D, respectively. Site visit
Executive Summary xvii

reports were also prepared for two sites in Brazil, and they are found in Appendix E.
A final workshop to summarize findings in Asia and the United Kingdom and to
discuss the findings with reference to research efforts in Europe took place at Fishers
Lane Conference Center, Rockville, MD, on 21 November 2013. Details and docu-
ments presented at this workshop are available at www.tvworldwide.com/events/
nih/131121/.
Scientific panel members:
• Daniel A. Fletcher, Ph.D., D.Phil. Professor of Bioengineering and Biophysics at
the University of California, Berkeley
• Sharon Gerecht, Ph.D., Associate Professor of Chemical and Biomolecular
Engineering at Johns Hopkins University
• Paul Janmey, Ph.D. (study chair) Professor of Physiology, Physics, and
Bioengineering at the Institute of Medicine and Engineering at the University of
Pennsylvania
• Ross Levine, M.D., Laurence Joseph Dineen Chair in Leukemia Research,
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer
Center
• Parag Mallick, Ph.D., Assistant Professor of Radiology, Bio-X Program, at the
Canary Center for Cancer Early Detection, Stanford University
• Owen McCarty, Ph.D., Associate Professor of Biomedical Engineering at the
Oregon Health and Science University
• Lance L. Munn, Ph.D., Associate Professor of Radiation Oncology at the
Massachusetts General Hospital/Harvard Medical School
• Cynthia A. Reinhart-King, Ph.D., Associate Professor of Biomedical Engineering
at Cornell University
Expert advisors to the study panel:
• Antonio Tito Fojo, M.D., Ph.D., Head, Experimental Therapeutics Section
Medical Oncology Branch and Affiliates at the National Institutes of Health
• Denis Wirtz, Ph.D., Theophilus H. Smoot Professor, Department of Chemical
and Biomolecular Engineering at Johns Hopkins University
Short biographies of the panel members and advisors are provided in Appendix A.
The goals of the APHELION study are:
1. Compare the US research and development activities related to the interface
between physics and oncology, or more generally between physical science and
biomedicine, with similar work being done in Europe and Asia.
2. Identify the gaps and barriers for research groups and clinicians in the United
States by working with leading European and Asian institutions.
3. Identify major innovations that are emerging abroad.
4. Identify opportunities for cooperation and collaboration with research groups
and industry in Europe and Asia.
5. Guide US research investments at the physics/oncology interface.
xviii Executive Summary

The initial meeting of the working group and sponsors allowed for extensive
discussion of the more important topics. We identified areas of research and tech-
nology development with the greatest potential to advance understanding and treat-
ment of cancer and other diseases. As a result of this exchange, six topic areas were
identified. Each study group member took responsibility for one topic, analyzed
information collected during the site visits, and integrated their findings with the
current state of understanding.
The following topics form the basis for each of the chapters in this book:
1. Information and complexity: New methods for dealing with the enormous data
sets generated by modern imaging methods and integrating methods developed
by the physics community to understand complex, nonlinear systems and emer-
gent properties that cannot be predicted by traditional biological models.
2. Microenvironment: The influence of chemical composition, spatial patterning,
nutrient supply, oxygen stress, and other features of the tissue and extracellular
environment on the growth and homeostasis of normal tissues and tumors.
3. Cell and tissue mechanics: How the forces generated by cells and the viscoelas-
ticity of the cell and extracellular matrix affect cell growth, survival, differentia-
tion, and movement.
4. Transport: How the movement of cancer cells, nutrients, growth factors, drugs,
and fluids affects cell survival and tissue mechanics. How the removal of meta-
bolic waste products and cell debris is controlled and how they are altered in the
tumor environment.
5. Dynamics: How the rates and patterns of cell shape change, migration, and divi-
sion can be measured, understood, and integrated with biochemical and genetic
information.
6. Devices and new diagnostic principles: New technologies based on physical
principles, especially those in which the physical properties of tissues are
exploited for cancer diagnosis or treatment.

Outcomes and Summary of Findings

The purpose of our visits was focused on learning about new scientific advances and
plans for future studies. We also examined each institution’s facilities, traditions,
advantages, and challenges related to performing interdisciplinary or multidisci-
plinary work. There was a clear perception among the investigators at every site that
the interface of physical and biomedical sciences is a growth area with potential for
both scientific discovery and medical applications. In the context of cancer research,
there is also a clearly evident trend to engage physicists in roles beyond those of
traditional “medical physics” focused on radiation physics or diagnostic instrumen-
tation. New research programs throughout the world increasingly engage scientists
to consider cancer as a physical process that, despite its complexity and
Executive Summary xix

heterogeneity, nonetheless has limits imposed by physical laws that can be addressed
by thermodynamics, information theory, mechanics, hydrodynamics, and other
fields in which physicists and engineers can act as partners with biologists.
It is impossible to generate a comprehensive analysis of the relative strengths of
research efforts throughout Europe and Asia from the limited sites that were visited
and the personnel constraints of this project, but several consensus views emerged
from the study group. It is also evident that, especially in multidisciplinary projects,
national boundaries are blurred and nearly all large groups include partners from
other countries and very often collaborators in North America or other important
research centers in India, Australasia, South America, and other sites to which visits
could not be arranged.
At several sites, new research programs were explicitly motivated by the initia-
tives taken by OPSO and, in some cases, have involved researchers in the United
States as advisors. More frequently, the initiatives started by the NCI have guided
funding and scientific policy agencies in other countries to facilitate related efforts
tailored to the expertise and traditions of existing research institutions. In other
cases, for example, at the Institut Curie in France, integrated physics/biology pro-
grams have a long tradition and have become part of the established curriculum and
research programs. At institutions in Heidelberg and Munich, Germany, there was
even a sense that a critical mass of researchers at this interface might already have
been reached. In most institutions we visited, interdisciplinary studies at the phys-
ics/biomedicine interface were highly attractive to graduate students and young fac-
ulty and were often increasingly supported by granting agencies. The funding
mechanisms that support these efforts vary widely, ranging from support of indi-
vidual researchers or groups by focused interdisciplinary grants (common in many
countries) to massive investments in infrastructure, instrumentation, and new hiring
in rapidly developing academic systems in Singapore and China Many of our hosts
told us that interdisciplinarity cannot be optimized without a firm basic grounding
in a specific physical or biological science in the education of students and young
researchers.
Throughout Europe and Asia there is evidence that the vision of NCI and NSF to
engage physics more deeply in cancer research coincided with initiatives based on
similar beliefs that engagement of not only physicists but the concepts and methods
of physics research could benefit cancer research. One example of this type of initia-
tive is the document, “Progress in the Domain of Physics Applications in Life
Science with an Invention for Substantial Reduction of Premature Cancer Deaths:
The Need for a Paradigm Change in Oncology Research” (www.crosettofounda-
tion.org/uploads/371.pdf) which received nearly 1,000 signatures from 29 to 31
January 2010. The document argues for the need to engage new ways of thinking in
cancer research, including using physical science to combat cancer. This study sur-
veyed the World Health Organization data to conclude that “despite annual cancer
costs of $741 billion/year ($750/citizen), the 38 most industrialized nations had
only a 5% reduction in cancer deaths over the past 50 year (heart disease was
reduced by 64%).”
xx Executive Summary

Such considerations have led to many new conferences and funding initiatives.
For example, in 2012, the Cancer ITMOs and Health Technologies ITMOs of the
French National Alliance for Life and Health Sciences, in partnership with the
French National Cancer Institute, initiated a call for research projects in physics,
mathematics, or engineering sciences related to cancer (https://www.eva2.inserm.
fr/EVA/jsp/AppelsOffres/CANCER/index_F.jsp). New laboratories of excellence
have also been funded in France, including CELTISPHYBIO, initiated in 2012 at
the Institut Curie, to establish a center for physics in cell biology. In Sweden, the
Science for Life Laboratory (http://www.scilifelab.se/), which integrates research
across multiple intuitions to enable collaborations between technical universities,
medicals schools, and basic science research, is one of the largest scientific invest-
ments in Swedish history. New funding programs for interdisciplinary projects at
the physical science/biomedicine interface funded by the German Science
Foundation and the Max-Planck-Society are almost too numerous to list. Overall,
despite the many funding constraints for science throughout the world, this area of
research appears to be robust and in some cases even growing. An expanded list of
recent conferences focused on the interface of physics and biomedical research is
provided in Appendix F.
Investments in new research efforts that combine physical and biological science
are especially strong in Asia, in particular in Singapore and parts of China. A signifi-
cant part of the research programs established by Singapore’s Agency for Science,
Technology and Research in 2002 have helped foster collaboration between bio-
logical and physical scientists and have helped provide momentum for more recent
large programs such as the Center for Biomedical Imaging and the Mechanobiology
Institute at the National University of Singapore, where collaboration of physical
and biological scientists is integral to the future of these new facilities. State-of-the-
art imaging by both light and electron microscopies, adapted to problems in cancer
biology and other fields of biomedicine, appears to be especially active in Asia, with
world-class imaging facilities also developed in Japan, Hong Kong, and elsewhere.
An integrated approach involving a wide range of expertise in experimental as well
as theoretical work to study specific problems in biology has long been developed
in Japan with groundbreaking results; some examples are detailed in Appendix C.
Taiwan also has active and highly productive collaborations among scientists at the
biology/physics interface, with research groups in physics making important
advances in improved methods for diagnostics, imaging, and design of new materi-
als for biomedical research. In Asia as well as Europe, the integration of researchers
with clinicians, as well as access of clinical specimens and data for laboratory
research, depends on traditions of training clinical investigators or the existence of
M.D./Ph.D. training programs, which vary widely from one country to another.
In summary, the vision of the NCI to bring fresh ideas and expertise from physi-
cists and engineers to the study of cancer biology is now actively pursued in major
research and clinical centers throughout the world. Some new or growing programs
Executive Summary xxi

have been directly influenced by the initiatives of the PS-OC, whereas in other cen-
ters such work has a long and independent history that provides opportunities for
collaboration and new perspectives. The potential of physics and engineering
approaches to contribute to cancer biology is in many places no longer a novel idea,
but an established practice that is increasingly becoming a mainstream interest of
young researchers. The following chapters in this volume provide some examples of
the scientific directions where this field is now heading.

Paul Janmey
Preface

The National Cancer Institute (NCI) Office of Physical Sciences Oncology (OPSO)
has initiated a large-scale interdisciplinary research effort at the interface of the
physical sciences and oncology through 12 centers located throughout the United
States. The NCI Physical Sciences-Oncology Center (PS-OC) program brings
together experts from physics/engineering and cancer biology/oncology to enable
cross-disciplinary research that merges these fields and defines a new physics of
cancer. Physicists strive to explain nature by precise mathematical equations, which
could bring a new perspective to cancer research.
From a molecular perspective, cancer is not a specific disease. Cancer arises as a
result of a succession of randomly occurring mutations. Tumors are inherently
molecularly diverse. This complexity might give the wrong impression that cancer
is not accessible to physics, which strives to describe nature by precise quantitative
laws. Nevertheless, statistical physics has proven to be able to find the laws behind
the stochastic processes underlying thermodynamics, and nonlinear dynamics has
even uncovered the principles that govern chaotic behavior in nature. Molecular
background and pathogenesis of solid tumors may vary, but the pattern of tumor
progression—uncontrolled proliferation, invasive growth, and metastasis—is the
same. Defining and unifying physical laws that are rooted in soft matter physics are
required to understand these three functions. The concept of functional modules
developed in biological physics will greatly facilitate understanding the laws that
govern tumor progression. In tumor cells, the modules that are responsible for divi-
sion, tumor growth, and metastasis may not have identical molecular architecture,
but the same physics is essential for their functions. All cells in a tissue can be
motile and are viscous on long time scales, behaving very much like liquid droplets.
Consequentially, tissue boundaries are comparable to fluid boundaries. Tissues can
be described as a new form of fluid matter, which is a significant topic in the novel
research area of active soft matter.
The most common chemotherapy agents act by killing cells that divide rapidly.
Newer anticancer drugs act directly against cancer-specific proteins or inhibit tumor
angiogenesis. In all these cases the goal is to reduce the tumor. Yet, the primary
tumor can often be removed by surgery and radiation. It is the residual tumor cells

xxiii
xxiv Preface

and their ability to transgress boundaries that have to be hindered. Inducing changes
in physical and material properties of tumor cells that disrupt the functional mod-
ules required for metastasis will provide a broad treatment option.
The physics of cancer is substantially more than providing new techniques for
oncology. Soft matter physics as a basis for the physics of cancer has been strong in
Europe. Institutions such as the Institute Curie in Paris have traditionally demon-
strated that a solid connection between physics and medicine is feasible. As well,
the German strength in cell biophysics has provided a good foundation. The NCI
PS-OC program, which is unfortunately not yet paralleled in Europe, will jump-
start the physics of cancer throughout the United States and will serve to guide simi-
lar initiatives worldwide.

Soft Matter Physics Division, Josef A. Käs

Institute for Experimental Physics I,
Faculty of Physics and Earth Science, University of Leipzig,
Leipzig, Germany
Contents

1 Introduction .............................................................................................. 1
Paul Janmey
2 Complexity and Information: Cancer
as a Multi-Scale Complex Adaptive System .......................................... 5
Parag Mallick
3 Mimicking the Microenvironment.......................................................... 31
Sharon Gerecht
4 Cancer Cell Mechanics ............................................................................ 49
Cynthia A. Reinhart-King
5 Fluid Mechanics and Transport in Tumors ........................................... 73
Lance L. Munn
6 The Dynamics of Cell Motility ................................................................ 89
Owen McCarty
7 Devices and New Diagnostic Principles.................................................. 111
Daniel A. Fletcher
8 Clinical Perspective .................................................................................. 131
Ross Levine

Appendix A. Aphelion Study Panelists and Advisors.................................... 137

Appendix B. Site Visit Reports – Europe ....................................................... 143

Appendix C. Site Visit Reports – Asia ............................................................ 265

Appendix D. Site Visit Reports – United Kingdom ....................................... 365

xxv
xxvi Contents

Appendix E. Site Visit Reports – Brazil ......................................................... 387

Appendix F. Recent Conferences .................................................................... 397

WTEC Publications ......................................................................................... 401

List of Figures

Fig. 2.1 Two possible topologies of a regulatory network......................... 11

Fig. 2.2 The structure of the lac operon..................................................... 11
Fig. 2.3 Quantitative modeling of control gene expression by
modulated self-assembly of the retinoid X receptor (RXR)......... 12
Fig. 2.4 Two computational approaches for determining
the 3D structure of genomic domains and genomes..................... 13
Fig. 2.5 A partially unwrapped nucleosome with exposed
nucleosomal binding sites (stars). The nucleosome
can lower its energy by closing those binding sites
at the cost of bending the DNA .................................................... 13
Fig. 2.6 A pendulum example can be used to explain
a dynamical system ...................................................................... 14
Fig. 2.7 Nested model structure ................................................................. 15
Fig. 2.8 Schematic description of the example model ............................... 16
Fig. 2.9 The long-term phenotypic response of a cell
can be described as a state space .................................................. 18
Fig. 2.10 Schematic diagram of the adaptive landscape of the
phage lambda genetic switch, where the dynamic state
of the biological system is represented as a black dot .................. 18
Fig. 2.11 Activation of ErbB receptors by epidermal growth
factor (EGF) or heregulin (HRG) determines distinct
cell-fate decisions, although signals propagate
through shared pathways .............................................................. 20
Fig. 2.12 A 2D microwell molded in hydrogel ............................................ 21
Fig. 2.13 An actin/myosin motility assay that shows
that the motion is density dependent ............................................ 22
Fig. 2.14 High-resolution maps of stress components
within an advancing monolayer sheet of cells.............................. 22
Fig. 2.15 Spatial distribution of evolving cell populations .......................... 24

xxvii
xxviii List of Figures

Fig. 2.16 Colon cancer model for understanding

the growth of intestinal epithelial cells out of the crypt ............... 24
Fig. 2.17 Mathematical population dynamics model................................... 25
Fig. 3.1 Micellar block copolymer lithography
and biofunctionalization ............................................................... 33
Fig. 3.2 Formation of a micro-epidermis on a collagen island .................. 35
Fig. 3.3 The microfluidic cell culture chip used in this study.
(a) Structure and (b) fluidic channels of the cell
culture chip with pneumatic microvalves ..................................... 36
Fig. 3.4 Microfluidic gas exchanger (From Martewicz et al. 2011)
(a) Schematic representation of the three-layered microfluidic
system; inlet/outlet flow rates and oxygen partial
pressure are shown for both the gas, G, and liquid, L, phase.
(b) Top view of the fluidic layer channel network (all
dimensional values are in µm). (c) Image of a glass-etched
microfluidic channel network obtained with a wet-etching
technique and observed under an inverted optical microscope.
(d) Schematic view of the three different layers of the
gas exchanger. Red and blue arrows show gas and liquid
phase inlet and outlet inside the platform. (e) Image of
the gas-exchanger with inlet/outlet connections for liquid
and gas phase perfusion. The microfluidic channels
are perfused with 1 mM fluorescein solution ............................... 39
Fig. 3.5 Compliance and nanoparticle decoration
properties of PEG- diacrylate (DA) hydrogels ............................. 41
Fig. 3.6 Schematic of experimental set-up. Systematic testing
of the effect of PA hydrogel substrate stiffness, topography,
and dimension on MSCs behaviors .............................................. 42
Fig. 3.7 Concept of light-controlled enzymatic biomolecule
patterning of hydrogels................................................................. 42
Fig. 3.8 Engineered 3D microenvironment ............................................... 44
Fig. 4.1 Multiscale computational mechanobiology
of epithelial tissue morphogenesis ............................................... 50
Fig. 4.2 The field of cell mechanics can be divided into
three main subsections: cellular mechanical properties,
imposed forces, and cell-generated forces ................................... 51
Fig. 4.3 The metastatic cascade (a, b) Fluorescence micrograph
of invasion of a polyoma middle T (PyMT) mammary tumor.
(c) Fluorescence images of tumor cells within a blood vessel ..... 52
Fig. 4.4 Methods to measure the mechanical properties of cells.
(a) Atomic force microscopy (Bao and Suresh 2003);
(b) micropipette aspiration (Bao and Suresh 2003);
(c) particle-tracking microrheology (Wirtz 2009);
and (d) optical stretching (Guck et al. 2001)................................ 54
Exploring the Variety of Random
Documents with Different Content
lasted even through death, and which is still isolated from everything
by the mysterious marble-lace which enfolds them and which floats
above them like a dream.
Very high overhead, as if through a thick vapour, we see the
dome loom through the shadows, although its entire outlines are not
perceptible; its walls seem made of mist, and its marble blocks
appear to have no solidity. Everything is aërial here, nothing is
substantial or real: this is a world of shadowy visions. Even sounds
are unearthly. A note sung under this vault is echoed above our
heads in an invisible region. First, it is as clear as the voice of Ariel,
then it grows fainter and fainter until it dies away and then is re-
echoed very far above, but glorified, spiritualized, and multiplied
indefinitely as if repeated by a distant company, a choir of unseen
angels who soar with it aloft until all is lost save a faint murmur which
never ceases to vibrate over the tomb of the beloved, as if it were
the very soul of a musician.
I have seen the Taj again; this time at noon. Under the vertical
sun the melancholy phantom has vanished, the sweet sadness of
the mausoleum has gone. The great marble table on which it stands
is blinding. The light, reflected back and forth from the immense
surfaces of white marble, is increased a hundred-fold in intensity,
and some of the sides are like burning plaques. The incrustations
seem to be sparks of magic fire; their hundreds of red flowers gleam
like burning coals. The religious texts and the hieroglyphs, inlaid with
black marble, stand out as if traced by the lightning-finger of a
savage god. All the mystical rows of lotus and lilies unfolding in
relief, which just now had the softness of yellowed ivory, spring forth
like flames.—I retrace my steps, passing out of the entrance, and for
an instant I have a dazzling view of the lines and incandescent
surfaces of the building with its unchanging virgin whiteness.—
Indeed, this severe simplicity and intensity of light give it something
of a Semitic character: we think of the flaming and chastening sword
of the Bible. The minarets lift themselves into the blue like pillars of
fire.
I wander outside in the fresh air under the shadows of the leafy
arches until twilight. This garden is the conception of one of the
faithful who wished to glorify Allah. It is the home of religious delight:
—“No one shall enter the garden of God unless he is pure of heart,”
is the Arabian text graven over the entrance-gate. Here are flower-
beds, which are masses of velvet,—unknown blooms resembling
heaps of purple moss. The trunks of the trees are entwined with blue
convolvulus, and flowers like great red stars gleam through the dark
foliage. Over these flowers a hundred thousand delicate butterflies
hover in a perpetual cloud. Many pretty creatures, little striped
squirrels and numerous birds, green parrots and parrots of more
brilliant plumage, disport themselves here, making a little world,
happy and secure, for guards, dressed in white muslin, menace with
long pea-shooters the crows and vultures and protect them from
everything that would bring mischief or cruelty into this peaceful
place.
On the surface of the still waters lilies and lotus are sleeping,
their stiff leaves pinked out and resting heavily upon the dark mirror.
Through the blackness of the boughs English meadows are
revealed, bathed in brilliant sunlight, and spaces of blue sky, across
which a triangle of white storks is sometimes seen flying, and, at
certain moments, the far-away vision of the phantom tomb seems
like the melancholy spectre of a virgin.—How calm, how superb this
solitude, charged with voluptuousness at once solemn and
enervating! Here dwell the beauty, the tenderness, and the light of
Asia, dreamed of by Shelley.

Dans l’Inde (Paris, 1891).

THE CATHEDRAL OF NOTRE-DAME.
VICTOR HUGO.

MOST certainly, the Cathedral of Notre-Dame is still a sublime and

majestic edifice. But, despite the beauty which it preserves in its old
age, it would be impossible not to be indignant at the injuries and
mutilations which Time and man have jointly inflicted upon the
venerable structure without respect for Charlemagne, who laid its
first stone, and Philip Augustus, who laid its last.
There is always a scar beside a wrinkle on the face of this aged
queen of our cathedrals. Tempus edax homo edacior, which I should
translate thus: Time is blind, man is stupid.
If we had leisure to examine one by one, with the reader, the
various traces of destruction imprinted on the old church, Time’s
work would prove to be less destructive than men’s, especially des
hommes de l’art, because there have been some individuals in the
last two centuries who considered themselves architects.
First, to cite several striking examples, assuredly there are few
more beautiful pages in architecture than that façade, exhibiting the
three deeply-dug porches with their pointed arches; the plinth,
embroidered and indented with twenty-eight royal niches; the
immense central rose-window, flanked by its two lateral windows,
like the priest by his deacon and sub-deacon; the high and frail
gallery of open-worked arches, supporting on its delicate columns a
heavy platform; and, lastly, the two dark and massive towers, with
their slated pent-houses. These harmonious parts of a magnificent
whole, superimposed in five gigantic stages, and presenting, with
their innumerable details of statuary, sculpture, and carving, an
overwhelming yet not perplexing mass, combine in producing a calm
grandeur. It is a vast symphony in stone, so to speak; the colossal
work of man and of a nation, as united and as complex as the Iliad
and the romanceros of which it is the sister; a prodigious production
to which all the forces of an epoch contributed, and from every stone
of which springs forth in a hundred ways the workman’s fancy
directed by the artist’s genius; in one word, a kind of human creation,
as strong and fecund as the divine creation from which it seems to
have stolen the two-fold character: variety and eternity.
And what I say here of the façade, must be said of the entire
Cathedral; and what I say of the Cathedral of Paris, must be said of
all the Mediæval Christian churches. Everything in this art, which
proceeds from itself, is so logical and well-proportioned that to
measure the toe of the foot is to measure the giant.
Let us return to the façade of Notre-Dame, as it exists to-day
when we go reverently to admire the solemn and mighty Cathedral,
which, according to the old chroniclers, was terrifying: quæ mole sua
terrorem incutit spectantibus.
That façade now lacks three important things: first, the flight of
eleven steps, which raised it above the level of the ground; then, the
lower row of statues which occupied the niches of the three porches;
1
and the upper row of the twenty-eight ancient kings of France which
ornamented the gallery of the first story, beginning with Childebert
and ending with Philip Augustus, holding in his hand “la pomme
impériale.”
Time in its slow and unchecked progress, raising the level of the
city’s soil, buried the steps; but whilst the pavement of Paris like a
rising tide has engulfed one by one the eleven steps which formerly
added to the majestic height of the edifice, Time has given to the
church more, perhaps, than it has stolen, for it is Time that has
spread that sombre hue of centuries on the façade which makes the
old age of buildings their period of beauty.
But who has thrown down those two rows of statues? Who has
left the niches empty? Who has cut that new and bastard arch in the
beautiful middle of the central porch? Who has dared to frame that
tasteless and heavy wooden door carved à la Louis XV. near
Biscornette’s arabesques? The men, the architects, the artists of our
day.

THE CATHEDRAL OF NOTRE-DAME.

 And when we enter the edifice, who has overthrown that colossal
Saint Christopher, proverbial among statues as the grand’ salle du
Palais among halls, or the flèche of Strasburg among steeples? And
those myriads of statues that peopled all the spaces between the
columns of the nave and choir, kneeling, standing, on horseback,
men, women, children, kings, bishops, warriors, in stone, wood,
marble, gold, silver, copper, and even wax,—who has brutally swept
them away? It was not Time!
And who has substituted for the old Gothic altar, splendidly
overladen with shrines and reliquaries, that heavy marble
sarcophagus with its angels’ heads and clouds, which seems to be a
sample from the Val-de-Grâce or the Invalides? Who has so stupidly
imbedded that heavy stone anachronism in Hercanduc’s
Carlovingian pavement? Is it not Louis XIV. fulfilling the vow of Louis
XIII.?
And who has put cold white glass in the place of those richly-
coloured panes, which made the astonished gaze of our ancestors
pause between the rose of the great porch and the pointed arches of
the apsis? What would an under-chorister of the Sixteenth Century
say if he could see the beautiful yellow plaster with which our vandal
archbishops have daubed their Cathedral? He would remember that
this was the colour with which the executioner brushed the houses of
traitors; he would remember the Hôtel du Petit-Bourbon, all
besmeared thus with yellow, on account of the treason of the
Constable, “yellow of such good quality,” says Sauval, “and so well
laid on that more than a century has scarcely caused its colour to
fade;” and, imagining that the holy place had become infamous, he
would flee from it.
And if we ascend the Cathedral without stopping to notice the
thousand barbarities of all kinds, what has been done with that
charming little bell-tower, which stood over the point of intersection of
the transept, and which, neither less frail nor less bold than its
neighbour, the steeple of the Sainte-Chapelle (also destroyed), shot
up into the sky, sharp, harmonious, and open-worked, higher than
the other towers? It was amputated by an architect of good taste
(1787), who thought it sufficient to cover the wound with that large
plaster of lead, which looks like the lid of a pot.
This is the way the wonderful art of the Middle Ages has been
treated in all countries, particularly in France. In this ruin we may
distinguish three separate agencies, which have affected it in
different degrees; first, Time which has insensibly chipped it, here
and there, and discoloured its entire surface; next, revolutions, both
political and religious, which, being blind and furious by nature,
rushed wildly upon it, stripped it of its rich garb of sculptures and
carvings, shattered its tracery, broke its garlands of arabesques and
its figurines, and threw down its statues, sometimes on account of
their mitres, sometimes on account of their crowns; and, finally, the
fashions, which, ever since the anarchistic and splendid innovations
of the Renaissance, have been constantly growing more grotesque
and foolish, and have succeeded in bringing about the decadence of
architecture. The fashions have indeed done more harm than the
revolutions. They have cut it to the quick; they have attacked the
framework of art; they have cut, hacked, and mutilated the form of
the building as well as its symbol; its logic as well as its beauty. And
then they have restored, a presumption of which time and
revolutions were, at least, guiltless. In the name of good taste they
have insolently covered the wounds of Gothic architecture with their
paltry gew-gaws of a day, their marble ribbons, their metal pompons,
a veritable leprosy of oval ornaments, volutes, spirals, draperies,
garlands, fringes, flames of stone, clouds of bronze, over-fat Cupids,
and bloated cherubim, which begin to eat into the face of art in
Catherine de’ Medici’s oratory, and kill it, writhing and grinning in the
boudoir of the Dubarry, two centuries later.
Therefore, in summing up the points to which I have called
attention, three kinds of ravages disfigure Gothic architecture to-day:
wrinkles and warts on the epidermis,—these are the work of Time;
wounds, bruises and fractures,—these are the work of revolutions
from Luther to Mirabeau; mutilations, amputations, dislocations of
members, restorations,—these are the Greek and Roman work of
professors, according to Vitruvius and Vignole. That magnificent art
which the Vandals produced, academies have murdered. To the
ravages of centuries and revolutions, which devastated at least with
impartiality and grandeur, were added those of a host of school
architects, patented and sworn, who debased everything with the
choice and discernment of bad taste; and who substituted the
chicorées of Louis XV. for the Gothic lace-work, for the greater glory
of the Parthenon. It is the ass’s kick to the dying lion. It is the old oak
crowning itself with leaves for the reward of being bitten, gnawed,
and devoured by caterpillars.
How far this is from the period when Robert Cenalis, comparing
Notre-Dame de Paris with the famous Temple of Diana at Ephesus,
so highly extolled by the ancient heathen, which has immortalized
Erostratus, found the Gaulois cathedral “plus excellente en longueur,
largeur, hauteur, et structure.”
Notre-Dame de Paris is not, however, what may be called a
finished, defined, classified monument. It is not a Roman church,
neither is it a Gothic church. This edifice is not a type. Notre-Dame
has not, like the Abbey of Tournus, the solemn and massive
squareness, the round and large vault, the glacial nudity, and the
majestic simplicity of those buildings which have the circular arch for
their generative principle. It is not, like the Cathedral of Bourges, the
magnificent product of light, multiform, tufted, bristling, efflorescent
Gothic. It is out of the question to class it in that ancient family of
gloomy, mysterious, low churches, which seem crushed by the
circular arch; almost Egyptian in their ceiling; quite hieroglyphic,
sacerdotal, and symbolic, charged in their ornaments with more
lozenges and zigzags than flowers, more flowers than animals, more
animals than human figures; the work of the bishop more than the
architect, the first transformation of the art, fully impressed with
theocratic and military discipline, which takes its root in the Bas-
Empire, and ends with William the Conqueror. It is also out of the
question to place our Cathedral in that other family of churches, tall,
aërial, rich in windows and sculpture, sharp in form, bold of mien;
communales and bourgeois, like political symbols; free, capricious,
unbridled, like works of art; the second transformation of
architecture, no longer hieroglyphic, immutable, and sacerdotal, but
artistic, progressive, and popular, which begins with the return from
the Crusades and ends with Louis XI. Notre-Dame de Paris is not
pure Roman, like the former, nor is it pure Arabian, like the latter.
It is an edifice of the transition. The Saxon architect had set up
the first pillars of the nave when the Crusaders introduced the
pointed arch, which enthroned itself like a conqueror upon those
broad Roman capitals designed to support circular arches. On the
pointed arch, thenceforth mistress of all styles, the rest of the church
was built. Inexperienced and timid at the beginning, it soon broadens
and expands, but does not yet dare to shoot up into steeples and
pinnacles, as it has since done in so many marvellous cathedrals.
You might say that it feels the influence of its neighbours, the heavy
Roman pillars.
Moreover, these edifices of the transition from the Roman to the
Gothic are not less valuable for study than pure types. They express
a nuance of the art which would be lost but for them. This is the
engrafting of the pointed upon the circular arch.
Notre-Dame de Paris is a particularly curious specimen of this
variety. Every face and every stone of the venerable structure is a
page not only of the history of the country, but also of art and
science. Therefore to glance here only at the principal details, while
the little Porte Rouge attains almost to the limits of the Gothic
delicacy of the Fifteenth Century, the pillars of the nave, on account
of their bulk and heaviness, carry you back to the date of the
Carlovingian Abbey of Saint-Germain des Prés, you would believe
that there were six centuries between that doorway and those pillars.
It is not only the hermetics who find in the symbols of the large porch
a satisfactory compendium of their science, of which the church of
Saint-Jacques de la Boucherie was so complete an hieroglyphic.
Thus the Roman Abbey, the philosophical church, the Gothic art, the
Saxon art, the heavy, round pillar, which reminds you of Gregory VII.,
the hermetic symbols by which Nicholas Flamel heralded Luther,
papal unity and schism, Saint-Germain des Prés and Saint-Jacques
de la Boucherie; all are melted, combined, amalgamated in Notre-
Dame. This central and generatrix church is a sort of chimæra
among the old churches of Paris; it has the head of one, the limbs of
another, the body of another,—something from each of them.
 I repeat, these hybrid structures are not the least interesting
ones to the artist, the antiquary, and the historian. They show how
far architecture is a primitive art, inasmuch as they demonstrate
(what is also demonstrated by the Cyclopean remains, the pyramids
of Egypt, and the gigantic Hindu pagodas), that the grandest
productions of architecture are social more than individual works; the
offspring, rather, of nations in travail than the inspiration of men of
genius; the deposit left by a people; the accumulation of ages; the
residuum of the successive evaporations of human society; in short,
a species of formation. Every wave of time superimposes its alluvion,
every generation deposits its stratum upon the building, every
individual lays his stone. Thus build the beavers; thus, the bees; and
thus, men. The great symbol of architecture, Babel, is a beehive.
Great buildings, like great mountains, are the work of centuries.
Often the fashions in art change while they are being constructed,
pendent opera interrupta; they are continued quietly according to the
new art. This new art takes the edifice where it finds it, assimilates
with it, develops it according to its own fancy, and completes it, if it is
possible. The result is accomplished without disturbance, without
effort, without reaction, following a natural and quiet law. It is a graft
which occurs unexpectedly, a sap which circulates, a vegetation
which returns. Certes, there is material for very large books and
often a universal history of mankind, in those successive solderings
of various styles at various heights upon the structure. The man, the
artist, and the individual efface themselves in these vast anonymous
masses; human intelligence is concentrated and summed up in
them. Time is the architect; the nation is the mason.

Notre Dame de Paris (Paris, 1831).

 THE KREMLIN.
THÉOPHILE GAUTIER.

THE Kremlin, always regarded as the Acropolis, the Holy Place, the
Palladium, and the very heart of Russia, was formerly surrounded by
a palisade of strong oaken stakes—similar to the defence which the
Athenian citadel had at the time of the first invasion of the Persians.
Dmitri-Donskoi substituted for this palisade crenellated walls, which,
having become old and dilapidated, were rebuilt by Ivan III. Ivan’s
wall remains to-day, but in many places there are restorations and
repairs. Thick layers of plaster endeavour to hide the scars of time
and the black traces of the great fire of 1812 which was only able to
lick this wall with its tongues of flame. The Kremlin somewhat
resembles the Alhambra. Like the Moorish fortress, it stands on the
top of a hill which it encloses with its wall flanked by towers: it
contains royal dwellings, churches, and squares, and among the
ancient buildings a modern Palace whose intrusion we regret as we
do the Palace of Charles V. amid the delicate Saracenic architecture
which it seems to crush with its weight. The tower of Ivan Veliki is not
without resemblance to the tower of the Vela; and from the Kremlin,
as from the Alhambra, a beautiful view is to be enjoyed, a panorama
of enchantment which the fascinated eye will ever retain.
It is strange that when seen from a distance the Kremlin is
perhaps even more Oriental than the Alhambra itself whose massive
reddish towers give no hint of the splendour within. Above the
sloping and crenellated walls of the Kremlin and among the towers
with their ornamented roofs, myriads of cupolas and globular bell-
towers gleaming with metallic light seem to be rising and falling like
bubbles of glittering gold in the strong blaze of light. The white wall
seems to be a silver basket holding a bouquet of golden flowers, and
we fancy that we are gazing upon one of those magical cities which
the imagination of the Arabian story-tellers alone can build—an
architectural crystallization of the Thousand and One Nights! And
when Winter has sprinkled these strange dream-buildings with its
powdered diamonds, we fancy ourselves transported into another
planet, for nothing like this has ever met our gaze.
We entered the Kremlin by the Spasskoi Gate which opens upon
the Krasnaïa. No entrance could be more romantic. It is cut through
an enormous square tower, placed before a kind of porch. The tower
has three diminishing stories and is crowned with a spire resting
upon open arches. The double-headed eagle, holding the globe in its
claws, stands upon the sharp point of the spire, which, like the story
it surmounts, is octagonal, ribbed, and gilded. Each face of the
second story bears an enormous dial, so that the hour may be seen
from every point of the compass. Add for effect some patches of
snow laid on the jutting masonry like bold dashes of pigment, and
you will have a faint idea of the aspect presented by this queenly
tower, as it springs upward in three jets above the denticulated wall
which it breaks....
Issuing from the gate, we find ourselves in the large court of the
Kremlin, in the midst of the most bewildering conglomeration of
palaces, churches, and monasteries of which the imagination can
dream. It conforms to no known style of architecture. It is not Greek,
it is not Byzantine, it is not Gothic, it is not Saracen, it is not Chinese:
it is Russian; it is Muscovite. Never did architecture more free, more
original, more indifferent to rules, in a word, more romantic,
materialize with such fantastic caprice. Sometimes it seems to
resemble the freaks of frostwork. However, its leading characteristics
are the cupolas and the golden-bulbed bell-towers, which seem to
follow no law and are conspicuous at the first glance.
Below the large square where the principal buildings of the
Kremlin are grouped and which forms the plateau of the hill, a
circular road winds about the irregularities of the ground and is
bordered by ramparts flanked with towers of infinite variety: some
are round, some square, some slender as minarets, some massive
as bastions, and some with machicolated turrets, while others have
retreating stories, vaulted roofs, sharply-cut sides, open-worked
galleries, tiny cupolas, spires, scales, tracery, and all conceivable
endings. The battlements, cut deeply through the wall and notched
at the top like an arrow, are alternately plain and pierced with little
barbicans. We will ignore the strategic value of this defence, but from
a poetic standpoint it satisfies the imagination and gives the idea of a
formidable citadel.

THE KREMLIN, MOSCOW.

Between the rampart and the platform bordered by a balustrade

gardens extend, now powdered with snow, and a picturesque little
church lifts its globular bell-towers. Beyond, as far as the eye can
reach, lies the immense and wonderful panorama of Moscow to
which the crest of the saw-toothed wall forms an admirable
foreground and frame for the distant perspective which no art could
improve....
 The Kremlin contains within its walls many churches, or
cathedrals, as the Russians call them. Exactly like the Acropolis, it
gathers around it on its narrow plateau a large number of temples.
We will visit them one by one, but we will first pause at the tower of
Ivan Veliki, an enormous octagon belfry with three retreating stories,
upon the last of which there rises from a zone of ornamentation a
round turret finished with a swelling dome, fire-gilt with ducat-gold,
and surmounted by a Greek cross resting upon the conquered
crescent. Upon each side of each story little arches are cut so that
the brazen body of a bell may be seen.
In this place there are thirty-three bells, among which is said to
be the famous alarm-bell of Novgorod, whose reverberations once
called the people to the tumultuous deliberations in the public
square. One of these bells weighs not less than a hundred and
ninety-three tons, and is such a monster of metal that beside it the
great bell of Notre-Dame of which Quasimodo was so proud, would
be nothing more than the tiny hand-bell used at Mass....
Let us enter one of the most ancient and characteristic
cathedrals of the Kremlin, the first one built of stone, the Cathedral of
the Assumption (Ouspenskosabor). It is not the original edifice
founded by Ivan Kalita. That crumbled away after a century and a
half of existence and was rebuilt by Ivan III. Notwithstanding its
Byzantine style and archaic appearance, the present Cathedral
dates only from the Fifteenth Century. One is astonished to learn that
it is the work of Fioraventi, an architect of Bologna, whom the
Russians called Aristotle because of his astounding knowledge. One
would imagine it the work of some Greek architect from
Constantinople whose head was filled with memories of Santa Sofia
and models of Greco-Oriental architecture. The Assumption is
almost square and its great walls soar with a surprising pride and
strength. Four enormous pillars, large as towers and massive as the
columns of the Palace of Karnak, support the central cupola, which
rests on a flat roof in the Asiatic style, flanked by four similar
cupolas. This simple arrangement produces a magnificent effect and
these massive pillars contribute, without any heaviness, a fine
balance and extraordinary stability to the Cathedral.
 The interior of the church is covered with Byzantine paintings on
a gold background. The pillars themselves are embellished with
figures arranged in zones as in the Egyptian temples and palaces.
Nothing could be more strange than this decoration where
thousands of figures surround you like a mute assemblage,
ascending and descending the entire length of the walls, walking in
files in Christian panathenæa, standing alone in poses of hieratic
rigidity, bending over to the pendentives, and draping the temple with
a human tapestry swarming with motionless beings. A strange light,
carefully disposed, contributes greatly to the disquieting and
mysterious effect. In these ruddy and fawn-coloured shadows the tall
savage saints of the Greek calendar assume a formidable
semblance of life; they look at you with fixed eyes and seem to
threaten you with their hands outstretched for benediction.... The
interior of St. Mark’s at Venice, with its suggestion of a gilded cavern,
gives the idea of the Assumption; only the interior of the Muscovite
church rises with one sweep towards the sky, while the vault of St.
Mark’s is strangely weighed down like a crypt. The iconostase, a
lofty wall of silver-gilt with five rows of figures, is like the façade of a
golden palace, dazzling the eye with fabled magnificence. In the
filigree framework of gold appear in tones of bistre the dark heads
and hands of the Madonnas and saints. The rays of their aureoles
are set with precious stones, which, as the light falls upon them,
scintillate and blaze with celestial glory; the images, objects of
peculiar veneration, are adorned with breastplates of precious
stones, necklaces, and bracelets, starred with diamonds, sapphires,
rubies, emeralds, amethysts, pearls, and turquoises; the madness of
religious extravagance can go no further.
It is in the Cathedral of the Assumption that the coronation of the
Czar takes place. The platform for this occasion is erected between
the four pillars which support the cupola and faces the iconostase.
The tombs of the Metropolitans of Moscow are placed in rows
along the sides of the walls. They are oblong: as they loom up in the
shadows, they make us think of trunks packed for the great voyage
of eternity....
 At the side of the new palace and very near these churches a
strange building is seen, of no known style of architecture, neither
Asiatic nor Tartar, and which for a secular building is much what
Vassili-Blagennoi is for a religious edifice,—the perfectly realized
chimæra of a sumptuous, barbaric, and fantastic imagination. It was
built under Ivan III. by the architect Aleviso. Above its roof several
towers, capped with gold and containing within them chapels and
oratories, spring up with a graceful and picturesque irregularity. An
outside staircase, from the top of which the Czar shows himself to
the people after his coronation, gives access to the building and
produces by its ornamented projection a unique architectural effect.
It is to Moscow what the Giants’ Stairway is to Venice. It is one of the
curiosities of the Kremlin. In Russia it is known as the Red Stairway
(Krasnoi-Kriltosi). The interior of the Palace, the residence of the
ancient Czars, defies description; one would say that its chambers
and passages have been excavated according to no determined
plan in some curious block of stone, for they are so strangely
entangled, so winding and complicated, and so constantly changing
their level and direction that they seem to have been ordered at the
caprice of an extravagant fancy. We walk through them as in a
dream, sometimes stopped by a grille which opens mysteriously,
sometimes forced to follow a narrow dark passage in which our
shoulders almost touch both walls, sometimes having no other path
than the toothed ledge of a cornice from which the copper plates of
the roofs and the globular belfries are visible, constantly ascending,
descending without knowing where we are, seeing beyond us
through the golden trellises the gleam of a lamp flashing back from
the golden filigree-work of the shrines, and emerging after this
intramural journey into a hall with a rich and riotous wildness of
ornamentation, at the end of which we are surprised at not seeing
the Grand Kniaz of Tartary seated cross-legged upon his carpet of
black felt.
Such for example is the hall called the Golden Chamber, which
occupies the entire Granovitaïa Palata (the Facet Palace), so called
doubtless on account of its exterior being cut in diamond facets. The
Granovitaïa Palata adjoins the old palace of the Czars. The golden
vaults of this hall rest upon a central pillar by means of surbased
arches from which thick bars of elliptical gilded iron go across from
one arc to another to prevent their spreading. Several paintings here
and there make sombre spots upon the burnished gold splendour of
the background.
Upon the string-courses of the arches legends are written in old
Sclavonic letters—magnificent characters which lend themselves
with as much effect for ornamentation as the Cufic letters on Arabian
buildings. Richer, more mysterious, and yet more brilliant
decorations than these of the Golden Chamber cannot be imagined.
A romantic person would like to see a Shakespearian play acted
here.
Certain vaulted halls of the old Palace are so low that a man who
is a little above the average height cannot stand upright in them. It is
here, in an atmosphere overcharged with heat, that the women,
lounging on cushions in Oriental style, spend the hours of the long
Russian winter in gazing through the little windows at the snow
sparkling on the golden cupolas and the ravens whirling in great
circles around the bell-towers.
These apartments with their motley wall-decorations of palms,
foliage, and flowers, recalling the patterns of Cashmere, make us
imagine these to be Asiatic harems transported to the polar frosts.
The true Muscovite taste, perverted later by a badly-understood
imitation of Western art, appears here in all its primitive originality
and intensely barbaric flavour.
I have frequently observed that the progress of civilization seems
to deprive nations of the true sense of architecture and decoration.
The ancient edifices of the Kremlin prove once again how true is this
assertion, which appears paradoxical at first. An inexhaustible
fantasy presides over the decoration of these mysterious rooms
where the gold, the green, the blue, and the red mingle with a rare
happiness and produce the most charming effects. This architecture,
without the least regard for symmetry, rises like a honey-comb of
soap-bubbles blown upon a plate. Each little cell takes its place
adjoining its neighbour, arranging its own angles and facets until the
whole glitters with colours diapered with iris. This childish and bizarre
comparison will give you a better idea than anything else of the
aggregation of these palaces, so fantastic, yet so real.
It is in this style that we wish they had built the new Palace, an
immense building in good modern taste and which would have a
beauty elsewhere, but none whatever in the centre of the old
Kremlin. The classic architecture with its long cold lines seems more
wearisome and solemn here among these palaces with their strange
forms, their gaudy colours, and this throng of churches of Oriental
style darting towards the sky a golden forest of cupolas, domes,
pyramidal spires, and bulbous bell-towers.
When looking at this Muscovite architecture you could easily
believe yourself in some chimerical city of Asia, fancying the
cathedrals mosques, and the bell-towers minarets, if it were not for
the sober façade of the new Palace which leads you back to the
unpoetic Occident and its unpoetic civilization: a sad thing for a
romantic barbarian of the present day. We enter the new Palace by a
stairway of monumental size closed at the top by a magnificent grille
of polished iron which is opened to allow the visitor to pass. We find
ourselves under the large vault of a domed hall where sentinels are
perpetually on guard: four effigies clothed from head to foot in
antique and curious Sclavonic armour. These knights have a noble
air; they are surprisingly life-like; we could easily believe that hearts
are beating beneath their coats of mail. Mediæval armour disposed
in this way always gives me an involuntary shiver. It so faithfully
suggests the external form of a man who has vanished forever.
From this rotunda lead two galleries which contain priceless
riches: the treasure of the Caliph Haroun al-Raschid, the wells of
Aboul-Kasem, and the Green Vaults of Dresden united could not
show such an accumulation of marvels, and here historic association
is added to the material value. Here, sparkling, gleaming, and
sportively flashing their prismatic light, are diamonds, sapphires,
rubies, and emeralds—all the precious stones which Nature has
hidden in the depths of her mines—in as much profusion as if they
were mere glass. They glitter like constellations in crowns, they flash
in points of light from the ends of sceptres, they fall like sparkling
raindrops upon the Imperial insignias and form arabesques and
cyphers until they nearly hide the gold in which they are set. The eye
is dazzled and the mind can hardly calculate the sums that represent
such magnificence.

Voyage en Russie (Paris, 1866).

 THE CATHEDRAL OF YORK.
THOMAS FROGNALL DIBDIN.

LET us go immediately to the Cathedral—the deepening tones of

whose tenor bell seem to hurry us on to the spot. Gentle reader, on
no account visit this stupendous edifice—this mountain of stone—for
the first time from the Stonegate (Street) which brings you in front of
the south transept. Shun it—as the shock might be distressing; but,
for want of a better approach, wend your steps round by Little Blake
Street, and, at its termination, swerve gently to the left, and place
yourself full in view of the West Front. Its freshness, its grandeur, its
boldness and the numerous yet existing proofs of its ancient
richness and variety, will peradventure make you breathless for
some three seconds. If it should strike you that there is a want of the
subdued and mellow tone of antiquity, such as we left behind at
Lincoln, you must remember that nearly all this front has undergone
a recent scraping and repairing in the very best possible taste—
under the auspices of the late Dean Markham, who may be said to
have loved this Cathedral with a holy love. What has been done,
under his auspices, is admirable; and a pattern for all future similar
doings.
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