Table Of ContentThese papers were first presented at the NATO Advanced Research
Workshop 'Theoretical Models for Cell to Cell Signalling' held in
Knokke-Zoute, Belgium, during September 1988. The Workshop was
further supported by the Commission of the European Communities.
Cover design : Geluck Suykens and Partners, after a photograph of slime mould aggregation
provided by Dr P. C. Newell.
The lithograph by P. Alechinsky facing p. xvi is reproduced by kind permission of the artist.
Cell to Cell Signalling:
From Experiments to Theoretical
Models
Edited by
A. GOLDBETER
Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
ACADEMIC PRESS
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British Library Cataloguing in Publication Data
Cell to cell signalling.
1. Organisms. Cells. Interactions
574.87'6
ISBN 0-12-287960-0
Typeset by Latimer Trend & Company Ltd, Plymouth.
Printed in Great Britain by University Press, Cambridge.
List of contributors*
*Where a paper is by more than two authors, only the first is listed below.
ADAMS, W.B.: Department of Pharmacology, Biozentrum der
Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
ALLESSIE, M.A.: Department of Physiology, Rijksuniversiteit Limburg,
Biomedicai Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
ANDERSON, R.M.: Department of Pure and Applied Biology, Imperial
College, London SW7 2BB, UK.
BENSON, J.A.: CIBA-GEIGY Ltd., Entomology Basic Research,
R-1093.P.47, CH-4002 Basel, Switzerland.
BERRIDGE, M.J.: Department of Zoology, Cambridge University,
Cambridge CB2 3EJ, UK.
BONNER, J.T.: Department of Biology, Princeton University,
Princeton, NJ 08544, USA.
COOKE, J.: National Institute for Medical Research, MRC, Mill Hill,
London NW7 1AA, UK.
CUTHBERTSON, K.S.R.: Dept. of Human Anatomy and Cell Biology,
University of Liverpool, Liverpool L69 3BX, UK.
DE BOER, R. J.: Bioinformatics Group, University of Utrecht,
Padualaan 8, 3584 Utrecht, The Netherlands.
DEMONGEOT, J.: Service d'Informatique Médicale, Faculté de
Médecine, Université de Grenoble, Domaine de la Merci, F-38700 La
Tronche, France.
DE REFFYE, Ph.: CIRAD, Laboratoire de Biomodélisation, Av. du Val
de Montferrand, BP 5035, F-34032 Montpellier Cedex, France.
DEVREOTES, P.N.: Department of Biological Chemistry, Johns
Hopkins University, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
DUD AI, Y.: Department of Neurosciences, The Weizmann Institute of
Science, 76100 Rehovot, Israel.
ix
x LIST OF CONTRIBUTORS
DUPONT, G.: Service de Chimie Physique, Université Libre de
Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
ERMENTROUT, G.B.: Department of Mathematics, University of
Pittsburgh, Pittsburgh, PA 15260, USA.
FILICORI, ML: Department of Reproductive Medicine, University of
Bologna, Via Masserenti 13, 40138 Bologna, Italy.
GOLDBERGER, A.L.: Harvard Medical School, Beth Israel Hospital,
330 Brookline Ave, Boston, Mass. 02215, USA.
GOLDBETER, A.: Service de Chimie Physique, Faculté des Sciences,
Campus Plaine, CP 231, Université Libre de Bruxelles, B-1050 Brussels,
Belgium.
GOODWIN, B.C.: Department of Biology, The Open University,
Walton Hall, MK7 6AA Milton Keynes, UK.
GRILLNER, S.: The Nobel Institute for Neurophysiology, Karolinska
Institutet, Box 60400, S-104 01 Stockholm, Sweden.
GUEVARA, M.R.: Department of Physiology, McGill University, 3655
Drummond Street, Montreal, Quebec H3G 146, Canada.
GUNDERSEN, R.E.: Department of Biological Chemistry, Johns
Hopkins University, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
HESS, B.: Max-Planck-Institut für Ernährungsphysiologie, 201
Rheinlanddamm, 46 Dortmund, FRG.
HINDMARSH, J.: Department of Applied Mathematics, University
College, Cardiff CF1 1XL, UK.
HUNDING, A.: Kemisk Laboratorium III, H.C. 0rsted Institutet,
Universitetsparken 5, 2100 Kobenhavn 0, Denmark.
KAUFFMAN, S.A.: School of Medicine, Dept. of Biochemistry and
Biophysics. University of Pennsylvania, Philadelphia, Pa. 19104-6059,
USA.
KAUFMAN, M.: Service de Chimie Physique, Université Libre de
Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
KEENER, J.P.: Department of Mathematics, University of Utah, Salt
Lake City, Utah 84112, USA.
KNOBIL, E.: Laboratory for Neuroendocrinology, The University of
Texas Health Science Center at Houston, Houston, Texas 77225, USA.
KOPELL, N.: Boston University, Department of Mathematics,
Boston, Mass. 02215, USA.
LIST OF CONTRIBUTORS xi
LACKER, H.M.: Department of Biomathematical Sciences, Mount Sinai
Medical School, Box 1023, Gustave Levy Place, New York, NY 10029,
USA.
LEFEVER, R.: Service de Chimie Physique, Faculté des Sciences,
Campus Plaine, CP 231, Université Libre de Bruxelles, B-1050 Brussels,
Belgium.
LI, Y.X.: Service de Chimie Physique, Faculté des Sciences, Université
Libre de Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
LLINAS, R.: Dept. of Physiology and Biophysics, New York University
Medical Center, 550 First Avenue, New York, NY 10016, USA.
MAINI, P.K.: Department of Mathematics, University of Utah, Salt
Lake City, Utah 84112, USA.
MAY, R.M.: Department of Zoology, University of Oxford, Oxford
OX1 3PS, UK.
MEINHARDT, H.: Max-Planck-Institut Für Entwicklungsbiologie,
Spemanstrasse 35/IV, D-7400 Tübingen I, FRG.
MOORE, H.-P.H.: Department of Biology, University of California,
Berkeley, Ca. 94720, USA.
MÜLLER, S.C.: Max-Planck-Institut für Ernährungsphysiologie, 201
Rheinlanddamm, 46 Dortmund, FRG.
MURRAY, J.D.: Department of Applied Mathematics FS-20, University
of Washington, Seattle, Wa. 98195, USA.
NANJUNDIAH, V.: Departments of Microbiology and Cell Biology,
Centre for Theoretical Studies, Indian Institute of Science, Bangalore
560012, India.
OSTER, G.F.: Departments of Entomology and Biophysics, Wellman
Hall, University of California, Berkeley, CA 94720, USA.
PARNAS, H.: Department of Neurobiology, The Hebrew University,
Jerusalem, Israel.
PARNAS, L: Department of Neurobiology, The Hebrew University,
Jerusalem, Israel.
PERELSON, A.S.: T-10 Division, Mail Stop 710, Los Alamos Nati.
Labs., Los Alamos, NM 87545, USA.
RIGNEY, D.R.: Harvard Medical School, Beth Israel Hospital, 330
Brookline Ave, Boston, Mass. 02215, USA.
xii LIST OF CONTRIBUTORS
RINZEL, J.: Mathematical Research Branch, NIADDK, National
Institutes of Health, Building 31, Room 4B-54, Bethesda, MD 20892,
USA.
ROSE, R.M.: Department of Physiology, University College, Cardiff
CF1 1XL, UK.
SEGEL, L.A.: Department of Applied Mathematics, The Weizmann
Institute of Science, 76100 Rehovot, Israel.
SHERMAN, A.: Mathematical Research Branch, NIADDK, National
Institutes of Health, Building 31, Bethesda, MD 20892, USA.
THALABARD, J.-C: Unité 292, INSERM, Paris, France, presently at
Laboratory for Neuroendocrinology, The University of Texas Health
Science Center at Houston, Houston, Texas 77225, USA.
TYSON, J.J.: Department of Biology, Virginia Polytechnic Institute and
State University, Blacksburg, Virginia 24061, USA.
URBAIN, J.: Service d'Immunologie, Département de Biologie
Moléculaire, Université Libre de Bruxelles, Rhode St-Genèse, Belgium.
VAN CAPELLE, F.J.L.: Academisch Ziekenhuis, Universiteit
Amsterdam, Department of Cardiology, Meibergdreef 9,
1105 AZ Amsterdam, The Netherlands.
WAGNER, T.O.F.: Medizinische Hochschule Hannover, Abt. Klinische
Endokrinologie, Konstanty-Gutschow-Str. 8, D-3000 Hannover 61, FRG.
WINFREE, A.T.: Department of Ecology and Evolutionary Biology,
University of Arizona, Tucson, AZ 85721, USA.
WOLPERT, L.: Anatomy and Developmental Biology, University
College and Middlesex School of Medicine, Windeyer Building, Cleveland
Street, London W1P 6DB, UK.
WURSTER, B.: Fak. Biologie, Universität Konstanz, Postf. 5560,
D-7750 Konstanz, FRG.
Preface
Cell to cell signals govern the development of multicellular organisms and
most of their functions. Given the complexity of dynamic phenomena
involved in intercellular communication, it is often advantageous to comple
ment their experimental study by a theoretical approach. The aim of this
book is to present an up-to-date account of the contribution and usefulness
of theoretical models in the main fields of cell to cell signalling. The
peculiarity of this volume, reflected in its title, is to link experimental and
theoretical work. This link is emphasized in all 44 contributions written by
leading experts in the fields. Moreover, the models considered are primarily
discussed with respect to their biological rather than mathematical interest.
Although far from being exhaustive, the volume is divided into seven parts
which cover most domains where cell to cell signals play a prominent role.
The scope of the project explains the unusual size of this book.
It is only fitting that the first part be devoted to nerve cells and neural
networks. After all, the fertility of theoretical models in neurobiology has
long been recognized since the work of Hodgkin and Huxley on the nerve
impulse: the series of papers that they published in 1952 dealt with experi
mental aspects as well as with the mathematical modelling of the action
potential. This seminal work still represents a prototypic combination
between the experimental and theoretical approaches in biology.
As a follow-up of these classical studies devoted to excitability of the squid
axon, papers in Part 1 start at the cellular level by addressing more complex
modes of behaviour such as bursting or multiple modes of neuronal
oscillations. Thalamic neurons and the R15 burster cell of Aplysia are dealt
with in detail. Another topic is that of neurotransmitter release. At the
multicellular level, several aspects are considered. The first is how the
coupling between secretory cells modifies their dynamic behaviour. The
second is how neural networks behave as central pattern generators that
control, for example, locomotion in invertebrates; the latter topic is covered
from an experimental and theoretical point of view. Finally, the process of
learning is discussed at the molecular level and in terms of neural networks.
Part 2 is devoted to morphogenesis and development. Here also, a classical
paper published in 1952 by A.M. Turing set the theoretical foundations for
understanding the physicochemical bases of pattern formation. Current
theories of morphogenesis are presented in relation to experimental observa-
xiii
xiv PREFACE
tions. Included is a comparative discussion of reaction-diffusion and mecha-
nochemical models, together with applications of the two types of structure-
generating mechanisms. Particular attention is given to pattern formation in
the amphibian embryo and in Drosophila. The closing paper deals with the
modelling of plant growth.
Immunology is one of the fastest growing fields for the application of
theoretical ideas in biology. In Part 3, some of the most salient examples of
immunological modelling are presented. These pertain to the dynamics of
immune networks based on clonai or idiotypic regulation, and to the immune
control of tumour growth. The last paper investigates the complex immune
dynamics that follows infection with HIV.
Hormonal signalling is one of the primary modes of intercellular commu
nication. Rather than covering all types of hormonal control, Part 4 focuses
on the signals which govern the reproductive function in mammals. Experi
mental, clinical and theoretical papers address two main aspects, namely,
selection of the dominant follicle in the ovarian cycle, and the effectiveness of
pulsatile hormone secretion which allows for encoding of periodic signals in
terms of their frequency. The case of the gonadotropin-releasing hormone
secreted by the hypothalamus represents a prototype for the other hormones
or growth factors which exert their physiological effect only when delivered
in a pulsatory manner.
An increasing number of hormones and neurotransmitters are found to act
on target cells by triggering intracellular calcium oscillations. The experimen
tal evidence and the theoretical bases for this phenomenon are discussed in
Part 5.
Another system in which intercellular communication occurs through
pulsatile signals is the slime mould Dictyostelium discoideum to which Part 6
is devoted. The temporal aspects of signalling are considered in papers
dealing with the molecular basis of cyclic AMP oscillations which control
aggregation of the amoebae after starvation. The mechanism of this wavelike
aggregation is also discussed and related to experimental examples of
spatiotemporal order in chemical systems.
The last part of the volume deals with signal propagation in the heart.
Here also, experimental and theoretical aspects are closely intertwined.
Among the topics discussed are the relationship between chaos and cardiac
dynamics, the response of periodically stimulated cardiac cells, and the role
of anisotropie impulse propagation in ventricular tachycardia and in the
process of re-entry.
Is there a common theme that emerges from the presentation of experi
mental and theoretical aspects of intercellular communication in such
different fields of cell biology? Looking for general, unifying principles can be
misleading and somewhat ludicrous, since the usefulness of models is directly
related to their predictive power; the latter, in turn, requires them to be
highly specific rather than vague. However, despite the diversity of the
phenomena considered, some common themes do appear: excitable and
PREFACE xv
oscillatory behaviour occurs for nerve as well as cardiac cells; pulsatile
signalling is a neuronal property which is also found for an increasing
number of hormones and for Dictyostelium amoebae. Encoding of an
external signal in terms of its frequency is observed in all these instances of
intercellular communication and might also underlie signal transduction
based on intracellular calcium oscillations. On the other hand, wavelike
phenomena are observed in Dictyostelium as in the myocardium. Wave
propagation in excitable media has become a subject of choice for modelling
studies in biology. It is in view of this long-standing fascination exerted by
waves that the original drawing by Royer (which owes its spiral jolt to a
suggestion from Art Winfree) is included at the end of the book.
Being closely related to experimental data, the models discussed in this
volume retain the specificities of their respective fields. Most studies never
theless deal with dynamic events which often lead to instabilities and
nonequilibrium self-organization. Therefore, bifurcations associated with
oscillations or with transitions between multiple steady states are recurrent
themes, from neurobiology to immunology and hormonal regulation, while
spatial pattern formation arises in morphogenesis as in cardiac physiology or
slime mould aggregation.
This volume originates from a NATO Workshop that took place in
September 1988 in Knokke-Zoute (Belgium). The suggestion to organize the
Workshop came from the panel of the special NATO programme 'Cell to
Cell Signals in Plants and Animals'. I would like to express my gratitude to
the members of this panel, particularly Professor Kees Libbenga, for their
invitation to organize this meeting, and to Dr Alain Jubier, in charge of this
programme at the NATO Division for Scientific Affairs, for his constant
help. Thanks are also due to Professor Paolo Fasella and the Commission of
the European Communities for their complementary support. Further help
came from the Belgian National Fund for Scientific Research (FNRS) and
from the Belgian Ministry for Education, as well as from the Science Policy
Programming Unit of the Prime Minister's Office (SPPS).
Finally, I am deeply grateful to the two co-organizers of this Workshop,
John Rinzel, from the Mathematical Research Branch of the NIH (Bethesda,
USA), and Lee A. Segel, from the Weizmann Institute of Science (Rehovot,
Israel) for their most precious support and help in selecting themes and
contributors.
In a lithograph entitled Ophtalmologie', the Belgian painter Pierre
Alechinsky represented a human face probing the world with two pairs of
eyes. This figure could serve as metaphor to illustrate the purport of this
book, which is to demonstrate the added insight that the combined
approaches of experiment and theory provide into the dynamics of living
systems and, in particular, into the various modes of intercellular communi
cation.
Albert Goldbeter
Brussels
