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This page intentionally left blank
The Shaping of Life

Biological development, how organisms acquire their form, is one of

the great frontiers in science. While a vast knowledge of the molecules
involved in development has been gained in recent decades, big
questions remain on the molecular organization and physics that
shape cells, tissues and organisms. Physical scientists and biologists
traditionally have very different backgrounds and perspectives, yet
some of the fundamental questions in developmental biology will
only be answered by combining expertise from a range of disciplines.
This book is a personal account of an interdisciplinary approach to
studying biological pattern formation. It articulates the power of studying
dynamics in development: that, to understand how an organism is
made, we must know not only the structure of its molecules; we must
also understand how they interact and how fast they do so.

L i o n e l G . H a r r i s o n (1929–2008) was Professor Emeritus in the

Department of Chemistry, University of British Columbia, where he was
a Faculty member for 50 years. A physical chemist by training, he was
inspired to study biological form and ‘in developmental biology . . .
found something different and immensely exciting: a field with a Great
Unknown’ as he wrote in his 1993 book, Kinetic Theory of Living Pattern.
‘To pursue it is like trying to account for the rainbow in the 14th
century, to do celestial mechanics before Newton, or to pursue
quantum theory in the 1890s.’
The Shaping
of Life
The Generation of
Biological Pattern

lionel g. harrison
University of British Columbia
(1929–2008)
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore,
São Paulo, Delhi, Dubai, Tokyo, Mexico City
Cambridge University Press
The Edinburgh Building, Cambridge CB2 8RU, UK

Published in the United States of America by

Cambridge University Press, New York

www.cambridge.org
Information on this title: www.cambridge.org/9780521553506

# Lionel Harrison Interdisciplinary Research Trust 2011

This publication is in copyright. Subject to statutory exception

and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without
the written permission of Cambridge University Press.

First published 2011

Printed in the United Kingdom at the University Press, Cambridge

A catalogue record for this publication is available from the British Library

Library of Congress Cataloging-in-Publication Data

Harrison, Lionel G.
The shaping of life : the generation of biological pattern / Lionel G. Harrison.
p. cm.
ISBN 978-0-521-55350-6 (Hardback)
1. Pattern formation (Biology) 2. Morphogenesis. 3. Developmental
biology. I. Title.
QH491.H35 2011
571.3–dc22
2010029820

ISBN 978-0-521-55350-6 Hardback

Cambridge University Press has no responsibility for the persistence or

accuracy of URLs for external or third-party internet websites referred to
in this publication, and does not guarantee that any content on such
websites is, or will remain, accurate or appropriate.
 Contents

Foreword Page viii

Acknowledgements xi
Preface xv

1 Organizer, organize thyself 1

1.1 Pattern, patron, process 1
1.2 Breaking out 5
1.3 Krespel 8
1.4 Looking for the Organizer 11
1.5 The Organizer of what? 13
1.6 Described where? (The organization of this account) 17

Part I Watching plants grow 21

2 Branching: how do plants get it started? 23

2.1 Bridges, branches, plants and protists 23
2.2 Entities and waves 32
2.3 Numbers of parts, spacings, wavelengths 34

3 Whorled structures 41
3.1 Acetabularia acetabulum vegetative whorls 41
3.1.1 The morphological event 41
3.1.2 Reaction–diffusion: looking for circumstantial
evidence with a magnifier 45
3.2 Larix x leptoeuropaea cotyledons 54

4 Dichotomous branching 59
4.1 Breaking symmetry 59
4.2 Mechanical buckling: the potato chip et al. 61 v
vi Contents

4.3 An interlude on fungal hyphae: Neurospora crassa 66

4.4 Patterning on a hemisphere 69
4.5 So why do we need to do complicated computations? 73

5 ‘Micrasterias’, and computing patterning

along with growth 77
5.1 Patterning and its morphological expression 78
5.2 Micrasterias: developmental facts
and 2-D computations 79
5.2.1 Developmental facts 79
5.2.2 2-D computations 83
5.3 3-D computations (by L.G. Harrison and David
M. Holloway) 89
5.3.1 Going from 2-D to 3-D, and some results 89
5.3.2 Available software 97
5.4 Back to 1-D: the moving boundary; and what
is polarization? 100

Part II Between plants and animals 105

6 The emergence of dynamic theories 111

6.1 From Wigglesworth to Turing 111
6.2 The components of Turing dynamic pattern-forming
mechanisms 117
6.3 No avoiding equations 121
6.3.1 Diffusion: the need to think of curvature
of a gradient 121
6.3.2 Bringing in the reaction rates 124
6.3.3 Exponential growth and pattern wavelength 127
6.3.4 From exponential growth to steady-state pattern 131
6.3.5 Activator and inhibitor distributions:
what proves what? 134
6.4 Is reaction–diffusion only Turing? 138
6.4.1 Only one morphogen: the exponential gradient 138
6.4.2 More than two morphogens 139

7 Classifying developmental theories as physical chemistry 142

7.1 Structure, equilibrium, kinetics 142
7.2 Just for a change, equilibrium: or is it? 144
7.2.1 A phase transition with a beating heart 144
7.2.2 A phase transition in a condensing nucleus? 151
 Contents vii

7.3 Diverse provocations, in brief 155

7.3.1 Definitely reaction–diffusion, but not alive: CIMA 155
7.3.2 Polar coordinates 157
7.3.3 Identities of Turing morphogens? 159

Part III But animals are different 161

8 The dreaded fruit fly 163

8.1 Body planning 164
8.1.1 Animal plans and plant plans 164
8.1.2 ‘Fushi’ 165
8.2 The earliest appearance of segmentation in Drosophila 167
8.3 Positional variation, error and noise in wild-type
populations 178
8.4 Effects of temperature 184

9 Various vertebrate events 186

9.1 The heart of the salamander 187
9.2 The angel in the fishbowl, and other sets
of stripes or spots 194
9.3 Somites in space and sequence 200
9.4 Gastrulation: geometry, topology or cytology? 205
9.4.1 A note on cellular slime moulds 212
9.5 Is that all there is? 212
9.5.1 Vertebrate limb development 213
9.5.2 Growing like plants? 215

Epilogue 218
References 226
Index 243
 Foreword

The Shaping of Life is Lionel’s second book, completed shortly

before his death in March 2008. It is in part an update of his earlier
volume, Kinetic Theory of Living Pattern (Cambridge University Press,
1993), following developments in the field and in his own research.
Lionel was always an energetic individual, both physically and intellec-
tually, climbing mountains and arguing points of scientific theory with
equal determination. Those interested will find a tribute covering sali-
ent aspects of his personal and professional life in The Globe & Mail for
26 April 2008. He experienced a great loss in the early 1980s with the
deaths, within the space of a few weeks, of both his wife and only son.
His life afterward was increasingly centred on scientific activities, and
he continued with research to retirement and after. This book is a
chronicle of his observations and insights during that time, and of the
people who influenced him and helped along the way. His proximate
goal was to discover how patterns of living things are formed or, to use
the title from an earlier draft of this book, ‘how life devises its shapes
and sizes’. Though it contains considerable experimental detail, the
book is addressed to a non-specialist audience, and especially to those
interested in how science is done in a field still in embryo, whose
mature form is as yet unknown.
Working in an emerging area of science is a challenge and an
adventure, and can be terribly exciting. There are, however, definite
risks to reputation and career, as the methods may be unconventional
or untried, and there is often no clear criterion for what constitutes
progress. Cautious academics will avoid such fields until the ground
rules are better worked out, and until it is clear that a predictable and,
hence, grant-worthy rate of progress can be sustained. Coming from the
relatively mature discipline of surface chemistry, Lionel, by contrast,
viii was immensely excited by the prospect of doing research on aspects of
 Foreword ix

biology still at a very early stage of their development. It was, to him,

like doing ‘celestial mechanics before Newton’. All things were possible,
and even very simple observations might lead to far-reaching insights.
Like others in the physical sciences, he was particularly struck by the
elephant in the room, one that working biologists are usually loath to
acknowledge: that biology today, excepting the great insight of Darwin,
is essentially a descriptive science devoid of a set of fully developed
principles. Most physical scientists assume this situation is simply tem-
porary, and that biology will proceed along the path already taken by
physics and chemistry, from the specific and descriptive to the synthetic
and analytical, using, eventually, a mathematical formulation.
What will this ‘new biology’ look like? First, it will need to
improve on the vague way we currently deal with the concepts that,
so far as we can tell, must lie at the core of biology. ‘Organization’ is one
example. ‘Order’ is another, including spatial pattern, but also the
ordering of genomic and metabolic networks in living cells, as is ‘dif-
ferentiation’, the process by which such things change over time. None
of these is as yet more than a name attached to a notion, and none are
properly defined and measurable. What, for example, are the dimen-
sions (units of measure) of organization, and what precisely is its role in
a subsidiary process like pattern formation? To answer this, one needs
to be quantitative, so that the amount of the former (organization) that
is required for, involved in or used up by the production of the latter
(pattern) can be calculated. Only then do the words take on concrete
meaning, and only then can the analysis be fruitfully carried forward.
Consider, for example, the production of the five-digit human hand
from its flattened, paddle-like beginnings: this is generally accepted as a
form of differentiation, and the end product does look more ordered, or
at least anatomically more complicated, than the beginning. But the
cells involved, of cartilage, connective tissue and skin, are still doing
pretty much the same jobs, only the locations have changed. So how
much ordering has actually occurred, and if this is truly differentiation,
is it a trivial amount in quantitative terms, or something worth account-
ing for in relation to the cost paid in disorder by the rest of the universe?
Thermodynamics is the way to deal with such questions, but we as
yet have only the most rudimentary beginnings of a thermodynamics
applicable to the complexities of living systems. Lacking this, Lionel’s
approach, best exemplified in his Acetabularia experiments (Chapter 3),
was necessarily empirical, and as such, entirely characteristic for a
physical chemist: measure patterns and pattern change directly, vary
the conditions over which you have control, and analyse the outcome.
x Foreword

Here he came closest to putting meaningful numbers on an otherwise

mysterious process, deducing such exotic thermodynamic beasties as
DH and DS from measurements requiring only a dissecting micro-
scope, thermometer and micrometer measuring scale. A complete
thermodynamics of living systems is clearly some distance in the
future, but of various routes to that future, this is certainly one.
Lionel’s book is, in this respect, as much an object lesson in scientific
methodology as an exploration of pattern in nature.
Lionel’s wide-ranging interests within and outside science are
evident in his writing, which is liberally supplied with references to
literature, historical anecdote and, especially, music. The operas of
Wagner were a particular interest, especially where these touched on
issues of creativity and intellectual challenge. Two of his favourites:
first, Act I of Die Meistersinger, which beautifully captures the unavoid-
able and sometimes comic conflict inherent in any human endeavour,
but especially academic ones. On the one side is accepted convention
and governance by rules, here represented in the character of Beckmes-
ser. On the other, the need for periodic inspiration and renewal
through the intervention of a more gifted practitioner – the headstrong
young knight Walther von Stolzing in this case. No prize is offered for
guessing how Lionel saw himself in this context. A second favourite was
Act I of Siegfried, which offers a different sort of confrontation, between
Mime, a dwarf, and Wotan, King of the Gods, here in the guise of the
one-eyed Wanderer. Mime is obsessed with the task of re-forging the
magical sword Notung, which, despite his mastery of dwarvish technol-
ogy, he is unable to do. Wotan knows precisely what is needed, but
given the chance to question Wotan, Mime instead wastes the oppor-
tunity on set questions for which he already knows the answers. For
scientists confronting Nature, and especially those outside the confines
of an established discipline, one needs bold questions indeed. Lionel’s
questions were always as bold as he could make them, and he clearly
hoped by example to encourage others to do the same.

Thurston Lacalli
Victoria, May 2009
 Acknowledgements

Lionel inspired a great many of us over the years with his energy
and brilliance. It is with great pleasure that we are able to present the
fruits of his last decade of labour, and hopefully inspire many more
with his ideas and questions.
It took the efforts of many friends and colleagues to bring
this book to completion. Thurston Lacalli (in addition to writing the
Foreword), Michael Lyons and Harold Kasinsky made careful readings
and many comments on the text, as Lionel left it in February 2008. Axel
Hunding supplied some of the updated references in Chapters 8 and 9.
Members of the UBC Chemistry Department have been extremely help-
ful and supportive – to single out a few, but not exclude the many
others: Elliott Burnell, Ed Grant, Elena Polishchuk, Nick Burlinson,
Gren Patey, David Walker, Yoshi Koga and Elizabeth Varty, who helped
on many of the figures. Thanks go to the Belkin Gallery at UBC and the
Shadbolt estate for the cover image.
I have coordinated this job, finalized the text and figures and
written the Epilogue to provide a current context. I have done minimal
editing within the text; rather opting to insert comments and bring
references up to date in footnotes throughout the book. The aim is to let
Lionel’s ideas shine through, and give pointers to further reading in the
current literature. I am very grateful for the support and guidance of
the Cambridge University Press production team, in particular Katrina
Halliday and Lynette Talbot. My institution, the BC Institute of Technol-
ogy, has supported my time on this work. The outpouring of support
and remembrances by Lionel’s friends and colleagues is a testament to
his life; and it has made finishing this book much easier. To Lionel.

David Holloway
Burnaby, April 2010 xi
xii Acknowledgements

Having used ‘once upon a time’ to start the preface of my previous

Cambridge University Press book, Kinetic Theory of Living Pattern (1993),
what else could I do but use a Lewis Carroll quotation as the epigraph to
the preface of its sequel,1 especially since my interest in mechanisms of
biological development began from the looking-glass problem of optical
resolution? As a physical chemist, hitherto concerned only with inor-
ganic materials, I was certainly wandering into unknown territory,
demanding of me a grand survey that I was certainly not about to make
when, through 1972–3, a couple of chance occurrences redirected me
into this field of enquiry. These, as mentioned in my 1993 preface,
were attending a talk by my colleague R. E. Pincock on an instance of
‘spontaneous optical resolution’ that he had observed in careful experi-
ments, and my first introduction to studies of biological morphogenesis
by taking the chair at the PhD defence of Thurston Lacalli, who received
a degree in zoology by working on development of an alga. Those two
afternoons led me to get excited about the concept of ‘non-linear
dynamics’ as probably being a major part of the explanation of both
classes of phenomena. I might quite easily have decided that I could
attend neither of these events; and in that case, I might never have
undertaken any work in this field. My first enthusiastic thanks must
therefore be to both of these gentlemen, and to whosoever among
the gods does play dice in arranging human encounters. (For further
commentary on optical resolution, non-linear dynamics and gods
playing dice, see the introductory paragraphs to Part II.)
From the later 1970s, I was greatly encouraged by the late Paul
Green, a botanist who insisted that ‘there is no escaping the calculus
when studying development’. He proposed the writing of my previous
book, and is hence responsible (at one remove) for the existence of this
sequel. His death from a rapidly fatal cancer in 1998 was the loss to
biology of an important scientist whose work had not yet reached its
proper fulfilment, and to me also of a very congenial friend.
In the projects from my own work that I describe here, much was
collaborative and I have many thanks to give to: Beverley R. Green,
University of British Columbia, a biochemically trained botanist
whose work on the alga Acetabularia gave me a highroad into experi-
mental biology; John B. Armstrong, University of Ottawa, who studied

1
These acknowledgements of Dr Harrison’s are a year older than his final
version of the text; the final preface did not have the Carroll quote. Taken from
Through the Looking Glass, it is: ‘Of course the first thing to do was to make a
grand survey of the country she was going to travel through.’
 Acknowledgements xiii

embryonic development of the axolotl (a salamander) and got suffi-

ciently interested in the possibilities of reaction–diffusion theory in
this topic that the exploration of that possibility made most of the
PhD thesis of my student, David M. Holloway, who remains a close
collaborator; Patrick von Aderkas, University of Victoria, BC, who
worked experimentally on somatic embryos of conifers, giving me the
chance to do some measurements myself and find the Bessel functions
in the seed leaves; Harold E. Kasinsky, University of British Columbia,
who kept bothering me about patterns of condensing DNA in sperm
until I got to believe that even these could have a dynamic explanation,
and collaborated with him and his collaborators Manel Chiva and Enric
Ribes at the University of Barcelona; Jacques Dumais, now at Harvard,
whose Master’s thesis work with me led on to a PhD with Paul B. Green
at Stanford University and continuing interaction on mechanical forces
in plant surfaces; and once again but fully deserving a second mention,
Thurston C. Lacalli, successively of the Universities of British Columbia,
Saskatchewan and Victoria, whose intensive collaboration with me for
several years in the 1970s, which has continued less intensively ever
since, was the way we both developed our understandings in some
depth of Turing’s ‘chemical basis of morphogenesis’.

Lionel Harrison
Vancouver, November 2006
 Preface

This book is intended for anyone who is interested in contem-

plating the question posed in the title,1 and who has a modicum of
general scientific education. It is not directed specifically to people
working in the sciences; and of those who are, it is not specifically for
physical or biological scientists. It is mainly for people who would like
to think about unsolved questions rather than to receive answers. Thus,
it is not a review of any specific specialized field, and particularly not of
those aspects of biology that have recently been producing answers
most rapidly – the aspects to do with genes and genomes and the daily
increasing number of words ending in the sacred syllable –ome. My
subtitle, ‘the kinetic aspect’,2 implies that I am interested much more
in how rapidly things happen to various objects than in what the
objects are. Further, I believe that the study of rates of change can often
be pursued as a primary objective, independent of knowing in advance
the material composition of the objects that are changing. (Perhaps not
only the primary objective, but also the ultimate – philosophers have
long pondered whether the deepest understanding of the universe must
be in terms of matter or motion.) This implies that if I consider a
biological phenomenon and have the urge to find out ‘what is doing
it’, I am not usually trying to find the name or formula of a substance
or molecule, but rather the forms of some expressions showing how the
amounts or concentrations of a few substances must be changing in
space and time.
This attitude can, however, seem old-fashioned, and I am vulner-
able, like all emeritus professors, to the sneer that I have passed the

1
The question in an earlier draft was ‘How does life devise its shapes and sizes?’
2
This was an earlier subtitle, referring back to Dr Harrison’s 1993 book, Kinetic
Theory of Living Pattern. xv
xvi Preface

‘philosopause’ (a word I learned as current from Natalie Angier’s The

Canon, 2007). Indeed, my attitude can be seen as representing the way
D’Arcy Thompson expected biology to advance when he first wrote On
Growth and Form in 1917 (the frequently referenced version of 1942 was
the second edition). Neither he nor anyone else at that time anticipated
that in the twentieth century, via electron microscopy and molecular
chemistry, anatomy would advance to its ultimate limit of minuscule
size, the very sequences of molecules and hence of atoms in living
beings. I think also that many scientists intensely concerned with
continuing the elaboration of such detailed descriptions, and therefore
immersed in the work of the past few years or even months, may find
something apparently philosopausal in the habit of theoreticians to
reach back to treatments of kinetics or diffusion or vibrations of discs
or whatever was published between the 1920s and 1950s. But this is
a necessary feature of such work; to be sure, we do not regularly
reference Newton’s original writings of three and a half centuries ago
whenever we relate forces to accelerations, but 60 years or so ago is
yesterday. When theory has been founded upon rocks, we have to
keep on digging back all the way to the rocks as the foundations on
which to build.
It has been opined to me by a reviewer of the penultimate draft of
this book that biologists reading it ‘are going to be hostile because of
the fact that genomes and bioinformatics etc do not get much of a
treatment’. I can see that many people absorbed in those popular
branches of biology might be uninterested in my topic, and might
therefore decide not to read this book beyond this sentence. But I do
not understand hostility to it, because my topic is entirely complemen-
tary to the molecular aspects, and in no way inimical to them. (Never-
theless, I have indeed encountered negative attitudes, as indicated at
places in my account.) Still less do I comprehend the attitude well
described by the same reviewer in the words, ‘the biological world,
almost hysterically, embraces “systems biology” with a zeal and faith
that can only be described as “religious”’. The attitude thus defined
disturbs me in two ways: first, in my home discipline of chemistry,
people working in manners ranging from almost a mathematician’s
to almost a biologist’s and everything in between are not only tolerated
but welcomed into the community of the discipline. I appreciate the
chasms across which different people gaze at each others’ viewpoints,
often without finding the means to cross over, but not why this should
lead to hostility. The source of enmity is more usually covetousness for
land that is easy for both opponents to grab because there is no chasm
 Preface xvii

to cross. But second, even in regard to the analogue of religion, I hold

pantheistic views that, when two religions are such that it seems neces-
sary for the adherents of one to regard the other as necessarily untrue,
I am inclined to think that both have equal quanta of the truth, but
neither has the monopoly on it that its adherents think.
Let’s get back to the chasm. There is one, between dynamical
theorists and molecular biologists, and it is desirable that it should
soon be spanned by one or more bridges in other than ramshackle
shape, so that equations of motion and structural details of genes and
proteins can become parts of the same territory in which everyone is
free to wander. Living organisms have for centuries (or even millennia)
provided much inspiration for research in all of the sciences (even
astronomy, when its practitioners go looking for distant planets likely
to have life-supporting conditions or little shreds of organic stuff
littering the solar system).
Many of these sub-disciplines need no mutual interaction. But for
finding out how organisms organize their development, a junction
between molecular detail and the vastly larger macroscopic scale of
spatial patterning does need to be built. It has been suggested to me
that I should write a chapter describing that bridge. I both appreciated
the suggestion and found it quite alarming, because it amounted to
describing in some detail the middle of something of which only the
extreme end sections have yet been built by anybody. But one should
never refuse the challenge to write an essay about nothing. And while
bridges are being built, there are structures in place at crucial stages
called the falsework. They are made of wood, and show where the
bridge is going to be, but give very little idea of what it is eventually
going to look like, and no idea at all of what it will be made of. I can
describe the existing falsework adequately in this prefatory account;
and quite recently, at the time of writing, it has acquired at least one
thin line that seems to span the entire chasm.
To begin at my end: dynamics can be studied for instances involv-
ing known substances, sometimes even for reactions with known values
of rate constants. In the general realm of cell biology, it is becoming
fairly popular for applied mathematicians to tackle such systems.
A contrasting approach is to characterize the properties of particular
kinds of dynamics without regard for the particular matter that may
display them. The simplest well-known example is what is variously
known as an exponential decay, first-order decay or relaxation process.
It has mathematical properties, such as the constant time for a concen-
tration to halve, that are the same whether one is thinking of
xviii Preface

radioactive decay, degradation of a protein or free induction decay of

a set of nuclear spins in an NMR experiment. It is important to many
types of scientist to know the properties of such dynamics.
I contend that, for the phenomena of developmental biology,
the scope of pattern-forming dynamics should likewise be common
knowledge, at least in fairly general terms. The route towards this
knowledge has been well indicated by Hans Meinhardt, especially in
his book on sea-shell pigmentation patterns (1995, 1998, 2003 editions),
which makes some characteristics of solutions of partial differential
equations accessible at the level of coffee-table presentation. I have
seen Meinhardt’s approach described (by an anonymous reviewer) as
‘toy models’, a term used by some trendy physicists to downgrade what
I think of as a proper route into theory by setting out hypotheses.
That approach stems from four essential preconceptions (or
paradigms, for any who prefer that much-misused word):

(1) a pattern, as formed by an event in biological development,

frequently starts as a single entity on the macroscopic scale,
often tens of micrometres between repeating parts in
examples as diverse as whorls in single-celled algae (Chapter 3)
and somites in vertebrate embryos, including human
(Chapter 9). The pattern often starts out as a harmonic spatial
waveform (Sections 3.2 and 4.4), and needs to be studied as
an entity.
(2) These events are capable of setting up quantitative scales
of distance, and therefore, wherever possible, it is useful
to characterize the events by spatially quantitative
measurements. This is good for a physical chemist blundering
into biology and wanting to do experiments, because much
can be done by high-school methods at low magnifications.
One graduate student I converted from a chemist to
a developmental biologist remarked that I had taught him
that research can be done with a dissecting microscope.
(3) The mechanisms that control such pattern formation are
likely to be matters that it is the proper business of physics
and physical chemistry to address, with, therefore, a modicum
of mathematical language used in even the first tentative
interpretation of the experimental results.
(4) Many patterns may be kinetically generated and kinetically
maintained, and theories of their formation must deal
in depth with rates of reaction and transport of substances
 Preface xix

in mechanisms belonging to non-linear dynamics (and

mechanical forces may also be involved in ways that demand
mathematically expressed theory).

The obvious basis for the start (in 1973) of my own work in this
field was the well-known (but still to my mind lamentably under-used
in developmental biology) theory of pattern generation by activator–
inhibitor interactions initiated by Alan Turing (1952) and elaborated by
Prigogine, Meinhardt and others so that ‘reaction–diffusion’ is now a
familiar and extensively studied branch of applied mathematics.
Should this type of theory, in which no more than a handful of sub-
stances do the whole job of making complex repeated patterns out of
uniformity, be thought of as out-of-date when enormous networks of
genetic interactions now loom over the discipline and it is repeatedly
said that no-one has positively identified a Turing morphogen pair?
The latter point brings me back to my example of a thin line that now
seems to span the chasm: a group in Freiburg (Sick et al. 2006) have
made the definite statement that ‘WNT and DKK determine hair
follicle spacing by a reaction–diffusion mechanism’. That paper identi-
fies these two proteins as activator and inhibitor in a Turing mechanism
(see Section 6.3.5).3
As to the question of a few substances versus a vast network,
I believe that knowledge of what a few substances can do dynamically
with a particular pattern of interactions between them is akin to having
a divining rod that, on a wander through the tangles of the network,
will twitch when one reaches the small region that has what it takes to
make spatial pattern. Here, perhaps, is some reason for the ‘hostility’
that I have mentioned as puzzling me. The twitch may delight the
theorist anxious for a source of equations that quench the thirst for
unification and understanding, but cast into despondency the careful
cartographers of a broad landscape of genes and proteins, who are
being told that most of their country has only dry wells for the particu-
lar pattern-forming phenomenon being considered. Fear not, cartog-
rapher, nor cast out the theorist into the unmapped desert. The gene
you have discovered will turn out to be nectar in another pattern-
forming event that neither of you has yet ever thought of.
But what do I think is necessary to make a divining rod that
twitches at the right places? Does it have to have a phoenix feather

3
See also Digiuni et al. (2008), identifying GLABRA and TRIPTYCHON as acting
through Turing dynamics to control the spacing of trichome structures on leaf
surfaces.
xx Preface

embedded in it, or anything that the experimental biologist will believe

equally mythical and unlikely to be findable? In other words, what
different kinds of experiments need to be done? To approach this kind
of question, I was effectively forced into making large parts of this book
effectively a memoir of large parts of the work of me and my group
since about 1973 (most of Part I, and Section 9.1). I have already stated
(as my ‘essential preoccupation (2)’ above) that much of this involves
spatially quantitative work on a large enough spatial scale that it
requires only low magnifications and may seem to be a reversion to
high-school biology. The essence of this kind of work is that it is like
classical chemical kinetics (yes, of the 1930s). One does not leave a
system to make something and come back later to see what it has made.
One keeps on observing and measuring as a function of time, and
particularly in the hope of catching the system at exactly the point at
which it seems to be making the rudiment of the pattern. Geneticists
tend to avoid any encouragement I give them to look for mutants in
pattern formation, because what I want to see is no spectacular change
in development, but, for instance, a quantitative change in the spacing
between repeated parts in a pattern; and that is in no way easy to spot,
except by multitudinous painstaking measurements, most of which
may turn out to be wasted effort.
From the first encouragement I received from Cambridge Univer-
sity Press editors to write this book, it was intended to be in a more
‘popular’ style than my 1993 book – ‘popular’ meaning readily readable
by anyone with fairly substantial education in any of the sciences. In
the earlier book, I tried to hit a level of mathematical presentation
accessible to anyone with a good first course in calculus, which wasn’t
difficult since I have never taken a university course in mathematics
and have always been coasting along on a knowledge of calculus from
sixth-form high school in England in 1944–6. But even that level of
presentation led me to put 143 numbered equations in Chapters 6, 7
and 9 of that book. (One does not need a high level of sophistication to
be unconscionably verbose, or should I say ‘equationose’.)
The present book contains only a handful of equations. (Despite
having heard that Stephen Hawking was told, when he was writing
A Brief History of Time, that putting in even one equation halves the sales
of the book, I couldn’t get rid of them all.)
This account is, above all, interdisciplinary; I advocate attempts to
bring together some aspects of the physical and biological sciences for
the common aim of finding out by what means biological organisms go
about developing the myriad complexities of their shapes. And one only
 Preface xxi

brings together aspects by bringing together people. What difficulties

does this involve? First, there is language. Science, as a whole, has
become enormous, and therefore divided into numerous almost com-
pletely separated specialties, each with its own little language unknown
to any of the others. Twenty-first-century science has far surpassed the
Tower of Babel in this property. Science is becoming a multicellular
organism with practitioners like molecules that can’t cross membranes.
I am disturbed at the number of seminars I attend at which the speakers
know they are addressing general audiences but have made no attempt
to adjust their use of specialized terminology to that situation. A lot of
time has to be devoted to this if the Tower of Babel is to become
syncytial, with passages like gap junctions or plasmodesmata between
all its rooms. (Now, how many readers have I lost with the terminology
in that sentence? I’m just talking about routes by which substances
manage to pass from cell to cell.)
Never let it be said that the chasm between the sciences is just
that biologists can’t do mathematics. The barrier is both ways across
every interdisciplinary boundary. But I still believe that many more
developmental biologists must make the effort to understand some-
what more mathematics if some essential aspects of their discipline
are to advance at all. As I understand the meaning of ‘science’, the
essence of it lies in putting experiment and theory together. Far fewer
people can achieve real science than can do reliable experiments or
manipulate mathematical formalisms well; the greater part of science
lies in putting these two together. In physics and chemistry, that union
can commonly be made at a social level, with any particular individual
identified as an experimentalist or a theoretician. Not so, I believe, in
developmental biology at the present time. The connection between
theory and experiment is still at a rudimentary level at which totipo-
tency in the scientific enterprise needs to be present at the level of the
small research group. While I advocate more knowledge by everyone of
what’s on the other side of the fence, I don’t generally anticipate that
plant-breeding in culture vessels and model-breeding in computers will
be done most usually by the same person. The interdisciplinary perspec-
tive needs only to be enough that both people can talk to each other to
the extent of designing research projects together, and be trained
enough in each others’ disciplines to understand their relative precon-
ceptions and expectations and be interested in talking!
With the above list, serving as acknowledgement and as advocacy
of small-group but broad-perspective collaborations, I may unwittingly
have provided evidence to condemn me as an incurable dilettante, who
xxii Preface

never stays long with work on one organism. I prefer to say that
I thoroughly deplore the concept of basing biology chiefly on the study
of a few ‘model organisms’; that one cannot establish the unifying
nature of concepts in biology other than by looking for them in a wide
range of biological diversity; and that the value of the comparative
approach was best put a long time ago by William Harvey (1578–1657),
who established the concept that blood circulates, and wrote:
The common practice of anatomists in dogmatizing on the general
make-up of the animal body, from the dissection of dead human subjects
alone, is objectionable. It is like devising a general system of politics, from
the study of a single state, or pretending to know all agriculture from
an examination of a single field. It is fallacious to attempt to draw general
conclusions from one particular proposition . . . . Had anatomists only
been as conversant with the dissection of the lower animals as they are
with that of the human body, the matters that have hitherto kept them in
a perplexity of doubt would, in my opinion, have met them freed from
every kind of difficulty. (copied as quoted by Crombie 1953, from Chapter
6 of Harvey’s De Motu Cordis, On the Movement of the Heart).

Following Harvey’s attitude perhaps even more broadly, I am

quite happy to present an account of developmental concepts, the
greater part of which is about plants when the greater part of biology
today is about animals. Where would our knowledge of genetic diseases
have got to without Mendel’s groundwork on peas? In regard to the
concepts of developmental theory that I like to pursue, a big advantage
of plants is that, because of the rigidity of their cell walls, they are more
amenable than animals to quantitative spatial measurements on pat-
terns as they form. Paradoxically, this implies that organisms that
display the least cellular motion within tissues during development
may be the best for studies seeking to explore the roles of dynamics
in pattern formation.
Since I wrote my 1993 book, there have been some substantial
advances in the recognition that there are places for mathematical work
in biology. University departments are establishing mathematical biol-
ogy groups and making faculty appointments in them. The complete
determination of genome composition in a number of species has led, on
the one hand, to another version of stamp-collecting in the matter of
proteomes, but also to the recognition that when one has all the struc-
tures, the next focus of attention should be on the functions of all these
molecules. And that means looking at changes, and hence rates of
change, and hence using differential equations. Or am I over-interpreting
the trends with a bit of wishful thinking? I tend to get interested when
 Preface xxiii

I hear (increasingly often) the terms ‘genetic networks’ and ‘systems

biology’, and then to be rather disappointed when I find that what is
being presented is not approaching my interests at all directly.
But surely, schematics of networks of interactions between genes
via, for instance, a protein product of one gene activity being a tran-
scriptional regulator for the activity of another gene, are likely to
contain many of the processes having non-linear dynamics capable of
pattern formation. (I write ‘many’, not ‘all’ of the processes because
I believe that pattern formation may often involve biochemistry very
distant from such relatively direct interactions of genes; see my opin-
ions on identities of Turing morphogens in Section 7.3.3.) Between
thousands of genes there are potentially millions of pairwise inter-
actions. The kinds of dynamics my work is devoted to can produce
complex spatial patterning out of the four self and mutual interactions
of two substances. To find these in a network can be the needle-in-a-
haystack problem; but this needle must be found because a prick from
it can change the shape of the whole haystack.
To clarify this point, in Section 1.5, especially Fig. 1.1, I compare
two diagrams: one is of my devising (Harrison 1993, Fig. 1.1). It has four
columns; the second column from the left contains a partial differential
equation. The other figure is from Bornholdt (2005), in an article
entitled ‘Less is more in modeling large genetic networks’. It has four
columns; the second from the left contains two ordinary differential
equations. There is at some level a similarity between the approaches
symbolized in these two schematics, and at other levels strong con-
trasts. I present this, and everything else in the following pages, to let
readers make up their own minds what approaches are going to lead to
bridge-building between people from diverse academic disciplines all
fascinated by the shaping of life. One of the commonest and simplest-
looking events around us is the branching of one plant stalk into two;
and the fact is, we don’t yet know the spatial controls that decide when
this is going to happen. Perhaps there is a clue to this and many
problems of development somewhere through the looking-glass: how
can my body have grown both a left hand and a right hand when all the
aminoacid molecules in its proteins are left-handed? Geometrical self-
assembly should fit together parts of either left or right handedness to
give a whole of one handedness, and the term self-assembly is conven-
tionally used, both in developmental biology and increasingly in chem-
istry to mean that kind of geometrical fitting. When the macroscopic
patterns of development defy the inevitable consequences of self-
assembly, the mechanisms of their formation must belong to some
xxiv Preface

broader class of ways in which symmetry-breaking can arise. It is in that

wider sense that I use the term ‘self-organization’. The most obvious
way for a system to escape from the dictates of geometry is to use
mechanisms dependent directly on dynamics, such as the rates of reac-
tion provided by the catalytic activities of enzymes, and thus only quite
indirectly on the structural features that give those enzymes their
activity. That this type of mechanism can account for the loss of one
handedness on the molecular scale has been known since 1932 (see the
introduction to Part II). By the same token, it can take particles of a
single handedness and generate both right and left hands. This book is
about how that kind of self-organization may work, and what evidence
there is that it does in diverse instances of biological development.
My interest in working on development was triggered by the
doctoral research of Thurston Lacalli on the alga Micrasterias (see
Chapter 5). In his thesis (1973a), he gave an analogy (following an idea
of J. Needham) for the two contrasting ways to go about investigating
development, which I further elaborated in my 1993 book. It concerned
the study of a Swiss watch to discover how it functions:

One may take the watch apart and examine, list and diagram the springs,
gears, shafts and so forth, and how they fit together. Yet one does not have
a full explanation without the application of equations of motion to the
whole. These involve concepts of momentum, moments of inertia, and
simple harmonic motion arising from a restoring force proportional
to displacement.
If in the light of such a study . . . one were to set up a team to examine
some other oscillating system of unknown contents, one might designate
some people to take it apart and describe its contents in ever greater
detail, and others to tackle other questions: what is the displacement that
produces a restoring force, and what is the origin of that force? To be sure,
these two parts of the team should exchange information, and the whole
team is needed to produce the whole story.

In this analogy, the Swiss watch does not stand for a fully formed
living organism. All its parts symbolize the genome and its products
that are in active use during development to make patterns. And the
oscillations of the watch movement correspond to the spatial periodi-
cities of those patterns. But to appreciate what is in ‘the whole story’
one needs to consider what one is going to do with that story. What
parts of it must one give most attention to if one wants to know: how to
make a Swiss watch; how it works; or how to design some quite differ-
ent oscillatory system. For pattern-forming systems, this book is about
how they work, and how one tries to find out how they work.
 1
Organizer, organize thyself

1.1 pattern, patron, process

This book is about the great mystery of how living organisms

develop the shapes and proper relative positions both of the whole
organism and of all the parts that make it up. These are large-scale
structures, ranging from parts of a cell visible by optical microscopy up
to gross anatomy. My primary interest is not in the structures them-
selves, most of which remain after life has departed and are indeed
commonly described from studies of dead material. Nor is my attention
given mainly to structural details on the molecular scale within the
provinces of the biochemist and molecular geneticist, details that could
be regarded as the ultimate limits of anatomy, cutting-up that has
reached the atomic scale. I am concerned mainly with how the tiny,
partly fragmentary and partly one-dimensionally ordered genetic begin-
nings are transformed into the three-dimensional organism by the
processes of development. This book is about processes, as they occur
during life and make up a large part of what distinguishes living from
inanimate matter.
The proper study and description of processes may involve
diverse branches of the physical and chemical sciences (Harrison
1993, Chap. 8), but must quite often be primarily based on dynamics.
That is the kind of explanation of developmental events to which
I have devoted most of my effort, and is the main topic of this book.
The postulation of ways in which diverse and complex shapes can
readily be generated by dynamics is as old as the double helix model
of DNA (Turing 1952). But the study of developmental dynamics still
attracts only small numbers of researchers. Therefore this book is
more about unanswered questions than about established explan-
ations. My only certainty, for this as part of a generality for most fields
1
2 Organizer, organize thyself

of science, is that processes must in the end receive as much attention

as structures if we are to understand the workings of the universe and
all its parts.
Visitors to the increasingly fuzzy three-way intersection of sci-
ence, pseudo-science and science fiction often wonder what life is like
if it exists somewhere else in the universe, in forms that have origin-
ated quite independently of those on Earth. Is the DNA–RNA-protein
molecular basis of all known life a unique set of building materials
that will inevitably be found wherever there is anything that can be
recognized as alive? My guess is that the essence of life does not reside
in such molecular detail, indeed not in anything structural, but in
processes and their dynamics, most particularly those that make up
the development of the organism, its maintenance by assimilation of
foodstuffs and excretion of waste products, and its reproduction.
When Isaac Newton looked at the skies, he envisaged and established
laws of motion that are the same for little things on Earth and huge
objects in space. He and his scientific successors had no philosophical
scruples against applying these laws to objects of unknown compos-
ition, and establishing that the laws worked very well to explain an
enormous diversity of motions. They remain the primary basis of
modern science, and explain the motion of the moon equally well
whether its mass is made up of green cheese, Dante’s nuns who failed
to keep their vows, or a glob of interstellar rocky garbage. The cos-
mologist expects Newtonian concepts of motion and gravity and their
Einsteinian modifications to apply to everything, including dark matter
of still unknown composition. (Some readers of a philosophical bent may
perhaps have the word Newtonian attached to a concept called ‘clock-
work universe’, regarded as inadequate and out-of-date. I am not here
concerned with that. The application of Newton’s laws to whatever tiny,
little or big bit of matter one happens to be considering is as timely today
as when he formulated the laws.)
Does biological development yet await its Newton despite half
a century of non-linear dynamics, just as evolutionary ideas had to
await Charles Darwin despite the thinking of such ‘transformists’ as
Lamarck, St-Hillaire and Erasmus Darwin up to half a century earlier?
I hope not. The history of the evolutionary concept involved a most
unusual sequence. The first step beyond data in the scientific method
is supposed to be the formulation of a type of law defined as general-
ization from data. That the evolutionary succession is a valid general-
ization was recognized by some, but not generally accepted until
Charles Darwin provided a mechanism for how it can happen. That
 1.1 Pattern, patron, process 3

is the second kind of law, theoretical explanation, and is supposed to

arise out of already accepted generalizations.
In biological development, there is now quite a different situ-
ation. There is a plenitude of both data and theory; but they seem to
be looking at each other from opposite sides of an apparently unbridge-
able gulf. This is not at all what was expected by D’Arcy Thompson
(1917, 1942, 1961). His title, On Growth and Form, clearly implied a
preconception that form was a manifestation of the processes of
growth, and that this would soon (after 1917) become a major direction
for the advance of biology. Part of his basis for this was that he thought
the possible limits of microscopy to have been almost reached. (The
electron is to blame for many aspects of our lives today.) In the event,
twentieth-century biology became in great part the quest for nanoanat-
omy, if I may be excused for using such a word, in the forms both of
electron microscopy and of the molecular structure of the genome. The
spectacular advances in this field have quite overwhelmed what could
have been (and I hope some day will become) other large fields of
biology much closer to the spirit of D’Arcy Thompson.
The developmental biology I discuss in this book can be cat-
egorized in a sub-discipline often called ‘pattern formation’. But I do
not distinguish between pattern and form, nor in any clearly defined
way between pattern formation, morphogenesis, epigenesis and
indeed most of biological development. All are concerned with essen-
tially the same thing: the unfolding in space of the organization of
the organism, something that is not in the first instance spatial, nor
intrinsically structural. The essence of living organization is that a
multitude of processes start running in sequences and in relation-
ships to each other that permit their mutual support and minimize
mutual destructive interactions with each other. But as part of the
strategy of both necessary separations and proper couplings of these
processes, living organisms develop significant shapes that announce
pictorially the existence of this organization of continuing events.
Spatial compartmenting is one of the most powerful methods used by
organisms to convert a complexity of processes into a set of mutually
interacting but semi-independent simplicities. Each of these simplici-
ties is a pattern; and their mutual organization on many levels is a
multitude of patterns.
Here, I am using the word ‘pattern’ to refer primarily to an
abstraction in our minds, a pattern of interaction of processes. We
may convert this into a picture that Nature has not drawn in the
organism – for instance, a diagram of biochemical cycles. But Nature
4 Organizer, organize thyself

has gone beyond this, using the biochemistry as an artist to paint a self-
portrait, the shape of the organism and its parts, which we can often
appreciate statically as a pattern in the pictorial sense.
Is this, the obvious appearance of the biological world that every-
one knows, perhaps more to be thought of as the abstraction, where the
hidden but essential and down-to-earth reality is actually the set of
processes generating the shapes? Of course, living shapes are most
easily seen in very practical terms as enabling the organisms to run,
swim, eat, use sunlight, extract nutrients from the soil and so forth. But
all of these functions are ultimately ways that the organism goes about
maintaining the organization of its processes of life. Spatial, pictorial
pattern is a showing forth of the existence of these processes. The
German word corresponding to pattern, ‘muster’, is derived from the
Latin ‘monstrare’, to show.
But the English word is derived from the Latin ‘pater’, father, and
the meaning of ‘pattern’ up to the sixteenth century was rather similar
to ‘patron’. This raises the question: when organization is evident,
where may we find the Organizer? Formulations of this question go
back at least to Aristotle, who wrote in his Generation of Animals:
It would appear unreasonable to suppose that anything external fashions
all the individual parts, the viscera or any others, because unless it is in
contact it cannot set up any movement, and unless it sets up a movement
no effect can be produced by it. Therefore there is already present in
the foetus itself that which is either an integral part of it or separate
from it. To suppose it is some other thing, and separate from it, is not
reasonable. If it were, the question arises: when the animal’s generation
is complete, does this something disappear, or does it remain within the
animal? We cannot detect any such thing, which is in the plant or
animal and yet is no part of the organism. (Translation slightly modified
by Harrison and Holloway from that of Peck 1942)

This quotation is from a few pages of Aristotle’s work that are

commonly referred to as indicating a belief in epigenesis (ab initio
generation of its shape by each new organism) in contrast to preform-
ation (pre-existence of the shape in miniature, e.g. the idea of a
‘homunculus’ within the human sperm). Aristotle did not use the word
epigenesis, which was a nineteenth-century invention of von Baer.
But the question in the quotation is very clear, and is the earliest
statement I am acquainted with on the problem of self-organization.
How can the organizer and the organized be identical? Twenty-three
centuries after Aristotle, this is still being asked. For instance, in
a review of wing and leg morphogenesis in the fruit fly Drosophila,
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