Mathematics in Biology!

!
Introduction!

Math in Bio?
Every attempt to employ mathematical methods in the study of
biological questions must be considered profoundly irrational and
contrary to the spirit of biology.
If mathematical analysis should ever hold a prominent place in
biologyan aberration which is happily almost impossibleit
would occasion a rapid and widespread degeneration of that
science.
Auguste Comte, 1830
French philosoph, founder of sociology

Source: http://www.cs.utah.edu/~crj/quotes.html

Math in Bio!
"mathematics ... was repugnant to me ... from my not being able to see
any meaning in the early steps in algebra... This impatience was very
foolish ... I have deeply regretted that I did not proceed far enough at
least to understand something of the great leading principles of
mathematics, for men thus endowed seem to have an extra sense".
(From Charles Darwin's Autobiography, 1876;
cited by R. May in Science 303:790-793, 2004)

"The important thing in science is not so much to obtain new facts as to

discover new ways of thinking about them".
(By Sir William Henri Bragg, 1862-1942;
Physics Nobel Prize for X-ray crystallography.)

Source: http://www.math.rutgers.edu/~sontag/336.html

A brief historical overview

Fibonacci
Leonardo of Pisa (best known as Fibonacci)
(~1175 - ~1250)!
Italian mathematician,
("the most talented western
mathematician of the Middle Ages"?)

published "Liber Abaci " ("Book

of Calculation") in 1202.
Introduced arabic numbers in
occident (more convenient than
roman numbers!).
Fibonacci numbers.

Liber Abaci (1202)

In his Liber Abaci, Fibonacci also posed, and solved, a problem
involving the growth of a population of rabbits based on
idealized assumptions. The solution, generation by generation,
was a sequence of numbers later known as Fibonacci numbers."

Source: wikipedia

Giovani Alfonso Borelli

Giovanni Alfonso Borelli (Italy, 1608-1679)

Italian physiologist, physicist, astronom,

philosoph, and mathematician.
Father of biomechanics.
Relates animals to machines and utilizes
mathematics to prove his theories.
Published De Motu Animalium (1680).
Pope MH (2005) Giovanni Alfonso Borelli - the father of biomechanics. Spine (Phila Pa 1976). 30:2350-5.

Thomas Robert Malthus

Thomas Robert Malthus (England, 1766-1834)

Reverend, political economist, interested in demography,

developed (initiated) theories of population growth.
Published "An Essay on the Principle of Population" (Six
editions, from 1798 to 1826)
"The power of population is indefinitely greater than the
power in the earth to produce subsistence for man".!
Proposed solution: celibacy (sexual abstinence) before
marriage, postponement of marriage, especially in poor
families (malthusianisme - 1st step towards eugeny?)

Sources: wikipedia + Jacques van

Helden (cours "Biologie & Socit")

Pierre-Franois Verhulst
Pierre-Franois Verhulst (Belgique, 1804-1849)!
Belgian mathematician, interested in number theory and in
population dynamics
Professor at Universit Libre de Bruxelles from 1835 to 1840.
Published:
- "Notice sur la loi que la population poursuit dans son
accroissement". Correspondance mathmatique et physique
10:113-121 (1838).
- "Recherches mathmatiques sur la loi d'accroissement de la
population". Nouveaux Mmoires de l'Acadmie Royale des
Sciences et Belles-Lettres de Bruxelles 18:1-42 (1845).
Proposed the "logistic equation" (1838) as a more
realistic alternative to the Malthus law.
Using data on the belgian population in 1815, 1830
and 1845, he determined the 3 parameters of the
logistic function and estimated to 6,6 millions the
maximum (asymptotic) population in Belgium...
Source: wikipedia + wiki KULeuven

Pierre-Franois Verhulst

Lotka & Volterra

Alfred James Lotka (US, 1880-1949)
mathematician, physical chemist, and statistician, famous for his
work in population dynamics and energetics.
published "Elements of Mathematical Biology" (1925)
known for his energetics perspectives of evolution. Lotka
proposed that natural selection was, at its root, a struggle
among organisms for available energy; organisms that survive
and prosper are those that capture and use energy at a rate and
efficiency more effective than that of its competitors.

Vito Volterra (Italy, 1860-1940)

Italian mathematician, known for his contributions to
mathematical biology and integral equations.
Published "Leons sur la thorie mathmatique de la
lutte pour la vie", Paris, 1931.

Lotka and Volterra both (independently) proposed models

for competing populations and predator-prey systems. "

Lotka & Volterra

Lotka & Volterra

Lotka (1925)
Elements of
Physical Biology,

Lotka A.J. (1920)

PNAS 6: 410-415

Chemical kinetics
Antoine-Laurent de Lavoisier (1743-1794):
=> quantitative measurements in chemistry
+ notion of stoichiometry
Claude Louis Berthollet (1748-1822):
=> first qualitative form of the law of mass action
Maximilian Guldberg (1833-1902) and Peter Waage (1839-1900):
=> first quantitative expression of the law of mass action
Svante August Arrhenius (1859-1927) and Vant Hoff (1852-1911):
=> effect of temperature on reaction rate

Michaelis & Menten

Leonor Michaelis (Germany 1875- 1949)
Biochemist, physical chemist, and physician
Professor at HU Berlin, Nagoya (Japon) and Rockefeller (USA)

NB: Besides his work on enzyme kinetics, he found that thioglycolic acid
could dissolve keratin, a discovery that would come to have several
implications in the cosmetic industry, including the hair permanent wave.

Maud Leonora Menten (Canada, 1879-1960)

Physician who made significant contributions to enzyme
kinetics and histochemistry.
Professor at Toronto, Chicago and Berlin

NB: She realized the first separation of

proteins by electrophoresis in 1944.

Michaelis & Menten are known for the derivation of kinetic

equations for enzyme-catalyzed biochemical reactions
(they originally studied the invertase, which catalyzes the
hydrolysis of sucrose into glucose and fructose).

D'Arcy Thompson
D'Arcy Wentworth Thompson (Scotland, 1860-1948)

W. Arthur (2006)
Nature 7:401-406

D'Arcy Thompson

W. Arthur (2006)
Nature 7:401-406

D'Arcy Thompson
D'Arcy Thompson philosophy
In his introduction he makes the following point: in dealing with the facts of embryology or
the phenomena of inheritance, the common language of the books seems to deal too much
with the material elements concerned. And he goes on to explain that in his view biologists
should place less emphasis on matter (such as a piece of embryonic tissue) and more on
the forces that shape it.

W. Arthur (2006) Nature 7:401-406

D'Arcy Thompson
Problems and limitations of the theory
Working as he was in the early twentieth century, DArcy Thompson was well within the era of
evolutionary trees (a generalized one of which is, famously, the only picture in the whole of
Darwins Origin of Species). But he was working well before the rigorous treatment of such trees
that began with the advent of phylogenetic systematics in the mid-twentieth century. This limitation
shows in the fact that he was usually content to note that the morphologies of a group of related
genera could be derived from each other by appropriate transformations, and he was not
terribly concerned with mapping the genera to a phylogeny so that it became apparent which
way round the transformations had taken place.

W. Arthur (2006) Nature 7:401-406

D'Arcy Thompson
Problems and limitations of the theory
Direct versus indirect development. It is interesting that DArcy Thompson generally used, as
examples, direct rather than indirect developers. He used many crustaceans as examples (FIG.
2), but no insects. Likewise, in the vertebrates, he used many fish (FIG. 3), but no amphibians.
This is a limitation of the theory (so far anyway), but not a problem indeed it was a wise strategy
to limit his examples in this way. It is difficult enough to understand how a directly developing
system evolves in quantitative terms, without adding the complexities of metamorphosis.
The main deficiency of the theory of transformations, from a genetic or developmental point of
view, is that no causal mechanism was proposed for their occurrence. Of course, we cannot
blame DArcy Thompson for a failure to incorporate ideas about transcription factors into his theory,
as they were then unknown. Nor can we blame him, at least in the first edition of On Growth and
Form, for omitting the embryological ideas of gradients, fields and morphogens, as these also
awaited articulation. But there is one thing that we can and perhaps should blame him for a
neglect of juvenile morphologies. Notice that all the forms shown in here (and in the book of D'arcy
Thompson) are those of adults. This concentration on adults is strange, given two facts. First, it
must have been as obvious to DArcy Thompson as it is to biologists today that there is no way
evolution can turn one sort of adult form into another except by modifying the course of
development. Second, many of the chapters leading up to the one on transformations, such as the
one on spirals mentioned above, did explicitly deal with both adult and juvenile morphology. It is as
if the developmental and evolutionary parts of the book were disconnected from each other.
See also: "D'Arcy Thompson Fantome de la Biologie - Des outils
mathmatiques et physiques pour expliquer les formes du vivant",
by N. Witkowski, La Recherche (janvier 1998)

W. Arthur (2006) Nature 7:401-406

Ronald Fisher
Ronald Aylmer Fisher (1890-1962)
genetics, mathematics, statistical biology
Apart from his central role in the development of the field of
statistics, Fisher was among the most prominent of twentieth
century workers in the fields of genetics and statistical biology,
and one of the primary founders of the field of population
genetics.
His work included mathematical investigations that helped
provide a statistical foundation for the emerging neo-Darwinist
synthesis: clarification of the notion of degrees of freedom,
development of the maximum likelihood estimation concept and
analysis of variance technique, and in general the working out of
modern statistical principles of experimental design.
In genetics his 1930 book The Genetical Theory of Natural
Selection, with its ground-breaking treatment of the concepts of
fitness and dominance, was a milestone work in that field.

Source: http://www.wku.edu/~smithch/chronob/FISH1890.htm

Erwin Schrdinger
Erwin Schrdinger (Austrian, 1887-1961)
Physicist, contribution to quantum theory
Nobel Price (with Paul Dirac, 1933)
Published "What is life?" (1946), where he
introduced the concept of a complex molecule with
the genetic code for living organisms. According to
James D. Watson's memoire, "DNA, the Secret of
Life", Schrdinger's book gave Watson the
inspiration to search the gene, which led to the
discovery of the DNA double helix structure in 1953.

Alan Turing
Alan Mathison Turing (UK, 1912-1954)
mathematician, logician, cryptanalyst, and
computer scientist.
contributed to the development of computer
science, giving a formalisation of the concepts
of "algorithm" and "computation" with the
"Turing machine".
father of computer science and artificial
intelligence.
interested in mathematical biology; wrote a
paper on the chemical basis of morphogenesis
(cf. "Turing patterns"), and predicted oscillating
chemical reactions such as the BelousovZhabotinsky reaction (discovered in the 1960s).

Alan Turing

Ilya Prigogine
Ilya Prigogine (Russian/Belgian, 1917-2003)
Physicist and chemist (ULB)
Interested dissipative structures, thermodynamics
of systems far from equilibrium complex systems,
irreversibility, self-organization.
Nobel price in chemistry,1977
Published (with G. Nicolis) "Self-Organization in
Non-Equilibrium Systems", Wiley, 1977.

Arthur Winfree
Arthur Winfree (USA, 1942-2002)
Theoretical Biologist (developed mathematical
models and theories for circadian clocks, cardiac
rhythms, developmental processes, etc)
The Geometry of Biological Time (1980/2001)

Belousov-Zhabotinsky reaction (in Petri dish)

Mathematical biology today

Math in Bio today

Mathematics arising from
biological problems
Source: Mathematics Is Biologys Next
Microscope, Only Better; Biology Is
Mathematics Next Physics, Only Better
Joel E. Cohen
PLOS Biol 2:e439 (2004)
Biology will increasingly stimulate the
creation of qualitatively new realms of
mathematics.

Todays biologists increasingly recognize

that appropriate mathematics can help
interpret any kind of data. In this sense,
mathematics is biologys next
microscope, only better.

Math in Bio...
Biological challenges that
needs Mathematics &
Mathematical challenges
arising from Biology
Source: Mathematics Is
Biologys Next Microscope, Only
Better; Biology Is Mathematics
Next Physics, Only Better
Joel E. Cohen
PLOS Biol 2:e439 (2004)

Math in Bio...

R. May (2004) Science 303:790-793

Math in Bio today

Bialek & Botstein (2004) Science

303:788-790

Math in Bio...
Mathematics is now widespread in all fields of biology!
large-scale data analysis

sequence analysis
CTAGCTCTCATATCGCT
AGTCGAGCATCTAGCTG
ACTGCTAGGGCGTATCT
AGTCTCTAGTCTAGCTA
CTCATCGTCGATCGTAG
CTGATCGGACTACTGAC!

structural biology

signal analysis

Mathematics
&
Computers

biological network analysis

dynamics of regulatory networks

Large-scale data analysis

Large-scale data analysis

Another challenge for the bioinformatician
pertains to the analysis of large-scale
data. Indeed, today many new
experimental techniques allows to perform
"genome-scale" experiments (sequencing,
microarrays, two- hybrid,...).
We thus face the analysis of data sets
consisting of many variables (for example
all the genes of an organism) to which are
associated many parameters (for example
the expression level of the genes in many
different conditions or mutants).
To extract useful information from those
data, we need to apply multi-variate
statistic methods.
Among those techniques, we will see the
principal component analysis and
discriminant analysis. Application of
those methods of real biological data sets
will be presented.

Large-scale data analysis

Large-scale data analysis

Analysis of the variance (ANOVA)

number of genes

Gene expression

level of expression

which genes are overexpressed

in this condition?

Genes whose the expression level

is greater than a given threshold
(which will depend on the mean and
standard deviation) will be
considered as over-expressed.

Large-scale data analysis

Multivariate Statistical Analyses (MANOVA)
In this course, we will briefly present the principles of two methods often used
in Bioinformatics to reveal structures in the data or to classify the data:

Principal Components Analysis

Discriminant analysis
Correlation analyses - regression
Clustering methods

Large-scale data analysis: PCA

Principal Components Analysis (PCA)
PCA is a method used to reduce the number of variables in a data set by
selecting only the most "representative" ones. Those "representative"
variables (or factor) are in fact a combination of the original ones.

Large-scale data analysis: DA

Discriminant analysis (DA)
The aim of DA is to determine the variables characterizing objects that
discriminate the best between two (or more) classes.
discriminant function
class 1

x2

x2
object of unknown class
=> predicted as class 1

class 1
class 2

x1

class 2
object of unknown class
=> predicted as class 2

x1

Large-scale data analysis: clustering

Example: microarray data analysis

microarray data
(gene expression)

clustering (group of
co-expressed genes)

regulatory sequence analysis

(co-regulated genes)

Modeling the dynamics of

regulatory networks

Biological networks
Biologists have identified many (genetic) regulatory
motifs. Here are some examples:

The question is then what is the

role of those regulatory motifs?

Typical regulatory motifs

identified in the gene regulatory
network of E. coli (from U. Alon)

Biological networks
Those regulatory motifs
are embedded in larger
regulatory networks.

Regulatory gene network for

endomesoderm development in
see urchin (from E. Davidson )

Biological networks
Regulatory networks can
also involve proteins
(translational and posttranslational regulations,
complex formation,...)

Cell cycle regulatory network in mouse

Biological networks
Regulatory
networks can
also involve
signal
transduction
(ligand/receptor
recognition)

Signalling cascade

Biological networks
Regulatory
networks can
also involve
biochemical
reactions and
metabolic
pathways.

Glycolytic pathway
(from KEGG)

Biological networks
How to understand the dynamics of such
huge regulatory networks?
How to predict the behavior of the such
systems under new conditions or in
response to some perturbation?
How to modify the system to get a
particular response?

Modeling dynamical biological systems

=> Modeling the dynamics of biological systems
Mathematical modeling provides another way of looking at
biological systems. Models can be used to better understand the
dynamics of a system, to explore (molecular) mechanism underlying
the observed dynamical behaviors, and to predict the behavior of
the system in conditions so far untested experimentally.
Models can be seen as a simplified map of complex processes. The
use of a model depends on its scale and on the informations it
contains.

Model = Map
Of Exactitude in Science...
In that Empire, the craft of cartography attained such
perfection that the map of a single province covered the
space of an entire city, and the map of the Empire itself
an entire Province. In the course of time, these extensive
maps were found somehow wanting, and so the College
of Cartographers evolved a map of the Empire that was
of the same scale as the Empire and that coincided with
it point for point. Less attentive to the study of
cartography, succeeding generations came to judge a
map of such magnitude cumbersome, and, not without
irreverence, they abandoned it to the rigours of Sun and
Rain.
From Travels of Praiseworthy Men (1658) by J. A. Suarez Miranda. The
piece was written by Jorge Luis Borges and Adolfo Bioy Casares. English
translation quoted from J. L. Borges, A Universal History of Infamy,
Penguin Books, London, 1975.
Source: http://www.kyb.tuebingen.mpg.de/bu/people/bs/borges.html

Jorge Luis Borges

Argentinian writer
(1899-1986)

Model = Map

The different maps are all related to the same city (Berlin), but they represent different selected
aspects of the city; they have different scales and gives complementary informations.

Modeling dynamics of biological systems

"Complex assemblies of interacting proteins carry out most of the
interesting jobs in a cell, such as metabolism, DNA synthesis,
movement and information processing. These physiological properties
play out as a subtle molecular dance, choreographed by underlying
regulatory networks. To understand this dance, a new breed of
theoretical molecular biologists reproduces these networks in
computers and in the mathematical language of dynamical systems."
(From "Network dynamics and cell physiology", by Tyson, Chen, & Novak,
Nature Reviews in Molecular Cell Biology, 2001.)

"The slippery gooiness of biology is a consequence of its incredible

complexity, consisting as it does of complex systems based upon
chemistry. And chemistry obeys the rules of physics, which exists
because of, and is consequently best described by mathematics."
(From the Mathematics in Biology page at Brandeis University;
http://www.bio.brandeis.edu/biomath/top.html)
Source: http://www.math.rutgers.edu/~sontag/336.html

Roles and advantages of modeling

Analysing and understanding complex situations that become difficult to
describe in verbal terms and for which sheer intuition becomes unreliable.
Rapid exploration of different mechanims and large ranges of conditions.
Clarification, validation or invalidation of working hypotheses.
Identification of key interactions and parameters, and their qualitative or
quantitative influence on the system's behaviour.
Determine precisely the conditions in which different behaviours will occur.
To address questions that are difficult or impossible to approach
experimentally.
Provide testable predictions, suggestions for new experiments or model
modifications, and sometimes counter-intuitive explanations that may
corroborate (or not) conclusions drawn from experimental observations.
Provide a unified framework to account for the experimental observations and
bring into light possible similarities between apparantly unrelated processes.
Leloup & Goldbeter (2000) BioEssays 22:83-92

Why is mathematical biology so hard?

Where is the Newton's Law? The phenomena that mathematical biology seeks
to understand and predict are very rich and diverse and do not derived from
simple and universal principles. "Dogma" like "evolution by natural selection" or
"DNA-mRNA-enzyme" can not be translated into mathematical equations
without additional facts and assumptions that are context-dependent.
Diversity: Because of evolution biological systems are exceptionally diverse,
complex and special at the same time, and this present several difficulties to the
mathematician. Formalisms exist to account for this diversity (e.g. stochastic
approaches), but the question is to which extend do we have to account for the
diversity.
Levels: In many biological problems, our goal is to understand how the behavior
of the system at one level arises from structures and mechanisms at lower
levels. Choosing the right variables is therefore a challenge for the modeler.
Difficulty of experimentation: It is often not as easy for an experimentalist to
acces interesting variables of the system as for the mathematician. Changing
the michaelis constant (KM) in an equation is trivial for the mathematician but
challenging for the biologist.
M.C. Reed (2004) Notices of the AMS 51:338-342

Modeling vs experiments
Experimental data
define the question
identify the system

Scheme of the model

approach
equations

New experiments

Mathematical model
calculation,
computer
simulations
if predictions not ok

Predictions

if prediction ok

Modeling vs experiments

Building a model

Bibliography

Scheme of the model

Calculations
or computer
simulation

Interpretation
of the results
Comparison with
experimental data

Kinetic equations

Applications
Nearly all biological systems have been modeled
Examples in molecular biology:
Developmental processes (segmentation in Drosophila, somitogenesis in
vertebrates, embryogenesis...)
Cell differentiation
Immunology
Cell cycle and related processes (apoptosis, DNA repair)
Circadian clock and seasonal rhythms
Signaling cascades (MAPK,...)
Pulsatile hormone secretion
Calcium dynamics
Metabolic pathways (glycolysis, amino acids metabolism)
Genetic switches (ex: lysis-lysogeny switch in phage)
Neuronal activity
...

Applications
Nearly all biological systems have been modeled
Examples in ecology:
Population growth
Predator-Prey systems
Inter-species competition
Host-parasites systems
Epidemiology
...

Predator-Prey dynamics
Evolution of predator and prey populations in time

Schnell, Grima, Maini (2007), American Scientist 95, 134

Modeling Ca++ dynamics in cells

Evolution of Ca++ concentration in time

numerical
integration
(computer)
kinetic
differential
equation
From G. Dupont

Modeling cAMP pattern

Spatio-temporal organisation
Spatio-temporal models account not only for
the dynamics in time, but also in space.
Those approaches includes the
"compartimentalization" of the space and the
diffusion of the chemical species.
The model obtained is then based on
reaction-diffusion equations (partial
differential equations).

Simulated waves of cAMP emitted by

Dictyostelium amoebae after starvation.
Halloy, Lauzeral, Goldbeter (1998)
Biophys Chem. 72:9-19.

Pattern formation

Murray (1988), Sci Am 258:80-87

Pattern formation
An important feature of the model is that the
patterns it generates bear a striking
resemblance to the patterns found on a wide
variety of animals such as the leopard, the
cheetah, the jaguar, the zebra and the giraffe.
I should like to suggest that a single patternformation mechanism could in fact be
responsible for most if not all of the observed
coat marking.
It is not clear as to precisely what happens
during embryonic development to cause the
patterns. There are now several possible
mechanisms that are capable of generating
such patterns. The appeal of the simple
model comes from its mathematical richness
and its astonishing ability to create patterns
that correspond to what is seen. I hope the
model will stimulate experimenters to pose
relevant questions that ultimately will help to
unravel the nature of the biological
mechanism itself.
Murray (1988), Sci Am 258:80-87

Towards multi-scale modeling

From DNA to whole organism modelling
Multi-scale models are the key to understanding the
function of complex organs based on their genetic and
cellular composition. The picture illustrates the different
components and processes in the chain which must be
modelled and integrated ranging from genetic information
through cells and tissue to the behaviour of whole organs

Source: http://www.integrativebiology.ox.ac.uk/

Synthetic biology
Synthetic biology
The term synthetic biology refer to a new area of research that
combines science and engineering in order to design and build
("synthesize") novel biological functions and systems.
The goal of synthetic biology is to get a better understanding of the
dynamics of biolgical systems by building and studying simple
systems that are fully under control.
The design of such networks is guided by mathematical models.

Synthetic biology
A synthetic oscillatory network of transcriptional regulators
Elowitz, Leibler (2000) Nature 403:335-338

Mathematical model

Design of the genetic regulatory network

Genetic construction in E. coli

In vivo measurement

Synthetic biology
Construction of a genetic toggle switch in Escherichia coli.
Gardner, Cantor, Collins (2000) Nature 403:339-342.
Design of the genetic regulatory network

Genetic construction

Kinetic equations

Analysis in the phase plane

Experimental

Need for mathematics in biology

Tyson JJ, Albert R, Goldbeter A, Ruoff P, Sible J (2008)

Biological switches and clocks. J R Soc Interface. 5:S1-8.

The tools we need

Here are some tools and theories, highly used in
modeling, which will be presented in this course:
Difference equations + applications in population
dynamics
Chemical and enzyme kinetics
Theory of differential equations (in particular non-linear
ODE) + applications in population dynamics and in
molecular biology

Because most of the models need to be analyzed by

numerical simulations with a computer, the following
tutorials will be proposed:
Linux
R (a statistical package) + MATLAB
Numerical methods to "solve" ODE (XPP-AUTO)

http://www.mhs.ox.ac.uk/blackboard/
(Robert May)

Further reading
Text books on mathematical biology
Edelstein-Keshet (1988; 2005) Mathematical Models in Biology,
SIAM.
Voit E (2012) A First Course in Systems Biology, Garland
Segel (1984) Modeling dynamic phenomena in molecular and
cellular biology, Cambridge
Cornish-Bowden (1995) Fundamentals of enzyme kinetics,
Portland Press.
Murray (1989) Mathematical Biology, Springer-Verlag,
Heidelberg, 1989.
De Vries et al (2006) A Course in Mathematical Biology:
Quantitative Modeling With Mathematical And Computational
Methods, SIAM.
Strogatz (2001) Nonlinear Dynamics and Chaos: With
Applications to Physics, Biology, Chemistry, and Engineering,
Perseus.

Several chapters of the course

will be directly taken from the
book by Edelstein-Keshet (2005)

Further reading
Some review papers
Murray JD (1988) How the leopard gets its spots, Sci. Am. 258:80-87.
May RM (2004) Uses and abuses of Mathematical Biology, Science 303: 790-791.
Reed (2004) Why is mathematical biology so hard, Notices of the AMS 51: 338-342.
Cohen JE (2004) Mathematics is biology's next microscope, only better; biology is
mathematics' next physics, only better. PLoS Biol. 2:e439.
Arthur W (2006) D'Arcy Thompson and the theory of transformations, Nature Rev Genet 7:
401-406.
Schnell, Grima, Maini (2007) Multiscale Modeling in Biology, Am Sci 95: 134-142.
Bascompte (2007) Biology and Mathematics.

Further reading
Some (more advanced) review papers
Di Ventura et al (2006) From in vivo to in silico biology and back, Nature 443:527-533.
Endy & Brent (2001) Modelling cellular behaviour, Nature 409:391-395.
Goldbeter A (2002) Computational approaches to cellular rhythms. Nature 420:238-45.
Tyson JJ, Chen K, Novak B (2001) Network dynamics and cell physiology. Nat Rev Mol Cell
Biol. 2:908-16.