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Robert M. May
Uses and Abuses of Mathematics in Biology
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tions provide models of the same general
form. Although the different systems have
important special features (e.g., the conserva-
tion laws), surely we would like to commu-
nicate the more general idea that dynamics
are described by differential equations and
encourage students to discover the applicabil-
ity of this approach to the dynamics of more
complex biological systems through well-
designed laboratory exercises. In a similar
spirit, statistical physics and kinetic theory
provide probabilistic models of the world, but
Mendelian genetics is also a probabilistic
model and an understanding of probability is
at the heart of all practical data analysis.
Today, not only can we integrate subjects
that share common mathematical structures,
we can also integrate these abstract structures
with their practical implementation through
computation. If the students are taught to
program and to use simple algorithms and if
they learn to use high-level languages (e.g.,
Matlab or Mathematica), they can visualize
and verify for themselves the mathematical
ideas and thereby become comfortable with
those they find less intuitive or more abstract.
In statistics, for example, it is possible to
begin by applying simulation and bootstrap
algorithms (e.g., for finding P values). By
starting in this way, students will more easily
come to appreciate parametric methods and
closed-form solutions and learn to understand
and to use them appropriately.
We believe that integrating mathemat-
ics, computation, and the scientific context
for these ideas will allow students in an
introductory course practical access to con-
ceptual tools that are much more sophisti-
cated than those currently taught in the
standard first-year mathematics courses.
Although real mastery over these ideas will
require continuing reinforcement through-
out the undergraduate curriculum (as is cur-
rently done for physical science students), a
unified introduction can empower the stu-
dents to explore ideas far beyond what is
currently accessible to them.
A final and, in the context of biology,
possibly the most important synergy derives
from the judicious use of nonstandard exam-
ples for basic principles and methods of phys-
ics and chemistry. For example, it makes
sense, in modern times, to introduce students
to the idea of molecular motion and thermo-
dynamics in solution rather than focusing
only on the world of ideal gases. With afford-
able modern instrumentation, students can
observe and record Brownian motion in a
microscope, for example, and satisfy them-
selves quantitatively how this motion derives
from invisible molecules bouncing around in
the solution and even how many such mole-
cules there must be. This hands-on approach
has the advantage that the phenomena (and of
course the underlying principles) are directly
and obviously relevant to research in biology.
In a similar vein, much of basic combinato-
rics, probability theory, and statistics can be
presented in tandem with basic genetics, re-
sulting a substantial saving in overall time
when compared with separate courses in dif-
ferent departments. Again, the concurrent use
of computation will provide students with
tools that will serve them well in all of their
scientific careers thereafter.
Our proposal for an integrated introduc-
tory education for quantitatively oriented bi-
ologists really is an experiment in a more
general problem: science education in the
modern world. This is a problem whose so-
lution will require collaborations among
scientists who now reside in quite different
departments and cultures; enthusiastic as we
are, we also are cognizant of the difficulties
that will no doubt arise. On the other hand,
the necessary collaborations among the fac-
ulty from several disciplines may well set a
wonderful example for students.
To conclude, we believe there is a great
opportunity to construct a unified, mathemat-
ically sophisticated introduction to physics
and chemistry, which draws on examples
from biology wherever possible. Such a
course would provide a coherent introduction
to quantitative thinking about the natural
world, and invite all students, including biol-
ogists of the future, to partake of the grand
tradition, which flows from Galileos vision.
References and Notes
1. Committee on Undergraduate Biology Education to
Prepare Research Scientists for the 21st Century,
Board on Life Sciences, Division of Earth and Life
Sciences, National Research Council, BIO 2010:
Transforming Undergraduate Education for Future Re-
search Biologists (National Academies Press, Wash-
ington, DC, 2003).
2. C. P. Snow, The Two Cultures and the Scientic Rev-
olution (Cambridge Univ. Press, New York, 1959).
V I E W P O I N T
Uses and Abuses of Mathematics in Biology
Robert M. May
In the physical sciences, mathematical theory and experimental investigation
have always marched together. Mathematics has been less intrusive in the life
sciences, possibly because they have until recently been largely descriptive,
lacking the invariance principles and fundamental natural constants of physics.
Increasingly in recent decades, however, mathematics has become pervasive in
biology, taking many different forms: statistics in experimental design; pattern
seeking in bioinformatics; models in evolution, ecology, and epidemiology; and
much else. I offer an opinionated overview of such usesand abuses.
Darwin once wrote 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.
With the benefit of hindsight, we can see
how much an extra sense could indeed
have solved one of Darwins major prob-
lems. In his day, it was thought that in-
heritance blended maternal and paternal
characteristics. However, as pointed out to
Darwin by the engineer Fleeming Jenkin
and others, with blending inheritance it is
virtually impossible to preserve the natural
variation within populations that is both
observed and essential to his theory of how
evolution works. Mendels observations on
the particulate nature of inheritance were
contemporary with Darwin, and his pub-
lished work accessible to Darwin. Fisher
and others have suggested that Fleeming
Jenkins fundamental and intractable ob-
jections to The Origin of Species could
have been resolved by Darwin or one of his
colleagues, if only they had grasped the
mathematical significance of Mendels
results (1). But half a century elapsed
before Hardy and Weinberg (H-W) re-
solved the difficulties by proving that par-
ticulate inheritance preserved variation
within populations (2).
Today, the H-W Law stands as a kind of
Newtons First Law (bodies remain in their
state of rest or uniform motion in a straight
line, except insofar as acted upon by external
forces) for evolution: Gene frequencies in a
Zoology Department, Oxford University, Oxford OX1
3PS, UK.
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population do not alter from generation to
generation in the absence of migration, selec-
tion, statistical fluctuation, mutation, etc.
Subsequent advances in population genetics,
led by Fisher, Haldane, and Wright, helped
make the neo-Darwinian Revolution in the
early 20th century. Current work on the one
hand provides illuminating metaphors for ex-
ploring current evolutionary problems, par-
ticularly in molecular evolution, whilst on the
other hand having important applications in
plant and animal breeding programs (Fig. 1).
Before I embark on chauvinistic elaboration
of other uses of mathematics in biology today,
it is well to reflect on the varied encounters with
mathematics that todays nascent biological re-
searcher is likely to have as undergraduate and
earlier. First encounters are usually with
the simpler aspects of pure mathemat-
ics such as numbers, algebra, elemen-
tary trigonometry. Taught well, the em-
phasis is on clarity of thought, rigor,
even elegance: assume this, prove
that. Taught badly, you get rote learn-
ing and mechanical tricks. No one taught
well will ever forget the sheer wonder of
e
i
1 (a magical result connecting
two fundamental constants, e and , and
the ethereal square root of 1). But it can
all seem rather abstract, or even off-
putting (particularly if taught badly), and
for some this will color attitudes to
mathematics for the rest of their lives.
In the typical curriculum, applica-
tions come later, often in physics where
the fundamentals are cast in mathemati-
cal terms (whence Einsteins reflection
on the unreasonable effectiveness of
mathematics in describing the natural
world). Others will encounter applied
mathematics in the form of probability
theory and statisticssome through
misspent youth playing bridge or poker,
others more formally in the design of
experiments to separate significant re-
sults from statistical fluctuations and
other noise. Among the younger gener-
ation, many will have first met applied
mathematicsoften without realizing itin
computer games.
A paradigmatic account of the uses of math-
ematics in the natural sciences comes, in delib-
erately oversimplified fashion, from the classic
sequence of Brahe, Kepler, Newton: observed
facts, patterns that give coherence to the obser-
vations, fundamental laws that explain the pat-
terns. These days, mathematics enters at every
stage: in designing the experiment, in seeking
the patterns, in reaching to understand underly-
ing mechanisms. In biology, of course, every
stage in this caricature is usually vastly more
complex than in the early days of physics. But
the advent of computers, and the extraordinary
doubling of their capability roughly every 18
months for the past several decades, permits
explorationand sometimes understanding
we could not have dreamed of 50 years ago.
Consider the role played by applications of
mathematics in sequencing the human and oth-
er genomes. This adventure began with the
recognition of the doubly helical structure of
DNA and its implications, an oft-told tale in
which classical mathematical physics played a
central role. Brilliant biochemical advances, al-
lowing the 3 billion-letter-long human se-
quence to be cut up into manageable fragments,
were a crucial next step. The actual reassem-
bling of the sequence fragments, to obtain a
final human genome sequence, drew on both
huge computational power and complex soft-
ware, itself involving new mathematics. The
sequence information, however, represents only
the Tycho Brahe stage. Current work on various
genomes uses pattern-seeking programs to sort
out coding sequences corresponding to individ-
ual genes from among the background that is
thought to be noncoding. Again, elegant and
sometimes novel mathematics is involved in
this Keplerian stage of the work in progress.
We are only just beginning, if that, the Newton-
ian stage of addressing the deeper evolutionary
questions posed by these patterns (not least, the
surprising finding of how many genes we share
with other species, and how numbers of genes
appear to be uncorrelated with what we regard as
complexity of the organism; rice, for example,
appears to have more genes than we do).
In this Newtonian quest, mathematical mod-
els will help in a different way than in the
earlier stages. Various conjectures about under-
lying mechanisms can be made explicit in
mathematical terms, and the consequences can
be explored and tested against the observed
patterns. In this general way, we can, in effect,
explore possible worlds. Some hard-nosed ex-
perimentalists may deride such exploration of
imaginary worlds. And such derision may have
some justification when the exploration is in
vaguely verbal terms. The virtue of mathemat-
ics in such a context is that it forces clarity and
precision upon the conjecture, thus enabling
meaningful comparison between the conse-
quences of basic assumptions and the empirical
facts. Here mathematics is seen in its quintes-
sence: no more, but no less, than a way of
thinking clearly.
A point that arguably deserves more
emphasis than it usually gets is that, in
such exploration of mathematical mod-
els, the understanding emerging from
complex computer-based simulations
can often be substantially less complete
than that from the analytic methods of
classical applied mathematics and theo-
retical physics. In the World War II
Manhattan Project, the worlds smartest
theoretical physicists used a mixture of
mechanical calculators (the computers
of their day) and analytic approximation
techniques to go from basic equations to
the design of the atom bomb. At every
stage in this process, there was preserved
an intuitive understanding of the relation
between the underlying physical as-
sumptions and the results. Today, mete-
orological predictions are based on sat-
ellite data and the Navier-Stokes (N-S)
hydrological equations, using computers
whose power is beyond the wildest
imaginings of an earlier generation.
Amongst other things, we now believe
that the nonlinear N-S equations can
give so-called chaotic dynamics, where
the sensitivity to initial conditions (the
satellite data) is such that prediction be-
yond 10 to 20 days can be effectively
impossible, no matter how powerful the
computer. In many ways, this has greatly in-
creased our understanding of local weather pre-
diction. Butan important buta rigorous
mathematical proof that the N-S equations have
chaotic solutions, as distinct from computer
simulations that look chaotic, is in effect one of
the century-old unsolved Hilbert problems (and
the Clay Foundation in Boston will give you 1
million dollars if you solve it).
More generally, the increasing speed and
sophistication and ease of use of computers
enables an increasingly large number of life
scientists who have no substantial background
in mathematics to explore mathematical mod-
els and draw conclusions about them. Such
activity usually consists of representing sensible
and evidence-based assumptions as the starting
Fig. 1. Difference between the outcomes from blending and
from particulate inheritance. In post-Mendelian terms, we
assume a single diallelic locus, and hence three diploid geno-
types (AA, blue; Aa, green; aa, yellow). Under particulate
inheritance, the populations variability is preserved from gen-
eration to generation. In contrast, the conventional wisdom of
Darwins day saw offspring inherit a blend of parents charac-
teristics, here represented as the average of the two parental
shadings. The result is that the variability diminishes in suc-
cessive generations (the variance is halved each generation if
mating is at random).
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point for a complicated and usually nonlinear
dynamical system, assigning particular param-
eters (often in an arbitrary way), and then let-
ting this complicated system rip. This repre-
sents a revolutionary change in such theoretical
studies. Until only a decade or two ago, anyone
pursuing this kind of activity had to have a solid
grounding in mathematics. And that meant that
such studies were done by people who had
some idea, at an intuitive level, of how the
original assumptions related to the emerging
graphical display or other conclusions on their
computer. Removing this link means that we
arguably are seeing an increasingly large body
of work in which sweeping conclusions
emergent phenomenaare drawn from the
alleged working of a mathematical model, without
clear understanding of what is actually going
on (Fig. 2). I think this can be worrying.
This cautionary note can be fleshed out
with a couple of examples. The first
comes from HIV/AIDS in the mid-1980s,
when Roy Anderson and I published the
first, rough estimate of its likely demo-
graphic impact in some central African
countries. The main unknown at that time
was the probability, , that an infected
individual would infect a susceptible part-
ner. Available data suggested that de-
pended relatively little on the number of
sexual acts within a partnership. On this
basis, we used a relatively simple model
to suggest that the future demographic
impact of HIV/AIDS could be severe in
some such countries. In contrast, the
World Health Organization and the Pop-
ulation Council in New York produced
models that were much more complex,
including very detailed demographic data,
but where HIV transmission probability
was treated as if for measles, compound-
ing independently randomly for each in-
dividual sex act. Thus, in effect, their
models assumed that, knowing nothing of
the infective status of individuals, 1 sex
act with each of 10 different sex workers
was effectively equivalent to 10 acts with
1; our data-governed, but otherwise much
simpler, model saw the former as roughly 10
times more risky. So it was not surprising that
the later models, apparently more realistic by
virtue of their computational complexity, sug-
gested a less gloomy view than ours. Sadly, but
understandably, our predictions have proved
more reliable (3, 4).
An interestingly different but rather com-
mon sin is exemplified in a risk-assessment
study commissioned by the U.K. Government a
few years ago to help determine whether to ban
beef-on-the-bone (T-bone steak; hereafter
BOTB) in the aftermath of the BSE or mad
cow epidemic. Three factors are involved in
any assessment of the likely number of cases of
vCJD in humans prevented by such a ban: the
number of infected animals still liable to enter
the human food chain, after the precautionary
measures taken earlier; the amount of infected
meat additionally removed by banning BOTB;
the probability, P, of contracting vCJD after
eating, say, 1 g of infected meat. Of these three,
the first can be estimated fairly reliably (cer-
tainly to within a factor 10). The second can be
estimated to stupefying precision, which indeed
forms the bulk of the report. The infection
probability, P, is essentially unknown. So the
study ran computer simulations, with an arbi-
trary distribution of P values ranging over six
orders of magnitude. For any one assumption
about the P value, you could roughly assess the
number of vCJDcases saved by banning BOTB
by a calculation on the back of an envelope. In
the published study, however, these arbitrary
assumptions were magically transmogrified
into a probability distribution by passage
through a big computer. The resulting 95%
confidence interval included the possibility of
saving one life. This, along with other consid-
erations, led to the ban. Of course, an alterna-
tive assessment could have asked what is the
ratio of the cases of vCJD saved by banning
BOTB to the number of casesat that time
hard to estimatecoming down the pipeline
from cattle that entered the human food chain at
the height of the epidemic, before effective
measures were taken. This ratio depends mainly
on the number of cattle still entering the human
food chain to the number entering at the epi-
demics height, with the great uncertainty in P
canceling out of the ratio. On this basis, you
would conclude that for every case of vCJD
prevented by banning BOTB, you were looking
at 100,000 (give or take a factor 10!) cases of
vCJD yet to come from the earlier epidemic.
Put another way, given the best guess of a few
hundred cases of vCJDfromthe earlier epidem-
ic, the ban prevented 10
3
of a case. The public,
with admirable common sense, saw the ban as
silly, and they were right. Sadly, examples of the
application of statistical confidence intervals to
distributions resulting from making arbitrary as-
sumptions about essentially unknown parameters,
and then endowing this with reality by passage
through a computer, continue to proliferate.
The history of useful mathematical models,
and of mathematics more generally, varies
among different areas in the life sciences. I
referred earlier to population genetics;
ecology and immunology provide two fur-
ther, and interestingly different, examples.
Ecology is a relatively young subject,
and much early work was largely descrip-
tive. Seminal studies by Lotka and Volt-
erra explored mathematical metaphors for
competition and other interactions among
species, but things did not really take off
until the 1960s, when Hutchinson and
MacArthur began to ask focused and test-
able questions in the idiom of theoretical
physics: How similar can species be yet
persist together. How do the patterns of
species interactions within a food web
affect its ability to withstand disturbance.
Why are some natural populations rela-
tively steady from year to year, others
cyclic, and others fluctuate widely (5)? At
first, some ecological empiricists resented
arrivistes, who had paid no dues of years
of toil in the field, presuming to math-
ematicize their problems (sometimes
sweeping aside arguably irrelevant, but
certainly much loved, details in the pro-
cess). Others welcomed the newcomers
too uncritically. Look at the ecology texts
of 50 years ago, and you will find very
few equations. Todays, by contrast, con-
tain a blend of observation, field and lab-
oratory experiment, and theory expressed
in mathematical terms. I think this reflects the
maturing state of this vital subject, although it
still has more questions than answers. The
mathematical traffic, moreover, has not been all
one-way: Some of the seminal developments in
chaos theory were prompted by ecological
problems (6, 7).
Immunology offers a somewhat different
picture. Here there are truly remarkable advanc-
es in describing and understanding, at the mo-
lecular level, how individual viruses and other
infectious agents interact with individual im-
mune system cells. And on the basis of such
knowledge, so brilliantly detailed on the molec-
ular scale as almost to defy intuitive compre-
hension, we can, for example, design drugs that
suppress viral replication. Chemotherapy
Fig. 2. The predictions for the numbers of animals infected
with foot-and-mouth disease, under a controlled program
that combines culling with reactive vaccination. The red
curve shows the mean, and the shaded region the range, for
simulations of a detailed stochastic model in which spread
of infection is modeled using the actual spatial distribution
of farms in England and Wales. The blue curve is from a
highly simplied toy model, using gross averages of
relevant parameters. The comparison between the simple
model, in which the dynamics can be clearly understood,
and the complex computer simulations is illuminating both
for the similarities and the differences (the latter helping to
explain why, in reality, local outbreaks continued to erupt
many months after the endpoint predicted by deterministic
models). Reprinted with permission (10).
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against HIV is one notable example. At the
same time, however, there is as yet no agreed
explanation for why there is so long, and so
variable, an interval between infection with
HIV and onset of AIDS. Indeed, I guess that
many researchers in this field do not even think
about this question. But I suspect the answer
may necessarily involve understanding how
whole populations of different strains of HIV
interact with whole populations of different
kinds of immune system cells, within infected
individuals. And understanding the nonlinear
dynamics of such a system will require mathe-
matical models with similarities to and differ-
ences from those that have helped us under-
stand population-level problems in ecology and
infectious diseases (8). It may even be that the
design of effective vaccines against protean
agents like HIV or malaria will require such
population-level understanding. As yet, this
mathematically theoretical aspect of immunol-
ogy is even less to be found in textbooks than
were mathematical models in ecology texts a
generation ago. I venture to predict that the
corresponding immunology texts will indeed
look different in 20, or even 10, years time.
In short, mathematical models have proved
to have many uses and to take many forms in
the life sciences. We all, by this time, acknowl-
edge the usefulness of statistical recipes to help
design and analyze experiments. More familiar
in some areas than others are the benefits of
mathematical studies that underpin pattern-
seeking and other software that is indispensable
in elucidating genomes, and ultimately in un-
derstanding how living things assemble them-
selves. Very generally useful are still-unfolding
advances that illuminate the frequently counter-
intuitive behavior of nonlinear dynamical sys-
tems of many kinds.
Mathematics, however, does not have the
long-standing relation to the life sciences that it
does to the physical sciences and engineering. It
is therefore not surprising to find occasional
abuses. Some have been sketched above. Par-
ticularly tricky are instances in which con-
ventional statistical packages (often based on
assumptions of an underlying Gaussian distri-
butionthe central limit theorem) are applied
to situations involving highly nonlinear dynam-
ical processes (which can often lead to situa-
tions in which rare events are significantly
more common than Gaussian distributions sug-
gest) (9). Perhaps most common among abuses,
and not always easy to recognize, are situations
where mathematical models are constructed
with an excruciating abundance of detail in
some aspects, whilst other important facets of
the problem are misty or a vital parameter is
uncertain to within, at best, an order of magni-
tude. It makes no sense to convey a beguiling
sense of reality with irrelevant detail, when
other equally important factors can only be
guessed at. Above all, remember Einsteins dic-
tum: models should be as simple as possible,
but not more so.
References and Notes
1. R. A. Fisher, The Genetical Theory of Natural Selection
(Dover [reprint], New York, 1958).
2. G. H. Hardy, Science 28, 49 (1908).
3. For a more full discussion see R. M. Anderson and
R. M. May [Infectious Diseases of Humans (Oxford
Univ. Press, 1991), chap. 11].
4. J. Bongaarts, Stat. Med. 8, 103 (1989).
5. R. MacArthur, Geographical Ecology (Harper & Row,
New York, 1972).
6. For further discussion, see G. Farmelo (Ed.) [It Must
be Beautiful: Great Equations of Modern Science
(Granta, London, 2002), pp. 212229] and (7).
7. J. Gleick, Chaos: Making a New Science (Viking, New
York, 1987).
8. M. A. Nowak, R. M. May, Virus Dynamics: Mathemat-
ical Principles of Immunology and Virology (Oxford
Univ. Press, Oxford, 2000).
9. N. Goldeneld, L. P. Kadanoff, Science 284, 87
(1999).
10. M. J. Keeling et al., Nature 421, 136 (2003).
11. I thank many colleagues, particularly S. Levin, A.
Grafen, D. Rubenstein, and M. Stumpf for helpful
conversations, and the Leverhulme Trust and the
Nufeld Foundation for their support.
R E V I E W
Evolutionary Dynamics of Biological Games
Martin A. Nowak
1
* and Karl Sigmund
2,3
Darwinian dynamics based on mutation and selection form the core of mathe-
matical models for adaptation and coevolution of biological populations. The
evolutionary outcome is often not a tness-maximizing equilibrium but can
include oscillations and chaos. For studying frequency-dependent selection,
game-theoretic arguments are more appropriate than optimization algorithms.
Replicator and adaptive dynamics describe short- and long-term evolution in
phenotype space and have found applications ranging from animal behavior and
ecology to speciation, macroevolution, and human language. Evolutionary game
theory is an essential component of a mathematical and computational approach
to biology.
Evolution through natural selection is often
understood to imply improvement and
progress. A heritable trait that confers to its
bearer a higher fitness will spread within
the population. The average fitness of the
population would therefore be expected to
increase over time. This is often pictured as
a steady ascent on a so-called fitness land-
scape. The landscape metaphor suggests
some solid ground over which the popula-
tion moves. This paradigm (1), which is
also widespread in the theory of genetic
algorithms (2), neglects one-half of the
evolutionary mechanism: Although the en-
vironment selects the adaptations, these ad-
aptations can shape the environment. By
moving across a fitness landscape, popula-
tions change that landscape (Fig. 1).
This is particularly clear if several pop-
ulations interact, because each population
can be part of the fitness landscape of the
other. A hosts successful immune response
to a pathogen, for instance, will exert se-
lection pressure leading to adapted strains
of pathogens, and vice versa (35). But
even within a single population, the fitness
of a trait often depends on the prevalence of
that trait: The selective advantage of a giv-
en tree height, for example, depends on the
heights of neighboring trees. Similarly, the
success of a given sex ratio depends on the
overall sex ratio in the population.
Therefore, the fitness landscape is
shaped by the phenotypic distributions of
the involved populations. As the population
moves through the fitness landscape, new
peaks and valleys form, channeling its fur-
ther motion. This viewpoint affects not
only the intuition of evolutionary biologists
but also their theoretical tools. The proper
technique for describing uphill motion on
solid ground is optimization theory, a set of
mathematical techniques developed in the
past 300 years, mostly to solve physical or
technical problems. If the adaptive steps,
however, imply changes in the environ-
1
Program for Evolutionary Dynamics, Department
of Mathematics, Department of Organismic and
Evolutionary Biology, Harvard University, 1 Brattle
Square, Cambridge, MA 02138, USA.
2
Faculty for
Mathematics, University of Vienna, Nordberggasse
15, A-1090 Vienna, Austria.
3
International Institute
for Applied Systems Analysis (IIASA), A-2361 Lax-
enburg, Austria.
*To whom correspondence should be addressed.
E-mail: [email protected]
M A T H E M A T I C S I N B I O L O G Y
www.sciencemag.org SCIENCE VOL 303 6 FEBRUARY 2004 793
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