Why do tigers have stripes?

Turings work on
mathematical biology

Bjarni V. Halldrsson
 Overview

What might have motivated Turing

Turings work on morphogenesis
- impact of this work
How he motivated others
Turings legacy
 Turings work

3 seminal works with over 5000 citations

each.
- Turing machine
- Turing test
- Pattern formation
 Turings puzzle

Life of an organism starts from a single

cell, this cell has virtually no pattern to
it.
Yet, it evolves to a very complicated
organism, sometimes exhibiting
complex patterns.
Pattern often same across species.
 Turings Interest
Turing worked from 1952 until his death in 1954 on
mathematical biology, specifically morphogenesis. He
published one paper on the subject called "The
Chemical Basis of Morphogenesis" in 1952, putting
forth the Turing hypothesis of pattern formation His
central interest in the field was understanding
Fibonacci phyllotaxis , the existence of Fibonacci
numbers in plant structures. He used reaction-
diffusion equations which are now central to the field
of pattern formation.
Morphogenesis : a study concerned with the shapes of
tissues, organs and entire organisms and the
positions of the various specialized cell types
 Fibonacci pattern

1,1,2,3,5,8,13,21,34
55,89,144,233
 Morphogen

A morphogen is a substance governing the pattern of

tissue development, and the positions of the various
specialized cell types within a tissue. It spreads from
a localized source and forms a concentration gradient
across a developing tissue
In developmental biology a morphogen is rigorously
used to mean a signaling molecule that acts directly
on cells (not through serial induction) to produce
specific cellular responses dependent on morphogen
concentration
A mathematical model for the growing embryo
A very general program for modeling
embryogenesis: The `model is a
simplification and an idealization and
consequently a falsification.
Morphogen: is simply the kind of substance
concerned in this theory in fact,
anything that diffuses into the tissue and
somehow persuades it to develop along
different lines from those which would
have been followed in its absence
qualifies.
 3
Diffusion of molecules in a gas

(a) (b)

As a result of their random movements the

molecules become evenly distributed

Clearly not a sufficient model.

 Background in Chemistry

The rate of reaction

A + B -> C
Is dependent on the concentration of A
times the concentration of B.
Diffusion generally balances the amount
of each material.
 Multiple cells

Consider each cell as a unit.

Diffusion means that if there is high
concentration of a material in one cell it
will flow to another cell that has less
concentration.
 Turing Instabilities

The Chemical Basis of Morphogenesis,

1952
Steady state but one which varies in
space, resulting in a spatially
inhomogeneous pattern
Fundamental as diffusion thought of as a
stabilising mechanism
 Two morphogens

Two morphogens, X and Y.

If we allow for multiple reactions these
The rate of production of X is dependent
on X and Y, gx(X,Y)
The rate of production of Y is dependent
on X and , gy(X,Y)
 Two morphogens

Production of X is at rate 5X - 6Y + 1
Production of Y is at rate 6X - 7Y + 1
If X = 1, Y=1 in two adjacent cells we have equilibrium.
If X is increased slightly production of X and Y will
increase
 Reactions sufficient to describe above
(i) A set of reactions producing the first morphogen at the constant
rate 1, and a similar set forming the second morphogen at the
same rate.
(ii) A set destroying the second morphogen (Y) at the rate 7Y.

(iii) A set converting the first morphogen (X) into the second (Y) at
the rate 6X.
(iv) A set producing the first morphogen (X) at the rate 11X.
(v) A set destroying the first morphogen (X) at the rate 6Y, so long
as any of it is present.
 put The
X, most h +x,,assumption
= general -
Y, kthaty,.+ can beOne
made mayis that foralso
concentrations
write ax +X andbYychemic
forf
+x,reactions
y -tk).are Sincetending tof(h,
increase the ratek)f(X,=Y)0and
k) X=atg(h, noY atconstant
the rate g(X,terms
Y). Whenat
changes in X and
are supposed Y due tothe
small diffusion
terms are also
in taken
higher into account
powersthe behaviour
of x andof theysyste
wi
Equations on a ring of cells
d onemayisbejustisfied
described by in the ignoring
2N differentialthem.
equationsThe four quantities a, b, c
reaction rates'. Collectively they may be described as the ' m
When there are Mmorphogens this matrix consists of M 2num
has the dimensions of the reciprocal of a time, like a radioa
t an example of a marginal (nuclear) reaction rate.
assumptions the equations can be rewritten as
If-f(h, k) : g(h, k) = 0, then an isolated cell has an equilibrium with concentrations X =
Y = k. The ring system also has an equilibrium, stable or unstable, with each X, equal to
and each Y, equal to k. Assuming that the system is not very far from this equilibrium it
+ -+ +
convenient to put X, = h x,, Y, k y,. One may also write ax by forf (h x, y i-k) an +
+
cx dy for g(h +x, y -tk). Since f(h, k) = g(h, k) = 0 no constant terms are required, an
e equations one introduces new co-ordinates to,. ..,EN',_, a
since x and y are supposed small the terms in higher powers of x and y will have relative
 Reaction diffusion Model

Let C be the vector of morphogen concentrations. The

vector equation giving the spatial and temporal
dynamics of morphogen concentrations is:

C/t = F(C) + D2C

where F(C) is a nonlinear vector function and D is

diagonal matrix.
 Turing reaction diffusion model
Turing said in effect that if D=0 and C goes to the
steady state solution of F(C*)=0, then under some
circumstance the introduction of nonzero D can
create spatial variations that produce patterns.
For the problem to be properly formulated there must be
boundary and initial conditions specified. Let B be the
domain of the problem and let B be the boundary of
the domain. Then the boundary and intial conditions
are:
nC = 0 on B
C(r,0) = G(r).
 Equations
Let C* be a solution to F(C)=0. C* is a solution which is
uniform over space and thus 2C* = 0. Now
consider a linearization of the equation about the
point C*. Thus
C/t = F(C) + D2C
C*/t=F(C*)+D2C*
c/t = Ac+ D2c

where c = C - C* and A = [F/C], where is a

nondimensional scale parameter that is proportional
to the square of the linear dimension of a one
dimensional system and the area of a two
dimensional system.
 Turings equations

Reaction-Diffusion Equation (1) Reaction Equation (2)

A constant solution u(t,x)=u0, v(t,x)=v0 can be a stable

solution of (2), but an unstable solution of (2). Thus the
instability is induced by diffusion.
On the other hand, there must be stable non-constant
equilibrium solutions which have more complicated
spatial structure.
 Turings contribution

Noticed that these differential equations

will be instable in the presence of
diffusion.
Characterized the solutions to these
equations.
Mapped the solutions of these equations
biological phenomena.
 Solutions to these equations

Solutions of these include

wave functions,
exponential functions
Growing waves
Reaction-diffusion: an example
 On an Interesting Note

For a periodic solution in an essentially

linear domain, as for example in a
snake skin, coloration of all regions
above a threshold level would result in
stripes. In more rectangular domains
there could also be stripes, but there
can also be spots.
 Reaction diffusion equations

Two-component systems allow for a much larger range

of possible phenomena than their one-component
counterparts.
An important idea that was first proposed by Alan
Turing is that a state that is stable in the local system
should become unstable in the presence of diffusion.
This idea seems unintuitive at first glance as diffusion is
commonly associated with a stabilizing effect.
 Morphogenesis

my mathematical theory of embryology is yielding to treatment, and it will so

far as I can see, give satisfactory explanations of

i) Gastrulation

ii) Polygonally symmetrical structures, e.g. starfish, flowers

iii) Leaf arrangements, in particular the way the Fibonacci series comes to be
involved

iv) Colour patterns on some animals, e.g. stripes, spots and dappling
 On Turings paper
Turings argument involved a mathematical trick: he created a
nonlinear system by turning on diffusion discontinuously in an
otherwise linear system at a specific instant. Without diffusion,
the system is stable and homogeneous, but with diffusion, it
becomes unstable and forms spatial pattern. The brilliance of
the trick is that the nonlinearity is confined to a single point in
time, so that at all other times, only the theory of linear equa-
tions is needed. Turing cleverly arranged to have diffusion
generate pattern, rather than blur it, as it usually does.
 Further observation in morphology paper

He raised deep questions that are still

unsolved, noting for instance that all
physical laws known at the time had
mirror - image symmetry, but biological
systems did not.
 Nature 2012

Paper marked transition point from

analytical mathematics to that of
computational mathematics.
 Morphogenesis 5701 citations
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 Turings impact in computational biology

Suggested that life could be considered

as a computational machine.
Turing machine
Turing test
Central dogma
 Biological background
The eukaryotic cell!
 Turing Von Neumann

Turing invented the stored-program computer, and von

Neumann showed that the description is separate
from the universal constructor. This is not trivial.
Physicist Erwin Schrdinger confused the program
and the constructor in his 1944 book What is Life?, in
which he saw chromosomes as architects plan and
builders craft in one. This is wrong. The code script
contains only a description of the executive function,
not the function itself.
 Turing machines

Von Neumann: Construct a machine that

could replicate itself.
Biology can be seen as an example of a
Turing and Von Neumann machine
 Regulation of Gene Expression

Animals can be viewed as highly

complex, precisely regulated spatial and
temporal arrays of differential gene
expression.
Gene expression is regulated by a
complex network of interactions among
proteins, genomic DNA, RNA and
chemicals within the cell.
 RNA, Genes and Promoters
A specific region of DNA that determines the synthesis of
proteins (through the transcription and translation) is
called a gene
Originally, a gene meant something more abstract---a
unit of hereditary inheritance.
Now a gene has been given a physical molecular
existence.
Transcription of a gene to a messenger RNA, mRNA, is
keyed by a transcriptional activator/factor, which
attaches to a promoter (a specific sequence adjacent to
the gene).
Regulatory sequences such as silencers and enhancers
Promoter control the rate of transcription Terminator
10-35bp
Transcriptiona Gene Transcriptiona
l l
Initiation Termination
 Turings position at time of publication

In charge of building on of the first computers.

Recently elected Fellow of the Royal Society.
Also liked to work on pure science.
 Turing, Von Neumann axioms

Axiom 0. Be an automata theorist

Axiom 1. Work on the most theoretical and most
practical at the same time
Axiom 2. Be a mathematician of the discrete and
continuous
Axiom 3. Be intra math, intersciences, cross
cultures scientist
Axiom 4. Work on the hardest problems
Axiom 5. And in the end, the love you take is equal to
the love you make.
What followed the publication

Got involved in a romantic

relationship.
For which he was arrested
and sentenced for.
 References

Alan Turing -
Pattern formation John Reinitz
Lifes code script Sydney Brenner
Pattern formation Patrick Lucey
Understanding science through the computational lense
Richard Karp
Computational Systems Biology Bud Mishra
Alan Turing, the Enigma - Andrew Hodges
Sorin Istrail working papers