()

2007 9

?
Systems biology is the science of discovering, modeling, understanding and ultimately engineering at the molecular level the dynamic relationships between the biological molecules that define living
organisms.

Leroy Hood, Ph. D., M.D.,

President
Institute for Systems Biology
All biological phenomena, whether its digestion of a sugar molecule, beating of the human heart,
or neutralizing an invading virus, are the result of complex systems. Thus our approach is to focus
research on biological systems as a whole, rather than pursue the traditional approach of focusing on
individual genes, proteins, or parts of an organism.
?
?
Scientists from multiple disciplines (biology, chemistry, mathematics, physics, etc.) work closely
together to fully understand all aspects of the inherently complex systems intrinsic to living organisms.
Such in-depth understanding is ultimately essential to realizing our goal of predictive, preventive,
personalized medicine.
?
()
......


I
@
@
@
?
@

Most readers of this publication will know that post-genomics and proteomics are phrases
that mean little that is specific but herald an encyclopaedic era of information about the way biological
cells and their genes and proteins behave. But how best to make sense of it all? It is, at last, possible
to anticipate mathematics becoming useful in the modelling of the systems.
Nature 407 2000, 819.
?

Toggle switches

2

(Master equation, Langevin equation, Fokker-Plank equation)
()
()
()
:
1. Mackey, M. C., Santillan, M., Mathematics, Biology, and Physicss: Interactions and interependence, Notices AMS, 52(2005)(8).
2. Sontga, E. D., Molecular systems biology and dynamics: an introduction for non-biologists.
3. Alon, U., An introduction to systems biology, Chapman & Hall/CRC, London, 2007.
4. Fall, C. P., Marland, E. S., Wagner, J. M., Tyson, J. J., (Eds.) Computational cell biology,
Springer-Verlag, New York, 2001.
5. Alberghina, L., Westerhoff, H. V. (Eds.) Systems biology: Definitions and perspectives. Springer,
Berlin, 2005.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.1 . . . . . . . . . . . . . . . . . .
1.2 . . . . . . . . . . . . . .
1.3 . . . . . . . . . . . . . .
1.4 . . . . . . . . . . . .
1.5 . . . . . . . . . . . . . . .
1.5.1 . . . .
1.5.2 . . . . . . .
1.5.3 Fokker-Plank . . .
1.5.4 . . . . .
1.6 Michaelis-Menten and Hill Equations
1.7 . . . . . . . . . . . . .

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1 . . . . . . . .
2.2 . . . . .
2.3 . . . . .
2.4
2.5 . . . . .
2.6 . . .

.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1 Toggle Switches . . . . . . . . . . . . . . . . . . . . . . . . .

3.1.1 Bistability . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2 A model for repressor expression[21] . . . . . . . . .
3.1.3 Noise induce switchesextrinsic noise . . . . . . . . .
3.1.4 Noise induce switchesintrinsic noise . . . . . . . . .
3.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1 Atkinson Oscillator . . . . . . . . . . . . . . . . . . .
3.2.2 A synthetic gene-metabolic oscillator . . . . . . . . .
3.2.3 Mechanisms of noise-resistance in genetic oscillators
3.2.4 . . . . . . . . . . . . . . . . . . . . . . .
3.2.5 . . . . . . . . . . . . . . . . . .
3.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.1 Dimerization and proteolysis of PER and TIM . . .
3.3.2 Circadian rhythm generator . . . . . . . . . . . . . .
3.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5 Morphogen gradient . . . . . . . . . . . . . . . . . . . . . .
3.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7 . . . . . . . . . . . . .
i

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

1
1
2
2
5
7
7
7
8
8
9
12
13
13
13
13
16
16
16
18
18
18
20
22
23
26
26
28
29
34
39
42
42
45
49
50
52
57

 3.7.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.1 Nernst
4.2 . . . . . . .
4.3 .
4.4 Morris-Lecar . . .
4.5 Hodgkin-Huxley .

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.1 . . . . . . . . . . . . . .
5.2
5.2.1 . . . . . . . . . .
5.2.2 . . . . . . . . . .
5.3 . . .
5.4 . . . . . . . . . . . . . .

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

57
60
63
63
64
64
64
64
65
65
66
66
68
71
72

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

74

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79

{ch3}

1.1
N 1 {S1 , , SN } . ()
. M 1 {R1 , , RM }. X(t) = (X1 (t), , XN (t))
t ,
Xi (t) Si t , (i = 1, , N ).
X(t) , ,
. , Propensity Function aj ,
aj (x)dt X(t) = x , Rj [t, t + dt) ,
(j = 1, . . . , M ).
.Rj (state-change vector) vj
:
vji Si Rj (j = 1, , M ; i = 1, , N ). vji > 0 Rj
Si , vji < 0 Rj Si .
aj vji Rj . , ,
.
, Propensity function aj (x) :
aj (x) = cj hj (x).

(1.1.1)

cj Rj specific probability rate constant, cj dt Rj

, dt . dt
, Rj . cj
(reaction rate constant) kj . hj (x) X(t) = x , Rj
. (, v1 = (+1, 1, 0, , 0) v2 = v1 .)
Rj , , cj , .
hj (X) .
:
R1 : X1 + X2 2X1 ,
a1 (x) = c1 x1 x2 .

R2 : 2X1 X1 + X2

propensity function a2 (x) = c2 x1 (x1 1)/2.

1.2
t , X(t). [t, t + dt) , Rj aj (X)dt.
, Si Xi (t) + vji . , t + dt , Si
Xi (t + dt) Xi (t) =

M
X
j=1

aj (X)vji dt (i = 1, , N ).

dt, dt 0,
M

dXi X
aj (X)vji (i = 1, , N ).
=
dt
j=1

(1.2.2) {eq:1.2:1}

, , Xi (t) . t
. , , .
, , , Z = (Z1 , , ZN ), Zi = Xi /.
(chemical rate equation)
M

dZi X
a
j (Z)vji (i = 1, , N ).
=
dt
j=1

(1.2.3) {eq:cre}

a
j (Z) =

aj (Z)
.

: ,
dZ1
dt
dZ2
dt

= k1 Z1 Z2 k2 Z1 (Z1 1/)

(1.2.4) {eq:1.2:3}

= k1 Z1 Z2 + k2 Z1 (Z1 1/)

k1 = c1 , k2 = c2 /2 R1 R2 . + ,
(chemical rate equation)
dZ1
= k1 Z1 Z2 k2 Z12
dt
(1.2.5) {eq:1.2:4}
dZ2
= k1 Z1 Z2 + k2 Z12
dt
, (1.2.5) ().
, , , ,
, . , .

1.3
, ,
, (chemical master equation).
P (x, t|x0 , t0 ) :
P (x, t|x0 , t0 ) = Prob{X(t) = x, given that X(t0 ) = x0 }.

(1.3.6) {eq:1.3:1}

, P (x, t|x0 , t0 ) . , dt ,
dt . , t
t + dt :

M
M
X
X
[P (x vj ), t|x0 , t0 )aj (x vj )dt].
aj (x)dt +
P (x, t + dt|x0 , t0 ) = P (x, t|x0 , t0 ) 1
j=1

j=1

dt 0,
M

[aj (x vj )P (x vj , t|x0 , t0 ) aj (x)P (x, t|x0 , t0 )] .

P (x, t|x0 , t0 ) =
t
j=1

(1.3.7) {eq:cme}

(1.3.7) . P ,
X(t). , , (1.3.7) ,
, .
, X(t) .
,
X
E(t|x0 , t0 ) =
xP (x, t|x0 , t0 ).
x

X(t0 ) = x0 , t t0 . .
P RN [t0 , +), X(t) = x , P (x, t|x0 , t0 ) = 0,
RN :
X
E(t|x0 , t0 ) =
xP (x, t|x0 , t0 ).
(1.3.8) {eq:1.3:2}
xRN

, , E(t) = (hX1 (t)i, , hXN (t)i).

(1.3.7),
M
X
dhXi i X
vji
aj (x)P (x, t)
=
dt
N
j=1

(1.3.9) {eq:1.3:3}

xR

(1.3.9) .
haj (X)i =

aj (x)P (x, t)

xRN

dhXi i X
vji haj (X)i
=
dt
j=1

(1.3.10) {eq:1.3:4}

, haj (X)i = aj (hXi), (1.2.2). ,

, (1.3.10) (1.2.2). , aj (X) = cj Xjk , haj (X)i = aj (hXi).
(1.3.10) (1.2.2). , , (1.2.2) .
, , (1.2.2) .
, x vj , (1.3.7) x . ,
()

N
M
2
X
X
X

aj (x)P (x, t)
aj (x)P (x, t)vji +
aj (x)P (x, t)
P (x, t) =
t
x
2
x
x
i
i
k
i=1
j=1
1i,kN

M
X
j=1

aj (x)P (x, t) +

vji .
Ai (x) =

M
X

M
X

vji aj (x), Bik =

vji vjk aj (x)

(1.3.11) {eq:1.3:5}

j=1

j=1

N
X

1
Ai (x)P (x, t) +
P (x, t) =
t
xi
2
i=1

1i,kN

2
Bik (x)P (x, t).
xi xk

(1.3.12) {eq:fk}

Fokker-Plank . Ai (x) Bik (x) . ,

Fokker-Plank , .
,
ik = h(Xi hXi i)(Xk hXk i)i

(1 i, k N ).

(1.3.13) {eq:var}

ik t . P ,
X
ik (t) =
(xi hXi (t)i)(xk hXk (t)i)P (x, t).
xRN

ik :
dik
dt

X
dhXi i
dhXk i
)(xk hXk i)P (x, t) +
)(xi hXi i)P (x, t)
(
dt
dt
N

xRN

xR

xRN

xRN

(xi hXi (t)i)(xk hXk (t)i)

(xi hXi i)(xk hXk i)

M X
X

j=1 xRN

j=1 xRN

j=1 xRN

j=1 xRN

xRN

(aj (x vj )P (x vj , t) aj (x)P (x, t))

(xi hXi i)(xk hXk i)aj (x)P (x, t)

(xi + vji hXi i)(xk + vjk hXk i)aj (x)P (x, t)

M X
X

j=1

(xi hXi i)(xk hXk i)aj (x vj )P (x vj , t)

M X
X

M X
X

M
X

P (x, t)
t

(xi hXi i)(xk hXk i)aj (x)P (x, t)

[Ai (x)(xk hXk i) + Ak (x)(xi hXi i)] P (x, t) +

Bik (x)P (x, t).

xRN

Ai (x), Bik (x) . , ik .

X
X
dik
=
[Ai (x)(xk hXk i) + Ak (x)(xi hXi i)] P (x, t) +
Bik (x)P (x, t)
dt
N
N
xR

xR

(1.3.14) {eq:var:1}

, xi hXi i , Ai (x) Bik (x) :

Ai (x)

= Ai (hXi) +

N
X
Ai (hXi)
l=1

Ak (x)

= Ak (hXi) +

= Bik (hXi) +
X

1p,qN

xl

(xl hXl i) +

N
X
Bik (hXi)
l=1

(xl hXl i) +

N
X
Ak (hXi)
l=1

Bik (x)

xl

xl

(xl hXl i)

2 Bik (hXi)
(xp hXp i)(xq hXq i) +
xp xq

(1.3.14),
X
X
x RN (xi hXi i)P (x, t) = 0,
x RN P (x, t) = 1


N 
X
Ak (hXi)
Ai (hXi)
dik
il +
lk + Bik (hXi) +
=
dt
xl
xl
l=1

1p,qN

2 Bik (hXi)
pq .
xp xq

(1.3.15) {eq:var:2}

= (ik ), A = (Ai (hXi)/xl ), B = (Bik (hXi), C =

2 Bik (hXi)
xp xq

d
= (A + AT + C) + B.
dt
Fluctuation-Dissipation Theorem (C).

(1.3.16) {eq:df}

1.4
, X(t) . t, X = xt .
Kj (xt , ) ( > 0)Rj [t, t + ] .
Si vji , Si t +
Xi (t + ) = xt,i +

M
X
j=1

Kj (xt , )vji , (i = 1, , N ).

(1.4.17) {eq:1.4:1}

, Kj (xt , ) . , . ,
.
: , , [t, t + ] , , ,
propensity function :
aj (X(t )) aj (xt ), t [t, t + ], j [1, M ].

(1.4.18) {eq:1.4:2}

, 1 , , 1 ,
, .
, [t, t + ] propensity function. ,
[t, t + ] . , Kj (xt , ) propensity function aj (xt ) , Rj . Possion Pj (aj (xt ), ).
5

P(a, t) dt adt , t
. Q(n; a, t) P(a, t) n () ,
Q(0; a, t + dt) = Q(0; a, t) (1 adt)

Q(0; a, t)
= at,
t

Q(0; a, 0) = 1.

Q(0; a, t) = eat . n 1, ,
Z t
Q(n; a, t) =
Q(n 1; a, t ) adt Q(0; a, t t ).
t =0

,
Q(n; a, t) =

eat (at)n
, (n = 0, 1, 2, ).
n!

, P(a, t)
hP(a, t)i = var{P(a, t)} = at.
at 1 ,



(n at)2
eat (at)n
1/2
.
(2at)
exp
n!
2at

, at 1, P(a, t) :
P(a, t) N (at, at), if at 1.

(1.4.19) {eq:1.A3}

, (1.4.17)
xi (t + ) = xt,i +

M
X
j=1

vji Pj (aj (xt ), ), (i = 1, , N ).

(1.4.20) {eq:1.4:3}

: , [t, t + ] 1,
hPj (aj (xt ), )i = aj (xt ) 1,

j [1, M ].

(1.4.21) {eq:1.4:4}

, , : . ,
. , , , ,
. aj (xt ) , , .
, Possion Pj (aj (xt ), )
. ,
xi (t + ) = xt,j +

M
X
j=1

vji Nj (aj (xt ), ), (i = 1, , N ).

(1.4.22) {eq:1.4:5}

N (m, 2 ) m, 2 . , Possion
. , Xi . , M
. Possion Pj .

N (m, 2 ) = m + N (0, 1),

(1.4.22) :
xj (t + ) = xt,j +

M
X
j=1

vji aj (xt ) +

M
X
j=1

vji [aj (xt ) ]1/2 Nj (0, 1), (j = 1, , N ).

6

(1.4.23) {eq:1.4:6}

Nj (0, 1) .
, , dt. , j (t)
Nj (0, 1) . ,
hj (t)i = 0, hi (t)j (t )i = ij (t t ),

i, j [1, M ], t.

Xj (t) = xt,j , (1.4.23)

xi (t + dt) = xi (t) +

M
X

vji aj (xt )dt +

M
X
j=1

j=1

1/2

vji aj (xt )j (t)(dt)1/2 , (j = 1, , N ).

(1.4.24) {eq:1.4:7}

(Winer process) Wj ,
dWj = Wj (t + dt) Wj (t) = j (t)(dt)1/2

dxi (t) =

M
X

vji aj (xt )dt +

M
X
j=1

j=1

1/2

vji aj (xt )dWj , (j = 1, , N ).

(1.4.25) {eq:1.4:8}

dxj (t) = xj (t + dt) xj (t). (Chemical Langevin Equation).

1.5
, , (),
(Fokker-Plank ), . ,
. .

1.5.1
, : xppaut.

1.5.2
Gilliespie :
1. Xi t = 0.
2. a ( = 1, , M )a0 =

PM

=1

a .

P
3. [0, P
1] r1 r2 , = (1/a0 ) ln(1/r1 ) 1
=1 <

r2 a0 =1 a (, )

a ea0 ,
if 0 < and = 1, , M
P (, ) =
0
otherwise

4. t = t + , R Xi Xi + vi .
Here P (, ) is the reaction probability density function that defined as
P (, )d = probability that, given the state (X1 , , XN ) at
time t, the next reaction in V will occur in the infinitesimal time interval (t + , t + + d ), and will
be an R raction.
7

The probability P is the product of P0 ( ), the probability that, given the state (X1 , , XN ) at
time t, no reaction will occur in the time interval (t, t + ); times a d , the subsequence probability
that an R reaction will occur in the time interval (t + , t + + d ):
P (, )d = P0 ( ) a d.
P
To find and expression for P0 ( ), we first note that [1 a d ] is the probability that no
reaction will occur in time d from the state (X1 , , XN ). Therefore,
X
P0 ( + d ) = P0 ( ) [1
a d ]

from which it is readily deduced that

P0 ( ) = exp[

M
X

a ],

=1

Thus, we obtain the reaction probability density function


a ea0 ,
if 0 < and = 1, , M
P (, ) =
0
otherwise

(1.5.26) {eq:1.5:1}

1.5.3 Fokker-Plank
.

1.5.4
:
Wt , :
1. ;
2. : t1 < t2 < t3 < t4 ,
h(Wt2 Wt1 )(Wt4 Wt3 )i = 0;
3. t, 0, Wt+ Wt , h(Wt+ Wt )2 i = ;
Wt . ,
dx = f (x, t)dt + g(x, t)dWt .
x(t) (1.5.27), x(t)
Z t
Z t
x(t) = x(0) +
f (x(s), s)ds +
g(x(s), s)dWs .
0

(1.5.27) {eq:sde}

(1.5.28) {eq:isde}

It
o .
It
o : x(t) (1.5.27), V (x, t) :


V
V
1 2V
V
2
g(x, t) dt +
+
f (x, t) +
g(x, t)dWt .
(1.5.29) {eq:ito}
dV =
t
x
2 x2
x
(1.5.29) It
o .
,
dXtj = aj (Xt , t)dt +

m
X

k=1

bjk (Xt , t)dWtk ,

(1.5.30) {eq:app1}

j = 1, , n, X = (X 1 , , X n ), Wtk k Wiener t . 1.0 Runge-Kutta

:[27]
Xtji+1

Xtji + aj (Xti )t +

m
X

bjk (Xti )Wtki

(1.5.31)

k=1
m

bj
1 XX l
bk (Xti ) kl (Xti )((Wtki )2 t),
2
Xt
k=1 l=1

t = ti+1 ti , Wtki = Wtki+1 Wtki .

1.6 Michaelis-Menten and Hill Equations

[4] . , DNA
. X DNA (promoter) D ,
[XD]. promoter (). ,
, . , :
D + [XD]1 = DT

(1.6.32) {eq:mm1}

DT , .
X D , , . X D
kon . kon , X D.
, koff . , [XD] :
d[XD]
= kon XD koff [XD].
dt

(1.6.33) {eq:mm2}

, d[XD]/dt = 0,
Kd [XD] = XD
Kd = kon /koff . (1.6.32), :
D
1
=
.
DT
1 + X/Kd

(1.6.34) {eq:mm3}

:
kon 108 1011 M 1 sec1 , koff > 1sec.

(1.6.34) (, 1 sec), X
. X = Kd , %50 .
, . mRNA (promoter activity)
X

.
(1.6.35) {eq:mm4}
promoter activity =
1 + X/Kd
Kd repression coefficient.
, , X SX [SX X] . X
SX ,
X + [SX X] = XT
XT X . X SX jon ,
joff . ()
d[SX X]
= kon XSX joff [SX X].
dt
9

(1.6.36) {eq:m21}

SX , . ,
KX [SX X] = XSX
KX [SX X] . [SX X] SX
Michaelis-Menten ():
[XSX ] =

X T SX
.
SX + K X

(1.6.37) {eq:mm11}

X n , n SX [nSX X] .
[nSX X] + X0 = XT .

(1.6.38) {eq:mm16}

X0 X, (X n ) . [nSX X]
X n SX . jon ,
n
collision rate = jon X0 SX
.

(1.6.39) {eq:mm12}

dissociation rate = joff [nSX X].

(1.6.40) {eq:mm13}

joff :
joff X SX . [nSX X]
d[nSX X]
n
= jon X0 SX
joff [nSX X]
dt

(1.6.41) {eq:mm14}

S , . ,
n
joff [nSX X] = jon X0 SX
.

(1.6.42) {eq:mm15}

(1.6.38),
n
(joff /jon )[nSX X] = (XT [nSX X])SX
.

Sn
[nSX X]
= n X n
XT
K X + SX

(1.6.43) {eq:mm17}

n
KX
= joff /jon . Hill equation, n Hill (Hill coefficient). n > 1 ,
.
X

X0
1
=
.
XT
1 + (SX /KX )n

(1.6.44) {eq:mm18}

, S. [XSX ].
, , . , X :
, DNA , :
XT = X0 + [XD] + [nSX X].

(1.6.45) {eq:mm5}

, :
d[XD]
dt
d[nSX X]
dt

kon X0 D koff [XD],

(1.6.46)

n
jon X0 SX
joff [nSX X].

(1.6.47)

, [nSX X] D , SX , .
,
n
KX [nSX X] = X0 SX
, Kd [XD] = X0 D

10

(1.6.48) {eq:mm8}

KX = joff /jon (for lac repressor, KX 1M 1000 inducer (IPTG) molecules/cell).

(1.6.45) (1.6.48)
1
X0
=
n /K .
XT
1 + D/Kd + SX
X
DNA (1.6.34), promoter activity (f =
f (SX ))SX
f=

n /K ) .
1 + (XT /Kd)/(1 + f DT /(Kd ) + SX
X

(1.6.49) {eq:mm19}

n
SX
/KX DT /Kd ,

f=

n /K ) .
1 + (XT /Kd )/(1 + SX
X

(1.6.50) {eq:mm20}

. SX = 0 , f (SX = 0) /(1 +
XT /Kd ). basal promoter activity, promoter .
SX = S1/2 (XT /Kd )1/n KX
, (f = /2).
: X D , mRNA .
, promoter activity Michaelis-Menten :
promoter activity =

X
.
Kd + X

(1.6.51) {eq:mm10}

X (DNA ) .
SX (n ), n
[nSX X], (, X n
). ,
X + nSX X , X + D D
,
X = [nSX X] =

n
X T SX
n + Sn .
KX
X

,
f (SX ) =

X
.
Kd + X

(1.6.52) {eq:mm22}

SX = S1/2 = (Kd /XT )1/n KX

, .
, , ,
P
i (Xi /Ki )ni
iP
f (X1 , , Xm ) =
1 + i (Xi /Ki )mi

Xi , Ki .

11

(1.6.53) {eq:mm22}

1.7
1. van Kampen, N. G. 1992. Stochastic process in physics and chemistry. North-Holland, Amsterdam, 1992.
2. Gillespie, D. T. 1977. Exact stochastic simulation of coupled chemical reactions. J. Phys. Chem.
81:2340-2361.
3. Gillespie, D. T. 2000. The chemical Langevin equation. J. Chem. Phys. 113:297306.

12

2.1
, , DNA (RNA) .
, DNA , -,
, , . DNA
(gene expression), .

2.1:
:
1. (transcriptional regulation);
2. mRNA (differential processing of RNA transcript);
3. (differential translation of mRNA).

2.2
2.3
:

13

{fig:dogma}

Property
Proteins/cell
Time to transcribe a gene
Time to translate a protein
Typical mRNA
lifetime
Cell generation
time
Timescale
of
transcription
factor binding
to DNA site

Yeast (S. cerevisae)

E. coli
4 10

4 109

1min

1 min

2min

2 min

2 5min

10 min to over 1 h

30min (rich
medium to several
hours

2 h (rich medium
to several hours

1sec

2.1: Typical parameter values for the Bacterial E. Coli cell and Saccharonmyces cerevisae
(Yest)(Alon , 2007)
{tab:1}

dX1
dt
dX2
dt
dX3
dt

+
1 (n X1 ) 1 X1

2 X1 2 X2

3 X2 3 X3

:
dP (X1 , X2 , X3 )
dt

+
+
1 (n X1 + 1)P (X1 1, X2 , X3 ) 1 (n X1 )P (X1 , X2 , X3 )

+
1 (X1 + 1)P (X1 + 1, X2 , X3 ) 1 X1 P (X1 , X2 , X3 )

+ 2 X1 P (X1 , X2 1, X3 ) 2 X1 P (X1 , X2 , X3 )
+ 2 (X2 + 1)P (X1 , X2 + 1, X3 ) 2 X2 P (X1 , X2 , X3 )
+ 3 X2 P (X1 , X2 , X3 1) 3 X2 P (X1 , X2 , X3 )
+ 3 (X3 + 1)P (X1 , X2 , X3 + 1) 3 X3 P (X1 , X2 , X3 ).
(0 X1 n, X2 , X3 0)
Chemical Langevin equation

14

2.2: Intrinsic and extrinsic noise in gene expression (Elowitz et. al. 2002)

dX1
dt

= +
1 (n X1 ) 1 X1
q
q
+ +

1 (n X1 )1 (t)
1 X1 2 (t)

(2.3.1)

+ f+ (n X1 )+ (t) f X1 (t),
1

dX2
dt
dX3
dt

p
p
= 2 X1 2 X2 + 2 X1 3 (t) 2 X2 4 (t)
+ f2 X1 2 (t) f2 X2 2 (t),
p
p
= 3 X2 3 X3 + 3 X2 5 (t) 3 X3 6 (t)

(2.3.2)

(2.3.3)

+ f3 X2 3 (t) f3 X3 3 (t),

2.3: A model of the expression of a single gene. Each step represents several biochemical reactions,
which are associated with transition between promoter states, production and decay of mRNAs
and proteins.
{fig:gene}
15

60
md-1.dat using 1:3

50

mRNA

40

30

20

10

0
0

20

40

60

80

100

120

140

Time

2.4: (Gillespie ): [mRNA] vs. Time.

{fig:ge1}

60
md.dat using 1:3

50

mRNA

40

30

20

10

0
0

50

100
Time

150

200

2.5: (Langevin ): [mRNA] vs. Time.

2.4
2.5
2.6
1. Orphanides, G., Reinberg, D., (2002) A unified theory of gene expression, Cell 108, 439-451.
2. Smolen, P., Baxter, D. A., Byrne, J. H., (2000) Mathematical modeling of gene networks. Neuron
26, 567-580.
3. Krn, M., Elston, T. C., Blake, W. J., Collins, J. J., (2005) Stochasticity in gene expression:
from theories to phenotypes. Nat. Rev. Genet. 6, 451-464.
4. Paulsson, J., (2005) Models of stochastic gene expression. Phy. Life Rev. 2, 157-175.

16

{eq:ge2}

5. Elowitz, M. B., Levine, A. J., Siggia, E. D., Swain, P. S., Stochastic gene expression in a signle
cell. Science 297(2002), 1183-1186.
6. Swain, P. S., Elowitz, M. B., Siggia, E. D., Intinsic and extrinsic contributions to stochasticity
in gene expression. PNAS 99(2002), 12795-12800.

17

3.1 Toggle Switches

3.1.1 Bistability
. , .
White-opaque switching is an epigenetic phenomenon, where genetically identical cells can exist
in two distinctive cell types, white and opaque. Each cell type is stably inherited for many generations,
and switching between the two types of cells occurs stochastically and rarelyroughly one switch in 104
cell divisions. The gene Wor1 was identified as a maser regulator of white-opaque switching[39, 28].
In opaque cells, Wor1 forms a positive feedback loop: it binds its own DNA regulatory region and
activates its own transcription leading to the accumulation of high levels of Wor1.
3.1 .

3.1: .

{fig:3:bistabili

GA (, ), M
mRNA , P . ,
(). Pn n-. ,
, , n-. .

k+
+
1
nP Pn , Pn + GR GA .
k

(3.1.1) {eq:3:fast1}

mRNA
+

3
3
2
2
2
.
P
, M
GA
M, GR
M, M

18

(3.1.2) {eq:3:slow}

(, GR = 1 GA )
dPn
dt
dGA
dt
dM
dt
dP
dt

= k + P n k Pn

(3.1.3)

= +
1 Pn (1 GA ) 1 GA

(3.1.4)

= +
2 GA + 2 (1 GA ) 2 M

(3.1.5)

= 3 M 3 P k + P n + kn Pn

(3.1.6)

, (3.1.3)-(3.1.4) ,
Pn = KP n , GA =

Pn
An + P n

+
K = k /k + n-, An = (
1 /1 )/K. ,


dM
Pn
= 2 1 + a n
2 M
dt
A + Pn

dP
dt

3 M 3 P

(3.1.7) {eq:3:5}

(3.1.8)
(3.1.9)

2 =
2 , a = (2 2 )/2 .

x = M/(3 A/3 ), y = P/A, t = 3 t

dx
dt
dy
dt

= (1 + ay n /(1 + y n )) x

(3.1.10)

= xy

(3.1.11)

t ,
=

2
2 3
, = .
A32
3

,
g(y) = y



yn
g(y) = 1 + a
1 + yn

. n = 1 ,

y =

+ a + +

p
( + a + )2 + 4
.
2

n > 1 , , , . .
1 < 2 , = 1 = 2 , . < 1 > 2 ,
. 1 < < 2 , .
(x , y ),


g (y )
A=
1
1
19

y*

gHyL
15

2.0

1.5
10
1.0
5
0.5

0.5

1.0

1.5

2.0

2.5

4.5

5.0

(A)

5.5

6.0

6.5

(B)
3.2: ( = 4, a = 4, n = 4)

{fig:3:bistabili

. A

p
1
1,2 =
(1 + ) ( + 1)2 + 4(g (y ) ) .
2

Re(1,2 ) < 0 , . , : g (y ) > ,

, g (y ) < , . 1 < 2 , ,
(). < 1 > 2 , ,
. , 1 < < 2 , . 2 2 ,
, 1 1 , . ,
switch .

3.1.2 A model for repressor expression[21]

In the context of the lysis-lysogeny pathway in the virus, the autoregulation of repressor
expression is well characterized. In the section, we present two models describing the regulation of
such a network.
The full promoter region in phage contains the three operator sites known as OR1, OR2 and
OR3. We first consider a mutant system whereby the operator site OR1 is absent from the region.
The basic dynamical properties are as follows: The gene cI expresses repressor (CI), which in turn
dimerizes and binds to the DNA as a transcription factor. In the mutant system, this binding can take
place at one of the two binding sites, OR2 or OR3. Binding at OR2 enhances transcription, which
takes place downstream of OR3, whereas binding at OR3 represses transcription, effectively turning
off production.

3.3: Dynamical properteis of repressor cI.

: . ,
. , (), .
20

{fig:sw1}

X, X2 D , dimer DNA promoter site ,

K1

2X X2
K2

D + X2 DX2
K3

(3.1.12) {eq:sw1}

D + X2 DX2
K4

DX2 + X2 DX2 X2
DX2 DX2 dimer OR2 OR3 , DX2 X2
. Ki , K3 = 1 K2 , K4 = 2 K2 . 1 2
dimer-OR2 .
mRNA :
k

t
DX2 + P + nX
DX2 + P

d
X
A,

(3.1.13) {eq:sw2}

P RNA , n mRNA .
.
X = [X], Y = [X2 ], D = [D], U = [DX2 ], V = [DX2 ], Z = [DX2 X2 ] ,

dX
= 2k1 X 2 + 2k1 Y + nkt P0 U kd X + r.
dT

(3.1.14) {eq:sw3}

, RNA P0 . r CI basal rate of production,

cI .
, Y, U D X (3.1.12) :
Y
U
V
Z

=
=
=
=

K1 X 2
K2 DY = K1 K2 DX 2
1 K2 DY = 1 K1 K2 DX 2
2 K2 U Y = 2 (K1 K2 )2 DX 4

(3.1.15) {eq:sw4}

, DNA , dT :
DT = D + U + V + Z = D(1 + (1 + 1 )K1 K2 X 2 + 2 K12 K22 X 4 ).

(3.1.16) {eq:sw5}

(3.1.15)-(3.1.16) Y, U , (3.1.14), (K1 = k1 /k1 ):

dX
nkt K1 K2 P0 DT X 2
kd X + r.
=
dT
1 + (1 + 1 )K1 K2 X 2 + 2 K12 K22 X 4

(3.1.17) {eq:sw6}

, . M T ,
M , 1 , 2 , (??) .
[K1 ] = [K2 ] = M 1 , [kt ] = M 1 T 1 , [kd ] = T 1 , [r] = M T 1 .
(3.1.18) {eq:sw7}

, x = X K1 K2 t = T (r K1 K2 ),
x =

x2
x + 1.
1 + (1 + 1 )x2 + 2 x4

t .
p
= nkt P0 DT /r, = kd /(r K1 K2 ).

(3.1.19) {eq:sw8}

,
.
21

phage , 1 1 2 5. (3.1.19) .
. . ,
, .
x2
+1
f (x) =
1 + (1 + 1 )x2 + 2 x4

f (x) = x
. , 1 < 2 , < 1 > 2 , ;
1 < < 2 , ; = 1 = 2 , .
fHxL
20

15

10

0.2

0.4

0.6

0.8

1.0

3.4: Bifurcation plots for the variable x and concentration of repressor ( = 50, 1 = 1, 2 = 5)
x = x , y = x x , ,
y = (f (x ) )y.
, f (x ) < 0, , f (x ) > 0,
. , 1 < < 2 , (x1 < x2 < x3 ), x2
, (high level x3 low level x1 ) . .
, = 2 , low level high level ; , = 1 ,
high level low level . (switch) .

3.1.3 Noise induce switchesextrinsic noise

We now focus on parameter values leading to bistability and consider how an additive external
noise source affects the production of repressor. Physically, we take the dynamical variable x described
above to represent the repressor concentration within a colony of cells and consider the noise to act
on many copies of this colony. In the absence of noise, each colony will evolve identically to one of the
two fixed points, as discussed above. The presence of a noise source will at times modify this simple
behavior, whereby colony-colony fluctuations can induce novel behavior.
If an additive noise source alters the background repressor production. As an example, consider
the effect of a randomly varying external filed on the biochemical reactions. The field could, in
principle, impact the individual reaction rates, and because the rate equations are probabilistic in
origin, its influence enters statistically. We posit that such an effect will be small and can be treated as
a random perturbation to our existing treatment; we envision that events induced will affect the basal
production rate, and that this will translate to a rapidly varying background repressor production. In

22

{fig:sw2}

order to introduce this effect, we generalize that aforementioned model such that random fluctuations
become
x2
x + 1 + (t).
(3.1.20) {eq:sw9}
x =
1 + (1 + 1 )x2 + 2 x4
where (t) is a rapidly fluctuating random term with zero mean (h(t)i = 0), is a parameter to
indicate the strength of the perturbation. In order to encapsulate the rapid random fluctuations, we
make the standard requirement that the autocorrelation be -correlated, i.e., the statistics of (t)
are such that h(t)(t )i = (t t ).
(x), (3.1.20)
x =

(x)
+ (t).
x

(3.1.21) {eq:sw10}

(3.1.21) (x) . ,
(). , , , .
.
, . , (3.1.19)
+ (t). ,
x =

x2
x2

x
+
1
+
(t)
.
1 + (1 + 1 )x2 + 2 x4
1 + (1 + 1 )x2 + 2 x4

(3.1.22) {eq:sw11}

, . , + (t). ,
x =

x2
x + 1 (t)x.
1 + (1 + 1 )x2 + 2 x4

0.9

(3.1.23) {eq:sw12}

0.7
output1.dat

output2.dat

0.8
0.6
0.7
0.5
0.6
0.4
x

0.5

0.4

0.3

0.3
0.2
0.2
0.1
0.1

0
0

20

40

60

80

100

200

400

600

800

1000

(A)

(B)

0.9

0.8
output3.dat

output4.dat

0.8

0.7

0.7

0.6

0.6
0.5

0.5
0.4

0.4
0.3
0.3
0.2

0.2

0.1

0.1

0
0

200

400

600

800

1000

500

1000

1500

2000

(C)

(D)

3.5: : = 50, = 15, 1 = 1, 2 = 5. (A): , = 15 (t < 20) = 10

(t > 20). (B): (3.1.20) ( = 0.3). (C): (3.1.21) ( = 5). (D):
(3.1.23) ( = 0.5).
{fig:sw-sim}

3.1.4 Noise induce switchesintrinsic noise

switches , switches ([26]).

[A]

[B]
[rA ]
[rB ]

=
=
=
=

gA (1 [rB ]) dA [A] 0 [A](1 [rA ]) + 1 [rA ],

gB (1 [rA ]) dB [B] 0 [B](1 [rB ]) + 1 [rB ],
0 [A](1 [rA ]) 1 [rA ],
0 [B](1 [rB ]) 1 [rB ],
23

(3.1.24) {eq:3:brepressor

3.6: Mutual repression circuit.

{fig:brepressor}

gX , X = A, B X , dX . , mRNA
, . [rX ] X
. rA A , B , rB B ,
A . , 0 [rX ] 1. 0 promoter
, 1 .
, -, 0 , 1 dX , gX . , [rX ]
, [rX ] [X] ,
=
[A]

[B] =

gA /(1 + k[B]) dA [A],

gB /(1 + k[A]) dB [B],

(3.1.25) {eq:3:bre1}

k = 0 /1 .
. , gA = gB = g dA = dB = d ,

p
1 + 4kg/d 1
[A] = [B] =
2k

.
, Master . P (NA , NB , rA , rB )
t NX X rX , NX = 0, 1, 2, , rX = 0, 1.
Master
P (NA , N, rA , rB ) =

gA rB ,0 P (NA 1, NB , rA , rB ) + gB rA ,0 P (NA , NB 1, rA , rB )
+ dA (NA + 1)P (NA + 1, NB , rA , rB ) + dB (NB + 1)P (NA , NB + 1, rA , rB )
(gA rB ,0 + gB rA ,0 )P (NA , NB , rA , rB ) (dA NA + dB NB )P (NA , NB , rA , rB )
0 [(NA + 1)rA ,1 P (NA + 1, NB , 0, rB ) + (NB + 1)rB ,1 P (NA , NB + 1, rA , 0)]
1 [rA ,0 P (NA 1, NB , 1, rB ) + rB ,0 P (NA , NB 1, rA , 1)]
0 (NA rA ,0 + NB rB ,0 P (NA , NB , rA , rB ) 1 (rA ,1 + rB ,1 )P (NA , NB , rA , rB ).
(3.1.26) {eq:3:breme}
Gillespie . ,
X
P (NA , NB , rA , rB )
P (NA , NB ) =
rA ,rB

. , gA = gB = g = 0.05(s1 ) dA = dB = 0.005(s1 ).
, (0 = 0.005, 1 = 1.0, k = 0.005) (0 = 1.0, 1 = 0.02, k = 50)
. 3.7 . , , ,
. , , A , B , . ,
, (Fig. 3.8). .

24

(A)

(B)

3.7: The probabilities P (NA , NB ) for the switch, under condition of (A) weak repression (k = 0.005)
where there is one symmetric peak and (B) strong repression (k = 50) where three peak appear,
one dominated by A, the second dominated by B, and the third in which both species are
mutually suppressed. [26]
{fig:intrinsicsw

25
md2.dat using 1:2
20

[A]

15
10
5
0
0

50000

100000

150000

200000

250000

Time (t)
25
md2.dat using 1:3
20

[B]

15
10
5
0
0

50000

100000

150000

200000

250000

Time (t)

3.8: The population of unbound A and B proteins vs time, obtain from Gillespie simulations of the
switch with parameters g = 0.05, d = 0.005, 0 = 1.0, 2 = 0.02. [26]
{fig:intrinsicsw

25

3.2
3.2.1 Atkinson Oscillator
Atkinson Oscillator 3.9 .

3.9: Modules and connectivity for the genetic clock. The top construct contains the gInAp2 promoter fused to gInG. Transcription from gInAp2 requires the phosphorylated form of the
enhancer binding protein NRI(gInG product). This promoter is repressed by Lac1 binding to
2 perfect lac operator sites O*. The bottom construct contains the gInK promoter. The gInK
for activation, however the enhancer binding sites are less peten
prmoter also requires NRIP
that thos at gInAp2 (replotted from [5]).
{fig:4:atkoscill
[lacI], [LacI] LacI mRNA LacI , [nri], [NRI] NRI mRNA
, NRI-P [NRI P], :
d[lacI]
dt
d[LacI]
dt
d[nri]
dt
d[NRI]
dt
d[NRI P]
dt

f1 ([NRI P]) 1 [lacI]

2 [lacI] 2 [LacI]

f2 ([NRI P])f3 ([LacI]) 3 [nri]

4 [nri] 4 [NRI] k1 [NRI] + k1 [NRI P]

k1 [NRI] k1 [NRI P] 5 [NRI P].

(3.2.27) {eq:4:atk1}

i mRNA , i , k1 k1
NRI . fi , :
f1 ([NRI P] =

1,0 + 1,1

f2 ([NRI P]) =

2,0 + 2,1

f3 ([LacI]) =

3,1

([NRI P]/K1 )n1

1 + ([NRI P/K1 )n1
([NRI P]/K2 )n2
1 + ([NRI P/K2 )n2

1
.
1 + (LacI/K3 )n3

mRNA , ,
d[NRI P]/dt = 0
26

[NRI P] = keq [NRI], keq =

k1
.
k1 + 5

, :
x1 =

[lacI]
[LacI]
[nri]
[NRI]
, x2 =
, x3 =
, x4 =
, t = 2 t
2 K3 /2
K3
(4 + 5 keq )(K1 /keq )/4
K1 /keq

(3.2.28) {eq:4:atk2}

1
3
(4 + 5 keq )
, 3 = , 4 =
2
2
2
1,1
2,1
K2
1 =
, 2 =
,a =
1,0
2,0
K1

1 =

1 =

4 keq 2,0 3,1

1,0 2
, 3 =
,
1 2 K 3
3 (4 + 5 keq )K1

(t )

 

xn4 1
dx1

x
= 1 1 1 + 1
1
dt
1 + xn4 1
dx2
= x1 x2
dt


 
(x4 /a)n2
1
dx3

x
= 3 3 1 + 2
3
dt
1 + (x4 /a)n2 1 + xn2 3
dx4
= 4 (x3 x4 ).
dt

(3.2.29) {eq:4:atk3}

3.10 . , , .
x2 HtL

x4 HtL
2.5

35
30

2.0
25
1.5

20
15

1.0

10
0.5
5

20

40

60

80

100

20

40

60

80

100

(B)

(A)

3.10: Atkinson oscillator . : 1 = 3 = 30.0, 4 = 1.0, 1 = 3 =

2.0, 1 = 2 = 20.0, 3 = 1.0, a = 1.0, n1 = 4, n2 = 5, n3 = 1, xi (0) = 0.0.
{fig:4:atk1}
, . mRNA ,

dx1 /dt = dx3 /dt = 0.

,
dx2
dt
dx3
dt



xn4 1
x2
= 1 1 + 1
1 + xn4 1


(x4 /a)n2
1
x4 .
= 3 1 + 2
1 + (x4 /a)n2 1 + xn2 3

, n3 = 1.


xn4 1
x2 = 1 1 + 1
1 + xn4 1
27

(3.2.30) {eq:atk:4}

3
x2 =
x4


1 + 2

(x4 /a)n2
1 + (x4 /a)n2

. , , .
. , , , . 3.11
.
x2 HtL

x2

x4 HtL
1.4

40
20

1.2
1.0

30

15
0.8

20

10

10

0.6
0.4
0.2

x4
20

40

(A)

60

80

100

20

60

80

100

80

100

80

100

80

100

(A)

(A)
x2 HtL

x2

40

x4 HtL
2.5

35

40
30

2.0

25

30

1.5

20
15

20

1.0

10
0.5

10

5
1

x4
20

40

60

(B)

80

100

20

60

(B)

(B)
x4 HtL

x2 HtL

x2

40

4.0
40
3.5

35
30

3.0
2.5

30

20

2.0

x4
20

40

60

80

100

1.5

20

(C)

(C)

60

(C)

x2 HtL

x2

40

x4 HtL

2.0

40

0.20
1.5

0.15

30

1.0

0.10

0.5

0.05

20

x4

20

(D)

40

60

(D)

80

100

20

40

60

(D)

3.11: . (A): n2 = 4, 2 = 10.5; (B): 2 = 20, n2 = 5; (C)

3 = 0.5, 2 = 100, n1 = 4, x2 (0) = 30.0, x4 (0) = 4.0, x1 (0)x3 (0) = 0; (D): (C),
xi (0) = 0.0 3.10 .
{fig:4:atk2}

3.2.2 A synthetic gene-metabolic oscillator

3.12 . M1 , E1 M1 M2 . M2
, E1 , , E2 M2 . E2 , M2 M1 .
. Escherichia coli[15](3.13).
Such a conceptual design was realized using the acetate pathway in E. coli(Fig. 3.13). The M1
pool is acetyl coenzyme A (acetyl-CoA) and the M2 pool consists of acetyl phosphate (AcP), acetate
(OAc ) and the protonated form acetate (HOAc). Acetyl-CoA is a metabolic product of sugar, fatty
acids and some amino acids, and is the entry point into the tricarboxylic acid (TCA) cycle (
). Acetyl-CoA is concerted to acetyl phosphate in E. Coli by phosphate acetyltransferase
(Pta), which corresponds to enzyme E1 in Fig. 3.12, and then to acetate by acetate kinase (Ack).
28

The protonated form of acetate is permeable across the cell membrane. Under aerobic conditions,
acetyl-CoA is further oxidized in the TCA cycle. The remaining flux goes to produce either acetate
in the TCA cycle. The remaining flux goes to produce either acetate or ethanol. In wild-type E.
coli, the enzyme acetyl-CoA synthetase (Acs) is induced in the presence of acetate. However, such
induction is under catabolite repression by glucose in the wild-type strain so as to avoid futile cycling.
In our design, acetyl-CoA synthetase is used as enzyme E2 in Fig. 3.12. Thus, both phosphate
acetyltransferase and acetyl-CoA synthetase need to be re-wired to respond to the M2 pool.

(A)

(B)

3.12: Conceptual diagram of the oscillatory dynamics, highlighting the two metabolite pools (M1
and M2 ) and their controls. Solid lines indicate metabolic fluxes. Dashed lines indicate
positive (arrow) and negative (blunt bar) transcriptional or translational regulation(ref. [15]). {fig:4:metabolic
. (AcCoA, AcP, OAc1 , HOAc)

dAcCoA
= VAcs VPta + Vgly VTCA
dt
dAcP
= VPta VAck
dt1
(3.2.31) {eq:4:met1}
dOAc
= VAck VAcE VAcs
dt
dHOAc
= VAcE Vout
dt
Vi , 3.1 . glycolytic . TCA EtOH HOAc
AcCoA HOAc . Pta, Ack Acs MichaelisMenten .
, LacI, Pta Acs :
dLacI
dt
dPta
dt
dAcs
dt

RLacI Rd,LacI

RPta Rd,Pta

RAcs Rd,Acs

(3.2.32) {eq:4:met2}

R , Rd . mRNA , Hill
, ()(3.1). 3.14
. , Vgly . Vgly ,
, , Vgly , , .

3.2.3 Mechanisms of noise-resistance in genetic oscillators

. 3.15 . .
, A R. A A R ,
. R A , A. , R .
29

3.13: Biological realization of the conceptual design in Fig. 3.12. The yellow boxes highlight the two
metabolic pools, M1 and M2 . Ack, acetate kinase (); Acp, acetyl phosphate (
); Acs, acetyl-Coa synthetase; OAc , acetate(); Pta, phosphate acetyltransferase.
(adopt from [15])
{fig:4:ecolisuga

Vgly =0.001

Vgly =0.01

Metablite concentrations

Metablite concentrations
AcP

AcP

0.1

0.1

0.001

0.001

AcCoA

AcCoA
-5

-5

10

-7

10-7

10

10

500

1000

1500

2000

2500

3000

100

Vgly =0.05

200

300

400

500

400

500

Vgly =0.5

Metablite concentrations

Metablite concentrations
10
AcP

0.1

1
AcP
0.1

0.001
AcCoA

AcCoA

0.01
10-5
0.001

100

200

300

400

500

100

200

300

3.14: Computational characterization of the metabolator. The metabolator is prone to oscillate at

increasing glycolytic rates Vgly . Vgly in the four panels (from left to right) are 0.001, 0.01,
0.05 and 0.5.(replot from [15])
{fig:4:meta2}

30

Glycolytic flux, Vgly

Flux to TCA cycle and
EtOH production, VTCA

Flux
AcP

Rate expression
Vgly = S0

Parameters
S0 = 0.001 0.5

VTCA = kTCA AcCoA

kTCA = 10

k1 Pta AcCoA
Km,1 + AcCoA
k2 Acs OAc1
=
Km,2 + OAc1

Pta flux, VPta

VPta =

k1 = 80, Km,1 = 0.06

Acs flux, VAcs

VAcs

k2 = 0.8, Km,2 = 0.1

for the reaction

Ack
OAc1

GGGGGGBG
FGGGGGGGG

Acid-base equilibrium for

acetic acid, VAcE
HOAc intercellular
transport rate, Vout
LacI synthesis rate, RLacI
Acs synthesis rate, RAcs
Pat synthesis rate, RPta
Degradation rate Rd,X ,
(X = LacI, Acs, Pta)

VAck = kAck,f AcP kAck,r OAc1

kAck,f = 1, kAck,r = 1

VAcE = C(AcP H+ Keq OAc )

C = 100, H+ = 107 , Keq = 104.5

Vout = k3 (HOAc HOAcE )

k3 = 0.01, HOAcE = 0

1 (AcP/Kg,1 )
+ 0
1 + (AcP/Kg,1 )n
n
2 (AcP/Kg,2 )
RAcs =
+ 0
1 + (AcP/Kg,2 )n
3
RPta =
+ 0
1 + (LacI/Kg,3 )n

RLacI =

Rd,X = kd X

1 = 0.1, Kg,1 = 10, n = 2, 0 = 0

Kg,2 = 10, n = 2, 0 = 0,
2 = 2
Kg,3 = 0.001, n = 2, 0 =
0, 3 = 2
kd = 0.06

3.1: Rate expression and values used for parameters[15]

3.15: Biochemical network of the circadian oscillator model.(replot from [37])

31

{tab:4:met1}

{fig:4.circadian

dDA /dt
dDR /dt

dDA
/dt

dDR /dt
dMA /dt
dA/dt
dMR /dt
dR/dt
dC/dt

A D A
A DA A

R D R
R DR A

A DA A A DA

R DR A R DR

A DA + A DA MA MA

A M A + A D A
+ R D R
A(A DA + R DR + C R + A )

= R DR
+ R DR MR MR
= R MR C AR + A C R R
= C AR A C.

=
=
=
=
=
=

(3.2.33) {eq:4:osc3}

DA
and DA denote the number of activator genes with and without AA bound to its promoter

respectively; similarly, DR
and DR refere to the repressor promoter; MA and MR denote mRNA of
A and R; A and R correspond to the activator and repressor proteins; and C corresponds to the
inactivated complex formed by A and R. The constants and denote the basal and activated
rates of transcription, the rates of translation, the rates of spontaneous degradation, the rates of
binding of A to other components, and denotes the rates of unbinding of A form those components.
The cellular volume is assumed to be the unity so that concentration and number of molecules are
equivalent. Notice that we assume that the complex breaks into R because of the degradation of A,
and therefore, the parameter A appears twice in the model.
3.16 .

Concentrations

1500

1000

500

100

200

300

400

500

(A)

(B)

3.16: Oscillations in repressor and activator protein numbers obtained from numerical simulations
of the deterministic (A) and stochastic (B) descriptions of the model. The values of reac
tions rates are: A = 50h1 , A = 500h1, R = 0.01h1 , R = 50h1 , A = 40h1 , R
=
1 1
1
1
1
1
1
5h , MA = 10h , MR = 0.5h , A = 1h , R = 0.2h , A = 1mol h , R =
1mol1 h1 , C = 2mol1 h1 , A = 50h1 , R = 100h1 . The initial conditions are

DA = DR = 1mol, DA
= DR = MA = MR = A = R = C = 0, which require that the cell has

single copy of the activator and repressor genes: DA + DA

= 1mol and DR + DR
= 1mol. [37] {fig:4.circadian
, . .
, . , promoter
(promoter A )(A = 50h1 , R = 100h1).
(A = 50h1 , A = 500h1 , R = 0.01h1, R = 50h1 ). ,
promoter mRNA , (3.2.33)

dDA
dDR
dDA
dDR
dMA
dMR
=
=
=
=
=
= 0.
dt
dt
dt
dt
dt
dt

32

, :
R
A
, DR =
A + A A
R + R A
A A
R A

DA
=
, DR
=
A + A A
R + R A
1 A A A + A A
1 R R A + R R
MA =
, MR =
.
MA
A + A A
MR
R + R A
DA =

(3.2.34) {eq:4:osc3-equi1

, A promoter , A ,
dA
= 0.
dt

A=

1 A A + A A
A
.
C R + A MA A + A A

(3.2.35) {eq:4:osc3-equi2

,
1
1

A = A(R)
= (A (R) Kd ) +
2
2

(R) =

q
(A (R) Kd )2 + 4A (R)Kd

(3.2.36) {eq:4:osc3-equi3

A
, Kd = A /A .
MA (C R + A )

dR
R R R + R R A(R)

+ A C R R
C A(R)R
=

dt
MR
R + R A(R)

dC

A C
= C A(R)R
dt

(3.2.37) {eq:4:osc3-slow}

3.17 , , ,
, . ,
.
Concentrations

Concentrations
1500

2000

1500

1000

1000
500
500

50

100

150

200

50

(A)

100

150

200

(B)

3.17: : (A) , (B) .

(3.2.37) . , .
, , , (:
?). , . ,
, . :
dR/dt = dC/dt = 0,

R R R + R R A(R)
= R R,

MR
R + R A(R)
33

C = (C /A )A(R)R.

{fig:4.simplify}

, , (R , C ). , ,
, . ,
(R , C ) = (66.7491, 363.47).

1,2 = 0.405797 0.5565i.

, , . , ,
.
. ,
, . ,

)  R ( R )R R
A(R
R
) + R + A ).
C R (C A(R
=
2

R
MR (R + R A(R))
> 0 , . , = 0.811594 > 0. ,
. , . , A R :
(A , R ) (KA , R )
0.024 < K < 10.7 , > 0 (3.18). ( ) K > 0.08 ,
mRNA 0.0009 < K < 3.5 , > 0. ,
, ,
. ??(A) . .

1.0

0.5

10

12

14

-0.5

-1.0

3.18: K .
, . , ,
, . , ,
. , , (3.20).
3.19(B) .

3.2.4
. , ,
, . .
, , .
. , .
34

{fig:4.cirosciro

(B)

(A)

3.19: ([37]).

{fig:4:cirophase

2000

1500

1000

500

100

200

300

400

500

(A)

(B)

3.20: : (A) , (B) . R = 0.005, .

35

{fig:4:noise-osc

3.21 . ,
, LacI tetR promoter, TetR cI promoter, CI
lacI promoter. . , N ,
(). , N . ,
. , (AI), ,
, .

3.21: The schematic diagram of a synthetic gene regulatory network.

{fig:5:syn1}

xk , yk , zk k lacI, tetR, cI mRNA , Xk , Yk , Zk

k LacI, TetR CI . A AI .

dxk
dt
dyk
dt
dzk
dt

=
=
=

k A
+
,
n
1 + Yk
1+A

yk +
,
1 + Zkn

zk +
,
1 + Xkn
xk +

dXk
dt
dYk
dt
dZk
dt

= (xk Xk ),
= (yk Yk ),

(3.2.38) {eq:4:syn1}

= (zk Zk ).

, promoter Hill , Michaels-Menten

. mRNA , , 1. ,
. AI . , G(t):
dA
= kA A + G(t).
dt

(3.2.39) {eq:5:syn2}

:
: G(t) = sin(t);
: G(t) = (t), h(t)i = 0, h(t)(t )i = (t t );
P
: G(t) = j=1 j (t tj ), tj = j , , j 1/2
.

36

, , (3.22).
,


N

1 X


wk exp (ik (t)) ,
(3.2.40) {e33}
R(t) = 

N
k=1

PN

k k , k = |k (t)/ n=1 |k (t)| k , i .

wk , ,
. , R = 1 N , R = 0 , 0 < R < 1
. , . . ,
Z(t) , T = 2/,
Z(t) = Z + r(t) cos((t)),

Z Z(t) , r(t) t . Z = Z Z,
cos .
= r(t) exp(i(t)) i(r/
Z iZ/
)

, r(t) , i.e., r |r/
|,

r(t) exp(i(t)) Z iZ/,

exp(i(t))
, :

Z iZ/
.

|Z iZ/|



N
1 X
Zk (t) iZ k (t)/k 

R=
,

N

k=1 |Zk (t) iZk (t)/k |

(3.2.41) {eq:33-1}

Zk (t) = Zk (t) Zk , k k .

(b)
250

800

200
Number of cells

Number of cells

(a)
1000

600
400
200
0

t=100
t=2000

150
100
50

0.4

0.5
Frequency

0.6

0.7

0
2

Phase

3.22: When no stimulus is presented, the cells oscillate with the same frequency (a) with different
phases (b). Without stimulus, the distribution of the phases of the oscillators is invariant over
time (b), and thus the system fail to synchroniszated. The parameters used in the simulation
are: N = 1000, = 216.0, = 2.0, = 2.0, = 1.0, = 1.0, n = 2.0. The intrinsic frequency
for the oscillators with above parameters is estimated as 0 0.54.
{fig:4:f9}
, , ,
. , , .
, (3.2).

37

(a)

(b)

1000

120
t=20
t=2000

100
80

600

TetR

Number of cells

800

60

400
40
200
0
2

20
0

50

100
t (min)

Phase
(c)
1
=0.2
=0,4
=0.6
=0.8
=1.0

0.8
0.6
R

0.6
0.4

0.4

0.2

0.2

0
0.4

200

(d)

1
0.8

150

0.45

0.5

0.55

0.6

0.65

0.2

0.4

0.6

0.8

3.23: The synchronization in the present of sinusoidal periodic stimulus. When the stimulus with
resonance frequency is presented ( = 0.8, = 0.54), the initial phase space is reduced to
a single phase for all cells and thus the system is completely synchronizated (a). (b) shows
the time evolutino of the TetR concentations of 10 cells. The oscillations with different
initial phase are synchronizated under stimulus for less than 200 minutes. (c) shows the
synchronization effect of the sitmulus with strength vary from 0.2 to 1.0. Its evident that the
strength only have marginaly effect for the synchronization in the case of resonance. (d) shows
the synchronization effect for different value of frequency ( = 0.8 and is vary from 0 to
1.2). The result suggest that the system has partly synchronization in the case of subharmonic
resonance. Other parameters used in the simulation were given at Figure 3.22. In (c) and (d),
the order parameters R are calculated as the average over the time interval 1800 t 2000]. {fig:4:syn1}

/0

control
0.1

1/3
0.56

1/2
0.99

2/3
0.41

1
1.00

2.0
0.64

is the averge of order

3.2: The synchronization under subharmonic stimulus. Here the value R
parameter over 1800 t 2000. The control vaule is taken as order parameter for the system
without stimulus.
{tab:4:syn1}

38

, ,
. , (3.24). t, .
,
R (t) =

1
,
1 + exp[a(t) b(t)(1 + 2 )]

(3.2.42) {eq:4:fit1}

a(t), b(t) t. , a 6.10, b(t) t:

b(t) 3.68 + 0.56 103 t.
, Rc


1 Rc
1
10.89

1.79

ln
103 min.
T
1 + 2
Rc

(3.2.43) {eq:4:fit2}

(3.2.44) {eq:fit3}

, (), (3.25).
. , .
, hi, . .
3.26 . , 0 1.0 , ,
, .

3.2.5
:
G 1 2 , t ,
dx1
= X1 (x1 , x2 ),
dt

dx2
= X2 (x1 , x2 )
dt

(3.2.45) {eq:4:system}

1 2 (), G , G
()(). X1 X2 ,
() .
(3.2.45) (x1 , x2 )


a11 a12
A=
a21 a22

aij =

Xi (x1 , x2 )
.
xj

p = tr(A) = (a11 + a22 ), q = det(A) = a11 a22 a12 a21 ,

1,2 =

:
1. p < 0, .
2. p > 0 q > 0, .
3. p > 0 q < 0, .

39

p
p2 4q
.
2

(a)

(b)

0.9

0.8

0.8

0.7
0.6
R

0.6
0.5

0.4

0.4

0.2

=0.7
=0.8
=0.9

0.2

0.3
0

0.5

1
t (min)

1.5

500

x 10

(c)

1000
t (min)

1500

2000

(d)
8

0.8

0.6

0.4

0.2

a(t)
b(t)

0.2

0.4

0.6

0.8

800

1000 1200 1400 1600 1800 2000

t (min)

3.24: Synchronization in the present of white noise stimulus. (a) shows the time evlution of order
parameter of the system under the white noise stimulus with = 0.2. It suggest that a weak
weak is able to synchronizate the oscillators. (b) shows the time evlution of order parameters
under the white noise stimulus with different values of the variance ( = 0.7, 0.8, 0.9). It
shows that the time it takes the sytem to archive the complete synchronizated depends on
the variance 2 . For different value of that vary from 0 to 1.0, the order parameter of the
system at time t = 2000 is shown at (c). In general, the order parameter at a fix time is
increase with respect to . The dashed line shows that fitting curve by function (??) with
a = 6.53, b = 5.03. The order parameter R (t) at any time t can be approximated by function
(3.2.42), with coefficients a(t) and b(t) given by (d). When the time t is large, a(t) approach
constant limits a 6.10, and b(t) depends on the time t linearly. The dashed line represent
the fitting curve of b(t) by (3.2.43). The parameters used in this simulation are given at
Figure 3.22.
{fig:4:f5}

40

1
=1000
=2000

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

10

11

12

13

14

15

3.25: The order parameter for 1000 cells with period varies from 5 to 15, and different values of
(red circles for = 1000 and blue squares for = 2000).
{fig:4:f7}

1
Sinusoidal periodic stimulus
White noise stimulus

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

3.26: The relation between the order parameter and the variability of the cells (measured by .
The parameter used are = 0.54 and = 0.8 for the sinusoidal periodic stimulus.
{fig:4:f8}

41

3.3
. 24 .
, , .
, PER TIM .
, , , ,
.

3.3.1 Dimerization and proteolysis of PER and TIM

, (Fig. 3.27). ,
PER TIM , . PER ,
PER/TIM , . , PER , . , PER
, , . , PER
. PER . PER TIM
. , , promoter ,
.

3.27: A simple molecular mechanism for the circadian clock in Drosophila, adopted from [35]. PER
and TIM proteins are synthesized in the cytoplasm, where they may be destroyed by proteolysis or they may combine to form relatively stable heterodimers. Heteromeric complexes
are transported into the nucleus, where they inhibit transcription of per and tim mRNA. We
assume that PER monomers are rapidly phosphorylated by DBT and then degraded. Dimers,
we assume, are poorer substrateds for DBT.
{fig:4:cir1}
. , . , PER TIM
, . , . ,
, . ,
, mRNA M , P1 , P2 .

42

dM
dt

vm
km M
1 + (P2 /Pcrit )2

dP1
dt

vp M

dP2
dt

ka P12 kd P2

(3.3.46)

kp1 P1
kp3 P1 2ka P12 + 2kd P2
Jp + P1 + rP2

(3.3.47)

kp2 P2
kp3 P2 .
Jp + P1 + rP2

(3.3.48)

, ( Hill 2). ,

DBT , (kp1
kp2 ).
DBT , (kp3 ). , (3.3.47)
(3.3.48) Michaelis-Menten DBT . .

P1 + DBT DBT P1 DBT,

P2 + DBT DBT P2 DBT

, D DBT , D1 DBT P1 , D2 DBT P2 ,

dP1
dt
dP2
dt
dD1
dt
dD2
dt

= k1 P1 D + k1 D1

(3.3.49)

= k2 P2 D + k2 D2

(3.3.50)

= k1 P1 D k1 D1 k1 D1

(3.3.51)

= k2 P2 D k2 D2 k2 D2 .

(3.3.52)

,
DT = D + D1 + D2 .
, ,
dD1 /dt = dD2 /dt = 0

D1 = keq,1 P1 D, D2 = keq,2 P2 D, D =

DT
,
1 + keq,1 P1 + keq,2 P2

keq,1 =

k2
k1
, keq,2 =
.
k1 + k1
k2 + k2

,
dP1
dt

DT k1 P1
1/keq,1 + P1 + (keq,2 /keq,1 )P2

(3.3.53)

dP2
dt

DT k2 (keq,2 /keq,1 )P1

1/keq,1 + P1 + (keq,2 /keq,1 )P2

(3.3.54)

Michaelis-Menten ,

kp1
= DT k1 , kp2 = DT k2 (keq,2 /keq,1 ), Jp = 1/keq,1 , r = keq,2 /keq,1 .

, kp1
kp2

k1 keq,1 k2 keq,2 ,
k2 k2
k1 k1

k1 + k1
k2 + k2
43

mRNA & Protein Level

3.5

mRNA & Protein Level

Protein

3.0

3.0

Protein

2.5

2.5
2.0

2.0

mRNA

1.5

1.5

1.0

1.0

mRNA

0.5

0.5
20

40

60

80

100

Time HhrL

20

40

(A)

60

80

100

Time HhrL

(B)

3.28: . : vm = 1, km = 0.1, vp = 0.5, kp1

= 10, kp2 = 0.03, kp3 =
0.1, Pcrit = 0.1, Jp = 0.05, r = 1.2, ka = 800, kd = 4. (A): (3.3.46)-(3.3.48). (B):
(3.3.56)-(3.3.57).
{fig:4:cirsol1}

k1 k2 k1 k1 , k2 k2 , DBT , ,
. .
(3.28)(A) . , , 24
. , .
(ka kd ), , 2P1 P2
. , PT = P1 + 2P2 , ,
P2 = Keq PT , Keq = ka /kb .
P1 = qPT , P2 = 21 (1 q)PT ,
q=

1+

2
p
.
1 + 8Keq PT

(3.3.55) {eq:4:cirq}

vm
km M
1 + (PT (1 q)/(2Pcrit ))2

dM
dt

dPT
dt

= vp M

kp1 PT q + kp2 PT
kp3 PT .
Jp + qPT + (r/2)(1 q)PT

(3.3.56)
(3.3.57)

q (3.3.55) , kp1 = kp1

kp2 kp1
. 3.28(B).
. ,

f (PT ) =

vm
kp1 PT q + kp2 PT
, g(PT ) =
+ kp3 PT .
2
1 + (PT (1 q)/(2Pcrit ))
Jp + qPT + (r/2)(1 q)PT

km M = f (PT ), vp M = g(PT )
, M = f (PT )/km M = g(PT )/vp . (M , P ) ,



km f (P )
A=
vp
g (P )
tr(A) = km + g (P ) < 0 , . , ,
,
g (P ) < km
(3.3.58) {eq:4:cond}
M = g(PT )/vp (). (3.3.58)
. (),
. , g (P ) , 3.29(A) Keq .
, 3.28 , Keq > 8.3, g (P ) < km , .
Keq = 200 , 3.29 .
44

, kp1 (3.30). .
, kp1 , Keq . Keq kp1
3.31 .
, .
, . , ,
Keq . , kp1, kp2 . 3.32 Tyson
, , [35].
M

g'HP* L

1.0
0.5

3
Keq
50

100

150

200

-0.5
1

-1.0
-1.5

0.5

1.0

1.5

(A)

2.0

2.5

3.0

PT

(B)

3.29: (A) g (P ) Keq . (B) .

g'HP* L

{fig:4:circond}

Protein Level

2
kp1 =30

6
kp1 =20
5

4
10

20

30

40

kp1

3 kp1 =10
2

-1
1
-2

20

40

60

80

100

Time HhrL

(B)

(A)

3.30: (A) g (P ) kp1 . (B) kp1 . kp1 10, 20, 30,

.
{fig:4:circond2}

3.3.2 Circadian rhythm generator

.
.
3.33A . , ,
. , , , , ,
, . ,
, . , . ,
, , .
3.33B . mRNA . , mRNA
, . .
mRNA , .
, Hill .

45

3.31: Two-parameter bifurcation diagram for the model(adopt from [35]).

{fig:4:cirbif}

3.32: Period of the endogenous rhythms of wild-type and mutant files. [35]

{fig:4:cirmutant

46

3.33: (A). Schematic representation of the biological elements of the protein synthesis cascade, assumed to be elementary to the circadian rhythm generator. These include the auto inhibition
of the protein at translational or transcriptional level and posttranslational processing such
as phosphorylation, dimerization, and transport. Protein denotes the effective protein, being in the molecular state capable of inhibiting mRNA production, as well as expressing the
circadian rhythm. (B). Model interpretation of A, emphasizing the delay ( ) and nonlinearity
in the protein production cascade, the nonlinear negative feedback, as well as the mRNA and
protein production and degradation. The mRNA and protein production (rM , rP ) and degradation (qM , qP ) rate constants, respectively, are also used as targest for external stimulation.
(Adopt from [32])
{fig:4:SCN1}

47

:
dM
dt

rM
qM M
1 + (P/K)n

(3.3.59)

dP
dt

rP M (t )m qP P.

(3.3.60)

3.34 . , , 24 .

3.34: (3.3.59)-(3.3.60) . : rM = 1.0hr1 , rP =

1.0hr1 , qM = 0.21hr1 , qP = 0.21hr1 , n = 2.0, m = 3.0, = 4.0hr, k = 1(Replot from
[32]).
{fig:4:scnsim}
, , . ,
.
x = M/(rM /qM ), y = P/K, t = qM t

1
x
1 + yn

(3.3.61)

rx(t c )m y.

(3.3.62)

d
, :
dt
r = (1/K)(rP /qM )(rM /qM )m , = qP /qM , c = qM .

, (x , y ) :
x = 1/(1 + y n ), y = (r/)x m .
, . , ,


x
=
x a
y
(3.3.63) {eq:SCN5}
y = y + b
x(t c )

a=

ny (n1)
, b = mrx (m1) .
(1 + y n )2

x
= c1 et , y = c2 et (c1 , c2 6= 0)
48

,


1+
bec

a
+

c1
c2

,
f () = (1 + )( + ) + abec = 0.

(3.3.64) {eq:4:cireig}

: (3.3.63) (3.3.64) ().

, , (3.3.63) .
, c = 0 (),
p
( + 1) ( + 1)2 4( + ab)
.
1,2 =
2
, , . , .
, . , = i,
f () = 0
2 + + ab cos c = 0, (1 + ) ab sin c = 0.
, > 0, ab c

(ab)2 = 4 + (1 + 2 ) 2 + 2 ,
(0, /c )

( 2 ) tan c = (1 + ).

ab c a (), ,
(3.35).
ab
40

30

20
Unstable
10

Stable

0.2

0.4

0.6

0.8

1.0

3.35: (3.3.59)-(3.3.60) . () = 1.5, 1.0, 0.5.

3.4

Waston
Crick (DNA)

DNA

49

{fig:4:scnstable

1978 Edward B. Lewis

[25]
Christiane Nusslein-Volhard Eric F. Wieshaus
15
1980 [31]

Edward B. LewisChristiane Nusslein-Volhard Eric F.

Wieshaus 1995

1.
2.
3.
, :
(Morphogen) . , .

FlyBase (http://www.flybase.org/)

(fertilization)(cleavage)(gastrulation)(organogenesis)(metamorphosis)
(maturity) 6 (cell division)(cell differentiation)
(pattern formation)(cell migration)(apoptosis)

(wing imaginal disc)

(morphogen)

(anteroposterior axisA-P )(dorsoventral axis, D-V )

Decapentaplegic (Dpp)Hedgehog (Hh)Wingless (Wg) Dpp

A-P A-P (morphogen
gradient)Dpp (ThickveinsTkv )
Potomotorblind(Omb)Spalt(Sal)

(concentration thresholds)

3.5 Morphogen gradient

Morphogen gradient is an important concept in developmental biology, because it describes a
mechanisms by which the emission of a signal from one part of an embryo can determine the location,
differentiation and fate of many surrounding cells[20].
50

3.36: Morphogen gradient

{fig:1}

Morphogens are secreted signaling molecules that organize a field of surrounding cells into patterns. They form a gradient of concentration emanating from a localized source, and determine the
arrangement and fate of responding cells according to different concentrations of morphogen perceived by the cells. The morphogens associate with the development of drosophila wing are listed at
Tab. 3.3. The idea of a morphogen gradient is intimately associated with the concept of positional
information[38]. A cell is believed to read its position in a concentration gradient of an extracellular
signal factor, and to determine its developmental fate accordingly[20].
Developmental
process

Signal source

Morphogen
(range)

Drosophila imagial
wing disc[?]

Antero-posterior
boundary

Dpp
(long)

Drosophila imagial
wing disc[?, ?]

Dorso-ventral
boundary

Wg
(long)

Antifactor
Brk

Receptors
Tkv
Punt

Fz

Response
(concentration)
sal(high)
omb(low)
neur (high)
Dill(middle)
vg (low)

Response
(time, h)
24-72

24-72

Short range, 20 m; long range, 100 m or more.

Includes repression as well as activation.
Only after 50h is Omb expression further from the source than sal.

3.3: Examples of morphogens

The major factors shaping a gradient are not only different for each morphogen, but may differ
for the same morphogen in different stages of development. There has been much activity in analysing
the mechanism of transmission of a morphogen across its field. There ideas prevail: (1) diffusion in
the extracellular matrix; (2) relay by sequential internalization and re-emission from cell to cell; and
(3) cytoplasmic contact by threads of cytoplasm connecting distant cells [20].
The timing of gradient formation is likely to be rapid. In later development, as in the Drosophila
wing disc, a Dpp gradient is normally formed slowly, extending over 25 cell diameters in 3 days.
Nevertheless, the same Dpp gradient can be reformed, after temperature interruption, as the rate of 4
cells in 1 hour[14, 34]. In Xenopus embryos, however, an activin gradient can be formed experimentally
over 100 m in 1 hour[19], and natural gradients are normally formed in Xenopus and Drosophila in
2 hours or less.
The cells response to the morphogen through different response thresholds of morphogen concentration. According to this idea, each cell would have only a binary choice: respond to the morphogen
or not. Some cells can make more sophisticate response than an on/off switch[20].
Another important question concerning the cellular basis of morphogen perception asks whether
a cell needs its neighbours to determine its position in a gradient, or whether it can measure concentration on its own. The experiments argue that cells interpret position in a concentration gradient
independently of their neighbours[20].
A cell may respond to morphogen concentration throug its receptors in two ways. One is to be
armed with receptors having different binding characteristics(type I receptor); for example, high- and
low- affinity receptors and their transduction pathways could operate at low and high concentrations
51

{tab:1}

of ligand, respectively. The other is to vary the occupancy of one type of receptor(type II receptor),
and hence its signaling activity, accoding to ligand concentration. We therefore need to know whether
different morphogen responses are transmitted by one or more kinds of receptor. Experimental results
show that the choice of gene response depends on the absolute number of occupied receptors, entirely
independently of how many unoccupied receptors are present [13, 20] .
Here are three ideas on how cells make direct response to morphogen gradients[20]
1. The availability of ligand(morphogen) is the limiting factor in determining the level of response
to concentration.
2. Cells respond to ligand concentration according to the absolute number of receptors cooupied
at any time.
3. A cell with a particular number of occupied receptors will continue to express the same gene
until either the occupancy of receptors goes up or the period of competence terminates.
An understanding of morphogen gradients requires answers to two different questions. The first
asks how a desired concentration gradient is formed. The second question asks how cells
interpret a morphogen concentration[20].

3.6
, Morphogen Dpp A-P , ,
(??). 3.38.

3.37: Dpp gradient[14].

{fig:21}

, , Dpp .
. (3.39).
: Diffusion and Reversible Binding (Kerszberg & Wolpert [22]).
d[L]
dt
d[LR]
dt
The

= D

2 [L]
kon Rtot [L](1 [LR]) + koff [LR]
dX 2

= kon Rtot [L](1 [LR]) koff [LR].

overexpression, by up to tenfold, of the activin type II receptor in Xenopus embryo.

52

(3.6.65)
(3.6.66)

3.38: Wing imaginal disc of Drosophila[33].

{fig:dpp21}

Rtot :
Rtot = [R] + [LR].
, :

[L] 
= v, [L]|X=Xmax 0.
D
X X=0

(3.6.67) {eq:4:bvc}

X = 0 Dpp , X = Xmax , Dpp

.
: Diffusion, Reversible Binding, and Degradation(Lander, Nie & Wan[23]).
d[L]
dT
d[LR]
dt

2 [L]
kon Rtot [L](1 [LR]) + koff [LR]
dX 2

(3.6.68)

kon Rtot [L](1 [LR]) koff [LR] kdeg [LR].

(3.6.69)

: Diffusion, Reversible, Binding, Reversible Internalization, Degradation(Lander, Nie &

Wan[23]).
[L]
T
[LR]out
T
[LR]in
T
[R]out
T
[R]in
T

2 [L]
kon [L] [R]out + koff [LR]out
X 2

(3.6.70)

kon [L] [R]out koff [LR]out kin [LR]out + kout [LR]in

(3.6.71)

kin [LR]out kout [LR]in kdeg [LR]in

(3.6.72)

kon [L] [R]out + koff [LR]out kp [R]out + kq [R]in

(3.6.73)

R kg [R]in + kp [R]out kq [R]in

(3.6.74)

: Diffusion, reversible binding with receptor and non-receptor, reversible internalization,

degradation(Lander, Nie & Wan, 2007[24]).

53

(A)

(B)

(C)

(D)

3.39: Dpp : (A) Diffusion and reversible binding. (B) Diffusion, reversible binding and
degradation. (C) Diffusion, reversible binding, reversible internalization, degradation. (D)
Diffusion, reversible binding with receptor and non-receptor, reversible internalization, degradation.
{fig:dppmodels}

[L]
T
[LR]out
T
[LR]in
T
[R]out
T
[R]in
T
[LN]out
T
[LN]in
T
[N]out
T
[N]in
T

2 [L]
kon [L] [R]out + koff [LR]out
X 2
jon [L] [N]out + joff [LN]out

(3.6.75)

kon [L] [R]out koff [LR]out kin [LR]out + kout [LR]in

(3.6.76)

kin [LR]out kout [LR]in kdeg [LR]in

(3.6.77)

kon [L] [R]out + koff [LR]out kp [R]out + kq [R]in

(3.6.78)

R kg [R]in + kp [R]out kq [R]in

(3.6.79)

jon [L] [N]out joff [LN]out jin [LN]out + jout [LN]in

(3.6.80)

jin [LN]out jout [LN]in jdeg [LN]in

(3.6.81)

jon [L] [N]out + joff [LN]out jp [N]out + jq [N]in

(3.6.82)

N jg [N]in + jp [N]out jq [N]in

(3.6.83)

Dpp, , .
. , , T
, . ,
54

(3.6.67) . , , ,
. .
,
[R]
[L]
=
=0
T
dT

2 [L]
kon Rtot [L](1 [LR]) + koff [LR]
dX 2
kon Rtot [L](1 [LR]) koff [LR] kdeg [LR].

0 =

0 =
[LR]:

kon Rtot
[L]
koff + kdeg
[LR] =
,
kon Rtot
1+
[L]
koff + kdeg
,
2 [L]
D
kdeg
X 2

kon Rtot
[L]
koff + kdeg
=0
kon Rtot
1+
[L]
koff + kdeg

(3.6.84)


[L] 
D
= v, [L]|X=Xmax =0.
X X=0

K=

[L]
X
koff + kdeg
,u =
,x =
kon Rtot
K
Xmax

2
v Xmax
kdeg Xmax
, =
K D
K D

u
= 0, u (0) = , u(1) = 0.
1+u

(3.6.85) {eq:4:bvp1}

, (3.6.85). u , x ,
Z x
Z x
u
0 =
u u dx

u dx
1
+
u
0
0
Z x
Z x
u
du
=
u du
0
0 1+u
=
=

1 2 x
u |0 (u log(1 + u))|x0
2
1 2
(u 2 ) (u log(1 + u) (u(0) log(1 + u(0)))
2

a2 =

2
(u(0) log(1 + u(0)),
2

p
u = 2 (u log(1 + u) + a2 ),

u(1) = 0.

, u = u(x)

p
du
p
= 2(1 x)
2
(u log(1 + u) + a )
55

(3.6.86) {eq:4:bvp2}

, u(0)
Z

u(0)

p
du
p
= 2
2
(u log(1 + u) + a )

(3.6.87) {eq:4:bvp3}

. , .
. ,
u log(1 + u)

1 2
u .
2

, u < 1 . , (3.6.86)-(3.6.87)
Z

w(0)

p
dw

= ,
w2 + 1

u
w = . ,
2a

p
dw
= (1 x)
w2 + 1

p
w(x) = sinh( (1 x)).

u(x) w(x) 2a. ,

p
u(0)2
= w(0)2 = sinh2
2
2a

( 2 /) sinh2
u(0) =
.

1 + sinh2
2

,
a2 =

1
2
.
2 1 + sinh2

,
p

sinh( (1 x)).
u(x) = q

(1 + sinh2 )

, sinh( (1 x)) , .

, Dpp , [LR]
, . , ,
Morphogen . , , . , ,
. , , Dpp
, 3%,
[L](Xmax )
3%
[L](0)
5.
u , u(0) . , Dpp
, u (1) = a 0. , u , 2 / . ,
, Dpp .
[LR] ,

q
sinh( (1 x))

(1 + sinh2 )
u(x)
=
y(x) =

1 + u(x)
1+ q
sinh( (1 x))

(1 + sinh2 )
56

.
, Dpp , ,
. .
Dpp ( 1),
p

sinh( (1 x)).
y(x) u(x) = q

(1 + sinh2 )

, y(x) . (),
, .
, Dpp . , . Dpp ,
, , (3.40).
yHxL

yHxL

0.8

0.4

0.3

=10

=20

0.6

=2
=1

0.2

0.4

0.1

0.2

0.2

0.4

0.6

0.8

1.0

0.2

(A)

0.4

0.6

0.8

1.0

(B)

3.40: Dpp Morphogen Gradient ( = 5).

{fig:4:dppgrad}

, .
, . , , ,
Morpohgen , Dpp . ,
. .

3.7
Morphogen , . ,
.

w f (w, x) = 0
(aw + bw )|x=0 = h0 , (cw + dw )|x=1 = h1 .

(3.7.88) {eq:4s:bvp1}

3.7.1
, , , , .
. .
, . Hp = C 2 ([0, 1], R) p
, Li : H2 7 H0 , . ,
L1 u =
L2 u =
L3 u =

d2
u
dx2



d
(a + b )u
dx x=0


d
(c + d )u
dx x=1
57

Li . L2 L3 , .
. L : H2 H03 L = (L1 , L2 , L2 ). f : H2 H03

f (u) = (f (u(x), x), h0 , h1 ), u H2

Lw + f (w) = 0.
,
w = (L1 f )(w)
. , L . ,
(L )w + (f (w) + w) = 0
= diag{1 , 2 , 3 }. ,(L ) ,
, ,
w = ((L )1 (f + ))w := T (w)
u0 , v0 . , u0 < v0 , T , u < v
T (u) < T (v). ui = T (ui1 ), vi = T (vi1 ), {ui }, {vi }, ui < vi . , T
u0 , v0 ui < T (ui ), vi > T (vi ),
u0 < u1 < < v1 < v0 .
u = limi+ ui v = limi+ vi , ,
.
,
Lu + f (u) = 0
(3.7.89) {eq:4:a1}
u0 H2

Lu0 + f (u0 ) 0.

(3.7.90) {eq:4:a2}

Lv0 + f (v0 ) 0.

(3.7.91) {eq:4:a3}

u0 (3.7.89) . , v0 H2

v0 (3.7.89) .
T : H0k H0 , H0k , 0, T 0, T .
= (1 , k ) 0 i i 0. u(x) 0 x [0, 1], u(x) 0.
(3.7.89) :
{th:4:a1}
1. (3.7.89) u0 v0 , u0 > v0 ;
2. i > 0(i = 1 , k)
u0 1 2 v0
1 , 2 H2 ,

fi (1 ) fi (2 ) > i (1 2 ),

3. : H2 7 (H2 )k u = (1 u, , k u). (L )1 .
(3.7.89) u(x) H2 , v0 u u0 .
:
(??)
(L )u + g(u) = 0

g(u) = f (u) + u.

58

g , g(1 ) > g(2 ) u0 1 2 v0 .

g(1 ) g(2 ) = f (1 ) + 1 f (2 ) 2 > (1 2 ) + (1 2 ) = 0.
T : H0 H2 , = T
(L ) + g() = 0.
, T = (L )1 g().
T . , T , v0 1 2 u0 , T 1 T 2 .
,
T 1 T 2

= (L )1 g(1 ) + (L )1 g(1 )

= (L )1 (g(2 ) g(1 ))
0.

, , > T . , = T ,
(L )( ) 0
(L )1 , 0.
, , < T .
, {un } {vn } (un , vn ) = (T un1 , T vn1 ) (n 1). ,

u0 u1 un vm v1 v0 .

u
= lim un
n

, u0 u v0 .
u (3.7.89) . 
, 1 2 , L, 3 .
.
(1).
w f (w, x) = 0, w(0) = h0 , w (1) = h1
(3.7.92) {eq:4s:b1}
, L

Lu = (

d2
, u(0), u(1)).
dx2

= diag(, 0, 0)
T = (L )

H03 .

= T
(L ) =

T . ,
= 1 (x), (0) = 2 , (1) = 3 .

, 2 , 3 0, 1 (x) 0, (0 < x < 1), (x) 0, x [0, 1].

: (0) 0, (1) 0. 0 < x1 < 1 (x) = 0, (x1 ) > 0.

(1) 0, , x1 < x2 < 1, (x2 ) > 0, (x2 ) = 0. , (x2 ) =

(x2 ) + (x2 ) > 0 .
(2).
w f (w, x) = 0, w (0) = h0 , w (1) = h1
(3.7.93) {eq:4s:b1}
, L

Lu = (

d2
, u (0), u (1)).
dx2

= diag(, 0, 0)
59

T = (L )1 = T

H03 .

(L ) =

T . ,
= 1 (x), (0) = 2 , (1) = 3 .

, 2 , 3 0, 1 (x) 0, (0 < x < 1), (x) 0, x [0, 1].

.
, . , .
. u = w (k1 + k2 x), k1 , k2
ak1 + bk2 = h0 , c(k1 + k2 ) + dk2 = h1 ,
(3.7.88) u = u(x) .
, .

u f (u, x) = 0,

u(0)u (0) = u(1)u (1) = 0.

{le:4:2}

(3.7.94) {eq:4:a4}

f u , (3.7.94) .
: , u1 u2 (u1 (x) 6 u2 (x)). (x) = u1 (x) u2 (x), (x)
q(x) = 0, (0) = (1) = 0,

q(x) =
,
Z

f (u1 (x), x) f (u2 (x), x)

0.
u1 (x) u2 (x)

dx

q(x)2 (x)dx = 0.

,
Z
Z 1
q(x)2 (x)dx
0=

(x)dx,

, (x) 0, . 

3.7.2
: .
:
(f (w, x) x ).

w f (w) = 0,

H(w) =

1 2
w
2

f (u)du

dH(w)
|(3.7.95) 0.
dx
, (3.7.95) w(x), H(w(x)) .
Z w
1 2
f (u)du = h
H(w(x)) = w
2
0
60

(3.7.95) {eq:4s:bvp3}

h .
s
Z
w

w = 2(h +

f (u)du)

,
w(x)

w(0)

dv
q
= 2x
Rv
(h + 0 f (u)du)

(3.7.96) {eq:4s:bvp4}

. w(0), .
Green : Green . , (3.7.88)

w 2 w g(w, x) = 0
(3.7.97) {eq:4s:bvp5}
(aw + bw )|x=0 = 0, (cw + dw )|x=1 = 0.

g(w, x) = f (w, x) 2 w.

w 2 w = f (x)

(3.7.98) {eq:4s:bvp6}

(aw + bw )|x=0 = 0, (cw + dw )|x=1 = 0.

(3.7.99) {eq:4s:bvp7}

w(x) = C1 (x)ex + C2 (x)ex .

w (x) = C1 (x)ex + C2 (x)ex + C1 (x)ex C2 (x)ex .

C1 , C2

C1 (x)ex + C2 (x)ex = 0.

(3.7.100) {eq:4s:green1}

w (x) = 2 C1 (x)ex + 2 C2 (x)ex + C1 (x)ex C2 (x)ex .

(3.7.98)

C1 (x)ex C2 (x)ex = f (x).

(3.7.100), (3.7.101) C1 (x), C2 (x):

C1 (x) =
,

1 x
e
f (x),
2

C2 (x) =

1 x
e f (x).
2

Z x
Z x
1
1
s
C1 (x) =
(
e
f (s)ds + c1 ), C2 (x) = (
es f (s)ds + c2 ).
2 0
2 0

, (3.7.98)
Z x
Z x
1
1
w(x) =
es f (s)ds + c1 )ex
es f (s)ds + c2 )ex .
(
(
2 0
2 0
c1 , c2 (3.7.99) .
0
0

1
1
(c1 c2 ) + b (c1 + c2 )
2
2
 Z 1

Z 1
1

e
e
f (s)ds + e c1 e
e f (s)ds e c2
= c
2
0
0
 Z

Z 1
1 1 s

e
+d
e
f (s)ds + e c1 + e
e f (s)ds + e c2
2
0
0
= a

61

(3.7.101) {eq:4s:green2}





a
b
b
a
+

c1
c2
2 2
2 2




c
d
d
c
c1 e
c2
+

e
2 2
2 2

sinh((1 s))f (s)ds d

cosh((1 s))f (s)ds.

c1
c2

(a b)
p()

(a + b)
p()

q(, s)f (s)ds

0
1

q()f (s)ds)

p()
q(, s)

= (ac bd2 ) sinh() + (ad cb) cosh()

= (c sinh((1 s)) + d cosh((1 s))

,
Z
1 x
w(x) =
sinh((x s))f (s)ds +
0
Z
1 x
=
sinh((x s))f (s)ds
0
Z
1 x
sinh((x s))f (s)ds
=
0

1
(c1 ex c2 ex )
2
Z
1 (a b)ex + (a + b)ex 1
q(, s)f (s)ds

2p()
0
Z
1 a cosh(x) b sinh(x) 1
q(, s)f (s)ds

p()
0

1
(p() sinh((x s)) + (b sinh(x) a cosh(x))q(, s)) , 0 s < x
p()
G(x, s; ) =
1

(b sinh(x) a cosh(x))q(, s),

xs<1
p()

,
1

(b sinh(s) a cosh(s))(c sinh((1 x)) + d cosh((1 x))),

p()
G(x, s; ) =
1

(b sinh(x) a cosh(x))(c sinh((1 s)) + d cosh((1 s))),

p()

Green .
Green , (3.7.98)-(3.7.99)
w(x) =

G(x, s; )f (s)ds.
0

, (3.7.97)
w(x) =

G(x, s; )g(w(s), s)ds

62

0s<x
xs<1

4.1 Nernst
Nernst

G = RT ln

[ion]in
+ V F z
[ion]out

(4.1.1) {eq:nernst1}

F Faradays const, V , z . , G = 0,
V = Vm =

RT
61.5
[ion]in
[ion]in
=
(37o C).
ln
log10
zF
[ion]out
z
[ion]out

(4.1.2)

Nernst .
.

Na
K+
Cl
Ca2+

Na
K+
Cl
Ca2+

(mM)
50
400
40
0.4 M

(mM)
440
20
560
10
(A)

(mV)
+55
-76
-66
+ 145

(mM)
18
140
7
100 M

(mM)
145
3
120
1.2
(B)

(mV)
+56
-102
-76
+125

4.1: (A) (B) .

GHK (Goldman-Hodgkin-Katz) equation():
Vm =

PK [K+ ]out + PNa [Na+ ]out + PCl [Cl+ ]out

RT
ln
F
PK [K+ ]in + PNa [Na+ ]in + PCl [Cl+ ]in

Pi . ,
PK : PNa : PCl = 1.00 : 0.04 : 0.45.
63

(4.1.3) {eq:GHK}

(20o C) 62mV .

4.2
C

X
dV
gi (V Vi ) + Im IL
=
dt
i

(4.2.4) {eq:memeq}

gi (V Vi ) , Im , IL .

4.3
4.4 Morris-Lecar
dV
dt
dw
dt

gCa m (V VCa ) gK w(V VK ) gL (V VL ) + Im

(4.4.5)

(w w)

(4.4.6)

m (V ) =

0.5(1 + tanh((V v1 )/v2 ))

w (V ) =

0.5(1 + tanh((V v3 )/v4 ))

(V ) =

1/ cosh((V v3 )/(2v4 ))

4.5 Hodgkin-Huxley
C

dV
dt
dm
dt
dh
dt
dn
dt

gNa m3 h(V VNa ) gK n4 (V VK )

(4.5.7)

(m m (V ))/m (V )

(4.5.8)

(h h (V ))/h (V )

(4.5.9)

(n n (V ))/n (V )

(4.5.10)

64

(,,).
, . ,
, .
, (Cyclical neutropeniaCN), (Periodic
chronic myelogenous leukemia, PCML), (Cyclical thrombocytopenia),
(Periodic hemolytic anemia) . ,
. , ,
, . ,
, .
, Michael C. Mackey(McGill Univeristy)
. 1978 , Mackey
, .
, Mackey
, . , ,
,
. 1997 ,
. 2005 , Colijn Mackey //
. ()
. , Colijn MackeyCNPCML
, .
, ,
, .
.
, .

5.1
1.5 109 cells/kg day (Dancey et al., 1976 [12]). ,
70 kg 70 , (granulocyte production rate, GPR)
GP R 2.7 1015
(GP R = 1.5 9

cells
kg day

70kg

cells
lifetime

70365 days
lifetime

cells
= 2.7 1015 lifetime
)

, 5 106 cells/mm3 blood, 120 (Beutler et al., 1995

[7]). 71ml/kg (Dancey et al., 1976). , 70 kg ,
(erythrocyte production rate, EPR)
EP R 3.0 109

cells
cells
5.4 1015
kg day
lifetime
65

(EP R = 5 106 mmcells

3 blood

71103 mm3
kg

1
120day

= 3.0 106 kgcells

days )

, 3 106 cells/mm3 blood, 10 (Beulter et al., 1995),

(platelet production rate, PPR)
P P R 2.1 109

cells
cells
3.8 1015
.
kg day
lifetime

, (haematopoietic production rate, HPR = GPR + EPR + PPR)

HP R 1.2 1016

cells
.
lifetime

92fl = 92 1012 cm3 . (),

92 1012 g. ,
EP R 5.4 1015

g
kg
cells
92 1012
= 497
.
lifetime
cell
lifetime

8fl,
P P R = 2.1 109

cells
kg
30
.
kg day
lifetime

, 60fl,
GP R 162

kg
.
lifetime

HP R = 689

kg
,
lifetime

70 70 689 , 10 .
, (Novak & Necas (1994) , 2 )
EP R 8.6

g
g
g
, P P R 4.2
, GP R 2.6
.
lifetime
lifetime
lifetime

,
HP R 15.4

g
.
lifetime

25 , 60% .

5.2
5.2.1
(5.1)
dP
dt
dN
dt

P + (N )N e (N )N

(5.2.1)

((N ) + )N + 2e (N )N

(5.2.2)

N G0 , P , , (N )
, , S , ,
N = N (t ).
66

5.1: Ctem Cell model

(5.2.1) , (5.2.2) . t ,
= .

= ((N )N N )t
= 2P (t, )t

P (t, ) (M), :
P (t, a)
= P (t, a), P (t, 0) = (N )N .
a
,
P (t, ) = e (N )N .
, t 0, (5.2.2).
(N ) , (Bernard et. al.(2003)[6]):
, . ,
. N .
DNA . (),
. R . L . G
,
R + L = mN,
m . n ,
R + nG L.
,
RGn = kL.
k .

R = mN L,
L=

mN Gn
.
k + Gn

,
= 0

L
Gn
.
= 0
mN
k + Gn
67

{fig:5:1}

, , , , . ,
[G]
dG
= P N G,
dt
P , . , ,
G = P/N.
,
(N ) = 0

n
,
N n + n

.
n
k

5.2.2
. ,
. , , ,
. , . ,
: , .
N . 105
8 (Abkowitz et. al. (1988)), 105 1 50
(Boggs et.al., 1982[8], Micklem et. al., 1987[30]). 1.4 1010
. 1.4105 7106 ,
1.1 106 . , N = 1.1 106cells/kg body weight.
Mackey (2000 [29]) , S (0.069, 0.228)day1
(N) (0.020, 0.053)day1 , S (1.41, 4.25) ,
(0.010, 0.024)day1 .

5.2:
. , , ,
. DNA (S ), .
fL (t), . .

fL (t) =

PL (t) + NL (t)
,
P (t) + N (t)
68

{fig:5:2}

Parameter
fL
fN
fP
b(day1 )

Mouse, Bradford et al. (1997)

0.01
0.93
0.07
0.0305

Mouse, Cheshier et al. (1999)

0.05
0.94
0.06
0.0768

tS (day)
0.54 0.7
1.14 0.24
1
(day )
0.069(0.200)
0.228(0, 0.599)
1
(day )
0.020(0.015, 0.031)
0.053(0.038, 0.077)
(day1 )
0.010(0, 0.015)
0.024(0, 0.038)
(day)
4.25(3.40, 9.86)
1.41(1.15, 1.67)
Bradford et al. (1997)Cheshier et al. (1999)
12 6 .
. ,
, , ,
. fL (t).
fL , fN G0
, fP = 1 fN . b
fU (t) = 1 fL (t) fU (t) = aebt b.
. tS DNA , tS,av = tS,min
tS tS = (tS,max tS,min)/2. tS ,
tS,av , tS . ,
G0 ,
, .
5.1:

{tab:5:1}

P (t) , N (t) G0 .

P (t)
,
fP (t) =
P (t) + N (t)
G0
fN (t) = 1 fP (t) =

N (t)
.
P (t) + N (t)

(5.2.2), ,
(??)

Parameter
(day1 )
(day1 )
(day1 )

= (2e 1).

(5.2.3) {eq:5:6}

P = N (1 e ).

(5.2.4) {eq:5:7}

Mouse, Abkowitz et al.(2000)

0.07(0, 0.071)
0.057(0.022, 0.08)
0.042(0.011, 0.075)

Cat, Abkowitz et al. (1996)

(0, 0.034)
0.018(0.005, 0.047)
0.011(0.002, 0.043)

5.2:
69

{tab:2}

,
fP =

(/)(1 e )
P
=
.
P + N
(/)(1 e ) + 1

(5.2.5) {eq:5:8}

, S ,
fL

(/)(1 e tS )
PS
=
.
P + N
(/)(1 e ) + 1

(5.2.6) {eq:5:9}

(5.2.5) (5.2.6), tS


1
fP
= ln 1
(1 etS )

fL

(5.2.7) {eq:5:10}




fL
.
fN 1 etS

(5.2.8) {eq:5:11}

, (t > tS ), P ,
G0 , , b = + . (5.2.3), (5.2.7) (5.2.8)



2fL
fP

tS
b=
1

)
(5.2.9) {eq:5:12}
(1

e
fN 1 etS
fL
(5.2.9), (5.2.8), (5.2.7), (5.2.3) fL , fP , fN = 1 fN tS , , , .
tS . , . 0, = 0 ,
( = 0) = ( = 0) =

fP
fL
, ( = 0) =
tS .
tS f N
fL

(5.2.10) {eq:5:15}

(5.2.3) > 0, 2e 1 > 0,

< ln 2.
(5.2.7),


fP
ln 1
(1 etS ) < ln 2,
fL

"
#
1
1
<
ln
c .
tS
1 12 ffPL
= c ,



tS ln 2
fL
fP
i.
, (c ) = 0, c = h
ln 1
(c ) = 2
tS f N
2fP
ln 1 fL
2fP

btS = ( + )tS ,

tS = ( + )tS /b.

(c ) + (c ) < + < (0) + (0)

, (5.2.10), (5.2.11)
tS,min = 2

fP
2fL
1
tS
ln
= tS,max
f
L
bfN 1 2f
bfN
P

tS,av = (tS,min + tS,max )/2.

70

(5.2.11) {eq:5:19}

5.3
, .
. ,
. , .

dP
dt
dN
dt

P + (N )N e (N )N

(5.3.12)

((N ) + )N + 2e (N )N

(5.3.13)

(N ) = 0

n
.
+ n

Nn

: . ,
. , N
. , (5.3.13) .
, :
t
Q
q = ,t =

b1 = 0 , 1 = 2e , = .
(5.3.13)
b1
b1
dq
q + 1
q1 q.
=
dt
1 + qn
1 + q1n

(5.3.14) {eq:5:s3}

q1 (t) = q(t 1), t . , : b = 22.4, =

1.64. n , n 2 4. , n = 4.
, < b( 1) , (5.3.14)
q =

b( 1)
1

1/4

. . ,

dx
= ax + bx1
(5.3.15) {eq:5:s4}
dt
x = q q ,
a=

(3b1 (1 1) + b1 (1 1)2 + 4),

b1 (1 1)2
b=

1
(3b1 (1 1) + 4).
b1 (1 1)2

, ,
a b = 0
. , S R2 a b .
(5.3(A))
S = {(a, b) R2 | a sec < b < a, where = a tan , a < 1, (0, )}.

71

4
0.5

-3

-2

-1

1.5

2.5

3.5

-1

-4

-2

-3

-2

-4
-4

(B)

(A)
5.3: :

{fig:5:ss}

, :
0.06 < < 0.26, 20 < b1 < 30, 1.1 < 1 < 2
a > 0 b < 0,
b = 1 (a + ).
, , , (a, b) S , (5.3(B)).
5.4 . , (), ,
.

5.4: Bifurcation diagram[11]

{fig:5:ss2}

5.4
5.5
:
dQ
dt
dN
dt
dR
dt
dP
dt

= (Q)Q (N (N ) + R (R) + P (P ))Q + 2eS S (QS )QS

(5.4.16)

= N N + AN N (NN )QN

(5.4.17)

= R R + AR {R (RRM )QRM eR RS R (RRM +RS )QRM +RS }

(5.4.18)

= P P + AP {P (PP M )QP M eP P S P (PP M +P S )QP M +P S }

(5.4.19)

72

5.5:
where

2s
+ Qs

p
P (P ) =
1 + Kp P m
(Q) = k0

22

N (N ) = f0
R (R) =

73

{fig:5:full}

1n

1n
+ Nn

r
1 + Kr R r

74

75

[1] Abkowitz, J. L., Holly, R. D., Hammond, W. P. 1988. Cyclic hematopoiesis in dogs: studies of
erythroid burst forming cells confirm an early stem cell defect, Exp. Hematol. 16: 941-945.
[2] Abkowitz J, Catlin S, Guttorp P. 1996. Evident that haematopoiesis may be a stochastic process
in vivo, Nature Med. 2: 190-197.
[3] Abkowitz J, Golinelli D, Harrison D, Guttorp P. 2000. The in vivo kinetics of murine hemopoietic
stem cells, Blood 96: 3399-3405.
[4] Alon, U. 2006. An introduction to systems biology, design principles of biological circuits. Chapman & Hall/CRC. London.
[5] Atkinson, M. R., Savageau, M. A., Myers, J. T., Ninfa, A. J. 2003. Development of genetic
circuitry exhibiting toggle switch or oscillatory behavior in Escherichia coli. Cell 113: 597-607.
[6] Bernard, S., B`elair, J., Mackey, M. C. 2003. Oscillations in cyclical neutropenia: new evidence
based on mathematical modeling, J. Theo. Bio. 223: 283-298.
[7] Beutler E, Lichtman MA, Coller BS, Kipps TJ. 1995. Williams hematology, McGraw-Hill, New
York, 1995.
[8] Boggs, D., Boggs, S., Saxe, D., Gress, L., Canfield, D. 1982. Hematopoietic stem cells with high
proliferative potential: assay of their concentration in marrow by the frequency and duration of
cure of W/Wv mice, J. Clin. Invest. 70: 242-253.
[9] Bradford G, Williams B, Rossi R, Bertoncello I. 1997. Quiescence, cycling, and turnover in the
primitive haematopoietic stem cell compartment, Exper. Hematol. 25: 445-453.
[10] Cheshier S, Morrison S, Liao X. Weissman I. 1999. In vivo proliferation and cell cycle kinetics of
long term self renewing haematopoietic stem cells, Proc. Natl. Acad. Sci. USA 96: 3120-3125.
[11] Colijn, C., Mackey, M. C. 2005. Bifurcation and bistability in a model of hematopoietic regulation.
preprint submitted.
[12] Dancey JT, Deubelbeiss KA, Harker LA, Finch CA, 1976. Neutrophil kinetics in man, J. Clin.
Invest 58: 705-715.
[13] Dyson, S., Gurdon, J. B. 1998. The interpretation of position in a morphogen gradient as revealed
by occupancy of activin receptors. Cell 93: 557-568.
[14] Entchev, E. V., Schwabedissen, A., Gonzalez-Gaitan, M. 2000. Gradient formation of the TGF-
homolog Dpp. Cell 103: 981-991.
[15] Fung, E., Wong, W. W., Suen, J. K., Bulter, T., Lee, S., Liao, J. C. 2005. A synthetic genemetabolic oscillator. Nature 435: 118-122.
[16] Gillespie, D. T. 1977. Exact stochastic simulation of coupled chemical reactions. J. Phys. Chem.
81:2340-2361.
[17] Gillespie, D. T. 2000. The chemical Langevin equation. J. Chem. Phys. 113:297306.

76

[18] Gillespie, D. T. 2002. The chemical Langevin and Fokker-Planck equations for the reversible
isomerization reaction. J. Phys. Chem. A 106: 5063-5071.
[19] Gurdon, J. B., Harger, P., Mitchell, A., Lemaire, P. 1997. Activin has a direct long range signaling
activity and can form a concentration gradient by diffusion. Curr. Biol. 7: 671-681.
[20] Gurdon, J. B., Bourillot, P. Y. 2001. Morphogen gradient interpretation. Nature 413: 797-803.
[21] Hasty, J., Pradines, J., Dolnik, M., Collins, J. J. 2000. Noise-based switches and amplifiers for
gene expression. Proc. Natl. Acad. Sci. USA 97: 2075-2080.
[22] Kerszberg, M., Wolpert, L. 1998. Mechanisms for positional signalling by morphogen transport:
a theoretical study. J. Theor. Biol. 191: 103-114.
[23] Lander, A. D., Nie, Q., Wan, F.Y.M. 2002. Do morphogen gradients arise by diffusion? Dev.
Cell, 2: 785796.
[24] Lander, A. D., Nie, Q., Wan, F. Y. M. 2007. Membrane-Associated Non-Receptors and Morphogen Gradients. Bull. Math. Biol. 69:33-54.
[25] Lewis, E. B. 1978. A gene complex controlling segmentation in Drosophila. Nature, 276: 565-570.
[26] Lipshtat, A., Loinger, A., Balaban, N. Q., Biham, O. 2006. Genetic toggle switch without cooperative binding. Phy. Rev. Lett. 96, 188101.
[27] Kloeden, P. E., and E. Platen. 1992. Numerical Solution of Stochastic Differential Equations.
Springer-Verlag, New York.
[28] Huang, G., Wang H., Chou S., Nie, X., Chen, J., Liu, H. P. 2006. Bistable expression of WOR1,
a master regulator of white-opaque switching in Candida albicans. Proc. Natl. Acad. Sci. USA,
103, 12813-12818.
[29] Mackey, M. C. 2000. Cell kinetic status of haematopoietic stem cells, Cell Prolif. 34: 71-83.
[30] Micklem, H., Lennon, J., Ansell, J., Gray, R. A. 1987. Numbers and dispersion of repopulating
hematopoietic cell clones in radiation chimeras as functions of injected cell dose, Exp. Hematol
15(3): 251-257.
[31] Nusslein-Volhard, C., Wieshaus, E. 1980. Mutations affecting segment number and polarity in
Drosophila, Nature, 287: 795801.
[32] olde Scheper T., Klinkenberg, D., Pennartz, C., van Pelt, J. 1999. A mathematical model for the
intracellular circadian rhythm generator. J. Neurosci., 19, 40-47.
[33] Tabata, T. 2001. Genetics of morphogen gradients. Nat. Rev. Genet. 2: 620-630.
[34] Teleman, A. A., Cohen, S. M. 2000. Dpp gradient formation in the Drosophila wing imagianl
disc. Cell 103: 971-980.
[35] Tyson, J. J., Hong, C. I., Thron, C. D., Novak, B. 1999. A simple model of circadian rhythms
based on dimerization and proteolysis of PER and TIM. Biophys. J., 77, 2411-2417.
[36] van Kampen, N. G. 1992. Stochastic process in physics and chemistry. North-Holland, Amsterdam, 1992.
[37] Vilar, J. M. G., Kueh, H. Y., Barkai, N., Leibler, S. 2002. Mechanisms of noise-resistance in
genetic oscillators. Proc. Natl. Acad. Sci. USA, 99, 5988-5992.
[38] Wolpert, L. 1989. Positional information revisited. Development 107(Suppl.): 3-12.
[39] Zordan, R. E., Galgoczy, D. J., Johnson, A. D. 2006. Epigenetic properties of white-opaque
switching in Candida albicans are based on a self-sustaining transcriptional feedback loop. Proc.
Natl. Acad. Sci. USA, 103, 12807-12812.
[40] http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html.

77


2.1
2.2
2.3
2.4
2.5

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Intrinsic and extrinsic noise in gene expression (Elowitz et. al. 2002) . . . . . . . . . . 15
A model of the expression of a single gene. Each step represents several biochemical reactions, which are associ
(Gillespie ): [mRNA] vs. Time. . . . . . . . . . . . . . . . . . . . . . . . 16
(Langevin ): [mRNA] vs. Time. . . . . . . . . . . . . . . . . . . . . 16

3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13
3.14
3.15
3.16
3.17
3.18
3.19
3.20
3.21
3.22
3.23
3.24
3.25
3.26
3.27
3.28
3.29
3.30
3.31
3.32
3.33
3.34
3.35
3.36

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
( = 4, a = 4, n = 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Dynamical properteis of repressor cI. . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Bifurcation plots for the variable x and concentration of repressor ( = 50, 1 = 1, 2 = 5) 22
: = 50, = 15, 1 = 1, 2 = 5. (A): , = 15 (t < 20) = 10 (t > 20). (B): (3.
Mutual repression circuit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
The probabilities P (NA , NB ) for the switch, under condition of (A) weak repression (k = 0.005) where there is
The population of unbound A and B proteins vs time, obtain from Gillespie simulations of the switch with para
Modules and connectivity for the genetic clock. The top construct contains the gInAp2 promoter fused to gInG
Atkinson oscillator . : 1 = 3 = 30.0, 4 = 1.0, 1 = 3 = 2.0, 1 = 2 = 20.0
. (A): n2 = 4, 2 = 10.5; (B): 2 = 20, n2 = 5; (C) 3 = 0.5, 2 = 100, n1 = 4,
Conceptual diagram of the oscillatory dynamics, highlighting the two metabolite pools (M1 and M2 ) and their
Biological realization of the conceptual design in Fig. 3.12. The yellow boxes highlight the two metabolic pools
Computational characterization of the metabolator. The metabolator is prone to oscillate at increasing glycolyt
Biochemical network of the circadian oscillator model.(replot from [37]) . . . . . . . . 31
Oscillations in repressor and activator protein numbers obtained from numerical simulations of the deterministi
: (A) , (B) . . . . . . . . . . . . . . . . . . . . . . . . . 33
K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
([37]). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
: (A) , (B) . R = 0.005, . . 35
The schematic diagram of a synthetic gene regulatory network. . . . . . . . . . . . . . 36
When no stimulus is presented, the cells oscillate with the same frequency (a) with different phases (b). Withou
The synchronization in the present of sinusoidal periodic stimulus. When the stimulus with resonance frequency
Synchronization in the present of white noise stimulus. (a) shows the time evlution of order parameter of the sy
The order parameter for 1000 cells with period varies from 5 to 15, and different values of (red circles for
The relation between the order parameter and the variability of the cells (measured by . The parameter use
A simple molecular mechanism for the circadian clock in Drosophila, adopted from [35]. PER and TIM protein

. : vm = 1, km = 0.1, vp = 0.5, kp1

= 10, kp2 = 0.03, kp3 = 0.1, Pcrit = 0.1, Jp = 0.05, r

(A) g (P ) Keq . (B) . . . . . . . . . . . . . . . . . . . . . . 45

(A) g (P ) kp1 . (B) kp1 . kp1 10, 20, 30, .
Two-parameter bifurcation diagram for the model(adopt from [35]). . . . . . . . . . . 46
Period of the endogenous rhythms of wild-type and mutant files. [35] . . . . . . . . . . 46
(A). Schematic representation of the biological elements of the protein synthesis cascade, assumed to be elemen
(3.3.59)-(3.3.60) . : rM = 1.0hr1 , rP = 1.0hr1 , qM = 0.21hr1 , qP = 0
(3.3.59)-(3.3.60) . () = 1.5, 1.0, 0.5. 49
Morphogen gradient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

78

3.37
3.38
3.39
3.40

Dpp gradient[14]. . . . . . . . . . . . . . . . . . . . . . .
Wing imaginal disc of Drosophila[33]. . . . . . . . . . .
Dpp : (A) Diffusion and reversible binding. (B)
Dpp Morphogen Gradient ( = 5). . . . . . . . . . . .

. . . . . . . . . . . . . . . . . 52
. . . . . . . . . . . . . . . . . 53
Diffusion, reversible binding and degradation. (C) Diff
. . . . . . . . . . . . . . . . . 57

5.1
5.2
5.3
5.4
5.5

Ctem Cell model . . . .

. . . . . .
: . . . . .
Bifurcation diagram[11]
. . . . .

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

79

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

67
68
72
72
73