A General Model for the Origin of Allometric Scaling Laws in Biology

Author(s): Geoffrey B. West, James H. Brown and Brian J. Enquist

Source: Science, New Series, Vol. 276, No. 5309 (Apr. 4, 1997), pp. 122-126
Published by: American Association for the Advancement of Science
Stable URL: https://www.jstor.org/stable/2892614
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 A General Model for the Origin of Allometric
p888, which contains a Bam HI to Not I fragment
encoding a full-length profilin cDNA (16); p989,
which encodes a mutant form of profilin, Pfyl p-3,
lacking the last three amino acids (18); p890, which Scaling Laws in Biology
contains the Bgl II to Stu I fragment from p182 (26),
encoding Bnilp(1227-1397); p813, which con-
tains the Bgl II to Not I fragment from p182, encod-
Geoffrey B. West, James H. Brown,* Brian J. Enquist
ing Bnilp(1414-1953); and p951, which contains Allometric scaling relations, including the 3/4 power law for metabolic rates, are char-
the Hpa I to Not I fragment from p182, encoding
Bnil p(1 647-1953). The pJG4-5-derived plasmids
acteristic of all organisms and are here derived from a general model that describes how
were p561, which contains the Bam HI to Not I essential materials are transported through space-filling fractal networks of branching
fragment from p532 (26), encoding Bnil p(1-1953); tubes. The model assumes that the energy dissipated is minimized and that the terminal
p717, which contains the Bam HI to Eco47 IlIl frag-
tubes do not vary with body size. It provides a complete analysis of scaling relations for
ment from p532, encoding Bnilp(1-1214); p558,
which contains the Eco 47111 to Not I fragment from mammalian circulatory systems that are in agreement with data. More generally, the
p182, encoding Bnilp(1215-1953); p913, which model predicts structural and functional properties of vertebrate cardiovascular and
contains the Bgl II to Stu I fragment from p182,
respiratory systems, plant vascular systems, insect tracheal tubes, and other distribution
encoding Bnilp(1227-1397); p929, which con-
tains the Bgl II to Not I fragment from p182, encod- networks.
ing Bnilp(1414-1953); p952, which contains the
Hpa I to Not I fragment from p182, encoding
Bnil p(1 647-1953); and p887, which contains the
Bam HI to Not I fragment encoding a full-length
profilin cDNA (16). The pACT-derived plasmid was
p1 124, encoding full-length Actl p as isolated in a Biological diversity is largely a matter of underlies these laws: Living things are sus-
catch and release screen (22). The pGAD-C-de- body size, which varies over 21 orders of tained by the transport of materials
rived plasmid was p688, encoding the COOH-ter-
magnitude (1). Size affects rates of all bio- through linear networks that branch to
minal 311 amino acids (478-788) of Bud6p, as
isolated in a catch and release screen (22). logical structures and processes from cellu- supply all parts of the organism. We de-
29. For localization of Bnil p, SY2625 (11) cells carrying a lar metabolism to population dynamics (2, velop a quantitative model that explains
multicopy plasmid encoding either HA-tagged Bni1 p 3). The dependence of a biological variable the origin and ubiquity of quarter-power
[pY39tetl (9)] or nontagged Bnilp were induced to
Y on body mass M is typically characterized scaling; it predicts the essential features of
form mating projections (12). HA-Bnil p was localized
by immunofluorescence with monoclonal antibody by an allometric scaling law of the form transport systems, such as mammalian
HA. 1 1 (Berkeley Antibody Company) as described [J. blood vessels and bronchial trees, plant
R. Pringle, A. E. M. Adams, D. G. Drubin, B. K. Haarer, y = YoMb (1) vascular systems, and insect tracheal
Methods Enzymol. 194, 565 (1991)]. For localization
where b is the scaling tubes. It is based on
exponent andthree YO
unifying
a princi-
of Bud6p, SY2625 cells expressing GFP-Bud6p (23)
or containing the control plasmid pRS316 (26) were constant that is characteristic of the kind ples or assumptions: First, in order for the
induced to form mating projections (12), then ob- of organism. If, as originally thought, these network to supply the entire volume of
served by fluorescence microscopy with the use of a relations reflect geometric constraints, the organism, a space-filling fractal-like
fluorescein isothiocyanate filter set.
30. Yeast cells of strain B5459 (MATa pep4::HlS3
then b should be a simple multiple of branching pattern (9) is required. Second,
prb 1 A 1 -6R ura3 trp 1 Iys2 leu2 his3A200 canone-third.1) car- However, most biological phe- the final branch of the network (such as
rying p1 025 (26) were grown to mid-log phase in nomena scale as quarter rather than third the capillary in the circulatory system) is a
raffinose medium, and galactose was added to
powers of body mass (2-4): For example, size-invariant unit (2). And third, the en-
induce the production of HA-tagged Bnil p(1 215 -
1953). After 1 hour, extracts were prepared by metabolic rates B of entire organisms scale ergy required to distribute resources is
grinding cells with glass beads in lysis buffer [0.6 M as M3/4; rates of cellular metabolism, minimized (10); this final restriction is
sorbitol, bovine serum albumin (1%), 140 mM
heartbeat, and maximal population basically equivalent to minimizing the to-
NaCI, 5 mM EDTA, 50 mM tris-HCI (pH 7.6), 0.06%
Triton X-100, 2 mM phenylmethylsulfonyl fluoride, growth scale as M-1/4; and times of talblood
hydrodynamic resistance of the system.
aprotinin (10 ,ug/ml)] as described (2). Escherichia circulation, embryonic growth and devel- Scaling laws arise from the interplay be-
co/i strain BL 21 (Novagen) was transformed with opment, and life-span scale as M1/4. Sizes tween physical and geometric constraints
pGEX-3X (Pharmacia) or p907 (26) and induced for
expression of GST or GST-profilin, respectively. of biological structures scale similarly: For implicit in these three principles. The
GST proteins were purified on glutathione-Sepha- example, the cross-sectional areas of mam- model presented here should be viewed as
rose (Pharmacia) and washed twice with phos- malian aortas and of tree trunks scale as an idealized representation in that we ig-
phate-buffered saline (PBS) [140 mM NaCI, 2.7
mM KCI, 10 mM Na2HPO4, 1.8 mM KH2PO4 (pH
M3/4. No general theory explains the ori-
nore complications such as tapering of
7.3)]. Glutathione-Sepharose beads with GST or gin of these laws. Current hypotheses, vessels, turbulence, and nonlinear effects.
GST-profilin bound were then added to the yeast such as resistance to elastic buckling in These play only a minor role in determin-
extract containing HA-Bnilp(1215-1953) and in-
cubated on ice. After 45 min, the beads were col-
terrestrial organisms (5) or diffusion of ing the dynamics of the entire network
lected and washed twice with PBS. The GST pro- materials across hydrodynamic boundary and could be incorporated in more de-
teins and associated proteins were eluted with glu- layers in aquatic organisms (6), cannot tailed analyses of specific systems.
tathione [10 mM glutathione, 50 mM tris-HCI (pH
explain why so many biological processes Most distribution systems can be de-
8.0)] and subjected to immunoblot analysis with
antibodies to GST (Pharmacia) or the HA epitope in nearly all kinds of animals (2, 3), plants scribed by a branching network in which
(29) as described (27). (7), and microbes (8) exhibit quarter-pow- the sizes of tubes regularly decrease (Fig.
31. We thank D. Amberg, B. Andrews, R. Brent, R. er scaling. 1). One version is exhibited by vertebrate
Dorer, S. J. Elledge, S. Givan, B. K. Haarer, J.
Horecka, P. James, I. Sadowski, M. Tyers, and J. We propose that a common mechanism circulatory and respiratory systems, anoth-
Zahner for plasmids and yeast strains; B. Brand- er by the "vessel-bundle" structure of mul-
horst, J. Brown, N. Davis, S. Kim, B. Nelson, and 1. G. B. West, Theoretical Division, T-8, Mail Stop B285, tiple parallel tubes, characteristic of plant
Pot for comments on the manuscript; and G. Poje Los Alamos National Laboratory, Los Alamos, NM
and 1. Pot for assistance with experiments. Support-87545, and The Santa Fe Institute, 1399 Hyde Park
vascular systems ( 11). Biological networks
ed by grants to C.B. from the Natural Sciences and Road, Santa Fe, NM 87501, USA. vary in the properties of the tube (elastic
Engineering Research Council of Canada and the J. H. Brown and B. J. Enquist, Department of Biology, to rigid), the fluid transported (liquid to
National Cancer Institute of Canada; by a grant from University of New Mexico, Albuquerque, NM 87131, and
the Swiss National Science Foundation to M.P.; and The Santa Fe Institute, 1399 Hyde Park Road, Santa Fe,
gas), and the nature of the pump (a pul-
by NIH grant GM31006 to J.R.P. NM 87501, USA. satile compression pump in the cardiovas-
*To whom correspondence should be addressed. E-mail: cular system, a pulsatile bellows pump in
2 December 1996; accepted 10 February 1997 jhbrown@unm.edu the respiratory system, diffusion in insect

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 X REPORTS
tracheae, and osmotic and vapor pressure Fig. 1. Diagrammatic examples of
in the plant vascular system). In spite of segments of biological distribu-

these differences, these networks exhibit
essentially the same scaling laws.
For convenience we shall use the lan-
guage of the cardiovascular system, name-
ly, aorta, arteries, arterioles, and capillar-
ies; the correspondence to other systems is
straightforward. In the general case, the
network is composed of N branchings from
the aorta (level 0) to the capillaries (level
N, denoted here by a subscript c) (Fig.
tion networks: (A) mammalian cir-
culatory and respiratory systems
composed of branching tubes;
>ZII. 5 (B) plant vessel-bundle vascular
Mammal Plant system composed of diverging
vessel elements; (C) topological
representation of such networks,
C E D where k specifies the order of the
< APk > level, beginning with the aorta
< k - > (k = O)and ending with the capil-
lary (k = N); and (D) parameters of

1C). A typical branch at some intermedi- Elk t l )a typical tube at the kth level.
ate level k has length 1k, radius rk, and
pressure drop 4Pk (Fig. 1D). The volume k=O 1 2 3 4. N
rate of flow is Qk = rrkuk where uk is the
flow velocity averaged over the cross sec- Model Parameters

tion and, if necessary, over time. Each

tube branches into nk smaller ones (12), so
the total number of branches at level k is serving, that is, the sum of the cross-sec-
+ 1) - 1 cNV (4)
Nk = nkn1 . . . nk* Because fluid is con- tional areas of the daughter branches equals
served as it flows through the system that of the parent, so rrr2 = nTrr2+1. Thus,
where the last expression reflects the fractal = n = 1, independent of k.
Pk rk+l/rk
o N=Qk = NkTrrtJk = NciTri7uc (2) nature of the system. As shown below, When the
onearea-preserving branching rela-
tion, 1 = n- 1/2, is combined with the
which holds for any level k. We next intro- can also prove from the energy minimiza-
duce the important assumption, the second tion principle that Vb oc M. Because space-filling
ny132 < result for y, Eq. 5 yields a =
above, that the terminal units (capillaries) 1 and N >> 1, a good approximation 3/4,
toso B oc M3/4. Many other scaling laws
Eq.
are invariant, so rc, lC, uc, and, consequently, 4 is Vb = VO/(1 - ny p2) = Vc(,y12)N/ follow. For example, for the aorta, r =
APC are independent of body size. Because (1 - ny 32). From our assumption that cap- -Nrc = NC 1/2 rc and 10 = N r = Nc c'
the fluid transports oxygen and nutrients for illaries are invariant units, it therefore fol- yielding ro oc M3/8 and 10 oc M1/4. This
metabolism, Q0 oc B; thus, if B oc Ma (where lows that (y12)-N oc M. Using this relationderivation of the a = 3/4 law is essentially a
a will later be determined to be 3/4), then in Eq. 3 then gives geometric one, strictly applying only to sys-
0oc Ma. Equation 2 therefore predicts that ln n tems that exhibit area-preserving branch-
the total number of capillaries must scale as ing. This property has the further conse-
ln(y 32) (5) quence, which follows from Eq. 2, that the
B, that is, NC oc Ma.
To characterize the branching, we in- To make further progress requiresfluidknowl-
velocity must remain constant
troduce scale factors Pk rk+l/rk and yk edge of y and P. We shall show throughouthow thethe network and be indepen-
1k+1'lk* We shall prove that in order to former follows from the space-filling dentfractal
of size. These features are a natural
minimize the energy dissipated in the sys- requirement, and the latter, from theconsequence
energy of the idealized vessel-bundle
tem in the sense of the third principle minimization principle. structure of plant vascular systems (Fig. 1B),
above, the network must be a convention- A space-filling fractal is a natural struc-
in which area-preserving branching arises
al self-similar fractal in that Pk = PI yk ture
= for ensuring that all cells areautomatically
serviced because each branch is as-
y, and nk = n, all independent of k (an sumed tosobe a bundle of n N-k elementary
by capillaries. The network must branch
important exception is Pk in pulsatile sys- that a group of cells, referred to vessels
here asof athe same radius (I1). Pulsatile
tems). For a self-similar fractal, the num- mammalian
"service volume," is supplied by each capil- vascular systems, on the other
ber of branches increases in geometric pro- lary. Because rk << 1k and the totalhand, do not conform to this structure, so
number
portion (Nk = n k) as their size geometri- of branchings N is large, the volume for them,
sup- we must look elsewhere for the
cally decreases from level 0 to level N. plied by the total network can be origin of quarter-power scaling laws.
approxi-
Before proving self-similarity, we first ex-mated by the sum of spheres whoseSome diame-features of the simple pipe model
amine some of its consequences. ters are that of a typical kth-level vessel,
remain valid for all networks: (i) The quan-
Because NC = IN, the number of gener-namely 4/3,a(lk/2I)3Nk. For large tities N, thisy andes-1 play a dual scaling role: they
ations of branches scales only logarithmi- timate does not depend significantly determine
on the not only how quantities scale
cally with size specific level, although it is most from level 0 (aorta) to N (capillary) within
accurate
for large k. This condition, that the a single organism of fixed size, but also how
fractal
a ln(M/M0)
N = (3) be volume-preserving from one generation a given quantity scales when organisms of
lnn
to the next, can therefore be expressed as
different masses are compared. (ii) The frac-
where Mo is a normalization
4I37rr(lk2)3 Nk 4I3*(lk+l/2)3 Nk+l. This tal nature of the entire system as expressed,
scale
(13). Thus, a whale is 107 times heavier relation gives y3k (1k?/1k)3 Nk/Nk?l for example, in the summation in Eq. 4
than a mouse but has only about 70% more 1/n, showing that Yk - y must be leads to a scaling different from that for a
branchings from aorta to capillary. The to- independent of k. This result for Yk is asingle tube, given by an individual term in
tal volume of fluid in the network ("blood" general property of all space-filling fractal the series. These network systems must
volume Vb) is systems that we consider. therefore be treated as a complete integrat-
N N
The 3/4 power law arises in the simple ed unit; they cannot realistically be mod-
case of the classic rigid-pipe model, where eled by a single or a few representative
Vb = E NkVk = E lTrklknk
k=O k=O the branching is assumed to be area-pre- vessels. (iii) The scaling with M does not

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depend on the branching ratio n. blood Vb(rk, 1k, nk, M), the minimization In the linearized incompressible-fluid,
We next consider the dynamics of the principle requires that the cardiac output be thin-wall approximation, this problem can
network and examine the consequences of minimized subject to a space-filling geome- be solved analytically to give
the energy minimization principle, which is try. To enforce such a constraint, we use the
particularly relevant to mammalian vascu- standard method of Lagrange multipliers (X, 2 j(i32t) c2c
lar systems. Pulsatile flow, which dominates Xk, and XM) and so need to minimize the j(i2o) - iand Z lTr2c (8)
the larger vessels (aorta and major arteries), auxiliary function
must have area-preserving branching, so Here ot (pl)112r is the dimensionless
F(rk, lk, n) = W(rk, lk, nk, M)
that 1 = n7-1/2, leading to quarter-power Womersley number (13), and co (Ehl
scaling. The smaller vessels, on the other N
2pr)1/2 is the Korteweg-Moens velocity. In
hand, have the classic "cubic-law" branch- + XVb(rk, lk, nk, M) + I XkNklk + XMM general, both c and Z are complex functions
k=
ing (10), where 1 = n-1/3, and play a of c, so the wave is attenuated and disperses
(7)
relatively minor role in allometric scaling. as it propagates. Consider the consequences
First consider the simpler problem of Because B oc Q0 and W = Q02Z, this prob- of these formulas as the blood flows through
nonpulsatile flow. For steady laminar flow lem is tantamount to minimizing the im- progressively smaller tubes: For large tubes,
of a Newtonian fluid, the viscous resistance pedance Z, which can therefore be used in ot is large (in a typical human artery, t
of a single tube is given by the well-known Eq. 7 in place of W. First, consider the case 5), and viscosity plays almost no role. Equa-
Poiseuille formula Rk = 8plk/ITrr4r, where pt is where nk = n, so that we can use Eqs. 4 and tion 8 then gives c = co and Z = pco/lTr2;
the viscosity of the fluid. Ignoring small 6 for Vb and Z, respectively. For a fixed mass because both of these are real quantities,
effects such as turbulence and nonlineari- M, the auxiliary Lagrange function F, the wave is neither attenuated nor dis-
ties at junctions, the resistance of the entire which incorporates the constraints, must be persed. The r dependence of Z has changed
network is given by (14) minimized with respect to all variables for from the nonpulsatile r-4 behavior to r-.
the entire system (rk, 1k, and n). This Minimizing
re- energy loss now gives hk/rk (and,
N Rk N 8p1k therefore, Ck) independent of k and, most
quires aFlalk = aF/ark = aF/an = 0, which
k = 0 k k= o rrkn importantly, an area-preserving law at the
straightforwardly leads to Pk = n-1/3. More
generally, by considering variations with junctions, so Pk = n-1/2. This relation en-
[1 - (np4/y)N +1]R
respect to nk, one can show that nk = n, sures that energy-carrying waves are not
(1 - n134/)N (6)
independent of k. The result, Pk = n-1/3, is reflected back up the tubes at branch points
Now, n14/y < 1 and N >> 1, so a good a generalization of Murray's finding (17), and is the exact analog of impedance
approximation is Z = Rc/(l - np4/y)Nc.derived for a single branching, to the com- matching at the junctions of electrical
Because Rc is invariant, Z oc NC-1 oc M-a plete network. Now varying M and mini- transmission lines (18). As k increases, the
which leads to two important scaling laws: mizing F in Eq. 7 (aF/aM = 0) leads to Vb sizes of tubes decrease, so ot -> 0 (in human
blood pressure Ap = QOZ must be indepen-oc M, which is just the relation needed to arterioles, for example, (x 0.05), and the
dent of body size and the power dissipated derive Eq. 5. Although the result Pk = n- 1/3role of viscosity increases, eventually dom-
in the system (cardiac output) W = QO0Ap cxis independent of k, it is not area-preserving inating the flow. Equation 8 then gives c
Ma, so that the power expended by the and therefore does not give a = 3/4 when i112ctCo/4 -> 0, in agreement with observa-
heart in overcoming viscous forces is a size- used in Eq. 5; instead, it gives a = 1. It does, tion (18). Because c and, consequently, X
independent fraction of the metabolic rate. however, solve the problem of slowing now have imaginary parts, the traveling
Neither of these results depends on detailed blood in the capillaries: Eq. 2 gives juii0 = wave is heavily damped, leaving an almost
knowledge of n, 1, or y, in contrast to (n132) -N = N -1/3. For humans, NC 101?, steady oscillatory flow whose impedance is,
results based on Vb oc M, such as Eq. 5, a = 50 UJUo i0-, in reasonable agreement from Eq. 8, given by the Poiseuille formula;
3/4, and ro ?' M3.8 From Eq. 2, Q0 = Trrouo, with data (18). On the other hand, it leads that is, the r-4 behavior is restored. Thus,
which correctly predicts that the velocity of to an incorrect scaling law for this ratio: for large k, corresponding to small vessels,
blood in the aorta iu oc MO (2). However, an uCI/ uo c M - 1/4. Incorporating pulsatile flow k = - 1/3. We conclude that for pulsatile
area-preserving scaling relation 1 = n-31/2 not only solves these problems, giving the flow, Pk is not independent of k but rather
also implies by means of Eq. 2 that u = u correct scaling relations (a = 3/4 and uC/uj0 has a steplike behavior (Fig. 2). This picture
for all k. This relation is valid for fluid flow oc MO), but also gives the correct value for
in plant vessels (because of the vascular bun- UC/ uo.
dle structure) (11, 15) and insect tracheae A complete treatment of pulsatile flow
(because gas is driven by diffusion) (16); is complicated; here, we present a simpli-
both therefore exhibit area-preserving fied version that contains the essential iYk P3k
branching, which leads to 3/4 power scaling features needed for the scaling problem.
E n-113 - -----
of metabolic rate. Branching cannot be en-When an oscillatory pressure p of angular
0.
tirely area-preserving in mammalian circula- frequency w is applied to an elastic (char- cm n-1/2

tory systems because blood must slow down acterized by modulus E) vessel with wall
to allow materials to diffuse across capillarythickness h, a damped traveling wave is
walls. However, the pulsatile nature of the created: p = p ei(ot - 2uz/X). Here, t is time, Cl) ~ -.
mammalian cardiovascular system solves the z is the distance along the tube, X is the ?k N
problem. wavelength, and p0 is the amplitude aver- Branching level k
Energy minimization constrains the net- aged over the radius; the wave velocity
Fig. 2. Schematic variation of the Womersley num-
work for the simpler nonpulsatile systems. c = 27rwX. Both the impedance Z and the
ber tk and the scaling parameters Pk and -Yk with
Consider cardiac output as a function of all dispersion relation that determines c are level number (k) for pulsatile systems. Note the
relevant variables: W(rk,, 1k,, nk M). To sus- derived by solving the Navier-Stokes steplike change in Pk at k - k from area-preserving
tain a given metabolic rate in an organism equation for the fluid coupled to the pulse-wave flow in major vessels to area-increasing
of fixed mass M with a given volume of Navier equations for the vessel wall (19). Poiseuille-type flow in small vessels.

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 M REPORTS

is well supported by empirical data (18, 20, space-filling geometry, it remains un- cardiovascular system (Table 1); data are
2 1 ). The crossover from one behavior to the changed, so we still have 10 oc M114. Blood
needed to test other predictions. For exam-
other occurs over the region where the wave volume Vb, however, is more complicated ple, the invariance of capillary parameters
and Poiseuille impedances are comparable in implies NC oc M314 rather than the naive
size. The approximate value of k where this expectation NC oc M, so the volume serviced
V V = _____ __ 1 - (np2 y)k by each capillary must scale as M114, and
occurs (say, k) is given by r-2/l1 8p/pco,
leading to N - k IN ln(81c/pcCrc2)/ln n,
Vb (2 )N 23y/ 1 - (nI37) capillary density per cross-sectional area of
independent of M. Thus, the number of tissue, as M-1112.
generations where Poiseuille flow dominates (n32 y)N - _ (n2 _ )k A minor variant of the model describes
should be independent of body size. On the the mammalian respiratory system. Al-
other hand, the crossover point itself
+ 1 - (n1 2 y) 1- (n2 y) (9) though pulse waves are irrelevant because
grows logarithmically: k x N ?' ln M. For the tubes are not elastic, the formula for Z is
humans, with n = 3 (21), N 15 and This formula is a generalization of Eq. 4 quite similar to Eq. 8. The fractal bronchial
N 22 (assuming NC 2 X 1010), where- and is dominated by the first term, which tree terminates in NA oc M314 alveoli. The
as with n = 2, N 24 and N 34. These represents the contribution of the large network is space-filling, and the alveoli play
values mean that in humans Poiseuille tubes (aorta and arteries). Thus, Vb oc the role of the service volume accounting
flow begins to compete with the pulse nN+1/3K xc n413N, which, because it must for most of the total volume of the lung,
wave after just a few branchings, dominat- scale as M, leads, as before, to a = 3/4. As which scales as M. Thus, the volume of an
ing after about seven. In a 3-g shrew, size decreases, the second term, represent- alveolus VA oc M1/4, its radius rA ?' Ml/12,
Poiseuille flow begins to dominate shortly ing the cubic branching of small vessels, and its surface area AA c rA2 oc M1/6, so the
beyond the aorta. becomes increasingly important. This be- total surface area of the lung AL = NAAA ?'
The derivation of scaling laws based on Pkhavior predicts small deviations from M11/12. This explains the paradox (22) that
derived from Eqs. 7 and 8 (Fig. 2) leads to thequarter-power scaling (a - 3/4), observed AA scales with an exponent closer to 1 than
same results as before. For simplicity, assume in the smallest mammals (2). An expres- the 3/4 seemingly needed to supply oxygen.
that the crossover is sharp; using a gradual sion analogous to Eq. 9 can be derived for The rate of oxygen diffusion across an alve-
transition does not change the resulting scal-the total impedance of the system Z. It is olus, which must be independent of M, is
ing laws. So, for k_> k, define k > = dominated by the small vessels (arterioles proportional to APO2AA/rA. Thus, AP02 ?'
n-1/3 and, for k < k, Pk < = n 12. and This capillaries) and, as before, gives Ap M -1/12, which must be compensated for by a
predicts that area preservation only persists and juo oc Mo. similar scaling of the oxygen affinity of he-
in the pulsatile region from the aorta In order to understand allometric scal- moglobin. Available data support these pre-
through the large arteries, at most until ing, k it is necessary to formulate an integrat- dictions (Table 1).
k. First consider the radius of the aorta ro: editsmodel for the entire system. The present Our model provides a theoretical, mech-
scaling behavior is now given by ro model should be viewed as an idealized anistic basis for understanding the central
rck k-NPk = r 1/3N+1/6k = r n1I2N-116Nzeroth-order approximation: it accounts role for of body size in all aspects of biology.
which gives ro oc M3/8 and, for humans, ro/rc many of the features of distribution net- Considering the many functionally inter-
104, in agreement with data (2) . Using works and can be used as a point of depar- connected parts of the organism that must
Eq. 3 we obtain, for the ratio of fluid ture for more detailed analyses and models. obey the constraints, it is not surprising that
velocity in the aorta to that in the capil- In addition, because it is quantitative, the the diversity of living and fossil organisms is
lary, u0/uC = Nc(rc/r0)2 = n uo uc coefficients, YO of Eq. 1, can also, in prin- based on the elaboration of a few successful
250, independent of M, again in agree- ciple, be derived. It accurately predicts the designs. Given the need to redesign the
ment with data. Because y reflects the known scaling relations of the mammalian entire system whenever body size changes,

Table 1. Values of allometric exponents for variables of the mammalian with empirical observations. Observed values of exponents are taken from (2,
cardiovascular and respiratory systems predicted by the model compared 3); ND denotes that no data are available.

Cardiovascular Respiratory

Exponent Exponent
Variable Variable
Predicted Observed Predicted Observed

Aorta radius ro 3/8 = 0.375 0.36 Tracheal radius 3/8 = 0.375 0.39
Aorta pressure Apo 0 = 0.00 0.032 Interpleural pressure 0 = 0.00 0.004
Aorta blood velocity uo 0 = 0.00 0.07 Air velocity in trachea 0 = 0.00 0.02
Blood volume Vb 1 = 1.00 1.00 Lung volume 1 = 1.00 1.05
Circulation time 1/4 = 0.25 0.25 Volume flow to lung 3/4 = 0.75 0.80
Circulation distance I 1/4 = 0.25 ND Volume of alveolus VA 1/4 = 0.25 ND
Cardiac stroke volume 1 = 1.00 1.03 Tidal volume 1 = 1.00 1.041
Cardiac frequency w -1/4 = -0.25 -0.25 Respiratory frequency -1/4 = -0.25 -0.26
Cardiac output E 3/4 = 0.75 0.74 Power dissipated 3/4 = 0.75 0.78
Number of capillaries NC 3/4 = 0.75 ND Number of alveoli NA 3/4 = 0.75 ND
Service volume radius 1/12 = 0.083 ND Radius of alveolus rA 1/12 = 0.083 0.13
Womersley number oX 1/4 = 0.25 0.25 Area of alveolus AA 1/6 = 0.083 ND
Density of capillaries -1/12 = -0.083 -0.095 Area of lungAL 11/12 = 0.92 0.95
?2 affinity of blood P50 -1/12 = -0.083 -0.089 ?2 diffusing capacity 1 = 1.00 0.99
Total resistance Z -3/4 = -0.75 -0.76 Total resistance -3/4 = -0.75 -0.70
Metabolic rate B 3/4 = 0.75 0.75 02 consumption rate 3/4 = 0.75 0.76

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either during ontogeny or phylogenetic di- p. 133; see also M. H. Zimmerman, Xylem Structure
and the Ascent of Sap (Springer-Verlag, Berlin,
versification, small deviations from quarter- 1983); M. T. Tyree and F. W. Ewers, New Phytol.
power scaling sometimes occur (3, 23). 119, 345 (1991).
However, when body sizes vary over many 12. The branching of a vessel at level k into nk smaller
vessels (Fig. 1) is assumed to occur over some small,
orders of magnitude, these scaling laws are
but finite, distance that is much smaller than either Ik
obeyed with remarkable precision. More- or Ik,,. This relation is similar to that assumed in the
over, the predicted scaling properties do not Strahler method [A. N. Strahler, Trans. Am. Geo-
phys. Union 34, 345 (1953); (11, 21)]. A generaliza-
depend on most details of system design,
tion to nonuniform branching, where the radii and
including the exact branching pattem, pro- lengths at a given level may vary, is straightforward.
vided it has a fractal structure (24). Signif- 13. Normalization factors, such as MO' will generally be
Mammals (CRC Press, Boca Raton, FL, 1996). Care
must be taken in comparing measurements with
prediction, particularly if averages over many suc-
cessive levels are used. For example, if Ak -k?r2 is
the total cross-sectional area at level k, then for the
aorta and major arteries, where k < k and the
branching is area-preserving, we predict AO = Ak.
Suppose, however, that the first K levels are grouped
together. Then, if the resulting measurement gives
AK, area-preserving predictsAK = K40 (but not AK =
AO). It also predicts rO3 n 112 Nkrk3. Using results
from M. LaBarbera [Science 249, 992 (1990)], who
used data averaged over the first 160 vessels (ap-

icantly, nonfractal systems, such as combus- suppressed, as in Eq. 1. In general, all quantities proximately the first 4 levels), gives, for human be-
should be expressed in dimensionless form; note, ings, AO 4.90 cm2, AK 19.98 cm2, r03 1.95
tion engines and electric motors, exhibit however, that this does not guarantee that they are cm3, and ZNkrk3 1.27 cm3, in agreement with area
geometric (third-power) rather than quar- size independent and scale as MO. For example, the preservation. LaBarbera, unfortunately, took the fact

ter-power scaling (1). Because the fractal
network must still fill the entire D-dimen-
sional volume, our result generalizes to a =
D/(D + 1). Organisms are three-dimension-
Womersley number, ac of Eq. 8, although dimension-
less, scales as M 1/4
14. This formula is not valid for plant vessel bundles
because plants are composed of multiple parallel
vessel elements. Their resistance is given by Z =
thatAK 0 AO and ro3 ENkrk3 as evidence for cubic
rather than area-preserving branching. For small
vessels, where k > k, convincing evidence for the
cubic law can be found in the analysis of the arteriolar
system by M. L. Ellsworth et al., Microvasc. Res. 34,

al, which explains the 3 in the numerator of 8A/ /N,'rrr,4, where / is the length of a single vessel 168 (1987).
element, rc is its radius, and N, is their total number. 21. Y. C. Fung, Biodynamics (Springer-Verlag, New
the 3/4 power law, but it would be instruc- 15. This relation holds for plant vessels from the roots to York, 1984).
tive to examine nearly two-dimensional or- the leaves, but not within leaves [M. J. Canney, Phi- 22. P. Gehr et al., Respir. Physiol. 44, 61 (1981).
los. Trans. R. Soc. London Ser. B 341, 87 (1993)]. 23. P. M. Bennett and P. H. Harvey, J. Zool. 213, 327
ganisms such as bryozoans and flatworms.
16. A. Krogh, Pfluegers Arch. Gesamte Physiol. Men- (1987); A. F. Bennett, Am. Zool. 28, 699 (1988); P. H.
The model can potentially explain how schen Tiere 179, 95 (1920). Harvey and M. D. Pagel, The Comparative Method in
fundamental constraints at the level of in- 17. C. D. Murray, Proc. Natl. Acad. Sci. U.S.A. 12, 207 Evolutionary Biology (Oxford Univ. Press, Oxford,
(1926). 1991).
dividual organisms lead to corresponding
18. C. G. Caro et al., The Mechanics of Circulation (Ox- 24. This is reminiscent of the invariance of scaling expo-
quarter-power allometries at other levels. ford Univ. Press, Oxford, 1978). nents to details of the model that follow from renor-
The constraints of body size on the rates at 19. J. R. Womersley, Philos. Mag. 46, 199 (1955); malization group analyses, which can be viewed as a
which resources can be taken up from the J. Physiol. (London) 127, 553 (1955). generalization of classical dimensional analysis.
20. See, for example, A. S. Iberall, Math. Biosci. 1, 375 25. J.H.B. is supported by NSF grant DEB-9318096,
environment and transported and trans- (1967) and T. F. Sherman, J. Gen. Physiol. 78, 431 B.J.E. by NSF grant GER-9553623 and a Fulbright
formed within the body ramify to cause (1981), which contain summaries of earlier data; also Fellowship, and G.B.W. by the Department of Energy.
quarter-power scaling in such diverse phe- M. Zamir et al., J. Biomech. 25, 1303 (1992) and J.
K.-J. Li, Comparative Cardiovascular Dynamics of 13 September 1996; accepted 12 February 1997
nomena as rate and duration of embryonic
and postembryonic growth and develop-
ment, interval between clutches, age of first
Flexibility in DNA Recombination: Structure of
reproduction, life span, home range and
territory size, population density, and max- the Lambda Integrase Catalytic Core
imal population growth rate (1-3). Because
organisms of different body sizes have dif- Hyock Joo Kwon, Radhakrishna Tirumalai, Arthur Landy,*
ferent requirements for resources and oper- Tom Ellenberger*
ate on different spatial and temporal scales,
quarter-power allometric scaling is perhaps Lambda integrase is archetypic of site-specific recombinases that catalyze intermolec-
the single most pervasive theme underlying ular DNA rearrangements without energetic input. DNA cleavage, strand exchange, and
all biological diversity. religation steps are linked by a covalent phosphotyrosine intermediate in which Tyr342
is attached to the 3'-phosphate of the DNA cut site. The 1.9 angstrom crystal structure
REFERENCES AND NOTES of the integrase catalytic domain reveals a protein fold that is conserved in organisms
ranging from archaebacteria to yeast and that suggests a model for interaction with target
1. T. A. McMahon and J. T. Bonner, On Size and Life
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11. K. Shinozaki et al., Jpn. J. Ecol. 14, 97 (1964); ibid., *Corresponding authors. complete site-specific recombination reac-

126 SCIENCE * VOL. 276 * 4 APRIL 1997 * http://www.sciencemag.org

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