Download 2.3 Evolution of biological safety factors: a cost/benefit analysis

2.3
Evolution of biological safety factors:
a cost/benefit analysis
JARED
M. DIAMOND
A central problem of integrative biology is to understand quantitative
biological design at every level, from the molecular level to the whole
animal. The elements of quantitative design are familiar. For example,
molecular biologists measure activities of enzymes and transporters; cell
biologists measure numbers of ion permeation channels or receptors per
square micrometer of membrane; anatomists measure masses of organs
and surfaces of tissues; and physiologists measure functions such as the
diffusing capacity of the lung.
How are all of these quantities ultimately determined by the loads
imposed upon them? For example, how did we humans come to be
genetically programmed such that the glucose transporter makes up
about 0.1 percent of our intestinal brush-border protein, when it could
instead have made up 1 percent as in hummingbirds, or 0.001 percent as
in snakes? That quantity of glucose transporter in each species is evidently a matter of some consequence, since its interindividual variation
in each species is only about 15 percent. Would there be serious penalties
for possessing either double or one-half of the usual amount of glucose
transporter? What are those penalties? How has natural selection finetuned our glucose transporter capacity so as to match it to the glucose
loads that our particular lifestyle places on it? Are we designed with
capacities in excess of loads, and if so, by how much?
Safety factors in engineering and biological design
Let us consider the corresponding problem for engineered structures.
Engineers define the “safety factor” as the ratio of a component’s capacity (or strength, or performance) to the maximum expected load upon
that component during operation. A typical example would be the ratio
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J. M. Diamond
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Table 2.3.
Evolution of biological safety factors
Safety factors of some engineered structures
Cable of fast passenger elevator
Cable of slow passenger elevator
Cable of slow freight elevator
Wooden building
Cable of powered dumbwaiter
Steel building or bridge
11.9
7.6
6.7
6
4.8
2
of the load under which a structure (for example, an elevator cable)
would break to the expected maximum load. Table 2.3 summarizes safety
factors for some actual engineered structures; most of their safety factors
fall within the range 2 to 12.
The proximate explanation for this variation in safety factors is clear: it
involves the strength selected for materials, the size selected for components, and the overall design selected for the whole object. The ultimate
explanation for the variation is also clear: engineers specify safety factors
after doing a cost/benefit analysis.
One consideration is the penalty for failure: the higher the penalty, the
higher the specified safety factor. For example, the penalty is much higher
for a cable snapping on a passenger elevator than on a freight elevator, so
engineers specify a higher safety factor for passenger elevators. Other
considerations are variation in capacity (for example, due to variations
in material strength), the variation in expected load, and the amount of
deterioration expected in a component that cannot be readily replaced or
repaired (such as the steel beams inside a skyscraper). The safety factor
specified increases with each of these quantities. On the other hand, the
higher the cost of materials, and the more that the costs of maintenance
and of use increase with component strength, the lower will be the safety
factor specified.
In the case of these engineered safety factors, the arena of the decision
is the marketplace with its competing manufacturers, and the selective
factor is consumer choice. The biological analog is the marketplace of
competing individuals and species, and the selective factor is natural
selection operating through differential survival and reproduction. The
result is some selected ratio of capacity to load for each biological component.
Of course, excess biological capacity would be desirable if it cost nothing. But the resources available to an animal are generally finite, so that
excess devoted to one component comes at the expense of another com-
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ponent. That is, there is an evolutionary basis to biological capacities, but
the magnitudes of biological safety factors have been little explored. Do
biological capacities typically exceed their loads by 10, 100, or 1,000
percent? How much biological machinery constitutes “enough but not
too much”? These questions define a research program consisting of three
subprograms: (1) measuring safety factors for biological components; (2)
explaining the observed variation in safety factors; and (3) explaining the
costs leading to evolutionary elimination of excessive safety factors.
Safety factors are most straightforward to define and measure for loadbearing biological structures such as bones, tendons, shells, and spiders’
webs, which are directly analogous to engineered load-bearing structures
(Table 2.4). In these the ratio of breaking strength to actual operating
stress is the safety factor, and most fall within the range 1.3 to 6.
Physiological safety factors
An example of a physiological safety factor is that for the renal glucose
transporter. The renal transport maximum (so-called T,) for glucose is
approximately twice the normal renal filtration rate of glucose, yielding a
safety factor of approximately 2.
Another example is the value of approximately 2 for milk production
(or teat number, its anatomical surrogate). Aristotle noted over 2,000
years ago that teat number among mammal species varies from 2 to
16, but that in each species the teat number is approximately twice the
normal litter size and equal to the maximum natural litter size, giving a
safety factor of 2 for normal operation.
In order to obtain physiologically meaningful values of safety factors
at the molecular level, my colleagues and I have measured safety factors
for hydrolases and transport proteins of the small intestinal brushborder. By the everted sleeve method one can measure the functional
capacity of the brush-border as I’,,,,, values for hydrolases (such as
sucrase) and transporters (such as sugar and amino acid transporters)
in a preparation with epithelial and brush-border structure intact. We
then measure the loads upon these molecules as average rates of dietary
nutrient intake. From this we then calculate the molecular safety factors
as ratios of VmaX to intake, while experimentally manipulating both the
capacities, by surgical partial resection of the intestine, and the loads by
maintaining animals under conditions associated with high-energy output
(low ambient temperature, lactation, or exercise), thus stimulating the
animal to increase its food intake by up to five times normal values.
Evolution of biological safety factors
J. M. Diamond
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Table 2.4.
SAFETY FACTORS
Safety factors of some biological structures
Human pancreas
Cat intestinal brush-border arginine transporter
Wing bones of a flying goose
Leg bones of a galloping horse
Human kidneys
Leg bones of a hopping kangaroo
Mouse intestinal brush-border glucose transporter
Mouse intestinal brush-border sucrase
Leg bones of a running ostrich
Human small intestine
Lungs of a lazy big cow
Breasts of most mammals
Drag line of a spider
Backbones of a weightlifter lifting weights
Shell of squid
Lungs of a fast small dog
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10
7
6
4.8
4
3
2.7
2.7
2.5
2
2
2
1.5
1.0-1.7
1.3-1.4
1.25
Figure 2.2 shows the results of an experiment where dietary nutrient
intake by lactating mice was increased by increasing the number of pups
they nurse and by lowering the ambient temperature. The safety factor
for glucose intake declined as a greater fraction of uptake capacity was
used to accommodate the greater nutrient load.
We have measured safety factors for various transporters and hydrolytic enzymes of the intestinal brush-border, in numerous vertebrate species (mice, rats, rabbits, cats, chickens, frogs, and fish), at different ages
from birth or hatching to adulthood, and under different energy loads.
The measured safety factors prove typically to be around 2 and range up
to 7.
The meaning of biological safety factors
My discussion has so far been simplistic, in order to make the basic
concept clear. Let us now consider some of the complications that may
occur. Consider first the problems posed by a system of many components arranged in series. An evolutionary argument might suggest that
the capacities of the components would be matched to each other, and
that they would have evolved to possess approximately equal safety factors. If one component has a much lower capacity than other compo-
nents, this component would be rate limiting. The excess quantities of all
other components would be largely wasted, because of the bottleneck
i/&
,~. .k _. n .
Virgins
14 pups
5 pups 8 pups
Reproductive Demand
Figure 2.2. Safety factors for glucose uptake, proline uptake, and sucrase in
virgins and lactating mice at 23°C (0) and 5°C (0) as a function of reproductive
demand. (Reproduced from Hammond ef al. (1994) Physiol. Zoof., 67, 1479-506.
0 by The University of Chicago.)
imposed by the limiting component. Are the transporter capacities ratelimiting and the hydrolases present in excess, or vice versa, or do the
transporters and hydrolases possess similar capacities? It turns out that
both proteins possess similar Vmax values, corresponding to safety factors
around 2.7. Thus, neither constitutes a single rate-limiting step.
This conclusion is supported by the fact that, with increasing dietary
carbohydrate levels, there is upregulation of the quantities or Vmax values
of at least four steps in series in carbohydrate digestion: pancreatic amylase, brush-border sucrase and maltase, the brush-border glucose and
fructose transporters, and basolateral glucose transporter. Some biological systems do regulate their capacities depending on their loads. These
are the phenomena of load-dependent tissue growth and atrophy, and
enzyme and transporter induction and repression. For example, the mass
of the small intestine (hence the capacities of all of its transporters and
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J. M. Diamond
enzymes) increases with conditions stimulating increased food intake,
such as lactation or low ambient temperatures. The quantitative details
of this capacity/load relation for the mouse intestinal brush-border glucose transporter are such that the transporter’s safety factor declines
from about 2.7 at low loads to near 1.0 with increasing loads, and then
remains at 1.0 up to the highest loads that we have been able to produce
experimentally.
Cost/benefit considerations
Tissue atrophy and enzyme repression under low loads suggest that
excess tissues and capacities would incur significant costs. What are the
relevant costs? That is, what are the selective factors leading to elimination of excessive biological capacities? This is one of the major unsolved
problems of biological design.
Biologists usually think of costs as being measured in the currency of
biosynthetic energy for synthesis or maintenance. That reasoning is plausible in the case of components contributing a significant percentage of an
animal’s entire energy budget (for example, kidney, liver, and intestine),
but such energy-based reasoning can hardly apply to all of the very minor
components of our bodies. For example, the small intestinal brushborder glucose transporter constitutes only 0.1 percent of the protein
of the brush-border of the intestine, and probably much less than
0.0001 percent of our total energy budget. It would make no difference
to the whole animal’s energy budget if the amount of this quantitatively
utterly insignificant component were doubled. Why is the glucose transporter nevertheless regulated with an interindividual coefficient of variation of only about 15 percent?
A suggested alternative involves considerations of space, which is also
in short supply. The insides of an animal are crammed full of organs, so
that the volume of one organ could not increase without either decreasing
the volume of other organs or increasing the size of the whole animal.
These standing-room-only conditions apply at the molecular level as well.
For example, while the glucose transporter contributes a trivial percentage of the whole animal’s energy budget, it is one of the major
membrane-spanning proteins of the brush-border. One cannot increase
a membrane’s proportion of one membrane-spanning transport protein,
without decreasing the proportion either of other transport proteins or
of lipid bilayer, either of which would affect membrane function.
Similarly, most of the surface of the intestinal brush-border is covered
Evolution of biological
safety factors
27
with hydrolases that include sucrase, maltase, lactase, and peptidases.
Since these hydrolases are crammed together, one cannot increase the
quantity of one without reducing the quantity of others.
Thus, space considerations may create severe penalties for excessive
unutilized capacities of even quantitatively very minor components.
Hence I would suggest that, while considerations of biosynthetic energy
may explain the modest safety factors of large expensive components.
considerations of space are what limit the safety factors of minor
components.
Further reading
Buddington, R. K. and Diamond, J. M. (1989) Ontogenetic development of
intestinal nutrient transporters. Ann. Rev. Physiol., 51, 601-9.
Diamond, J. M. (1993) Evolutionary physiology. In Logic of Life: The
Challenge of Integrative Physiology, pp. 89-111. Eds. D. Noble and
C. A. R. Boyd. Oxford University Press, Oxford.
Diamond, J. M. and Hammond, K. A. (1992) The matches, achieved by nat-
ural selection, between biological capacities and their natural loads.
Experientia, 48, 551-l.
Dykhuizen, D. (1978) Selection for tryptophan auxotrophs of Escherichiu co/i
in glucose-limited chemostats as a test of the energy conservation hypoth-
esis of evolution. Evolution, 32, 125-50.
Ferraris, R. P. and Diamond, J. M. (1989) Substrate-dependent regulation of
intestinal nutrient transporters. Ann. Rev. Physiol., 51, 125-41.
Hammond, K. A. and Diamond, J. M. (1992) An experimental test for a ceiling
on sustained metabolic rate in lactating mice. Physiol. Zool., 65, 952-11.
Hammond, K. A., Konarzewski, M., Torres, R. and Diamond, J. M. (1994)
Metabolic ceilings under a combination of peak energy demands. Physiol.
Zool., 67, 1479-1506.
Toloza, E. M., Lam, M. and Diamond, J. M. (1991) Nutrient extraction by
cold-exposed mice: a test of digestive safety margins. Am. J. Physiol., 261,
G608-20.
Weibel, E. R., Taylor, C. R. and Hoppler, H. (1991) The concept of symmorphosis: a testable hypothesis of structure-function relationship. Proc. Ncz~l.
Acad. Sci. USA, 88, 10357-61.