[Paleopsych] Neese and Williams: On Darwinian Medicine

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Neese and Williams: On Darwinian Medicine
http://www-instruct.nmu.edu/biology/ALindsay/Evolution/Nesse_1999.pdf

Life Science Research
Published in China

Vol. 3, No 1, 1999 pp. 1-17 and
Vol. 3, No 2, 1999, pp. 79-91

On Darwinian Medicine
Randolph M. Nesse
George C. Williams

Address correspondence to:
Randolph Nesse, M.D.
Professor of Psychiatry,
The University of Michigan
Room 5057, Institute for Social Research
426 Thompson Street
Ann Arbor, MI 48106-1248 USA
nesse at umich.edu

It would appear, at first glance, that natural selection would have little 
to say about why work better, and decreases the frequency of genes that 
harm organisms, so it would seem that evolutionary theory would be able to 
explain adaptations, but not their failures. This illusion has been so 
strong that even now, over a century since Darwin showed how organisms are 
shaped by natural selection, evolutionary biology is just beginning to be 
applied to the problems of medicine. (1, 1991, 2, 3, Trevathan, In press 
#1220) We are just beginning to learn why we are vulnerable to so many 
diseases. Why do we have an appendix? Wouldn't we be better off without 
wisdom teeth? Why does the human fetus have to squeeze through the tiny 
pelvic opening? Why, after millions of years of natural selection, are we 
still susceptible to infection by the streptococcus organism? Why do we 
get fevers so high they cause seizures? And why do our own immune systems 
sometimes attack us, causing rheumatic fever, rheumatoid arthritis, and 
multiple sclerosis? Why is depression so common, and why is life, in 
general, so full of suffering? Why is pain so often excessive? And why is 
it so hard for so many people to find restful sleep, to say nothing of 
love and sexual satisfaction?

All these questions are about the design of the organism. More 
specifically, they are about why our bodies aren't better designed. In 
many cases, such as the appendix, it would seem to be child's play to 
improve the design. Were we able to change the body as we see fit, we 
could banish much disease. Or, could we? If the problem is just that 
natural selection is just not strong enough to improve the design of the 
body, then we certainly could do better. Selection operates on random 
mutations that constantly slip in, so perhaps the design flaws simply 
result from chance. Some certainly do. The vast majority of designs that 
go bad, are, however, not random mistakes, but products of natural 
selection. This poses a central mystery. If naturalselection is so 
powerful that it can shape bodies so perfect in so many respects, then why 
are our bodies also full of so many flaws and design oversights that leave 
us vulnerable to thousands of diseases?

There are only a few possible kinds of evolutionary explanations for such 
vulnerabilities. First, as already mentioned, there are random 
events--environmental mishaps that are too rare to be seen by natural 
selection and genetic changes that are outside the reach of natural 
selection. Second, there are problems that arise because our bodies were 
not designed from scratch, but from an unbroken lineage that goes all the 
way back to the simplest single-celled organisms. Path dependence--the 
result of this continuous lineage--means that many structure designs are 
actually maladaptive. Third, there is competition between living 
organisms. Natural selection shapes predators, bacteria and viruses, and 
other humans, all of whom may benefit from harming us. To protect 
ourselves from these dangers, natural selection has shaped a wide variety 
of protective defenses such as pain, fever, nausea, and anxiety. These are 
not causes of disease, but the body's ways of preventing damage, yet 
because they are painful and associated with problems, we often confuse 
them with diseases themselves. Fourth, there are trade-offs--every trait 
in the body could be improved to some degree if, that is, we were willing 
to accept the resulting compromises in other traits. Fifth, we were not 
designed by natural selection for our present environment and lifestyles, 
and much disease results because natural selection is not had time to 
transform us for living in the modern environment. Finally, there are 
genetic "quirks", variations that were of no consequence in the ancestral 
environment, but that now cause disease.

Natural selection is an extremely simple principle, but its elaborations 
are extremely subtle and this leads to much misunderstanding. Darwin, of 
course, did not know about genes--all he had to go on was the traits of 
organisms. As a result, he had to develop his ideas based on observations 
of how traits change in response to breeding, with only a vague notion 
about how the information that coded for an organism's traits was passed 
along. Now we know that the information code for organisms is stored in 
DNA, specifically, in approximately 100,000 protein coding sequences 
called genes. While much of this code is identical between two different 
human individuals, and, for that matter, between any two living organisms, 
there are also variations. If individuals with gene A, on the average in 
this environment have more offspring and grand-offspring than individuals 
with gene B, then the A gene will gradually become more common and B will, 
over the generations, become rare. Naturalselection consists of nothing 
more or less than 1) variation in the information code that results in 
variations in phenotypes, 2) differential reproductive success of those 
phenotypes, with the inevitable result of, 3) changes in the information 
code across the generations. (4) This logic is so straightforward that it 
is best described not as a theory, but as a principle. When variation in 
an information code leads to differential reproductive success, the 
information code changes to whatever works best at getting copies of 
itself in future generations.

Despite the simplicity of the principle of natural selection, it remains 
the focus of many misunderstandings. (5) In particular, contrary to the 
beliefs of many, the path of natural selection has no goal, no direction, 
and follows no plan. Yes, it is true that the first organisms were small 
unicellular creatures and the earth now has many large multi-cellular 
organisms with much greater complexity. This is not, however, because of 
any preexisting plan or magical force, it is simply because the first 
organisms were necessarily small and simple, so there was only one 
direction for variations to go. Organisms can evolve to simpler as well as 
more complex forms, as illustrated by the helminths that inhabit mammalian 
guts. Also, while humans are quite wonderful creatures with some unique 
abilities, there is no reason to think that we are a peak or a goal of 
this process. In fact, it appears more and more that our species is, at 
least in terms of the ecosystem it is ravaging, a malignantly successful 
replicator that is accidentally but systematically destroying most other 
organisms on Earth.

The key to understanding natural selection is recognizing that it changes, 
not organisms, but the information code that makes organisms. (4) Whatever 
information creates individuals who maximize copies of that information in 
future generations will become more common. This depends, of course, on 
the environment. There is no such thing as an adaptation in the abstract-- 
traits are adaptive only in reference to a particular environment. (6)

Another common misunderstanding arises from the understandable tendency to 
see individuals and groups as a product of natural selection, instead of 
genes. Different genes cooperate to do things that benefit the individual, 
so intuitively, it seems sensible that individuals should make sacrifices 
for the benefit of the species. There is a huge difference, however, 
between these levels. (7) The genes in each cell of an individual are 
identical. Even if they were not identical, the genes in somatic cells 
cannot be passed on, so they get no benefit whatsoever from doing anything 
except helping the individual. Different individuals, however, have 
different genes.

These genes inevitably induce behaviors that are in their own interests at 
the expense of other individuals. The only exceptions are in the case of 
identical twins or genetically identical individuals in species that can 
reproduce by nonsexual means.

This brings up an immediate, large, good, and unanswered question; why is 
reproduction sexual? Compared to simply budding, sex is expensive, 
troublesome, shuffles the genetic code in ways that cause unfortunate 
genetic combinations and, worst of all, results in related individuals 
with different interests who therefore are shaped to compete against one 
another. The very existence of sex is, from an evolutionary point of view, 
a mystery. (8) One plausible explanation is that the genetic code must be 
constantly varied, otherwise viruses and bacteria would be able to crack 
the code and make short work out every one of us. (9) Another idea is 
based on the best strategy for winning a lottery. (10) In most organisms, 
the vast majority of offspring never ever get to sexual maturity. Each one 
is much like a lottery ticket that probably will be worthless, but may 
have a big payoff. In this situation, the best strategy is obviously not 
to buy many lottery tickets that are identical, but to spread your bets 
among a wide variety of different tickets in hopes that one of them will 
payoff. The important point here is that while it is hard to explain why 
sex exists, it does, and the resulting genetic variation necessarily means 
that individuals within a species will compete, and will cooperate only in 
the service of that competition. We do, however, see individuals sacrifice 
for the good of the group on many occasions, a phenomenon that is the 
deserving focus of much current work (11). It is tempting to try to 
explain such phenomena as a result of selection acting for the benefit of 
the group by selecting for traits that benefit the group even though the 
harm the individual. Except possibly in some very special circumstances, 
however, this simply does not work. The force of selection at the 
individual level is so much more powerful than that at the group level, 
that group selection can explain only traits that are of very small cost 
to the individual and enormous benefit to the group.

One level further down the hierarchy is a parallel issue with important 
consequences for human health. We have already mentioned that genetic 
differences in somatic human cells cannot get into the genome and so act 
only in the interests of the individual. But are there circumstances in 
which genes can have effects that promote their interests in getting into 
the next generation even at the expense of the individual's health? Yes, 
indeed. In fact, such examples are common causes of much human illness and 
suffering. The most dramatic example is the longevity difference between 
the sexes. Males on the average live approximately seven years less than 
females. This is not true only for humans, but for essentially every 
species where males compete vigorously for mates. This phenomenon can be 
explained at one level, the proximate level, by reference to the effects 
of testosterone on tissues, and the effects of male aggression and 
fighting on accident rates. An entirely separate explanation, an 
evolutionary explanation, is necessary to reveal why testosterone has 
deleterious effects on tissues, and why men do aggressive and dangerous 
things. This explanation is based, like all evolutionary explanations, on 
how genes shape traits that influence reproductive success. Females invest 
more in each offspring, therefore the range of their range reproductive 
success is narrowed compared to men. Most women have from 1 to perhaps as 
many as 10 children. Some men, however, will have no offspring whatsoever, 
while some will have far more. Some men have had hundreds of children. 
(12) Thus, the competition between men for mates is extreme, while women 
tend to be choosy. (13) A man whose physiology is set to put increased 
effort into this competition by sacrificing tissue protection, tissue 
healing, immune function, and physical safety, will have a reproductive 
advantage over men who live safer, healthier, longer lives. For women, 
this is not true, at least to the same extent, so they live longer. This 
principle leads to other observable effects even in a modern civilization. 
People do things that are not particularly in their best interests, but 
are in the interests of their genes. For instance, many men will seek out 
additional sexual partners, despite knowing the risks of disease, jealous 
husbands and their own wife's wrath (14). Often they know ahead of time 
exactly what lies in store for them, but they go ahead, almost as if they 
cannot help acting in ways that benefit their genes, even when they know 
it will lead to their harm and ultimate unhappiness.

Still another example of genes taking advantage of individuals occurs in 
the process of meiosis. A gene that can somehow distort the process to get 
increased copies of itself into the egg or sperm will have a huge 
selective advantage so such genes can increase in frequency even if they 
do severe harm to the individual. No examples are known in humans, but the 
T-locus in mice and segregation-distorter locus in Drosophlia, document 
the existence of this phenomenon (15). Our purpose here is not to describe 
such phenomena in any detail, but simply to use them as examples that 
illustrate the crucial principle that natural selection is a mindless 
process that increases the frequency of any bits of information in the DNA 
code that, by whatever means, are especially successful at getting 
themselves into the next generation, even if that harms the individual.

Still another example illustrates the idea of pleiotropy. A gene that 
increase the rate of implantation of a zygote on the uterine wall from the 
usual 25% to, say 35%, will have such a huge selective advantage that it 
can rapidly increase in frequency even if it causes severe problems later 
in life. An example may exist in the DR3 allele on the HLA system, an 
allele that greatly increases the risk of childhood diabetes. (16) 
Phenylketoneuria also may be maintained by the same mechanism, as 
indicated by the presence of this recessive disease in more that the 
expected 50% of a couple's offspring. (17) Competition with other 
organisms

A large proportion of human disease results from competition with other 
organisms. This is most obvious in our competition with viruses and 
bacteria, but disease also arises from competition with predators and 
other humans. In all cases, natural selection is constantly improving our 
ability to cope with these threats, but because these organisms themselves 
are constantly changing products of natural selection who are in a race to 
escape our defenses, there is no end to the process, and much disease 
results. (18, 19) To simplify, consider rabbits and foxes. If a mutation 
makes some foxes a bit faster than others, they will catch more rabbits, 
and this mutation will soon become more common in future generations. This 
has an obvious effect on the rabbits.

Those who previously could handily escape foxes now are vulnerable. Only 
the very fastest rabbits can escape, so selection increases frequency of 
genes that make rabbits still faster, even when those genes may have other 
negative effects. This is a classic instance of a trade-off. A change in 
an organism that is all for the good with no new costs, is extremely rare. 
At the very least, rabbits that run faster are likely to be lighter, and 
therefore less likely to survive a period of food shortage. Or perhaps, 
the changes that make rabbits faster are also increase the speed with 
which energy is metabolized, perhaps with tissue-damaging side effects. As 
must be obvious, this competition between the rabbits and the foxes will 
shape both species in an escalating arms race. Such arms races result in 
much disease. Both foxes and rabbits could be heavier and better able to 
get through a harsh winter if they could just relax and cooperate. But, 
they can't. Similar arms races are even more obvious in the all-out 
competitions between pathogens and hosts (20). Streptococcal bacteria, for 
instance, must somehow escape surveillance by our immune systems. One of 
their strategies seems to be to imitate our own cells so our antibodies 
against them sometimes attack our own tissues. This is obviously a tricky 
business, but we must do it to it escape their infections. So, some people 
and up get rheumatic fever that damages the joints and heart valves, or 
obsessive compulsive disorder from damage to the basal ganglia, or scarlet 
fever from damage to the skin. The layer on layer of intrigue and 
counter-intrigue in these competitions is breathtaking in its complexity, 
and tragic in its results (21). Consider the organism that causes sleeping 
sickness, the trypanosome. Its antigen coat stimulates a healthy immune 
response, but just at the time when antibodies are being made in quantity, 
the organism exposes a completely different antigen coat, thus eluding its 
pursuers as effectively as a spy who completely changes his disguise. (22)

Such arms races seem to be responsible for considerable genetic variation, 
some of which causes disease. The sickle cell trait is a well-known 
example. Individuals with a single sickle cell allele are protected 
against malaria but do not get sickle cell disease, while those with 2 
sickle cell alleles die young from sickle cell disease, and those who have 
no sickle cell alleles are vulnerable to malaria. This example has been 
widely discussed, but it is somewhat peculiar because it results from a 
single nucleotide substitution that apparently occurred in the 
neighborhood of ten thousand years ago, and, is found only in Africa and 
areas of the Mediterranean were malaria has been prevalent. (23) The 
alpha+-thalassaemias are of particular interest because they are the 
commonest known human genetic disorders. They have been thought to protect 
from malaria, but recent evidence suggests that they are associated with a 
higher incidence of malaria. The explanation seems to be that by 
increasing susceptibility to the more mild Plasmodium vivax they result in 
immunity that protects against the more severe P. falciparum malaria (24). 
G6PD deficiency also apparently protects against malaria and has increased 
in frequency in the times since humans began agriculture (25). There has 
been wide speculation that some of the genetic diseases characteristic of 
the Askanazi Jews, such as Tay Sachs and other sphingolipidoses, may 
protect against tuberculosis. (26)

These genetic variations are present only in small groups, but others may 
have become universal genetic characteristics that protect us against 
other pathogens despite causing us harm. Despite the difficulty of 
distinguishing harmful from useful genes, (27), it is important to 
recognize this mechanism as a source of vulnerability to disease, 
especially as we begin to unravel the entire genome. Some genes will, no 
doubt, appear to have wholly pathologicaleffects. Before we tamper with 
them, we should consider the possibility that they may have unsuspected 
benefits. What is the optimum level of virulence for a pathogen? On the 
surface it would seem senseless for a pathogen to kill its host. Why not 
simply coexist with a host so that the host lives longer and the pathogen 
can also? But this is not how natural selection works. Whatever 
information code in pathogens results in the most copies in future 
generations will become more common.

For some pathogens, such as those that cause minor upper respiratory 
infections, a low-level of virulence will facilitate spread. People who 
are too sick to leave bed will not be up and about coughing, sneezing, and 
touching other people. On the other hand, when a pathogen is spread by 
vector such as mosquitoes or dirty water, selection may favor increased 
virulence. Malaria may spread even better if the host is unable to slap at 
mosquitoes. In an environment where raw sewage may reach others, cholera 
may spread proportionate to the amount of diarrhea it produces. When the 
host is infected with a fatal pathogen, restraint by another pathogen is 
of no benefit.

Paul Ewald has investigated such situations in detail, and predicted and 
demonstrated that virulence should decrease when changed sanitary 
conditions shift the advantage to strains of an organism that allow the 
victim to be up and about. (20) Indeed, when public sanitation is 
successful, the more virulent type of cholera is displaced by the less 
virulent. Likewise with Shigella - when public sanitation is instituted, 
natural selection shifts the advantage to less virulent subtype. This 
principle has profound implications for modern hospitals as well, since 
doctor's and nurse's hands serve the same function as mosquitoes, 
transferring pathogens from and to passive victims in a cycle that selects 
for the more aggressive organisms.

Finally, we note the lengths to which pathogens go to insure their 
transmission. They can even take over the behavioral control machinery of 
the host to their own advantage. (28) Ants who are infected with a 
particular kind of fluke will, in the late stages of infection, climb to 
the top of a blade of grass and grab on in a spasm that will not let go. 
Why? The next phase of the life-cycle for this fluke is in sheep, so ants 
clasping the tip of a blade of grass are helpless prisoners doing the 
bidding of their internal masters. Similar pathogens induced snails to 
crawl up on the shore where they are exposed to sea gulls, the next stage 
in their life-cycle. A more common and gruesome example that affects 
humans, is offered by rabies. After it enters the skin, the rabies virus 
enters the nerves and arranges for its own transport directly to the 
central nervous system. There, it concentrates in the amygdala, a site 
that controls aggression, and in the brain locus that controls swallowing, 
so that the mouth fills with saliva, and in the salivary glands. Thus, the 
rabies virus essentially takes over the individual and turns it into a 
device for transmitting itself.

Defenses

Many manifestations of disease are caused directly by a pathogen or by 
some defect in the body. Paralysis, jaundice, and seizures, are examples. 
Other manifestations of disease are not themselves defects, but are 
defenses that have been shaped by natural selection to protect us in the 
face of certain dangers. Examples include pain, nausea, vomiting, 
diarrhea, fatigue and anxiety. It is very easy to mistakenly interpret 
such symptoms as pathological, when, in fact they are protections against 
pathology. Cough is the most obviously useful defense. The basic benefit 
of cough is clearing foreign from the respiratory tract. People who are 
unable to cough cannot clear secretions from their lungs and are likely to 
die from pneumonia. A variety of other mechanisms do the same thing for 
other passageways. Vomiting clears toxins and pathogens from the upper GI 
tract while diarrhea clears them from the lower GI tract. Coughing, 
sneezing and nasal secretions clear the respiratory passages. Inflammation 
leading to pus formation and extrusion on the surface of the body serves 
the same function for infections that have penetrated the tissue of the 
body.

Much of general medical practice consists in blocking the discomfort 
associated with these symptoms. We use these medication to block cough, 
relieve pain, stop vomiting and decrease diarrhea. Is this wise? Not 
always. In a clear demonstration of the value of diarrhea, Du Pont and 
Hornick compared the outcomes in people with Shigella infections who took 
medications to decrease diarrhea and those who did not. (29) Those who are 
left alone recovered faster, while those who took medication had extended 
illness, more complications, and were more likely to become carriers. 
Giving cough suppressants to patients shortly after surgery is well-known 
to cause pneumonia, so physicians therefore avoid this. Nonetheless, in 
many other situations we are able to use medications to block cough, 
diarrhea, and vomiting with no particular apparent ill- effects. How is 
this possible? Consider how natural selection shaped the mechanisms to 
regulate these defenses. Essentially natural selection acts on the outcome 
of a signal detection analysis.

Just as electrical engineer must set a system to decide correctly whether 
given click coming across a line is a signal or just noise, the body's 
regulation mechanisms must set the system for, say, vomiting, to expel the 
contents of the stomach only when that is worthwhile. But such signals are 
somewhat difficult to interpret. The only way to insure that no toxin is 
ever ingested, is not to eat all. This would not be good strategy. 
Conversely, to avoid wasting calories, it would be best never ever to 
vomit. This would not be wise either. The optimal regulation strategy 
depends on how likely it is that a toxin really is present, how costly it 
will be to mount a defensive response of vomiting, and how costly it would 
be to fail to mount such response if the toxin is actually present. In 
many instances the parameters of the system favor an apparently 
overly-sensitive defense responses. The cost of many defenses is 
relatively small--in the case of vomiting, only a few hundred calories. 
The cost of not responding could be death. As a result, natural selection 
has shaped the normal system to respond in many instances where a response 
is not actually necessary in order to ensure that the system will always 
respond when response is necessary. We call this the "smoke detector 
principle" because it also guides the design of smoke detectors. (2) We 
could design a smoke detector that would sound a warning only when the 
house was definitely on fire and never when the toast is burning. Such a 
system would, however, on occasion fail to sound off in when there was a 
real fire. Thus, we want our smoke detectors designed to sound some false 
alarms because that is what it takes to ensure that they will always warn 
us of a real fire.

This "smoke detector principle" also helps to explain how is possible to 
use medications to block defenses without necessarily causing harm. Nine 
times out of ten vomiting may not be necessary, so in most instances, 
medications to block it will cause little harm. Then again, there is that 
additional instance when it really is necessary. The same principle 
applies to many other defenses. Consider pain. Pain is a useful adaptation 
- people who lack the capacity for pain are usually dead by their early 
20s or 30s. (30) Overall, however, it seems that most of the pain that we 
experience in life, at least in the modern environment, is excessive and 
prolonged. Medical advances to block pain have been a great boon for 
humans. Furthermore, we now recognize disorders in which the pain system 
itself is dysregulated causing chronic pain. Defensive mechanisms, like 
any other real-world mechanisms, can malfunction.

Anxiety offers another instructive example. We often imagine that we would 
prefer life without the experience of anxiety, but people who lack anxiety 
entirely likely do as poorly in life as people who lack the capacity for 
pain. They do not come to psychiatrist's offices complaining of 
insufficient anxiety, but the defect is just as serious it as if their 
immune systems were hypofunctional. (31, 32) Therefore, while a few people 
may have anxiety deficiencies, the vast majority of us tend to have more 
anxiety that we need. Blocking this anxiety with medications only rarely 
leads to reckless behavior, although in case of driving automobiles, this 
certainly can cause accidents.

We have additional defenses that are specific against infection, including 
fever, inflammation and the immune response. Fever is not a simple 
increase in the rate of metabolism, but is a systematic and coordinated 
response to the presence of cues that indicate the presence of infection. 
(33) During a fever, the body will defend the new set point by increasing 
the temperature if attempts are made to reduce it and also by decreasing 
the temperature if attempts are made to increase it further . Pathogens 
are more susceptible to our defenses at the higher body temperature. Even 
cold-blooded animals raise their body temperature in the face of infection 
by moving to warmer places until the infection is controlled. All this 
leads to an obvious question--is it indeed wise to block fever during 
infection? Surprisingly, adequate studies have still not been done on this 
most routine medical question. Certainly in many individual instances the 
smoke detector principle applies, and we can block fever and rely on the 
body's other defense mechanisms to protect us. However, there may be 
situations in which we would get better faster if we did not block fever.

Also, in cold climates people have repeatedly discovered the sauna bath or 
other ways to raise body temperature, perhaps because this helps to 
improve health. In the case of chicken pox, there is some evidence that 
antipyretics slightly prolong the cause of illness. For influenza, would 
people get better faster if they did not take medications block fever? We 
don't know. None of these defenses are diseases themselves, but it is easy 
to fall into the illusion that they are problems, instead of parts of 
solutions. This illusion is fostered because they are constantly 
associated with pathology and because they can so often be blocked without 
untoward effects.

The illusion is still further fostered by the psychological and physical 
discomfort we experience in association with the expression of defenses. 
We don't like fever, we obviously don't want pain, vomiting, diarrhea and 
coughing are extremely unpleasant, and it's perfectly understandable that 
we should want to minimize them. This brings us to the next question, why 
do humans have capacities for suffering at all?

The capacities for suffering

The capacities for suffering are products of natural selection. If pain 
was not useful, we would not have the capacity for pain. If anxiety was 
not useful, we would not have anxiety. Anxiety and pain, perhaps in 
concert with the awful feelings we get when we lose someone we love, are 
close to purely negative experiences, their aversiveness almost certainly 
being central to their utility. People who didn't mind tissue damage, 
threats, and losses, have not passed on as many of their genes as people 
who did everything in their power to avoid these circumstances. The 
reaction of people to narcotic pain-killers is of great interest. Many 
report that they can still experience the pain but "it no longer bothers 
me." In essence, they report the perception is intact, but the affective 
representation of the experience has been reduced or eliminated. Much of 
the mission of medicine is, of course, to relieve suffering. This is best 
accomplished by eliminating the cause that has aroused the negative 
feeling, but very often we can safely and effectively use medications to 
directly block the brain mechanisms that gave give rise to negative 
feeling.

Many bodily defects, such as cancer or atherosclerosis are imperceptible 
for years, but almost every bodily defense is associated with discomfort. 
Nausea precedes vomiting and inhibits eating, thus preventing further 
intake of toxins. Diarrhea and cough are quite annoying. The physical 
fatigue that follows over-exertion is unpleasant enough to motivate 
avoidance of the situations that gave rise to it. The malaise that 
accompanies infection often seems excessive, and when we take medications 
that block this feeling we can often go about our business much more 
comfortably. In the ancestral environment, however, when predators were 
problem, this might not have been so wise. In that circumstance, to wander 
far from camp when unable to run fast might have been unwise indeed. 
Furthermore, simply resting during infection may allow the body's full 
resources to be commandeered for the fight.

Many forms of human suffering are not so physical. We also experience 
depression, anger, jealousy, anger, embarrassment, and many other 
unpleasant emotions. By extension, it seems likely that the very 
unpleasantness of these emotions is also a product of natural selection.

Indeed, most of them are aroused by situations that are not good for our 
health, status, or reproductive success. (34) Work to understand the 
emotions in this light is just beginning, but it is needed urgently if we 
are to cope wisely with the development of new psychopharmacologic agents. 
We already have effective anti-anxiety drugs, although they all have 
side-effects or cause dependency. We have increasingly good drugs to block 
depression, although they take weeks to work and also have side effects. 
It seems entirely likely, however, that the combination of brain science, 
the genome project, and improvements in chemistry will lead to agents that 
are far more specific with far fewer side-effects. We are ill-prepared to 
decide how to use such substances. If, for instance, a pill was developed 
that could eliminate jealousy, how would we use it? Certainly this could 
prevent much suffering, and even violence, but it would also undermine 
some deep human impulses that are responsible, in a considerable measure, 
for the fundamental structure of the family and society. Or, how would we 
use agents that block the experiences of greed and envy? On the surface it 
would seem fine to eliminate these nasty emotions, but we might find that 
we simultaneously eliminate the motives for much human effort and 
entrepreneurship that makes societies successful in competition with other 
societies. We expect that conflicts between individuals and their 
societies will arise over the use of such drugs. Perhaps the current war 
on drugs is already an example. (35)

Trade-offs

Every aspect of the body could be designed to be more resistant to 
disease, but only at a cost. Why for instance are our arms not stronger 
and less prone to fractures? Arm bones could be made thicker and less 
likely to break when we fall. Because of the design of these bones, 
however, making them thicker would drastically decrease our dexterity and 
make it impossible to rotate the wrist the way we can now. We could be 
even better protected from infection if our immune systems were more 
aggressive. Then, however, the untoward effects of the system, including 
tissue damage and rapid senescence , would become even more prominent and 
we might also experience more auto-immune disease. Our vision could be 
still more acute, like a hawk able to see a mouse from a kilometer way. 
The trade-offs, however, would be a drastic loss of peripheral vision, 
color vision and the ability to see complex shapes all at once. Our 
upright posture is still another trade-off. Many explanations have been 
proposed to explain why we walk on two feet, from the benefits of using 
tools and weapons, to the need to carry infants. Whatever the benefit is, 
we can be sure was a substantial one, because standing upright has so many 
costs. The most obvious one comes from the design of our spine which is 
optimized for a creature the goes about on all fours. On standing upright, 
however, enormous pressure is put on the lower spinal discs, causing pain 
and disability that is perhaps more common than any other medical 
disorder. On the much more mundane level it appears that hemorrhoids 
result from the changes in circulation that result from upright posture. 
The tendency to faint is greatly increased by standing upright. The 
tendency to lose one's balance and the need for extraordinarily complex 
brain mechanisms to regulate bodily position and balance are all secondary 
to standing upright. Even the design of the system that supplies blood to 
our bowel is very poorly designed for an upright posture. In an animal 
that goes about on all fours the omentum hangs like a curtain, supporting 
the bowel and providing easy access for vessels. But when we stand up, 
however, it is as if someone took the curtain rod and stood it upright, 
whereupon the folds tangle in on one another, giving rise to the 
possibility of bowel obstruction and arterial compromise. It's worth 
noting that these trade-offs can also be interpreted as novelties, in that 
there simply has not been enough time for natural selection to shape 
reliable mechanisms to protect us against of these ills. Perhaps in 
another million years back pain will be far less frequent. In the 
meantime, however, we will suffer.

Another trait that seems to be maladaptive, is our lack of hair. There is 
much disagreement about the evolutionary explanation for our nakedness, 
with proposals ranging from increased ability to sweat, to speculation 
that we spent much time in the water in our evolutionary past. Whatever 
the explanation, there are some obvious penalties, especially for paler 
individuals, including sunburn, and a risk of dying from malignant 
melanoma. Everything is a trade-off. It is foolish to describe a trait as 
perfect and there are few traits that are simply pathological. All have 
costs and benefits. All are trade-offs.

Such trade-offs also exist at the level of the gene. All genetic changes 
begin as new mutations, and it would be rare indeed for a mutation to have 
only benefits and no costs. Given the interaction effects among 100,000 
genes, acting in environments that vary from year to year and generation 
to generation, a detailed accounting of such costs and benefits is beyond 
our current understanding . What we do know, however, is that a gene that 
gives a net selective advantage will likely be selected for, even if it 
causes disease in some people, or disability or decreased function in all 
of us. It is extremely hard to recognize genes that cause disadvantages in 
all of us, because we have nothing to compare them to. What we do have are 
a few examples of genes that have obvious benefits that explain their 
selection despite their tendency to cause disease. Sickle cell disease has 
already been mentioned. It is the only solidly documented example. In our 
book, we described our expectation that the allele that causes cystic 
fibrosis would be found have some benefit, because it was so common and so 
reliably fatal. This speculation has since been supported by epidemiology 
(23) and by genetic studies of mice with a single cystic fibrosis allele . 
In more recent work, it has been discovered that this allele also inhibits 
Salmonella typhi, the cause of typhoid fever, from entering the cells in 
our gut. (36)

A further illustration may soon be available in the case of manic 
depressive illness. This illness is overwhelmingly genetic in its origins, 
affects approximately one percent of people worldwide with devastating 
consequences including a 20 percent risk of suicide and a 20 percent risk 
of early death from other causes. (37) The selection force acting against 
the genes that cause manic depression is so enormous that there is very 
likely some selective advantage unless a large number of genes are 
involved. What could the advantage be? For centuries, people have noted 
the increased creativity of people who have manic depressive tendencies 
and recent scientific evidence confirms this finding. (38) Perhaps this 
creativity somehow leads to selection for the manic depression genes. 
There's no need, however, for the benefit to accrue to people with manic 
depressive illness. In fact, it's more likely that their unaffected kin 
would experience a benefit, while those with the disease would experience 
mainly the costs. This general mechanism may apply to many genes, with 
some individuals suffering from a disease, while fitness benefits accrue 
to relatives who carry the same genes in combination with other different 
genes. The definitive test would be to look at the reproductive success, 
in the ancestral environment, of relatives of individuals with manic 
depressive illness. Such a study would be nearly impossible to do. We will 
likely sooner identify the specific genes. Once we have them, we will look 
at people who have these genes to see how they differ from other 
individuals. Perhaps they are more creative and perhaps this creativity 
does give them increased reproductive success or other advantages. Or 
perhaps the genes protect them from some infection. The question will be 
difficult to answer but important as we approach a time when genes can be 
manipulated.

This example has important implications for those who would try to improve 
the human species by controlling reproduction. A long-standing dream of 
progressives has been to eliminate defective genes and thus improve the 
health of the population, presumably making the world better place. While 
this idea recurs often throughout history, it was the subject of early 
public policies in the United States at the very start of the 
20th-century. As everyone knows, a grander and more deadly version was 
practiced by the Nazis, leaving a lingering repugnance for eugenics that 
makes it almost impossible even to talk about the issue. (39) We will 
address the issue of human rights here only by saying that in our vision, 
Darwinian medicine is a field that benefits individuals, not nations or 
the species. The other issue is the scientific basis for eugenics. Much 
has already been said about the lack of scientific foundation for such 
efforts as conducted in the past. Many supposedly genetic diseases, such 
as cretinism, turned out to be caused by environmental factors, and others 
resulted from many genes or rare recessive genes so that eugenic efforts, 
and the associated restrictions of individual reproductive rights, were in 
vain. An evolutionary view of disease helps to reveal the complexity of 
these matters. Population geneticists have worked out the details of how 
certain rare recessive genes persist in the population irrespective of 
their possible selective costs, and these principles show the 
extraordinary practical difficulties faced by anyone who would try to 
reduce the frequency of such genes through selective breeding. An even 
more important factor is that many genetic diseases involve many genes, 
often in complex interactions with environmental factors. Even specific 
harmful genes may give rise to disease in only a small proportion of 
individuals, so restricting reproductive opportunities on the basis of 
manifest disease will have little impact on the frequency of most diseases 
even if eugenic policies were pursued rigidly for many generations.

The case of manic depressive illness, is instructive because the 
responsible genes may well be helpful as well as harmful. This case is 
peculiarly appropriate to consider for public policy because while the 
individual may suffer with manic depressive illness, the society may 
benefit from creations by the ill individual or his or her relatives. To 
eliminate the genes that cause manic depressive illness without careful 
thought could, therefore, be a catastrophic mistake. Furthermore, other 
genes that appear superficially to be simple defects, will likely turn out 
to have unanticipated adaptive benefits, although it is still very 
difficult to distinguish these from others. (40) We know enough now to 
suggest that it would be safe to do away with genes that cause cystic 
fibrosis, but it will be more difficult to discover if and what benefits 
accrue from other genes that cause disease. Finally, it is by no means 
certain that the future human environment will be the environment that we 
live and now, so eliminating disease causing genes that protect us against 
infections that are now rare may seem wise, but at some future date cause 
new suffering.

All of this is, of course, about to be changed by the unraveling of the 
human genome. On one hand we will finally have accurate information about 
individual genotypes, and will no longer have to rely on phenotypic 
expression of disease. On the other hand, it's likely that medical 
advances arising from the human genome project will make it possible to 
control vastly more diseases, including genetic diseases, that has ever 
before been possible. This will, no doubt, give rise to new calls for 
restricting reproduction among certain individuals with specific known 
pathological genotypes. While this argument goes on, further progress will 
be made in discovering ways to minimize the effects of these genetic 
defects or to allow people with such defects to have offspring in which 
manipulation of a single bit of DNA can prevent the problem. Of course, 
human tendencies will use these technologies to give rise to entirely new 
problems.

People will want to have offspring with the best possible genotype. We 
predict that a market will soon arise in which rich people will try to 
control the genotype of their offspring. Such a phenomenon of would likely 
lead to an arms race for genetic information between countries that are 
fearful that their populations would be left behind by genetically 
superior generations in other countries. This prospect seems both 
frightening and likely to us. While it would be easy simply to advocate 
for restrictions on such practices, they would both prove extremely 
difficult to enforce and, perhaps not in the interests of elites to 
enforce in their own country. What does seem likely is that the human 
species will, in a few hundred years, be different than it is now. No 
doubt it will in some ways be better, but much conflict and many mistakes 
lie along that road.

Novelty

The environment in which we live is considerably different from the 
environment in which we were designed to live. While much disease arises 
from environmental changes in the past 100 years, much disease also arises 
from changes since the advent of agriculture about 40,000 years ago (41). 
Prior to that, humans lived in small hunting and foraging groups of 20 to 
50 people who lived largely on fruits, tubers, grains, and meat. In most 
locations, salt was in short supply, sugar was available mainly in the 
form of ripe fruits or occasionally as honey, and high levels of fat were 
almost always unavailable. We are living in an unnatural environment.

It is easy to over-generalize this principle. The idea of the environment 
of evolutionary adaptedness (the EEA), proposed by John Bowlby, (42) has 
been extremely useful in reminding us about the differences between then 
and now. As pointed out by recent scholarship, however, there was no 
single environment of evolutionary adaptedness, but a constellation of 
situations in which our ancestors lived. (43) While these environments had 
much in common, they also differed. When humans moved out of Africa, 
perhaps one million years ago, their particular ability to adapt to new 
environments quickly lead to spread across the Eur-Asian land mass. As 
they moved to new environments, new selective forces began to act. In 
colder climates individuals with shorter arms and legs lost heat less 
quickly and had a selective advantage. In environments where lack of 
sunshine and wearing clothes lead to light deprivation on the skin causing 
vitamin D depletion and rickets, there was selection for decreased skin 
pigmentation. (44) In settings where humans raised animals and subsisted 
on milk, there was selection for maintenance of lactose activity into 
adult life. (45)

The big environmental changes however, have been those of our own making. 
The giant one was the invention of agriculture. By growing their own food, 
people were able to insure a much more consistent supply of calories at 
less effort. The price, however, was immediate increase in certain 
diseases. Studies of Native Americans give particularly clear evidence of 
the rise in disease after cultivation of maize and sorgum became common. 
The stature of adults declined, and arthritis and tooth decay suddenly 
emerged because the agricultural diet provided more sugar, and far fewer 
and more limited phytochemicals than the diet consumed by hunter 
gatherers. The diets of these early Native Americans were probably also 
deficient in protein and certain essential amino acids.

Cultural traits can do much to compensate for such problems. For instance, 
many native groups in the Americas soak their maize in alkali before 
cooking--a process that frees the niacin, an essential vitamin that is 
otherwise deficient in a maize based diet. (46) and may increase lysine, 
an amino acid deficient in a maize diet. Other deficiencies are not so 
easy to remedy. When eating natural fruits and vegetables, humans get 
plenty of vitamin C, a chemical they cannot synthesized friends (in 
contrast to other primates, most of which can). Because vitamin C is a 
necessary substance for us, we can be confident that it was in abundant 
supply as a routine part of our diets for long enough to allow the 
synthetic mechanism to be lost over the course or evolution. When sailors 
began to take voyages lasting months, subsisting only on hardtack and 
dried meat, scurvy quickly became a major problem. When Lind discovered 
that giving out rations of limes prevented scurvy, the way was paved for 
the discovery vitamin C. In Iceland, the same problem had long been 
recognized and prevented by storing blueberries especially for the time in 
late winter when scurry became a problem

We are vastly more healthy on the average now that we were even a few 
hundred years ago. In most locations infection is less likely and more 
curable, accidents are less common and more treatable, and general health 
has improved thanks to more adequate food supplies and sanitation. A 
Darwinian approach to medicine in no way advocates reverting to some 
imagined ancestral time of perfect health. On the other hand, it remains 
true that the majority of problems we see in medical clinics today arise 
from novel aspects of our modern environment to which our "thrifty 
genotype" not yet adapted. (47) The most common and devastating of these 
diseases arise from our abnormal diets, and the resulting triad of 
hypertension, obesity, and atherosclerosis. (48) Compared to our 
ancestors, are diets include vastly more fat, salt, and sugar and 
substantially less phytochemicals and fiber. (49) The result is the 
current epidemic of heart disease and stroke caused largely by 
atherosclerosis. Such diseases claim half of individuals in most modern 
countries. The defect in design, however, is not simply in our metabolism 
and our arteries, it is also in our brains. A hunter-gatherer who did not 
have a taste for sugar and fat would be at a disadvantage. One could 
hardly ever get enough of those substances in the ancestral environment. 
Today, we have the same preferences as our hunter-gatherer ancestors, but 
the world is different. The difference, of course, is that the 
hunter-gatherer had to work long hours to get even occasional taste of a 
high-fat high-salt, high sugar food, if it was possible at all. Nowadays, 
we can go to the grocery store and glut ourselves on a wide variety of 
snack foods that satisfy these cravings instantly. In United States more 
than half of individuals are now overweight and a third are clinically 
obese, conditions that contribute to much disease.

Individuals try to diet, but rarely succeed. They know what they should 
eat, but they eat fat and sugar instead. They know they should exercise, 
but they don't. The fault is not with their will- power, but with the very 
design of the brain mechanisms that regulate their exercise and diet, a 
design that is optimized for an entirely different environment. As the 
diets typical in technological societies spread to developing countries, 
the epidemic is predicted to be the single greatest cause of human 
disease. (50)

Eating disorders are problems that seem to have arisen mainly in the last 
generation. The ability to live with very little caloric expenditure, and 
eat whatever one chooses whenever one chooses, interacts with evolved 
preferences for mates with a particular shape with unfortunate results. It 
appears to be a cross-cultural universal that men prefer women with a 
waist/hip ratio of about 0.7. (51) This has been proposed to identify 
women who have recently become sexually mature but who have not yet borne 
many children, thus making them optimal reproductive partners. Heavy women 
obviously do not have this conformation. Furthermore, the human tendency 
to attend to caricatures interacts with mass media to create images of 
women that are exaggerations of this ideal. In the arms race that arises 
from sexual competition, women try to live up to these ideals, often with 
tragic consequences. Attempting to diet sets off protective mechanisms 
that were designed to protect a person from famine. When food is in short 
supply, these mechanisms induce preoccupation with food and a tendency to 
quickly gulp down large amounts of high calorie food. Such impulses to 
gorge make a woman on a calorie-restricted diet even more fearful that she 
will be unable to control her energy intake, so she tries even harder to 
diet. This sets off a vicious cycle in which the impulses to eat become 
still stronger, causing more loss of control, thus making her feel still 
worse, until a serious eating disorder is established. For most women, 
(with eating disorders) the cycle becomes one of the bulimia, eating large 
amounts of food and then vomiting. For those few women with extraordinary 
will-power, it is possible to restrict intake entirely causing anorexia 
nervosa, a disease that is sometimes fatal. Eating disorders are a product 
of the novel environment in which we live. They can be explained by the 
food intake regulation mechanisms that evolved in an entirely different 
environment and their interactions with innate sexual preferences that are 
exaggerated by modern media. Such problems will become much more common as 
technology and easy access to variable foods spreads across the world.

On a much more mundane level, millions of people suffer from pain at the 
inside edge of the heel. This is sometimes called "heel spurs", because a 
tiny bit of calcification is visible on x-rays, but the technical name is 
plantar faschitis. The plantar faschia is a band of tough tissue that 
stretches from the ball of the foot to the heel--essentially it is the bow 
string that holds arch of the foot taunt. When walking miles each day and 
sitting without chairs by squatting on the ground, this faschia is 
constantly stretched and exercised. When, however, people sit for long 
hours in chairs, this tissue is not stretched and contracts. When the 
contracted tissue is suddenly stretched by jogging or a long walk, it is 
vulnerable to ripping off from the heel--an injury that causes pain at the 
site of the injury. Certainly there are peculiarities of anatomy and 
walking posture that increase the vulnerability of some individuals to 
this problem, but the fundamental difficulty is the design of the organism 
and the mismatch with how we live our lives today. We are designed to seek 
comfort and minimize caloric expenditure. Plantar faschiitis is one of the 
several costs for following our evolved inclinations when they are no 
longer adaptive. The invention of reliable birth control has been enormous 
boon, not only for individuals, but also for populations, that at last 
have some hope of restraining their numbers without relying on disease, 
war, and starvation to control populations. The availability of birth 
control is, however, a completely novel aspect of the environment that 
causes many complications. In the ancestral environment, a woman would 
typically reached sexual maturity at about age 17, would become pregnant 
within a year or two, following which she would nurse or baby for two to 
three years and quickly become pregnant once again. The total number of 
menstrual cycles in a lifetime averaged around a hundred. (52) Nowadays, 
women reached sexual maturity much younger, probably because of a superior 
diet and increased fat stores earlier life. They may wait until age 30 to 
have children or may never become pregnant. After giving birth, a woman 
may feed the baby with a bottle, thus making it possible to become 
pregnant again in a matter of months, instead of the several years of 
infertility associated with breast feeding. The most common complication 
of this modern pattern is certainly iron deficiency anemia. The disorder 
is far more common in women than men because of loss of blood with each 
menstrual cycle. The system was never designed for as many menstrual 
cycles as now take place. High rates of breast cancer in modern societies 
may also be partly attributed to the use of birth control. (53) The cells 
in the breast that are most vulnerable to becoming cancerous begin 
dividing at menarche and stop dividing only with the first pregnancy. In 
the ancestral environment this interval lasted months to a year, but now 
it often lasts for decades. Studies are now being done to see if the use 
of pregnancy mimicking hormones for some years after menarche can prevent 
breast cancer in some young women whose family histories suggest a high 
risk.

The discovery of psychoactive drugs has also been a great boon for 
humankind, but like all other advances, it has brought complications, in 
this case drug abuse. While some individuals clearly are far more 
susceptible to addiction than others, and while social factors certainly 
help to account for why some people become addicted and others do not, an 
evolutionary approach to the problem highlights the universal capacity for 
humans to become addicted to drugs that act directly on motivational 
systems. (35) The ascending dopaminergic tracts that are stimulated by 
most drugs of abuse are intimately involved with reward mechanisms 
designed to control behavior. (54) Actions that led to success (as 
indicated by cues such as eating tasty food) are reinforced and become 
more common. When, however, these mechanisms are stimulated by direct 
action of drugs, they have no way of interpreting what is happening and 
they respond as if some huge bonanza of resources had just been gained. 
This gives a subjective enormous pleasure, the likes of which is hard to 
find in real life. It also entrains behavior to repeat, over and over 
again, whatever action brought such enormous pleasure. The great irony is 
that after continued drug use, the drug addict may get very little 
pleasure. Apparently the mechanisms that regulate subjective experience 
damp out after repeated exposure to the drug. The mechanisms that control 
behavior, however, tend to persist. Thus, the common picture of the 
drug-addicted individual who desperately wants to quit, who gets little 
pleasure from his habit, and yet who feels helplessly compelled to spend 
his life seeking out drugs of abuse. (55) We were simply never designed to 
live in an environment where drugs of abuse are readily available. It 
seems as if there should be some solution to the problem drug abuse, 
either by prevention, treatment or legalization of drugs. A Darwinian 
approach suggests, however, that this problem may not have any 
straightforward solution but may arise from an intrinsic vulnerability of 
organisms that reach an advanced enough state of technology if their 
motivational systems are chemically controlled, as ours are. In fact, we 
predict that when we make contact with intelligent organisms on other 
planets, we will discover that they either are continuing to cope with a 
chronic problem drug abuse or at least passed through that stage at great 
cost and suffering.

The amount of anxiety we experience nowadays is greatly excessive for the 
dangers we encounter. (31) Most of us would be better off cutting down our 
anxiety level by several notches. In this sense, anxiety can be seen as 
excessive, given that we live in novel environment. It also seems 
possible, however, that the anxiety system was fine-tuned during a 
life-time in ancestral environments by exposure to things that actually 
were dangerous. A modern person may see snakes only in zoos and so fear of 
snakes can become quite generalized and lead to a tendency to avoid any 
place a snake might conceivably be seen. If that same person had been 
living in an ancestral environment, however, there would be great pressure 
to keep going to places were snakes would be seen despite the fear, a 
process that which soon extinguish unwarranted fear. Furthermore, exposure 
to different kinds of snakes would soon lead to stimulus discrimination 
between snakes that are harmful and those that are harmless. Many modern 
phobias may, paradoxically, result from lack of exposure to different 
kinds of dangerous objects.

Genetic quirks

We have emphasized diseases that arise from novel aspects of the 
environment and diseases that arise from genes that may have benefits as 
well as costs. Much modern disease arises, however, from interactions 
between genetic variation and environmental novelty. Genes that had no ill 
effects in our ancestral environment now reliably cause disease. Myopia is 
an excellent example. Nearsightedness is a genetic disorder. If your 
parents have it, you almost certainly will as well. This prevalence is 
approximately 25 percent in all modern populations. How could such a 
serious defect be maintained despite the force of natural selection? The 
answer comes from recognizing that this is not purely a genetic defect, 
but a genetic variation that was harmless until people began doing close 
work, such as reading at an early age. Such early reading, in people who 
have the genes, reliably cause is myopia. People who do not have the 
genes, or do not do close work, never get nearsighted. Attempts to decide 
if it is a genetic or an environmental disease are confused. Like many 
other diseases, it is both.

Much atherosclerosis is probably the same. The genes that increase 
vulnerability to heart disease probably were not harmful in an environment 
where no one had high cholesterol. To call these genes defects is vastly 
simplistic. These variations were of minor consequence in the environment 
we were designed to live in. Genes that make some individuals especially 
susceptible to drug abuse, are still another example of "quirks" that 
caused no harm in the natural environment.

Path dependence

We have emphasized design features of the human body that offer some 
advantages as well as disadvantages. Other features are, however, simply 
mistakes. The eye, for instance, that wonder of wonders, is inside out. 
The vessels and nerves enter at the back of the eye ball causing a blind 
spot, and they spread out of the inside of the retina casting shadows. The 
eye of an octopus is, in contrast, much better designed. The nerves and 
vessels run along the outside of the eyeball, penetrating were they are 
needed. This octopus has no difficulty with a blind spot, no shadows cast 
by the retina, and is protected against detachment of the retina. In this 
respect, the design of the octopus eye is extremely sensible, ours is a 
mistake. Why doesn't natural selection fix it?

Because the process of evolution is not based on planned design, but on 
continual tiny modifications in which each generation must survive and 
prosper. Once some semblance of a working eye gave a selective advantages 
to our ancestors, the process moved forward steadily until our eyes were 
as good as they could be, despite the gross disadvantages of having 
vessels on the inside. As Jacob Monod has put it so clearly, "Nature is a 
tinkerer, not an engineer."

Many other examples illustrate other anatomical difficulties that arise 
from path dependence. (56) The vas deferens, for instance, instead of 
going directly from the testicles to the penis, makes a long detour into 
the pelvis, looping around the inguinal arteries, and only then returning 
to the urethra. This path makes it vulnerable to damage, at least in 
surgery. But, because the original routing of the vas deferens and the 
iliac vessels was the it was, there is no going back. The recurrent 
laryngeal nerve offers another example. This nerve controls some motions 
of the vocal cords and muscular contraction of the upper eyelid and the 
pupil. It descends from the brain down into the neck and proceeds 
immediately behind the thyroid gland on the surface of the trachea. From 
there, it does its work at the vocal cords and goes back up to the eye. 
All along this long course it is subject to injury, especially at the 
hands of surgeons working on the thyroid gland. It is a faulty design that 
cannot be changed.

Choking is the cause of death for many people worldwide each day and it 
too is simply a design defect resulting from path dependence. It would be 
ever so much better if the trachea and the esophagus were completely 
separate, however, some of our amphibian ancestors seem to have swum at 
the very surface of the water so their nostrils could take air into a 
common passage way shared by the food and air. That common cavity has 
never been eliminated, thus there is always the possibility of aspirating 
food that will clog the wind pipe and cause death.

Finally there's a matter of the appendix. A very thin blind loop of gut, 
it extends from the large bowel and seems for all the world as if it is 
there just to cause problems. In our ancestors it may have been a larger 
cavity that which useful in digestion, but for us, it appears to be 
nothing but a potentially fatal nuisance. Its tendency to cause problems 
is directly proportional to its narrowness. Any minor bit of inflammation 
can compress the artery that supplies it with blood and this lack of blood 
supply that opens the way to further bacterial invasion unencumbered by 
protective defenses. Such infection further compresses the blood supply, 
at which point bacteria can grow completely unhindered until the appendix 
bursts, whereupon the patient very often dies. Has natural selection 
simply not had enough time to eliminate this troublesome organ? It 
certainly does not seem to give any selective advantage. Paradoxically, 
however, the appendix may be maintained by natural selection precisely 
because it causes appendicitis. People who have an appendix that is 
somewhat larger are less likely to get appendicitis, while people who have 
a long thin appendix, are more likely to die. This is perhaps the ultimate 
example of a "blind loop" in the process of natural selection, an organ 
that is wholly useless for any task, but is nonetheless maintained by 
natural selection because as it gets smaller, it increased the risk of 
death. Such examples suggest that the very idea of a normal, perfect body 
is probably incorrect.

The body is a bundle of trade-offs and problematic arrangements 
jury-rigged into a miraculous machine.

Random events

We began by emphasizing the randomness of natural selection and we return 
to this theme here at the end. There are many accidents and diseases for 
which natural selection can offer no protection. If an asteroid hits our 
neighborhood, there's nothing natural selection can do to protect us. If 
we are exposed to high levels of radioactivity, we have no way of 
detecting the danger, so would likely go about our business with possibly 
fatal results. Many toxins, especially novel toxins, are colorless and 
tasteless, thus making it difficult for us to protect ourselves. Events 
that are very rare, or that we cannot detect, do not shape protection and 
simply must be chalked up to the unfortunate randomness and 
uncontrollability of life.

Likewise, the genetic code can never be perfect. Mutations are always 
creeping in, at the rate of approximately one per individual per 
reproductive episode. Selection will gradually eliminate some of these, 
but some, even some that cause decreases in reproductive success, will 
become more common or even widespread by the mere process of genetic drift 
and there is no rhyme our reason or controlling such mutations, they are 
simply random events that happen.

At the next stage, selection, there is further randomness. Some genes that 
cause harm will drift to a higher frequency despite the harm they cause. 
Some genes that would protect us or otherwise be beneficial may 
nonetheless be eliminated from gene pool by simple stochastic accident. 
Such random factors are real and important, but they are not as 
all-important as they have sometimes been portrayed. Many of the body's 
vulnerabilities are, by contrast, direct products of natural selection. 
There is no such thing as one universal normal genome, there is no such 
thing as a perfect body, there is no such thing as a perfectly safe diet, 
and there is no such thing as life without senescence, but there are a 
remarkable number of humans who have miraculously healthy periods in their 
life. Given the myriad vulnerabilities and the number of things that can 
go wrong, this is astounding indeed.

Senescence

Perhaps the most serious trade-off at the level of a trait is that of 
aging. More specifically, there is the mystery of senescence. Why should 
individuals age and inevitably die? It is perfectly possible for organism 
to recreate body parts that have been lost, so why isn't it possible to 
systematically and steadily replace every body part as it ages so that the 
individual can be eternal?

The explanation here is very similar to the explanation offered earlier 
for why men die younger than women. While it might be possible to design a 
body that would be eternal, this individual would not be as effective a 
replicator as an individual that put more resources into competition and 
less into preservation of the body. (57)

Actually, genes that cause aging can be assigned globally to just two 
categories. Some have simply never been exposed to the force of natural 
selection because they cause disorders that are too rare and too late in 
life for selection to have had much of any effect in the natural 
environment. Certain diseases that become extremely common for people in 
their 90s, for instance, would have had only a minuscule effect on natural 
selection in the natural environment and so it's not surprising that we 
remain vulnerable. The same is observed in laboratory animals who are fed 
and protected so they can grow to ages that they would never reach in the 
wild. On the other hand, the effects of aging may well influence fitness 
in the wild for some species. Alex Comfort, going along with ecologists of 
previous generations, believed that there was no evidence for aging in 
wild animals because he had never seen a decrepit animal in the wild. 
However, most animals in the wild are prey for other animals. Long before 
they become decrepit, they become a meal for some other predator. Thus, 
just because we do not see feeble old rabbits, does not mean there is no 
senescence for wild rabbits The other explanation for the continued 
presence of genes that cause aging is that they give some pleiotropic 
benefit. (58) By this we mean that the very same gene that offers a 
benefit, for instance, strengthening bones during childhood and early 
adulthood, may also cause some disadvantage that causes disease or even 
death later in life, for instance, calcification of the arteries. While no 
such specific gene has yet been identified in animals, the likelihood of 
such genes has been demonstrated in fruit flies and other insects. (59) 
Before we began to tamper with genes that appear to be causes of aging, we 
should look carefully to see if they perhaps have been maintained because 
of some pleiotropic benefit.

An evolutionary view gives a somewhat pessimistic outlook on the 
possibility of eliminating senescence. If genes cause disadvantages in 
midlife this will select for other modifier genes that postpone the 
expression of the deleterious effects to later in life. At some point, the 
expression of many of these genes will be seem to be coordinated in later 
life because the force of selection will fall quite rapidly at the age 
when they are expressed. One can thus imagine their manifestations as 
grains of sand that have been swept to later in the life-span by other 
modifier genes so that they now form something of a hill beyond which it 
is impossible to go.

This is not to say that much may not be accomplished by gerontologic 
research and by slowing some aspects of aging. For instance, taking a 
small those of aspirin each day decreases risk of dying for heart attack. 
Does this have disadvantages is well? Yes, it thins the blood somewhat and 
that makes death from bleeding more likely. However, injuries are less 
likely now, and medical care is available, so on the whole we benefit by 
having blood that is a bit thinner than that designed for the natural 
environment. These circumstances offer an example where taking medications 
regularly may improve our adaptation to the current environment. Likewise, 
a tendency for rapid oxidation may be essential to destroy certain 
bacteria but toning down this capacity may currently not harm us much at 
all, but may protect our tissues from aging. In fact, it appears that this 
may be the explanation for gout. Gout occurs when crystals of uric acid 
precipitate in the joint fluid, causing excruciating pain. So why don't 
humans have lower levels of uric acid, like other primates do? A 
cross-species comparison shows a very strong linear relationship between 
plasma uric acid levels and longevity in different species. Uric acid 
turns out to be a potent antioxidant, and may well have been selected for 
to help make our long life spans possible. A few people, the unfortunate 
ones, get gout.

Implications

Natural selection and our evolutionary history has been well understood 
for nearly a hundred years now. Why is it only now being applied to the 
problems of medicine? In part, the explanation probably depends on the 
illusion that we referred to at the beginning of this article. Natural 
selection shapes things that work, so it is a bit hard to see on first 
glance how can also help explain why things don't work. There also more 
practical reasons, however, why it is only now that evolutionary biology 
is being recognized as a basic science for medicine. Medicine is a 
practical endeavor. Doctors treat individual patients with individual 
diseases and are usually far more interested in why this patient is sick 
now and what to do about it, than they are about why all members of the 
species are vulnerable to a particular problem. The patient comes in with 
a painful gouty big toe and the physician wants to help that individual 
immediately. The possibility that high levels of uric acid protect all of 
us from aging is not especially relevant at that moment.

Nonetheless, an evolutionary approach to medicine can be profoundly 
relevant. For instance, some well-meaning genetic engineer might well 
decide to adjust things so that we all have lower levels of uric acid in 
order to protect us from gout. This would be fine, except for the 
possibility that we would probably all begin aging more quickly. Natural 
selection creates many designs that are substandard, but when it has a 
chance to act on some variable parameter, that shows continuous variation, 
such as the circulating level of uric acid, it will usually approach an 
optimum, given trade-offs, and given the specific environment in which the 
trait was shaped.

Even in everyday practice, however, there is much that is immediately 
useful from an evolutionary approach to medicine. Recognition that 
diarrhea, fever, pain, nausea, vomiting and anxiety are useful defenses 
allows us to treat them in a far more sophisticated way. On the one hand, 
it helps us to hesitate and think carefully about the normal function of 
the defense before we block it. It also may allow us to feel comfortable 
that in this particular instance, blocking the defense is of no 
consequence to the person's health so we can act aggressively to make the 
person feel better more quickly. This is especially common in the case of 
pain.

In the area of public health, an evolutionary approach is of great 
importance in assessing environmental changes that might influence changes 
in virulence. In particular, settings in which vectors can transmit 
pathogens between passive hosts are recognized as particularly dangerous 
for shaping more virulent organisms, whether the vector is a mosquito or a 
doctor's hands. The use of condoms not only prevents transmission of 
sexual diseases, it also can decrease their virulence.

A sexually transmitted disease that causes quick death or incapacitation 
will tend to increase in virulence if the person is having many sexual 
partners, but if the person uses protective devices or abstains from 
dangerous sexual practices, this will tend to select for strains of the 
pathogens that are less virulent. Similar principles may also be useful 
for vaccine design.

We could go on at great length about other potential benefits from an 
evolutionary approach to medicine but we wish to emphasize that most of 
the relevant research has not yet been done. Evolutionary questions have 
not been asked systematically about disease, and the methods for testing 
them are still being developed. What is needed now is not to jump quickly 
to a new theory of medical practice based on evolutionary biology, but to 
begin to educate physicians and patients about the evolutionary nature of 
the body and its vulnerabilities to disease. This will, we believe, 
quickly lead to specific advances in the treatment of individual diseases 
that will benefit individual patients. Even before that, however, it will 
help us all to a deeper understanding of the nature of the organism, and 
the nature of its vulnerabilities to disease. From this viewpoint, the 
body is not a Platonic ideal, and the genetic code is not correct in any 
one particular version. Instead, genes, with considerable variation, makes 
phenotypes, that interact with environments and other individuals, to 
result in more or fewer offspring depending on the genes, the environment, 
their interactions, and chance factors. An extraordinary number of people 
are blessed with years and even decades a good health, and sometimes even 
happiness. Despite all our knowledge about how this is possible, it still 
seems nothing short of miraculous, even though no miracle is needed to 
explain.

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