Thursday, January 17, 2008

Fish out of Water: Your Inner Fish

Retrieved from the University of Chicago:

My knee was swollen to the size of a grapefruit, and one of my colleagues from the surgery department was twisting and bending it to determine whether I had strained or ripped one of the ligaments or cartilage pads inside. This, and the MRI scan that followed, revealed a torn meniscus, the probable result of 25 years spent carrying a backpack over rocks, boulders, and scree in the field. Hurt your knee and you will almost certainly injure one or more of three structures: the medial meniscus, the medial collateral ligament, or the anterior cruciate ligament. So regular are injuries to these three parts of your knee that these three structures are known among doctors as the “Unhappy Triad.” They are clear evidence of the pitfalls of having an inner fish. Fish do not walk on two legs.
Our humanity comes at a cost. For the exceptional combination of things we do—talk, think, grasp, and walk on two legs—we pay a price.
This is an inevitable result of the tree of life inside us. Imagine trying to jerry-rig a Volkswagen Beetle to travel at speeds of 150 miles per hour. In 1933 Adolf Hitler commissioned Dr. Ferdinand Porsche to develop a cheap car that could get 40 miles per gallon of gas and provide a reliable form of transportation for the average German family. The result was the VW Beetle. This history, Hitler’s plan, places constraints on the ways we can modify the Beetle today; the engineering can be tweaked only so far before major problems arise and the car reaches its limit.
In many ways, we humans are the fish equivalent of a hot-rod Beetle. Take the body plan of a fish, dress it up to be a mammal, then tweak and twist that mammal until it walks on two legs, talks, thinks, and has superfine control of its fingers—and you have a recipe for problems. We can dress up a fish only so much without paying a price. In a perfectly designed world—one with no history—we would not have to suffer everything from hemorrhoids to cancer.
Nowhere is this history more visible than in the detours, twists, and turns of our arteries, nerves, and veins. Follow some nerves and you’ll find that they make strange loops around other organs, apparently going in one direction only to twist and end up in an unexpected place. The detours are fascinating products of our past that, as we’ll see, often create problems—hiccups and hernias, for example. And this is only one way our past comes back to plague us.
Our deep history was spent, at different times, in ancient oceans, small streams, and savannahs, not office buildings, ski slopes, and tennis courts. We were not designed to live past the age of 80, sit on our keisters for ten hours a day, and eat Hostess Twinkies, nor were we designed to play football. This disconnect between our past and our human present means that our bodies fall apart in certain predictable ways.
Virtually every illness we suffer has some historical component. The examples that follow reflect how different branches of the tree of life inside us—from ancient humans, to amphibians and fish, and finally to microbes—come back to pester us today. Each of these examples show that we were not designed rationally but are products of a convoluted history.
I. Our hunter-gatherer past: obesity, heart disease, and hemorrhoids.
During our history as fish we were active predators in ancient oceans and streams. During our more recent past as amphibians, reptiles, and mammals, we were active creatures preying on everything from reptiles to insects. Even more recently, as primates, we were active tree-living animals, feeding on fruits and leaves. Early humans were active hunter-gatherers and, ultimately, agriculturalists. Did you notice a theme here? That common thread is the word “active.”
The bad news is that most of us spend a large portion of our day being anything but active. I am sitting on my behind at this very minute typing this, and a number of you are doing the same reading it (except for the virtuous among us who are reading it in the gym). Our history from fish to early human in no way prepared us for this new regimen. This collision between present and past has its signature in many of the ailments of modern life.
What are the leading causes of death in humans? Four of the top ten causes—heart disease, diabetes, obesity, and stroke—have some sort of genetic basis and, likely, a historical one. Much of the difficulty is almost certainly due to our having a body built for an active animal but the lifestyle of a spud.
In 1962 the anthropologist James Neel addressed this notion from the perspective of our diet. Formulating what became known as the “thrifty genotype” hypothesis, Neel suggested that our human ancestors were adapted for a boom-bust existence. As hunter-gatherers, early humans would have experienced periods of bounty, when prey was common and hunting successful. These periods of plenty would be punctuated by times of scarcity, when our ancestors had considerably less to eat.
Neel hypothesized that this cycle of feast and famine had a signature in our genes and in our illnesses. Essentially, he proposed that our ancestors’bodies allowed them to save resources during times of plenty so as to use them during periods of famine. In this context, fat storage becomes very useful. The energy in the food we eat is apportioned so that some supports our activities going on now, and some is stored, for example in fat, to be used later. This apportionment works well in a boom-bust world, but it fails miserably in an environment where rich foods are available 24/7. Obesity and its associated maladies—age-related diabetes, high blood pressure, and heart disease—become the natural state of affairs. The thrifty genotype hypothesis also might explain why we love fatty foods. They are high-value in terms of how much energy they contain, something that would have conferred a distinct advantage in our distant past.
Our sedentary lifestyle affects us in other ways, because our circulatory system originally appeared in more active animals. Our heart pumps blood, which is carried to our organs via arteries and returned to the heart by way of veins. Because arteries are closer to the pump, the blood pressure in them is much higher than in veins. This can be a particular problem for the blood that needs to return to our heart from our feet. Blood from the feet needs to go uphill, so to speak, up the veins of our legs to our abdomen. If the blood is under low pressure, it may not climb all the way. Consequently, we have two features that help the blood move up. The first are little valves that permit the blood to move up, but stop it from going down. The other feature is our leg muscles. When we walk we contract them, and this contraction serves to pump the blood up our leg veins. The one-way valves and the leg-muscle pumps enable our blood to climb from feet to abdomen.
This system works superbly in an active animal, which uses its legs to walk, run, and jump. It does not work well in a more sedentary creature. If the legs are not used much, the muscles will not pump the blood up the veins. Problems can develop if blood pools in the veins, because that pooling can cause the valves to fail. This is exactly what happens with varicose veins. As the valves fail, blood pools in the veins.The veins get bigger and bigger, swelling and taking tortuous paths in our legs.
Needless to say, the arrangement of veins can also be a real pain in the behind. Truck drivers and others who sit for long stretches of time are particularly prone to hemorrhoids, another cost of our sedentary lives. During their long hours of sitting, blood pools in the veins and spaces around the rectum. As the blood pools, hemorrhoids form—an unpleasant reminder that we were not built to sit for too long, particularly not on soft surfaces.
II. Primate past: talk is not cheap.
Talking comes at a steep price: choking and sleep apnea are high on the list of problems we have to live with in order to be able to talk.
We produce speech sounds by controlling motions of the tongue, the larynx, and the back of the throat. All are relatively simple modifications to the basic design of a mammal or a reptile. The human larynx is made up mostly of gill arch cartilages, corresponding to the gill bars of a shark or fish. The back of the throat, extending from the last molar tooth to just above the voice box, has flexible walls that can open and close. We make speech sounds by moving our tongue, by changing the shape of our mouth, and by contracting a number of muscles that control the rigidity of this wall.
Sleep apnea is a potentially dangerous trade-off for the ability to talk. During sleep, the muscles of our throat relax. In most people, this does not present a problem, but in some the passage can collapse so that relatively long stretches pass without a breath. This, of course, can be risky, particularly in people who have heart conditions. The flexibility of our throat, so useful in our ability to speak, makes us susceptible to a form of sleep apnea that results from obstruction of the airway.
Another trade-off of this design is choking. Our mouth leads both to the trachea, through which we breathe, and to our esophagus, so we use the same passage to swallow, breathe, and talk. These three functions can be at odds, for example, when a piece of food gets lodged in the trachea.
III. A hiccup in our tadpole past
This annoyance has its roots in the history we share with fish and tadpoles.
If there is any consolation for getting hiccups, it is that our misery is shared with many other mammals. Cats can be stimulated to hiccup by sending an electrical impulse to a small patch of tissue in their brain stem. This area of the brain stem is thought to be the center that controls the complicated reflex that we call a hiccup. The hiccup reflex is a stereotyped twitch involving a number of muscles in our body wall, diaphragm, neck, and throat. A spasm in one or two of the major nerves that control breathing causes these muscles to contract. This results in a very sharp inspiration of air. Then, about 35 milliseconds later, a flap of tissue in the back of our throat (the glottis) closes the top of our airway. The fast inhalation followed by a brief closure of the tube produces the “hic.”
But we rarely experience only a single hic. Stop the hiccups in the first five to ten hics, and you have a decent chance of ending the bout altogether. Miss that window, and the bout of hiccups can persist for an average of about 60 hics. Inhaling carbon dioxide (by breathing into the classic paper bag) and stretching the body wall (taking a big inhalation and holding it) can end hiccups early in some of us. But not all. Some cases of pathological hiccups can be extremely prolonged. The longest uninterrupted hiccups in a person lasted from 1922 to 1990.
Our tendency to develop hiccups is another influence of our past. There are two issues to think about. The first is what causes the spasm of nerves that initiates the hiccup. The second is what controls that distinctive hic, the abrupt inhalation–glottis closure. The nerve spasm is a product of our fish history, while the hic is an outcome of the history we share with animals such as tadpoles.
First, fish. Our brain can control our breathing without any conscious effort on our part. Most of the work takes place in the brain stem, at the boundary between the brain and the spinal cord. The brain stem sends nerve impulses to our main breathing muscles. Breathing happens in a pattern. Muscles of the chest, diaphragm, and throat contract in a well-defined order. Consequently, this part of the brain stem is known as a “central pattern generator.” This region can produce rhythmic patterns of nerve and, consequently, muscle activation. A number of such generators in our brain and spinal cord control other rhythmic behaviors, such as swallowing and walking.
The problem is that the brain stem originally controlled breathing in fish; it has been jerry-rigged to work in mammals. Sharks and bony fish all have a portion of the brain stem that regulates the rhythmic firing of muscles in the throat and around the gills. The nerves that control these areas all originate in a well-defined portion of the brain stem. We can even see this nerve arrangement in some of the most primitive fish in the fossil record. Ancient ostracoderms, from rocks over 400 million years old, preserve casts of the brain and cranial nerves. Just as in living fish, the nerves that control breathing extend from the brain stem.
This works well in fish, but it is a lousy arrangement for mammals. In fish the nerves that control breathing do not have to travel very far from the brain stem. The gills and throat generally surround this area of the brain. Mammals have a different problem. Our breathing is controlled by muscles in the wall of our chest and by the diaphragm, the sheet of muscle that separates chest from abdomen. Contraction of the diaphragm controls inspiration. The nerves that control the diaphragm exit our brain just as they do in fish, and they leave from the brain stem, near our neck. These nerves, the vagus and the phrenic nerve, extend from the base of the skull and travel through the chest cavity to reach the diaphragm and the portions of the chest that control breathing. This convoluted path creates problems; a rational design would have the nerves traveling not from the neck but from somewhere nearer the diaphragm. Unfortunately, anything that interferes with one of these nerves can block their function or cause a spasm.
If the odd course of our nerves is a product of our fishy past, the hiccup itself is likely the product of our history as amphibians. Hiccups are unique among our breathing behaviors in that an abrupt intake of air is followed by a closure of the glottis. Hiccups seem to be controlled by a central pattern generator in the brain stem: stimulate this region with an electrical impulse, and we stimulate hiccups. It makes sense that hiccups are controlled by a central pattern generator, since, as in other rhythmic behaviors, a typical sequence of events happens during a hic.
It turns out that the pattern generator responsible for hiccups is virtually identical to one in amphibians. And not in just any amphibians—in tadpoles, which use both lungs and gills to breathe. Tadpoles use this pattern generator when they breathe with gills. In that circumstance, they want to pump water into their mouth and throat and across the gills, but they do not want the water to enter their lungs. To prevent it from doing so, they close the glottis, the flap that closes off the breathing tube. And to close the glottis, tadpoles have a central pattern generator in their brain stem so that an inspiration is followed immediately by a closing glottis. They can breathe with their gills thanks to an extended form of hiccup.
The parallels between our hiccups and gill breathing in tadpoles are so extensive that many have proposed that the two phenomena are one and the same. Gill breathing in tadpoles can be blocked by carbon dioxide, just like our hiccups. We can also block gill breathing by stretching the wall of the chest, just as we can stop hiccups by inhaling deeply and holding our breath. Perhaps we could even block gill breathing in tadpoles by having them drink a glass of water upside down.
IV. What’s fishy about hernias
Our propensity for hernias, at least for those hernias near the groin, results from taking a fish body and morphing it into a mammal.
Fish have gonads that extend toward their chest, approaching their heart. Mammals don’t, and therein lies the problem. It is a very good thing that our gonads are not deep in our chest and near our heart (although it might make reciting the Pledge of Allegiance a different experience). If our gonads were in our chest, we wouldn’t be able to have babies.
Slit the belly of a shark from mouth to tail. The first thing you’ll see is liver, a lot of it. The liver of a shark is gigantic. Some zoologists believe that a large liver contributes to the buoyancy of the shark. Move the liver away and you’ll find the gonads extending up near the heart, in the “chest” area. This arrangement is typical of most fish: the gonads lie toward the front of the body.
In us, as in most mammals, this arrangement would be a disaster. Males continuously produce sperm throughout our lives. Sperm are finicky little cells that need exactly the right range of temperatures to develop correctly for the three months they live. Too hot, and sperm are malformed; too cold, and they die. Male mammals have a neat little device for controlling the temperature of the sperm-making apparatus: the scrotum. As we all know, the male gonads sit in a sac. Inside the skin of the sac are muscles that can expand and contract as the temperature changes. Muscles also lie in our sperm cords. Hence, the cold-shower effect: the scrotum will tuck close to the body when it is cold. The whole package rises and falls with temperature. This is all a way to optimize the production of healthy sperm.
The dangling scrotum also serves as a sexual signal in many mammals. Between the physiological advantages of having gonads outside the body wall, and the occasional benefits this provides in securing mates, there are ample advantages for our distant mammalian ancestors in having a scrotum.
The disadvantage is that the plumbing that carries sperm to the penis is circuitous. Sperm travel from the testes in the scrotum through the sperm cord. The cord leaves the scrotum, travels up toward the waist, loops over the pelvis, then goes through the pelvis to travel through the penis and out. Along this complex path, the sperm gain seminal fluids from a number of glands that connect to the tube.
The reason for this absurd route lies in our developmental and evolutionary history. Our gonads begin their development in much the same place as a shark’s: up near our livers. As they grow and develop, our gonads descend. In females the ovaries descend from the midsection to lie near the uterus and fallopian tubes. This ensures that the egg does not have far to travel to be fertilized. In males the descent goes farther.
The descent of the gonads, particularly in males, creates a weak spot in the body wall. To envision what happens when the testes and spermatic cord descend to form a scrotum, imagine pushing your fist against a rubber sheet. In this example, your fist becomes equivalent to the testes and your arm to the spermatic cord. The problem is that you have created a weak space where your arm sits. Where once the rubber sheet was a simple wall, you’ve now made another space, between your arm and the rubber sheet, where things can slip. This is essentially what happens in many types of inguinal hernias in men. Some of these inguinal hernias are congenital—when a piece of the gut travels with the testes as it descends. Another kind of inguinal hernia is acquired. When we contract our abdominal muscles, our guts push against the body wall. A weakness in the body wall means that guts can escape the body cavity and be squeezed to lie next to the spermatic cord.
Females are far tougher than males, particularly in this part of the body. Because females do not have a giant tube running through it, their abdominal wall is much stronger than a man’s.
This is a good thing when you think of the enormous stresses that female body walls go through during pregnancy and childbirth. A tube through the body wall just wouldn’t do. Men’s tendency to develop hernias is a trade-off between our fish ancestry and our mammal present.
V. Mitochondria’s bacterial legacy
Mitochondria exist inside every cell of our bodies, doing a remarkable number of things. Their most obvious job is to turn oxygen and sugars into a kind of energy we can use inside our cells. Other tasks include metabolizing toxins in our livers and regulating different parts of cell function. We notice our mitochondria only when things go wrong. Unfortunately, the list of diseases caused by malfunctioning mitochondria is extraordinarily long and complex. If there is a problem in the chemical reactions in which oxygen is consumed, energy production can be impaired. The malfunction may be confined to individual tissues, say the eyes, or may affect every system in the body. Depending on the location and severity of the malfunction, it can lead to anything from weakness to death.
Many of the processes we use to live reflect our mitochondria’s history. The chain reaction of chemical events that turns sugars and oxygen into usable energy and carbon dioxide arose billions of years ago, and versions of it are still seen in diverse microbes. Mitochondria carry this bacterial past inside of them: with an entire genetic structure and cellular microstructure similar to bacteria, it is generally accepted that they arose from originally free-living microbes over a billion years ago. In fact, the entire energy-generating machinery of our mitochondria arose in one of these kinds of ancient bacteria.
The bacterial past can be used to our advantage in studying the diseases of mitochondria—in fact, some of the best experimental models for these diseases are bacteria. This is powerful because we can do all kinds of experiments with bacteria that are not possible with human cells. One of the most provocative studies was done by a team of scientists from Italy and Germany. The disease they studied invariably kills the infants who are born with it. Called cardioencephalomyopathy, it results from a genetic change that interrupts the normal metabolic function of mitochondria. In studying a patient who had the disease, the team identified a place in the DNA that had a suspicious change. Knowing something about the history of life, they then turned to the microbe known as Paracoccus denitrificans, which is often called a free-living mitochondrion because its genes and chemical pathways are so similar to those of mitochondria. Just how similar was revealed by the European team. They produced the same change in the bacteria’s genes that they saw in their human patient. What they found makes total sense, once we know our history. They were able to simulate parts of a human mitochondrial disease in a bacterium, with virtually the same change in metabolism. This is putting a many-billion-year part of our history to work for us.
The example from microbes is not unique. Judging by the Nobel Prizes awarded in medicine and physiology in the past 13 years, I should have called this book Your Inner Fly, Your Inner Worm, or Your Inner Yeast. Pioneering research on flies won the 1995 Nobel Prize in medicine for uncovering a set of genes that builds bodies in humans and other animals. Nobels in medicine in 2002 and 2006 went to people who made significant advances in human genetics and health by studying an insignificant-looking little worm (C. elegans). Similarly, in 2001, elegant analyses of yeast (including baker’s yeast) and sea urchins won the Nobel in medicine for increasing our understanding of some of the basic biology of all cells. These are not esoteric discoveries made on obscure and unimportant creatures. These discoveries on yeast, flies, worms, and, yes, fish tell us about how our own bodies work, the causes of many of the diseases we suffer, and ways we can develop tools to make our lives longer and healthier.


Aaron said...

Cool post!

Reminds me of a book I just picked up called "Survival of the Sickest". Check it out -- the premise is that many of the genetic diseases that are present in humans today are the products of evolutionary reactions to various environmental conditions.

- Hemachromatosis helps prevent bubonic plague
- Diabetes helps prevent freezing
- Cholesterol + Sunlight = Vitamin D

Neat stuff!

Anonymous said...

Sounds like Kipling!

Daniel Catlover/Knight said...

Yet another ranting moron who thinks his ranting lies have defeated God, his word, and's thousands of articles refuting morons like himself. Grow up deluded one.