Human Errors

by Nathan H. Lents

  If we couldn’t differentiate the innocuous proteins from the dangerous kind, we’d be allergic to everything, but fortunately, the body can usually tell the harmful and nonharmful molecules apart. When a foreign protein is harmless, the immune system generally ignores it. When, however, it’s a harmful bacteria or virus, the immune system mounts an attack in order to neutralize the invaders. Such an attack is known as an immune system response—a misleadingly innocuous phrase.

  One of the principal phenomena of an immune response—and one of the key mechanisms in allergies—is something called inflammation. There are two types of inflammation, systemic (whole body) and localized, and they share some features. The four main characteristics of inflammation have been known since classical times and are still often taught with their Latin names: rubor (redness), calor (heat), tumor (swelling, also called edema), and dolor (pain). You will easily recognize these four features in an infected cut, but they are also present during a systemic immune response, such as when you have the flu. You will be flushed (rubor) and feverish (calor); you will possibly have fluid (tumor) in your lungs; and your whole body may ache (dolor).

  Many of these same symptoms appear during an allergic response, which demonstrates that these symptoms are not due to the infectious invader per se. Rather, they are the work of the immune system in fighting the invader. The redness and swelling are the result of blood vessels dilating and becoming more leaky, which accelerates the process of delivering immune cells and antibodies to the sites of infection. A fever is mounted in an effort to inhibit bacterial growth. Pain is the body’s way of nudging you to nurse and protect an infected wound or, in the case of a systemic infection, to lie down and rest, conserving energy for the immune fight. All of the symptoms of inflammation are the result of your body’s attempt to fight whatever is ailing you.

  Inflammation is definitely beneficial when fighting an infection but it is totally unhelpful in the case of allergies. An allergic antigen, say, the oil from a poison ivy plant, poses no actual threat to the body. Mounting an immune response to poison ivy oil is downright silly. Yet most of us do exactly that whenever we come in contact with it.

  Stop and think for a second about how ridiculous allergies are. Some people’s bodies go so crazy over a bee sting that they die. The bee stings don’t kill them; their immune systems do. Even if bee stings were truly dangerous (which they’re not), suicide still seems like an overreaction. Because of hypersensitive allergies, some people’s immune systems are like ticking time bombs. The biggest health dangers they’ll ever face in life is right inside them.

  One of the main culprits in allergic responses is a specific type of antibody that is normally used only to fight parasites and thus is one of the least commonly used antibody types, at least in the developed world. This antibody’s main function is to induce and maximize inflammation. For some reason, this parasite-fighting antibody gets released during an allergic response and that’s why the inflammation that occurs during an allergic response is so much worse than a standard inflammatory response. Inflammation is all that this antibody knows how to do. When you’re a hammer, everything looks like a nail.

  Allergies are a conundrum because we are all bombarded by foreign material all the time. We eat food from a variety of plant and animal species. We inhale pollen, microbes, and particulates from a whole variety of sources. Our skin comes in contact with a whole host of substances, including clothing, soil, bacteria and viruses, and other people’s bodies. We contend with that onslaught of foreign material just fine, but if a person has a peanut allergy and so much as tastes some peanut butter, he might find himself fighting for his life.

  So how does the body tell the difference sometimes and not others? We still really don’t know. One thing we do know, however, is that the body needs practice to do this correctly and the environment in which it practices does matter. The training of the immune system takes place in two phases, first in utero, then in infancy.

  A fledgling embryo develops immune cells while in utero. The very first thing that these cells do is participate in a phenomenon called clonal deletion. Clonal deletion is the process by which the developing immune cells in a fetus are presented with small bits of chewed-up proteins from the fetus’s own body. The immune cells that react to those bits of self-protein are then eliminated; they are “deleted” from the immune system. This process goes on for weeks and weeks, and the goal is to eliminate every single immune cell that has the potential to react to its own body. Only then is the immune system ready for action.

  It’s okay that the immune system is not functional prior to birth because, while the womb is not perfectly sterile, it is pretty close to it. In this safe environment, the fetus attempts to entrap its own immune system: it dangles little bits of self-antigens, and any immune cells that pounce on it are killed. The result is an immune system whose cells attack only foreign cells. Not long before birth, those cells are activated and the fetus is ready to face a dirty world full of microscopic danger.

  Once infants are born, the challenge gets more difficult. As the baby bursts into the very septic world, his immune system is bombarded by antigens it has never seen before. It has to learn who is friend and who is foe, and quickly. From a newborn’s first day of life, its immune system faces various infectious agents that it doesn’t yet know how to deal with, some mild, some serious. How does the body know to fight one strain of Staphylococcus aureus with everything it has but ignore another strain? No one really knows. One thing seems certain: the early immune system reacts slowly and adopts a “wait and see” approach.

  Many scientists think this is the key to phase two of immune training—the body figures out which foreign proteins are dangerous and which are harmless by going slow with the immune reaction at first and seeing if an infection takes hold. If it does, it’s time to kick things into high gear; if it doesn’t, the foreigner is seen as a big deal. The immune system has an incredible memory, as evidenced by the fact that vaccines to now extremely rare infections are still effective decades after people received the vaccinations. But initially it must learn who is friend and who is foe, and there is simply no other way to learn except firsthand experience.

  The result of this slow immune response is that truly dangerous infections get a head start on infants. Any parent will tell you that kids are constantly sick. Part of this is because they’re still building immunity to viruses, such as those that cause chest and head colds, but another part is that their immune systems are learning what bugs to fight and how to fight them. When the immune system does decide to jump into action, it usually does so very strongly, which compensates for the late start. This is why children tend to run much higher fevers than adults do. I once measured a fever of over 106o F in my son for nothing more serious than strep throat (though at the time, racked by the jitters of a first-time parent, I assumed he had the plague). If my temperature goes above 101o F, I feel like I’m dying.

  Importantly, our immune systems learn to be tolerant of the daily grind of life on earth. Most of the foreign molecules in the air, in our food, and on our skin are completely harmless. The majority of bacteria and viruses are harmless too. Our immune systems get used to the constant barrage of foreign material and learn not to fight it. Beginning at just a few months of age but continuing for the first few years, the immune system starts to settle into a mature state, assuming that it has seen most of the harmless stuff by then.

  As it transitions out of the infant learning phase, however, the immune system begins to change. It becomes more sensitive to new foreign material that it comes in contact with. This is when allergies rear their ugly head. Instead of learning that a harmless substance like peanut oil poses no health threat, the immune system decides to fight it, a reaction that will become more potent with increasing exposure. In other words, the immune system learns the exact opposite lesson than it should.

  There is no evolutionary explanation for why we get allergies, and all animals can
suffer from them. However, as with autoimmune disease, no species suffers from allergies as much as humans do. Prevalence of both food and respiratory allergies has been skyrocketing in the past two decades, and currently over 10 percent of children in the United States have at least one food allergy. When I was in elementary school in the early 1980s, I didn’t know a single kid with a peanut allergy except my sister, who was eleven grades ahead of me. Nowadays, both of my children usually have multiple kids in their classes every year who are deathly allergic to peanuts or other nuts. Many schools and daycares have opted to go entirely nut-free rather than deal with the constant worry of protecting the allergic kids from the scourge of nuts that could send them into anaphylaxis. Knowing what we know about how the immune system is trained and what goes wrong in the development of an allergy, what has changed over the past few decades to send allergy rates through the roof ?

  The likely answer is something called the hygiene hypothesis. Beginning in the 1970s and ’80s, people started going to great lengths to minimize children’s, especially infants’, contact with germs. Today, parents sterilize their babies’ bottles and ask visitors to wash their hands before holding or touching them. They keep infants mostly indoors and definitely off the bare ground. Only the cleanest food and liquid for their tummies and always freshly washed clothes for their bodies. If the pacifier falls on the floor—Stop! We must sterilize that now!

  This is all very well intentioned and it’s hard to argue with any of these daily decisions. I have instructed my children in no uncertain terms never to eat anything off the floor, to avoid using public bathrooms, and to touch nothing while riding the subway. I insist on these precautions because I don’t want them to get sick.

  Furthermore, if you have a cold, it just seems like common sense that you shouldn’t hold a two-week-old infant. In some circles, it is even considered a faux pas to visit someone with a newborn if you have young children. It doesn’t matter if you leave them at home; you might have germs on your clothes and your person that could make the infant sick. Again, this is a well-intentioned protective parental reaction.

  Good intentions aside, when safeguards like these are taken to extremes, they unwittingly wreak havoc with how evolution has shaped the development of our immunity.

  It turns out that the sterilization of infant life may be the reason behind the rise of allergies. Several studies have now implicated an excessively clean environment during infancy in the development of food allergies later. This is the hygiene hypothesis. It makes a whole lot of sense because the one thing we know about immune system function is that it requires a lot of practice to work well. This is why most vaccines are not given to children immediately at birth. Their immune systems just aren’t ready. It’s not that vaccines harm infants; they just don’t work. The same principle applies in the other direction—minimizing exposure to antigens will prevent children’s immune systems from getting accustomed to them. Only by seeing a lot of both harmful and harmless foreign substances can our immune systems learn to tell the difference.

  If this hypothesis is correct, we are collectively taking a relatively minor design flaw—allergies—and blowing it up to epic proportions. For that, we couldn’t blame nature. The fault would be ours.

  Matters of the Heart

  Cardiovascular diseases are the number-one cause of natural death in the United States and Europe. Collectively, in fact, coronary artery disease, stroke, and hypertension are the ultimate cause of about 30 percent of deaths in the developed West. Most of these fatalities are attributable to problems with the heart itself, but dysfunction of blood vessels are also frequently to blame. (Most kidney diseases, for instance, are actually circulatory problems that happen to occur in the kidneys because there are so many blood vessels concentrated there.)

  Some heart disease is age-related or the result of poor lifestyle choices; if you live long enough or behave unhealthily enough, you are likely to suffer from these cardiovascular conditions. This isn’t exactly a design flaw. We really have nobody to blame but ourselves—and odds are, you have already heard plenty on this topic and don’t need to hear more about it now. (Surprise: you should eat healthy foods and get plenty of exercise!)

  But humans do face some unusual design defects when it comes to matters of the heart. For example, every year in the United States alone, about twenty-five thousand babies are born with a literal hole in the heart.

  The clinical term for a hole in the heart is a septal defect, and it can occur between the two upper chambers of the heart or the two lower chambers. When this happens, blood sloshes between two chambers that are normally not connected to each other in the sequence of blood flow. During the heart’s contraction, the hole allows blood to flow from the left side of the heart to the right side. When the heart is resting, blood may inadvertently flow from the right side back to the left. The hole results in an improper mixing of venous and arterial blood.

  A human heart with a septal defect: a hole in the septum that allows blood to flow from the left side of the heart to the right side. This common yet life-threatening birth defect suggests that the genes governing the development of the human heart are less than fine-tuned.

  Normally, when blood returns from delivering oxygen to the tissues of the entire body, it enters the right side of the heart. From the right side, the blood is propelled to the lungs, where it picks up oxygen and unloads carbon dioxide. Then the blood returns to the heart, this time to the left side, where it is repressurized and pumped out to the body. This two-step process is important because blood has to be pumped out at high pressure in order to flow out to the body, but it has to circulate at low pressure so the tissues have time for the gas exchange that is the whole purpose of blood to begin with. Pump out, gas exchange (lungs), pump out, gas exchange (whole body). That is the pattern.

  When there is a septal defect, however, blood mixes between the two steps. This is like a short circuit of the normal flow of blood. A tiny hole makes no difference at first, though it may grow over time due to the friction of blood flowing through it. A large hole can disrupt blood flow so completely that it is lethal, either in utero or shortly thereafter. The bottom line is that inefficiencies caused by septal defects place an additional load on the heart. It must work that much harder to circulate blood properly.

  Currently, clinical outcomes for children born with septal defects are pretty good. Many defects are so small that no intervention is necessary (though regular checkups are called for). Larger ones must be repaired surgically, a procedure that became an option only in the late 1940s. The septal walls are deep inside the heart chambers, so this means open-heart surgery. This is about as invasive as it gets and requires a complete heart-lung bypass during the operation. It carries all kinds of risks. Nevertheless, doctors have refined the surgery to such a degree that in developed countries, almost all children born with septal defects now survive and live completely normal lives.

  This obviously would not have been so just a few decades ago. Severe septal defects were once a substantial cause of immediate postnatal death. If a baby had a gaping hole in her heart, she usually lived for just a few hours, gasping for breath, before slowly suffocating due to the inability to properly circulate oxygen.

  Of course, most of us do not have holes in our hearts, and the frequency with which this developmental error occurs indicates that the genes responsible for the genesis of the heart are a little rusty. While septal-development defects are sporadic, they are not due to sporadic mutations but rather sporadic failures in the embryonic development of the heart. It’s just sort of bad luck, but there seems to be a predisposition for this very specific type of bad luck.

  To understand how someone can be predisposed to experience a particular problem, consider your shoelaces. If your shoelaces are tied properly, the odds of you taking one hundred steps without tripping are pretty good, but not zero. If your shoelaces are untied but pretty short, you might still take one hundred steps without tripping,
and if you do trip, you probably won’t do so more than a few times. If the untied laces are very long, however, you will almost certainly trip multiple times within the one hundred steps, but still, you most likely won’t trip every single step.

  As this example demonstrates, the odds of a problem—tripping—can be low or high depending on a variety of factors. There is no perfect situation in which tripping is entirely impossible, nor is there a situation where tripping every step is guaranteed. There is just a range of probabilities.

  The influence of genes on development is akin to the influence of shoelaces on tripping. There is a low chance of a baby being born with a hole in his or her heart. However, the fact that in the United States alone, a couple of thousand babies a year are born with holes in their hearts indicates that the genetic shoelaces are untied. Somewhere in the genes for heart development, some things are not quite what they should be. The laces may be short, but they are definitely untied.

  If you think that’s weird, consider this: Some babies are born with the blood flowing in the wrong direction through their circulatory systems. This is a severe problem that must be corrected immediately. Circulation is a closed system, so, in principle, flipping things around in the circuit would still result in blood going to the right places: being refreshed with oxygen in the lungs, sent to the tissues, returned to the lungs for more oxygen, and so on. However, it cannot run effectively in reverse because both the vessels and heart muscle are configured to meet the needs and pressures of different systems. The right side of the heart is built to pump blood only to the lungs and back out to the heart, and it is not strong enough to push blood through the whole body. In addition, the pulmonary arteries, which normally carry blood to the lungs, are built very differently than the aorta, which normally carries blood to the whole body. If their roles are reversed, neither will perform its function very well.