High-Risk Defenses – the illness glucose-6-phosphate dehydrogenase
The sum of the squares of the legs of a right triangle equals the square of the hypotenuse. This mathematical insight, passed down over the centuries, is credited to Pythagoras, the Greek philosopher and mathematician who lived in southern Italy 2,500 years ago. We also credit Pythagoras with saying, “Do not eat broad beans!” History does not record his reason for this injunction, and it was long the subject of speculation by historians and philosophers alike. On the face of it, the whole issue seems bizarre. For millennia, broad beans have been a nutritious and palatable staple in Europe, the Middle East, and Africa.
But for a significant minority of people from southern Italy and Greece, eating broad beans can result in a severe, sometimes fatal anemia. This illness, called glucose-6-phosphate dehydrogenase (G6PD) deficiency, or favism, arises in people with two copies of a mutant gene. Having one copy of the gene affords protection against infection by malarial parasites. But those unlucky enough to inherit two copies–one from the mother and one from the father–suffer from abnormal sensitivity to moderately toxic compounds, such as those found in broad beans. In southern Italy and Greece, about one-third of the population has a mutation in the gene that codes for G6PD–an enzyme that aids energy extraction in red blood cells. So there may well have been a simple, practical reason for the Pythagorean admonition: broad beans were actually dangerous to many in the local population.
Malaria was probably endemic in southern Italy from ancient times until the 1940s, when the Anopheles mosquitoes that carry it were largely eradicated with DDT. Thus, people in the region who carried one copy of the G6PD mutation received a great boost in evolutionary “fitness”–that is, they were more likely than others to survive and propagate their genes into the next generation.
This account should be sounding familiar. If we look around the world, we repeatedly see evidence that certain genetic diseases are themselves defenses against infectious disease. G6PD deficiency in the Mediterranean region is like sickle-cell anemia in Africa: both are the body’s scorched-earth tactics, keeping invaders from using the resources of the invaded. A single copy of the G6PD deficiency gene (even though it keeps red blood cells from efficiently metabolizing energy) prevents the malarial parasite from efficiently invading red blood cells. Likewise, a single gene for sickle-cell hemoglobin (even though it diminishes the function and longevity of the red blood cells) thwarts attack by the malarial parasite. When someone inherits two copies of the gene coding for sickle-cell hemoglobin, however, the red blood cells are distorted into a sickle shape. The deformed cells rupture easily, block capillary beds, and increase vulnerability to infection.
Northern Europeans have evolved their own genetic defenses against infection. A recent study by Gerald B. Pier and his associates at the Brigham and Women’s Hospital of the Harvard Medical School indicates that cystic fibrosis–a disease affecting mainly northern Europeans–is probably an adaptive defense against Salmonella typhi, the bacterium that causes typhoid fever. The most serious feature of cystic fibrosis is obstruction of the small airways of the lungs. A defective protein in the cells lining the respiratory tract thickens the mucus, trapping pathogens and reducing the lungs’ capacity to clear infection.
The Pier team found that a gene coding for that defective lung-cell protein also codes for a defective protein in the intestine–where it may hinder S. typhi from attaching itself to the intestinal lining. We call this the boarded-window defense–boarding up the windows of a house may block out light and air, but it also makes the house less vulnerable to burglars. In the case of cystic fibrosis, a single copy of the gene codes for the protein that bars entry to S. typhi but still allows the intestinal cell to perform its normal activities. Having two copies of the gene causes cystic fibrosis–a disease that, before antibiotics, killed most of its victims before the age of two. This tragic disease is the price paid for protection against typhoid fever, but in Europe prior to the twentieth century, S. typhi (ubiquitous in contaminated water) infected almost everyone early in life and typically killed about 5 percent of the population.
Like sickle-cell anemia, hemoglobin C in northwest Africa and hemoglobin E in Southeast Asia are scorched-earth defenses–they defend against malaria and are also caused by a change in a single amino acid on the hemoglobin molecule. Another malarial defense, Melanesian ovaloctosis, is caused by a mutation that alters red blood cell membranes. It is lethal in those who have two copies of the gene.
What accounts for the evolution of such seemingly crude and self-destructive defenses? Sometimes a crude defense may be better than none at all, and crude defenses are easy to generate. While most adaptations involve an orchestration of several genes, self-destructive defenses typically consist of a simple change that interferes with only one gene’s primary function. Even though such mutations may harm us by altering biological machinery fine-tuned over millennia by natural selection, they help us by interfering with the similarly finely calibrated mechanisms of an infectious adversary.
These high-risk genes maintain a constant level in populations: they are fairly common but do not affect the majority because their spread is self-limited. When the sickle-cell gene first appears, for example, it is beneficial to its host, who may then pass on single copies of the new mutant to a few offspring. Those who inherit it have a survival advantage because they cannot be felled by a widespread cause of death–malaria. The trait’s subsequent spread through the population is virtually cost free until the gene becomes so common that children begin inheriting it from both parents. At that point, the death rate of these children (without intervention, sickle-cell anemia kills its victims long before they reach reproductive age) acts as a brake against the trait’s spread into subsequent generations.
Ironically, the high cost of such defenses is also the very reason they stick around, in stable form, over the long run. Why? Because if the defense had no disadvantage, the gene coding for it would spread through the host population until it was more common than any other variant. With no suitable hosts, the pathogen would either vanish entirely (leaving no clue that it had ever afflicted us or that we had ever adapted to it) or (if a timely mutation appeared) bounce back in a mutant form that could get around the original defense. But with very devastating diseases like sickle-cell anemia and cystic fibrosis, the proportion of people carrying the gene never rises above a low frequency. If only one in ten carries the defense gene, there may be little or no selection pressure favoring a mutant form of the pathogen. The malarial parasite continues to perpetuate itself by infecting the 90 percent of people who lack the defense gene entirely.
To some people, the story of sickle-cell anemia demonstrates that natural selection is such a feeble process that it cannot generate an effective defense against malaria without botching up the blood system. But the evolutionary reasoning presented above offers an alternative viewpoint. Selection may be continually presenting effective defenses against many terrible diseases, but such defenses are not apparent because selection is acting powerfully on both host and pathogen. As a consequence, the effective defense of one era becomes the impotent defense of a later era. In addition, because the malaria protozoa are more damaging than most other parasites, the defenses against them offer greater fitness benefits; hence, more incidental harm can be tolerated. Self-destructive defenses against milder pathogens may also exist, but scientists may have overlooked them because so few people have two copies of the defense genes.
One benefit of this evolutionary approach to understanding disease is its usefulness in analyzing the past. But what about its predictive value? We think that the concept of self-destructive defenses, coupled with insights about how genes persist in populations, has predictive possibilities. When a genetic defect is too common to be sustained by a random mutation and too widespread or stable to be accounted for by a founder effect (persistence of a gene in a small population of closely related people), then we have the smoking gun of a self-destructive defense.
Using this logic, we predict that hemochromatosis–a syndrome in which iron builds up in the body and which is found primarily in northern Europeans–will eventually prove to be the result of a defense against a pathogen. About one in ten northern Europeans carries a single copy of the hemochromatosis gene; those with two copies usually develop a combination of serious ailments, including liver disease, diabetes, infertility, heart failure, and increased susceptibility to rare pathogens. These individuals have a defective protein in their intestines and other organs. The normal protein is embedded in the cell membrane, but the defective protein is not. This switch in location is just the kind of alteration–a boarded-window defense–that could block a pathogen that would normally latch onto the protein to enter a cell. In addition, the trait is too common to be maintained by random mutation and too widespread geographically to be the result of a founder effect. Some researchers hypothesize that an increased ability to absorb iron may be the hidden benefit of the hemochromatosis gene. But the disease is most common where iron-rich foods, such as meat, are the rule in local diets. Moreover, a crude defense that destroys a gene’s function would more likely be favored because of its utility against an invader–not as a device to absorb more of a nutrient. We therefore suspect that hemochromatosis, like cystic fibrosis, is a boarded-window defense that evolved in response to an as yet unknown pathogen.
Other self-destructive defenses are more like rogue cops than boarded windows. We suspect that [alpha.sub.1]-antitrypsin deficiency falls into this category. This enzyme deficiency causes emphysema and liver disease in northern Europeans who inherit two copies of the gene. The affected protein controls the level of elastase, an enzyme that makes elastic cartilage more permeable to the cells of the immune system. In an [alpha.sub.1]-antitrypsin-deficient individual, absence of this control may cause maverick elastase activity, improving access for the immune-system cells but damaging tissue in the process. Like a rogue cop, the cells’ trypsin may fire first and ask questions later, causing much collateral damage. The net result may be increased protection against pathogens, along with increased risk of the tissue damage associated with emphysema and cirrhosis. If this line of reasoning is correct, having one copy of the [alpha.sub.1]-antitrypsin deficiency gene should reduce susceptibility to some unknown infectious disease. Although this prediction awaits definitive testing, researchers at Cambridge University, England, reported some intriguing findings in 1998. Patients with both cystic fibrosis and [alpha.sub.1]-antitrypsin deficiency had less severe respiratory problems than did patients with cystic fibrosis alone. The researchers were somewhat puzzled by this apparent paradox, but a medical evolutionist might posit that the unleashing of rogue cops through [alpha.sub.1]-antitrypsin deficiency helps control some of the infections that are so problematic to cystic fibrosis patients. There are practical reasons to investigate whether genetic diseases are self-destructive defenses.
The solution to these problems will come from future research. If hemochromatosis and alphas-antitrypsin deficiency prove to be self-destructive defenses, then the evolutionary synthesis of genetics, epidemiology, and medicine will have moved up one notch in credibility and utility.
Paul W. Ewald and Gregory Cochran (“Catching On to What’s Catching” and “High-Risk Defenses”) met after Ewald became intrigued by a paper Cochran submitted to a journal. A professor of biology at Amherst College, Ewald, left, has long been interested in coevolutionary relationships, and most of his work now focuses on pathogens and their hosts. “All organisms evolve by natural selection” says Ewald, “and the cost-benefit trade-offs are the same–whether it’s birds and flowers or humans and bacteria.” Physicist Cochran is based in Albuquerque. His three children–as well as his job as a consultant on adaptive optics tar observatories and the aerospace industry–Keep him tram spending all his time cogitating about disease evolution. “When a serious disease of unknown causation is common and has a long history,” says Cochran, “the theory of natural selection points to a pathogen.”
COPYRIGHT 1999 American Museum of Natural History
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