High-Risk Defenses

Natural History, Feb, 1999 by Gregory Cochran, Paul W. Ewald

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.