Penny le Couteur & Jay Burreson (57 page)

Until recently sickle-cell anemia was usually fatal in childhood; cardiac problems, renal failure, liver failure, infection, and strokes took a toll at an early age. Present-day treatments—but not cures—can allow patients to live longer and healthier lives. Carriers of sickle-cell anemia can be affected by sickling, though usually not enough to compromise blood circulation.

For carriers of the sickle cell trait who live in malarial areas, the disease offers a valuable compensation: a significant degree of immunity to malaria. The definite correlation between incidence of malaria and high carrier frequency of sickle-cell anemia is explained by the evolutionary advantage of being a carrier. Those who inherited the sickle-cell trait from both parents would usually die from it in childhood. Those who did not inherit the trait from either parent were much more likely to succumb, often in childhood, to malaria. Those inheriting the sickle cell gene from only one parent had some immunity to the malarial parasite and survived to a reproductive age. Thus the inherited disorder of sickle-cell anemia not only continued in a population, it increased over generations. Where malaria did not exist, there was no benefit from being a carrier, and the trait would not have persisted in the inhabitants. The absence of an abnormal hemoglobin that provides malarial immunity in the American Indian population is considered crucial evidence that the American continents were malaria-free before the arrival of Columbus.

The red color of red blood cells is due to the presence of molecules of hemoglobin—the function of which is to transport oxygen around the body. One extremely small change in the chemical structure of hemoglobin is responsible for the life-threatening condition of sickle-cell anemia. Hemoglobin is a protein; like silk, it is a polymer comprising amino acid units, but unlike silk, whose chains of variably arranged amino acids may contain thousands of units, hemoglobin's precisely ordered amino acids are arranged in two sets of two identical strands. The four strands are coiled together around four iron-containing entities—the site where oxygen atoms attach. Patients with sickle-cell anemia have just a single amino acid unit difference on one of the sets of strands. On what is called the β strand, the sixth amino acid is valine instead of the glutamic acid present in normal hemoglobin.

The β strand consists of 146 amino acids; the α strand has 141 amino acids. So the overall variation in amino acids is only one out of 287—about a third of 1 percent difference in amino acids. Yet the result for the person inheriting the sickle-cell trait from both parents is devastating. If we say that the side group is only about a third of the structure of the amino acid, then the percent difference in actual chemical structure becomes even less—a change in only around a tenth of 1 percent of the molecular structure.

This alteration in protein structure explains the symptoms of sickle-cell anemia. The side group of glutamic acid has COOH as part of its structure, while the side group of valine doesn't. Without this COOH on the sixth amino acid residue of the β strand, the deoxygenated form of sickle-cell anemia hemoglobin is much less soluble; it precipitates inside red blood cells, accounting for their changed shape and loss of flexibility. The solubility of the oxygenated form of sickle-cell anemia is little affected. Thus there is more sickling when there is more deoxygenated hemoglobin.

Once sickled cells start to block capillaries, local tissues become deficient in oxygen, oxygenated hemoglobin is converted to the deoxygenated form, and even more sickling occurs—a vicious cycle that rapidly leads to a crisis. This is why carriers of the sickle-cell trait are also susceptible to sickling: though only about 1 percent of their red blood cells are normally in a sickled state, 50 percent of their hemoglobin molecules have the potential to become sickled. This may happen at low oxygen pressures in unpressurized planes or after exercise at high altitudes; both are conditions in which the deoxygenated form of hemoglobin can build up in the body.

More than 150 different variations in the chemical structure of human hemoglobin have been found, and although some of them are lethal or cause problems, many others are apparently benign. Partial resistance to malaria is thought to be conferred on carriers of the hemoglobin variations that produce other forms of anemia, such as alpha thalassemia, endemic among people of Southeast Asian heritage, and beta thalassemia, most common in those of Mediterranean ancestry, such as Greeks and Italians, and also found in those from the Middle East, India, Pakistan, and parts of Africa. It is probable that as many as five in every thousand humans have some sort of variation in the structure of their hemoglobin, and most will never know.

It is not just the difference in the side group structure between glutamic acid and valine that causes the debilitating problems of sickle-cell anemia; it is also the position in which this occurs in the β strand. We do not know if the same change at a different position would have a similar effect on hemoglobin solubility and red blood cell shape. Nor do we know exactly why this change confers immunity to malaria. Obviously something about a red blood cell containing hemoglobin with valine at position six hinders the life cycle of the
Plasmodium
parasite.

 

 

The three molecules at the center of the ongoing struggle against malaria are very different chemically, but each one has had a major influence over events of the past. The alkaloids of the cinchona bark, throughout their long history of benefit to man, brought little economic advantage to the indigenous people of the eastern slopes of the Andes where the
quina
trees grew. Outsiders profited from the quinine molecule, exploiting a unique natural resource of a less developed country for their own advantage. European colonization of much of the world was made possible by the antimalarial properties of quinine, which like many another natural product has provided a molecular model for chemists attempting to reproduce or enhance its effects by making alterations to the original chemical structure.

Although the quinine molecule, in the nineteenth century, allowed the growth of the British Empire and the expansion of other European colonies, it was the success of the DDT molecule as an insecticide that finally eradicated malaria from Europe and North America in the twentieth century. DDT is a synthetic organic molecule that has no natural analogue. There is always a risk when such molecules are manufactured—we have no way of knowing for sure which will be beneficial and which may have harmful effects. Yet how many of us would be prepared to give up entirely the whole spectrum of novel molecules, the products of chemists' innovation that enhance our lives: the antibiotics and antiseptics, the plastics and polymers, the fabrics and flavors, the anesthetics and additives, the colors and coolants?

The repercussions of the small molecular change that produced sickled hemoglobin were felt on three continents. Resistance to malaria was a crucial factor in the rapid growth of the African slave trade in the seventeenth century. The vast majority of slaves imported to the New World came from the region of Africa where malaria was endemic and where the sickle-cell anemia gene is common. Slave traders and slave owners quickly exploited the evolutionary advantage of valine replacing glutamic acid at position six on the hemoglobin molecule. Of course they did not know the chemical reason for the immunity of African slaves to malaria. All they knew was that slaves from Africa could generally survive the fevers in the tropical climates suitable for sugar and cotton cultivation, whereas native Americans, brought from other parts of the New World to labor in the plantations, would rapidly succumb to diseases. This small molecular switch doomed generations of Africans to slavery.

The slave trade would not have flourished as it did had the slaves and their descendants fallen victim to malaria. The profits from the great sugar plantations of the New World would not have been available for economic growth in Europe. There might not have been any great sugar plantations. Cotton would not have developed as a major crop in the southern United States, the Industrial Revolution in Britain might have been delayed or taken a very different direction, and there might not have been civil war in the United States. The events of the past half millennium would have been very different but for this tiny change in the chemical structures of hemoglobin.

Quinine, DDT, and hemoglobin—these three very different structures are united historically by their connections to one of our world's greatest killers. They also typify the molecules discussed in previous chapters. Quinine is a naturally occurring plant product, as are many compounds that have had far-reaching effects on the development of civilization. Hemoglobin too is a natural product, but of animal origin. As well, hemoglobin belongs to the group of molecules classified as polymers, and again polymers of all types have been instrumental in major changes throughout history. And DDT illustrates the dilemmas often associated with man-made compounds. How different our world would be—for better or for worse—without synthetic substances produced through the ingenuity of those who create new molecules.

EPILOGUE

H
ISTORICAL EVENTS almost always have more than one cause, so it would be far too simplistic to attribute the events mentioned in this book solely to chemical structures. But neither is it an exaggeration to say that chemical structures have played an essential and often unrecognized role in the development of civilization. When a chemist determines the structure of a different natural product or synthesizes a new compound, the effect of a small chemical change—a double bond moved here, an oxygen atom substituted there, an alteration to a side group—often seems of little consequence. It is only with hindsight that we recognize the momentous effect that very small chemical changes can have.

Initially, the chemical structures shown in these chapters may have appeared foreign and perplexing to you. Hopefully we've now removed some of the mystery from such diagrams, and you can see how atoms that make up the molecules of chemical compounds conform to well-defined rules. Yet within the boundaries of these rules there are seemingly endless possibilities for different structures.

The compounds we selected as having interesting and important stories fall into two main groups. The first includes molecules from natural sources—valuable molecules sought after by man. Desire for these molecules governed many aspects of early history. Over the past century and a half the second group of molecules became more important. These are compounds made in laboratories or factories—some of them, like indigo, absolutely identical to molecules from a natural product, and others, like aspirin, variations of the structure of the natural product. Sometimes, like CFCs, they are totally new molecules with no analogs in nature.

To these groups, we can now add a third classification: molecules that may have a tremendous but unpredictable effect on our civilization in the future. These are molecules produced by nature but at the direction and intervention of man. Genetic engineering (or biotechnology, or whatever term is used for the artificial process by which new genetic material is inserted into an organism) results in the production of molecules where they did not previously exist. “Golden rice,” for example, is a strain of rice genetically engineered to produce β-carotene, the yellow-orange coloring matter abundant in carrots and other yellow fruits and vegetables and also present in dark green leafy vegetables.

β
-carotene

Our bodies need β-carotene to make vitamin A, essential to human nutrition. The diet of millions of people around the world, but particularly in Asia, where rice is the staple crop, is low in β-carotene. Vitamin A deficiency brings diseases that can cause blindness and even death. Rice grains contain virtually no β-carotene, and for parts of the rice-eating world where this molecule is not generally obtained from other sources, the addition of β-carotene to golden rice brings the promise of better health.