Penny le Couteur & Jay Burreson (56 page)

Organic natural product chemists have a saying: “The final proof of structure is synthesis.” In other words, no matter how much the evidence points to the correctness of a proposed structure, to be absolutely sure it is correct, you have to synthesize the molecule by an independent route. And in 2001, 145 years after Perkin's now-famous attempt to make quinine, Gilbert Stork, professor emeritus at New York's Columbia University, together with a group of coworkers, did just that. They started with a different quinoline derivative, they followed an alternative route, and they carried out each and every step of their synthesis themselves.

As well as being a reasonably complicated structure, quinine, like many other molecules made in nature, presents the particular challenge of determining which way various bonds around certain of the carbon atoms are positioned in space. The quinine structure has an H atom pointing out of the page (indicated by a solid wedge
) and an OH directed behind the page (indicated by a dashed line ----) around the carbon atom adjacent to the quinoline ring system.

An example of the different spatial arrangements of these bonds is shown on page 341 for quinine and a version inverted around the same carbon atom.

Nature often makes only one of a pair of compounds like this. But when chemists attempt to make the same molecule synthetically, they cannot avoid making an equal mixture of the two. Because they are so similar, separating the two molecules of the pair is tricky and time-consuming. There are three other carbon atom positions in the quinine molecule where both the natural and the inverted versions are unavoidably made during a laboratory synthesis, so these painstaking operations must be repeated four times in all. It was a challenge that Stork and his group overcame—and there is no evidence that the problem was even fully appreciated in 1918.

Quinine continues to be harvested from plantations in Indonesia, India, Zaire, and other African countries, with lesser amounts coming from natural sources in Peru, Bolivia, and Ecuador. Its main uses today are in quinine water, tonic water, and other bitter drinks and in the production of quinidine, a heart medication. Quinine is still thought to provide some measure of protection against malaria in chloroquine-resistant regions.

While people were searching for ways to harvest more quinine or make it synthetically, physicians were still trying to understand what caused malaria. In 1880 a doctor in the French army in Algeria, Charles-Louis-Alphonse Laveran, made a discovery that ultimately opened the way for a new molecular approach to the fight against this disease. Laveran, using a microscope to check slides of blood samples, found that the blood of patients with malaria contained cells that we now know are a stage of the malarial protozoa
Plasmodium.
Laveran's findings, initially dismissed by the medical establishment, were confirmed over the next few years with the identification of
P. vivax
and
P. malariae,
and later
P falciparum.
By 1891 it was possible to identify the specific malaria parasite by staining the
Plasmodium
cell with various dyes.

Although it had been hypothesized that mosquitoes were somehow involved in the transmission of malaria, it was not until 1897 that Ronald Ross, a young Englishman who was born in India and was serving as a physician in the Indian Medical Service, identified another life stage of
Plasmodium
in gut tissue of the anopheles mosquito. Thus the complex association between parasite, insect, and man was recognized. It was then realized that the parasite was vulnerable to attack at various points in its life cycle.

The life cycle of the
Plasmodium
parasite. The merozoites periodically (every 48 or 72 hours) break out of their host's red blood cells, causing a fever to spike.

There are several possible ways to break this disease cycle, such as killing the merozoite stage of the parasite in the liver and blood. Another obvious line of attack is the disease “vector,” the mosquito itself. This could involve preventing mosquito bites, killing adult mosquitoes, or preventing them from breeding. It is not always easy to avoid mosquito bites; in places where the cost of reasonable housing is beyond the means of most of the population, window screens are just not feasible. Nor is it practical to drain all stagnant or slow-moving waters to prevent mosquitoes from breeding. Some control of the mosquito population is possible by spreading a thin film of oil over the surface of water, so mosquito larvae in the water cannot breathe. Against the anopheles mosquito itself, however, the best line of attack is powerful insecticides.

Initially the most important of these was the chlorinated molecule DDT, which acts by interfering with a nerve control process unique to insects. For this reason, DDT—at the levels used as an insecticide—is not toxic to other animals, even while it is lethal to insects. The estimated fatal dose for a human is thirty grams. This is a considerable amount; there are no reported human deaths from DDT.

Thanks to a variety of factors—improved public health systems, better housing, fewer people living in rural areas, widespread drainage of stagnant water, and almost universal access to antimalarial drugs—the incidence of malaria had, by the early years of the twentieth century, greatly decreased in western Europe and North America. DDT was the final step necessary to eliminate the parasite in developed countries. In 1955 the World Health Organization (WHO) began a massive campaign using DDT to eliminate malaria from the rest of the world.

When DDT spraying started, about 1.8 billion people lived in malarial areas. By 1969 malaria had been eradicated for nearly 40 percent of these people. In some countries the results were phenomenal: in 1947 Greece had approximately two million cases of malaria, while in 1972 the number was seven. If any one molecule can be said to be responsible for the increase in economic prosperity of Greece during the last quarter of the twentieth century, it surely must be DDT. Before DDT spraying began in India, in 1953, there were an estimated 75 million cases a year; by 1968 there were only 300,000. Similar results were reported from countries all around the world. It was no wonder that DDT was considered a miracle molecule. By 1975 the WHO had declared Europe to be malaria free.

As it was such a long-lasting insecticide, treatment every six months—or even yearly where the disease was seasonal—was sufficient to give protection against the disease. DDT was sprayed on the inside walls of houses where the female mosquito clung, waiting for nighttime to seek her meal of blood. DDT stayed in place where it was sprayed, and it was thought that very little would ever make its way into the food chain. It was an inexpensive molecule to produce, and it seemed at the time to have little toxicity for other forms of animal life. Only later did the devastating effect of DDT bioaccumulation become obvious. We have also since realized how overuse of chemical insecticides can upset ecological balance, causing more serious pest problems.

Although the WHO's crusade against malaria had initially looked promising, the global eradication of the parasite proved more difficult than expected for a number of reasons, including the development of resistance to DDT by the mosquito, human population increase, ecological changes that reduced the number of species preying on mosquitoes or their larvae, war, natural disasters, decline of public health services, and the increase of
Plasmodium
resistance to antimalarial molecules. By the early 1970s the WHO had abandoned its dream of complete eradication of malaria and concentrated its efforts on control.

If molecules can be said to go in and out of fashion, then in the developed world DDT is definitely unfashionable—even the name seems to have an ominous ring. Although it is now outlawed in many countries, this insecticide is estimated to have saved fifty million human lives. The threat of death from malaria has largely gone from developed countries—a direct and huge benefit from a much-maligned molecule—but for millions who still live in malarial regions of the world it remains.

In many of these places few people can afford the insecticide molecules that control anopheles mosquitoes or the synthetic quinine substitutes that provide protection for tourists from the West. But nature has bestowed quite a different form of defense against malaria in these regions. As many as 25 percent of sub-Saharan Africans carry a genetic trait for the painful and debilitating disease known as sickle-cell anemia. When both parents are carriers of this trait, a child has a one-in-four chance of having the disease, a one-in-two chance of being a carrier, and a one-in-four chance of neither having the disease nor being a carrier.

Normal red blood cells are round and flexible, allowing them to squeeze through small blood vessels in the body. But in sickle-cell anemia patients, approximately half of the red blood cells become rigid and take on an elongated crescent or sickle shape. These stiffer sickled red blood cells have difficulty squeezing through narrow blood capillaries and can cause blockages in tiny blood vessels, leaving the cells of muscle tissue and vital organs without blood and oxygen. This leads to a sickling “crisis” causing severe pain and sometimes permanently damaging affected organs and tissue. The body destroys abnormal sickle-shaped cells at a faster rate than normal, resulting in an overall reduction in red blood cells—the source of the anemia.