Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (32 page)

Anatomy of an Erection

The human penis is made up of three cylindrical bodies: the corpus spongiosum (spongy body), which contains the urethra and includes the glans penis, or head of the penis, and the paired corpora cavernosa, or erectile bodies. These two bodies, functioning as one unit, are actually responsible for the erection, as their sinusoidal tissue, fine-walled empty spaces, expands as it fills with blood. The sinusoidal tissue can be thought of as a myriad of small, interlacing vascular spaces lined by endothelial cells and smooth muscle.

The key element necessary for the production of an erection is smooth muscle relaxation within the walls of the sinusoidal tissue. This engorgement with blood from dilated arteries is dependent upon release of nitric oxide by nerves in the penis following sexual stimulation. Viagra blocks an enzyme known as phosphodiesterase-5 (PDE-5), allowing smooth muscle cells in the penis to relax, so it magnifies the effect of nitric oxide.

With studies suggesting that more than 150 million men worldwide and at least 30 million in the United States suffered from erectile dysfunction, drug companies knew the market would expand rapidly. Pfizer soon had competitors. Bayer, GlaxoSmithKline, and ScheringPlough, the makers of Levitra, which was approved for sale in August 2003, claimed their drug acted somewhat more quickly than Viagra.
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Another competitor, Cialis, made by a partnership of Eli Lilly and the
Icos Corporation, was approved shortly thereafter and is said to be effective for thirty-six hours, as opposed to four to five hours for Viagra and Levitra.

In 2004 combined global sales of the three ED remedies reached about $2.5 billion, with Viagra claiming the lion's share of the market. It accounted for 61 percent of prescriptions, compared with 25 percent for Cialis and 14 percent for Levitra.

28

What's Your Number?

We are all used to certain numbers in the determination of our physical health. Temperature: 98.6. Blood pressure: 120 over 80. Vision: 20/20. Other familiar indices may involve caloric intake or body fat ratio. In the last several years, another number has entered the national consciousness. Even in casual conversation between friends, the question “What's your number?” is taken to mean your level of blood cholesterol. This is in widespread recognition of a factor critical to our health.

Heart disease from clogged arteries is the number one killer in the West. (It is the number two killer in the United States, second only to cancer.) Cholesterol is the primary culprit. It causes plaque to build up on artery walls. Several consequences may ensue from this buildup. As the plaques enlarge, they may induce clots to form; together they may block the coronary artery, or a piece may break off to float downstream and obstruct blood circulation. Even while the plaque remains small, it may induce the coronary artery to go into spasm, shutting off the heart's blood supply.

The underlying causes of atherosclerosis long remained elusive. The first experiments on its nature were undertaken in the early twentieth century. In 1909 a clinical investigator at the Russian Imperial Military Medical Academy in St. Petersburg found that rabbits fed a mixture of eggs and milk developed atherosclerotic plaques. He purposely chose dietary staples of rich Russians in contrast to the peasant
class, but he wrongly concluded that the atherosclerosis resulted from the
protein
in these foods. Within a few years, at the same institution, the pathologist Nikolai Anichkov established that cholesterol, a soft waxy substance, was to blame.
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Cholesterol, a pale yellow substance in dairy products and beef, is produced naturally by the liver and is essential to the creation of cell walls and certain steroid hormones.

This Russian breakthrough in understanding remained unrecognized by European and American scientists for decades for several reasons. The St. Petersburg medical school was simply unknown as a research center to Western medicine, and most of its investigators’ papers were published in Russian. Moreover, the cause or development of aortic or coronary atherosclerosis was not a subject interesting mainstream Western scientists at the time. The electrocardiogram was not in general clinical use for the diagnosis of heart attack until the mid-1920s.

Then, in 1950, Western scientists learned of an important finding in a report in
Science.
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Stimulated by previous observations that atherosclerotic plaques contain cholesterol, phospholipids, and fatty acids, a team of researchers led by John Gofman had worked to develop atherosclerosis in rabbits by feeding them a high-cholesterol diet. (Gofman was not dissuaded by the simplistic criticism that the rabbit is herbivorous and thus ordinarily ingests essentially no cholesterol.) Cholesterol moves throughout the bloodstream by attaching itself to water-soluble proteins called lipoproteins. When the Gofman team spun the rabbits’ fatty serum—that is, all the fats (cholesterol and triglycerides) in the serum, the noncell liquid part of blood—in tubes in a high-powered ultracentrifuge, they found that it separated into two distinct compartments. They designated the lighter portion of the fatty serum, composed of much more fat than protein, low-density lipoprotein cholesterol, now referred to as LDL. They designated the other portion, richer in protein and lower in fat content, high-density lipoprotein, now referred to as HDL.

In not only these atherosclerotic rabbits but also in a large group of patients who had recovered from a heart attack, they found that most of the cholesterol in the blood was carried in the LDL complexes. Since many individuals with atherosclerosis show blood cholesterol
in the accepted normal range, it became apparent at this time that LDL concentration is more significant than total blood cholesterol content. For this reason, LDL is referred to as “bad cholesterol.”

Awareness of the contribution of diet subsequently arose from several sources. In 1952 Louis Dublin, senior statistician at the Metropolitan Life Insurance Company, declared that Americans “are literally eating themselves to death.” His exposure of the “epidemic” of heart disease was based on decades of actuarial research.
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Further convincing proof that diet does cause human coronary disease was then demonstrated in a report on young American soldiers killed in the Korean War. Their average age was only twenty-two years, yet autopsies showed that three-fourths of them already had fat streaks in their coronary arteries. In contrast, the Korean and Chinese soldiers, having spent their lives eating no milk products and little egg or meat fat, had no cholesterol in their coronary arteries. Following President Eisenhower's widely publicized heart attack in 1955, the dangers of high-fat diets were openly discussed in the general press as well.

In 1958 a strongly worded editorial in
Circulation,
the official publication of the American Heart Association, served as a call to arms. It rebuked cardiac researchers for their inattention over the years to the key role of diet in the primary pathology of atherosclerosis.

Twenty-five years later, two dedicated young researchers, Michael Brown and Joseph Goldstein, brought about a conceptual revolution when they told the world that the fundamental problem lay not in the blood but in the body cell.

Goldstein, from South Carolina, and Brown, from Brooklyn, became close friends when both were medical residents at Boston's Massachusetts General Hospital from 1966 to 1968. Their mutual interest in pursuing an academic career in molecular biology led to one of medicine's great creative research partnerships. Both physicians joined the National Institutes of Health in Bethesda, Maryland, and worked in different labs concerned with how genes regulate enzymes—Goldstein in biochemical genetics, and Brown in digestive and hereditary diseases. Their diverse talents and training were particularly complementary and would lead to the illumination of a whole new area of biologic medicine.

By 1972 the two scientists were on the faculty of the University of Texas Southwestern Medical School, in Dallas and began collaborative research on cholesterol and cholesterol-related disease.
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Brown and Goldstein began their studies to isolate the crucial mechanism of cholesterol metabolism by focusing on a striking genetic disorder, known as familial hypercholesterolemia, in which patients develop sky-high cholesterol. People with this disorder have blood cholesterol that is up to eight times greater than normal, yellow accumulations of cholesterol in the skin, and a greatly increased risk of recurrent heart attacks. The two researchers concentrated their efforts particularly on the homozygous form, in which a child receives a defective gene from both parents. The condition is very rare, occurring in one in one million people.

The key problem was why cholesterol builds up to dangerous levels in some people and not in others. Initially, Brown and Goldstein pursued the obvious hypothesis: that excessive cholesterol was being overproduced in the liver, perhaps by a deranged enzyme.

Brown and Goldstein decided to use tissue cultures of skin cells from patients suffering from inherited high cholesterol and from normal individuals. The NIH turned down their application for a grant, but fortunately they were able to tap other funds. They began their work by tagging the LDL molecules with radioactive iodine, which enabled them to trace their course after their introduction into the cell culture.

As conventional belief held that LDL flowed freely into cells to be assimilated and utilized, these investigators were stunned to find that the fat-laden molecules attached to specific receptor sites on the skin cell membranes. Only at these receptor sites on the cell membrane could the cholesterol-laden LDL gain entrance to the cell to be utilized. Furthermore, they noted an important distinction in what was going on in the cells of normal people versus the cells of people with inherited high cholesterol. The cells from the latter either completely lacked or were deficient in LDL receptors. In effect, these patients’ blood was awash in cholesterol that couldn't be absorbed by cells.
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Brown and Goldstein, barely in their thirties, had discovered a
new phenomenon, the mechanism by which a cell extracts cholesterol from the blood: cholesterol receptors.
⁶

Like a space shuttle mooring at one of several docking stations on a satellite to deliver its contents, the LDL particle attaches to certain receptor protein sites clustered in coated pits on the surface of the cell membrane. And then a most remarkable series of events follows. The pit pinches off, and all are drawn into the cell. Inside the cell contents, the cholesterol is extracted, the protein of the lipoprotein complex is digested into its constituent amino acids, and the receptor itself is recycled back to the cell membrane. The cholesterol can be used in manufacturing cell membrane or other products. In the liver, excess cholesterol is excreted in the bile into the intestinal tract. In the other cells, it passes back into the bloodstream, where it is prevented from building up in the arteries by being transported by HDL to the liver, which leads to its removal from the body. For this reason, HDL is referred to as “good cholesterol.”

The significance of the process was evident: if the regulatory mechanism of the receptors could be explained, drugs might be designed to influence that mechanism and rid the body of excess cholesterol before it clogged arteries. Of this insight, Goldstein recalled, “It was the most exciting moment of my life.”

They promptly uncovered that the LDL receptors in the cultured cells are controlled by a discrete feedback mechanism as a foreman controls inventory in a busy factory. The more LDL is brought to a cell, the fewer receptors are made. If a cell is given less cholesterol, more receptor sites appear.
⁷

But certain critical questions remained unsolved. How are blood cholesterol concentrations controlled? Where in the body are the functions of LDL receptors most important? How can blood cholesterol levels be lowered in patients at high risk of heart disease? The researchers were stymied at this point. All this time, they had been conducting their studies on tissue cultures of skin cells. What they needed for further progress was an animal model. Their meticulously planned basic scientific studies, a model of disease-specific research, needed a stroke of luck.

A serendipitous discovery by a veterinarian in Japan could not have been a more propitious deus ex machina in enhancing the prospect for LDL receptor research. In 1973 Yoshio Watanabe of Kobe University noticed that a rabbit in his colony had ten times the normal concentration of cholesterol in its blood. By appropriate breeding, Watanabe obtained a strain of rabbits all of which had this very high cholesterol level, and all of these animals developed a coronary heart disease that closely resembled human heart disease. The rabbits were also found to lack functional LDL receptors in their cells, as do humans with inherited high cholesterol.
⁸

The serendipitous mutation in the Watanabe rabbit “proved invaluable,” in Brown and Goldstein's words, in putting together the puzzle. They now were able to establish the mechanism by which LDL receptors in the liver control blood cholesterol levels in humans. Normally, the liver accounts for about 70 percent of the removal of LDLs from the bloodstream. Within the cell, LDL is broken down to release cholesterol, which then reduces the level of the enzyme responsible for making more cholesterol. This rate-controlling enzyme would prove to be the therapeutic target. Increased amounts of cholesterol within the cell inhibit production of more LDL receptors and thereby the influx of more LDL. Thus, this process normally balances the cell's own synthesis of cholesterol and the cholesterol it obtains from the circulating blood influenced by diet.