by Rob Dunn
The economy of Argentina began to collapse in 1998, precipitated by the breakdown of the economies of Russia and Brazil. Suddenly, the Favaloro Foundation found itself seventy-five million dollars in debt. Everything Favaloro had fought for seemed to have stalled. Favaloro was depressed. His wife, who had been at his side through everything, had recently died. Favaloro was seventy-seven years old and had seen many ways of dying. Whatever the reckoning, he wrote a letter in which he laid out what he had accomplished and what he had failed to accomplish. He noted that he was sick of “being a beggar” on behalf of his people and their broken hearts. He then picked up his gun and shot himself in his own beating, bleeding heart.
Favaloro had gone home to Argentina to give back to his people, but Gruentzig had taken a different trajectory. On the back of his successes, he lived an ever more adventurous lifestyle and had no interest in returning to Germany. In 1980, he had been given U.S. citizenship on the grounds of his being a “national treasure.” In his lifetime, more and more people had stents implanted. But Gruentzig would never need to undergo this procedure himself. On October 27, 1985, Gruentzig and his wife decided to fly from St. Simons Island to Atlanta in a rainstorm. Their plane crashed near Forsythe, Georgia. Gruentzig was just forty-six years old, and his wife, Margaret Anne Gruentzig, a medical resident, was just twenty-nine. The hearts of Gruentzig and Favaloro never faced the atherosclerosis the men fought so hard to remove.
But Bachman, the first angioplasty patient, lives on. In 2007, the coronary artery Gruentzig had worked on was checked by Bernhard Meier, the doctor who took over Bachman’s care in Switzerland after Gruentzig moved to Atlanta. The artery was slightly more occluded than it had been but not enough to warrant treatment. Bachman finally quit smoking in 2007 and has tried to reduce the stress in his life. His doctors did not recommend a stent, but Bachman insisted, and so his wish was granted. As of the writing of this book, Bachman lives, as do the techniques of Favaloro and Gruentzig.
By 1970, coronary bypass had become one of the most common surgical procedures in the world. By 1990, angioplasty12 (to be augmented by stents) had become even more common than bypass surgery. In some places, such as the United States, success would be measured purely in terms of medical success—the additional years of life someone lived, his or her health and well-being (in such places, both angioplasty and bypasses are common). However, success can also be measured by the time patients spend in the hospital and the money hospitals make. Medically, Gruentzig’s stents seemed similar to bypass surgery in terms of their success, no better, and maybe they were worse, though the benefits seem to depend to a great extent on the condition of the patient. But stents required the patients to spend far less time in the hospital and made hospitals far more money, and so they quickly became the most prescribed treatment for blocked arteries. The fingers of surgeons continued to relocate veins from legs and groins and use them to reroute blood around blocked arteries, but fewer times each year. Heart surgeries in general became less common.
While stents and bypasses both let the river of blood flow freely again, they do not change what causes the atherosclerosis in the first place. Atherosclerosis is like a busy beaver. It finds the flow, wherever it might be, and stops it. I spent much of my childhood unclogging the culverts that drained a pond at my house. A beaver clogged the culverts with feces, spit, sticks, and mud, and it was my job to clean them out so that the water might flow. But as long as that beaver was there, the culverts would clog again.
The beavers in your body never stop when you have atherosclerosis. This is a problem neither Gruentzig nor Favaloro nor any of the other great minds of their surgical generation solved. They cleared out the debris, but bypasses could clog again. About 15 percent of bypasses clog in the first year, and by ten years, 40 percent have clogged.13 Reopened arteries can clog again. These procedures were beautiful, miraculous, and mere stopgaps.
Someone would need to find and stop whatever it was that was creating the clogs in the first place.
11
War and Fungus
In 2004 Akira Endo went to his doctor. He was feeling fine but was due for his checkup. At the doctor’s office, the doctor did the ordinary tests. He drew some blood, he checked Endo’s pulse, he took notes—and then he sent him home and told him to wait. Endo was at an age when the body has a tendency to break down without notice. Endo felt well, but he might not have been.
Days later, the phone rang. It was the doctor with bad news. Endo’s cholesterol level was too high, 240 mg/dl, with an LDL of 155.1 There was also good news. Some “very good drugs,” called statins, could be used to lower cholesterol.
Endo began to laugh.
Endo’s prescription from the doctor was among the most universal of modern medicines. In the United States, one in ten adults is now taking a statin drug. One in three people over the age of sixty-five takes a statin. Some researchers have suggested that every adult should take statins, so useful are they perceived to be in preventing heart disease and strokes. Endo’s prescription was ordinary. Less ordinary was Endo’s longer relationship with these drugs and the fungi that originally produced them.
In July of 1945, when Endo was eleven, atomic bombs were dropped on Hiroshima and Nagasaki. Mushroom clouds rose above those two towns, evidence of the powers of science and of the horrors of man. The war ended, but not before it had taken hundreds of thousands of lives, along with Japan’s prosperity. Endo lived on a farm in northeast Japan, far from Hiroshima and Nagasaki but well within the reach of the war’s economic consequences. After the bombs, the country was occupied, and food grew scarce, so Endo, like many, honed his expertise in gathering, both for his family and for his community.2 Endo and his friends spent many hours picking wild mushrooms and plants from the forests near the farms; this work was sustaining, and fateful.
In Japan, as elsewhere, some mushrooms can kill. Others are so prized, so full of delicate flavor, they command thousands of dollars per pound. Endo learned about the mushrooms in order to tell the delicious from the deadly; he learned about them in order to eat. The distinctions among kinds of mushrooms can be subtle—a difference in spore color, gill formation, stem shape and size, or simply preparation—but these distinctions are important, the difference, it turns out, between sustenance, medicine, and death.
Fungi cannot move. Ever since they colonized land hundreds of millions of years ago, fungi have been at the mercy of the conditions into which they are born and so have evolved an incredible arsenal of weapons of self-defense. They can only fight; flight is not an option. As a boy, Endo did not learn the names of these chemical weapons, but he learned their consequences. Years later, he would recall a day when his grandfather went with him to gather a mushroom called, in English, fly agaric (Amanita muscaria).3 His grandfather released a handful of houseflies near a pile of these mushrooms. The flies flew toward the pile, attracted to its earthy smell. Once there, they began to eat. The flies gorged and then, one by one, died. His grandfather then took those same mushrooms and boiled and ate them. What seemed innocent could be deadly, and what was deadly could be made edible, delicious even. (Though it is worth noting that it is possible Endo’s grandfather was making a mistake. Japanese mushroom guidebooks list fly agaric as poisonous even once cooked.) These local secrets spoke to broader mysteries that attracted Endo the way the fungus calls to the fly.
Even at the age of eleven, Endo knew that he wanted more than what could be harvested from the place he was growing up. He wanted to go to high school and then college; he wanted to do something grand. Endo wanted to heal people. The more Endo persevered, the more he faced new limits of his circumstances. His grandfather was the closest thing to a doctor in his town, and yet he was incapable of curing most diseases. Many in the town got sick and, simply, died. Of what, no one could say. When Endo was in fourth grade, his grandmother developed a cancer that none of his grandfather’s local remedies could cure. Endo stood beside his grandmother’s bed and felt the lump in
her stomach, with its hard diameters. Before his grandmother died, he held his hands on her. Here was a moment when he needed magic. He had none—not yet, anyway.
Endo left his village at the age of seventeen to go to high school in the larger city of Akita. There, his interests in medicine and fungi intensified. It was more than professional interest; it was an obsession, one that led him to revisit the fly-killing mushroom. Endo wanted to know more about the poison in it. It seemed to be the boiling that took away the poison. Endo wondered if the boiling water simply washed away the poisons. It was an overly simple idea, but he was, after all, still in high school. Endo boiled some of the fly-killing mushrooms and then put the mushrooms out on one plate and the broth on another. Flies came to both, but only those flies that fed on the broth died. Clearly, the toxin was being washed away. These are the preoccupations of an unusual boy,4 and yet it was out of the germ of precisely this sort of preoccupation that his greatness fermented.
When the time came for Endo to apply to college, his parents did not want him to go. They could not afford the tuition and sent Endo’s older brother to talk him out of applying. Endo was unconvinced; he would pay his own tuition. He left the village for the Agricultural College of Tohoku University in Sendai, one of the seven Imperial Universities. Once there, he often went hungry. He would go to school late in the day to eat the food that others had left. Endo, as he would later say of himself, “always had his chopsticks ready” for the bell that would announce that the poor students such as Endo could come eat what the wealthier children had left on their plates. Sometimes, even after these extras, Endo was still “too hungry to concentrate and could not hear a lecture,” so close was he to fainting.
Upon his graduation in 1957, it would have been natural for the struggling Endo to try to work in a well-funded scientific field, one where jobs were likely, one in which struggle might be unnecessary. Had Endo listened to his parents and common economic sense, he might have chosen the well-trodden road, but Endo wanted to do something new, which, he seemed to know even from an early age, required him to choose the more difficult of each pair of options he would be given. The hard task he set for himself was to look to nature, to biodiversity’s wild pharmacy of fungi in particular, for potentially useful compounds like those that had killed the flies. Few in the world worked in this field, but as a Japanese scientist, Endo had the advantage of his childhood experience with wild species, particularly mushrooms, an experience common in rural areas and also reflected in the scientific knowledge of Japanese mushrooms.
His first job was at the Sankyo Company in Tokyo. Tokyo was an enormous city, quickly becoming among the largest and most sophisticated in the world, but it had still not yet risen from the ashes of war. There, Endo was to study the enzymes of wild fungi to see if any might break down the pectin found in fruit. Pectin from fruit-contaminated wine and ciders, making them bitter. If something could break it down, that something would be of huge value.
Thinking like an evolutionary biologist, Endo had decided to search for such a fungus on wild grapes, where he reasoned that fungi would need to evolve compounds to break down grape pectin if they were to use all of the nutrients in grapes. Within a year, he found a fungus, Pilidiella diplodiella, that worked. Sankyo quickly commercialized the active compound from the fungus. The endeavor of learning from wild nature could bear fruit! Endo had tasted the flavor of his accomplishment. But he wanted more. He knew he would look to the fungi, but he wanted to move away from food. He wanted to work in medicine and save people—not just luxury drinks—and he thought he knew a way: by curing the problem associated with high levels of cholesterol in the blood by lowering those levels.
Cholesterol is a sterol, a kind of natural steroid, in the family of testosterone and cortisol, and it is found in cell membranes and, in animals, in blood, wherein it is moved from one place to another in the body. Nearly all organisms, from bacteria to dogs, need cholesterol. It is particularly vital to brain function; each of your thoughts requires a little. Yet, although cholesterol is necessary, beginning with work in Russia in the early 1900s, studies on rabbits had begun to suggest that too much cholesterol could lead to atherosclerosis. It would take decades and many more studies before these results were taken seriously, and yet, by the time Endo was doing his work, high cholesterol was viewed as a key feature of atherosclerosis, even if not yet a well-understood one. Perhaps if cholesterol could be lowered, atherosclerosis could be prevented. Ironically, blood cholesterol levels in Japan were, at the time Endo began his work, among the lowest in the world, but Endo imagined that as Japanese lifestyles became Westernized, the Japanese would be at risk too.
While Endo was still working on fruit and searching for new and useful fungi, a key step was taken in the study of cholesterol that would set the stage for Endo’s idea to take full shape. Konrad Bloch at Harvard University worked out how the body makes cholesterol and saw that while some of the cholesterol in blood and cells comes from diet, most of it is produced by the body itself. In the liver, the enzyme HMG-CoA reductase carries out the slowest step in the thirty-step process of cholesterol production: altering HMG-CoA. This is the step every other enzyme must wait for, impatiently. Speed up that step, and more cholesterol is produced; slow it down, and less is produced. When someone eats more cholesterol, the system is naturally balanced, as the excess of cholesterol (in low-density lipoproteins, LDL) prevents HMG-CoA reductase from doing its job, and as a result, the body produces less cholesterol. Because of this balancing act, when lower levels of cholesterol are consumed, there is very little effect on the levels of cholesterol in the body; it is only when large amounts of cholesterol are consumed that the body’s ability to regulate cholesterol levels in the blood becomes overwhelmed.
Individuals vary greatly in the levels of cholesterol their bodies try to maintain, and much of this variation is purely genetic. In those who suffer from the genetic disorder familial hypercholesterolemia, cholesterol levels tend to reach about 800 mg/dl if an individual has two copies (one from each parent) of the high-cholesterol gene variant; 300 to 400 mg/dl if he or she has just one. These high cholesterol levels are due to the relatively weak regulation of HMG-CoA reductase; the enzyme acts largely unchecked. Individuals with this kind of hypercholesterolemia are treated as diseased, but they really represent one extreme of the general phenomenon whereby individuals vary in their cholesterol levels (independent of diet) due to the versions of genes they’ve inherited from their parents. Endo did not understand the relative influences of diet and lifestyle on cholesterol yet, but he knew enough to realize that even once such influences were understood, the ability to chemically alter cholesterol levels in the body would be useful, lifesaving even.
Upon reading about Bloch’s work, Endo immediately wrote a letter to him. He proposed to Bloch that he would discover a drug that lowered cholesterol, and he described the details of his plan. Since his childhood, Endo had imagined working in the United States, where his boyhood idol, the Japanese scientist Hideyo Noguchi, did his great work discovering and documenting the syphilis bacterium, Treponema pallidum. But Bloch—who had just won the Nobel Prize—did not answer Endo. He was a busy guy. One suspects that Endo was not the only promising young scientist who’d sent a letter. Instead, Endo went to Albert Einstein College of Medicine in New York City to work with Professor Bernard Horecker. There, Endo studied lipopolysaccharides in the cell walls of bacteria for two years before returning to Japan to work, once again, at the Sankyo Institute. The research in New York was not what Endo dreamed of; it taught him new skills he needed, but he felt as though he was biding his time, waiting to figure out how to lower cholesterol using fungi. If anything, the time in the United States, where so many people seemed to be dying of the consequences of high cholesterol, emboldened him. So he returned to Sankyo, eager to get started, but there were roadblocks. It took him three years to convince his supervisors that the idea he had for a big project on cholesterol, the same one he had ori
ginally written Bloch about those years before, was worthwhile.5
Most of the research that built on Bloch’s discoveries focused on understanding the fate of cholesterol in the body or on the contribution of diet to cholesterol. But while diet and lifestyle were important, genes (and culture) seemed, at least to Endo, to be more important. If this was right, cholesterol levels might be lowered with reasonable diets and changes in lifestyle. But for those individuals who had a greater risk of high cholesterol and heart attacks in the first place, it required something more: a rebalancing of the equilibrium level of cholesterol. This is just what Endo wanted to do.
The need for more than just diet and exercise to deal with high cholesterol is widely discussed now, but it was relatively ignored for many years. In focusing on pharmaceutical approaches to controlling cholesterol, Endo again chose an unusual direction. He wanted to do something radical; just as with the pectin problem, he would take an evolutionary perspective. He made several intellectual jumps that no one else would make for years, and, at least in his retelling, he made these jumps more than five years before he could implement his ideas.
He decided to focus on slowing the production of cholesterol by the liver. To do so, he would search for some natural compound that would stop the key enzyme, HMG-CoA reductase. Endo’s theory for how to do this was inspired by his childhood forays among the fungi and the work of Alexander Fleming, whom he read about in college. Alexander Fleming was both a scientist and an artist of sorts. He dabbled and he poked. One of the things at which Fleming dabbled was bacterial art. He would paint on bacterial culture plates with different strains of bacteria in such a way that they would grow at precisely the right rate (and produce the right color) so as to make, for a moment, an image—be it a baby, a policeman, or something else. In order to produce this art, Fleming needed a precise understanding of the growth rates, growth forms, and colors of different bacterial strains. This meant that Fleming was always on the lookout for unusual bacteria. One way to find them was to leave plates out to grow longer than he should. One time, in 1928, when he did just this, some microbes grew on his plates in a circle, and around that circle, there was a halo of, for lack of a better term, death. Within that halo, nothing seemed to be growing. The microbe in the middle was the fungus that produces penicillin, a species of Penicillium. The ring around it was the ring of antibiotics it produced to kill off the Staphylococcus bacteria with which it competed for food. Penicillium kill by releasing compounds (beta-lactams) that prevent bacteria from producing peptidoglycan, the mortar in their cellular walls.
