Open Heart Page 32

  In their 1994 book, Why We Get Sick: The New Science of Darwinian Medicine, Randolph M. Nesse and George C. Williams (in a chapter titled “Aging as the Fountain of Youth”) write that “the whole immune system is age biased [because] it releases damaging chemicals that protect us from infection, but these same chemicals inevitably damage tissues and may ultimately lead to senescence and cancer.”*

  Eight years later, on January 22, 2002, the New York Times headlines a feature article about inflammation and disease (“Body’s Defender Goes on the Attack”) with a similar statement: “Inflammation, a normal response of the body to infection or disease, can also cause problems.* Scientists now consider that inflammation may have a major role in many chronic diseases not previously associated with it.” Inflammation, the body’s “fundamental way of protecting itself,” the Times notes,

  can harm the very tissues it is meant to heal [and] its destructive side has long been evident in diseases such as rheumatoid arthritis, which cripples the joints, and multiple sclerosis, in which it destroys the insulation surrounding nerve endings.

  But now scientists are coming to realize that inflammation may underlie many other common chronic diseases that come with aging, including atherosclerosis, diabetes, Alzheimer’s disease and osteoporosis. Inflammation is also implicated in asthma, cirrhosis of the liver, some bowel disorders, psoriasis, meningitis, cystic fibrosis and even cancer.

  The article then quotes Dr. Russell Tracy, a professor of pathology and biochemistry at the University of Vermont. “It’s beginning to look as if getting old and ultimately wearing down and dying,” he says, “are tied inextricably with the defense mechanism that keeps you alive and in good repair when you’re younger.” The reason this is so “may reach far back into human history to the hunter-gatherers who lived in peril of infections and injuries,” the Times hypothesizes. “Natural selection would have favored those with a vigorous inflammatory response and few would have lived long enough to suffer the long-term consequences.”

  The Times devotes much of the rest of a lengthy article to what both cardiologists and evolutionary biologists have been paying attention to for several years: the role of inflammation in atherosclerosis.

  In an article published in Nature nearly three weeks before the Times article, a team of American, German, and English researchers reveal that a chance discovery about cellular life in mice has led them to the conclusion that the processes that inhibit the growth of cancers in our early lives, as in mice (whose cells are similar to our own), are probably responsible for hastening senescence and the aging process.*

  The discovery concerns p53, a protein present in every cell of our body (and in those of every mouse), one which, in reaction to any abnormality, especially one that endangers a cell’s DNA, forces the cell either to stop growing or to destroy itself. Extensive studies have convinced scientists that cancer occurs when the P53 system in our bodies is somehow damaged, a belief validated by the knowledge that in 50 percent of all cancers, the DNA of the P53 gene is itself directly damaged and rendered useless; and in tumors where the P53 gene is not damaged, it appears that nearby components in its network are somehow made dysfunctional, thereby inactivating P53 indirectly.

  In the course of studying P53, one of the researchers, Dr. Lawrence A. Donehower of the Baylor College of Medicine in Houston, engineered a strain of mice that lacked a working gene for P53. As expected, the mice without p53 died of cancer at an early age. Next, Dr. Donehower attempted to create a strain of mice in which the P53 had only a single inactivating change, one commonly found in human cancers.

  The experiment did not go as planned, however, and Dr. Donehower and his colleagues were disappointed. “We made the mice and kind of forgot about them for a year,” he says. He expected that the mice would, like those without any P53, develop cancer early. They did. “But first we noticed they were not just getting cancer when they should have gotten it,” he reports. “We also noted that they looked kind of decrepit; they just looked like old mice.”

  What seems to have happened is that Dr. Donehower’s team had inadvertently created mice that possessed unusually large amounts of p53, and that at the same time that the P53 protein was vigorously suppressing various cancers, including lymphomas, osteosarcomas, soft tissue sarcomas, and carcinomas, it was also aging the mice at a rapid pace—they lost weight and muscle, developed osteoporosis, hunched backs, and brittle bones, had generalized organ atrophy, diminished stress tolerance, sparser hair, and thinner skin, healed poorly from wounds, and died much sooner than mice with normal amounts of P53.

  Although it is possible the mice suffered from some subtle pathology that resembles the aging process but is different from it, biologists such as Dr. Scott Lowe, of the Cold Spring Harbor Laboratory, are persuaded that the Baylor experiments “raise the shocking possibility that aging may be a side effect of the natural safeguards that protect us from cancer.”

  Like the blood and tissues of mice, our blood and tissues—our skin, the linings of our stomach and our other internal organs—suffer continual wear and tear, and are continually being repaired by new cells generated by a group of special cells known as stem cells. While we are young, stem cells are highly productive, and the fact that the P53 mechanism may be destroying lots of cells has little apparent effect on our early development. As we grow older and our stem cells become less prolific, however, more stem cells are forced to self-destruct, and our tissues weaken and stop functioning properly. “The mice [with the excess of P53] eventually reach a point in which the proliferative capacity of stem cells is so reduced,” the study reports, “that sufficient numbers of mature cells cannot be provided to maintain organ homeostasis. The resulting phenotypes may include reductions in organ mass, function and tolerance for stress.”

  “The data presented here support a role for P53 in the regulating of aging and longevity in mice,” the researchers conclude. “The association of early aging and tumor resistance in [these] mice is also consistent with the idea that senescence is a mechanism of tumor suppression. We propose that an aging-related reduction in stem cell proliferation may have a more important role in longevity than previously recognized.”

  What the study suggests, then, is that the process that connects childhood survival to aging with respect to inflammation has a parallel in a process that connects early survival from cancer to processes that cause our body’s tissues to break down, deterioriate, and die.

  “With the current study we realize the double-edged sword of P53,” Dr. Lowe comments.* “Without it we’d probably all die of cancer before the age of thirty, which is what happens to Li-Fraumeni patients [a syndrome wherein patients have a defective P53 gene]. With it, only one in three of us gets cancer late in life.”

  But why does only one in three of us get cancer? And why is it that two out of the two hundred mice with the extra p53 neither got cancer nor grew old prematurely? What enabled these two mice to avoid the cancer-or-aging syndrome—and will the same process that occurs in mice occur in us? Are the mice truly aging, or are they being affected by some pathology that mimics aging—and are there ways of cheating the p53 system genetically somehow by, say, creating a molecular pathway around it that will encourage its cancer-inhibiting qualities while simultaneously inhibiting its tissue-destroying qualities? Is the p53 mechanism merely modulating some more complex and as yet unknown mechanism implicated in the relation between metabolism and aging—and is it possible that the discovery of such a mechanism will enable us to understand more fully why it is, for example, that a mouse lives, on average, for three years, and an elephant for seventy?

  And: Will the discovery of such a mechanism, should it exist, help explain why it is that though we have been able to increase our own average life expectancy considerably during this past century, the average life span of a human being remains fixed and finite?

  Nesse and Williams explain: “During the past few hundred years, the average length of life (life expectancy) in m
odern societies has steadily increased, but the maximum duration of life (life span) has not.* Centuries ago a few people may have lived to 115; today this maximum remains about the same. All the wonders of medicine, all the advances in public health have not demonstrably increased the maximum duration of life. “If aging is a disease,” they conclude, “it seems to be incurable.”

  One way scientists who study the multitude of factors that contribute to the aging process have of understanding what happens, especially as it involves ways our DNA is damaged over time, is to note that the amount of maintenance and repair of our body tissues and DNA seems always to be less than what is required for indefinite survival.* Researchers estimate, for example, that in the United States and Europe the complete elimination of mortality before the age of fifty, which now accounts for about 12 percent of all deaths, would result in an increase of only three and a half years to life expectancy.

  There seem, then, to be inherent limits to how long we will, on average, be able to live, no matter the wondrous technologies we create to save and prolong our lives. That recent discoveries strongly suggest this is so with particular regard to the two major killers of our time, cancer and heart disease, is sobering news to anyone obsessed with what Phil calls “the Ponce de León thing.” Just as heart disease may be the necessary price we pay for suppressing inflammation and infectious disease when we are young, that is, so the aging of our cells—the source of our mortality—may be the price we pay for suppressing cancer in our early years.

  What impresses, too, when we consider the implications of studies suggesting such intimate connections between disease and our immune system—between survival and mortality—is that the more we learn about how and why we survive, and how and why we age and die—how what saves us at one point in our lives may do us in at another—the more natural and inevitable these processes seem, and the more our ignorance of nature becomes palpable.

  Although we may, in what many consider the major scientific enterprise of our time, succeed in fully decoding the human genome and so map our genetic endowment in comprehensive detail, our immense genetic diversity, along with our evolutionary history, suggests that the more we discover, the more abundant and complex will be the new questions arising from our discoveries.

  But how can this not be, given the complexity of any individual human being? Our genes, for example, exist in pairs, one gene coming from each parent, and the mathematical implications of this, as David Weatherall demonstrates, are staggering. “Genes that reside at the same place, or locus, on a pair of chromosomes are called alleles,” he writes.* “If the genes at these positions are identical we are said to be homozygous, whereas if one of these genes differs from the other we are called heterozygotes. It turns out that on the average we are heterozygous at about 6.7 percent of our gene loci. At first this does not sound like much genetic variability. However, since we have up to 100,000 genes, it follows that 6700 of them have different alleles. That means there are 26700, or in base ten arithmetic about 102000 potential new combinations of genetic material that we can pass on to our children. This figure is so large that it is impossible to comprehend.”

  When it comes to the extraordinary medical procedure that saved my life—coronary bypass surgery—once again it turns out that the technology has been made possible in large part by innovations and discoveries that were not initially directed toward solving cardiological problems, much less toward enabling open-heart surgery.

  In his study of the scientific origins of modern cardiology, Weatherall details the ways modern cardiology is, in fact, “a highly technical field that relies on the fruits of work in many disciplines, among them electrophysiology, physics, immunology, and pharmacology.”* When researchers tried to determine how much of the research that has produced benefits in cardiology was “basic,” Weatherall informs us—that is, not directed at a particular clinical question—and how much of it “set out with the express objective of tackling a medical problem,” they “found that only 60 percent of the seminal work in modern cardiology was clinically directed and that the remainder was in the basic sciences and had not been carried out with any particular end in view.”

  There would be no coronary bypass surgery (or coronary transplant surgery), for example, without the heart-lung machine—our ability to shut down the heart and continue to oxygenate the body’s circulatory system so as to keep us alive during the hours needed for surgeons to repair (or transplant) our hearts. And here, again, the story of how the heart-lung machine came into being, like that of the discovery of penicillin, is wonderful in the ways it is informed by the chance turns of experience—by what we ordinarily call timing (as in “timing is everything”)—and by the vagaries and quirks of individual human character.

  John Gibbon, the man most responsible for the development of the heart-lung machine, did not, like my friends, start out intending to become a doctor.* Raised in an atmosphere of privilege—French governess, private schools, Princeton education, country properties, European tours—he wanted to become a poet or painter, but enrolled in medical school to appease his father, who was himself a professor of surgery (the second American to try to suture a wound in the heart). Gibbon’s grandfather, great-grandfather, and great-great-grandfather had also been physicians.

  Like Rich, Gibbon was bored by the first two years of medical school. He decided to quit, and told his father he would be doing so. Like Rich, however, he finished medical school, and accepted a two-year internship at Pennsylvania Hospital, during which time he assisted in carrying out a hypertension study. This exposure to research excited his imagination, and he next went to Massachusetts General Hospital to continue his studies under the direction of Dr. Edward D. Churchill. It was here that he was assigned to a team that was caring for a woman on the verge of death. As with Rich, what happened next—or rather, in Gibbon’s circumstance, what did not happen—changed his life, as well as the course of cardiac care.

  The woman had had a gall bladder operation and was recovering well until, two weeks after surgery, she developed a pulmonary embolism—a blood clot in her lungs. On October 3, 1930, Gibbon sat by the woman’s bedside for seventeen straight hours, checking her pulse rate and monitoring her blood pressure at fifteen-minute intervals. After seventeen hours, the woman lapsed into unconsciousness, and her pulse and breathing stopped. Gibbon called in his mentor, Dr. Edward D. Churchill, who attempted to save the woman’s life by surgically removing the clot and closing the artery, which operation he performed in the incredibly swift time of six and a half minutes. Gibbon’s mentor, alas, was not as successful as Rich’s mentor would be three decades later. Deprived of blood for more than six minutes, the woman’s brain died, and then she died too.

  The experience so disturbed Gibbon, he later wrote, that while “helplessly watching the patient struggle for life as her blood became darker and her veins more distended,” he began considering the possibility that lives such as this woman’s could be saved by a machine that would “do part of the work of the patient’s heart and lungs outside the body.”

  After completing his fellowship in Boston, Gibbon returned to the University of Pennsylvania Hospital, where for the next three and a half years he operated in the mornings and worked on a heartlung machine in the afternoons—and at home, at night, and on weekends.

  He assembled his first heart-lung machine—the prototype for the one we use now—from a secondhand air pump he bought for a few dollars, and from one-way valves he produced by cutting flaps on the sides of rubber stoppers with a razor blade and inserting glass tubes through their centers, after which he fitted these stoppers into slightly larger tubes. He worked assiduously and obsessively, and he persisted in this work for thirty-three years.

  In 1970, he described some of what he had done in order to bring into existence a machine that has, in the last four decades, enabled several million people to survive previously inoperable, intractable, and often fatal conditions.

  “My wife and
I carried out…slightly bizarre experiments on ourselves and our friends,” he wrote. “We were particularly anxious to learn how slight a shift in body temperature would cause vasoconstriction or vasodilation of the extremities. We got a very sensitive mercury thermometer about three feet long, which would measure temperatures to a hundredth of a degree Centigrade. The bulb of this thermometer would be stuck into my rectum or that of a friend, and the subject would then swallow a stomach tube, down which we poured as much ice-cold water as could be tolerated, measuring the effect on skin temperature of the fingers. I also once got my wife to give me an ice-cold intravenous solution for the same purpose.”

  (When I say to Rich that if more than a half century ago Gibbon and his friends had not stuck three-foot thermometers up their asses while chugging down ice-cold water, I probably wouldn’t be alive today, he nods. “You got it,” he says.)

  In 1952, after practicing open-heart surgery on dogs, Gibbon attempted for the first time to use his heart-lung machine while operating on the hearts of human beings. The results were disastrous. All his patients died, and Gibbon was so discouraged that he never again attempted open-heart surgery. Nor was Gibbon the only one who was discouraged. “Pessimism was rampant,” writes Dr. Walter Lillehai, whose experiments with cross-circulation (a procedure wherein blood is passed not through an oxygenator but through a human volunteer) became a crucial element in the eventual success of open-heart surgery, “[and] by early 1954 the surgical world had become thoroughly discouraged and disillusioned of the feasibility of open-heart surgery.”*

  Although Lillehai believed, in 1954, that “the concept of open-heart correction, however attractive, was doomed,” his success in that same year, using the technique of cross-circulation in repairing the hearts of children afflicted with Fallot’s tetralogy (a birth defect afflicting so-called blue babies, and resulting from defects in the blood vessels and walls of the heart chamber), dispelled the notion that open-heart surgery was impracticable. Encouraged by their successes with children, Lillehai and others began working to see what modifications and improvements they could make on Gibbon’s pump.