by Rob Dunn
As is the case with most medical discoveries of novel compounds, no one ever went back to consider just what cyclosporine does in the natural world. Why does a fungus produce such a potent immunosuppressant? Recently, a clue has emerged, thanks to a group of undergraduate students and two fungus biologists (mycologists).
The discovery began when the mycologist Kathie Hodge, a professor at Cornell University, decided to look at two specimens of fungus collected by students who’d taken a fungus course taught by Cornell professor Richard Korf in the fall of 1994 at Michigan Hollow State Forest in Danby, New York. The specimens were small, each composed of white-tipped stalks of fungus crowned by yellow fungal “fruits” (perithecia). The stalks flowered out of the white tumescent bodies of scarab beetle larvae. The beetle larvae looked as though they had been living in piles of shit, a common place for many beetles.25 Kathie Hodge decided to try to identify these unusual fungi.
Hodge is a preeminent expert on fungus, and to her, the fungus looked weird. It was the sexual phase of the fungus, she knew that much. But when it came to identifying it, she had trouble. It looked to be a representative of a group of fungi, Cordyceps, known for altering the behavior of insects. When everything goes right for them, Cordyceps fungi land on an insect’s body. They then grow through the exoskeleton into the body cavity and up into the head, where they alter the insect’s behavior and cause it, in some cases, to climb up into the branches of trees. So elevated, the fungus grows out of the insect head, produces a reproductive structure, and waits to be dispersed through the air. Such fungi are common and diverse. They differ in their particulars and yet share the ability to flower out of the bodies of living insects. In some forests, if one looks carefully, whole colonies of ants can be seen with their mandibles dug into leaves and stems, fungi growing tall out of their heads. To Hodge, the fungi in the beetles looked to be a Cordyceps, but which one?
Hodge cultured the dry samples, and when she did, they looked like another sort of fungus with which she was familiar—a kind that had never before been linked to Cordyceps. It looked like the fungus from which cyclosporine was isolated. It was. Cyclosporine had, it turns out, been isolated from the asexual stage of the same fungus Hodge found in the beetles, and as is often the case with fungi, the asexual stage and the sexual stage look so different (much as we look different from our sperm and eggs) that each had been given its own species name. Hodge realized the two species were just the sexual and asexual stages of the fungus Cordyceps subsessilis (it was later renamed Eucordyceps subsessilis).26 Suddenly, the Norwegian fungus had a more complicated story. It lived in New York too, and it lived in beetles. It seems possible that cyclosporine is produced by the fungus in order to get past the immune systems of beetles and take over their bodies, much in the way that a transplanted heart needs to get beyond the immune system of the recipient. The real innovation for suppressing the immune system had come from evolution’s innovation, just as with the use of penicillin to fight bacterial infection.
It was thanks in part to the ancient story of the beetles and fungus that heart transplants eventually became an honest form of medicine. Annual sales of cyclosporine are now in the billions of dollars. More important, heart transplants now number in the thousands. In 2012, more than thirty-five hundred heart transplants were performed. Eighty percent of heart-transplant recipients now live more than a year, 77 percent more than three years, and 70 percent more than five years. One man, Tony Huesman, lived for thirty-one years with a donated heart—eleven thousand days of extra life: eleven thousand breakfasts, eleven thousand nights of sleep, eleven thousand mornings. Heart transplants are as routine as a procedure that requires one person to die so that another may live can be. Though just how many are performed seems to depend as much on culture as on medicine or science. Two-thirds of all heart transplants in the world are done in the United States, where much of heart-transplant research was pioneered and where both court and cultural cases favor brain death as the end of life. This is true even though fewer than one in twenty of the roughly one million people who need heart transplants live in the United States.
The trajectory of heart transplants. The first surgeons to perform heart transplants hoped they would one day be routine, but this routineness was delayed by the wait for immunosuppressive drugs and then later, until the present day, by the limited supply of living human hearts. Inset image shows the beetle larvae in which the fungus that produces cyclosporine grows. (Courtesy of Kathie Hodge)
For those who get heart transplants, the surgery is a miracle. For this, there are many to thank, including Hardy and Barnard, and especially Shumway and Lower. But if one looks at the big picture of lives lost and saved and money spent (the average heart transplant costs a million dollars), success seems more complicated to define. At any moment, tens of thousands of people’s lives could be extended through heart transplants. Thousands more would be saved if more people donated their organs, but there will always be too few hearts, tens of thousands or even hundreds of thousands too few. Early on in the race for heart transplants, it became obvious an additional solution was necessary. Maybe it would be better to build directly on the mechanical innovations of Gibbon and, later, Greatbatch; maybe one could build a new heart from scratch.
8
Atomic Cows
Man is no more than electrified clay.
—PERCY BYSSHE SHELLEY
Michael DeBakey was a pioneer in open-heart surgery, a demanding genius of ingenuity, a perfectionist, a man who believed there would be time for sleeping in death. He wanted each of his waking hours to be spent intensely, achieving. He demanded no less of those around him. By the time DeBakey died, in 2008, he had conducted, by his own count, more than a hundred and sixty thousand heart surgeries, many of them the first of their kind. He was neither polished nor handsome. What marked him was his ferocious intent to revolutionize whatever lay before him, and also whatever was to the side.
Much of what DeBakey did pointed him squarely in one direction: the building of an artificial heart, a machine of a thing that might tick for years or even forever inside the body of every person suffering from any of the heart’s myriad diseases. When he thought about artificial hearts, he did not think of them as scientific novelties. To him, as to many other surgeons, they were the future, the secret to the longevity of millions, maybe billions, of women and men. His was a hopeful, bionic vision of our future, one in which the problems of the heart might be solved through technology and time.
DeBakey had been part of the race to transplant hearts. He and his onetime collaborator and eventual archrival Denton Cooley1 vied with each other for the fourth and fifth heart transplants, respectively; these two men would go on to vie for much in life. Cooley was the handsome, smooth, well-coiffed, and cheery Texan to DeBakey’s, well, opposite. But DeBakey did not want to replace hearts with other hearts; he wanted to replace hearts with artificial hearts, little machines elaborately constructed by surgeon-tinkerers the way that a clock maker might build clocks, clocks out of which entire human lives, rather than cuckoos, emerge. DeBakey became, in addition to one of the world’s leading surgeons, the man in the machine shop pounding out the metal, welding the bits, fabricating a version of what nature had spent millions of years carving out of cells. More accurately, he was the man who hired whole teams of men to work in the machine shop. He also solicited the donations to build the machine shop.
The idea of replacing a broken part of the human body with an artificial one is ancient. In one fifteenth-century Egyptian tomb, close inspection of a man’s foot revealed an artificial big toe made of leather and wood. Rig Veda, an Indian text written somewhere between 3500 and 1800 BC, speaks of the warrior queen Vishpala who lost her leg in war and had it replaced with an iron prosthesis good enough to be worn into battle. The Greeks built iron hands, wooden legs, and much more.2 In ancient Rome, Galen is said to have produced an artificial eye. But the heart is, of course, different. It is one thing to replace a toe,
quite another to do the same for a beating muscle, a muscle responsive to the body’s temperature, activity, and emotional state.
Some surgeons focused on artificial hearts that were, in essence, extensions of the heart-lung machine, large external devices intended as stopgaps. But DeBakey imagined something different. He wanted to build a small artificial heart that could be placed inside the body and would last for decades, even centuries. Others had dreamed similar dreams in the past. In 1937, Vladimir Petrovich Demikhov invented a device that, when squeezed, could replicate the ventricles of a dog’s heart. The device was, by the accounts of those who saw it, amazing, and yet neither a practical solution nor a well-documented one.
When DeBakey began to dream of an artificial heart, between seventeen thousand and fifty thousand patients a year could reasonably be considered recipients;3 that was a big market, an army of humans who might live years or even decades rather than months. But DeBakey needed more money. The whole field needed more money. DeBakey visited with his famous patients and asked for cash, but he also went to Congress, where he and other scientists pleaded for the development and funding of a federal program to produce an artificial heart. As Joshua Lederberg, a Nobel Prize–winning professor of genetics at Stanford University, put it, an artificial heart was a system “about as complicated as a guided missile or a subsonic bomber,” both of which had already been built. The next year Congress responded by forming the Artificial Heart Program within the National Heart Institute (itself within the National Institutes of Health), the first targeted research program in the institute.4 The program was viewed as so important that it was given a direct line to Capitol Hill. In 1965, the National Heart Institute asked six contractors to come up with plans for an artificial heart.
Even very early on, DeBakey understood the problem with mechanical hearts would be energy, just as it had been for pacemakers. A real heart is fed by food. Food fuels mitochondria. Mitochondria produce energy, constantly, to stoke the heart’s contracting cells. Technology had no equivalent, at least none that might last the years one would hope for in an artificial heart. The only options anyone could think of were hearts that plugged into electrical sockets (which was not the sort of grand future people envisioned) and ones that ran on batteries. Batteries seemed the better of the two options, but, given the technology of the time, they wouldn’t last long. Even Greatbatch’s lithium batteries would be short-lived when asked to run an entire mechanical heart (rather than just signaling a real heart to beat). Surgery after surgery would need to be performed to replace the batteries and restore power to the heart. Then came an idea of the times that seemed to solve everything: nuclear power. A nuclear-powered heart might run forever, or at least forever relative to the longevity of the body’s other parts.
Nuclear hearts were first proposed by one of the companies the National Heart Institute contracted to come up with ideas, the Thermo Electron Corporation (now Thermo Fisher Scientific). DeBakey almost immediately felt nuclear hearts were the answer, as did the National Heart Institute and the Atomic Energy Commission. But no one thought the people at Thermo were the right ones to make such hearts. They lacked an understanding, it was said, of the challenges ahead.
Glenn Seaborg was in charge of the Atomic Energy Commission at the time. He was not a physician. He was a physicist, arguably among the greatest of his generation. For much of his career, he sought to find new elements in the universe, and he succeeded. In a series of breakthroughs made possible by technology, perseverance, brilliance, and luck, he and his colleagues had extended the periodic table, adding eight new elements. With each discovery, man’s understanding of the materials of which the universe is composed expanded. The elements Seaborg’s team discovered included one that justifiably bore his name, Seaborgium. It also included element 94, plutonium. In 1940, Seaborg realized that one particular isotope of plutonium (plutonium 239) produced an astonishing amount of energy when hit by a neutron, enough to make an atomic bomb. Soon, Seaborg was recruited to the Manhattan Project, where he helped figure out how to produce more plutonium, a lot more.5
The bomb dropped on Nagasaki, Japan, several years later was a plutonium bomb, a bomb inspired by Seaborg’s science. With the energy from plutonium atoms, it killed roughly seventy thousand people and wounded more than a hundred thousand. With this bomb, the war ended in Japan. Seaborg returned to the University of California at Berkeley to live a scholarly life, but he was soon called by President John F. Kennedy to direct the Atomic Energy Commission. He was being asked once more to work on plutonium. The Atomic Energy Commission sought to find as many peacetime uses as possible for nuclear energy, and that included the development of a nuclear heart.
Working with the NHI, Seaborg helped figure out how an atomic heart might best be built and by whom. The best approach, Seaborg thought, was to contract with many groups and see which one proved itself outstanding. Six companies were funded to design their own versions of atomic hearts. Using the best design, the United States would build an atomic heart that would allow people to walk around for years, their every action fueled by the decay of plutonium. Never one to shrink from grand possibilities, DeBakey, who worked constantly behind the scenes during the whole process, persuaded the Soviet government to become involved. That he did so at the height of the Cold War was viewed (at least by DeBakey) as a “supreme act of peace.”
Congress suggested Seaborg’s Atomic Energy Commission and the Artificial Heart Program together should choose which group would be contracted to build the final working model. The members of the Atomic Energy Commission, with Seaborg at the helm, were supportive, imagining a world in which plutonium had many central uses. The Artificial Heart Program was supportive because this seemed like a way forward to DeBakey’s dream of an artificial heart. The two groups agreed to the goal of mass-producing artificial hearts in just five years, by 1970. Together, the Atomic Energy Commission and the Artificial Heart Program were funded to the tune of more than $50 million in 2013 dollars (a relatively great sum, though just one-sixth of what was estimated to be needed).6 Atomic artificial hearts, it seemed clear, would be a reality in the near future.
The first challenge was that, while hearts are complex but predictable, humans, scientists in particular, can be complex and unpredictable. In theory, Seaborg’s group (which knew atoms) and the Artificial Heart Program (which knew hearts) were two parts of a perfectly complementary team. In practice, the two groups worked together only fleetingly before turning the quest to cooperatively make an artificial heart into a kind of passive-aggressive war.7 The animosity began with disagreement about the order in which the different pieces of the atomic heart should be built.
Choosing the steps necessary to build an artificial heart and their order posed a thicket of challenges. One was how to install the heart in the first place. It had to match up with arteries and veins. It also had to resist decay of any kind, as well as rejection by the body’s immune system. This was something that DeBakey, working with his team in Texas, had already begun to focus on. The heart also had to move blood and do so with great force. Then there was the issue of power, the issue the plutonium would solve. The Atomic Energy Commission thought all of these problems should be worked on simultaneously with collaboration between the AEC and the NHI. The NHI disagreed, strongly. It wanted to work first on the heart pump (ignoring how it might be powered) and second on the atomic power source. This and other conflicts could not be resolved, and so the AEC and NHI worked separately toward atomic hearts. The NHI contracted five companies to work on the nonatomic elements of an atomic heart. The AEC sought to develop everything at once and eventually hired Westinghouse Electric to do so.
When plutonium decays, the decay releases energy. With plutonium 239, this is an awful lot of energy, but with the lighter isotope plutonium 238, what is released is more manageable. A pill-size amount of plutonium 238—fifty-three grams—might provide energy sufficient to run a heart for decades, but a plutonium heart would requir
e the invention of a wholly new kind of pump, one very different from the native squeeze box of the heart. In such a pump, nuclear energy had to be converted into mechanical energy, which then would be used to power a pump. Seaborg was ready for such a possibility. He had calculated that hundreds of kilograms of plutonium 238 could be produced each year by the Atomic Energy Commission (by thermal irradiation of neptunium) if, or when, it became necessary.8 Once the atomic heart was built, Seaborg was sure it could be supplied with energy; he was sure it would soon save many lives.
