An Elegant Defense

by Matt Richtel

  With Cooper monitoring by phone from the nearby University of Minnesota, the mother’s cells were pulled from her hip with a long needle and were then injected into the ailing boy. Twelve days later, the boy developed a fever and lesions that looked like measles. The diarrhea returned. The boy died.

  For all Dr. Cooper’s brilliant work in his career, he was left defenseless and scarred by the immune-challenged boy. The boy couldn’t fight off the disease and his condition was perhaps made even worse ultimately by the introduction of the mom’s foreign cells.

  “The boy was clearly going to die without our doing something, but the idea that I pulled the trigger is a pretty awful feeling,” Dr. Cooper recalled.

  Why wasn’t it possible to just replace one immune system with another? Imagine how elegant and simple it would be to extract the T cells and B cells from a healthy and thriving person and inject them into a person whose body was failing to combat disease.

  Or for that matter, how wonderful to be able to transplant healthy skin from one person onto the diseased and gangrenous leg of, say, a felled soldier? Why aren’t our parts interchangeable?

  Saint Cosmas and Saint Damian, patron saints of transplantation. Infallible they weren’t.

  I visit the idea of transplantation here for two reasons. One is that it helps explain the challenge of interchanging our parts. The other is that it shows the interplay between the deepening scientific exploration by immunologists and the practical implications of their work. With each successive discovery, not surprisingly, came more life-saving and life-improving procedures and medicines. The two, revelation and real-life use, fed on each other as the twentieth century moved ahead, the Argonauts of the immune system journeying deeper and deeper, finding treasure and tools and putting them to use. Few examples illustrate this as well as transplantation.

  The idea of transplantation has long been a perilously seductive and deadly prospect. The reasons for its ultimate complexity tell us about an essential balancing act necessary for the survival of the species. Humans must be incredibly similar and also fundamentally diverse. The similarity is necessary to allow us to work together, communicate—share resources, ideas, food. But we must be different enough to provide diverse talents, including the innate ability to fight off different threats. Simply put, if all of our defense systems were the same, a single deadly disease could come along and wipe out the lot of us.

  This tension between sameness and individuality leads to certain trade-offs. One of them is that we cannot easily exchange our parts—say, my leg for yours or my immune system for yours. In fact, a defense system that works wonders protecting one person can be quite deadly in the life of another.

  The broader history of transplantation helped yield key clues to the extraordinary specificity of our defense networks.

  That history includes the legend of two Catholic saints, twin brothers, Saint Cosmas and Saint Damian, who were miracle workers in the third century—in their own minds. The saints reported transplanting an entire leg from one person to another—a “successful” early transplant, according to two of the world’s current transplant leaders, Dr. Clyde F. Barker at the University of Pennsylvania and Dr. James F. Markmann at the University of Massachusetts, who wrote of this miracle in a rich and wonderful history of transplantation.

  They used quotation marks around the word successful because the transplanted leg miracle was actually an abject failure. (No, these self-proclaimed miracle-working brothers didn’t successfully sew one person’s leg onto another one’s body, which maybe is why Cosmas and Damian were later made the saints of pharmacy, not saints of transplantation.)

  Over the centuries, stories abounded of successful transplants, like skin flaps used to replace missing noses. “Legends and claims of miracles,” the two transplant specialists wrote in their history. “Centuries of sloppy observation and self-deception.” It sounds carnivalesque, the stuff of hair tonic salesmen.

  The reason these attempts didn’t work has to do squarely with the immune system.

  “Transplant is the parent and sibling of immunology,” Dr. Markmann told me when we spoke about the history. Transplantation and immunology are siblings because a transplant—whether of skin or an immune system—can’t work if the body rejects the transplant as “alien.” And transplantation is also immunology’s parent because the failure of the body to accept human or animal tissue was one of the clearest, earliest signs that something in our bodies was rejecting and attacking tissues that seemed so similar. It was a clue to the power and precision of our elegant defense.

  Science experimented with all kinds of transplants without success. Human transplants of kidneys were tried and failed; dog kidney transplantation was a flop; and the ethics of the field were questioned.

  At last, though, came a scientific breakthrough, thanks to a zoologist.

  Peter Medawar—eventually Sir Peter Medawar—was a zoologist from Oxford who had been called upon during World War II to help a plastic surgeon treat burn victims. Sir Medawar tried in vain to graft skin from donors onto the charred victims of shelling and bombing. The results were cruel. Even the failed grafts looked for several days or weeks like they were succeeding. That’s because skin doesn’t have as many blood vessels and as much blood flow as, say, kidneys or other internal organs. It would take time for the immune system cells, carried in the blood, to assess and reject the skin.

  “The skin would sit there and look pretty good,” Dr. Markmann said; the soldier and Dr. Medawar would feel cautiously optimistic. “Then the graft would turn sour. It looked so nice and happy, and it would ultimately always fail.”

  Many of these battlefield and deathbed stories would lead me to realize a hard reality about science and scientists, especially immunologists. Often, great discoveries have been made on the cusp of death through experimentation on a patient. The patient would be complicit, usually agreeing to take a chance at living through a Hail Mary. Revelation had the deeply perverse quality of being born of desperation, not just from science’s grand yearning to save lives, but from the excruciating intrapersonal despair that allows a human to become a guinea pig. Experiment on me so that I don’t die. This would eventually become clear to me as I watched Jason on the precipice of death, putting himself in the hands of a well-meaning, informed oncologist who was half blinded by science’s limitations.

  After World War II, Dr. Medawar continued his transplant work—on rabbits and humans alike. He tried performing skin grafts between siblings. Presumably, immune systems would be less likely to reject tissue with related genetics, like that of siblings. Would you believe, though, it sometimes made matters worse? Take the example of a woman burned in a gas stove incident who was brought to a clinic and given a skin graft from a sibling. After a few weeks, the graft was rejected. In some cases, a second sibling graft was tried, yielding a surprise: rejection happened faster, from, say, two weeks down to a week.

  In other words, the immune system was more deliberate the first time around in rejecting a sibling’s tissue, but once the skin was determined to be “alien,” the rejection came more quickly. This underscored the ability of the immune system to learn; the first time the elegant defense took a while to assess the skin as foreign and build the machinery to reject it, but the second time, with the machinery in place, judgment was fast and merciless.

  Eventually, Medawar turned his attention to working on transplantation in cows. Unknown to him, across the Atlantic Ocean, a key contribution to transplant science was being made in the 1950s, also in cows—specifically thanks to the story of one very lusty Hereford bull. The bull lived in Wisconsin, where, feeling its oats, it escaped its confines and mated with a cow that had already been impregnated by a Guernsey bull. The cow in turn had fraternal twins, each from a different father.

  There was an oddity about these calves. Despite having different dads, they had profound similarities in their blood. In fact, each actually carried blood from the other’s father. It appeared
that when the calves were in utero, they had shared cell types in an unexpected way.

  All this came to the attention of an immunology pioneer at the University of Wisconsin named Ray Owen, who asked why the in utero calves would accept the foreign blood of a different father rather than reject it. After all, this stepfather’s blood was presumably being treated as foreign to the gestating calf. Owen floated the idea that the result of these mysterious cow couplings held some key to successful transplant and tolerance by the immune system.

  Back across the Atlantic, Dr. Medawar and other scientists were making similar strides working with twin cows. They discovered that skin transplants could be made with high rates of success among twins, both fraternal and identical. What was becoming clear was that a mixture of the blood at the very early stages of life—even if the mixing involved different genetic subsets of fraternal twins and with a sibling from another father—set the stage for the way the immune system selected for alien and self. “The new science of immune tolerance was born,” wrote a geneticist in a 1996 paper published by the Genetics Society of America.

  Soon Dr. Medawar would go on to work in other species, eventually performing the first successful kidney transplant. (Dr. Medawar, tired of and always uncomfortable working with large animals, is reported to have said, “Thank God we’ve left those cows behind.”)

  In the Festival of Life, organ failure is, while not commonplace, hardly unusual. Livers, hearts, kidneys, and other organs succumb to disease, overuse, and injury from behaviors like drinking alcohol and smoking, to say nothing of the inevitable wear and tear of aging. So obviously it would highly limit the lifesaving possibilities if the only viable transplants came from twins. Fortunately, we’ve moved well beyond that.

  The ultimate success of transplantation owes as much to the early experimentation of sew-and-error as it does to the discovery of drugs and the use of other tactics that suppress the immune system. The essential idea, if it’s not already obvious, is to lessen the reactivity of the body’s defenders so they do not attack the transplanted organ as foreign. This broadens the possible transplant matches.

  Early attempts to dampen the immune system were made using radiation, but this failed (meaning that patients died) and a second wave of immunosuppression in transplants was tried using steroids. (Steroids are a class of drugs that is extremely important in the conversation about our elegant defenses and efforts to keep them in balance. I will elaborate later on the mechanics of steroids and their significance in the stories of Linda and Merredith, the women who embody autoimmunity in this book. One particular drug, cyclosporine, changed the game. The drug, approved for use in 1983, interrupts the ability of the T cell to receive an attack signal.)

  The use of immunosuppressive drugs is decidedly a mixed blessing, as you might imagine. If you took this drug and contracted an infection, you would risk a muted response and serious illness. On the other hand, if you needed a new kidney to survive at all, this drug—in combination with other treatments or now more advanced treatments—would stop your T cells from full-fledged attack.

  Holy cow, the human lives saved. In 2017, in the United States, there were nearly 35,000 transplants of lungs, hearts, kidneys, intestines, and other organs, according to the United Network for Organ Sharing, and by no means were the transplants done between identical twins, let alone siblings. The best possible matches are made on a number of bases, including blood type and the similarity of antigens. Even after a successful transplant, though, the recipient can need a lifelong regimen of immunosuppression.

  There is another type of transplant too, one that would ultimately help save Jason’s life. It is known as a bone marrow transplant, and it involves the transplantation of one immune system to another. It’s the very thing that Dr. Cooper was attempting.

  The possibilities for this type of transplant expanded greatly in the 1950s with a discovery that helped explain the underlying chemistry behind why one person accepts or rejects tissue from another. Work by a French immunologist, and others, isolated in human beings the first antigen that reacted against other human beings. These are called isoantigens—antigens within the same species. If two people are a poor fit for bone marrow, the isoantigens in one will provoke an antibody response in the other, setting off a defensive attack. The discovery of isoantigens earned its discoverer a Nobel Prize. This development made it possible for doctors to test ahead of time which transplant matches might be the best fits by eliminating candidates whose tissues were likely to clash. The fancy immunological term to describe isoantigens is human leukocyte antigen (HLA).

  As a discovery, “it’s major, major,” a Stanford immunologist explained to me, and there’s little doubt about that. It is central to the question of how the body sees “self and nonself.”

  Decades later, the modern version of this technology would allow Jason to receive immune cells from his older sister and help fight off a cancer his own immune system had grown helpless to confront.

  But there were many more steps, as they say, between the discovery of isoantigens and Jason’s bone marrow transplant. One big leap was taken by a veterinarian who helped us comprehend in a much deeper way how we (and our immune systems) understand and recognize ourselves. He found the immune system’s fingerprint.

  14

  The Immune System’s Fingerprint

  For a Nobel Prize–winning immunologist, Peter Doherty is a funny guy.

  He graduated from veterinary school in Australia in 1962, initially focusing on how vertebrates—like sheep (and humans)—control infection. He did so with zeal. Even in the latter half of his seventies, when I had the privilege to interview him, he talked a blue streak, an enthusiast with a sense of humor. When he was a teenager, he told me, he read Aldous Huxley, Jean-Paul Sartre, and Ernest Hemingway, and was inspired but confused. Dr. Doherty, in his own words, was a man “who was either going to go big, or crash and burn.”

  In his 2005 book The Beginner’s Guide to Winning the Nobel Prize, he reflected with humor on his adolescent naiveté. “I decided to be the man of action rather than the philosopher, and resolved to graduate in veterinary science and pursue a research career,” he wrote. “At this stage I was just seventeen years old, and would probably have made a very different decision if I had been more mature.”

  When we spoke, Dr. Doherty colorfully explained that while much had been discovered about the immune system by the time he was delving into his research, even more was still in doubt. In fact, there were still holdouts who were not convinced that there even were two main immune system cell types, the T cells and B cells. “That fact had become obvious. But some of the old guys were horrified by having to confront such complexity,” Dr. Doherty told me. “They’d say that B and T were the first and last letters of bullshit.”

  As the pioneering immunologists pushed ahead, there was predictable resistance from people unsure if the course was correct. This was true with every advance. Meanwhile, the progress and pace of the breakthroughs were accelerating. It was here that science would discover the levers and knobs to permit more precision health treatment, care, and counsel. The next few chapters, before I return fully to Jason, Bob, Merredith, and Linda, will carry you deeper, joining the scientists on their journey beyond ideas and into the very molecules and systems that make you tick and that are responsible for your health. When we surface again, you’ll be equipped to see more clearly the profound role of the immune system in virtually every facet of your health—both physical and emotional.

  Dr. Doherty earned a PhD in 1970 at the University of Edinburgh in Scotland, where he studied sheep brain inflammation (meningoencephalitis). He returned to Australia and applied that work to mice, then started a historically significant collaboration with a visiting Swiss doctor and scientist, Rolf Zinkernagel, who had used mice to become expert at a technique for looking at the concentration of T cells when they are called into action to attack a virus.

  The two scientists infected mice with a vir
us that can cause meningitis—an infection of the lining of the spinal cord. Then they watched as the T cells gathered around the infected cells and unleashed their fury. Most of this was actually done in a test tube. The mouse would be infected; then its infected cells were mixed together with T cells isolated from the spinal canal.

  Dr. Doherty told me that “right from the outset, our brain-derived T cells were causing the most dramatic killing anybody had ever seen.

  “As disease and death guys,” he added, “we were delighted!”

  With further experimentation, the pair realized something crucial about the nature of this mass murder: The T cells weren’t just killing free-floating infection; they were targeting mouse cells that were infected, meaning the cells that were being annihilated were part alien and part self. This was very interesting but maybe obvious. It meant the T cells were diagnosing illness inside the cell, not merely identifying freestanding viruses.

  Then came a punch line—“an unexpected discovery,” the Nobel Prize committee wrote in its 1996 award for the science (for work published in 1974). “The T-lymphocytes, even though they were reactive against that very virus, were not able to kill virus-infected cells from another strain of mice.”

  In other words, the immune system was able to discern a cell that was self and had been infected from a cell that was not self. The immune system killed only the infected ones that were self. An individual’s elegant defense didn’t care simply about the infection; it cared about the infection when it attacked its own personal habitat. Italicized because it’s a key scientific insight.

  If you pull back the lens, and picture the day-to-day cinema inside our bodies, what the pair of scientists had discovered was that our “killer” T cells are roaming widely to discern whether other cells that make up the tissues and organs of our bodies are normal and healthy or have been damaged in some way that’s dangerous—infection, mutation to cause cancer, etc. These T cells are often considered the equivalent of hit men. But this work showed these cells have a broader function. They carry specific “receptors” that prompt them to ask questions first before they attack.