An Elegant Defense Page 3

  Just prior to her two P.M. tee time, her gruff, standoffish local caddy, Victor McCauley, had stunned her by taking her to the parking lot. “I’ve got something to show you,” he said. He opened the trunk to reveal a dozen beautiful red roses. “Linda,” he said, “let’s go win this thing.”

  It wasn’t going to be easy. Linda, twenty-two, had never won a professional golf tournament, and she was up against a woman who was the leading money winner for two years running on the European tour. She’d hardly slept the night before the final round.

  On the other hand, much about Linda’s life had been storybook—storybook, not fairy tale. She hadn’t been handed everything, wasn’t a princess. She worked her tail off, and she liked to work. As a girl, starting at age seven, she’d poured herself into horseback riding, reaching competitive heights. She pushed herself, looked for her edges, even to the point of occasionally putting herself while in her early teens on protein-only diets—meat and eggs and no fruits or vegetables—to stay lean and graceful on the mare.

  She became the best competitor in the barn. “You could give me a terrible horse, and I could make it perform.”

  And brains? Linda, excelling in particular in math, emulating her older sister, had skipped third grade.

  She was well liked, maybe not the most popular, a touch nerdy, but content and self-motivated. Her mom had been a professional golfer, her dad a scratch golfer too, and eventually Linda moved from horseback riding to the family business. From almost a standing start at age fifteen, she worked relentlessly at golf and elbow-greased herself a Stanford University golf scholarship. Drives flew 230 yards, a feat in those days.

  In the final round of the Ulster Open that May day in 1982, Linda kept even with the tour leader, Jenny Lee Smith. On 18, the last hole, Linda scrambled after her second shot, which trickled over the green into a bunker. Her sand blast landed six inches from the cup, and her par sent the match into a sudden death play-off.

  The two players went head-to-head, one hole at a time. If one of them won a hole, a single hole, she would take all the marbles. Linda and Jenny played even for four holes, and then, on the fifth, a 500-yard par five, Linda cracked. After the two ladies hit nearly identical solid drives, Linda pulled out her three-wood, swung, and. . . . topped the ball. It lazily spun on the ground 90 yards, well less than half the distance she’d hoped for. Jenny stood up next and crushed it. Jenny had only to hit a decent wedge shot and the tournament would be hers.

  Victor, Linda’s rose-bearing caddy, calmly handed Linda a five-iron and told her she knew what to do. Swing gracefully, with power and confidence, and put the ball near the pin, stay in the match, put pressure on her opponent.

  Linda struck her five-iron “right on the stick,” and the ball landed three feet from the hole. Jenny hit her wedge shot over the green. When Linda made her birdie putt and won, her American teammates put her on their shoulders. Later, in after-party celebration, she danced with that old caddy to “Forty Shades of Green.”

  Linda Bowman had many gifts, chief among them work ethic, grace under pressure.

  Until her body turned on her.

  Fourteen years later, in 1996, it seemed from the outside that much of Linda’s life had continued in storybook fashion. She had a Stanford MBA to go with everything else, two kids, including a newborn, a husband employed at one of Silicon Valley’s most elite law firms. She was on the cusp of becoming only the sixth female partner at the Boston Consulting Group.

  She lived in a nice home in San Mateo, a suburb of San Francisco. One night in September of that year, she was cooking dinner for a group of colleagues when she felt pain in her left big toe. Not just a twinge. PAIN! She looked and saw that the toe had swollen to the size of a golf ball. In agony, she powered through dinner and then took a rare step for such an overachiever and politely asked her dinner guests to leave early.

  Then, even more uncharacteristically, she cancelled the meeting she had scheduled for the next day. She had been supposed to fly to Los Angeles to meet with a major client, one of the world’s largest banks. But she couldn’t imagine herself getting to and through the airport.

  To go to sleep, she took a Vicodin she had left over from the birth of her son. The pill didn’t work. She took a second. No relief. She swallowed a third.

  The next day or so, she went to the doctor and unveiled a toe that was the size of the Titleist balls she once crushed. It was red and puffy, a balloon of excruciating pain.

  Linda’s doctor examined her. “I’m not sure what this is,” the doctor said.

  Linda was under attack by her own body. She suffers from rheumatoid arthritis. Her story will sound familiar to legions dealing with autoimmunity. She has dealt with terrible pain and swelling—swelling of one thing or another, bowels, organs, and joints in particular.

  Broadly, it is hard to overstate the toll taken by autoimmunity. Of the five top-selling drugs on the market, three treat autoimmunity, including the world’s bestselling medication, Humira, used to suppress the immune system for treatment in a variety of illnesses. It boasts nearly $20 billion in annual sales.

  For all the sufferers of autoimmune disorders, the medicines show how far science has come in treating these conditions and understanding them. What we can see clearly now is that arthritis sufferers, people with celiac disease or lupus, even people who suffer seemingly mysterious bouts of fatigue, fever, and pain, all share an often-invisible threat: an elegant defense that is out of balance, an immune system that has overcompensated, been triggered to act without proper constraint. These conditions impact millions—well more than get diagnosed—whose own defenders attack or reject themselves, and sometimes their food or environment, as if it were hostile.

  Linda’s story provides one intimate window into the way autoimmunity plays out, not just the physical agony but the often unending frustration involved in trying to diagnose these complex medical conditions.

  That frustration is underscored with the story of a second autoimmune sufferer, Merredith Branscombe. Her condition made her feel invisible in the sense that there is no foreign agent inside to identify, just Merredith. For decades, sufferers like Linda and Merredith have been overlooked, even dismissed by many friends, family, even medicine.

  In Linda’s case, the clues to and the catalyst of her illness were actually there all along to be discovered if given proper scrutiny. In addition to her family history, she suffered extreme stress, sleeplessness, and a case of strep throat that might have kicked her immune system into overdrive. Merredith’s case proved more vexing.

  Merredith was born in Denver, just two years after Linda, to a world of autoimmune minefields. Her family held a great secret she didn’t learn for years. Her grandparents and mother had escaped in harrowing fashion from the Nazis. It added trauma to a stark family history of odd symptoms, such as the fatigue and gastrointestinal struggles of her mother, and her grandfather’s own rare autoimmune disorder that attacked his nervous system.

  Merredith was a good student with politically active parents, her father a newspaperman, and she grew up a gifted writer. But she was plagued occasionally with odd physical symptoms—rashes, stomach problems, joint pain—that came and went. Life seemed good when she got into Northwestern University. Then, during her junior year she was sexually assaulted and returned home from college. She was an immune system tinderbox.

  When her condition exploded, it was truly something to witness.

  One day in September of 2017, I met with Merredith in Colorado. It was just after five in the afternoon, and Merredith stepped out of her beige Toyota, looking very much out of place. The temperature had just dipped below 80 and the sun was still piercing even at this hour, particularly at a mile above sea level. But Merredith, fifty-three, wore jeans, a long-sleeved black shirt, and a black baseball cap, her full blond hair spilling out onto her shoulders.

  She opened the back door of her aging Camry and out jumped Bam-Bam and Ringo, two mutts with hounds’ blood in their
genes.

  We were in Boulder, my hometown, and largely coincidentally, the place where Jason and I had grown up. As Merredith leashed the eager dogs, I began to assimilate her seemingly odd choice of clothing. Of course, I thought, it has to do with her ailment. Rather, ailments. Plural.

  Merredith had been diagnosed with at least three autoimmune disorders, including lupus and rheumatoid arthritis. Merredith’s immune system had turned on her own body as if it were itself an alien threat. She was almost never without a challenge, often running a low-grade fever twenty days or more every month, a few days of that as high as 100. It was just enough to create regular fatigue, not enough to knock her out completely. When the symptoms hit hard, “Ouf,” she said. There were middle-of-the-night emergency room visits with inflammation around her heart, blood in her stool, and pain “like someone had plunged knives into both sides of my body and were just . . . turning and driving those knives deeper and deeper into my muscles.”

  She shut the Toyota’s back door. “Want to see something cool?” she asked.

  “Sure.”

  “I’m going to show you what happens when I get into the sun.”

  I was pretty sure the thing she was going to show me was not cool. It was going to be riveting, maybe, or instructive about the power of the immune system. Not cool, not if you’re Merredith.

  “It’s a little heartbreaking, because in general I have a fair amount invested in an image of myself as not stoic exactly, but I don’t want to be the person for whom being sick is the biggest thing that ever happened to her,” she told me.

  Dogs leading the way, we walked up a street called Linden Avenue toward the foothills. As we moved past the tree cover, we reached a dirt walking path, the mountains and yellow-orange sun to our left, and to our right, the tree cover of an affluent neighborhood. For the moment, we were exposed.

  “Check this out,” Merredith said. She pulled her black shirt over her left hand, protecting it from the sun. She held her right hand out in front of me, palm down. “It’s going to happen fast.”

  “What is?”

  “Just watch.”

  The uncovered hand began to swell. It turned red.

  “Are you okay?”

  “Eh.” It seemed this was par for the course.

  “Let’s get out of the sun,” I said.

  We walked another ten yards.

  “There it is,” she said. She withdrew her left hand from her shirt, and put the pair of them side by side. Now it was more glaring, her left hand white and a touch puffy, which reflected the regular inflammation, her right hand red and visibly swollen.

  “My immune system,” she said, “is always attacking me.”

  Merredith’s immune system is far out of whack, unrestrained, a killer inside her. So is Linda’s. With Jason, his immune system didn’t do enough, not on its own. In the case of Bob Hoff, his immune system accomplished the rarest of feats. It was a marvel. So why was he so shunned by society?

  In combination, theirs comprise a kind of immunological Goldilocks story: Two people had too powerful an immune system, one had too weak a system, and one’s system was just right.

  In these pages are their stories and other intimate medical tales, including some from leading scientists and, in a spot, my own health struggles. The personal accounts bring to life the powerful and complex immune system science.

  What is happening inside our bodies will make more sense if I start at the beginning, with how scientists came to understand the true meaning of the immune system, and return in detail to the stories of Jason, Bob, Linda, and Merredith.

  It’s a tale that begins with a bird, a dog, and a starfish.

  Part II

  The Immune System and the Festival of Life

  5

  The Bird, Dog, Starfish, and Magic Bullet

  A case can be made that the field of immunology originated with a chicken.

  The setting was the University of Padova in northern Italy, at the end of the sixteenth century. There was at that time a young researcher named Fabricius ab Aquapendente who liked to cut things up. He dissected eyes, ears, animal fetuses, and occasionally humans. But history remembers him for a chicken.

  Dissecting a fowl one day, Fabricius noticed an odd region beneath the chicken’s tail. He found a saclike organ, which he called the bursa, a word that shares its derivation with the modern word purse. Henceforth, the bursa of Fabricius.

  This thing appeared to have no purpose. What the heck was it? Why would God (this was the sixteenth century) leave on a bird a saclike purse that didn’t seem to do anything?

  Would Fabricius have believed it held the key to understanding our survival? Could he have known this simple observation would someday save the lives of millions of people, including Jason’s?

  So too it would be for a handful of other seemingly unconnected discoveries that would build the foundation of our understanding of our immune system.

  On July 23, 1622, an Italian scientist named Gaspare Aselli dissected a “living well-fed dog,” recounts one history of this seminal surgery. In its stomach, he observed “milky veins.” This observation wasn’t consistent with an understanding of a circulatory system carrying red blood. Instead, these milky veins looked like they contained white blood. Aselli’s dissection set off a period of exploration that the history calls lymphomania, a fascination with a little understood bodily fluid called lymph, along with the dissection and vivisection of hundreds of animals.

  The role of the milky veins wasn’t clear for many years. As Nature magazine put it centuries later, Aselli’s observation “languished in relative obscurity for decades.”

  What was this alternate circulatory system?

  In northeast Sicily in the summer of 1882, Élie Metchnikoff peered through a microscope. Metchnikoff was a zoologist from Odessa who had gone to Italy to visit with his sister and her family during a period when trouble was brewing in Russia. Jewish farmers faced intensifying persecution from the government and peasants. At one point, the peasants murdered a farmer. Metchnikoff took his microscope to Sicily, where lightning struck: “The great event of my scientific life took place.”

  The name Fabricius will be forever linked to the chicken bursa. For Metchnikoff, the association is with a starfish larva. This was the medium of his great observation.

  Élie Metchnikoff was years ahead of his time in observing immune cells. (Wellcome Collection)

  One day while his family was at the circus—“to see some extraordinary performing apes”—Metchnikoff turned his microscope on embryonic starfish, which are transparent. He noticed cells moving throughout the tiny organisms. He described them as “wandering cells,” and he was struck by an instant of revelation.

  “A new thought suddenly flashed across my brain. It struck me that similar cells might serve in the defence of the organism against an intruder,” he wrote.

  He had an idea how to figure it out. What if, he wondered, he put a splinter into a starfish? Would cells like these somehow swarm, as if coming to the rescue?

  There was a small garden to our dwelling, in which we had a few days previously organised a “Christmas tree” for the children on a little tangerine tree; I fetched from it a few rose thorns and introduced them at once under the skin of some beautiful star-fish larvæ as transparent as water.

  I was too excited to sleep that night in the expectation of the result of my experiment, and very early the next morning I ascertained that it had fully succeeded.

  Indeed, a bunch of these wandering cells swarmed around the splinter. They appeared to eat away at the offending or troubled tissue.

  That experiment formed the basis of the phagocyte theory, to the development of which I devoted the next twenty-five years of my life.

  The word phagocyte is taken from the Greek and can be roughly translated as “devourer of cells.”

  Phagocytosis is the process by which the devouring happens. (And congratulations, reader! You’ve been introduced to the la
nguage of immunology, at times one of the most maddening and even counterintuitive lexicons ever contrived.)

  Paul Ehrlich, immunology godfather, in his lab. (Wellcome Collection)

  Metchnikoff’s sister wrote his biography and eloquently captured her brother’s theory, one that took years for scientists to fully embrace. “This very simple experiment struck Metchnikoff with its intimate similarity to the phenomenon which takes place in the formation of pus,” she wrote, as passing of cells leads to “inflammation in man and higher animals.” In the biography, she defined inflammation as “a curative reaction of the organism, and morbid symptoms are no other than the signs of the struggle between the mesodermic cells and the microbes.”

  In other words: At the moment of invasion, the body has an initial reaction that involves the swarming of eater cells, and the experience is not always pleasant. This is what we call inflammation.

  Know this about Metchnikoff: The man was way ahead of his time.

  Nine years later, in 1891, a contemporary of Metchnikoff’s named Paul Ehrlich—a godfather of immunology who was based in Berlin—began a search for a “magic bullet.” Dr. Ehrlich aimed to explain one of the most elusive questions in all of immunology: How was it that our defense system could recognize and attack dangerous foreign agents, called pathogens, organisms like viruses, bacteria, and parasites? How did the cells in the body of the starfish, for example, know to show up and start eating?

  He was building on a personal obsession with a scientific technique that allowed tissue to be stained. In this way, he could see that some chemicals have “a marked affinity” for certain parts of the body, explains a history in the journal Pharmacology. For instance, the history notes, the chemical methylene blue seemed to travel to the nervous system. Or was the nervous system attracting the chemical?

  Was there a magic bullet or some other substance or process that would allow a defense cell to attack a bad guy?