by Matt Richtel
The first place she put that drive was into horse riding. When Linda was seven, her parents took her and her older sister to Wyoming to a family ranch, where you got to play cowgirl. Linda started playing for keeps. Back at home in a community north of San Francisco, Linda spent her afternoons and weekends practicing at a barn. Her family was privileged but not rich, her dad a midlevel executive at Chevron, and they lived in an Eichler home in Marin and got Linda her first quarter horse when she was ten.
She tried to stay lean so she’d look great on that horse. There was a period when she was around fourteen years old when Linda, of her own accord, would go on an all-protein diet for several weeks at a time, a regimen that was the precursor to the Atkins diet—meat and eggs, her only snack pork rinds, occasional cottage cheese. “My parents were a little worried, but I didn’t have any eating disorder.” She just liked to win. But horseback riding competitions were subjective. She hated not being in control of her results.
“It’s what I love about golf.” She started to attack the links as she had the stable.
At about this time, Linda first exhibited a health oddity. For years, her stomach had bothered her, even predating the periodic diets. Mostly it was constipation, sometimes terrible gas.
When she was fifteen, she went to play a round of golf with her parents at the Richmond Country Club. Just prior to tee-off, Linda went to the clubhouse restroom and had a bowel movement. It was partly a huge relief because she hadn’t defecated in days. But immediately afterward she also felt weak and dizzy.
Her mother saw her, wobbly, heading from the bathroom and to the first tee box.
“What’s going on?”
Linda explained, then swallowed some water and tried to shake the feeling.
Her mother responded: “Oh no. I hope you didn’t get my stomach.”
Linda’s mother, Carol, suffered from irritable bowel syndrome. This is a condition that causes a range of stomach disorders—pain, constipation, diarrhea, gas. It is not an autoimmune disorder per se, but it can often involve inflammation, which is caused by an excessive or prolonged immune response. It is a cousin of irritable bowel disease and Crohn’s disease, which are autoimmune disorders characterized by excessive inflammation. Imagine if the plumbing inside your body became inflamed, red and painful, swollen. For one thing, this causes physical discomfort simply because of the tight confines of your body; the space inside you has been engineered to near perfection by evolution, no space wasted. So when things swell, it hurts—potentially a lot.
Linda went right along, gifted, sure, but also willing and forging one success after the next. She worked her way into a golf scholarship at Stanford, eventually graduating with a degree in economics. Then she was tabbed to play on the European golf tour, at the time a struggling operation. The American women selected for the team, in addition to their golfing ability, all looked good, which was part of the marketing effort to sell the sport. This led to fun years for Linda, 1982 to 1985, before she’d had enough and moved on to the next stage of her life, as an MBA student at Stanford.
Linda married a man who would become a partner at one of Silicon Valley’s big-name law firms and took his last name, becoming Linda Segre. She joined the Boston Consulting Group, an elite organization of consultants where she headed down the partner track, matching her husband work hour for work hour. She’d call him from her office at eight P.M.
“How you doing?” he’d ask.
“I could use another hour.”
“Me too.”
He’d swing by to pick her up in the Porsche 911 at ten.
With success came added responsibility and pressure. She met each challenge. That’s how she saw it anyhow. One time, in 1989, she was vying for a project and stayed up ten nights in a row to compete for the deal. She won it.
“There were very, very few women, and plenty of very, very smart people and I felt a little insecure,” she reflected. “I can prove I’m as smart as the rest of you guys. I did it by just killing myself.”
Her husband worked no less hard, she recalled. Just like so many people in Silicon Valley—and in New York and Hong Kong and London and lots of other type A enclaves. Many of those people do not get autoimmune disorders. So this lead-up is not intended to suggest that Linda brought her condition on herself. Her genetics were expressly at play too.
But it is fair to say that Linda was building a life that was not consistent with her own limits—nor with those of most people’s. She was losing track of what was true and consistent with her, what was her real self. In a certain way, her life was being driven by the pathology of nonstop work, a foreign invasion that was threatening not just her emotional health but also her physical health.
In the late 1980s, the stomach pains got worse. Once every few months, she’d have such bad gas that she’d come home and crawl into bed. The swelling would be gone by morning. She kept pressing the limits until the bottom fell out.
In early September 1995, Linda gave birth to a son. He was the couple’s second child; their daughter was two. The family lived in San Mateo, a comfortable suburb south of San Francisco. It happened to be just a ten-minute drive from one of Boston Consulting Group’s major clients—a billion-dollar financial services company—and Linda was playing point on the account. The client relied heavily on her.
Linda convinced herself that she could continue to have it all. She took ten days of maternity leave. She was exhausted. “I would be taking calls at midnight and be up with my son every two hours breastfeeding.”
She got a terrible sore throat that December, as bad as she’d ever had. She suspected it was strep, a highly contagious illness caused by the streptococcus bacteria. Typically, it is treated by an antibiotic. Not in her case. “I didn’t have time to go to the doctor.”
It lasted weeks, coupled with the exhaustion.
Then in March 1996, she got the rash—raised and bumpy, red, all over the upper parts of her limbs. Now she did go to the doctor, who told her: “I don’t know what it is.”
Linda pressed on. Still working sixty-five-hour weeks, with her husband seeing and raising her work hours, she had the newborn and her daughter and was now trying to be the type of mother she idealized. She’d have conference calls in her Ford Explorer with the kids in the back seat. In September 1996, she had the dinner party with colleagues from Boston Consulting Group when her left big toe exploded to golf-ball size.
Her doctors didn’t know what it was. They speculated it was Lyme disease. They were wrong, but this is indicative of the mindset of medicine: There must be a pathogen or foreign agent at work.
Two weeks later, her right big toe blew up the same way. Then it was her left knee—like a grapefruit.
Linda was under full-fledged assault. Her primary care doctors weren’t sure why. No wonder. For as prevalent as autoimmunity is, its diagnosis can be worse than tricky. For a long time, the condition was invisible.
28
The Wolf
When a person goes to a doctor, he or she starts with the symptoms. My throat hurts, my leg aches, I’ve got fever, there’s this rash.
The doctor starts with the symptoms too. The first question: What’s bothering you?
With much of disease, the medical questions then move into the cause of the symptoms. You have a cold, pneumonia, a virus or bacteria, a parasite, cancer.
The thing about autoimmunity is that the questions and answers sometimes don’t get any further than focusing on the symptoms. My joints ache, I have fever, I’ve got this rash, I have diarrhea, constipation, mind-numbing fatigue.
And the doctor says: I believe you, but I can’t find anything wrong.
Something is wrong, all right. But there is nothing to point to. There is no pathogen. There is no infection. There is no foreign disease.
No aspect of the immune system story is as pointed or pure as that of autoimmunity.
The mystery began with the werewolf.
As early 963 AD, one history notes,
scientists observed an unusual condition that left people looking as if they’d been bitten by an animal. Hippocrates was the first to describe symptoms consistent with the skin disease, and Hebernus of Tours is thought to be the first to apply the term lupus to it. The word derives from the Latin word meaning wolf. Its sufferers showed sores, “ill-favored lesions,” and various other colorful descriptors—gnawing dermatosis—that I read in accounts of the medieval history of the illness. These “grotesque” lesions appeared on the face, lower limbs, all about. These symptoms—some caused by lupus and some not—were considered the product of a wolf bite and even a sign that someone had turned into a werewolf, according to the Lupus Endeavor, an advocacy project.
The vernacular and diagnosis were equaled in their primitive nature only by the treatment: “cutting away diseased tissue or burning it with caustic chemicals. These interventions rarely provided a cure, and patients suffered gradual disfigurement over decades,” reads a case history of lupus that appeared in 2016 in the vaunted medical journal The Lancet.
In 1872, the Vienna School of Medicine employed a doctor named Moritz Kaposi, who associated lupus with other conditions in the body, including arthritis. In the latter half of the nineteenth century, a Canadian physician, Sir William Osler, connected lupus lesions with even more conditions, including impacts on the heart, lung, and liver. Dr. Osler gets credit for the name systemic lupus erythematosus.
The key word here is systemic. The condition was not just about the skin. Something bigger was going on.
A nineteenth-century woodcut depiction of a woman suffering from arthritis, long before the agony of women like Linda and Merredith was taken seriously by the medical community. (Wellcome Collection)
On a parallel path, scientists had begun identifying and exploring an unusual condition that led to pain in the joints. In Paris in 1800, a doctoral student assessed nine patients and determined that the joint pain they were suffering was different from the overarching diagnosis of gout that many people suffered from. The student initially called it asthenic gout. Then in 1859, at University College Hospital in London, a pioneering doctor and researcher, Alfred Garrod, gave this condition its modern name: rheumatoid arthritis.
This was a disease characterized by inflammation, typically impacting the joints. Remember that inflammation is the body’s own response to disease. Inflammation is not “other.” It is “self.”
Did that mean the disease was caused by self?
The very idea that the body would attack itself was still relatively new. The pioneering immunologist Paul Ehrlich introduced the term horror autotoxicus right around 1900. Autoimmunity. The body attacking itself.
As immunology spun forward into the twentieth century—a relatively tiny community in a field thought by many to be a backwater—the people exploring these unusual inflammatory conditions were an even smaller subset. One research hub was the Mayo Clinic in Rochester, Minnesota. In 1926, according to a Mayo history, 574 patients were admitted to the rheumatology service with joint swelling and pain. The presumption was that the cause was chronic infection—something foreign was sparking it. This was, of course, wrong. Vaccines were tried. They led to serious side effects, even death.
Imagine: an overheated immune system getting a boost from medicine and vaccine.
Other patients were treated with “fever” treatments—meaning that fever was induced to try to reverse the symptoms, an effort to stop a mysterious condition by literally igniting the immune system.
Then, in 1929, there came a revelation.
Doctors who work on joint pain are called rheumatologists. A pioneering rheumatologist named Dr. Philip Hench, working at the Mayo Clinic, noticed an oddity with one particular rheumatoid arthritis patient. Her joint pain and stiffness seemed to get better when she developed acute jaundice. She got a disease and her joint pain got better, not worse.
The doctor also noticed that other rheumatology patients saw their symptoms recede after surgery and during pregnancy. Dr. Hench theorized that the patients under duress had secreted a compound that countered whatever was attacking their joints, explains a history in the journal Clinical Chemistry.
Dr. Hench had a hunch. When patients experience stress and are under duress, it typically means that they are secreting adrenaline. Dr. Hench theorized that joint pain and inflammation were being dulled by a secretion from the adrenal gland, a small, triangular-shaped nub located atop each kidney that produces essential hormones. Fueled by the hypothesis, Dr. Hench and a biochemist named Edward Calvin Kendall made one of the most important discoveries in the history of autoimmunity.
In an effort to discover the substance that had improved the condition of these Mayo patients, Kendall started trying to isolate secretions from the adrenal glands of cows. The biochemist took regular shipments of adrenal tissues from Chicago slaughterhouses, according to the history published in the journal Clinical Chemistry. The biochemist discovered a handful of hormones that were labeled with letters of the alphabet: A, B, C, etc. The one that changed science was called Compound E.
It was studied initially because it seemed relatively simple. It also made patients feel better, sometimes euphoric.
It took many years to refine and isolate. Then in 1948 at the Mayo Clinic, the very scientists who had begun working there in 1929 gave Compound E to a twenty-nine-year-old woman immobilized with severe rheumatoid arthritis. “Two days and two more injections later, the patient could walk and left the hospital to enjoy a three-hour shopping spree,” reads a recounting of the story published in the same 2010 scientific article.
“This startling result stunned people throughout the world,” another history recounts. The two Mayo researchers won the Nobel Prize for this in 1950.
You might know Compound E by a different name, cortisol. Cortisol is a steroid that suppresses the immune system. Steroids are the first line of defense against many autoimmune disorders. They are a mixed blessing, as you’ll see later on. For the moment, though, the discovery of steroids in the field of immunology and medicine was analogous to the discovery of a vaccine or antibiotic; they were a tremendous revelation, a response to a vexing problem, but a response that came without an understanding of the underlying mechanism of the disease they were meant to treat—autoimmunity.
As in so much of immunology, other major pieces began to fall into place in the late 1950s, as scientific technology improved. For instance, lupus researchers could now see that the condition involved a patient’s own immune cells eating away at free-floating material in the bone marrow. This was a double whammy of sorts. The bone marrow helps gestate and stimulate the immune system, and it was under attack by the very system it had helped spawn.
Another major break in the autoimmune mystery came in the late 1950s and 1960s from Dr. Henry George Kunkel, widely considered one of the pioneers in the field of autoimmunity. Dr. Kunkel spent his entire career working at the Rockefeller Institute in New York. His patient and research base there included women suffering from liver disease. Many of the women also had arthritis. This was thought to be largely coincidental; after all, arthritis can have many causes, including aging and repetitive physical stress. It is not always an autoimmune issue.
In studying these liver patients, Dr. Kunkel isolated some of the women’s antibodies—those large specialized molecules on cell surfaces that help our bodies target what to attack. Among the molecules he collected, Dr. Kunkel observed and isolated nineteen antibodies that did something quite disturbing. These antibodies, rather than picking up on and reacting to signals from foreign cells, reacted to the patient’s own white blood cells.
Now he understood rheumatoid arthritis. He’d found a key test to prove the body was attacking itself, using the very properties that other immunologists had begun to understand as essential to defending ourselves against invaders. It was a brilliant and essential insight.
In 1948, a related test was developed to probe for the presence of antinuclear antibodies. These antibod
ies can bind to the nucleus of a normal cell and had been shown to be present in virtually everyone with systemic lupus. (Complicating matters, the antibodies also appear in people who don’t have lupus, so initially, the test worked only about half the time; by the mid-1960s, the effectiveness of the test rose to 95 percent.)
Thus, at the dawn of the nuclear age, there were somewhat effective tests for only two of nearly a hundred known autoimmune disorders. And there was little in the way of treatment.
This was largely the state of affairs in the late 1960s when a patient in her forties came to Johns Hopkins suffering terrible joint pain, sobbing, trying to hold it together. Among others who tended the woman was a medical student named Bevra Hahn, who would go on to become a prominent specialist in this area.
The woman’s story captures the reality of autoimmunity during the period. Despite all the fantastic science by Dr. Kunkel and others, autoimmunity remained difficult, if not impossible, to diagnose and treat. This challenge was compounded by the sexist way that women were viewed in society at that time. When women complained—whether about physical or emotional duress—they were often deemed “hysterical.” Society could be quick to dismiss the work of women solely as caretakers of children and the home, employment deemed second class and not particularly taxing. In reality, this work could be brutal on the joints and compound the pain.
“Women had very defined roles. The husband never did the laundry. The husband never made a meal. Diapering a baby is really hard when your joints are swollen and painful,” Dr. Hahn explained. This patient, a white woman from a middle-class family, wore pants, not skirts, to hide swollen joints.
Dr. Hahn didn’t have much to give her. Steroids didn’t work. “All I had was aspirin and gold shots,” she explained. There was a theory, she told me, that compounds with gold in them could kill tuberculosis germs, and there was another theory that TB was related to autoimmunity. The treatment, as Dr. Hahn pointed out, “was very primitive.”