An Elegant Defense

by Matt Richtel

  But Bob’s legacy is as powerful a statement as there can be about the immune system and human survival.

  This is particularly profound because Bob’s own diverse state—as a homosexual—left him, for most of his life, shunned, an outcast, like so many pitiful souls cursed by an ignorant society for being themselves. Now we can see, though, that Bob’s diversity isn’t just obviously one part of the human mosaic; it is one essential for our survival. The more diversity we have—physically, spiritually, intellectually—the better our balance. Just as in the immune system and microbiome. More diversity, more tools.

  Brian Baker and his husband, Bob Hoff. (Courtesy of Robert Hoff)

  Bob makes that point quite powerfully because he was shunned. “The irony or the sheer paradox is so powerful,” said Dr. Migueles. “How unique his immune system is, so beneficial to humanity, and has been, yet he acquired this disease as part of a social subculture who is unjustly received, shunned.”

  Diversity in this context has two meanings—one physiological and one cultural—and both play essential roles in survival.

  From a physiological standpoint, the broader the genetic pool, the better chance of having someone like Bob who will survive a pandemic and save a species. It’s also a way to have a broader microbiome, and all the benefits of that. If you doubt this, just ask yourself why we don’t allow incest. Such behavior leads to a narrowed gene pool, and survival rates plummet.

  But it’s also true that we need a diversity of viewpoints, of ideas. For proof, look no further than the lifesaving medicines I’ve written about in this book. They came from scientists drawn from the world over, bringing different perspectives and theories. Without them and many others, there well might not have been a more than doubling of the human life-span in recent centuries. We have diversity to thank.

  Xenophobia, blind nationalism and racism, is an autoimmune disorder. A culture, tone-deaf in its own defense, attacks so aggressively that it puts itself at serious risk. Biology’s lessons, honed like water-polished stone, teach us that cooperation with our species’ diversity is undeniably key to harmony and survival.

  47

  Linda

  On Friday, January 19, 2018, Linda walked up to the first tee at the Olympic Club, an elite golf course on the southern edge of San Francisco. The weather forecast had called for a predictable winter chill, but the sun shone and Linda felt warm in wool capri pants and a black turtleneck. She pulled out her driver.

  She’d made a New Year’s vow. This was to be the year she was just going to have fun on the golf course.

  It has been thirty-six and a half years since she won the Ulster Open. She carried that grace and elegance again, after a horrific interlude of crippling joint disease. Outwardly, there was no sign of the rheumatoid arthritis, but her hands did show the cruel angularity of osteoarthritis, which is a different degenerative joint condition, not autoimmune, due to wear and tear. The swelling and crooked turn at the end of both her right middle and index fingers were largely coincidental with the rheumatoid arthritis.

  Linda is right-handed, and the fact that the damage impacted her right hand was perversely good fortune for golf. A right-handed golfer grips the club most tightly with the left hand, wrapping the right hand over the top. Linda pulled out her driver. The wet ground was a mixed blessing; the ball would stick easier on the putting green, but it wouldn’t roll as far on a drive, making the green tougher to reach in the first place.

  Linda Segre, back on the tee. (Courtesy of Linda Segre)

  Linda had been playing more since she’d retired in March of 2016. It had been a long journey to get to that place.

  She and her husband had gotten a divorce many years earlier, her marriage suffering from all sorts of bumps and bruises, including her illness, the pace of their lives, the suicide of her ex-husband’s mother.

  In 2009, Linda took the position of executive vice president and chief strategist at Diamond Foods. She thought it would be less stressful than consulting. She was wrong. In 2011, for instance, when Diamond Foods announced plans to acquire the potato chip brand Pringles, she and the executive team, in an effort to vet the deal, traveled the world in nine days, stopping at Pringles plants and making related stops in Tennessee, Brussels, Geneva, Singapore, and Malaysia.

  She didn’t think much about whether the lifestyle would throw her back into disarray. “I was feeling good again. I thought: I’ve got this under control.”

  She was, in a way, playing with fire. But Linda wanted to make her own way in the world. She’d worked hard in her life and had financial ambitions. She wanted to “hit her number” so that she could retire with comfort and without fear. Like many women who become single—and despite having a boyfriend—she wanted to make enough money so that she would be totally financially secure.

  Her staying power seemed to be the very embodiment of the dream of scientists and drugmakers who had come up with targeted drugs like Enbrel to slow the immune system. “She is a remarkable case,” said her rheumatologist, Dr. Lambert.

  Dr. Lambert made that comment during the very week Linda teed off at the Olympic Club, when they had met for her annual checkup. It was their nineteenth such annual review. The fact that Linda came in only once a year to see Dr. Lambert was itself extraordinary. Many people with rheumatoid arthritis see their doctors more often to deal with regular pain and debilitating symptoms.

  At the visit, Linda got her lab results back. They were interesting only in how unremarkable they were. Nothing strange stood out. Doctor and patient went over the three drugs that Linda now takes: Enbrel, plus a second anti-inflammatory, and finally, a drug to keep the other two from upsetting her stomach. Linda asked for a refill of her Ambien to help her sleep when she travels. The sum is a quarter of the drugs that Linda took at the height of her symptoms.

  Dr. Lambert marveled at her patient. “This is the vision I had for Linda,” she said. Dr. Lambert recalled when Linda had first come in, thirty-six years old, in a wheelchair, because she couldn’t walk. “She needed a miracle.”

  Dr. Lambert explained that Linda was one of the first five of her patients who got Enbrel. “She’s the only one that’s left.” All four others have had to come off the drug because its effectiveness had ceased. This was news to Linda, who hadn’t heard before about the drug’s potential waning effectiveness.

  Dr. Lambert explained that there are two theories about why the wonder drug can stop working. Either the immune system finds a way around the drug, or it develops antibodies that attack the drug.

  The immune system, like an invisible pathogen, evolves too.

  During the doctor’s visit, Linda ticked off the complaints she has now, and they are modest. The twisted fingers from the osteoarthritis. A touch of wrist pain from the rheumatoid arthritis. Sometimes, she said, her big toes have painful episodes. These were the toes that started it all.

  “I’ll be walking fine, and all of a sudden the joint will lock up and the pain will be excruciating.”

  “How long does it last?” Dr. Lambert asked.

  “Ten minutes, and then it just suddenly goes away.”

  “Not hours?”

  “No.”

  Dr. Lambert didn’t think this was a problem in the grand scheme of things.

  Linda asked if she was doing so well she might even be able to go off the Enbrel.

  “We don’t know whether you’re in complete remission or not,” said Dr. Lambert. She noted that the American College of Rheumatology recommends staying on treatment.

  The mere question showed how far Linda had come.

  “Her biggest problem,” Dr. Lambert jokes, “is that she complains about her handicap.”

  Linda laced her opening drive that January morning. The wet ground kept it to 210 yards, plenty respectable, and straight. She pulled out a hybrid four-iron for her next shot to stop short of the sand traps that protect the green. But she didn’t hit the club squarely and still needed a seven-iron to get to the green.<
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  Twenty-two years ago, Linda couldn’t have dreamed of hitting a golf club, let alone even walking to her ball or into the doctor’s office, her body was so gripped by the suicide mission of her immune system. Now she walked calmly to the ball, as she’d done on her approach in 1982 in Ulster.

  Gracefully, she swung back and through the ball. The Callaway Chrome Soft ball sprang into the air, destined for the green. It fell two feet from the cup and stuck. She nailed the putt.

  “A birdie,” she said. “Not a bad way to start.”

  48

  Jan and Ron

  How far we’ve come! When Jacques Miller began his quest to understand the thymus, the leading causes of death were pneumonia and flu, followed by tuberculosis. Much farther down the list were heart disease and cancer. Thanks to science, we chipped away at these diseases that had decimated generations and made of them low-hanging fruit.

  The key had been to understand and bolster the immune system, do it with antibiotics, vaccines, and other medicines and surgical procedures that the system itself could not accomplish entirely on its own.

  But like death and taxes, some things just can’t be put off indefinitely. One is wasting brain.

  As science helped us evade the imminence of the deadliest threats of the past, a potent new danger rose on the list of mortal causes: neurodegeneration. Alzheimer’s, Parkinson’s, sometimes Lou Gehrig’s disease, in which the motor function of the brain disintegrates.

  Worldwide, 47 million people had Alzheimer’s in 2017, according to the Alzheimer’s Association, a figure expected to grow to 74 million by 2030. In the United States, there are more than 5 million, which means a disproportionate share of sufferers are here, nearly double the rate here as around the world. That’s likely because we have longer life-spans. Life expectancy had grown to nearly seventy-nine years, up from around seventy-five in the late 1980s (the opioid crisis has had a powerful negative impact here, and obesity was worsening it too). Alzheimer’s was the sixth leading cause of death in the United States. It’s part of the immune story.

  This is what happens when you live longer. Eventually, your brain fails, even as your body goes on.

  It’s terrifying up close, as a growing number of people experience. Our intimate window comes not from Jason or Bob or Linda and Merredith, but from two of the scientists I introduced earlier, Jan Kiecolt-Glaser and Ron Glaser. They were the scholars at Ohio State University who had spent their lives studying the relationship between health and stress. Their own relationship with stress turned highly personal in June of 2011.

  In the months just prior, Ron had become increasingly nervous when giving lectures. He made sure every idea that he wanted to speak about was on one of his PowerPoint slides. That way he wouldn’t forget what he was talking about.

  For years, Jan said, “he thought his memory was getting worse.”

  Ron was born in 1939. He was seventy-two. He looked physically fit at five-eleven, with silver hair and a touch of a belly. Around him, his colleagues and friends didn’t notice anything wrong. His mother had had Alzheimer’s, so he knew he might have a genetic predisposition to it.

  He and Jan secured an appointment with a neurologist.

  “When he wanted to make the appointment,” Jan said, “I was scared to death.”

  Jan and Ron sat across from the neurologist, who was the head of the memory disorders clinic at Ohio State. Prior to the visit, Ron had completed a handful of tests, including a drawing test in which he had been shown pictures he was supposed to copy. It should’ve been simple, particularly since Ron had been an art minor in college.

  When the couple met with the neurologist, they were shown Ron’s drawings. “It was incredibly bad,” Jan said. One of the images was an attempt at a three-dimensional box. “It was quite clear he could not copy the picture.”

  The neurologist told the couple “all the things they had ruled out,” like a brain tumor. “You’re doing well overall,” the neurologist told them, “but there are some issues.” He gave them a diagnosis of mild cognitive impairment.

  But Jan could read upside down from the other side of the desk what the neurologist had written: probably early Alzheimer’s.

  Jan went home and read the research on mild cognitive impairment. She was the patient now, or the patient’s wife, not the distant reader of her own work. She didn’t like what she learned. Twelve percent of people like Ron would, on average, progress to full-blown Alzheimer’s.

  Ron seemed to be defying that. Through each of the next few years, he kept functioning. “Everybody saw him as the person they’d always seen him as,” Jan said.

  “Then, in 2014, he fell off a cliff.”

  He’d gone to the neurologist regularly and gotten tests of cognition that showed him dropping about 3 points per year on the scale they were using. But around 2014, he went from a score of 24 to 5 over the course of about a year. What is likely to have happened is that he had been so high functioning during his life that he was able to go through the motions of his life, in effect masking the cognitive decay.

  When the mask came off, it was ugly. He couldn’t reliably answer the phone or use a microwave, brush his teeth. He once put toothpaste on a comb. “It was really fast,” Jan said, “and really awful.”

  This is an increasingly common experience. But what does it have to do with the immune system?

  Up until this point, as I’ve used the metaphor of life’s festival being protected by our immune system, I’ve essentially lumped together the entire human body.

  In reality, when it comes to the immune system, one part of the body stands largely apart. That’s the brain. It has proven more challenging to unpack than any other part of our elegant defense. One simple reason for this is that it’s not easy to get a slice of it or to peer into it, certainly in real time.

  The immune system and the brain, each by itself, are among the most complicated organic systems in the world, so dissecting their relationship has meant understanding each alone as well as their coordinated efforts.

  There was a period when it wasn’t even clear whether there was an immune system in the brain, at least like the one in the body. Part of the issue was a bottleneck known as the blood-brain barrier. This is a network of blood vessels that keeps close control over what flows between the brain and body, and that keeps many of the chemical reactions and other functions of the body from leaking into the brain. This has the profound and crucial function of keeping infection out of the brain. It’s hard for molecules to get in and out. (Instead, the brain corresponds with the body through nerves that carry the electrical signals that control motor functions.)

  But the immune system cells, so free-roaming in the body, are generally not crossing back and forth into the brain.

  “The brain was thought to be immune privileged,” said Dr. Ben Barres, a pioneering researcher in the field of Alzheimer’s and, ultimately, in its relationship to the brain’s own immune functions. “The brain has this special barrier. The immune system is not just leaking into the brain.”

  The brain has its own thing going on.

  Brain 101: There are cells called neurons, which communicate through synapses. These connections have an almost magical power to create networks that allow the mind and body to work together. The result is a veritable neural symphony of chemical reactions executed in perfect unison. Think, for instance, about all that has to go right when someone walks or talks, let alone does a more complex task, like hitting a tennis serve or playing a piano or solving a math problem while writing the answer down with a pencil.

  Graduate-level neuroscience: These neurons aren’t the lion’s share of the brain. A lot of the volume of the brain is consumed by a set of cells called the glia—comprising 80 percent of the brain, Dr. Barres told me. Broadly, glia are non-neuronal cells. These glia are central to the immune function of the brain. The glia come in three flavors: astrocytes, oligodendrocytes, and microglia.

  As we live longer, these cells
are going to be crucial in how we understand dementia and how we deal with it. What follows is a primer on the cells, their roles in the brain’s immune function and its relationship to aging.

  Astrocytes look like big stars. They play a critical role in helping the synapses communicate by enveloping them—a single astrocyte can envelop millions. “Astrocytes are orchestrators,” I was told by a Stanford researcher, Dr. Vivianne Tawfik. Coordinators and organizers, packagers and bundlers. Crucially, the astrocytes also encase blood vessels, influencing blood flow. This helps dictate where and how much blood concentrates in the brain, with more active regions needing extra blood at any given moment, just like an active muscle receives added blood flow.

  Oligodendrocytes help the neurons conduct faster signals. I think of them as speed amplifiers for your brain’s internal communications network, like a Wi-Fi booster that brings the signal farther faster.

  Then there are microglia. “They are the immune cells of the central nervous system,” Dr. Tawfik explained.

  Like the body’s immune system, which originated to no small extent in the thymus, the brain’s immune system also has origins in an organ long thought to be vestigial.

  When a child is conceived, one of the first organs to form is the yolk sac. It eventually becomes round and grows to an average of 6 millimeters. It is a sort of food filter, with nutrition coming from the mother through the yolk sac and into the tiny forming life.

  But the yolk sac performs another essential function. It is there, scientists discovered, that precursors to microglia originate, and from there move on to populate the brain. Once in the developing brain, the microglia play a key role. As the brain develops and neurons mature and die, the microglia consume the refuse. Does this sound familiar? It should. It is like the work of monocytes. It is phagocytosis. The microglia are eating neurons that must be pruned, and possibly synapses too.