An Elegant Defense

by Matt Richtel

  Scientists’ understanding of the role of the microglia and the astrocytes was embryonic in the mid-1990s, when Dr. Barres committed himself to trying to comprehend how this poorly understood system might be involved with neurodegeneration. Was our brain’s defense somehow causing Alzheimer’s?

  Ben Barres was born on September 13, 1954. His given name was Barbara. He was born a girl, and from the earliest days, that felt wrong. “I realized from the time I was a few years old I was feeling like a boy,” he said. Not much to be done about that. Not then. There wasn’t even a language for it, so Barbara Barres stuffed down the feelings, wavered with suicidal ideations—“the typical transgender stuff you hear about”—and threw herself into a medical and science career turning stratospheric. She went from MIT to Dartmouth to Harvard and then Stanford. She became an expert on the brain.

  In the mid-1990s, she read an article in the San Francisco Chronicle about a female-to-male activist in the region. She started to feel like she wasn’t alone, like there might be an answer.

  Then Barbara found a lump in her left breast. It was cancer. Barbara needed a mastectomy. She visited a surgeon at Stanford, and when he explained what he was going to do, she said to him: “While you’re taking the left one off, take the right one off too.”

  Dr. Barres became Ben, blessed with a terrific sense of humor, and these kinds of comments prompted him to burst out laughing. The surgeon, Dr. Barres said, “was the first one I ever told.”

  The surgeon told his then-female patient that there was no health reason to take off her right breast.

  “There’s no way you’re going to put those things back on me!” Dr. Barres told me he said, laughing. He’d go on to transition to becoming a man, and much later, he’d become something of an icon for the movement, even appearing on Charlie Rose to discuss it. With a new lease on life, having beat cancer and made peace with his identity, he committed himself to understanding the brain’s immune system. He became a world authority.

  Over time, Dr. Barres defined an immune system network inside the brain that was analogous to, but largely distinct from, the one functioning inside the rest of the body. Just like the body’s defenses, the brain’s defenses can cause issues. One particular paper explored the relationship by focusing on how mice develop glaucoma, a condition that in aging humans causes eye pain and can lead to blindness.

  The mouse paper focused on a molecule called C1q that is involved in the immune system in the brain. Inside the brain, C1q binds to things that do not appear to be self. If C1q binds to a foreign organism, it can lead to an immune response and the destruction of the foreign presence.

  In the case of mice with glaucoma, Dr. Barres and his coauthors found an extraordinary relationship between these immune functions and the disease. When mice develop glaucoma, it triggers the microglia to begin eating synapses, including healthy synapses. It’s like the brain’s immune system is turning on itself.

  I asked Dr. Barres the obvious question: Why?

  “If I knew that,” he said, laughing, “I’d get a Nobel Prize.”

  Over time, though, he developed several well-founded theories that do seek to answer the question of why the aging brain appears so vulnerable to degeneration, not just with glaucoma but Alzheimer’s and other conditions. One theory, Dr. Barres said, is that our brains wind up over the years with a lot of detritus—garbage—that needs to be eaten up. That spurs the microglia to eat synapses. The janitor starts doing its job, but then the janitor goes nuts and starts eating everything in sight. In the Festival of Life, the janitor is not just cleaning up but also taking cups and plates out of the hands of partygoers—booting out cells while the party lights are still on.

  Dr. Barres postulated to me that evolution has allowed such a process to go forward because older human beings are less valuable to the species. “There’s nothing in evolution that would select for good brain health when you’re aging. You’re already through reproduction.”

  You’ve passed on your genes. What good, then, is a healthy brain?

  This is speculation. For now, the science of the immune system and the brain is still embryonic, much less developed than our understanding of our body’s elegant defense.

  So for now, Alzheimer’s involves lots of coping, rather than solving.

  For nearly two years, since late 2015, Ron had lived in a memory care unit. He’d dropped to 140 pounds from 180. Jan came every few days, bringing him candy, usually jellies, and sat down and put her arm around him. He didn’t recognize her. He usually didn’t look at her. Sometimes, he talked to things that don’t exist. He was hallucinating. He took antipsychotics.

  “He’s pretty tame and easy compared to many people,” Jan said. Small comfort. “It’s like most of Ron has disappeared. There’s a shell that looks somewhat like him, and that’s about it.”

  The circumstances have forced Jan to take very personally a lifetime of work about stress and health, namely her own health. “I go through spells,” she told me. “I’ll be okay and he’ll take another step downwards and I’ll get sad and depressed again.”

  What Jan knows from her own research, and the research she follows closely, is to keep her stress low and her social activity up, all of this having an impact on her mood and health. She keeps up a daily meditation practice, usually twenty minutes in her office. She tries to eat well, meaning greens and beans, because she believes that junk food impacts the microbiome, which in turn interacts with her stress levels.

  “The gut-brain axis and the immune system, it’s a very close involvement,” she says, sounding as much like a patient looking for answers as she did the eminent scholar. She draws from a recent report from the National Academy of Medicine that relates physical health to strong relationships, good diet, factors you can control: “things that your grandmother or mother told you that mattered—you need to eat better, you need to move—but they are the hardest things to do when you’re stressed.

  “When we’re stressed we don’t want to reach for the greens and beans. A chocolate doughnut is really appealing. They may be briefly comforting, but they’re bad for the longer-term process.”

  It also helps to cry, she says. She means we need to release stress. Otherwise the stress leads to inflammation, poor mood, fatigue, and heightened inflammation, and that can have lots of correlates. It can affect mood.

  “Crying is beneficial,” she says. It’s an acknowledgement of who and where you are, an embrace of self at a given time and, as such, it helps the immune system by sparing it from having to deal with the repressed anxiety. Crying “is not fun. It’s painful. But you feel better in many cases thereafter, as opposed to eating the chocolate doughnut.”

  These ideas are, as you’ll see shortly, lessons to live by.

  49

  Jason Down the White Tunnel

  My phone rang on March 17, 2014, at seven P.M. It was Thursday, and I was at Yancy’s, a pub and sports bar in San Francisco’s Inner Sunset, hanging out with my college roommate and watching the NCAA basketball tournament. My phone screen read: Jason Greenstein. “I’ll be right back,” I told Erik.

  “What’s up, J?”

  “Who do you think is going to win the Syracuse game?”

  “No clue. I’ll take whoever you don’t want for five bucks.”

  “You’re on.”

  We wagered.

  “How’re you feeling?”

  “Great. Sitting in a sports bar, surrounded by TVs. If I didn’t know I had cancer, I wouldn’t know I had it.”

  So it went. Every few weeks I’d hear from Jason or check in with him, and it was always the same: I feel good and I don’t want to go back to chemo and suffer. “How are you doing, Rick?”

  I would keep it brief. “All systems go.”

  “How is Prodigy 2?”

  Prodigy 2 was the nickname that Jason had given to my son, Milo. At that point, Milo was seven, and Jason had nicknamed him Prodigy 2 because Milo was proving to be a very good athlete. Espe
cially in baseball. I’d experienced occasions when people would pause to watch him catch and throw and hit when we were playing at the park. On his teams, he tended to play a year up and often was chosen for the glory positions—shortstop, pitcher, and catcher. Once an older girl watched him whack a ball and yelled “You’re going to be in the hall of fame!” and Milo turned bright red. It was waaaay too soon to know if Milo had the gifts that Jason had, but regardless, Jason loved to see videos of Milo and hear stories. At this stage, conversing with Jason was a little bit like talking to an aging grandparent who wanted to hear about the kids but mostly wanted an ear to bend.

  “What’s the doc say, J?”

  Dr. Brunvand had been clear with Jason that the longer he waited, the worse his chances of catching the growing tumor. But Jason was following his own gut and his internal meter. If he didn’t feel bad, he wasn’t going to suffer any further. He’d had enough of that.

  Besides, he had the same sense of invincibility he’d always had. “I never really thought I was going to die,” he would later tell me.

  He surely was testing that theory.

  By the time Jason decided he was ready to return to treatment, it was the leading edge of summer 2014. Jason finally dragged his exhausted, bloated, cancer-ridden body back to Dr. Brunvand. “There had been an explosion of Hodgkin’s.” That’s how Dr. Brunvand put it in his note on their meeting that day, observing that Jason had a 10-centimeter mass on his neck, cancer of between 10 and 15 centimeters around his armpit, with the lymphoma beginning to stitch together as a quilt in and around the left side of his chest.

  This time Dr. Brunvand told Jason there could be no messing around. He told Jason that the best shot was trying to use a three-drug regimen, including brentuximab, to get the cancer into remission, and then to undergo a different kind of stem-cell treatment called an allogeneic stem cell transplant. The stem cells would come from his sister. The use of his sister’s cells would theoretically enable the rebooted immune system to recognize his cancer’s subtle differences and attack it. His own immune system was clearly not up to the task. They’d need a stronger one, uncompromised by this virulent Hodgkin’s strain, and even then, Jason couldn’t get the transplant unless he was in remission first.

  During this period, Jason would bring his brother-in-law, Paul, in with him for meetings and treatments. Paul was a molecular biology PhD, a patent lawyer, and a great listener with his science background. One day they found themselves sitting in the waiting room, and Jason started talking. “Do you want to know what it’s like to be a cancer patient?”

  “Let’s hear it.”

  “It’s like all the people in the world live in a Tahitian village on a beautiful beach. And I live in this canoe, and the canoe is attached to the pier by a rope. I can still see the village, and sometimes I’m allowed to come to rejoin the village. But I always have to go back to the canoe. One day I’m not doing so well, and I notice that the rope is longer and I’m farther from the pier. Then the doctors in the village pull on the rope and bring me back to the pier.

  “Over time, I drift farther and farther from the village. After a while, I don’t think I have the rope anymore. All around me are people, but they’re not in canoes, they’re in coffins. And I realize my canoe has turned into a coffin.”

  By the end of his story, he’d talked twenty minutes.

  Paul was crying. “It was the most telling isolation story I’ve ever heard.”

  The oddest thing would happen, though, at these meetings with Dr. Brunvand: Paul could see Jason cling so optimistically to the rope. After Dr. Brunvand would give his assessment, Paul would think to himself: “Oh my God, that’s grim.”

  “But Jason would always find the one to ten to twenty percent positive thing that Brunvand had said and turn it into ninety percent. I’d say, ‘Jason, you’re exactly right.’”

  Part of Paul wanted to believe it, even did. “Cancer is a very resilient thing. It reminds me of an NCAA basketball game, and sometimes someone like Jason hits that buzzer beater.”

  In August, Jason finished his third cycle of chemo. The cancer, while it had shrunk in some places, had increased in others. To extend the basketball analogy, he was down by double-digit points in the game’s final minutes.

  On September 4, he went to Las Vegas to deal with his business, the best that he could. He came back September 20 to start more chemo.

  He met with Dr. Brunvand on December 10, a year after he thought he’d at last been in the clear and free of all medications. Now he was on fifteen medicines, an alphabet soup of acyclovir, brentuximab, pain medications fentanyl and oxycodone, Zofran for nausea, and others.

  The balance of Jason’s immune system was more damaged than his cancer at this point. To support his defense network in its ineffective attack on cancer, he took chemo and targeted therapies that echoed throughout the body. With his ecosystem out of balance, he took drugs to dull the effects of inflammation, pain, stress, and depression, which themselves reflected the imbalanced immune system. Jason’s repetitive cytotoxic chemo had damaged his ability to make normal blood cells. He was neutropenic, with a severely low level of neutrophils, the white blood cells that are the first line of immune defense. Without neutrophils, Jason could die of any infection because bacteria double every twenty minutes. Imagine that, beating cancer only to die of a common infection.

  Jason’s analogy built around the Tahitian village makes a lot of sense to me. Another fair analogy to what was happening inside Jason’s body and to his immune system might be the war in Vietnam. Chemo was napalm, creating scorched earth. But that wasn’t the real problem. The crux was that the plan to use napalm in Vietnam in the first place grew from a desperate and complex set of circumstances that seemed otherwise impossible to untangle. Of course, there was one simple answer: Stop prosecuting the war.

  Jason was increasingly tempted to take that course. He was having suicidal ideations.

  “When you say that, Jason, are you saying you have a plan?” Dr. Brunvand asked him.

  “No. I just . . . sometimes it crosses my mind. I just don’t want to die in this much pain. I can’t take this.”

  They talked about whether to stop therapy. Jason said he wanted to go on. They’d need yet another new tactic. The brentuximab and other drugs given in combination were not working. But any new therapy could not be primarily cytotoxic, killing rapidly dividing cells, because that would further lower his white blood cells. Dr. Brunvand found one that had a slightly less toxic profile.

  “I am concerned that his marrow is stressed enough and might not be able to recover from standard . . . chemotherapy.”

  Jason still insisted, in spite of all of it, that he would “beat this thing.”

  One thing he’d come to terms with was his relationship with Beth. Dr. Brunvand’s doctor’s note, at long last, reflected what had been true for years: “He does have a long-term monogamous partner.”

  He also continued to keep his sense of humor, somehow, even in his darkest, near-death moments.

  On January 17, 2015, Jason, in Vegas, felt like shit. Everything hurt. Exhaustion overtook him. His vision blurred. Jason decided he probably should see a doctor. So what would you imagine Jason might do? He drove an all-nighter to the Colorado Blood Cancer Institute. He kept himself awake with chewing tobacco and a furious certitude that he could make it alive to Denver—the kind of will that once had earned him terrific respect from basketball coaches and foes. He drove over two mountain passes in excess of 12,000 feet with a quarter the amount of hemoglobin needed to carry oxygen.

  Somehow he pulled his van into the parking lot of the cancer center, whereupon he passed out.

  In and out of consciousness, he pulled out his cell phone and dialed the clinic. The team hustled out to the lot with a wheelchair, rushed him inside, and discovered his blood pressure and pulse were too low for the machines to get readings. They had to take his pulse manually. By the time they got to the elevators, Jason was able to
get some words out. That’s when Dr. Brunvand appeared.

  “Hey, doc.”

  “Jason, tell me what’s going on?”

  “I’ve been spending all my money in Vegas on hookers.” Jason smiled, let out one of his patented squeals. He was kidding, of course.

  Dr. Brunvand laughed, commenting, “We have bigger fish to fry right now. You are going to the hospital once we find a bed.”

  “It’s hard not to love a guy who sees God with one eye and the seedy side of life with the other,” Dr. Brunvand told me.

  Jason’s red blood cell count had been so low—20 percent of normal—that he well could’ve died en route. The Steel Bull, as Dr. Brunvand called him, was admitted to the hospital and treated.

  A few days after Jason had been admitted, he was visited by the medical team’s social worker, Melissa Sommers. Jason was still in the ICU and Melissa came in, trying to be somber and compassionate, and asked him how he was doing. He started to complain. After a few sentences, he ripped off the covers and burst out laughing. “You thought I was naked under here, didn’t you?”

  She couldn’t help but laugh.

  “Sorry,” he said. “I had to lighten the mood.”

  “I wish I could believe in God,” he told me.

  “Not your thing?”

  “I just envy people who can believe. I can’t find it. I’ve tried. It’s not for me. I think it would be comforting. I see it comforting people. But I just don’t see any evidence for it.”

  “I’m agnostic myself, J. No idea what’s out there.”

  “Sometimes I think about my dad being up there, somewhere out there. I’ll see something weird, like a light out on the highway, and I’ll think it’s a sign from him.”

  “What kind of sign?”

  “Like maybe whether I should bet on the Broncos.” High-pitched squeal.