The Family Gene

by Joselin Linder

  My thoughts were, I’m sorry to admit, mostly about yams. I told the admissions clerk about the blockage in my portal vein. I told her that my body was filled with varices. “Gastric varices,” I told her. “I’m having a bleed.”

  She looked at me kindly. She was too young to actually have a job at a hospital. Did she even know what a gastric varice was? A delicate pathway that could burst and cause internal bleeding? Could cause a stroke? Could pour out my entire blood supply through my mouth?

  I was shaking. I called Dr. Sigal, my doctor at NYU.

  “I’m in the ER,” I told him. My voice was so far away. He told me to have the doctor call him as soon as possible.

  Aaron was back with me now. He’d moved the car. I was mulling over the details of my life. What else did I wish I had taken care of before I died? Before my brain fell apart?

  In fact, in the midst of everything, I realized one important thing: I’m not very important. Maybe that wasn’t what I meant. I knew, like Jimmy Stewart had known, that Bedford Falls was better off because of him, and all that—but I was so mentally prepared for the moment that I would no longer be, that my thoughts, yams included, were fairly mundane.

  I worried for my husband. I worried that he would be consumed by rage. I worried that he would embrace his loneliness and isolate himself from the rest of the world. I worried that he would miss me as much as I would miss him if anything were to take him from my life. When I think about it, I am overcome, because I hate imagining that pain.

  I worry that my dogs will never understand why I left them. I worry that my nieces and nephews will read something I’ve written and misunderstand me and never get to ask me what I meant. I worry about these things. But there is no way to prepare for them.

  * * *

  The ER doctor came into the room and took everything I said very seriously. She nodded and wrote things down. She touched my wrist, feeling for my pulse. I was hooked up to machines and blood was drawn. I could still feel the searing-cold burn in my limbs, but the fog in my head was lifting. An intern asked me to raise my arms and touch my nose with a finger on each hand at the same time.

  “If you were having a stroke,” she explained, “you’d typically have different movement on each side. Or one side might be harder to control than the other.”

  Based on her logic, it seemed I was not having a stroke. Both of my fingers met my nose without confusion. But the searing. The haze. No, something was still definitely off. It was probably an internal bleed. I’d been coughing from a summer cold that wouldn’t go away. Each cough was violent and I couldn’t control them. I’d taken cough syrup but the coughing didn’t stop. I knew that coughing could cause a bleed. That involuntary spasm, the throaty scrape. It wasn’t good.

  In the gut-wrenching book Paula, Isabel Allende writes about the tragic and sudden death of her twenty-nine-year-old daughter. One line in particular resonated with me: “Life is nothing but noise between two infinite silences.”

  I thought that no one had ever put the truth of the matter so succinctly and beautifully. The thing is, I have always been living-centric. I think we are disposed to focusing on the times before and after living—because the living part is so short, so noisy. I understand the need to focus on those who have passed and those who are yet to come. Everyone we love, have loved, or will love has and will spend most of the time not living.

  I understand that having a belief in a place for the dead and preborn is part of the fabric of almost all religions. I hope it’s true, at least the stuff about the good places for the dead and preborn. Still, I am an optimist and am disposed to loving my here and now, which makes the living, and their ever-changing needs, the most appealing part of life to me. I care far less about what came before and what will come after.

  As I lay in that hospital ER dying, it became very clear to me that we must each make our peace with the mysteries we will die never understanding. We must be comfortable with the fact that we won’t know what the wrinkles will look like on our children’s faces when they are old, or how robots will take over the world—or become really good servants—or the conclusion to Game of Thrones. We must also make our peace with how each of us will be remembered, or forgotten.

  The thing was, I had just read a really good horoscope for August, and now I was going to die. And if I didn’t die, I was probably going to be severely impaired. This moment: this. It was the beginning of everything finally changing.

  Although my affairs were more or less in order, I was terrified.

  The ER doctor came back in. She’d spoken to Dr. Sigal.

  “We’ve done all the testing he asked us to do,” she explained. “Everything looks good. But stay here for another hour. We’ll check one more time.”

  The ER nurse who had been hovering nearby since I’d arrived explained that my blood draws had suggested I was not internally bleeding. If I were bleeding internally, my blood levels would be low, but they were not. So she asked me about my weekend.

  Aaron and I had driven to Boston for my cousin Becky’s birthday, I told her. It was just an overnight. Becky’s young, vibrant husband, Peter, was dying of cancer. He was swollen from his steroid cocktails, but still beautiful. Becky was trying so hard to act the hostess, helping her frail husband down the stairs. She was full of desperate laughter and kind attempts to make everyone feel at home, to make it all feel normal. Her sister and mother had prepared all the food. But Peter was still dying, and he was too young to die. Becky just wanted one night of normalcy, and all of us were trying to give it to her as best we could.

  The next day, as Aaron and I drove through Hartford on our way home to Brooklyn, we ate at an Olive Garden. We lamented how it is the one restaurant that always sounds better than it actually tastes. Afterward, we decided to stop at the Mark Twain house for a tour. I was coughing, thanks to my summer cold. Then my head filled with feathers.

  “I think I have to go to the hospital,” I told Aaron, quickly typing Emergency Room into my iPhone map app. Siri told us to return to the route.

  “Drive slowly,” I told Aaron. “Maybe I’m all right.”

  “Okay,” he replied. He was quiet, looking over at me occasionally, steady and calm.

  * * *

  The ER at the Hartford Hospital is a lovely place to fall apart. When the ER nurse asked me if I’d ever had a panic attack and I said no, she replied, “Oh, honey. If I had all the problems you described today, I would have had twenty by now. You were right to come.”

  After my second round of tests, I was discharged. My husband helped me take off the hospital gown and put on my clothes.

  I was alive.

  I didn’t care that it was a panic attack. That I had bothered my doctor on a Sunday. That I had missed Mark Twain. I was alive.

  The normalcy of the next few days overwhelmed me with their beauty.

  “I love you so much,” I told Aaron ninety times an hour. I hugged my dogs until they pulled away and hid under the bed.

  I made a lot of yams.

  I suppose I was bound to crack sooner or later. Next time, I vowed, I will understand my panic for what it is. Unless next time is the moment when everything changes.

  Thirty-Four

  The world of genomic medicine is a promising place.

  In the first half of the year 1999, gene therapy was all the rage. Articles touting the wondrous possibilities abounded in the media. Gene therapy was the panacea for everything from hemophilia to cardiovascular disease. It promised to change medicine. It promised to change the world. Using viruses to reconfigure genetic code, scientists theorized that they might actually be able to reprogram genes. It was an idea so fantastic that money poured in from everywhere in the hopes that gene therapy might someday cure everything from cancer to old age by changing our genes.

  Then the unthinkable happened: on September 13, 1999, Jesse Gelsinger, a relatively healthy eighteen-year-old, arrived at a hospital for an experimental injection. Jesse had a mild form of a liver
condition that kept sufferers from metabolizing ammonia, called “ornithine transcarbamylase deficiency.” He was participating in a gene-therapy trial. In infants, OTC deficiency nearly always proves fatal. The first gene-therapy trial in a human took place in 1990, and early testing was looking good. Jesse, who had been required to follow a special diet and take a steady dose of thirty-two pills a day for most of his life, was happy about the potential to rid himself of the illness. Moreover, he was happy to be part of something that could change other lives for the better as well.

  By the time this treatment became available to Jesse, its safety was a foregone conclusion. Animal models had already proven that any risks were limited. The administering doctors were confident that Jesse would not only survive the treatment, but he would benefit from it.

  Jesse received the injection. Four days later, he died. His official cause of death was listed as lung failure. However, the treatment Jesse had willingly subjected himself to (“for the babies,” the New York Times reported he’d told a friend) was something out of science fiction. Corrective genes were infused into a common-cold virus functioning as a “vector.” Vectors are the transportation devices that scientists use to drive DNA into cells and reprogram them. Researchers typically use them in order to change good information to bad—for example, to mutate the genes of mice in order to study human genetic illnesses. In Jesse’s case, they hoped these vectors would change his DNA from bad to good.

  Jesse’s death had a ripple effect. Medical studies involving gene therapy were suspended and in some cases stopped completely. For the next ten years, gene therapy and all the wonders it had promised screeched to a grinding halt, or so it might have seemed from the outside. In private labs, far from media scrutiny, gene therapies continued to be tested. They progressed at a much slower pace than before, but they were still being researched, and slowly, steadily, they were beginning to work.

  Fourteen years after Jesse Gelsinger died, three-year-old Eliza O’Neill was diagnosed with a recessive condition called Sanfilippo syndrome in 2013. After developing normally, at the age of two, Eliza began to regress. If her illness were left unchecked, she’d eventually lose the ability to speak and walk. Her parents, Glenn and Cara O’Neill, had only one option: prepare to watch their daughter die. The O’Neills decided to change that fate, for their daughter and every other child suffering from Sanfilippo’s.

  Cara was a doctor and Glenn had a background in business. Upon learning that there was a rudimentary gene therapy for Sanfilippo’s that had shown itself to be successful in models using mice but lacked the necessary funding to enter a human testing phase, they decided to raise the money themselves. The first thing they did was quarantine their family of four. If Eliza was going to remain eligible for the trial, her parents had to keep her from exposure to the AAV9 virus, which would exclude her from eligibility.* During the quarantine, her disease would progress, but her parents intended to do everything possible to keep their child eligible for the trial, so the family of four, including her now-nine-year-old brother, Beckham, stayed in virtual seclusion from the outside world for 726 days.

  Sanfilippo’s is a “lysosomal storage disease” in children that causes severe neurological degeneration and early death. A part of the cell designed to recycle specific molecules fails because a mutation robs it of one of forty-three necessary enzymes. A buildup of a substance called “heparan sulfate” causes all systems to eventually break down. Eliza was, at the present moment, as well as she would ever be. The O’Neills needed her to receive the treatment before things became worse, before she lost her ability to speak or other cognitive capacities. The clock was ticking.

  After Jesse Gelsinger’s death in 1999, many people were skeptical about gene therapy. In the summer of 2014, as the O’Neills barricaded themselves inside their home and prepared to fund-raise for a gene therapy that could save their daughter and others like her, something remarkable happened. Within eight months, their campaign, mostly limited to social media, had amassed 22,337 individual donors with donations totaling $1,040,000. That number is now in the multiple millions, and the foundation started by the O’Neills is finally funding urgent research.

  In May of 2016, Eliza was the first child to undergo a gene-therapy treatment for Sanfilippo syndrome. With a onetime injection, a corrected gene was sent directly into her bloodstream. Researchers are hopeful that Eliza’s outcome will mirror that of the mice models, which included restored cognition, improved mobility, and best of all, an extended life. In just a few months’ time, the O’Neills became hopeful about a bright future for their daughter.

  Gene therapies do one of three things: they replace a mutated gene with a healthy version of the gene; they “delete” a gene that is causing problems; or they introduce a new gene into the body, typically to fight a specific disease. In all three cases, genes are manipulated. Today, these therapies are only being tested on those patients who have no other options. Patients essentially have to be on their way out to become a part of one of these trials. What’s remarkable is that the trials are showing signs of working.

  Color-blindness is the basic inability to perceive color. Typically, a color-blind person can see some but not all colors. One gene for color-blindness, like my family’s gene, is on the X chromosome and is recessive. If an XY male gets an X from his mother with the gene for color-blindness, he will be color-blind. An XX female must get the color-blindness gene from both parents. Color-blindness isn’t deadly. It doesn’t make you swell or deplete your myelin sheath or fill your lungs with fluid. There was no cure for it because it was in the thirty-seven trillion cells of those who suffer from it.

  In 2009, that changed. Doctors at the University of Washington led by Dr. Jay Neitz came up with a revolutionary gene therapy. They injected a gene that produces a protein missing in color-blind rhesus monkeys directly into the monkeys’ eyes. Right now. Today. Gene therapy is changing something that was once an immutable fact—it is changing genes!

  Rhesus monkeys are a popular test subject for human medical genetic treatments largely because they share so much of our genome. The color-blindness gene, called “L-opsin,” when missing, eliminates red and green from the perceived color palette of both people and monkeys. Dr. Neitz doesn’t have all the answers yet, but five months after injecting L-opsin into his monkey subjects’ eyes, these animals suddenly had the neurological capacity to distinguish red and green. He believes it has something to do with their brains reconfiguring themselves to contain the new information in the injected gene.

  This therapy has blown open the door for treatments of multiple forms of congenital blindness. For example, Leber’s congenital amaurosis, a form of blindness caused by a breakdown in a sufferer’s ability to perceive light, has long been a contender for successful gene-therapy treatments.

  An even better contender for making gene therapy viable is a process called CRISPR. The acronym stands for “clustered regularly interspaced short palindromic repeats.” What CRISPR technology does is edit genes. It is like gene therapy—or is in fact gene therapy—except that the results of CRISPR are reliable and predictable where previous methods were a little more, shall we say, finger-crossy.

  In an episode of NPR’s Radiolab called “Antibodies, Part I,” hosts Jad Abumrad and Robert Krulwich very clearly articulate the amazing and wholly terrifying technology that is CRISPR. It all began when scientists who were reading the genetic code for some bacterial strains noticed short, strange sequences that, to the best of their knowledge, shouldn’t have been there. In the Radiolab episode, this situation is dramatized by having a single saxophone note sound repeatedly and suddenly tossing in a strange off-pitch note while the saxophone note continues. (Hence the name “clustered regularly interspaced short palindromic repeats”—CRISPR.) Biologists believed that this jarringly odd note in the middle of the series of expected notes had to have a purpose. What was it? Or, as Abumrad puts it, “Now scientists had this puzzle. If nature is preserving somethi
ng at this level, you figure, well, whatever this is, it’s doing something.”

  A biologist at the National Center for Biotech Information named Eugene Koonin suggested it was in fact doing something: it was acting as a defense system. To continue with the musical metaphor, the odd note imposing itself into the middle of a sequence of bacterial DNA was virus DNA that was being stored “like a mug shot,” Koonin says in the episode. You’ve probably heard of something like this in explanations of the phenomenon that our bodies tend not to get the same virus twice. This reasoning explains how immunizations work. Our immune system stores viral information so that it is prepared to fight that virus again later if it has to. With CRISPR technology, we can arm our own immune systems with a virtual mug shot, allowing them to recognize and target flawed genetic information with incredible specificity. “Immunotherapy” studies for cancer treatments are one area where we are already benefiting from this remarkable technology.

  What happened to Jesse Gelsinger wouldn’t have happened if CRISPR technology had been available. It’s the most powerful gene engineering we’ve ever had. It’s cheap and precise. Using CRISPR, we might be able to take the conversation from “How do we prevent global warming?” to “How can we alter the genes of corn so it needs less water in order to grow?” Or imagine answering this one: “How can we alter our genes so we can comfortably live underwater?”

  Of course, it is also possible that the powerful tools gene therapy is discovering may be beyond our understanding. Whether we are an empathetic enough animal to use CRISPR humanely or in humanity’s best interests remains to be seen.

  * * *

  While these treatments make me feel hopeful for myself and my family, right now they remain too costly. The Seidman lab, though, is still working on our case. To this day, they haven’t published their findings, and they haven’t yet given a name to our disease, but they’re working on it. In the fall of 2015, Dr. Kricket told me three things. The first was that three mice had been mutated with our gene. The second was that two of those three mice had already died.