The Family Gene

by Joselin Linder

  I laughed all the way to Forty-Second Street.

  Thirty-Two

  Aaron and I scheduled a trip to Boston in March of 2014.

  When we arrived at the Brigham, Barbara, the lovely nurse who worked with the Seidmans, sat with us in a room. Soon Dr. Kricket and a new postdoc fellow, who had taken over for Meredith Moore, joined us. Aaron and I sat at a round table, flanked by a laptop computer and a big-screen monitor. The room was small and felt crowded, but the atmosphere was electric as Dr. Kricket began her presentation.

  My father had worked so hard to understand his condition twenty years ago. He had tried out every possibility. Now he was gone, but every one of his questions still lingered, unanswered. In fact, seventy-five whole years had come and gone since my great-grandmother left her husband and her five young children to live on a screened-in porch so that she could figure out how to take in a full breath of air. Lymphedema had filled the limbs and bodies of five generations of my family, and had already killed five.

  Dr. Kricket began to speak.

  “We’re going back to ancient history, my friend,” she began, addressing me as she launched into her presentation full steam ahead. First, she reexplained the job of the lymphatic system.

  “The lymphatics,” she explained, “are a salvage pathway. They pick up all sorts of material—debris, fluids, electrolytes—that seep out of vessels during their normal processes.” She went on to say that initially, she and her team had looked into several very rare conditions that cause lymphedema. None of them fit, and she knew this largely because of the fluid that was present in my stricken family members—it wasn’t yellow and thin like the fluid in a blister; it was thick and sticky, lymphocytic exudate.

  The next step was to look into the mechanism that channels the fluid, the lymphatic system itself. It was easy to rule out a broken lymphatic system, largely because of the condition’s adult onset. If the problem originated in the vessels of the lymphatic system, those of us carrying the family gene probably would have had abnormal swelling our whole lives.

  “If you think about it,” she told us, “if you guys didn’t have working lymphatics, why would you start having this problem when you were forty? You would have had this problem when you were a kid. Kids get banged up all the time. You’d have swelled with every bruise. And you didn’t. So we didn’t really expect a broken lymphatic system.”

  When my great-aunt Norma died, Dr. Kricket conducted her autopsy and ruled out any abnormalities of the thoracic duct, the entry vessel between the lymphatic and the vascular systems. “Even the anatomist at Harvard Medical School, who analyzes autopsies for a living, came and found no abnormality there,” she said.

  At that time, she and her staff had begun talking to everyone in the family, and the first thing they discovered was that no one under the age of twenty had had any excess fluid anywhere. What most of us did have were heart murmurs, indicating a narrowing in a vessel of our hearts. “A little narrowing,” she said, “above the pulmonic valve.”

  At this point, Dr. Kricket put up a family tree—called a “pedigree” when used for medical or scientific studies—on the screen. It included every family member with the gene, and the symptoms they had exhibited.

  “So the reason I’ve put you through this torture,” she said with a wink, “is to tell you, we have found a very, very, very rare variant and it has never been described in anybody else.”

  The enormity of that statement momentarily made me dizzy. Never. In anybody else . . . except my great-great-grandmother, my great-grandmother, my grandmother, my great-uncle, my great-aunt, my father, my uncle, my sister, my five cousins, and myself.

  Twenty years ago, in one of the medical journals my father kept, he had written that there were “no additional recommendations or advice” because “no one knows what we are dealing with.” It had been a very long line of nonanswers. From my great-grandmother Mae’s misdiagnosis of pleurisy to my great-uncle Nathan’s ten months at the NIH that ended with a chart note that read “the basic disorder . . . is, after all these many months of hospitalization, still completely unknown.”

  Dr. Kricket was about to change all that. Once again, she was about to change everything.

  * * *

  One little note in one of the many lists of questions from my father’s personal medical journals simply reads, “It can’t be just the liver, can it?” He wrote exactly that.

  It can’t be just the liver. Can it?

  It was almost like he had to make the definitive statement: It can’t be just the liver. But then he’d thought about it for a second and wondered, “Can it?”

  Dr. Kricket began the rundown of what her lab’s extensive, twenty-year study had revealed. It was this: our condition was vascular. And that “vasculopathy,” as it’s called, seemed to be originating in the liver. So yes, to answer my father’s question: it can be just the liver.

  Everyone’s liver makes something called cysteinyl leukotrienes (CLs). Those in my family do it too. We all have these things in our livers called cysteinyl leukotriene receptors. The CLs are the keys and the CL receptors are the locks. When our keys get to our locks, they are supposed to unlock them. If they listen to our mutant gene, however, they will do something abnormal.

  “We have a very small idea about what and why that is, but I don’t want to drive you crazy,” Dr. Kricket added. “What we do know is that that system regulates pressure.”

  There are blood pressures in our liver that pull blood from our intestines and our spleens in order to purify it. That’s what our livers do—they clean our bodies of toxins. But in my family, a mutant gene causes liver pressures to become confused and the liver to no longer be able to properly siphon the toxins out of our blood.

  “We think that fundamentally there is an abnormal signaling pathway that changes the pressure,” she continued. “As a compensation, there is an expansion of vessels to get around the liver to get the blood so it circulates normally. The spleen gets larger, the lymphatics get compressed, and you end up with lymphedema.”

  It’s this little glitch that causes this complication throughout our bodies, and it is very likely impacting other parts of our vascular system as well. This includes our heart murmurs; my dad’s sticky heart valve; my great-uncle’s drooping eyelid, caused by a collapsed vein in the back of his eye; and even my cousin Valerie’s stroke. When it does its worst, it tackles our lymphatics, knocking out our body’s ability to absorb nutrients, causing us to slowly starve.

  And that is our breathtaking little gene.

  * * *

  After Dr. Kricket’s presentation, Barbara, the nurse, took my hand. I had known her for half of my life. She is one of Dr. Kricket’s right hands, juggling several of the Seidman “balls” at any given time, and always with smiling dimples and ruddy red cheeks. Her red hair has grown blonder the longer I’ve known her, while she somehow manages never to age.

  “I want to show you something,” she said.

  I had only been to the lab once before. It was a crowded, active space, with papers cluttering desktops covered with microscopes and old computers. Shelves housed piles of equipment I’d never seen before and some that took me back to my high school biology class.

  We walked into another room and then to a darkened room several turns from where we had begun.

  “I thought you might like to see this,” Barbara said, smiling. She pointed to a small sturdy metal cylinder about four feet high. It reminded me of the home kiln one of my mother’s best friends, a clay sculptor, kept in her basement.

  “It’s a freezer,” Barbara said, the apples in her cheeks getting redder. “It’s where we keep some of our immortalized cells . . .”

  These weren’t just any immortalized cells. These belonged to my family.

  “Your dad’s alive in there,” she said.

  I felt the hair on my arms stand up. My father had been dead for eighteen years. I smiled back at her as she squeezed my hand, tears filling our eyes.
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  Stranger still was my next thought: I’m alive in there too.

  * * *

  The meeting at the Seidman lab had energized me. All we had to do now was go to a pressure doctor and figure out how to maintain the pressures that were off in our veins. Or, as I so readily have taken to putting it at dinner parties, “We just have to figure out how to keep our veins pumping correctly.”

  At one such dinner party, however, someone quickly burst my bubble.

  “But veins are passive,” said a guest who knew what he was talking about.

  I mumbled something about how delicious the salad was.

  That person was right. Veins are passive. They don’t really do a whole lot. They are channels, receivers. It’s a little bit like saying that the congestion in the Holland Tunnel could be fixed if we could just get the Holland Tunnel to push the cars through, gulp them down into New Jersey. Veins don’t pump.

  What’s more, there aren’t really a great number of vascular specialists out there, largely because . . . and I hate to be redundant, but veins are passive. Most vascular specialists specialize, much like an engineer does with a tunnel, in helping to make sure the veins are routing things properly. The biggest job of most vascular specialists isn’t to worry as much about the stuff being transported—the blood, the lymph, the waste—but to worry about where it’s being transported.

  This brings us back to cardiologists. These are the people who are in charge of the thing that pumps—the heart. Remember, according to Dr. Kricket, there was something off in the pressures of our veins. Cardiologists, like Dr. Kricket, are on very intimate terms with things like pressures because they are focused on the thing that is exerting the force that is making the blood run through our veins—and arteries and lymphatics. Cardiologists know tons about the heart. As opposed to the vascular and the lymphatic systems, they know loads about the arteries—the first and largest channel into which the heart pumps. But—and this is not to suggest that cardiologists aren’t brilliant—as the arteries meet veins and blood moves onward, their area of expertise typically diminishes.

  Surgical radiologists spend a lot of time with veins. They love that veins are passive. They especially love that veins are passive and the pressure of the blood flow in them is much lower than arteries. It means they can explore a patient’s body with a camera, or guide a catheter or other device from outside of the body to a place requiring a corrective procedure without ever having to cut into a person’s flesh. “Surgical” radiologist is actually a misleading term, because surgical radiologists actually make what used to be a surgical procedure less surgical. Today, my father’s zipper scar from neck to navel would never have been cut. Instead, a small prick at the jugular vein in his neck, or in his groin, would allow a radiologist to drive a balloon through the veins to his heart and correct the narrowing by blowing that balloon up when it got there.

  Again, radiologists aren’t vein specialists per se.

  My friend Molly, the nurse who introduced me to the idea that a burst varice in my esophagus could lead to a bleed out of my entire blood supply through my mouth, is a PICC-certified nurse. “PICC” stands for “peripherally inserted central catheter,” and is pronounced pick. This certification actually allows a nurse or technician to access any part of a patient’s vasculature. Maybe a PICC-certified nurse is as close as we will ever get to a vein specialist. The key thing to note here is that these nurse specialists pretty much always access veins. Almost all of their procedures require an extensive and thorough understanding of veins and vein pressures. Like radiologists, they choose veins because veins are the best highways to navigate through a body. They have a relatively strong structure like an artery, but they don’t have blood flow like a barreling freight train—more like a slow and steady hand-crank locomotive.

  Here’s how the circulatory system basically goes. The heart pumps a giant squirt of clean, freshly oxygenated blood right into an artery and it moves through the body, delivering oxygen and nutrients while collecting toxins to flush out. As Molly explains, when she’s threading a wire to get to the edge of the heart, she knows she is in an artery when she loses control. She often has to pull the wire back out and start again. When you consider that the whole of the circulatory system is sixty thousand miles long—that’s two and a half times the circumference of the earth—you realize just how much work the heart has to do. With every new pump, it has to start a new cycle and push forward the rest of the blood supply already en route. However, it’s safe to say that pressures close to the heart are much higher than those in, say, your toes.

  Arteries carry all the good stuff from your heart and through the body. Your veins, meanwhile, are in charge of the return trip to the heart. They rely on whatever pressures are left after pushing blood through a very long and arduous journey through the arterial system.

  That isn’t all there is to it. Arteries are not passive. They actually provide resistance against what is hopefully a strongly beating heart. They aren’t just Holland Tunnels receiving a bunch of cars. They are helping to control the pace at which those cars move, pushing back—like the Highway Patrol—to keep the speedsters from driving at maximum speeds. The thing is, veins aren’t entirely passive either! Yes. I know what I said. Imagine if our veins just sat there, receiving blood and lymph and waste, and didn’t do anything. The vein would simply expand and expand, when it actually needs to channel blood. Even the veins, albeit at a diminished rate compared to the arteries, help control how much and how fast the blood moves through them. In fact, they help to control the pressures. I suppose they’re surprisingly active.

  So, could it be that the blood pressures that are controlled by the veins—minimal though they may be—are what was causing the blockages and lymphatic overspill in my family members? The eyelid drooping and the strokes? The murmurs and the enlarged spleens? Was I right at those dinner parties? The veins weren’t pumping correctly?

  * * *

  Dr. Kricket doesn’t think so, and she said as much during our Boston meeting, although it took some time for her words to settle in. Dr. Kricket said it: cysteinyl leukotriene receptors manage pressures in our livers. It turns out that Dr. Kricket now believes that something else besides the heart pumps blood: our livers. While studying our gene, she has been able to explore the fact that livers also help pump blood. This revelation is a pretty big deal.

  “The liver,” Dr. Kricket said that day, “is making molecules that regulate blood flow into the liver.” The protein that serves as a sensor for those regulatory molecules mutated in us, in our bodies, on a gene in our X-chromosome where that protein doesn’t exist.

  The liver plays a very important role in our bodies. As I said before, it purifies and removes unwanted materials from the blood. Food goes into our mouths, and after hitting the stomach, it gets absorbed into our bloodstream. Then those nutrients are taken to the intestinal tract and are processed into waste. A vein called the “portal” vein brings the blood into the liver so it can clean and detoxify whatever it has to clean and detoxify. This is an important function that keeps our bodies healthy, and it turns out that the liver helps regulate the flow of this blood: a surprising revelation. My family’s livers, because of our genetic mutation, were not correctly regulating the blood flow into them through the portal vein. In my family members’ bodies, the portal vein changes, withers, as a result of “weird” pressures causing blockages. Eventually, everything backs up.

  The Seidman lab was trying to figure out whether or not the pressures in the portal vein could be increased. In fact, a number of bioengineers are studying this question. At least, that’s what Dr. Kricket has told me.

  A cure for us remains hypothetical. It is far from guaranteed.

  But when you’re still feeling healthy, “hypothetical” and “far from guaranteed” don’t add up to “out of the question,” which makes a cure almost seem possible—even likely. When you are no longer healthy, “far from guaranteed” becomes about the same as �
�out of the question.”

  My father knew this well.

  “I am sure that if we get a diagnosis that’s complete,” reads the final sentence of an entry in his medical journal, “the treatment will not be easy.”

  Thirty-Three

  It is rational to fear death, but it is not logical.

  —Socrates

  My stroke started on a Sunday during a road trip. It had been a full year since Dr. Kricket had figured out the minutiae of my family’s genetic condition. I was staring at the clock on the far wall as I sat at the desk of the emergency room admissions clerk at a hospital in Hartford. It was taking too long. My head was filling with blood. I could feel it. I’m bleeding.

  “I’m bleeding,” I told the clerk outside the ER.

  Aaron was next to me.

  We’d left our car outside the ER door. We didn’t care that the signs said no parking. A uniformed police officer had come in and was now talking to Aaron. Maybe about the car. Aaron got up and followed the police officer outside, perhaps to move the car.

  Aaron is going to be alone, I thought. Does he know about the yams? Did I tell him that the yams are really important to me? I really wanted our dogs to eat a scoop of boiled yams with their kibble. I couldn’t remember if I’d ever said it.

  Oh, shit. What if, when he gets back, I’m too out of it to explain it to him? The blood was filling my brain. Maybe my body cavity. How would I explain the yams? I could barely speak. It’s all so white—everything in my line of vision was covered in a white foamy haze. What if all I could say was “Yams,” and then I died, and then Aaron had to be like, What the hell did she mean? What if “Yams” became my “Rosebud”? Would that just be the lamest thing? Did I really care if the dogs ate yams? How much did I care? I tried to quickly figure it out before I was too far gone.