The Family Gene

by Joselin Linder

  Twenty

  You can’t actually see DNA. Were you wondering? Were you asking yourself, how would Meredith Moore actually look at my DNA? Did she put a cell under a microscope and look at a floating little ladder-shaped double helix, maybe with a small cartoon gorilla smiling and waving from its rungs? The answer is, obviously, no. When scientists look at DNA, they look at colors. Researchers have to copy a single piece of DNA, made up of a nucleotide sequence, and just keep copying it over and over. To copy DNA, scientists heat up the two strands of DNA until they can be pulled apart. They use an enzyme to copy the information on each of those strands before putting them back together again. At that point, they have two double strands of the same DNA. They heat up those strands and separate them. Use that good old enzyme to copy them, and put them back together again. Then they have four strands of the same DNA. These strands are copied until finally there is enough so that when a bit of dye is added to the gobs of DNA copies, those copies will turn a certain color when exposed to different kinds of light. What these researchers are actually “seeing” when they look into the microscope is the dye that they have stuck onto the nucleotides. That light makes the dye glow in one of four colors: red, green, yellow, or blue.

  DNA is made up of only four nucleotides—one for each color that you see. That’s wild, right? There are only four of them, just showing up in some different order so that they are making the recipe for “eyeball” or “sit bone” or “hamster paw.”

  But it gets even more nuanced. How can it get more nuanced than four? you ask. Well, each of those four nucleotides has a buddy, or a significant other. The four nucleotides—cytosine, guanine, thymine, and adenine—are paired cytosine and guanine, and thymine and adenine. These are “base pairs.”

  By looking at the color they produce under a specific light, Meredith combed through my family’s DNA and “looked” for our gene, one base pair at a time. Let me be clear here. There are approximately 3 billion base pairs in the twenty-three chromosomes of the human genome. Around 153 million base pairs are in the X chromosome alone. And there can be as many as 27,000 base pairs on a single gene.

  Meredith was getting ready to look for our mutation somewhere on one of ninety-six genes. A mutation is basically a different or unexpected base pair (from anyone else’s base pairs on that same gene) showing up anywhere along twenty-seven thousand repeating base pairs. If I had been in Meredith’s shoes between the ages of twenty-seven and twenty-nine, this plan of attack—to simply read meticulously through thousands upon thousands of rows of the same two annoying couple of base pairs—would very likely have left me hiding under the nearest rock . . . or bottle of Jameson’s. But Meredith was ready for the challenge. She was excited by it.

  She immediately started looking for differences in the X chromosome of one male carrier and one female carrier against the X chromosome of a genetically unrelated member of the family, in our case a spouse of someone affected. She might have used, for example, me, my grandmother, and my uncle Norman’s wife, Ellen, who is genetically unrelated to either of us.

  That’s how Meredith got started: scanning colored traces looking for differences in the X chromosomes, specifically differences in colors, since those were what she was looking at. If she saw something promising, like a difference between a nucleotide sequence on a gene in Ellen’s X and a nucleotide sequence on a gene in my and my grandma’s X chromosomes, for instance, she would then look at the same gene of every single carrier. If we all had it, she then had to make sure it was also absent from every single spouse and additional unaffected family member.

  Meredith found thirty possible gene candidates out of the ninety-six genes she was studying. Those thirty candidates each had a code that was subtly different from the normal sequences of unaffected family members. Perhaps these different nucleotides directed the synthesis of protein somewhat differently than the “normal” ones.

  So that’s when her real work began. (Right? I know.)

  Meredith’s methodology at this point was pretty simple: start with the shortest genes. A gene is no bigger than the number of queued-up nucleotides that compose it. She picked the ones with the fewest nucleotides in order to knock those out first. Almost immediately, she stumbled upon a variant that segregated perfectly in that first set of samples. In other words, that variant showed up in one of mine and my grandma’s genes and not at all in Ellen’s. Then she checked a few more carriers, perhaps my cousin Valerie, Aunt Norma’s daughter, who also had the murmur, and my sister, Hilary. As she continued to compare it to people with both affected and unaffected X’s, she continued to get the result she hoped for.

  What was especially exciting about this discovery was that this gene was unknown. In other words, it had no known function. If Meredith, and by extension the Seidman lab, could prove that this gene was linked to our illness, leading to a catastrophic breakdown in the lymphatic system, it could prove to be an enormously valuable breakthrough for science, another puzzle piece latched on to the mysterious human genome. But the first crushing blow to this hypothesis came when one individual—my great-uncle Yussy, who was by then well past the age when the disease should have struck him down, turned out to have that variant as well. It turned out that that variant had just randomly worked out.

  Meredith used this experience to guide her in her testing. From that point forward, when she found an anomaly between my grandma and me, and my aunt Ellen, she’d start by looking at the genes of the “normal people.”

  Remarkably, Meredith honed in on the correct variant, or specifically four variants, all clustered in the same region of one gene, relatively early in her testing. The variants were on one of the short ones. In order to be thorough, she had to continue to lumber through each of the other twenty-nine genes, proving over and over that carriers had it and noncarriers didn’t. Like that early variant that had at first seemed so perfect, odds were she might have come across a second, or even a third potential variant that segregated. In that case, she would have had to come up with another way to narrow down the focus even more.

  But as luck would have it, no other mutations appeared, and the Seidman lab flew me to Boston to give me the good news. I would love to say I was immediately launched out of my black-hole life. I’d love to think that the news wowed me and shook me to my core.

  Because as Meredith Moore gave me her biggest fangirl smile and told me about her momentous accomplishment, she understood that she had done something meaningful and good for my family that would positively impact all of our lives. Even though she didn’t discover a new gene—she added to already existing information about a known gene, which was not something to sneeze at—she had done something monumental for our family. She had done what no one had been able to do in the five years my father lay dying: she had given us an answer that with any luck would lead to more answers.

  It occurs to me now that if I had been myself in those days, if I had been halfway interested in my own life, I might have swept her into a bear hug and wept for joy. Instead I got back on a plane and returned to San Francisco. My ankles still swollen, I likely turned on computer solitaire and continued to have no idea what to do next.

  Twenty-One

  In June of 2005, for lack of a better idea, I moved to Brooklyn. On a recent visit to New York City for my twenty-ninth birthday, a good friend had mentioned that come fall, she would be looking for a new place to live and that I could move in with her. Another friend had shown me the best websites for job hunting. I needed something to break me out of my funk and into some semblance of a life. Remarkably, this worked. When I told my therapist my plan to move, she had been wary. She suggested I wait six months to make sure it was what I really wanted to do. I am only partially kidding when I say that I think she might have enjoyed my twice-a-week, out-of-pocket checks. But I waited out those months, and then I drove back across the country, leaving my car in Ohio and taking a rental the rest of the way to Brooklyn. My lack of health insurance, and the increasi
ng bloat in my ankles, made living four hours by car from Boston and Dr. Kricket very appealing.

  Immediately I loved New York. I loved the energy and the palpable sense of possibility. Even more, I loved my friends, with whom I immediately fell into step. I got a job working for a small independent film company, and my friend Lisa and I got an apartment together.

  Dr. Kricket arranged for me to meet with a blood doctor at New York Presbyterian regarding my exceedingly low platelet count, or “thrombocytopenia.” My platelet count had been hovering somewhere around 60,000 since college. Normal is around 150,000 to 350,000 platelets. This hematologist, a colleague of Dr. Kricket’s from her medical school days, was going to use a brand-new machine to test my platelets. I was told that Matt Lauer had been the first person to ever get tested with this particular machine, on live TV. At the time, the machine was the most high-tech imaging machine available. It could investigate blood flow, including the manufacture and function of platelets, better than any other machine.

  The test was part of a study related to a long-shot theory a colleague of Dr. Kricket’s had about the function of platelets. Dr. Kricket asked that I be included in the study, almost exclusively as a favor, since very few of my symptoms fit the criteria. The research team was looking for something called “supersticky platelets.” According to their brand-new theory, some people struggling with chronically low platelets simply didn’t need normal platelet levels because the ones they had worked so well. They were supersticky, the clotting champions of the world. Hilary and I had platelet levels that made us contenders, however unlikely.

  I changed into a hospital gown and climbed into the strange spherical machine that had once held Matt Lauer, but I didn’t understand the study or my place in it. All I knew was that my ankles were swollen and Dr. Kricket said to go, so I went.

  With goodwill as my only health insurance since I’d graduated from college, I brought the team conducting the study some cookies. I met with the doctor, who glanced obligatorily at my swollen ankles and muttered a disinterested “uh-huh.” I leaned forward in a seated position, holding on to two bike-handle-like contraptions. Two X-ray strips encircled my body. One strip ran around my body lengthwise and the other crosswise, but unlike one would be in a traditional MRI machine, I was not wholly encased. A tech came in and pricked the crook of my arm to prepare an IV port. The mood was light. I was certain that we were going to find the answers to all of my questions, despite the fact that no doctor in the fifty-plus-years of treating my family illness could tell us what was going on. What can I say? I’m an optimist.

  The hope machine noisily shifted my body forward and backward and side to side, like a slo-mo version of the flight simulator Lea Thompson battles in the 1986 movie Space Camp. Dye was added to my blood through an IV. It tasted like I was drinking and subsequently peeing metal, a surprisingly common hallucination for anyone who has undergone an MRI with contrast. The dye helped the researchers visualize my blood flow. Something else was injected so the researchers could watch how my bone marrow (where platelets are produced) functioned, as well as how the platelets themselves behaved.

  After thirty minutes, I was released, then sent to change back into my street clothes and be on my way. No one called for several days, so I called them. No answer. Two weeks later, an intern called me back.

  “Everything looked good!” he said cheerily.

  “What do you mean?” I asked.

  “It looks good. Your blood looks good.”

  I thanked him, although I wasn’t sure why, and hung up. I called Dr. Kricket for further clarification.

  “Well, your platelets aren’t supersticky,” she admitted.

  “So what do you think is wrong?” I asked.

  “What do you mean? You’re anemic. A lot of people are anemic.” She’d resorted to her old answer. I’m not sure how knowing about the function of my platelets would have impacted my future one way or another, but it sure would have made a difference to have finally had a positive test result, good or bad.

  Dr. Kricket didn’t say it, but I knew that there were so many unknowns about my family’s illness that grasping at straws was almost as good as following actual leads. Genetic illnesses begin in places that we cannot see, with damage often originating at microscopic levels. Our genome has at least three billion places to look at and interpret. It’s like digging through a haystack for a needle when you don’t even know if you’re actually looking for a needle. Every strange object researchers find, they have to consider. It’s a slow, tedious process, and when all of this was happening, that process was at its slowest and most tedious, because all of it was new.

  * * *

  Several weeks later, I went to another hematologist for a second series of tests, including a complete blood work-up, to see if the mystery of my platelets could be solved. When the doctor came into the room, he shook my hand, and then he looked down my pants. As a blood doctor, his jurisdiction definitely did not extend to my underwear. Yet he pulled up my hospital gown, lowered my pants zipper with a quiet “May I?” then pulled back the elastic band of my colorful Hanes all-cotton hipster briefs.

  I understood what he was looking for because when I met him, I’d explained that I had a rare mutation on the X chromosome that led to an unnamed condition. The X chromosome is a famous chromosome. First of all, of all the twenty-three chromosomes, it is only one of two with two names. The X chromosome is also named “chromosome 23,” but that’s its boring name, and the X chromosome is a lot of things, but boring is not one of them.

  It’s like the Marilyn Monroe of chromosomes—Norma Jean, to those who didn’t know what she could become with a little red lipstick and a lot of peroxide. I might be a little biased toward the X because that’s where my mutation lives. Of course, if you have Down syndrome—which involves the occurrence of a third “chromosome 21”—that might be your most famous chromosome . . . your Tom Cruise of the chromosomal world, if you will. Or if you have Huntington’s disease, you might feel like its location on chromosome 4 makes it Mick Jagger to the other twenty-three chromosomes’ Ronnie Wood. But the truth is, the vast majority of us wouldn’t notice any single chromosome playing a day-to-day role in our lives. But chances are, if you know a chromosome, you know the X, because we all have one, and it does a lot.

  When the hematologist looked down my pants, he was probably looking for a vaginal anomaly. I don’t have one. The hematologist was misguided in looking for one, but possibly, as a blood doctor, he slept through the genetics portion of his medical school studies, which I’m told is a really short one anyway.

  The general consensus is that one single chromosome can code for multiple outcomes. In other words, no chromosome does only one thing. And X-chromosome–Marilyn Monroe, because she is so popular, is actually incredibly prolific, genetically speaking. What’s more, science knows a relatively good amount about the X chromosome, which is arguably very little, but in the world of chromosomes is a huge amount. We know that a gene on the X chromosome codes for seeing colors. Another gene codes for the size of your cornea. Another still has a direct correlation to myelin, the coating that protects the neurons that make up your nervous system. There are around two thousand genes on the X chromosome. Each gene, in large part, is coding for its own thing. Occasionally, they work in groups. However, just because a guy is color-blind because of a mutation on his X chromosome doesn’t mean there is anything wrong with his private parts. They just aren’t related, at least not like that.

  Meredith Moore had mapped my family gene on our X chromosome, and she saw something interesting. Our mutation was on the very same gene that sometimes has a mutation that serves as a marker for asthma. Since our symptoms were nothing like those of asthma, at least on the surface (lymphedema and starvation versus shortness of breath) it would seem obvious that this gene had other jobs outside of assisting with breathing. At that point, however, we weren’t certain what those jobs were. What we did know was that if our mutation had sim
ply chosen a different part of the gene to mutate, we might have all merely had a good old-fashioned case of asthma. But it hadn’t chosen a different part. Not by a long shot.

  I was visiting the hematologist on the off chance that he could tell me the cause of my low platelet count, which, along with my swollen ankles, remained an unexplained anomaly. During the autopsy of my great-aunt Norma, Dr. Kricket did not find low platelet counts or other physiological factors that might contribute to low platelet counts. And the hematologist, in addition to finding nothing remarkable in my pants (I can say that comfortably because I’m a woman), found nothing remarkable about my blood. I left that day with another diagnosis of “I don’t know” and a phone call from Dr. Kricket reminding me that I would live to be an old woman just like my grandmother.

  Except my grandmother, like her sister, didn’t have a low platelet count. My sister and I did. So maybe our platelet count was something else entirely. As siblings, Hilary and I shared a lot of genes. Since no one else had the platelet issue that we knew about—I had by this point forgotten about Valerie’s post-funeral mention of hers—it was possible that it was unrelated to the gene that had killed so many people in my family. Hilary and I did have a propensity for bruising, but we both had normal periods. When we cut ourselves, the bleeding would stop in short order. Platelets are the part of the blood that clots, or turns it from a liquid to a solid when it meets oxygen so that you won’t bleed out from a hangnail. It was clear our blood could and always did clot normally.

  Regardless, our platelets were going to have to wait. Soon after the results came back inconclusive from the hematologist, my phone rang. It was Hilary, my thirty-one-year-old sister, calling me from a bathroom stall, 530 miles away at her office in Columbus.