I’m the only one in the advanced lung disease and transplant center who is not barrel-chested, wearing a mask over my nose and mouth, or carrying an oxygen tank. Many of the patients have emphysema, which gets worse over time and can’t be cured. When I perform the six-minute walking test, the nurse marvels at my ability to speed-walk the hospital corridor, turning on my heels and returning at the same pace at which I started. On a scale of 1 to 10, how is your breathing now, she asks every second or third “lap.” I shrug my shoulders and say, 10? When I finish, she removes the band from my temples and the clips from my body, and tells me my oxygen is 100%. The center has never had a patient like me, so able and healthy at fifty-two.
So, how did I get here?
I spit into a test tube at home and mailed it to a company that tests your genes for $299. The test tells you if you are at elevated risk for or are a carrier of certain diseases, predicts how you would respond to common treatments like blood thinners, and whether you have, say, native Americans or Vikings in your bloodline.
From my spit, I learned that my DNA is 3.1% Neanderthal, I am distantly related to Katie Couric, and I am what my future support group calls an “Alpha.”
No, I’m not the dominant one. I have a genetic condition called Alpha-1 Antitrypsin Deficiency that causes emphysema and liver disease. When you have this deficiency, your liver doesn’t produce enough of a protein that your body needs to keep your lungs healthy. And what little it produces stays in the liver where the accumulation can cause scarring, cirrhosis, and liver cancer.
Most people with Alpha-1 start out healthy enough, but somewhere between the ages of thirty and fifty, they begin to suffer shortness of breath, wheezing, have recurring colds or even bouts of pneumonia. In some cases, their abdomen swells and the whites of their eyes turn yellow—signs of liver problems. Alphas with respiratory problems are usually misdiagnosed as having asthma. For seven years, on average, they’ll be prescribed medicines that don’t help them, their condition gradually deteriorating, before someone finally orders an inexpensive blood test. Even though Alpha-1 is one of the most common serious hereditary disorders, it takes doctors this long to figure out what’s really wrong. Discovered in 1963, it affects about the same number of Whites in the U.S. as cystic fibrosis: 1 in 2,500.1
For his book Am I My Genes? Dr. Robert Klitzman interviewed people with three different genetic disorders. He spoke with 32 women with BRCA mutations—which affect 1 in 300-500 women, raising their risk of breast and ovarian cancer—and 21 people with Huntington’s disease, which strikes 1 out of 20,000 people. But he only interviewed 11 Alphas.2 I was disappointed—I wanted to hear more about Alphas’ experiences and perhaps my future. But most Alphas don’t know they’re Alphas until they develop symptoms and eventually get tested.
I don’t have any symptoms. Yet.
So, why did I get tested? What was I looking for? In the school yard, looking for trouble meant you were looking for a fight.
I took the gene test partly out of scientific curiosity. As a public health professional, I’d heard and read that “personalized medicine,” healthcare tailored to an individual’s precise genetic make-up, was the wave of the future. And I got tested for personal reasons, as well.
My father died of liver failure at age thirty-nine. A beatnik poet, ex-con, and alcoholic, he was mostly absent from my life. I used to write about him in poems, like this one addressed to a half-sister I hoped to locate and did:
Of course, he died young.
You must know that.
Poetry is a dangerous thing
but it’s gentler on the liver.
It wasn’t my father’s early death, however, that prompted me to order the test. It was my mother’s at seventy-five, two years after she was diagnosed with lung cancer and emphysema.
A lifelong smoker, she had quit seventeen years earlier. Even though she’d done it for the wrong reasons—to protest rising cigarette taxes—I had been proud of her. In the two years I was shuttling my mother to doctors, lifting her out of the bath tub, and later, changing sheets with her still in them, I noticed I was getting more out of breath than I used to. The result of aging, stress or something else? I had been exposed to two packs a day or more of second hand smoke from before I was born until the day I left for college. Visiting the gym once in a while and taking a genetic test that wouldn’t require explaining my possibly groundless concerns to a doctor seemed like a sensible first step.
In fact, this is one of the things that worry health experts, bioethicists and others about direct-to-consumer gene tests: the results aren’t disclosed by a doctor. People read them online or receive them by mail and are left to interpret them alone. There is also concern that the tests, which are largely unregulated, may not always yield valid results. In 2011, there were at least twenty companies offering mail-in kits, and what was an $80 million industry in 20083 is expected to grow to $230 million by 2018.4 One company—23andMe—has sold nearly half a million kits since its founding in 2006.5 Their test and their competitors’ provide a potpourri of information, but not a map of your whole genome. While whole genome sequencing still costs thousands of dollars, in a matter of years it will become as affordable as the “genetics-lite” tests are today. This means that in the future there will be even more people like me, who are healthy enough—until they discover that maybe they aren’t.
Before being told by the Food and Drug Administration in 2013 to stop selling their unapproved gene tests,6 23andMe used to cheerlead: “Be your own best advocate!” The implication was that not only can you understand your results, but you know better than anyone else what to do with them.
I reacted to my results by getting the baseline testing that the genetic counselor and Alpha-1 sites recommended: I got lung function tests and a CT scan, and I got an ultrasound of my liver. All of this gives a snapshot of my susceptible organs now so that we can assess the damage from my deficiency thus far and measure changes over time. I reacted by scouring PubMed and pouring over peer-reviewed journals. I did all of this because I like to look, because I prefer knowing over not knowing, and because I am not comfortable with questions, particularly those with no answer.
Keats famously wrote of “negative capability,” “…that is when man is capable of being in uncertainties, Mysteries, doubts, without any irritable reaching after fact & reason…”7
While I adore Keats and share his vocation (I’m also a struggling poet—that is, I struggle to write poetry), I don’t have his vaunted negative capability. I may not reach after fact and reason irritably, but, boy, do I reach. This is probably what drove me to study biostatistics and epidemiology, in addition to literature.
In spite of my Master’s in public health and careful attempts on the part of genetic testing companies to warn consumers that some of the information they are about to receive could be upsetting, I didn’t realize right away that “variant present” for Alpha-1 Antitrypsin Deficiency was bad news. My Alpha-1 results weren’t contained in a padlocked folder like those for Alzheimer’s and Parkinson’s. Okay I’m a carrier, I thought, not realizing that in my case “variant present” meant I had inherited the same mutation—a “Z”—from each parent. I bear the mark of Zorro twice. With two Zs, I wasn’t just a carrier but a full-fledged Alpha—one who must prepare to live on the planet of not-enough-oxygen, Star Trek uniform and all.
But when the proverbial penny dropped, what did I do? I ran to my health scientist boss standing at the photocopier and announced breathlessly: I have this deficiency that means I will probably develop emphysema soon, and guess what? They think that my deficiency was probably beneficial centuries or millennia ago—providing an evolutionary advantage!
Is this negative capability?
Sickle-cell anemia is a debilitating disease that affects mainly black Americans and others of tropical or sub-Saharan African descent, but being a carrier of it also protects against malaria.8 Back when people didn’t live long enough to develop emphysema, and before antibiotics, the lung inflammation caused by Alpha-1 Antitrypsin Deficiency enabled people like Vikings and Celts to better resist infectious disease. The flu, pneumonia, and TB that were killing other people posed less of a threat to them.9 But as with most biologic responses that rescue us—histamines that help flush allergens from our bodies and inflammation that helps cure us and heal wounds—too much of a good thing can make life unbearable and even kill us.10 When inflammation lingers or becomes chronic, it promotes disease, including many cancers, instead of combating it.
If your body becomes a paranoid survivalist with duct-taped windows and seven years of canned foods in the basement, every concerned neighbor who knocks at the door is a threat. Instead of tearing up and sneezing out an irritant, your hair-trigger histaminic response will lead you to develop allergies to plants, pets, and foods that you encounter every day. Or worse still, your body will turn on itself, causing you to develop autoimmune diseases like lupus or rheumatoid arthritis.
Yeah, if I’d lived a long time ago, I would have been really cutting edge, I concluded. Fascinating, said my boss. Fascinating, I said.
Living in uncertainty shouldn’t be confused with positive spin or denial. We do have antibiotics, which used conservatively and correctly save us from life-threatening illness. And most of us do live past thirty or forty—well past. So, what was once a selective advantage was no longer.
While I was watching VHS tapes, everyone else was streaming.
After I shared my test results with my boss and before they scanned my lung and liver, before they tested my breathing, locking me into a Plexiglas cabinet and telling me to blow out with all my force—more, more, more—I would lie awake in bed and wonder: is that twinge in my right side my liver? Is the tiny cough and extra phlegm that sometimes wakes me in the night the beginning of emphysema?
With genetic knowledge, your body becomes a double agent in the service of two superpowers. It works for the country of health but it’s also in the employ of another nation, the one that will win the coldest war of all. After a certain age, all of us, even the most vital—the pole-vaulters, Sherpas, and Navy SEALs—are in the process of dying. We’ve climbed the rungs of that bell-shaped curve and are on our fannies sliding down. Maybe not hands raised and screaming for joy—maybe we’re using the sticky heels of our sneakers to slow the descent—but we’re sliding down, nevertheless.
Montaigne wrote, “We do not know where death awaits us: so let us wait for it everywhere. To practice death is to practice freedom.”11 When I try to explain the anxiety that comes with knowing my Alpha-1 status, my husband says in exasperation, we’re all going to die of something. My husband is from Mexico where freedom is practiced every November 2. There, you can celebrate Day of the Dead with a candy skull bearing your name and by picnicking in the graveyard, hired musicians serenading your loved ones below. On that day, a glass of tequila is left on altars and beside tombstones because even the dead need something to lift their spirits.
On my liver doctor’s orders, I’ve stopped drinking alcohol. I used to enjoy the occasional tequila but now I guess I’ll have to wait until… I’m dead. Cue the old joke: Doctor, will quitting smoking and drinking help me live longer? No, but your life will sure seem longer.
Months after getting my test results, I continue to reach after facts, after a reason I will be spared the outcome predicted by my genes. But how reliably do genes foretell our future?
Most of the diseases that direct-to-consumer genetic testing companies screen for, like heart disease or type-two diabetes, are “polygenic,” meaning your risk of developing them depends on many genes and their interaction. And if that’s not complicated enough, how you live and what you eat also have to be factored in. If polygenic diseases were horses, they would be the ones with the longest odds.
When it comes to predicting disease, the safest bets are monogenic disorders, such as Huntington’s disease, caused by a mutation in a single gene (HTT). As with any gene mutation, it’s only one little mistake, but it’s repeated in every cell. It’s as if every grocery list, report or email you’d ever written contained “hte” where you thought you had written “the.” A person with Huntington’s carries a pair of genes—one with spell check and one without—on the fourth chromosome, and it’s the one without that wreaks havoc. If you have it, you will eventually lose your coordination, forget things, become depressed and irritable, and suffer accelerated cognitive decline. And each of your children has a 50% chance of inheriting it and developing those same symptoms.
Because Huntington’s is autosomal dominant, your spouse’s typo-free fourth chromosome does nothing to protect your child or lower her risk.12 Like Huntington’s, sickle-cell disease and Alpha-1 Antitrypsin Deficiency are monogenic, but they’re recessive: children have to inherit the mutation from both parents to have the condition. The recessive pattern is much more equitable—the mother and father have joint custody of the guilt.
Dead parents know no guilt.
Denial, bargaining, anger, depression, and acceptance—not necessarily in that order—are Kübler-Ross’s five stages of grief. After playing Pollyanna with my boss, arguing with my unfeeling husband who just “didn’t get it,” and weeping inconsolably in a meeting with a financial advisor, I decided I’d experienced at least three stages. How were others, especially people without my health background, handling their genetic test results? How, I wondered, were they reacting to the news that, because of their genes, they are more likely to get sick, develop a chronic condition, or die early?
Some might be motivated by test results to take their prescription medicines more regularly (what doctors call increased “compliance”) or make “lifestyle changes,” such as cutting out saturated fats and going to Zumba class twice a week. Bioethicists and others in the public health field, however, fear that test results could cause overwhelming anxiety and even depression—particularly when people don’t really know how to interpret them. They have warned that test results will lead healthy people—the “worried well”—to demand unnecessary and costly screening tests.
It turns out that some of the concerns about direct-to-consumer genetic tests, as well as the hopes for them, are unwarranted. Several studies have been done to see what effect genetic tests and even genome-wide profiling have on people. In other words, do test results change the way people feel or behave? According to a 2011 article in the New England Journal of Medicine, over 90% of the approximately 2,000 people who participated in one study felt no “test-related distress.” They were no more anxious, ate just as much fat, and exercised about the same three months after getting their test results as they did before taking it. While 10% discussed their test results with a genetic counselor and over a quarter claimed to have shared their results with a doctor, there was no statistically significant change in their reported use of screening and other medical tests.13 One problem with this particular study was it relied on participants to remember and tell researchers what tests they took.
But another, more recent study published in 2012 in Genetics in Medicine circumvented the thicket of “self-reporting” by using electronic medical records to measure changes in health behavior. What’s more, this study had a control group: 400 people who did not undergo genetic testing who were very similar to the 217 who did. The researchers compared health care use between the two groups in the twelve months before the genetic tests were given and in the twelve months after. They found that the individuals who underwent genetic testing didn’t visit their doctor more frequently or get more lab tests or procedures than those who were not tested.14
After the Huntington Disease mutation was discovered in 1986, it was assumed that most people at risk would get tested. But according to studies published in 2000 and 2003, only 5%–20% actually wanted to know for sure if they were going to develop the disease.15
Dr. Klitzman writes: “Before undergoing testing, the assumptions many people make as to whether they possess a mutation or not can in fact verge on premonitions and reflect notions of fate. In looking back, many say that they not only felt destined, but foresaw their future.”16
When I was twelve, I swam competitively. All summer, I would practice my strokes—freestyle, breast, butterfly, back—as I walked the streets of Georgetown, barefoot, wearing cut-off jeans, flat-chested beneath my Peter Max tee-shirt. Arms moving like wings, I raced against air. Fifteen years later, a psychic would tell me that I had drowned in a past life.
My zodiac sign is Libra, an air sign. I tell people I have claustrophobia, which is fear of being shut in, cloistered, but what really makes me avoid caves, scuba diving, and crypts is fear of airlessness.
Hours before my mother died, she called me in a panic from her apartment down the street and announced: “I’m dying.” Her boyfriend and I were working with a hospice agency to keep her comfortable and allow her to die at home, in her own bed. This involved supervising her medications and morphine and making sure the oxygen machine was working properly. When she phoned at 11:00 p.m., I had just gotten home from visiting her. I had watched her use her inhalers and take her sleeping pill. And I had checked the clear plastic tubes that delivered oxygen to her nose, holding my finger to them like a mother to her sleeping newborn’s nose.
“How do you know you’re dying?” I asked. “I can’t breathe.” “You’re still able to talk, so you must be breathing,” I reassured her, and we both laughed. The hospice nurse had warned us that at some point my mother might feel panic over her labored breathing. The emergency kit in the fridge included anti-anxiety pills. I reminded my mother of them and she said, “Yes, yes, I need one of those pills—right now!” She took the Ativan and lay in her boyfriend’s arms in the dark until she was calm again, until she could fall asleep. In the morning, she was on her side of the bed once more, eyes open, truly breathless this time.
My Alpha status may make me outmoded but what if innovation, a quality more widely valued these days than negative capability, is embedded elsewhere in my genome?
Since getting my genetic test results, I have become fascinated by the non-gene parts of DNA—the part scientists previously dismissed as “junk” or “dark matter.” Four million or more switches are hidden in this junk. They control which genes a cell will use and when to turn them on. Despite all the knowledge acquired from the Human Genome Project, we are assembling furniture using instructions in a language no one understands. Rather than continue to strip screws, researchers are creating a dark matter dictionary: the Encode project.
There must be words in there that can help me, a counter-spell.
Epigenetics, too, seems to offer a possible escape hatch. “Bad genes” (and good ones) can be overridden by physical and emotional experiences. Only recently scientists have uncovered evidence that what happens to us—especially in the womb and during our early years—affects not only our health but the health of our children and grandchildren. If your mother was in prison while she was pregnant, given only Saltines and water and regularly burned with cigarettes, your epigenome might bear the tattoo teardrop of her experience. Your mother or father’s experiences don’t change your genetic code but they can alter its expression, and these alterations can be inherited. It’s called the epigenome because it sits above the genome, god-like.17
Will epigenetics be my deus ex-machina?
Given dark matter and the epigenome, I have begun to think of my body as a cacophony of opposing voices, a system of checks and balances. I have a baby tooth that has hung on into my fifties: call me conservative. Our mouths can no longer accommodate four wisdom teeth, and I adaptively grew only two: tick the box for “progressive.” Even my dentist conceded that in this regard I was the latest model—a hybrid. Does my body contradict itself? Like Whitman, it contains multitudes, or so I tell myself.
One of the two abnormalities found in all my baseline testing: I have a high bilirubin count. Bilirubin is broken down by the liver—mine still seems to be fine, no signs of cirrhosis—so that it can be excreted. It’s what oxygen-carrying red blood cells leave behind as they wear out and die, and it gives bile its nasty yellow tint. When babies are born with jaundice or a person gets sick with hepatitis, their pee turning the color of coffee and feces becoming ashen, they have too much bilirubin in their blood.18 The doctors don’t know for sure but they suspect that my high bilirubin level is the result of another predominantly Scandinavian mutation believed to be harmless: Gilbert’s Syndrome.19 Combing through the medical literature, I find a study published in 2011 in JAMA, the Journal of the American Medical Association, that draws as its conclusion: “Relatively higher levels of bilirubin were associated with a lower risk of respiratory disease and all-cause mortality.”20
Can a small, apparently benign abnormality keep a potentially deadly mutation at bay?
Sogyal Rinpoche writes in The Tibetan Book of Living and Dying: “It is absolutely certain that we will die, and it is uncertain when or how we will die.”21 Genetic testing would appear to challenge this wisdom. According to Klitzman, “A mutation can thus suggest not only the etiology, or cause of disease, but the timing of one’s demise.”22
Is this true for Alpha-1? The fact that Alpha-1 is under-diagnosed doesn’t just mean that many sick people who should be tested for it aren’t. It also means there are people alive and well into their eighties who, unbeknownst to them or anyone else, are Alphas. For now, I belong to neither group. I’m a member of a new tribe, one that will surely grow with the advent of easy and affordable genetic testing: the asymptomatic Alpha.
My genes don’t fit, and this is a good thing. Lest this comforting thought rob me of the chance to cultivate negative capability, I only need to turn to Big Pharma. There is no cure for emphysema or Alpha-1, but there are drugs that Alphas with emphysema can take called proteinase inhibitors (PIs) which raise the plasma level of the deficient protein.23 “Augmentation therapy” is usually given intravenously every week and costs about $100,000 a year.24
One augmentation therapy manufacturer, Prolastin, calls Alpha-1 “one of the most prevalent potentially fatal hereditary diseases.”25 The italics are mine. Meanwhile, competitor CSL Behring says on its website: “If undetected, 75-85% of patients with severe Alpha-1 Antitrypsin deficiency will develop emphysema.”26 Where did Behring get this statistic? I haven’t seen it cited anywhere else—not on the National Institutes of Health website,27 not in any medical journal article, and not even on any of the Alpha support sites, several of which receive funding from augmentation therapy manufacturers. And would Behring classify a ZZ with a blood concentration of 4.4 μM like mine (the range for ZZs is 2.6 to 9.1, with higher numbers being more protective against disease) as severe?
The Food and Drug Administration requires the manufacturer of Prolastin to include this on the drug label: “The effect of augmentation therapy on pulmonary exacerbations and on the rate of progression of emphysema has not been demonstrated in adequately powered, randomized, controlled trials for any Alpha-1 product.”28
In other words, there’s no proof yet that augmentation therapy works.
The only other abnormality the baseline tests turn up, besides my high bilirubin level, is a “nodular infiltrate” in the lower lobe of my right lung. Infiltrate: “to enter or take up positions in, gradually or surreptitiously, as for purposes of espionage or takeover.”29
The infiltrate could be a sign that I recently had a bacterial infection like pneumonia, which, as far as I know, I haven’t; it could be something growing there, benign or not. Given my years of exposure to cigarette smoke, my lung doctor wants me to have another scan. In six months she will look to see if the knotty mass in my lung has resolved or changed in any way.
Staring over her shoulder at the computer, I ask “But don’t CT scans turn up a lot of stuff that isn’t important?” “Yes,” Dr. Shlobin laughs, “they give you a lot of schmutz.” The CT sees your lung with the infinite detail of an autistic child, and it’s up to a trained human eye to filter and interpret. Most days I’m confident that the infiltrate will go the way of the garbage in my back alley, disappearing (less noisily, I hope) from my sight forever.
But the CT scan raises the same problem that genetic testing does: the problem of looking. When an archaeologist uncovers a ruin, her years of tedious labor are vindicated and her life’s dream is realized. Oh, the publications, the tenure, the fame…but there is a problem, one that is proportionate to the size of the find. How to conserve it? The minute the discovery is exposed to light and air, colors fade, vandals must be outwitted, and someone’s budget must accommodate the treasure-burden. Poorer countries are forced to weigh the benefits of potential tourism against the costs of protecting (from the elements and looters), displaying, and appropriately caring for this artifact.
I’m not a country or an archaeologist, but I have a family, including a daughter and two half-siblings, all of whom are carriers or possibly Alphas like me. Do I tell them, or do I leave this information in the ground for someone else to dig up? If they find out that they are Alphas, their right to health insurance would be protected under the 2008 Genetic Information Nondiscrimination (GINA) Act, but because of their status, they could be denied life insurance, disability insurance, and long-term care insurance.30
If my half-brother or sister or sixteen-year-old smoked, or drank enough for me to worry, I would have told them right away about their one, maybe two, Zs. Still, “there are the children to consider”—the ones they’ve had and will someday have. And always counterbalancing heritability, mitigating its worst effects, are the cures to come.
When they do, I’ll be looking.