Introduction
“He’s perfect,” pronounced the pediatrician at my two-week-old son’s inaugural check-up. I flushed with happiness. What a nice thing for a doctor to say to an insecure first-time mom. And yet he was wrong. We all have genetic mutations. In fact, each human being kicks off life with about sixty new mutations, or changes in their genes.
Some are more obvious than others. Some cause problems, others don’t. Nobody’s perfect, the adage goes. When it comes to our genes, that’s especially true.
In 2007, when I was pregnant with my third child, a routine ultrasound revealed a cyst on my daughter’s developing brain. Flat on my back in a darkened room, ultrasound goo smeared on my belly, I froze. Contending with any ominous-sounding “cyst” would have been bad enough, but processing the idea in conjunction with my baby’s brain, her tiny body’s command center, was chilling. I heard the doctor say that such bubbles frequently go away but may also indicate trisomy 18, a devastating genetic condition that is often fatal soon after birth, if not in utero. I could opt for what doctors call “watchful waiting,” keeping tabs on the cyst via ultrasound as my pregnancy progressed, or I could choose an amniocentesis—a needle inserted into my womb—to suction DNA for analysis from my daughter’s skin cells, free-floating in my amniotic fluid. In skilled hands, the risk of miscarriage is very low, but it still exists. What did I want to do?
I am an information junkie, so for me the decision was clear: my husband and I went straight from my doctor’s office to the office of the specialist who would do the amnio. It was a quick, if sharply painful, assault on my midriff. Predictably, I spent the next day or so panicked that I would miscarry, wondering if I’d made the right choice. Then, on a Saturday afternoon in January, on my middle child’s second birthday, the phone rang. The lab was calling to reassure me that initial results showed all the chromosomes where they should be. I sank onto the couch, folded the birthday girl, Shira, in her purple velvet frock and with her budding blond curls, into my arms, and cried with relief.
Imagine my confusion a few days later when our mail carrier shoved a copy of the lab report, which I’d requested, through the mail slot. The amnio had indeed ruled out trisomy 18, but it had inadvertently revealed that my baby had a different, unrelated condition: inversion 9, a transposed ninth chromosome. For some reason, the top portion of the chromosome had landed on the bottom; the segment that was supposed to be on the bottom had migrated to the top. All the relevant information was still there; it’s akin to putting your underwear in your socks drawer and your socks in the drawer reserved for undies. You could still find the wayward socks and undergarments, arranged neatly—they just wouldn’t be where they ordinarily reside.
It was, I learned, one of the most common genetic errors. Even the lab report dismissed its relevance, its technical language reassuring me that this genetic blooper was benign or, in the language of the lab, “not associated with clinical effects.” Perhaps, but I quickly found that knowing about it was strongly associated with emotional effects. One of my daughter’s chromosomes was upside down and I wasn’t supposed to worry? What’s more, it was highly likely that either my husband or I had the same inversion, considering that the lab report noted that this topsy-turvy presentation was considered a “normal familial variant.”
To allay my fears, I took the ill-advised yet irresistible path that so many of us tread when faced with unfamiliar health-related information: I paged Dr. Google. I came across one small study that indicated an increased risk of schizophrenia, a finding that still makes me blanch when my daughter, Orli, throws a tantrum or acts particularly irrational, traits that—let’s be honest—are not wholly uncharacteristic of the average grade-schooler.
Still, I wasn’t prepared for this surprise genetic discovery; nor are countless other parents who encounter similar situations. And yet our growing reliance on a constantly expanding arsenal of genetic tests to enhance our understanding of our children at their most basic cellular level means that this scenario is becoming routine. It’s not that I wish I didn’t know; I’m glad I know, because now, if new research is published that finds Orli’s error correlates with disease, I’ll be paying close enough attention to delve into that research and see what I can do, if anything, to reduce her risks. Over the years, I’ve assimilated the news of Orli’s genetic anomaly, incorporating it into the vivid panorama that is my tennis-playing, panda-obsessed youngest child. I can’t honestly say that I think about her chromosomal quirk on a daily or even weekly basis, but it does pop into my mind from time to time (remember those tantrums?), and sometimes I wonder: What if the lab report is wrong?
I first started paying attention to the increasing role that genetic testing is playing in children’s health back in 2011. I was covering parenting and pediatrics for Time and received an email from Pediatrics, the official journal of the American Academy of Pediatrics, about an intriguing study. The research explored parents’ eagerness to subject their children to tests that transcended the boundaries of the ever-growing catalog of genetic diseases comprising the routine “newborn screening” regimen that takes place in hospitals across the country. The research in question was fascinating: in a large group-practice health plan, 219 parents were offered testing for themselves for genetic variants associated with increased risk of eight fairly common adult-onset conditions—heart disease, high blood pressure, high cholesterol, Type 2 diabetes, osteoporosis, and cancers of the colon, skin, and lung. Asked if they’d like the same genetic testing for their children under age eighteen, the parents indicated that they thought the benefits of testing their kids outweighed any risks. Their gung-ho attitude seemed to stem from a belief that testing could certify their kids as grade-A healthy.
In fact, researchers had tried to talk the parents out of testing their kids (no kids were actually tested; researchers were simply trying to gauge interest) by telling them that there were no known health benefits to doing so, but the parents were not deterred. They may have assumed that their kids—whose average age was ten—would get a clean bill of health. Yet the fifteen different gene mutations associated with the eight diseases the parents were being screened for are so widespread that any particular child would likely have tested positive for nine mutations.
“What? Really?!” I exclaimed to Colleen McBride, senior author of the study and then chief of the Social and Behavioral Research Branch at the National Human Genome Research Institute (NHGRI). Parents, myself included until that moment, seemed pretty clueless about the stories that genes may whisper or shout within our bodies. Yet more and more genetic tests are being introduced—and more and more genes are being singled out as potential troublemakers. We are learning more and more about our genome, our genetic code, but at the same time we still don’t understand the basics. As McBride characterized the parents when I interviewed her for the Time story: “The more they anticipated feeling good, the more they wanted to test. But the reality is, those parents are going to get bad news. Their kids are going to be at risk for something. So how are they going to react to that?”
That question is at the heart of this book. Is genetic knowledge empowering or fear-inducing, or both? Will it heighten the anxieties of already hyper-anxious helicopter moms and dads, always waiting for the genetic shoe to drop? Will it make parents more diligent about their child’s health so that they offer broccoli over brownies and slather on the sunscreen? Will it stress parents out or make them savvier?
There’s no indication that parental enthusiasm for genetic information is waning. In fact, a 2014 survey revealed overwhelming support from newly minted parents. In the study, 514 of them were asked within forty-eight hours of their child’s birth if they’d be interested in having their baby’s genome sequenced, its DNA code deciphered and scanned for errors that may be associated with disease. Thirty-seven percent said they were “somewhat” interested, 28 percent indicated they were “very” interested, and 18 percent reported they were “extremely” interested—a total of 83 percent. Factors such as gender, race, education, and income level didn’t seem to make a difference one way or another: four out of five parents thought sequencing their baby’s genome seemed like a pretty sound idea.
Even notoriously nonchalant teenagers want a piece of the action. When 282 Cincinnati students in middle school and high school were asked if they’d want to know genetic results about hypothetical conditions that wouldn’t affect them for years, 83 percent of them said, “Yes, please.”
We are accustomed in our tech-savvy world to accumulating data on our children. There are apps to track a baby’s sleep, how often he eats, when she dirties a diaper. But tallying genetic mutations trumps tracking the daily toll of soiled Pampers.
In an information age that compels us to be connected 24/7, no longer do we run to the shelf to pull out a volume of the Encyclopaedia Britannica. We are all encyclopedias now with the help of an Internet connection. But all this information can be disconcerting. When I talk about my work, I find that people are either giddy with the promise of information or quaking at the thought of attempting to divine their destiny and that of their children and grandchildren. Even the scientists who are doing the research in the academic trenches, advancing these technologies from theory into practice, are on the fence about what they want to know about themselves and their loved ones. At one of the most esteemed children’s hospitals in the country, one geneticist I interviewed spoke proudly of having his genome sequenced; another, whose office is within earshot of the first’s, disparaged the trend as self-important and superfluous.
Regardless of differing views, there’s no doubt that genetics is reshaping pregnancy and childhood. In the process, it’s changing the experience of what it means to be a parent.
* * *
Not long ago, having a baby was a fairly straightforward venture. When a couple decided to have a child, they’d ditch the birth control pills and dim the lights. But with no plastic wand with twin purple lines to offer instant at-home confirmation, there was no easy way to gauge success.
The first home pregnancy test—a diagnostic tool now taken for granted by the 4 million women who give birth each year in the United States—wasn’t developed until the 1970s. For centuries before that, women relied on various methods, including the so-called “grain test,” which supposedly had the added benefit of sussing out gender. An Egyptian papyrus from 1350 B.C.E. explains the not-so-scientific theory behind the practice of a would-be mother urinating on wheat and barley seeds: “If the barley grows, it means a male child. If the wheat grows, it means a female child. If both do not grow, she will not bear at all.”
When I was conceived in 1971, my mother learned she was going to become one by heading to her doctor’s office after she missed her period. She was offered no genetic tests, got no real-time sonographic glimpse of her daughter-in-waiting doing weightless flips inside her abdomen, had no clue if I’d be a boy or a girl. She didn’t know if I’d emerge with ten fingers and the same number of toes, let alone the proper number of chromosomes. She was expecting, and she was oblivious to all the things that could go wrong.
Fast-forward four decades. We are a generation fueled by information, and at no time in our lives do we crave it more than when we are poised to become parents—and once we have our babe in arms. We snap up pregnancy books and memorize developmental milestones as we steep ourselves in the minutiae of a world so unfamiliar it might as well be another country. Even the language is foreign—hyperemesis gravidarum? Reciprocal babbling? As we struggle to find our footing in this strange new place, the cluster of cells nested deep inside is already under scrutiny.
Indeed, at a pregnant woman’s first prenatal visit, she rolls up her sleeve and lab techs promptly divest her of multiple vials of blood destined for testing. Soon after, more tests are offered via ultrasound and additional blood draws, and via samples of placental tissue and amniotic fluid, revealing a depth of information that scientists couldn’t have fathomed a generation, even a decade, ago. Nor is baby herself exempt.
Across the United States, before parents leave the hospital with their new charges, the infants have taken what a newborn screening education website cleverly dubs Baby’s First Test. No one, of course, is suggesting that infants be quizzed on their ABCs. This first test doesn’t require much of them, just a couple of drops of blood extracted from a pinprick of their heel. The blood is smeared on specially prepared filter paper, then sent to state labs, where it’s screened for rare genetic and metabolic conditions, some of which may quickly prove fatal if not detected.
Newborn screening has been a pillar of public health since 1963, when Massachusetts became the first state to routinely screen infants for phenylketonuria, or PKU, an inherited metabolic disorder that causes brain damage if left untreated. PKU achieved this distinction not because the condition is any more devastating than scores of other genetic diseases, but because it is treatable if detected early—and because the microbiologist Robert Guthrie developed a cheap, effective way to screen for it. This one test spawned the development of others, and what began as a public health measure to detect just PKU has expanded to include dozens of diseases.
There’s little question that newborn screening has saved countless lives. Each year, screening identifies more than 5,000 infants who have genetic disorders with severe, frequently deadly, consequences. Babies who screen positive undergo further testing to confirm a diagnosis and are referred for treatment.
The newborn screening program is a government-funded safety net designed to ensure a healthy start for the newest members of society. “Newborn screening occupies a very privileged place,” says Robert Nussbaum, former chief of the Division of Medical Genetics at the University of California, San Francisco. “It is a form of testing that undergoes the least amount of scrutiny of any genetic testing we offer in society. Newborn screening is a social contract between the population and the government.”
It’s a contract of which many parents remain unaware. Although newborn screening is technically optional, parents often have no memory of being asked about it. Detecting sick babies before they have symptoms is so critical for successful outcomes that parents are not specifically asked to consent. Most newborn screening is done in the hospital between twenty-four and forty-eight hours after birth, when a baby’s enzyme and metabolic levels are within a measurable, age-dependent range; babies born outside the hospital can have their testing done by a nurse midwife or a pediatrician. “It’s an opt-out model,” says Natasha Bonhomme, director of Baby’s First Test, a federally funded clearinghouse for information and education about newborn screening in all fifty states, administered by the health advocacy organization Genetic Alliance. “It’s considered so important that you just go and do it.”
That’s not the case with the ever-growing array of testing available prenatally, postnatally, and even pre-conception. The expanding number of options means that the act of parenting, of making choices for and about a child, now starts long before a baby’s first breath. Mothers and fathers are urged to leave less and less to chance. More testing, earlier than ever, means they don’t have to.
Now, not only do most parents know ahead of time what color to paint the nursery, but technology exists to tell them whether their developing cluster of cells has Down syndrome or a genetic deletion so tiny that it wouldn’t have been detected even a few years ago. Mutations that heighten the lifetime likelihood of developing a great variety of diseases can also be identified, a dicey dance considering that many conditions, such as early-onset Alzheimer’s, cannot be treated: What good is it to know about a risk of disease if there’s nothing that can be done to help? This information exchange about possible or actual progeny is often taking place before the end of the first trimester, maybe even before an embryo implants, forcing parents to make difficult decisions based on an unprecedented deluge of data. Information is usually seen as a good thing, especially in this digital age. But is it possible to have too much information?
* * *
Do parents like Laura—flat on her back on an exam table in midtown Manhattan, pants off, shirt on but pushed up over her pregnant belly, silver lamé high-tops glinting in the darkened room—really want to know their child’s future?
Laura is thirty-three and has come to see Ronald Wapner for chorionic villus sampling, or CVS, in which Wapner, director of maternal-fetal medicine at Columbia University Medical Center, will plunge a needle through her abdomen into her uterus to collect enough placental tissue (its genetic makeup reflects the fetus’s DNA) to determine whether her pregnancy is healthy. He snaps on clear latex gloves, small-talking as he swabs her belly with Betadine, and compliments her shimmery shoes while warning her she’s about to feel a “really strange sensation of pressure.” Laura grimaces. Wapner inserts the needle. When he removes it seconds later, the attached syringe is filled with whitish specks floating in a clear pinkish liquid. The white specks are placental cells; they look like goose down. The fluid is tissue culture media that was present in the syringe from the start. “This could not have been easier,” Wapner reassures Laura.
No one would make the case that CVS is an enjoyable way to spend a few minutes, but if you’re going to do it, wild-haired, charismatic Wapner is the go-to guy. He helped mainstream the first-trimester test and has about as much experience doing the delicate procedure as anyone else in the United States, where it’s been offered since the 1980s. It’s typically been used to diagnose Down syndrome and other major chromosomal disorders via karyotypes—essentially, chromosome counting—but in the last few years, Wapner has been at the forefront of obstetricians in the United States who are expanding the procedure’s purview. In a pivotal study published in 2012 in the New England Journal of Medicine, Wapner showed that the tissue collected via CVS can also be scrutinized using a technology called chromosomal microarray analysis. Microarray analyzes fetal cells for countless other, less apparent disorders that occur when a tiny snippet of DNA has been added somewhere it’s not supposed to be or deleted entirely, revealing genetic hiccups that previously could not be detected prenatally. Some of these changes are meaningless; others may be associated with autism or rare disorders such as DiGeorge syndrome, which is characterized by heart problems and a roughly 25 percent risk of developing schizophrenia.
This is the latest frontier of reproductive genetics: tests, such as microarray or fetal genome sequencing, so sensitive that they can uncover information no one fully understands. “What should we test a fetus for?” says Wapner. “I’m not suggesting at all that this is bad, but we need to have a discussion about where we’re going with this ability. The technology is fantastic. But the easier it is to get information, the more tempted we may be to let our guard down on what we look for.”
Microarray is just one of many tests that have been repurposed for pregnancy and beyond in the past few years, as the scope of genetic testing has broadened. In tandem with in vitro fertilization (IVF), more-targeted analysis has allowed women to weed out unhealthy embryos before attempting pregnancy, allowing parents to essentially rewrite their family’s medical history: they can stop a genetic disease from climbing up a family tree. Blood-based tests early in pregnancy can now identify Down syndrome and other major chromosomal errors before a woman is visibly pregnant, with unprecedented accuracy, although positive results still require confirmation via amnio or CVS. Genome sequencing—the new gold standard for DNA analysis—lays bare a child’s genetic blueprint, including predisposition to disease. (It’s particularly useful for sick children for whom doctors have been unable to land on a diagnosis; sequencing can help solve medical mysteries.)
Yet what use could come of telling parents of genetic findings—a gene for elevated Alzheimer’s risk found in a six-month-old, for example—that may not be relevant for decades to come? Is it good medicine, not to mention good parenting, to test a first-grader for a mutation that increases the risk of breast cancer, or does it deprive her, as some bioethicists argue, of her right to an “open future”? On the other hand, is it unethical to keep that information from parents, especially if new preventive treatments are developed that would need to be implemented in childhood? Put another way, if you’re a parent—or hoping to become one—imagine you’re lucky enough to be Angelina Jolie, who in 2013 intensified the national conversation surrounding hereditary susceptibility to breast cancer. The actress announced that she’d had a prophylactic mastectomy after testing positive for a BRCA gene mutation, which increases the risk of developing breast and ovarian cancer.
Jolie has three biological children; she must wonder if she’s passed on her mutation. If you were her, would you want to know if your daughter has a mutation that sharply increases her risk of breast cancer, years before she even begins to develop breasts?
Society is grappling with a landscape that is constantly remaking itself: tests are replaced so quickly by newer, more comprehensive versions that even professional genetic counselors are finding it hard to keep up. “The type of testing, even from last year to this year, is so different,” says Anna Norvez, one of Wapner’s genetic counselors, shortly before Laura’s arrival for her CVS procedure at Wapner’s office. “There is so much that’s unfamiliar, but we are all getting more comfortable with dealing with uncertainty. You have to be, if you’re going to be offering these tests.”
From the room next door where he’s dictating charts, Wapner can’t help himself. He trumpets: “You deal with uncertainty every freaking day!”
Norvez is unfazed by her boss’s outburst. He’s prone to passion. Still, he’s a good guy to work for; his immersion in research means that Norvez and her colleagues are au courant on the latest developments in genetics. Plus, he’s generous: nearly every day, Wapner orders in lunch—Neapolitan pizza the day I was there—and foots the bill.
“I know,” she yells back to him, before addressing me again. “There are a lot more databases, so we are increasingly able to give parents some sense of, is this going to be okay or not okay? Obviously, you can’t be sure. So it comes down to what the patient’s level of comfort is with uncertainty. If they have a very low threshold, they may choose to terminate. If they have a high threshold, they may say, ‘I’ll try not to think about it, but if the kids have problems, at least I’ll know what it might be.’”
In a counseling session before her CVS procedure, Laura tells Norvez that her goal is to set her mind at ease, to be assured she’s carrying a healthy baby. A mom of two, she’d lost her third pregnancy at eighteen weeks. “I would like to get this all wrapped up and know the pregnancy is okay,” she says.
Norvez nods, then tells Laura that she has an option—microarray—to peer even deeper into her baby’s DNA than she’d anticipated. Laura is uneasy. “As a patient, I would assume information like that could be overwhelming,” she tells Norvez.
Norvez doesn’t try to talk her into it. “That is why someone might not do it,” she says. “You’ve hit the nail on the head. It comes down to your threshold for uncertainty. Would you be okay if we found something unknown?”
“What kind of diseases are we talking about?” asks Laura.
“We can find something on par with Down syndrome, if not worse, which is why some people might say, ‘Do it,’” Norvez explains.
“Say I get my initial results and they’re good,” says Laura. “I’m feeling awesome, I can sleep again, then you call in two or three weeks to say there’s a slight deviation of this or that. That’s what I worry about.”
Like 40 percent of the women Norvez counsels, Laura decides to stick with the narrower spectrum of karyotyping over the more comprehensive microarray testing; her tissue is saved, though, in case she changes her mind.
“It’s not bad if you feel this is too much for you,” Norvez concludes, then adds her own dry commentary. “We like to overload people with information.”
It’s true. Having access to more information can enlighten and confuse. It can enable parents to prepare for a child with special needs. Or it can allow them to end the pregnancy before a woman’s belly starts to swell. This book is not about right or wrong answers, only extremely personal and intimate calculations. It’s not a finger-wagging tale of gloom and doom but an examination of incredible technological advancements. Ultimately, knowledge is power. We are lucky to live in an era when we can dig deep into who we are, although we need to do so carefully and with context from genetic counselors (of which there’s a serious shortage). The testing we elect and that which we forgo, and the choices we make based on the results, has profound implications for what sort of society we want to be.
Copyright © 2017 by Bonnie Rochman
