Is screening for disease in an embryo a humane form of family planning or a slippery slope toward eugenics? Should doctors tell you that your infant daughter is genetically predisposed to breast cancer? If tests revealed that your toddler has a genetic mutation whose significance isn’t clear, would you want to know?
In The Gene Machine, the award-winning journalist Bonnie Rochman deftly explores these hot-button questions, guiding us through the new frontier of gene technology and how it is transforming medicine, bioethics, health care, and the factors that shape a family. Rochman tells the stories of scientists working to unlock the secrets of the human genome; genetic counselors and spiritual advisers guiding mothers and fathers through life-changing choices; and, of course, parents (including Rochman herself) grappling with revelations that are sometimes joyous, sometimes heartbreaking, but always profound. She navigates the dizzying and constantly expanding array of prenatal and postnatal tests, from carrier screening to genome sequencing, while considering how access to more tests is altering perceptions of disability and changing the conversation about what sort of life is worth living and who draws the line. Along the way, she highlights the most urgent ethical quandary: Is this technology a triumph of modern medicine or a Pandora’s box of possibilities?
Propelled by human narratives and meticulously reported, The Gene Machine is both a scientific road map and a meditation on our power to shape the future. It is a book that gets to the very core of what it means to be human.
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The Gene Machine
How Genetic Technologies Are Changing the Way We Have Kidsâ"and the Kids We Have
By Bonnie Rochman
Scientific American/Farrar, Straus and GirouxCopyright © 2017 Bonnie Rochman
All rights reserved.
How the Jews Beat Tay-Sachs
Screening for Disease Before Pregnancy
When I was pregnant with my son in 2002, I was a gumshoe newspaper reporter in North Carolina covering a group of county commissioner curmudgeons. I earned a living by asking questions. As soon as I'd learned I was pregnant, I'd begun asking about genetic testing for myself and for my husband. A previous pregnancy — my first — had quickly, agonizingly, ended in miscarriage. Before that occurred, I had just begun to cast a wide net, researching which genetic tests I needed. As an Ashkenazi Jew, someone whose family hails from the shtetls of eastern Europe, I was aware of the devastation that can occur when a child is conceived by a carrier couple who both possess the defective gene on chromosome 15 that causes Tay-Sachs, a fatal neurological disease that robs affected children of sight, speech, and movement. Tay-Sachs is an autosomal recessive disease, which means that children conceived by a couple who are both carriers for that disease have a 25 percent chance of being unaffected, a 50 percent chance of being carriers like their parents, and a 25 percent chance of having the disease. Ashkenazi Jews are more likely than others to be carriers — perfectly healthy but harboring the genetic mutation that can prove deadly if paired with a partner's mutation during conception. One of every 27 Ashkenazi Jews in the United States is a carrier, compared to 1 in 250 in the general population. When I met my future husband, he had already been tested as part of an effort at a university Hillel, the organization for Jewish college students. Based on his negative result, my obstetrician said that we were in the clear for Tay-Sachs. But my research had shown there was plenty else to worry about.
In New York City, for example, where awareness of Jewish genetic disease corresponded to the density of the Jewish population, women with my same genealogical profile, descended from the same peasants and farmers and button sellers of Russia and Germany and Poland, were getting tested for an entire panel of diseases more likely to strike Jews who trace their roots to eastern Europe.
Could it really be possible that genetic testing was a function of geography — that a mom in the South, where Jews are a tiny minority, was more at risk of giving birth to a baby with a lethal disease than a mom in Manhattan, where Jews are so much a part of the fabric of the community that a Jewish Genetic Disease Consortium and a Program for Jewish Genetic Health coexist in the same city? I wasn't about to experiment — I wanted testing for the full complement of more than a dozen diseases for which people of my ethnic background were considered at greater risk at the time.
I went on a search for a genetic counselor, a partner in my quest to understand what secrets may lurk in my genes. I found her at a nearby hospital after making multiple inquiries at the state Department of Health and Human Services. She was amused but not surprised when I shared the bureaucratic maze I'd navigated to end up in her corner office. She assured me that I was doing the responsible thing by seeking carrier screening for inherited health conditions — screening my own genes — before I tried to get pregnant again. With the genetic counselor's help, I managed to get insurance coverage for the genetic testing she recommended. (She had advised me to get screened first; if I tested positive for a particular disease, then my husband should also be tested for the same disease.) I had to go to an independent lab to yield up samples of my blood, which was then flown to a lab in Texas for analysis. In 2002, a Jewish girl in the South had to jump through more than a few hoops to peer inside her DNA for markers of risk. My reports came back clear.
More than a decade later, my efforts seem almost byzantine. While some women are still unaware of their risks and options — or know they want genetic testing before or early in pregnancy but still struggle to get access to it — many others are now endeavoring to understand the ever-expanding array of tests made available to them once they're expecting. The first stage of this revolution is carrier screening. Scores of companies and laboratories, recognizing an opportunity, now advocate using newly efficient means of testing to screen all pregnant women in the United States. Many doctors, responding to marketing by these companies, have embraced that approach, offering testing for carrier status for more than 100 serious diseases to all newly pregnant women. Emory University even markets its comprehensive panel as a gift, a present someone can purchase for a beloved pregnant mama. But just because we can screen for more diseases, should we?
There are complicating factors: for one, more-powerful tests can unearth many more gene mutations than traditional means of testing. The mutations, or changes in a gene, might be so unusual that doctors don't have enough information to gauge their severity. As a result, the information can confuse more than clarify.
One company, Gene by Gene Ltd., has introduced a test that screens for more than 250 diseases. "In any genetics market, you'll have people skeptical about that much information," Patrick Miller, then director of clinical and research services for Gene by Gene, said in 2014. "We will be pushing the limits, but we believe in the power of the truly comprehensive test."
Many of the diseases that can be detected are uncommon tongue twisters: aspartylglucosaminuria or pycnodysostosis. Some of them are so rare that doctors may not encounter them even once in a decades-long career, although that renders them no less devastating when they do occur. "If you're the parent and you're caring for a child with a chronic or terminal disease on a daily basis, it's no longer rare for you," says Shivani Nazareth, director of women's health for Counsyl, the San Francisco–based carrier-screening company that is largely responsible for popularizing the concept of "universal" carrier screening, which is pretty much exactly what it sounds like: a vision to screen the universe — i.e., every would-be parent — for the same diseases before or early in pregnancy regardless of where in the world they come from. Of the more than 600,000 people that Counsyl has screened since 2009, at least one-quarter were found to be carriers for a genetic disease. A much smaller percentage of couples that Counsyl has screened in the United States, just over 2 percent, are both identified as carriers for the same disease, which puts them at risk of conceiving an affected child.
* * *
To understand the correlation between genes and disease, it's essential to first grasp what a gene is. Our genome, our genetic code, is composed of DNA, or deoxyribonucleic acid. DNA is the building block of life, but it's probably easier to conceptualize it as a how-to manual, a set of instructions for assembling and operating a living being. A two-stranded molecule that's suspended in the nucleus of nearly every cell (red blood cells don't have nuclei), DNA is our vehicle of heredity.
There are four letters in the DNA alphabet — A, T, C, and G, short for the names of four different molecules: adenine, thymine, cytosine, and guanine. The four molecules, called nucleotides, are strung together in sequences, like cultured pearls on a necklace. It's the order in which they are arranged within an individual's DNA that makes a person unique; this same order, or sequence, directs a body's operations. As with any alphabet, letters combine to make words, which are linked together to form sentences. It's these sentences that form the instructions that we call genes. Genes contain blueprints, or codes, for making proteins. Proteins are the chief operating officers of our cells; they're what make us tick. Different proteins do different things — they carry out functions and give our tissues and organs structure. Some transport oxygen; others sense light streaming into our eyes; still others, called enzymes, calibrate the many vital chemical reactions that keep our bodies running.
Our genes are then bundled onto chromosomes. Mike Bamshad, chief of pediatric genetic medicine at the University of Washington, suggests we think of DNA as an encyclopedia set, with each of our forty-six chromosomes representing a separate volume. But those volumes aren't static, ponderous tomes collecting dust on a shelf: they're dynamic and changing, shape -shifting according to the whims of various inputs from our bodies and our environment. Our bodies grow by making new cells, and each time a cell gets ready to divide into two cells, the DNA in that cell — six feet long, were it to be stretched out end to end — has to make a copy of itself. Invariably, mistakes happen in the process of replication. Amazingly, our cells are able to detect and repair many such errors. Our bodies are models of machine efficiency, continuously problem-solving; reuniting mismatched As, Ts, Cs, and Gs; stitching together frayed DNA strands. But the molecular machinery that detects and repairs mutations isn't perfect, and sometimes, like a sleepy proofreader, it lets a mistake slip by. Usually those changes don't matter much. But sometimes these mistakes, also called mutations or changes or variants, are significant enough that they can cause birth defects or cancer. It's those errors that genetic testing is designed to detect.
Carrier screening focuses on single-gene mutations, which are easily pinpointed because they affect an individual gene. Many of the more than 100 diseases screened for by Counsyl result in birth defects, intellectual disabilities, and shortened lifespans. Some can be treated if detected early. Others have no treatments and are fatal. Several of them are more common in the Jewish community, but even so-called Jewish diseases strike non-Jewish people. One of every 280 babies born worldwide has a genetic disease that could be detected by carrier screening, which makes these recessive diseases collectively more common than Down syndrome.
Counsyl considers itself first and foremost a technology company. Its lab is largely run by robots built by Kyle Lapham, the company's director of lab automation, and a team of engineers. In traditional labs, white-coated techs move from station to station, extracting DNA and pipetting it from one tube to another. They repeat that process for each gene under scrutiny, mirroring the way gene analysis is done in labs the world over. In Counsyl's lab, robots do the bulk of the work. "It is the lab of the future," says Nazareth.
Says Lapham: "When we look to other companies for how we should run, we look to Amazon or Google, not LabCorp." Lapham geeked out showing off his toys when I toured the facilities in early 2016. One, a robotic articulated arm commonly used in auto manufacturing, picks up trays of blood samples to be loaded into a centrifuge, revolves smoothly to the left, and drops its cargo into another networked robot. Many of the pieces that Lapham uses to innovate are 3-D printed in-house. When the articulated arm wasn't speedy enough for Lapham's liking, he and his team built a faster one and filed for a patent. More than 1,000 tubes of blood are processed every day, with each step of the process for every tube recorded on video.
"He can actually watch it from home," says Nazareth.
"Do you do that?" I ask. Lapham shakes his head no.
Despite the emphasis on robotics, people are at the core of Counsyl's work. A team of scientists and genetic counselors mulls which diseases to include among the 100 or so conditions screened for by the company. For the most part, only severe diseases with high detection rates and accompanying treatments or cures pass muster. "At the end of the day, it's about identifying more carrier couples," says Lapham.
Like many companies, Counsyl seeks to drive home the value of its product — preventing disease — through the personal stories of customers such as Brittany Madore, a hospice nurse. Her experience shepherding desperately ill people through their final weeks of life did not make it easier for her to lose her own son when he was four months old. Her patients' illnesses were rarely preventable; her son's was a different story.
Madore's son, Sullivan, arrived near his due date, an easy, uncomplicated birth after an easy, uncomplicated pregnancy. Sullivan's father delivered him. Their eight-year-old daughter cut the cord.
Sullivan was a great sleeper and an ace breastfeeder. But by the time he was a month old, Madore started to notice that Sullivan wasn't lifting his head as most babies do, nor was he kicking his legs. His cry was meekly quiet, not the four-alarm-fire wail of a typical newborn. By six weeks, when Madore brought Sullivan to the pediatrician, he was "doll-like" — no matter what position she placed him in, that's exactly how he remained.
Concerned, the doctor sent the family to a pediatric neurologist. The night before the visit, Madore went online. She searched and searched for two hours and found that Sullivan's symptoms matched up precisely with those of spinal muscular atrophy (SMA), which causes muscles to wither and, in the worst cases, is fatal in infancy.
Madore described her experience in a blog that Counsyl maintains to share the human faces behind its technology:
The ride into the neurology office was hell. I knew what we were going to learn at that visit and to have your worst fears confirmed is such a terrible feeling. The neurologist assessed him for about 30 seconds and asked if we had found anything online. I was holding my baby's hand with my face buried on the exam table next to him while trying to enunciate slowly and keep from crying and I said: Spinal. Muscular. Atrophy. Her reply was simple, and I will never forget the reluctance and the sadness in her voice. At the end of a long sigh she softly said "Yeah." I immediately sobbed all of the tears I had been holding back all morning. I didn't need any other information. I knew she had just given my beautiful 49-day-old son a terminal diagnosis with a prognosis of 4–8 weeks.
Although SMA is the leading genetic killer of infants and toddlers, many people have never heard of it. Madore and her mother, both nurses, hadn't. Neither had Madore's OB or her primary care doctor. And yet one in fifty Americans is an SMA carrier, meaning they have the potential to pass on the disease to their children although they themselves are perfectly healthy. Sullivan was four months old when he died in February 2013. SMA is a death sentence that can be prevented, one whose lethal march through a family can be stopped if it's detected by screening parents for the mutation that causes it.
Every person, you might recall from high school science class, has two copies of every gene, one from mom and one from dad. A recessive disease like SMA occurs when both copies of a gene are altered, or mutated. If only one copy has a change, that person is a carrier, typically with no symptoms.
Mutations can be good, bad, or even inconsequential. Try comparing a mutation to a typo. Depending on where a mutation, a genetic typo, falls within a sentence, it may render it unintelligible. Consider the sentence "I am very intelligent." Leave out every other letter in "intelligent," and the word becomes impossible to read. On the other hand, if you forget to add a second "l," it hardly hinders comprehension; the reader will just gloss over the missing letter and assume the writer spurned spell-check. In a similar way, some DNA errors don't significantly affect the "reading" of the genetic code.
The good news is that many mutations that slip by the repair machinery don't mean much. But some of them turn a key bit of the genetic code to nonsense — garbled instructions that, if carried out, would cause abnormalities in development and functioning. If such an error isn't fixed and it occurs in a cell destined for the big time — egg or sperm — the genetic change can be passed on to a child, assuming the altered egg or sperm ends up making a baby. These inherited mutations are called germline mutations since they come from egg or sperm cells, otherwise known as germ cells. A child with a germline mutation is born with that mutation in every one of his or her cells. With recessive diseases that are detected by carrier screening, the long arm of disease may silently extend generations back. Often, an initial mutation occurred in the egg or sperm of an ancestor and became part of the genetic blueprint of their children, their children's children, and even their future descendants. The mutation didn't present a problem until one of those carriers mated with another carrier.
Excerpted from The Gene Machine by Bonnie Rochman. Copyright © 2017 Bonnie Rochman. Excerpted by permission of Scientific American/Farrar, Straus and Giroux.
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Table of Contents
1 How the Jews Beat Tay-Sachs: Screening for Disease Before Pregnancy 17
2 Playing God: How Preimplantation Genetic Diagnosis Is Rewriting Family History 45
3 The Other Scarlet "A": Abortion's Relationship to Genetic Testing 73
4 Silencing a Gene: The Future of Down Syndrome 101
5 What Do Parents Want to Know? Grappling with Variants of Uncertain Significance 127
6 The Right to an Open Future: Navigating the Return of Results 153
7 How to Hunt a Zebra: Ending the Rare-Disease Diagnostic Odyssey 179
8 The Genie in the Bottle: Sequencing Newborn Babies 203