Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes

by Moalem MD PhD, Sharon

  Begin Reading

  Table of Contents

  Newsletters

  Copyright Page

  In accordance with the U.S. Copyright Act of 1976, the scanning, uploading, and electronic sharing of any part of this book without the permission of the publisher constitute unlawful piracy and theft of the author’s intellectual property. If you would like to use material from the book (other than for review purposes), prior written permission must be obtained by contacting the publisher at permissions@hbgusa.com. Thank you for your support of the author’s rights.

  For Shira

  Introduction

  Everything Is About to Change

  Remember the seventh grade?

  Can you recall the faces of your fellow students? Can you summon the names of the teachers, the secretary, and the principal? Can you hear the way the bell sounded? How about the smell of the cafeteria on sloppy joe day? The ache of your first crush? The panic of finding yourself in the bathroom at the same time as the school bully?

  Maybe it’s all strikingly clear. Or maybe, over time, your middle school years have been lost in the fog of so many other childhood memories.

  Either way, you’re carrying it all with you.

  For a long time now, we’ve understood that we shoulder our experiences in the knapsack of our psyche. Even things you cannot consciously recall are somewhere in there, swimming around in your subliminal mind, ready to emerge unexpectedly for good or ill.

  But it’s all much deeper than that, because your body is in a constant state of transformation and regeneration and your experiences, no matter how seemingly inconsequential, from bullies to crushes to sloppy joes, have all left an indelible mark within you.

  And more importantly, within your genome.

  Of course, this isn’t how most of us have been taught to think about the three-billion-letter equation that makes up our genetic inheritance. Ever since Gregor Mendel’s mid-nineteenth-century* investigations into the inherited traits of pea plants were used to set the foundations for our understanding of genetics, we’ve been taught that who we are is a resolutely predictable matter of the genes we’ve inherited from previous generations. A little from Mom. A little from Dad. Whip it up, and there’s you.

  That calcified view of genetic inheritance is what students in middle school classrooms are still studying to this day when they map out pedigree charts in an effort to make sense of their fellow students’ eye color, curly hair, tongue rolling, or hairy fingers. And the lesson, delivered as though on stone tablets from Mendel himself, is that we don’t have much of a choice in the matter of what we get or what we give, because our genetic legacy was completely fixed when our parents conceived us.

  But that’s all wrong.

  Because right now, whether you are seated at your desk sipping a coffee, slumped into a recliner at home, riding a stationary bike at the gym, or orbiting the planet on the International Space Station, your DNA is being constantly modified. Like thousands upon thousands of little light switches, some are turning on while others are turning off, all in response to what you’re doing, what you’re seeing, and what you’re feeling.

  This process is mediated and orchestrated by how you live, where you live, the stresses you face, and the things you consume.

  And all of those things can be changed. Which, in very certain terms, means you can change. Genetically.*

  This is not to say that our lives are not also shaped by our genes. They most certainly are. In fact, what we’re learning is that our genetic inheritance—every last nucleotide “letter” that makes up our genome—is instrumental and influential in ways that even the most fanciful science-fiction writer could not have imagined just a few short years ago.

  Day by day, we’re gaining the tools and knowledge we need to embark on a new genetic journey—to take hold of a timeworn chart, lay it out across the table of our lives, and mark upon it a new course for ourselves, our children, and everyone down the line. Discovery by discovery, we’re coming to better understand the relationship between what our genes do to us and what we do to our genes. And this idea—this flexible inheritance—is changing everything.

  Food and exercise. Psychology and relationships. Medication. Litigation. Education. Our laws. Our rights. Long-held dogmas and deeply felt beliefs.

  Everything.

  Even death itself. Until now, most of us have been under the assumption that our life experiences end when our lives end. That’s wrong, too. We are the culmination of our life experience as well as the life experiences of our parents and ancestors. Because our genes don’t easily forget.

  War, peace, feast, famine, diaspora, disease—if our ancestors went through it and survived, we’ve inherited it. And once we’ve got it, we’re that much more likely to pass it on to the next generation in one way or another.

  That might mean cancer. It might mean Alzheimer’s disease. It might mean obesity. But it might also mean longevity. It might mean grace under fire. And it might just mean happiness itself.

  For better or for worse, we are now learning that it is possible to accept and reject our inheritance.

  This is a guidebook for that journey.

  In this book, I’m going to talk about the tools I use as a physician and scientist to apply the latest advances in the field of human genetics to my daily practice. I’ll introduce you to some of my patients. I’ll dig through the clinical landscape for examples of research that is important to our lives, and I’ll tell you about some of the research I’m involved in. I’ll talk about history. I’ll talk about art. I’ll talk about superheroes, sports stars, and sex workers. And I’ll make connections that will change the way you look at the world and even the way you look at yourself.

  I’ll encourage you to walk along the tightrope that demarcates the border between the known and unknown. Sure, it’s wobbly up there, but it’s worth it. For one thing, the view is unforgettable.

  Yes, the way I see the world is unconventional. By using genetic diseases as a template to understand our basic biology, I’ve made groundbreaking discoveries in seemingly unrelated fields. This approach has served me well and has led to my discovery of a new and novel antibiotic named Siderocillin that specifically targets superbug infections as well as to the granting of twenty patents worldwide for new biotechnological innovations aimed at improving our health.

  I have also had the good fortune to collaborate with some of the best doctors and researchers on the planet, and I’ve been privy to some of the rarest and most complex genetic cases anyone has ever seen. Over the years, my career has brought me into the lives of hundreds of people who have entrusted me with the most important thing in their world—their children.

  In short: I take this stuff seriously.

  That doesn’t mean this is going to be a grim experience. Yes, some of the things we’re going to talk about will be heartbreaking. Some of these concepts may challenge many of our core beliefs. Still other ideas may be downright frightening.

  But if you open yourself up to this amazing new world, it can reorient you. It might make you think about the way you live. It might just make you reconsider how, genetically speaking, you got to this very moment in your life.

  I assure you: By the end of this book, your entire genome and the life it has helped shape for you will never look or feel the same again.

  So, if you’re ready to see genetics in a very different way, I’d like to be your guide on this journey through diverse places in our shared past, across a confounding collection of mome
nts in our present, and into a future rife with promise and pitfalls.

  In doing so, I’m going to invite you into my world and show you how I view our genetic inheritance. To start, I’m going to tell you how I think, because once you know how geneticists think you’ll be better prepared for the world we’re rocketing into.

  And let me tell you—it is one immensely exciting place. You’ve opened this book at the onset of a tremendous time of discovery. Where did we come from? Where are we going? What did we get? What will we give? All of these questions are up for grabs.

  This is our immediate and inexorable future.

  This is our Inheritance.

  * Gregor Mendel presented his work to the Brünn Natural History Society on February 8 and March 8, 1865. He went on to publish his results a year later in the Proceedings of the Natural History Society of Brünn. His paper was only translated into English in 1901.

  * This can include everything from acquired mutations and even small epigenetic modifications that can change the expression and repression of your genes.

  Chapter 1

  How Geneticists Think

  For a while there, it seemed like all of New York’s restaurateurs were chasing their customers’ diets into a rabbit hole of vegetarian, gluten-free, thrice-certified-organic labyrinth of healthiness. Menus came with asterisks and footnotes. Servers became experts in appellations of origins, flavor pairings, and fair trade certifications as well as a muddled medley of various fats and all those confounding omegas that are good for this and bad for that.

  But Jeff1 didn’t budge. Well-trained and perfectly aware of the ever-changing palates of his city’s restaurant class, the young chef wasn’t against healthy eating—he just didn’t figure that good-for-you menus were supposed to be his top priority. So while everyone else was experimenting with freekeh and chia seeds, Jeff was cooking up big, mouthwatering, and enchantingly delicious helpings of meat, potatoes, cheese, and a whole bunch of other artery-clogging morsels seemingly made in heaven.

  Your mother probably told you to practice what you preach. Jeff’s mom always told him to eat what he cooked. And he did. Boy, did he ever.

  But when his blood work began to show signs of higher levels of low-density lipoprotein cholesterol—the type associated with an increased risk of heart disease, often simply known as LDL—it was time to make a change. When Jeff’s doctor learned the young chef also had a significant family history of cardiovascular disease, he was adamant that change should happen fast. Without a substantial modification to Jeff’s diet, including a hefty daily increase of fruits and vegetables, the doctor reasoned, the only recourse to reduce his risk of a future heart attack would be medication.

  That wasn’t a hard verdict for the doctor to render—it was the same guidance he’d been trained to give every patient he’d ever seen with Jeff’s family background and LDL presentation.

  Jeff resisted at first. After all, having been given the nickname “The Steak” by others in the restaurant industry to describe his prodigious cooking and eating habits, switching to more fruits and vegetables would, he thought, hurt his reputation. Eventually, prompted by a beautiful young fiancée who wanted to grow old with him, he relented. Using his culinary training and flair for reductions, he decided to commence this new chapter of his life by first introducing fruits and vegetables into his daily repertoire, which necessitated hiding certain ones he didn’t particularly enjoy eating on their own. Like parents on a health kick who conceal zucchini in their kids’ breakfast muffins, Jeff started using a lot more fruits and vegetables in his glazes and reductions to go along with his black and blue porterhouse steaks. Soon enough, more than just theoretically understanding the idea of dietary balance that his doctor had preached, Jeff was living it. Smaller portions of red meat. Much bigger helpings of fruits and veggies. Sensible breakfasts and lunches.

  After three long years of “eating right,” and with ever-lowering cholesterol levels, Jeff figured he’d beaten back his medical problems. He was proud of himself for getting his health under control through diet—which for most people is no small accomplishment.

  After strictly sticking to his new diet he figured he should feel great, but the truth was, he felt worse. Instead of increased vitality, he started to feel bloated, nauseated, and tired. An investigation into his symptoms first revealed some mild liver function test abnormalities, which quickly proceeded to an abdominal ultrasound, then to an MRI, and eventually a liver biopsy—which revealed cancer.

  That was a surprise to everyone—especially his doctor—because Jeff wasn’t infected with hepatitis B or C (which can cause liver cancer). He wasn’t an alcoholic. He hadn’t been exposed to any toxic chemicals. He hadn’t done anything typically associated with liver cancer in such a young and relatively healthy person. All he’d done was change his diet, just like the doctor ordered. Jeff couldn’t believe what was happening.

  For most people, fructose is what gives fruit that extra sweet zing. But if you, like Jeff, suffer from a rare genetic condition called hereditary fructose intolerance, or HFI, you cannot fully break down fructose from your diet.* This causes a buildup of toxic metabolites within the body—especially within the liver—because you can’t produce enough of an enzyme called fructose-bisphosphate aldolase B. And that means that for people like Jeff, an apple a day isn’t healthy, it’s deadly.

  Thankfully, Jeff’s cancer was identified early and it was treatable. A change in diet—the right one this time, away from fructose—means he will be tantalizing Gotham’s palates for a long time to come.

  Not everyone who has HFI is so fortunate, though. Many people with this condition spend their lives complaining of the same nausea and bloating Jeff experienced whenever he ate a lot of fruit and vegetables, but they never really know why. Most of the time no one takes them seriously—not even their doctors.

  Not until it’s too late.

  Several people with HFI develop a natural strong—and therefore protective—dislike for fructose at some point in their lives and learn to avoid foods containing this sugar, even though they don’t know exactly why. As I explained to Jeff when we met a short time after he finally learned of his genetic condition: When people with HFI don’t listen to what their body is trying to tell them—or worse, when they’re given explicit medical advice to the contrary—they may eventually suffer seizures, coma, and an early death from organ failure or cancer.

  But luckily, things are changing. And fast.

  It wasn’t so long ago that no one—not even the richest person in the world—could get a peek into their genome. The science simply wasn’t there. Today, though, the cost of exome or whole genome sequencing, an invaluable genetic snapshot of the millions of nucleotide “letters” that make up our DNA, is less than the cost of a high-quality wide-screen TV.2 And it’s getting cheaper by the day. A veritable flood of never-before-seen genetic data has arrived.

  What’s hidden in all of those letters? Well, for starters, information that Jeff and his doctor could have used to make more accurate decisions about how to deal with HFI and his high cholesterol—information we all can use to make individualized decisions about what to eat and what to avoid. With that knowledge—a personally monogrammed gift from every relative who ever existed before you—you’ll be empowered to make educated decisions about what you eat and, as we’ll explore later, how you choose to live.

  None of this is to suggest that Jeff’s first doctor did anything wrong—at least not in the traditional way of medical thinking. You see, from the time of Hippocrates, physicians have based their diagnoses on how their previous patients looked when they were sick. In more recent years, we’ve expanded this concept to include sophisticated studies that help physicians understand what remedies work best for the greatest number of people, right down to painstaking statistical percentiles.

  And, indeed, that’s fine. For most of the people. Most of the time.*

  But Jeff wasn’t like most people. Not even some o
f the time. And neither are you. None of us are.

  It’s been more than a decade since the first human genome was sequenced. Today, people around the world have had all or part of their genome exposed in this way, and it has become clear that no one—and I mean absolutely no one—is “average.” In fact, in one research project I was recently involved with, people identified as “healthy” for the purposes of creating a genetic baseline always had some type of variation** in their genetic sequence that was out of place against what we’ve previously considered. Often, these variations can be “medically actionable,” meaning we already know what it is and have some idea of what can be done about it.

  Now, not everyone’s genetic variances are likely to be as profoundly impactful on their lives as Jeff’s was to his. But that doesn’t mean we should simply ignore those differences—particularly not now that we have the tools to see them, evaluate them, and, increasingly, intervene in very personalized ways.

  Yet not every physician has the tools and training to take those steps on behalf of their patients. Through no fault of their own, many health-care practitioners, and therefore their patients, are being left behind as scientific discoveries change the way we think about treating illness.

  Compounding the challenge we doctors face, it’s no longer enough to understand genetics. Today, physicians must also contend with epigenetics—the study of how genetic traits can change and be changed within a single generation and even be passed down to the next as well.

  An example of this is called imprinting, whereby it seems that which parent, your mother or father, you inherited a certain gene from can be more important than the actual gene itself. Prader-Willi and Angelman syndromes are illustrations of this type of inheritance. On the surface they appear to be completely separate conditions, which in fact they are. However, if you dig a little deeper genetically, you’ll discover that depending on which parent you’ve inherited imprinted genes from, you can end up with one condition or the other.