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

by Moalem MD PhD, Sharon

  ***

  Given the complexity of it all, it wouldn’t be unreasonable to give up on trying to wrap your head around where to go next from here. But let me suggest why there’s good reason to be excited about what we’re learning about ourselves and our diets—and where that genetic information will take us. And doing that means going back to the emergency department, where Cindy and her mother were already waiting when I arrived shortly before 4:30 a.m.

  The staff had started the intake process, and I was glad to see that Cindy already had an IV line running into her arm, bringing her the extra glucose and fluids she so desperately needed. Giving glucose to Cindy is crucial since her OTC deficiency will cause her ammonia levels to rise when she’s using protein as a source of energy. Rising levels of ammonia are harmful to the body, and especially to her sensitive and developing brain. This is what is partly responsible for the accompanying symptoms such as lethargy and vomiting that caused her mother to be so concerned.

  One of the reasons that the treatment for OTC is so much more aggressive than it was in the past is that we are now much more aware of the accompanying brain damage that comes from having elevated levels of ammonia. One of the treatment options, especially in severe cases, is “gene therapy with a knife,” where patients with OTC are given a liver transplant, specifically a liver that gives the patient a working copy of the damaged gene they inherited.

  Thankfully, Cindy’s case wasn’t severe enough to necessitate a liver transplant. But with the rapid change of treatment options that’s occurring, OTC deficiency is not the grim diagnosis it was formerly.

  As I waited for the results of her blood work (the blood sample had been rushed off to the lab on ice), I thought about all of the significant changes that have occurred in the way we practice medicine in the past few years. In Cindy’s case, we previously would not have known that she had a genetic condition until it was likely too late. Which today highlights the imperative of doctors knowing which tests to order to assess a patient’s condition.

  When Cindy’s lab results finally came back they showed that her body’s load of ammonia was not as high as we first had anticipated and that her organs weren’t showing any major signs of dysfunction.

  That was good news. After finishing up my consultation note and e-mailing the day team to hand over our night’s business, I left feeling a bit spent. Maybe three and a half hours of sleep wasn’t enough after all.

  On my bleary-eyed drive home to get showered and changed, I reflected on the sheer magnitude of the biochemical and genetic mysteries that often overshadow our attempts to understand conditions like Cindy’s. Witnessing what these brave children and their families go through day in and day out sparks new ways of thinking that occasionally lead me to new opportunities for clinical research. Odds are that I would surely miss new avenues of exploration if I didn’t have the honor of spending some time traveling along with these incredible families on their medical journeys.

  And as we’re going to see next, it was the development of new methods of screening to find children like Cindy early enough to make a difference in their lives that led us to discover that she was in need of a particular dietary regimen and specialized medical care. To see where we are headed in the field of personalized genetic nutrition, it might help to know where we got started. If you or someone you love was born after the late 1960s, you’re likely already a beneficiary of it.

  ***

  It all began in the late 1920s with another worried mother.

  She was a Norwegian woman by the name of Borgny Egeland, and she wanted desperately to help her two little kids. Both of her children, a girl named Liv and a boy named Dag, suffered from severe intellectual disability, though Egeland was convinced that they had been unaffected by the condition when they were infants. Her quest for help led her from doctor to doctor and even to faith healers in hopes of finding someone—anyone—who could help her children, all to no avail.14

  But fortunately, a physician and chemist named Asbjørn Følling decided to take Egeland seriously. While so many others had written Egeland off, Følling listened intently when he learned of her children’s plight—and appears to have been particularly interested when he heard that the children’s urine had a strange and very musty odor.

  When, at Følling’s request, a sample of Liv’s urine arrived at the laboratory, it seemed at first to be wholly unremarkable; all of the routine tests were normal. But there was one final test—a few drops of ferric chloride to check for the presence of ketones, organic compounds produced by the body when it is burning fat rather than glucose for fuel. If ketones were present, the ferric chloride test should have changed the color of Liv’s urine from yellow to purple. Instead it turned green.

  Intrigued, Følling asked for another sample, but this time from Liv’s brother, Dag. Again, the ferric chloride test turned the urine green. For two months, Egeland brought the scientist sample after sample of her children’s urine—and for two months the doctor worked to isolate the cause of the abnormal reaction, finally settling on a chemical compound known as phenylpyruvic acid.

  To see if he was right, Følling worked with Norwegian institutions that served developmentally disabled children to collect additional samples and located eight more samples of urine (including two from sibling pairs) from children that responded in the same way to ferric chloride.

  But although Følling had identified the chemical culprit for what would turn out to be thousands of cases of intellectual disability, it would be several more decades before other doctors worked out that the condition was due to an inborn genetic error of metabolism (not unlike Cindy’s OTC) that prevented these young individuals from breaking down phenylalanine, a chemical common in hundreds of protein-rich foods.

  Indeed, as Egeland had first suspected, her children had been born without any signs of intellectual disability. An inherited metabolic condition, ultimately to be named phenylketonuria, or PKU, had caused them to build up phenylalanine in their bloodstream at levels that ultimately became irreversibly toxic for their brains.

  Once they’d put that together, scientists developed a special diet that could be administered to those identified with PKU, literally preventing intellectual disability. The only catch was that the children had to be identified and switched to that new diet before they became irretrievably symptomatic.

  How to know who has PKU—and early enough to leave nothing to chance? That is a problem that ultimately was solved by a man named Robert Guthrie, a physician and scientist who started his career as a cancer researcher. Guthrie ultimately traveled a professional road very different from the one he first intended, leaving research in oncology to study the causes and prevention of intellectual disability, for very personal reasons.

  His son was affected with intellectual disability and so was his niece. But her cognitive impairment could have been prevented.

  Because his niece was born with PKU.

  Using his cancer research experience to tackle the problem of PKU detection, Guthrie designed a system by which small samples of blood, collected and stored on small cards from the heels of newborns, could be tested for PKU. These cards, which came to be known as Guthrie cards, were put into routine use in the 1960s across the United States and in dozens of other nations in the years to come. Over the decades, they’ve been expanded for use in detecting many other diseases as well.

  It took more than 40 years from the time that Borgny Egeland resolved, against all odds, to find the reason for her children’s intellectual disability to the time that Guthrie’s tests were in widespread use—and, of course, that development came much too late to help the Egeland children.

  How can anyone describe the depth of that tragedy? Nor can we adequately capture the glory of that long, long quest toward a brighter future initiated by Egeland and concluded by Guthrie. For that, I leave you in the capable hands of Nobel and Pulitzer Prize–winning author Pearl Buck, herself the mother of an adopted daughter who appears to ha
ve suffered from PKU:

  “What has been, need not forever continue to be so. It is too late for some of our children, but if their plight can make people realize how unnecessary much of the tragedy is, their lives, thwarted as they are, will not have been meaningless.”15

  And the Egeland children’s tragedy was far from meaningless.

  Today, Guthrie cards, and the newborn screening that was developed as a result, have been extended to dozens of other metabolic conditions, another example of how one seemingly rare condition can have broad implications for us all. But even newborn screening isn’t a catchall. For some people, only sophisticated genetic testing can uncover the big differences small nutritional decisions can have on our health.

  ***

  It was a rainy morning in Manhattan in the spring of 2010 when I first met Richard.

  He was pretty much bouncing off the examination room walls when I walked in. And that, I’d come to learn, was par for the course for this kid.

  Of course, rambunctiousness is very common in 10-year-old boys. But this boy in particular would have run circles around Max from Where the Wild Things Are—and as a result Richard had been getting into a considerable amount of trouble at school.

  But that wasn’t the reason for Richard’s first visit to the hospital. Rather, he was there because his legs hurt.

  In every other way, and by all visible impressions, Richard appeared to be a picture of good health. His newborn screening? Perfectly normal. His recent yearly checkup? Spot-on average. He seemed to be in such great shape, as a matter of fact, that it took a while for anyone to recognize that there was something wrong with him—and we might not have known at all if it weren’t for the fact that some very good doctors took heed of his repeated complaints, rejecting the easy but very unscientific diagnosis of “growing pains.”

  Without any other good explanation for the boy’s leg pain, the doctors ordered a test of his genes—and that test revealed that Richard suffered from OTC deficiency, the same condition we discussed earlier when I introduced you to Cindy.

  You might remember that Cindy’s OTC symptoms had resulted in many trips to the hospital. Richard’s OTC, on the other hand, expressed itself quite differently—it hardly seemed to impact him at all, other than those rather inexplicable leg pains, which might have been connected to the higher-than-normal ammonia levels in his body.

  But Richard’s other symptoms, to the extent that they existed at all, were so mild that he and his father had a bit of trouble believing there was anything wrong with him whatsoever. On the day I met him, in fact, there was a foil-wrapped pepperoni stick jutting out of his back pocket, even though Richard and his parents had been repeatedly told that people with OTC deficiency are advised to try to maintain a low-protein diet, since they don’t handle high loads of protein very well.

  That pepperoni stick was a clue as to why his symptoms wouldn’t resolve.

  What Richard’s family didn’t realize was that the reports of his lack of concentration at school and at home weren’t exactly behavioral but physiological. Higher-than-normal levels of ammonia in most people’s bodies can lead to tremors, seizures, and coma, but in Richard, it was likely that his elevated levels were prompting combativeness and difficulty concentrating.

  But I’ll be very honest—I didn’t see this at first, either. Richard had gone home from our first meeting with instructions to stick more closely to his diet because we figured that might help his aching legs.

  The only way anyone really knew that Richard’s problems were more than skin-deep was when he returned, three months later, this time having adhered much more strictly to his diet. His legs no longer hurt—and that was good—but the big surprise was that he was doing exceptionally well in school. He was calmer. More attentive. He was no longer king of the Wild Things.

  I thought a lot in the following months about the implications of Richard’s remarkable turnaround. There are, no doubt, more Richards out there. In fact, it’s likely that there are many, many more—and they’re also eating, quite unwittingly, foods that aren’t quite right for their genetic selves. Maybe their conditions aren’t severe enough to send them over a metabolic cliff, but perhaps just enough to warrant a trip to the principal’s office.

  The fact that the children I see are, for the most part, in very specialized medical centers makes me wonder how many patients with metabolic conditions we’re missing in primary care—and how many aren’t coming in for care at all.

  We really don’t know how many people who have been diagnosed with some form of cognitive impairment, or even autism spectrum disorder, actually have an underlying metabolic disease that has simply never been diagnosed and addressed. Before we understood PKU, for example, we couldn’t understand that these children’s intellectual disability was due to an untreated metabolic condition.

  The more our science advances, I hope, the more cases like Richard’s we’ll come to understand—and the more lives we can improve with medical interventions and simple life changes that address people’s individual genetic and metabolic needs.

  ***

  So what can Cindy, Richard, and Jeff teach the rest of us about nutrition? The answer is that we’re all individuals when it comes to our genomes, and completely unique when it comes to our epigenomes and even our microbiomes. Optimizing what we eat is not the same as preventing nutritional deficiencies. We can and should investigate our genes, and metabolism, for clues about what foods suit us best. The findings would have significant implications for what we should and should not be eating.

  We are at the point of moving beyond creating specialized diets for people with rare genetic conditions. Because of the information we are now privy to through genetic sequencing, we are now on the cusp of finally being invited to sit down to a meal that’s been prepared with our own individually inherited genetic profile in mind.

  As we’re going to consider next—it’s not just our diets that are becoming much more personalized to our genetic inheritance—it’s time we looked in our medicine cabinets as well.

  * A common by-product of the metabolic processes that occur when the body breaks down protein.

  * Even if you do know the types of foods your recent ancestors ate, you need to take into account that they might be too calorically rich (I’m thinking lard in apple pies, for example) for today’s comparatively lower levels of physical activity.

  ** And if you’re of West African or European descent there’s a good chance they did.

  Chapter 6

  Genetic Dosing

  How Deadly Painkillers, the Prevention Paradox, and Ötzi the Iceman Are Changing the Face of Medicine

  Each year many thousands of people die—and many more become acutely ill—precisely because they were taking the exact dosage of medications prescribed to them by their doctors.

  It’s not that their doctors were negligent. In fact, in most cases their prescriptions were exactly in line with recommendations provided by drug manufacturers and professional medical societies. The reason for many of these adverse drug reactions lies in our genes. Just like metabolizing caffeine, some of us are just genetically endowed to be better at breaking down some drugs than others. It’s not always the version of the genes themselves that you’ve inherited that can result in adverse drug reactions. Rather, it’s also the number of copies of a gene you’ve inherited that can be just as important. Some of us have inherited a little more or a little less DNA than others, and as you can imagine that sets us up for a lot of variation between people. It’s impossible to know what you’ve inherited unless you get genetic testing or sequencing done to find out.

  If you happen to have a deletion in your genome that results in missing sections of DNA that house information that is crucial for your development or well-being, then more likely than not the genetic change can cause a specific syndrome. But when there’s a duplication of DNA material it’s not always clear what the implications can be.

  Having a little extr
a DNA sometimes has no effect at all, while at other times, it can profoundly change your life. As we’re about to see, a little extra DNA can even make a common medication turn deadly. What you’ve likely clued into by now is that what you do with your genome is just as important as the genes you inherit. And these lifestyle choices include what medications you take.

  In one heartbreaking case, a young girl named Meghan died after a routine tonsillectomy, and not because her body couldn’t handle the anesthesia or the surgery. In fact, the surgery was a success and Meghan was sent home later the next day. The reason Meghan died was that her doctors didn’t know something about her that was vitally important. No one looked at Meghan’s genes.

  Now, there’s a good chance she might have lived her entire life without ever knowing of any differences in her genetic code. What Meghan inherited was a very small duplication in her genome, not unlike millions of other people who have slight differences in their DNA. Because of where the small duplication was located in her genome, instead of getting two copies of the CYP2D6 gene, one from each parent as we’ve come to expect, Meghan got three.1

  And like millions of patients before her, she was given the drug codeine to treat her pain after surgery. But because of Meghan’s genetic inheritance, her body was turning small doses of that medicine into big doses of morphine. And fast. The recommended dose that would have ameliorated pain in most children, making them more comfortable, resulted instead in overdose and death for Meghan.

  Which is why the U.S. Food and Drug Administration in 2013 finally decided to ban the use of codeine in children after tonsillectomies and adenoidectomies.2 The tragedy is compounded by the fact that this isn’t a rare reaction. As many as 10 percent of individuals of European descent and up to 30 percent of those of North African descent are ultrarapid metabolizers of certain drugs3 due to the versions of the genes they’ve inherited.