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

by Moalem MD PhD, Sharon

  My own journey of pharmaceutical discovery and development was anything but straightforward. Sometimes the road from an obscure genetic condition to a new treatment is not linear. My ongoing interest in studying rare diseases eventually led to my discovery of a novel antibiotic that I named Siderocillin. What makes this antibiotic innovative is that it works like a smart bomb, specifically targeting “superbug” infections.

  Back in the late 1990s, however, I wasn’t interested in antibiotics at all. I was intensely studying a condition called hemochromatosis. This genetic disorder results in the body absorbing too much iron from the diet, which in some people can lead to liver cancer, heart failure, and an early death. What my research into hemochromatosis taught me, though, was that I could use some of the principles from this genetic disease to create a drug that targets killer microbes instead.

  According to the Centers for Disease Control and Prevention, more than 20,000 people die every year in the United States alone due to infections by superbug microbes. What makes these organisms so deadly is that they are resistant to many, if not all, of the current antibiotics in our pharmaceutical arsenal. This is why my drug discovery has the potential to treat millions of people and save thousands of lives every year.

  But at the time when I first proposed my invention, there was no scientifically established linear relationship between hemochromatosis and superbug infections. In fact, many other researchers I was working with couldn’t understand why I seemed to be studying two separate problems simultaneously—resistant microbes and hemochromatosis. Now they do.

  The knowledge I gained from studying rare genetic diseases has led to my being awarded twenty patents worldwide, with human clinical trials for Siderocillin slated to start in 2015. This is the clearest example I can think of from my own professional sphere of the power of applying the knowledge gained from rare genetic diseases that affect only a few of us to new treatment options for the rest of us.

  Rare genetic conditions can help in other ways, too. As we’re about to see, they can also stop us from harming our children—all for the sake of a few extra inches.

  ***

  Imagine the freedom of escaping your genetic inheritance. Envision the possibility of leaving behind any genes that put you at risk for a multitude of cancers. Okay, there’s only one small catch. You would need to have Laron syndrome.

  Untreated, most people with this condition are typically less than 4 feet 10 inches tall, have a prominent forehead, deep-set eyes, a depressed nasal bridge, a smallish chin, and truncal obesity. We know of around 300 people in the world who have this condition, and about a third of them live in a small number of remote villages in the Andean highlands of Ecuador’s southern Loja Province.5

  And they all appear to be virtually immune from cancer.

  Why? Well, to understand Laron syndrome, it’s helpful to know a bit about another genetic condition—one that exists on the opposite side of the spectrum, called Gorlin syndrome. People with this disorder are susceptible to a type of skin cancer called basal cell carcinoma.* While basal cell carcinoma is relatively common among adults who have spent a good portion of their lives in the sun, people with Gorlin syndrome can develop this type of skin cancer in their teens and without much sun exposure.

  About one in 30,000 people are affected by Gorlin syndrome, though many are thought to go undiagnosed. Usually you don’t know you have it until you or someone in your family gets diagnosed with cancer. There are, though, a few visual dysmorphologic clues that are occasionally present and that you could probably easily identify. These include macrocephaly (a large head), hypertelorism (wide eyes), and 2-3 toe syndactyly6 (webbed second and third toes). Other common diagnostic features include small pits on the palms and uniquely shaped ribs that can be seen on a chest radiograph or X-ray.

  So why are people with Gorlin syndrome so sensitive to getting malignancies, such as skin cancer, without exposure to sun? To answer that question I need to tell you about a gene called PTCH1. Our bodies typically use this gene to makes a protein called Patched-1, which plays a crucial role at keeping cellular growth in check. But when a protein called Sonic Hedgehog* comes along in Gorlin patients, whose Patched-1 is not working properly, it releases the hold on growth that would usually be there and that makes cells free to divide. And divide. And divide.7

  This, of course, is a problem, because as we’ve now seen many times, unrestricted growth is like cellular anarchy. And unfortunately, cancer can result.

  Okay, so what does Gorlin syndrome teach us about Laron syndrome? Essentially, Gorlin syndrome represents, in a way, the genetic inverse to Laron syndrome. Whereas in one there is a promotion of cellular growth, the other experiences cellular growth restriction. Laron syndrome is caused by mutations in the receptor for growth hormone. This makes people with Laron syndrome insensitive or immune to it—one of the reasons they are often quite short.

  Rather than the cellular anarchy seen in people with Gorlin syndrome, in those with Laron syndrome there is a stranglehold on growth, a form of extreme cellular totalitarianism.

  Now, politically you might have some reservations about totalitarianism as an ideology, but from a purely biological perspective it has been incredibly successful. If it weren’t, you wouldn’t be here reading this right now. Neither would I. Neither would any of the other multicellular organisms on this planet.

  Because, like you and me and all the other multicellular creatures, we are the product of biological totalitarianism that promotes cellular obedience at all costs, an obedience enforced by receptors on the surface of any potentially misbehaving cells that result in cellular seppuku or hara-kiri—a programmed type of cell suicide known as apoptosis.

  Like samurai warriors who become dishonored, cells that have the impudence to have greater aspirations than just being one in a crowd of many trillion are programmed and occasionally commanded to end their own lives. By this same mechanism, cells that are infected with pathogens can also sacrifice themselves to protect the body from microbial invaders. It’s also the same mechanism we learned about previously that frees our fingers and toes from the webbing that’s there during development. If those cells don’t die—as happens in some genetic conditions—you can end up having mittens for hands.

  Which is why, as in all things, equilibrium is crucial. Processes that restrict growth need to be constantly balanced with times when growth is needed. Just think about every time you’ve sustained an injury, be it a simple cut or a much more serious accident. Consider the entire repair and remodeling your body did—automatically. All of this is a process of the balance being struck, millions upon millions of times each day, between cellular life and death.

  Would you want to mess with that balance?

  Well, you or someone you know probably already has.

  ***

  Being tall has its benefits. Taller kids are bullied less and get more playing time on the sports field. Taller adults, research has shown, are thought to more easily ascend to jobs of higher status and authority and earn more, on average, than their shorter coworkers.8

  Of course, there are exceptions. Among the most famous is Napoléon Bonaparte. As it turns out, the world’s most famous vertically challenged person might not have been that short after all. Back around the turn of the nineteenth century, French inches were a little longer than British ones. So while the Brits, who weren’t exactly Napoleon’s biggest fans, put his height at five feet and not much more, he was likely closer to five feet five, and may have been as tall as five feet seven, which was by no means short in his time.9

  But whether they’re French or English inches, when it comes to height, every one of them counts. And, let’s face it, people who are able to reach the top shelf without a stepping stool can be just plain useful at times.

  All of this is why short stature—or the perception of it—is the second most common referral to pediatric endocrinologists. It’s not that parents wouldn’t love their kids just as much if they m
axed out on the shorter side of things, it’s that height in our generation has become a real commodity. And after more than a half century of recombinant growth hormone (GH) therapy being made available for the small numbers of children with significant growth deficiencies, parents have now become quite aware that they can indeed have an impact on their child’s height—and theoretically give them a leg up on their future.10

  Today, there is an ever-growing list of conditions, some of which you’ve already read about in this book, for which GH, the manufactured version of human growth hormone, is prescribed. From Prader–Willi syndrome (the first human disorder linked to epigenetics) to Noonan’s syndrome (the disorder I identified in my wife’s friend Susan over dinner a few years ago), researchers are finding that more and more people may be able to benefit from an extra injection of GH here and there.

  Some of these conditions are very serious disorders for which GH is an essential component in addressing the needs of sick kids. But in many cases, the administration of GH (typically through regularly scheduled injections) is specifically used to address matters of height alone. Idiopathic short stature, for instance, is a condition in which a child’s height is more than two standard deviations below average, but without indications of any genetic, physiological, or nutritional abnormalities that we can identify. In other words, they’re likely normal kids who happen to be really short.

  And that’s what troubles Arlan Rosenbloom. When I asked the University of Florida endocrinologist (who was one of the individuals instrumental in the discovery that Laron syndrome patients rarely if ever got cancer) if he had any concerns about giving children growth hormone, he answered with a single word: endocosmetology. That’s what Rosenbloom (and a rapidly increasing number of his colleagues) somewhat derisively call the use of growth hormones for cosmetic purposes, including the desire to increase a child’s height.11

  But if GH has cleared all the regulatory hurdles (and there are many) for use in children, and epidemiological studies have not demonstrated an increased risk of cancer in children treated with GH, why should we be concerned?

  Well, to answer this it might be helpful to look at something called insulin growth factor 1, or IGF-1, which is released after the body senses a surge of growth hormone. IGF-1 doesn’t only promote vertical growth; it also promotes the survival of cells—and if you’re trying to push a few more inches onto a child’s short frame, that might be a good thing.

  But before you allow your child to be treated with GH, consider this: IGF-1 is also thought to inhibit apoptosis—cellular suicide—and in the case of a group of cells gone rogue, that could be dangerous.

  Or even deadly.

  In Rosenbloom’s view, giving children growth hormone just because they’re a little shorter than other kids exposes them to an unnecessary risk—possibly to cancer down the road—one we may not be able to fully comprehend today but only in the decades to come. And he believes that decisions being made to treat children with GH are increasingly the result of market-driven campaigns by drug companies rather than decisions made for the health and long-term well-being of our children.

  Today, the market for GH is worth billions, and millions are spent every year on marketing to advise worried parents that their precious child who may be on the short side requires a costly intervention for what might not be a real problem.

  If people with Laron syndrome do not get cancer because their bodies can’t respond to growth hormone, should we accept the risks and keep injecting our children with a synthetic version of the same hormone? If more parents learned about Laron syndrome, there’s a good chance that, given the potential cancerous implications of growth hormone administration, they might be a little less inclined to use it.

  ***

  When Laron syndrome was first described back in the mid-1960s, there was no way to predict that so many years later it would be offering us a rare glimpse of immunity to cancer—or that studying any rare disease would lead to anything more than esoteric medical knowledge.

  But as we’ve seen on this genetic odyssey, it’s often the rare family who have genes that predispose them to high cholesterol (for example) who ultimately turn around and help us make medical breakthroughs for countless others. After all, studying families with hemochromatosis led to my discovery of a new antibiotic. We owe an immeasurable amount of gratitude to every person with a rare disease and to their families for these medical gifts.

  Over the years I’ve met an incredible group of people with rare disorders. Still, I’d never presume to know what it’s like to walk in any of their shoes—the truth is that no one can.

  But my role gives me a unique perspective—indeed, a very close vantage point into the worlds of some of the toughest people I’ve ever met: Patients, parents, spouses, and siblings who have shown unbelievable courage in the face of a challenging diagnosis that tests their patience, compassion, physical endurance, and emotional fortitude.

  Take Nicholas’ mother, for instance. Over the years, Jen has developed a reputation as a “Kung-Fu Momma” for her resolute and steadfast advocacy on behalf of her son.

  I mentioned this nickname to Jen once, and she brimmed with pride (and Nicholas laughed hysterically). And that’s good—because the truth is that, as physicians, we really rely on parents like her to push us to go deeper and to think creatively about their children’s conditions.

  And then there’s always the lesson and reminder about what it means to be thankful for all those seemingly inconsequential things that need to happen, day in and day out, that have brought you to where you are today. Things you don’t even notice until the ever-so-rare occasion when something goes wrong. I’m not just talking about what’s going on inside all our genomes but about what it means to be human. About what it means to live. To overcome. To love.

  And that’s not all. As we’ve seen now many times over, these amazing patients and their inspiring families can also help us diagnose, treat, and cure countless of other conditions. Being around them reminds me that I often stand to learn more from my patients than they can from me.

  We all do.

  Because hiding deep inside of everyone with a rare genetic condition is a secret that, if they choose to share it, might one day serve to cure and help every last one of us.

  * Atorvastatin was not the first statin to be developed but is one of the most widely known.

  * With around two million new cases diagnosed every year, basal cell carcinoma is actually the most common type of skin cancer in the United States, although not the most deadly. Of course, not everyone with basal cell carcinoma has Gorlin syndrome.

  * In case you’re wondering, Sonic Hedgehog is in fact named after the Sega video game character.

  Epilogue

  One Last Thing

  We’ve covered a lot of ground, from the bottom of the Caribbean to the top of Mount Fuji, meeting genetically doped athletes, remarkable human pincushions, ancient bones, and hacked genomes.

  We’ve also seen how our genes don’t easily forget the trauma of being bullied, how a simple dietary change can turn workers into queen bees, and if you’re not careful on that next vacation, how even a small indiscretion can effortlessly alter your DNA.

  Through it all, we saw how our genetic inheritance can change and be changed by what we experience. We know that in our lives—as it is for all life on this planet—flexibility is key. And rigidity, as we’ve learned, can be the surprising enemy of strength.

  Even a tiny change in the expression of your genome during development can reverse a person’s sex. Ethan turned into a boy instead of becoming a girl, not simply because of what he inherited but because of a small change in the exquisite timing of his genetic expression. Remember, many others with genetic sequences similar to Ethan’s develop into girls.

  We’ve also explored how the understanding of the inner workings of your own DNA is a gift from people with rare genetic conditions—and we owe them much. Surprisingly, it is by understanding
the limitations we’ve inherited that we’re offered the best chance to transcend them. Knowing what to do with your genetic inheritance gives you the power to shape it.

  This is why you may someday be talking to a friend who will tell you that she’s been having more fruit and vegetables lately and it’s been making her feel very bloated and tired. And you’re going to remember Jeff the Chef. Maybe you won’t remember what his condition is called (hereditary fructose intolerance), but you’ll almost certainly remember something so much more important—that there’s no universally perfect diet. As we’ve learned from Jeff, diets that are good for many of us can be deadly for some.

  And maybe because of this book, after your children are born and one of them is a bit smaller than the others, you’ll overhear someone talking about growth hormone therapy. You’ll remember the genetic condition (Laron syndrome) that particularly affects a hundred or so people who live in the mountains of Ecuador. You just might recall that these people don’t appear to get cancer because they are immune to growth hormone, and in that way you’ll have information at your disposal that will help you make an informed decision.

  Remembering Meghan, for whom a few extra copies of a single gene, CYP2D6, turned a prescription for codeine into a death sentence will give you the courage to speak up, not only for your child but for all those with rare diseases whose lives so vitally inform our collective medical knowledge.

  That’s what Liz and David are doing for little Grace. Her bones won’t likely be as strong as most people’s, but she’s demonstrating every day both to me and to all those around her that her genome is not a completed book already written, edited, and published. It’s a story that she’s still telling.