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

by Moalem MD PhD, Sharon

  The most famous case of fibrodysplasia ossificans progressiva, or FOP, which is sometimes known as stone man syndrome, involved a Philadelphian named Harry Eastlack, whose body began to stiffen when he was five years old and, by the time he died at age 39, was fused so completely that he could do nothing more than move his lips. Today you can visit Eastlack’s skeleton at the Mutter Museum of the College of Physicians of Philadelphia, where it continues to interest researchers trying to unlock the mystery of FOP.

  Stone man syndrome is thought to affect about one in two million people, and it is aggravated by injury. That means that whenever Ali gets a bump or a bruise, her body responds by sending osteoblasts to the scene of the injury to make bone—and surgery intended to remove the excess tissue causes even more bone to grow back.

  In the past few years, those studying FOP have become energized by the discovery that mutations in a gene called ACVR1 can cause FOP.4 Some of these mutations are thought to result in a protein switch being made from the ACVR1 gene, which is always turned on. Instead of having healthy bone growth when and where it’s normally needed, it can throw the process of bone growth into overdrive.

  As of yet, though, the discovery of the gene is just the beginning in a long road to a cure for those who suffer from Ali’s condition. Early detection is key, as it provides a notice for parents and caregivers to help sufferers avoid injury as much as possible. Unfortunately, doctors didn’t know what was wrong with Ali until she was five—and if you think about all the bumps and bruises young children suffer, you can imagine how devastating that delay will be for her long-term health. That’s not to mention all of the medical procedures she underwent as her doctors struggled to understand what was going on within her, unknowingly doing far more harm than good.

  Most of the mutations in the ACVR1 gene are thought to be new, which we call de novo and therefore not inherited from either parent. This only complicates and delays the diagnostic process further since there would likely be no family history of anyone having FOP.

  And yet, sadly, there was a clue, albeit a subtle one that was understandably missed: Ali’s big toe, which was very short and bent toward the others.5 That dysmorphic sign, coupled with Ali’s other symptoms, could have been understood as a warning that might have helped clinch the diagnosis.6

  Think about that: Confronted with an amazingly complicated genetic disease, the least invasive and least technologically sophisticated approach to the problem—a long, hard look at Ali’s big toe—might have been the best approach to diagnose her condition.

  Even long after we’re gone, our bones can leave behind clues about the myriad experiences of our lives that have been impacted by our genes. Harry Eastlack’s well-studied skeleton is one obvious illustration—Mutter Museum visitors can see very clearly the way his disease fused his skeleton like a spider wrapping a fly in its web. But there are other, far more subtle examples.

  For instance, let’s say we had recovered some bones from the long-lost crew of the Mary Rose, the sixteenth-century English naval flagship of King Henry VIII, which sank on July 19, 1545, while fighting a French invasion fleet. What would those bones tell us?

  Although there are a lot of differing accounts, we still aren’t sure why the Mary Rose sank, nor do we know much about the identity of the men whose bodies settled to the bottom of the Solent Strait, just north of the Isle of Wight in the English Channel. But a modern scientific process called osteological analysis can help us decipher how their bones were used. And the Mary Rose’s sailors left us one huge hint: They had large left shoulder bones.7

  Researchers believe most of the physical tasks demanded of the sailors would have had them use both hands equally. Except, that is, for one important task—longbow archery was mandatory for all able seamen in Tudor England, and the Mary Rose carried 250 bows onboard (many of which, it appears, were used to shoot “fire arrows” at enemy ships).

  Unlike today’s carbon competition-caliber bows—the complex mechanical types you might see in the Olympics—the ones that were used in sixteenth-century England were very heavy. And while many things have changed in the centuries since the Mary Rose sank, one thing hasn’t. If you’re right-handed, as most of us are, you’re more likely to carry your bow with your left hand.8

  Of course, we already know that the repeated use of one arm over the other can result in differences in muscle shape, size, and tone. If you play tennis or just watch it closely, you know that a player’s racket-wielding arm is often significantly more muscular than the opposite arm. (Left-handed Spanish phenomenon Rafael Nadal is a great example of this—his dominant arm looks like it belongs to a smaller and less green version of the Incredible Hulk.)

  But constant use, strain, and weight isn’t just toning muscle, it’s also setting osteoclasts and osteoblasts to work, which changes genetic expression that helps to build stronger bones. It’s also weaving together an aspect of our life story that will last as long as our bones do.

  We don’t have to look back hundreds of years to see an example of our malleable skeletons at work. If you’ve ever laid eyes on a bunion you’ve witnessed the effects of the same phenomenon. Sitting on the Metropolitan Transportation Authority’s number 6 subway line during its run through Manhattan in the middle of summer when everyone’s wearing sandals provides one of the best opportunities for bunion viewing. If you’ve got one, or ever get one, don’t curse your bones for misbehaving—they’re only responding to the life of constrained foot apparel they’ve been subjected to. Not to mention an unfortunate genetic predisposition that seems to prime you for them.9 So don’t beat yourself up if you end up with bunions. Instead, this might be the only time when you can rightfully simultaneously blame both your parents and your fashionable shoes.

  As we’ve seen, regardless of our genetic predisposition, for the most part we’ve all inherited genes that allow us to have malleable skeletons. Another example of how our behaviors can cause changes to our bones is at play in the lives of our children. For years now we’ve begun to notice detrimental changes in the curvatures of the spines of elementary-age schoolkids, who have been paying the price for overloaded backpacks.10 As a result of increased attention to this problem, many parents have given their children packs with wheels, not unlike the carry-on suitcases many of us take with us to the airport.

  Not surprisingly, a lot of kids have bucked at taking rolling bags to school. “Dorky” is how my friend’s middle-school-aged son put it. That’s why one company’s inventive response to the problem—a scooter that folds, Transformer-style, into a backpack with wheels—has been a gold mine. Two years after launching its product online, Glyde Gear was still so flooded with demand that it was taking more than a month and a half to fulfill old orders and had to temporarily stop taking new ones.

  Not all good intentions go without consequences, though. Traditional backpacks were bad for kids’ posture. Roller bags, it seems, present a tripping hazard and school maintenance headache (they tend to scuff up floors and ding walls).

  Unfortunately, that’s often what happens when it comes to medicine, too. As we will see in the next few pages, new solutions to old problems often create new problems in need of even newer solutions. And sometimes by being too flexible, as when our bones are too malleable during our early years of development causes them to become permanently misshapen.

  An example of this started happening in the mid-2000s in response to the National Institute of Child Health and Human Development’s Back to Sleep campaign. Thanks to this successful initiative, the percent of parents dutifully putting their babies to sleep on their backs has soared from 10 percent only a few years earlier to a whopping 70 percent today.

  The campaign was born in response to recommendations from the American Academy of Pediatrics, which had been seeking to reduce sudden infant death syndrome (SIDS) cases by changing habits associated with a problem that was claiming the lives of about one in every 1,000 infants.

  Over a 10-year period foll
owing the introduction of the campaign, the rate of SIDS death fell by half. As with any medical innovation, with that success came a rather unforeseen but thankfully somewhat benign complication. Babies who sleep on their backs, while the boney plates that form the back of their skulls are still forming and fusing, become more likely to have slightly misshapen heads. And babies with misshapen heads became far from exceptional: During the years in which back sleeping became the norm, the incidence of such affects quintupled.11

  The technical term for this benign phenomenon is positional plagiocephaly, and for the most part we don’t consider it to be a very big deal medically. But with our society’s increased obsession with physical perfection, many parents have resorted to visiting an orthotist, a specialist in external devices designed to modify the functional or structural characteristics of our bones and muscles. Using something called a cranial remodeling helmet, orthotists can help correct a baby’s head shape. Positional plagiocephaly is an example of how our bodies are not functioning in a developmental vacuum but can be induced to permanently change in response to the circumstances of our lives.

  My first encounter with such a helmet came about a decade ago while I was walking through Central Park in Manhattan. At the time I had no idea what they were for and wrongly assumed that I was witnessing a new fad among very safety-conscious parents of children being helmeted while in their strollers.

  I eventually learned the details of how it works. The purpose of the helmet is to reshape a kid’s skull by removing pressure over the flatter parts, allowing the skull to grow into those areas. This device works best for children between four to eight months of age, needs to be worn 23 hours a day, and must be adjusted every two weeks. They can cost upward of $2,000 and generally aren’t covered by insurance.

  Because their children’s heads are quite malleable, though, studies are showing that parents who use stretching exercises and special pillows can see significant improvements in their child’s head shape even without the use of a helmet.12

  In the long run, though, the important thing isn’t shape but strength. As a species, we’re a rather clumsy lot—and given the importance and relative fragility of our brains, it’s vital that our skulls retain structural integrity.

  But strength isn’t just a matter of material hardness. When it comes to our bones and our genome—real strength lies in flexibility. Which is why I want to tell you about Michelangelo’s David.

  It was like walking into a photo by Edward Burtynsky.

  The much-lauded photographer, famous for his images of industrial landscapes, has spent a lot of time taking pictures of Italy’s Carrara marble quarries, which are renowned for the beautiful and plentiful white-blue marble that is harvested there and used by builders and sculptors around the world.

  As I traveled through the Italian Alps a few years ago and came upon one such quarry, I marveled at the audacity of the operation. Enormous tractors crawled along narrow mountain roads, moving marble blocks the size of minivans from deep inside the earth to preparation centers in nearby Tuscany. From there they travel by train, ship, and truck to many points across the globe.

  Marble is a product of the metamorphosis of sedimentary carbonate rocks formed millions of years ago as seashells settled on the bottom of the ocean. These sediments eventually became limestone, and after millennia upon millennia of the heat and pressure of tectonic processes, it is finally freed by operations like those in Carrara.

  Carrara marble is a relatively soft rock and easy under the chisel, which is why it is so sought after by sculptors and artisans. It is also very strong, which is why sculptures like Michelangelo’s David have survived intact for more than 500 years.

  Well, mostly. As it turns out, David has bad ankles, and over the years, the pitter-patter of millions of tourists’ feet at Florence’s Galleria dell’Accademia have taken their toll on the statue’s stability. In a way, David’s strength is his weakness—the inflexibility of his marble leaves him vulnerable to cracking.

  That is how we’d be, too, if not for our regenerative skeletons and the genes that code for things like collagen that gives them their structure.

  In humans, the production of collagen depends on our DNA and is produced in response to the demands imposed by our lives. Unlike Michelangelo’s David, our own ankles can heal after a sprain thanks to an increase in collagen being made through genetic expression.

  In humans, collagen comes in more than two dozen types, and besides being essential for healthy bones, is found in everything from cartilage to hair to teeth. Of the five main types, type I is the most abundant; it makes up more than 90 percent of the body’s collagen. This type of collagen is also found in artery walls, giving them the elasticity necessary to keep them from bursting every time our hearts contract and kick out a ventricle’s worth of blood.

  If there’s one place that we all really notice when collagen begins to fail and lose its tensile strength, though, it’s in our faces, where it provides structure to our skin. That’s why, when you hear of collagen, you might think of it as the substance that some people have injected into their cheeks to make them look younger.

  And that’s not a bad place to start, because it helps us understand the role that collagen plays as a structurally supportive protein. After all, no one would use it to create puffier cheeks and fuller lips if it wasn’t going to hold the shape, right?

  The word collagen originates from the ancient Greek word for glue, kolla. Before the modern industrial production of glue, most people had to rely on their own know-how to keep things bonded together. And it was glue made from the boiling of animal sinews and skins (rich in collagen) that was the source of strength in the bonding process. (This is where the expression “sending the horse to the glue factory” comes from.)

  Catgut, which is used in making strings for classical musical instruments, is also made mostly of collagen found in the walls of the intestines of goats, sheep, and cattle (but not, as it turns out, from cats). It has also been used, for many years, to make tennis rackets; it takes around three cows to make the strings for just one racket. It’s the tensile strength, derived from collagen in the serosa of animal guts, that makes catgut so desirable. Tensile strength is the measurable force at which a material can be stretched or deformed before failing. It can be thought of as the opposite of a substance being brittle.

  It’s also what makes certain foods so much fun to chew. If you’re into sausage or like to grill hot dogs for summer barbecues and tailgate parties, you’ll be happy to know that all the various parts and pieces used in the making of many frankfurters are held together by the super strength of collagen. And as many vegans will tell you, Jell-O, marshmallows, and candy corn all get their texture from gelatin, which is also derived from collagen. All told, some 800 million pounds of gelatin is produced every year worldwide and makes its way into your home or palate through different routes, from frosted Pop-Tarts to vitamin capsules and even certain brands of apple juice.

  From striking a ball with a tennis racket, to pinching the cheeks of a loved one, to the bouncing here, there, and everywhere joy of gummy bears, that elastic “snap back into shape” action you’re feeling is all thanks to collagen.

  The ultimate example of how flexibility equates to strength, though, is a two-meter-long freshwater fish called the arapaima. It is among the few animals that can live without fear in piranha-infested waters, thanks to genes that encode for collagen-backed scales that give, but don’t break, when struck with sharp objects. Researchers at the University of California at San Diego figure this makes the arapaima—which hasn’t evolved much in the past 13 million years13—a good model for building flexible ceramics that can be used in body armor—just one of the many ways that turning to the natural world for solutions can help us solve problems relative to our modern lives.14

  How does all this relate to genetics? Without our genome’s inherent flexibility, our bones become ill suited for the rough-and-tumble lives we lead. And
as we’ve learned with Grace, Ali, and Harry, it doesn’t take much to throw everything out of whack.

  In fact, all it really takes is a single letter.

  The human genetic code is made up of billions of nucleotides—adenosine, thymine, cytosine, and guanine, which we abbreviate with the letters A, T, C, and G—all lined up in a very specific pattern.

  Now, within the area that normally codes for building collagen in our bodies, in a corresponding gene known as COL1A1,15 the code generally goes a little something like this:

  G A A T C C—C C T—G G T

  But a single random mutation can make it look like this:

  G A A T C C—C C T—T G T

  And that’s all it takes for our body to change the way it makes collagen. One letter off in the code, and instead of a strong, and flexible skeleton, we get bones as stiff as marble, or brittle as sandstone.

  How could one single letter make such a profound difference?* Well, imagine for a moment listening to Beethoven’s well-known piano composition “Für Elise.” It begins as it always begins. But when the pianist gets to the tenth note, she misfires. Not by a lot, just by a little. Would you notice? Would the piece be the same? And if you were a classical music producer, recording the rendition for posterity, would you simply ignore that mistake?

  Beethoven was brilliant. His compositions were incredibly intricate. But compared to your genetic code, even Beethoven’s greatest masterpieces were as complicated as “Mary Had a Little Lamb.”

  Our code is like a journey of billions upon billions of steps. If the first one is just slightly askew, the rest of the journey will be, too.