And that was Tin-Tin’s story. She was born into a poor farming family in the northeastern city of Khon Kaen and moved to Bangkok when she was 14 to earn a living. She was 24 when we met and still trying to put enough money away for an operation that, she had long since come to accept, might never actually happen. Faithfully, each month, she was also sending money home to her mother and father. “Where I’m from it is expected that sons take care of their parents,” she told me. “Although I am more of a daughter to my mother and father now, I still feel that responsibility.”
Over the next few weeks of occasional conversations with Tin-Tin, I learned a lot more, and I was accepted into what became her ongoing dysmorphology course on the best ways to recognize a kathoey, which was fascinating.
“Take me,” she said one night. “The best place to start is with the height. That’s your first clue.”
She was right. Across all ethnicities, genetically speaking, males tend to be significantly taller than females.
“Okay,” I said, pointing to a shorter girl standing in front of a bar across the way. “What about that girl over there?”
“Kathoey,” Tin-Tin said. “Look at her throat—you can see a big—what do you call this thing?” She tilted her head back and pointed to her throat.
“Adam’s apple,” I said.
“Yes—that,” she said. “That’s clue number two.”
Again, she was genetically correct. The Adam’s apple, known technically as a laryngeal prominence, is the result of male hormones that change the expression of genes during puberty, triggering tissue growth.
“Well, the first clue for me was your voice,” I said.
“People can be so easily fooled by voices,” she said, lifting her voice two octaves, overriding the deeper vocal tone from her own Adam’s apple.
“Okay,” I said, pointing to yet another girl, this one a regular visitor to my booth. “What about Nit? She’s short. I’ve never noticed an Adam’s apple on her. And she’s got a high voice.”
“Kathoey,” Tin-Tin said.
“Are you sure?”
Tin-Tin looked at me and smiled knowingly, always the patient teacher.
“Of course, you can tell—look at her arms when she walks,” she said. “See her arms? So straight, like a man. You’re not looking at a real lady. She was born a boy. She’s had surgery everywhere—lucky girl—but the elbows never lie.”
What Tin-Tin was referring to was the carrying angle, the ever-so-slight way in which a female’s forearms and hands turn away from the body when the arms are bent at the elbow. You can check it out for yourself if you stand in front of a mirror and simulate carrying a tray with your arms bent.
Don’t be too concerned, though, if you find it more pronounced on yourself and you happen to be male. Tin-Tin’s advice was sound—the bigger the carrying angle the more likely you’re a female—but like many of our body parts, there’s significant variability.
***
Thailand isn’t the only nation where a nuanced view of gender prevails.
Up until 2007, homosexual relationships were illegal in Nepal. But by 2011, the small south Asian nation of about 27 million residents made history as the first country in the world to conduct a census in which they counted not just men and women but a “third gender” including people who did not feel they fit neatly into either category.
In nearby India and Pakistan, a group known as hijras—physiological men who identify as women (and who sometimes submit to castration)—have also gained special recognition. As early as 2005, Indian passport authorities began to permit hijras to be uniquely identified as such on their documents, and starting in 2009, Pakistan followed suit.
Critical in all of these places is the idea that gender identity—or a lack thereof—is not a matter of choice. That doesn’t impact in the slightest the prejudice that many people still unfortunately face, but it does set the stage for these relatively conservative societies to at least legally acknowledge and provide some measure of protection for those who don’t fit into the classic binary roles of gender.
It’s important to recognize that we’re not talking about individuals and groups that have acquired a more liberal and modern idea of fluidity regarding gender from Western societies. Hijras, in particular, have a 4,000-year history in both India and Pakistan.12
Castration is also certainly not only a south Asian phenomenon. It spans dozens of cultures, including several relatively modern Western ones. In Italy, for instance, hundreds if not thousands of young boys were relieved of their testes between the sixteenth and nineteenth centuries for the cause of music. These boys became known as castrati.
Gizziello, Domenichino, and Carestini are far from household names today, but in the eighteenth century these castrati—who combined male lung capacity with female range, thanks to voices frozen in prepubescence—were Italy’s A-listed singing stars. George Frideric Handel had a particular affinity for them; he wrote several operas, including Rinaldo, with castrati singers in mind.
Today there are only a few known recordings of a castrato, all of them made by Thomas Edison of the singer Alessandro Moreschi, who held the post of first soprano of the Vatican’s Sistine Choir for three decades until his retirement in 1913.13 Moreschi died in 1922 at the age of 63, an age that today would be quite young but, during that era, was more than a decade longer than the average life expectancy in Italy.
That might not be a coincidence. In addition to their distinctive voices, research into the lives of eunuchs who worked in the imperial court of Korea’s Chosun Dynasty shows they lived decades longer than others who worked in the palace, including members of the royal family themselves, a phenomenon that researchers have suggested is evidence that male sex hormones such as testosterone might be damaging to cardiovascular health or weaken the immune system over time through modifications in both genetic expression and repression.14
I’m certainly not advocating castration as a way to tack a few extra years onto your life. What I am suggesting, however, is that our sexual biology isn’t just about genetic sex, but rather the unique combination of genes, timing and the environment. As we keep seeing, people who fall away from the norm, for whatever reason, have a lot to teach the rest of us.
That’s not just the case for the one-in-a-billion cases like Ethan, but also for hundreds of millions of people around the world who don’t conform, genetically, biologically, sexually, or socially, to the rigid and traditional view of masculinity and femininity.
***
As we keep learning, our genes are incredibly sensitive. If it’s a change in your diet, exposure to sunlight, or even bullying, our lives are continually informing our genetic inheritance. And when it comes to the timing of genetic expression or repression, it often doesn’t take much to tip the scales.
In Ethan, after all, it didn’t take an entire encyclopedia set, or even a single volume of genetic material, to turn him from a girl into a boy. All it took was a little extra genetic expression at just the right moment during his development. And so Ethan, with just his little extra dash of SOX3, forever and completely altered many of our perceptions about how we develop.
You’ve probably heard the saying “What lies behind us and what lies before us are tiny matters compared to what lies within us.”15 It’s certainly a nice sentiment. But what we’re now learning is that the tiny matter within us has a whole lot to do with what’s behind us—and what’s before us, too. In ways we previously could not have imagined.
Our cultural milieu can also have a significant impact on our sexual landscape. Consider again what happened in China, for instance, as ultrasounds provided a basic, binary snapshot of fetal development to more and more people, giving parents who would prefer boys a chance to eliminate girls by the millions. Remember, this was not what medical sonar was originally developed for. It was intended to help bring life into the world.
Today, the way some Chinese parents are using prenatal ultrasounds to choose boys ove
r girls makes many people in the West feel uncomfortable. And yet we now live in a world in which gender is only one of many other things that can be chosen or eliminated before conception or during pregnancy using genetic testing.
Are we ready for a world in which children like Ethan, Tin-Tin, Richard, Grace, and all of the other people I’ve introduced you to in this book—not to mention the millions upon millions of others who exist outside of our social, cultural, sexual, aesthetic, and genetic norms—could be identified genetically and, like a submarine in the Caribbean, eliminated?
As we’re about to see, by striving for even greater genetic perfection we might be eliminating a lot more than just millions of people who don’t fit the societal norms we’ve created. We might actually be eradicating the very solutions to the medical problems we’re working so hard to solve.
Chapter 11
Putting It All Together
What Rare Diseases Teach Us about Our Genetic Inheritance
By now you’re very likely more attuned to all of the amazing, seemingly inconsequential genetic occurrences that have to happen—in just the right order, at just the right time—for a baby to be born.
And then, for that child to make it through her first day of life. And his first week. And their first year.
On and on it goes.
Through puberty. Into adulthood and parenthood. Through the changes of middle age. And as we learned in a previous chapter, against all the biological, chemical, and radiological influencers that conspire on a daily basis to change our genes.
However, it’s the moment-to-moment biological events we may be missing. From the beating of your heart, to your lungs stretching out to fill with air at every breath, most of your biological life and its genetic consequences happen in the shadows. It’s mostly in the extremes of physiological excess that you’re reminded that your heart has likely never stopped beating since before you were born. When it’s racing because you’re aroused, nervous, or even exercising, your attention shifts to what is happening inside your body—but you may not often reflect on how a specific change is orchestrated by, and simultaneously impacting, a multitude of genetic and physiological mechanisms. As we’ve seen, our genomes exist in concert with the environment in which we live, responding moment by moment, by expression and repression, to what we need, when we need it.
Some of these events may be as mundane as the need for the creation of molecular machinery, in the form of an enzyme, that helps you digest your breakfast. Other moments may be more significant, requiring your genome to provide the template for proteins such as collagen, that are used for structural support or scaffolding, which helps you to heal and recover from the physical trauma of surgery.
It’s unfortunate, I think, that whenever things are humming along seamlessly we spend most of our waking days blissfully ignorant of the details of the genetic underpinnings of our own inner workings, unaware that even at rest our bodies are in a constant state of motion. All too often, it’s only once something has gone terribly wrong for ourselves, or someone we love, that we start to become somewhat more attuned to all the inexplicably complex and mind-bogglingly enigmatic things that had to happen, and need to keep happening, day after day, to get any of us from conception to birth to wherever we are at this very moment.
Like shadows moving behind a rice-paper screen, we do occasionally catch glimpses of our inner workings. We feel our pulse race when we’re excited. We notice a cut scab over, then slowly disappear altogether. Through it all we are oblivious to the hundreds if not thousands of genes being continually expressed and repressed to make it all happen seamlessly until the inevitable happens.
As with a pipe that starts to leak in our home, we don’t really give much thought to what’s behind our walls or under our floors until they crack or burst. And then, when they do, it’s just about all we can think of.
Life is like that. For the most part, our bodies don’t ask for much in return for our continued existence. A few thousand calories a day, a little water, and some light exercise. That’s it. The only payment required to maintain our precious lives.
Our bodies can even help us along, for the most part, like a fairly unobtrusive personal trainer or nutritionist. Molecular signals are ordered up that gently (or at times not so gently) remind us to eat, drink, and sleep. In releasing these little messengers, our bodies urge us to behave. But it’s always a precarious sort of balance.
And if we ignore these demands, or if we do not have the means to satiate them, our bodies become restless until their needs are met (just think about the last time you needed, but couldn’t find, a restroom). It all happens so effortlessly that most of us, for most of our lives, live in a state of almost complete physiological and genetic ignorance.
It’s hard to recognize what’s going right until something goes a little off. And then as we’re about to see—almost as though you’ve removed a blindfold you had no idea that you were wearing—it all becomes crystal clear.
***
There’s no one exactly like you on this entire planet.
But let me be clear: Even though you’re genetically unique (unless you have a monozygotic twin and even then your epigenome is likely to be very different), there are a lot of people who might be really similar to you.
Sometimes, though, what makes us different are very small genetic changes—like Ethan’s in the previous chapter—that can significantly impact and change our lives. And some of these changes are so unique that it’s extremely difficult to find anyone else on the planet who shares them. If you’re a geneticist, finding and studying what makes a person unique can change how you see the rest of humanity. And if geneticists are fortunate to make that kind of discovery, it may even lead to a new treatment for millions of other people around the world.
Such can be the gift of rarity. By understanding what makes genetic outliers different, we get a totally unique perspective on our own lives. New ways of seeing our genetic selves, informed through a glimpse offered by someone with a rare genetic disorder, clears the way for medical discoveries and treatments for the rest of us.
Which is why I’d like you to meet Nicholas.
By many accounts, Nicholas was a young teacher. Given that his very existence was remarkably unlikely—he’s one of an exceedingly rare number of people in the world with a condition called hypotrichosis-lymphedema-telangiectasia syndrome, or HLTS—we knew that we had a lot to learn from him.
Now, you wouldn’t need to be a trained dysmorphologist to know, at a single glance, that there was something different about Nicholas. What you might need someone like me to point out, though, is that there’s a known genetic basis for that difference.
With brilliant blue eyes and a face that seemed to be fixed in a perpetual state of contemplation, this good-looking kid could also break out into a smile so big and contagious that you couldn’t stop yourself from matching it. He was a young teenager, yet something about his disposition gave you the impression of a wisdom that was well beyond his years.
So striking and transfixing were these characteristics that you might at first barely notice the other traits for which his syndrome was named: hypotrichosis, a lack of hair; lymphedema, a continual cycle of swelling; and telangiectasia, webbed blood vessels at the surface of the skin.
The absence of much hair (Nicholas had just a few ginger wisps on the top of his head) and the spidery veins that were subtly apparent on his skin were both largely cosmetic issues. That doesn’t mean those issues were unimportant, but neither of them were life threatening. The swelling, though, was another matter.
Under normal circumstances, our bodies do a remarkably good job of methodically moving around the various fluids that collect in our tissues as we go about our daily lives. Sometimes, in response to infection or injury, the fluid stays a bit longer in one area. Almost everyone experiences this at some point in their lives—if you’ve ever had a sprained ankle or wrist, you know how this goes. A bit of swelling is a very
normal part of the healing process and usually does the body good. But in the case of people with HLTS, the swelling doesn’t happen in response to injury but as a continual symptom of what appears to be a compromised lymphatic system, which isn’t healthy at all.
Although HLTS is extremely rare—fewer than a dozen people worldwide are affected—all of these symptoms combined are quite common among people who have it. But Nicholas was also suffering from renal failure, which made him in dire need of a kidney transplant. As far as we knew, that wasn’t “normal” for the other people who have been identified with HLTS. And that’s what sent us on a trip around the world looking for an explanation.
Like many journeys, this one started with a map. Rather than highway numbers and street names, this map included a particular genetic address that was found, as far as we knew at the time, only in Nicholas’ genome. By lining up all the letters of these DNA sequences against the known genomes of people who don’t have HLTS and then observing where they diverge, we could see that HLTS is an apparent consequence of mutations or changes in a gene called SOX18.
Sometimes I like to get friendly with the genes I study, and to do this, occasionally I give them nicknames. This one I like to call the Johnny Damon gene, for the once shaggy-bearded Red Sox player who wore number 18 in Boston and also in New York, once he defected to the other side of that storied rivalry.
The Yankees recruited Damon because they had some expectations about what he could do for their team. He was, at that point, a career .290 hitter over 11 seasons in the league, a consistent threat to steal bases, and a rock-solid force in the outfield.
As is true for our genes, when you know what a player has done in the past it becomes a lot easier to predict how he will perform in the future. In four seasons with the Yanks, Damon continued to hit near .290—but in his final season in the Bronx he struck out nearly a hundred times (an unfortunate personal record), stole fewer bases than he had in any season of his career, and tied for the lead in American League left fielders in errors. When he entered into free agency at the end of the 2009 season, the Yanks declined to re-sign him.
Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes Page 20