And by all appearances, she had been right.
When he was born, Ethan did have one potentially concerning but not altogether uncommon trait. In most boys, the urethral opening—the place they pee from—is somewhere near the center of the head of their penis. But Ethan had hypospadias, which meant that the location of the urethral opening wasn’t where it usually is but rather more toward the scrotum.
About one in every 135 boys is born with some form of hypospadias, from urethral openings down near the scrotum to all the way up near where it is on most boys—and it’s generally quite fixable.8 In most cases the correction is considered cosmetic, though surgeons sometimes must sacrifice the foreskin to make the repair. Sometimes parents decide that a slight, cosmetic case of hypospadias doesn’t justify an operation. But in more severe cases, where a boy won’t be able to stand to pee but will have to sit instead, surgery is often deemed to be important for psychosocial reasons.
As long as there’s no blockage to the flow of urine, though, the surgical procedures to repair hypospadias are not done on an extremely urgent basis. So within minutes of his birth, when his condition was first noticed, Ethan’s parents were informed and counseled about their options. And following all the usual first-day baby checks, they’d been sent home with the advice that they need not worry and could schedule a follow-up consultation with the surgical team to address his hypospadias in a few months.
Ethan’s parents did worry, though, particularly as the months went by and their son clung to the bottom percentile for height and weight. They wanted to understand more about what they could do to get him up to size. But what started as a routine appointment to check his growth quickly turned into a puzzle of global proportions.
Given Ethan’s size and seemingly benign physical trait, a common genetic test called a karyotype was ordered. In this test, a few of Ethan’s cells were extracted, placed in a petri dish, encouraged to grow, and then treated with a special stain to help give contrast to his chromosomes.
That’s when it began to become clear that Ethan was a little unlike other boys and men before him, who have all inherited a Y chromosome from their fathers. Though rare, it’s not unheard of for a child who is genetically a girl to develop as a boy when a very small piece of the Y chromosome that contains a region called SRY (which stands for sex-determining region Y) is inherited. When this happens, a person’s entire course of development can be shifted toward the male road instead of the female one.
In search of this little piece of SRY, the next step we employed in Ethan’s case was called FISH (fluorescence in situ hybridization). The FISH test involves using a molecular probe that binds only to parts of the chromosome that are complementary.
What we expected to see in Ethan was that the FISH for the SRY region would be positive, as it is in other cases that present in this way. But it wasn’t. In fact, it’s not only that Ethan didn’t inherit a Y chromosome from his father, he didn’t even get a microscopic trace of one. And that didn’t leave us with many known genetic explanations as to how Ethan could have turned into a boy.
Actually, according to the genetics textbook sitting on my desk, he really should have been a girl.
***
“It’s a boy!” That’s what Ethan’s parents, John and Melissa, had longed to hear. And when they did, they were thrilled.
So was nearly everyone else in their extended family, especially John’s parents, who were first-generation immigrants from mainland China. Even before the one-child policies took effect in their country, the birth of a boy was considered fortuitous—and so they were especially excited by the news that Melissa was pregnant with a boy.
And maybe just a little overprotective. At least once each day, Melissa would get a call at work from John’s mother inquiring about her state of health and reviewing, as per their family’s cultural traditions, what she should and shouldn’t be doing, thinking, and eating. The long list of banned foods included two of Melissa’s favorites: watermelons and mangoes.
That’s not all. Melissa was also instructed to avoid ever leaving sharp objects, such as scissors or knives, on the bed—not only because she might accidentally cut herself, but also because John’s mom had been raised to believe that such actions were bad luck and harbingers of undesirable omens that could cause the baby to have a “cut lip,” what we call today a cleft lip or palate.
Melissa was not particularly superstitious, but in an effort to avoid any unnecessary familial conflicts she did her best to play along. There was one area, however, where she felt she needed to draw the line, at least secretly. As her pregnancy progressed, Melissa was insatiably craving watermelon. As long as she managed to keep the big green rinds and little black seeds hidden when her in-laws came over, she figured everything would be fine. When her mother-in-law happened to “volunteer” to take out the trash and found some rinds and that distinctive red juice at the bottom of the garbage bag, a tremendous fight ensued. Nothing Melissa could say would alleviate her mother-in-law’s anger. Ultimately, she simply apologized and promised to stay away from all those “killer fruits” until long after her delivery, while quietly pledging to herself to be more careful about where she’d dump the evidence next time she had a secret snack.
Even though she knew her mother-in-law’s fears were outlandish, when I shared with Melissa the news of her baby’s genetic exceptionality, it made her wonder aloud if there could have been any truth to all those family superstitions. And while I’d never heard of anyone with this particular concern about watermelons before, her anxiety wasn’t unusual at all.
The first question I hear from parents whose children have genetic conditions is often, “Doctor, is there anything I could have done to cause this?”
In situations like this I feel obliged to help alleviate the misplaced guilt that parents may feel. So instead of talking about all the possibilities at play for “what went wrong,” I try very hard to frame the discussion in terms of what we know that has been scientifically established.
Of course, this usually requires that I have some idea. And in Ethan’s case, at least at first, I had absolutely no clue.
***
One of the possibilities that was brought up early on in Ethan’s case was congenital adrenal hyperplasia, or CAH, a group of genetic conditions (caused by a handful of genes) that can make females look externally male. People with CAH don’t naturally make enough of a steroid hormone called cortisol. When that deficiency is recognized by their bodies, their adrenal glands are stimulated to try to make more. The problem is, though, that’s not all that gets made. More sex hormones can be produced as well.
In some cases of CAH, a version of the gene called CYP21A can cause girls and young women to develop bad acne, excessive body hair, and a large clitoris that can, in certain circumstances, look like a penis at birth. This is why CAH is one of the most common causes of ambiguous genitalia, making female babies appear more male.
The excess of androgens, caused by inheriting this gene, also interferes with the normal ovulatory cycle and prevents some of these women from being able to get pregnant. About one in 30 Ashkenazi Jews, about one in 50 women of Hispanic descent, and lower ratios of women from various other ethnicities have inherited genes that cause CAH, but many don’t even know it.9
You don’t need to undergo genetic testing to find out. There’s a relatively simple blood test that can indicate whether a woman might be suffering from this form of CAH, but it’s not always ordered. As a result, a lot of women spend years receiving ineffective fertility treatments, not to mention spending thousands of dollars, before learning that the condition preventing them from becoming pregnant is not actually a fertility problem at all but rather a genetic disorder that can be easily treated with a drug called dexamethasone.
But what about Ethan? Could his case be an unusually pronounced form of CAH? After a short discussion, we quickly crossed that possibility off the board. Genetic mutations that cause CAH can cause virilization
in girls, even to the extent that they appear male at birth, but there’s one thing they can’t do, and that’s make testes. As a visual inspection and testicular ultrasound confirmed, Ethan did indeed have two normally formed testes.
There are a few even rarer conditions that can cause XX-sex reversal of this type, but none of them lined up with what we were seeing in Ethan. Slowly but surely, one by one, we moved from likely to unlikely for every possible known cause for Ethan’s condition and crossed them off the list.
Ultimately, our group coalesced around an idea made famous by Sir Arthur Conan Doyle’s Sherlock Holmes: “When you have eliminated the impossible, whatever remains, however improbable, must be the truth.” But as we whittled away at the impossible, what remained seemed so incredibly improbable that it took a long time for us to accept that it might indeed be true.
Maybe we’ve just been wrong about sex all along.
***
For a very long time the dogma has been that while chromosomally we may be male or female, developmentally we all start out the same. If we inherit a Y chromosome, or even a very small part of it, we take a detour toward maleness. In the absence of that, though, we’d all continue to head down the genetic path of being a female.
But in Ethan, as we saw, that wasn’t the situation. So we began to suspect that the conventional genetic wisdom was indeed wrong.
Like one of the early spy satellites that first orbited the earth, most of the information gleaned from early genetic karyotype tests was grainy and lacked good resolution. It was essentially a mile-high glimpse of our packaged genome.
But even going back many decades, what the test could tell us was whether large sections of the arms that make up each chromosome were present.10 In a way, performing a karyotype is like walking into an antiques store and staring at a bookshelf housing an encyclopedia. With a rather quick glance you can count the numbered volumes and see whether each one is present. The same goes for a karyotype, which provided a quick snapshot of whether each of our 46 chromosomes was present, though it would be impossible to say at that point whether all the pages upon which our genes are “printed” were inside, safe and intact.
In recent years, the resolution at which we can study genomes has increased phenomenally. We can now also use a detailed type of investigation, called a microarray-based comparative genomic hybridization in which we essentially “unzip” a person’s DNA and then mix it together with a known sample of DNA. By comparing the two, we can identify small stretches of DNA that are either missing or duplicated. This accomplishes the same goal as a karyotype, but at an incredibly more detailed level.11
However, if you’d like to get even more information, down to the single letter spelling of your genome—to the point that we can see not just your chromosomes but look for rare changes in the sequence of each of the billions of individual nucleotides—adenosine, thymine, cytosine, guanine—then you need to sequence your DNA.
When it came to Ethan, we found one thing in particular that we didn’t expect: He had a duplication of a gene called SOX3 that’s found on the X chromosome. Babies who develop into girls have two X chromosomes, so you’d expect them to have two copies of the SOX3 gene. And they do, but usually one of their X chromosomes is randomly turned off, or “silenced,” in every cell thanks to the product of a gene called XIST. Interestingly, Ethan’s duplication would provide an extra opportunity for the gene SOX3 to be expressed from nonsilenced X chromosomes. As we saw in an earlier chapter about gene dosage, where Meghan inherited extra copies of a gene that metabolized codeine, having extra numbers of genes can change or alter the overall amount of the protein product, which in Meghan’s case caused a fatal overdose from codeine.
As it turns out, having an extra copy of the SOX3 gene was significant for Ethan because it shares about 90 percent of its nucleotide sequence with the SRY region—a small piece of the Y chromosome that is a crucial signpost on the journey to becoming a male. The similarities are so significant that it’s likely that SOX3 is a genetic ancestor to SRY. The main difference: SRY exists only on the Y chromosome, while SOX3 exists on the X chromosome.
As Sherlock might say: The game was afoot.
***
Like an old baseball player coming out of retirement for one more game, it now seems clear, thanks to Ethan, that the SOX3 gene has the ability to pinch-hit for SRY. And when put in the right place, at the right time, and in just the right circumstances, it can create a boy out of a girl, regardless of whether a Y chromosome is present or not.
Today, we know of a small number of other people with a similar, though not identical, genetic makeup as Ethan’s. To further complicate things, what we’ve also learned is that some people who, like Ethan, have inherited a duplication of the SOX3 gene and a “female” XX chromosomal complement have been found to develop as anatomically normal females.
So why is Ethan so different?
If you had told a geneticist 35 years ago that you could transform a slim brown mouse into a fat orange one and make that change heritable by giving it folic acid that turns its genes off and on, you likely would have been laughed at.
As we come to better understand the new and fast-changing genetic landscape around us, we are being forced to keep an open mind. Jirtle’s agouti mice are just one very small example of the power of a singular environmental factor on the genome.
Our lives, of course, are seldom as singularly influenced as a lab mouse’s life can be, a humbling reminder of the multitude of interactions across a very vast spectrum of variables that are occurring beyond our technological—and even intellectual—grasp.
The truth is, with all our advanced genetic tools, we still don’t know exactly why Ethan turned into a boy, while others who’ve inherited a similar genetic makeup stayed the developmental course and became girls. But we know that in many other situations—Adam and Neil, the monozygotic twins with NF1, for instance—it doesn’t take much to push our genetic expression or repression one way or another to forever change the course of our lives.
We’ve only just scratched the surface of the broad spectrum of genetic and epigenetic factors that influence our sexual development. And yet for most children like Ethan, the impact is still being felt in a very binary way. Boy or girl? He or she? Pink or blue?
But it doesn’t have to be this way.
***
I first encountered a kathoey while I was taking part in an HIV-prevention program with the Population and Community Development Association, or PDA, a nongovernmental organization operating in Thailand.
Her name was Tin-Tin, and she worked every night just a few steps away from where I was manning an educational booth in Patpong, Bangkok’s world-famous red light district. One of PDA’s goals in Thailand was to increase the use of condoms to help prevent the spread of HIV. This was, of course, especially important among the city’s sex workers.
Tin-Tin’s goal, on the other hand, was slightly different; to entice as many paying customers as possible into one of the local clubs that featured burlesque-style sex shows.
Even in heels, she was rather tall for a Thai woman, and in a place where sex workers congregated like bees in a hive, maybe because of her height, she stood out.
Patpong got its start on what was then the outskirts of Bangkok in the late 1940s but really hit its seedy stride during the Vietnam War, when hundreds of American GIs would spend their leave days and dollars doing the kinds of things that soldiers have always done. Today, though, the place has the feel of a tourist trap—a never-ending Mardi Gras–infused flea market and sexual playground.
Girls like Tin-Tin haunt the entrances of the clubs, either as employees who are trying to get foreign men and sexually adventurous couples to come in, or as self-employed entrepreneurs, seeking to entice those coming out to spend a little more money on a bit more fun.
For days, she eyeballed my educational booth, but she didn’t come over to the table until one night when there was a sudden downpour and she skipped
over—rather gracefully given the wet streets and her seven-inch heels—and ducked under a nearby awning.
She picked up one of the flyers prepared by the organization I was working for and casually flipped it over to the side that was printed in Thai.
“So, you married?” she asked in remarkably good English—and in a much deeper voice than I’d expected.
The storm lasted 30 minutes or so, and we spoke until it passed. That half-hour period with Tin-Tin was incredibly informative.
Here is some of what she revealed. There are about 200,000 people in Thailand who are considered kathoey—which many Thais, even socially conservative ones, consider to be a “third sex.” Some are cross-dressers. Others are preoperative transgendered people. Others have surgically completed the full male-to-female transition.
And no, they’re not all sex workers. Kathoey individuals work in every facet of Thai society, from garment factories to airlines, and even to the Muay Thai boxing ring. It’s true: Arguably the most famous kathoey is a champion fighter named Parinya Charoenphol, a former Buddhist monk who pursued a Muay Thai career in order to raise enough money to pay for gender reassignment surgery. She would sometimes arrive in the ring wearing makeup and, after promptly dispatching her opponent, give him a postmatch kiss.
None of this is to say that kathoeys don’t face a significant amount of discrimination in Thailand. They do. For one thing, there is no mechanism for changing one’s legal gender from male to female, even for those who might indeed be genetically female. In a nation that conscripts about 100,000 young men into military service each year, this has caused some problems in the past.
Those seeking gender reassignment have other problems, too. The process in Thailand is relatively inexpensive by Western standards, which is why that nation is one of the most popular places in the world for people to go for sex change operations. But although it’s cheaper, it’s still out of reach for most Thais. Desperate, many kathoeys turn to prostitution to fulfill the dream of getting surgery.
Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes Page 19