Medical Genetics Redux: Yes, Virginia, There are More than Two Genders...

In July of 2012, I wrote my first and only article on working at Medical Genetics at Emory University (back in the early 80's), and considering the trans-hysteria of late, boy does it need an upgrade. 

My job at Emory wasn't especially technical.  It was the lab technicians would take the samples (from amniocentesis or, more often, a buccal smear of the cheek) and distill them down to one little drop that went under the electron microscope.  The next day I’d be handed a blurry 8 1/2 by 11 photograph, full of chromosomes no naked eye could ever, would ever see, transformed into inch-long fuzzy banded crosslets, tumbled and curled and overlaying one another like sleeping puppies. I was the grunt labor, and my job was to cut them out with a a pair of scissors, sort them, and line them up and tape them down to make a karyotype.  

I got to know those chromosomes really well.  Me and my trusty scissors untangled 9s from 4s, 18s from 21s, and set them in neat ordered pairs for the first time in their existence.  At first, like every Other, they all looked alike to me, but time and use and my own fancy gave them personalities.  The first five sets were large and strong and unmistakable -- any flaw in them and there would have been no being to be tested.  6 through 12 were like the dancing men of Sherlock Holmes:  jaunty, poised, often with one foot kicked up in dance or play.  16 through 20 were smaller but just as playful, children learning at their parents’ knees.  13 through 15 were Hopi women, with their looped hair risen above long blankets, or nuns in banded shawls; an elemental female image.  And then the mysterious, smaller shrouded shes, 21 and 22, solid, dark, impenetrable, unpitying, even when you winced with pain, even when you cried as you found a third come to join their pair, or one so damaged that nothing good could come...

The search for sex was a lot more fun.  I found the male in microcosm elusive, mainly because the Y chromosome looks nothing like a Y.  Half the time I thought it was a scrap of something else.  I started a lot of panics until I got it through my head that what looked to me like a tiny, flat-topped, spread-legged 21 was not a trisomic sister of doom, but a Y, a HE.  My only comfort, as I sat with my scissors and a worried look, was that over in the hospital, with the baby right there in front of them, they couldn’t tell either.  Parents panicking, doctors shrugging, nurses whispering, and all waiting for me (!) to find that other damn chromosome and tell them whether it was a girl or a boy.  

BTW, it's been determined that 1 out of every 1,000 babies are born with "indeterminate genitalia." 

1 out of every 5,000 female babies are born without a uterus.  

And sex chromosome aberrations are the most common of all chromosomal aberrations, because they are almost never lethal.  

Here are a few of the more common ones:

Klinefelter syndrome - males inherit one or more extra X chromosomes--their genotype is XXY or more rarely XXXY or XY/XXY mosaic. In severe cases, they have relatively high-pitched voices, asexual to feminine body contours as well as breast enlargement, and comparatively little facial and body hair. 1 in 500 and 1 in 1000 male births. (This makes it one of the most common chromosomal abnormalities.) 

XYY syndrome, a/k/a Jacobs Syndrome - males inherit an extra Y chromosome--their genotype is XYY. As adults, these "super-males" are usually tall (above 6 feet) and generally appear and act normal. However, they produce high levels of testosterone. During adolescence, they often are slender, have severe facial acne, and are poorly coordinated. Legend has it that this can cause strong criminal propensities. 

Triple-X syndrome - Also common:  occurs in women who inherit three X chromosomes--their genotype is XXX or more rarely XXXX or XXXXX. As adults, these "super-females" or "metafemales" as they are sometimes known, generally are an inch or so taller than average with unusually long legs and slender torsos but otherwise appear normal. There is a tendency towards ovarian abnormalities that can lead to premature ovarian failure (early menopause, infertility). 1 in 1,000 female infants are born with this, and it occurs more commonly when the mother is older.

Turner syndrome - occurs when females inherit only one X chromosome--their genotype is X0 (i.e., monosomy X). If they survive to birth, these girls have abnormal growth patterns. And they are born post-menopausal. 1 in 2,000 to 1 in 5,000 female infants are born with this.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis - can appear male OR female, and a significant number of individuals show genital abnormalities or intersex characteristics.  (This is probably what most of the old literature was referencing when they used the term "hermaphrodite.")  Rare: 1 in 15,000 live births.

46,XX/46,XY - is a chimeric genetic condition in which one human being has two distinct cell and sex lines. This is caused by two fraternal zygotes being absorbed in utero in one fetus. What will emerge in puberty is anyone's guess.  "The rate of incidence is difficult to determine as the majority of diagnoses go unreported in the literature."

XX gonadal dysgenesis - the baby is born without ovaries. Because of this, it's not diagnosed until puberty fails to develop, and it's unknown how many are born with it.  

XX male syndrome, also known as de la Chapelle syndrome - a rare syndrome where the baby is male, but has two X chromosomes, generally with one of them containing genetic material from the Y chromosome; this gene causes them to develop a male phenotype despite having chromosomes more typical of females.  Rare: occurs in approximately 1 in 20,000 newborn males.

(LINKS ARE HERE & HERE) 

Which brings up the Guevedoces (which literally means "penis at 12"):  

"In a small community in the Dominican Republic, some males are born looking like girls and only grow penises at puberty." Raised as girls - and generally hating it, they become male around 12. How did that happen? A 1970 study showed the following:

"When you are conceived you normally have a pair of X chromosomes if you are to become a girl and a set of XY chromosomes if you are destined to be male. For the first weeks of life in womb you are neither, though in both sexes nipples start to grow.  Then, around eight weeks after conception, the sex hormones kick in. If you're genetically male the Y chromosome instructs your gonads to become testicles and sends testosterone to a structure called the tubercle, where it is converted into a more potent hormone called dihydro-testosterone This in turn transforms the tubercle into a penis. If you're female and you don't make dihydro-testosterone then your tubercle becomes a clitoris.  

When Imperato-McGinley investigated the Guevedoces she discovered the reason they don't have male genitalia when they are born is because they are deficient in an enzyme called 5-alpha-reductase, which normally converts testosterone into dihydro-testosterone... So the boys, despite having an XY chromosome, appear female when they are born. At puberty, like other boys, they get a second surge of testosterone. This time the body does respond and they sprout muscles, testes and a penis."   (LINK)

The condition of 5-alpha-reductase type 2 deficiency (5-ARD) is an inherited disorder and is limited to male genetic. The affected males are usually identified as female in childhood but undergo striking virilization at puberty. While overall incidence for various countries are not established, increased incidence is reported in the Dominican Republic, some highland tribes in New Guinea (where they're 
called kwolu-aatmwol, literally 'a female thing changing into a male thing') Lebanon and Turkey. (LINK)

Now you may wonder what all this has to do with crime. Well, think about it - you're obviously born a girl, raised as a girl, and then you hit puberty and voila! you're male! If that wouldn't call for a charge of witchcraft in medieval times (are we done with those yet?), I don't know what does.

Or someone with 46.XX/46.YY commits a crime - but the DNA tests show a male did it and the DNA sample of the person shows a female? Or vice versa?

Or someone finds out - after marriage - that they're infertile due to genetics and that leads to... fill in the blank yourself. 

I'm sure we can all think of some more.

Meanwhile, Nature is not always "right" (and if you think it is, you've never seen a two-headed calf or a child with cancer or photograph of Joseph Merrick). 

Nature is not always limited to two genders (fish, gastropods, worms...). 

Nature mixes it up a lot (male seahorses carry and give birth to the young; rabbit does can absorb their litters before birth if there's a shortage of food).  

And, whether 1 in 1,000 or 1 in 5,000 or even 1 in 20,000 - with a population of  332 million, that means that an awful lot of Americans are / were born with some sort of sex chromosome disorder.  Personally, I am all for genetic testing of every baby, but that's not going to happen, because of freedom...  Meanwhile, often the only way to treat many of these conditions is genetic testing followed by gender affirming hormone treatments and sometimes surgery.  All of which are currently banned in 20 states and counting...  

And - since it is all too easy to screw up the visual determination of sex at birth (Guevedoces!), and in some cases even a genetic test can't determine it, can we just leave the whole #$%*%&@ bathroom issue alone and let people pee when and where they need to?  

Thanks.

Loose Genes

This is not going to be as cohesive as (I hope) most of my pieces here are, because I have three vaguely related things I want to talk about.  And they have only a slight connection to crime or mystery.  The fact that I'm fighting a cold doesn't help.

So if you prefer to skip this and go check your email you won't hurt my feelings. If you're still with me, here goes.

A relative recently told us she had her genome tested and invited us to do the same.  This feat, which would have been the wildest science fiction a few decades ago, now costs about a hundred bucks and takes a couple of weeks.  You spit in a test tube, and wait to get an email.  Not exactly Doctor Who, is it?

And the results, I have to say, are pretty cool.  My background, as far as I know, is one-half Italian, three-eighth English, and one-eighth Irish.  The computers spotted 10% Italian, 3% British/Irish, 2% French/German, and the rest is mostly vaguely European.  There is a tantalizing 0.2% Sub-Saharan African, which I assume comes from my Italian ancestors.  (To paraphrase Pete Seeger, where do you think those Roman emperors got their curly hair?)  Oh, and I am 2.8% Neanderthal.

But more interesting, the same service tells you if you have inherited health risks that are greater or lower than average.  And that is why the Food and Drug Administration just sent them an order to cease their business.  Because, says the FDA, they were giving out medical advice, which is illegal.  I look forward to seeing how it turns out in court, but I will say this: I have a higher-than-average level of one chemical and my doctor has been trying for years to figure out why.  The computer gurus (knowing nothing about my medical test results) were able to tell me that that higher level runs in my genome.

If you want to know more about the controversy, read this and this.

Now, on to the second topic.  I am reading a fascinating and infuriating non-fiction book by Rebecca Skloot entitled THE IMMORTAL LIFE OF HENRIETTA LACKS.     Ms.  Lacks suffered from bad luck nine ways from Sunday.  She was an African-American woman born in poverty in the rural south in the early-twentieth century.  (I am not saying it is bad luck to be born African-American.  But there have been better times and places for it.)  She died of cervical cancer in 1951 at age 31.

But before she died scientists took samples of her tumor, possibly with her permission (the phrase "informed consent" hadn't even entered the medical vocabulary by that point).  Scientists had been trying for years to grow cells in test tubes, but the cells always died after a few generations.  Not so the HeLa cells (named for their original source).  They were "immortal," and could be cultured, multiplied, sent through the mail, experimented on, etc.

And so cells that began in this poor, hard-luck woman, were used to develop polio vaccines, were sent into space, and became essential parts of thousands of other studies.  (The name of that genome company I was talking about is 23andme, which refers to the 23 chromosomes in the human genome. Guess whose cells were used in figuring out that number?)  Ms. Lacks' cells were so potent that years later many other colonies of cells that were growing around the world were discovered to be contaminated with HeLa cells - even though none had been used in that laboratory. They could sneak in on a dirty test tube, or a scientist's coat.

The book, which I highly recommend, also discusses the baffled horror of Ms. Lacks' family as they discovered, decades after the fact, what had been done to parts of her body without their knowledge or permission. The conflict between the scientists and the family takes on the inevitability of Greek tragedy: there was simply no common ground for communication.  You find yourself expecting the next unintentional outrage.  When it becomes necessary to explain the concept of "genetic markers" to Ms. Lacks's widower, a man with four years of schooling, of course the scientists had it done over the phone by a researcher with a thick Chinese accent and imperfect English.  How could it have been otherwise?

Reasonable people can disagree about whether persons whose cells are used in research deserve any control or compensation. (There are more than 17,000 patents based on HeLa cells.)  But it boggles the mind that  some scientists in the early fifties thought it acceptable to secretly inject HeLa cells (highly  active cancer cells, remember) into surgery patients just to see what would happen. This went on until some physicians refused to participate, pointing out that eight doctors were hanged at Nuremberg for that sort of research.

And on that cheerful note, let's move on to my third topic.  I just finished reading NECESSARY
LIES, the most recent novel by my sister, Diane Chamberlain.  You can certainly accuse me of nepotism for bringing it up here, but I think you will see the connection.  Diane's excellent book is fiction, of course, but it is firmly rooted in the Eugenics Sterilization Program, under which North Carolina sterilized 7,000 people between 1929 and 1975.  They focused on "mentally defective" epilectics, and people on welfare.  Most states with such programs gave them up after World War II (the shadow of Nuremberg, again), but the Tarheel State actually boosted theirs.

Diane's novel is set in 1960 when a brand-new social worker (after three whole days of training!) is given the job of preparing the sterilization request for a pregnant fifteen-year-old.  The idea is that the girl will wake up after giving birth with an "appendectomy scar" and never be told  she has been sterilized.

The book is not a mystery.  It is not a melodrama either: there are no cackling villains.  Everyone thinks they are doing the right thing (just like the scientists who used the HeLa cells).  And Diane is careful to include one woman who is thrilled to get the operation, since birth control was not easily available.

There are crimes and punishments in the book, but whether the crimes are what gets punished is open to interpretation.

Well, I'm going back to my sickbed.  I hope I gave you a few things to think about, anyway.

Medical Genetics

One of my many strange jobs was at a Medical Genetics Lab in the 80's.  It was your typical lab:  clean but shabby, hard-edged, hard-used.  The whole place reeked of what I called a "wrong smell" - which was basically amniotic fluid and chemicals.  Light came through glazed windows.  The samples came in bagged or bottled and sealed.  The results went out in plain brown envelopes.  The lab did buccal smears (cheek swabs) for babies, blood tests for children and adults, amniocenteses for pregnant women.

The technicians would take the samples and distill them down to that one little drop that went under the electron microscope.  The next day I’d be handed a blurry 8 1/2 by 11 photograph, full of chromosomes no naked eye could ever, would ever see, transformed into inch-long fuzzy banded crosslets, tumbled and curled and overlaying one another like sleeping puppies.  My job was to sort them out.

I got to know those chromosomes really well.  Me and my trusty scissors untangled 9s from 4s, 18s from 21s, and set them in neat ordered pairs for the first time in their existence.  At first, like every Other, they all looked alike to me, but time and use and my own fancy gave them personalities.  The first five sets were large and strong and unmistakable -- any flaw in them and there would have been no being to be tested.  6 through 12 were like the dancing men of Sherlock Holmes:  jaunty, poised, often with one foot kicked up in dance or play.  16 through 20 were smaller but just as playful, children learning at their parents’ knees.  13 through 15 were Hopi women, with their looped hair risen above long blankets, or nuns in banded shawls; an elemental female image.  And then the mysterious, smaller shrouded shes, 21 and 22, solid, dark, impenetrable, unpitying, even when you winced with pain, even when you cried as you found a third come to join their pair, or one so damaged that nothing good could come...


When I found a trisomy or a monosomy or any other abnormality, I took it to the lab director.  She would inspect my work carefully, assuming - usually correctly - that I had made a mistake.  But when I hadn’t, the whole lab went into panic, running and re-running the test.  When the results were certain, the phone call was made to the patient’s doctor and the sealed plain brown envelope, stuffed with test results and interpretation, was hand-delivered to the doctor’s office.  What happened next was between the patient and her doctor, her family, her God.  We knew what the options were:  we made no recommendations, rarely learned the outcomes. 

The search for sex was a lot more fun.  I found the male in microcosm elusive, mainly because the Y chromosome looks nothing like a Y.  Half the time I thought it was a scrap of something else.  I started a lot of panics until I got it through my head that what looked to me like a tiny, flat-topped, spread-legged 21 was not a trisomic sister of doom, but a Y, a HE.  My only comfort, as I sat with my scissors and a worried look, was that over in the hospital, with the baby right there in front of them, they couldn’t tell either.  Parents panicking, doctors shrugging, nurses whispering, and all waiting for me (!) to find that other damn chromosome and tell them whether it was a girl or a boy.  

This happened a lot more often than you might think.  Mother Nature does not always get it right, or perhaps she just has a very perverse sense of humor...