Then there was the sex.
Mendel, who like all of the monks at St. Thomas had taken a vow of consecrated chastity, seemed obsessively interested in how the furry little creatures were getting it on.
That, Schaffgotsch figured, was beyond the pale.
So the dour bishop ordered the inquisitive young monk to shut down his little mouse brothel. If Mendel were, as he professed, purely interested in how traits move from one generation of living creatures to the next, he’d have to be content with something less titillating.
Something like peas.
Mendel was duly amused. What the bishop didn’t seem to understand, the impish monk mused, was that “plants also have sex.”
And so, over the next eight years, Mendel grew and studied nearly 30,000 pea plants and discovered, through duteous observation and record keeping, that certain traits of the plants—stem size and pod color, for instance—followed particular patterns from one generation to the next. Those findings set the stage for our understanding that genes dance in pairs, and when one gene is dominant over another (or when two recessive genes come together to tango) it can prompt a specific trait.
It’s impossible to say what might have happened had Mendel continued to work with mice. In studying the far more behaviorally complex creatures, he might have missed altogether the discoveries he made while seeking to better understand how to breed consistently smooth, green, and long-stemmed peas. Then again, the meticulous monk, if given more time to watch his mice mix whiskers, might very well have stumbled onto something even more revolutionary—something that took more than a century for his disciples to begin to recognize. As it happened, though, when Mendel first published his findings in an obscure journal called Proceedings of the Natural History Society of Brünn, his work was met with a collective scientific “meh.” And by the time it was rediscovered at the turn of the twentieth century, he’d long since been buried in the city’s Central Cemetery.
But like many visionaries whose work is not appreciated until they are dead, Mendel’s revelations would live on, initially in the identification of chromosomes and genes and later in the discovery and sequencing of DNA. At every step of the way, though, one fundamental idea persisted: Who we are is an unwaveringly predictable matter of the genes we’ve inherited from previous generations.
Mendel called the laws he discovered inheritance,4 and over the years that’s how we’ve come to think of our genetic legacy—as somewhat binary instructions passed from one generation to the next, like a time-worn family heirloom an inheritor doesn’t always want but can’t throw away.
Or like Ralph’s tragic genetic legacy. So why, indeed, was Ralph deviating from Mendel’s pea and not showing any visible signs of being affected when so many of his offspring obviously were?
The genetic condition that was burning through Ralph’s bloodline follows an autosomal dominant pattern of inheritance. That means you only need one gene with a mutation to be affected with a specific disease. And if you did indeed inherit an offending gene, then chances are generally 50-50 that you’ll pass it along to each child you sire. The way we’ve long understood Mendel’s laws of inheritance suggests that if you were unlucky enough to receive a mutated gene that follows this type of inheritance pattern, you’d show the same signs of the disease.
That’s probably the genetics you learned about in school, where mapping out pedigree charts made it all too easy, and frankly alluring, to believe we know what we’re talking about when it comes to the microscopic molecular magic that makes us who we are. It got a bit more complicated over time, of course, but it all started with an idea, which soon became dogma, that genes come in pairs, and when one gene is dominant over another, it can prompt the same specific trait. Everything from brown eyes to the ability to roll your tongue, grow hair on the back of your fingers, and have detached earlobes were all seen as the result of dominant genes dominating. And correspondingly, it was thought, when two recessive genes pair up they would produce less likely traits such as blue eyes or a hitchhiker’s thumb.
But if genetic inheritance always works that way, how is it that Ralph—and all the people who saw him, day in and day out, at the various clinics where he donated his sperm—had no idea that he had such a life-altering disease? Because Mendel, for all he gave to science, missed something of vital importance: variable genetic expressivity.*
Like many other inherited conditions, neurofibromatosis type 1 articulates itself in all sorts of different ways, and sometimes so mildly that it’s not recognizable. That’s why no one—apparently not even Ralph himself—knew the terrible secret.
Ralph’s condition remained hidden because of variable expressivity. This is the reason the same genes can change our lives in very different ways. Identical genes don’t always behave identically in different people—even people with completely identical DNA.
Take Adam and Neil Pearson, for example. Born as monozygotic, or identical, twins, these brothers are thought to carry indistinguishable genomes, including a genetic change that causes neurofibromatosis type 1. But Adam has a face that is bloated and disfigured—so badly that a drunken nightclub patron once tried to rip it off, thinking it was a mask. Neil, on the other hand, could pass for Tom Cruise from a certain angle but suffers from memory loss and occasional seizures.5
Identical genes, completely different expression. So all of those physical signs I walked you through in chapter 1? They are common expressions and generally indicative of certain genetic conditions, but those traits certainly don’t encompass the spectrum of all expressions of those genetic conditions.
All of which prompts us to ask, why the difference in expression? Because our genes do not respond to our lives in a binary fashion. As we will come to learn, and contrary to Mendel’s findings, even if our inherited genes seem set in stone, the way they express themselves can be anything but. Whereas our inheritance may have been initially understood through a black-and-white Mendelian lens, today we’re starting to understand the power of seeing things in full and genetically expressive color.
Which is why now, as physicians, we have a new challenge. Patients look to us to have the answers in clean, discrete categories: benign or malignant, treatable or terminal. The hard part of explaining genetics to patients is that everything we thought we knew is not always static or binary. Figuring out the best way to explain that to patients has become much more critical, since they need the best information possible to help them make some of the most important decisions of their lives.
Because your behavior can and does dictate your genetic destiny.
Which is why I now want to talk to you about Kevin.
He was in his twenties. Tall and healthy. Handsome, charming, and smart. If I’d known someone at the time who was looking for an eligible bachelor—and if it wouldn’t have been an egregious breach of ethics—I might have tried to set him up.
Maybe it was because we were about the same age and came from similar backgrounds. Or maybe it was because we were both involved in health care at the time—he on the eastern and I on the western end of the medical spectrum. Whatever it was, we really seemed to connect.
I met Kevin not too long after his mother passed away from a long and courageous bout with metastatic pancreatic neuroendocrine tumors. Before she died, an astute oncologist suggested genetic testing—and that, in turn, revealed a mutation that sat smack in the middle of her von Hippel-Lindau tumor suppressor gene.
Von Hippel-Lindau syndrome, or VHL, is a genetic condition that predisposes people to tumors and malignancies, including those in the brain, eye, inner ear, kidney, and pancreas. Some researchers have suggested that the infamous Hatfield-McCoy feud may have developed, in part, because of VHL, since many McCoy descendants contemporaneously suffer from tumors of the adrenal gland, which can result in bad tempers.6 Of course, not everyone with VHL has that sort of symptom—another example of variable expressivity.
And just like the mutated gene that causes NF1 that Ralp
h was passing along, the gene that causes VHL is inherited in an autosomal dominant fashion. Which means that you only need to get one misbehaving copy from your parents to be affected. Because VHL is an autosomal dominant disorder, we knew that Kevin had a 50-50 chance of inheriting the problem gene from his mother. That was enough to convince him to get checked for the same mutation, which it turns out he had indeed inherited.
There’s no cure for VHL, but once we know someone has it, we can increase surveillance for tumors before they become symptomatic. That was what I’d assumed would be the case for Kevin. At least to start out, most people who inherit a mutated or deleted VHL gene can still rely on the other working copy to keep cell growth at bay and prevent tumors and malignancies from forming.
We call this the Knudson hypothesis, where two or more changes to our genes can set the stage for us to develop cancer. Knowing that you’re one gene away from cancer, as Kevin discovered through genetic testing, should make you more careful about how you treat your genes. Radiation, organic solvents, heavy metals, and exposure to plant and fungal toxins are just a few ways to damage and adversely change your genes.
The problem is that because VHL can express itself in so many different ways throughout the course of an affected person’s life, we never know where and when it’s going to pop up. That means we have to keep tabs on just about everything. This entails a regimen of screening and treatment from a team of doctors and allied health-care workers that will last for the rest of a patient’s life.
Not surprisingly, Kevin wanted to know what he could expect moving forward, but because VHL expresses itself in so many different ways, I found it very difficult to answer that question, other than to reiterate the monitoring regimen and which types of tumors and malignancies he’d be at greatest risk for.
“So what you’re telling me,” he said, “is that we don’t know what I’ll die from.”
“There are treatments for many of the tumors that VHL causes, especially if they’re caught early,” I replied. “We don’t know that you’ll die from VHL at all.”
“Everybody dies.” Kevin chuckled.
I blushed. “Of course. But with treatment—”
“For the rest of my life.”
“Yes, that’s likely, but—”
“Appointments and checkups, all the time. The stress of constant monitoring. Blood work. Never knowing—”
“Yes, it’s a lot, but the alternative—”
“There are always lots of alternatives,” he said with a smile, and with that I could see that he’d made his choice.
I was deeply saddened when a few years later he was found to have clear cell metastatic renal carcinoma, a form of kidney cancer. Once again, he resisted any conventional treatment, and he passed away shortly thereafter.
You might be wondering how this is an example of variable expressivity. After all, Kevin died prematurely and tragically, just like his mother. But Kevin died of a different type of cancer and at an earlier age than his mother, so variable expressivity does unfortunately sometimes entail genes behaving in different ways than in the previous or same generation. Using medical surveillance techniques applied by his medical team to keep tabs on his body, Kevin could have used the time after his diagnosis to initiate earlier treatment for his type of kidney cancer. But he chose not to. Given his genetic inheritance, if Kevin simply had asked what types of imaging surveillance his condition required, and then followed through with them, he might not have died prematurely. When it comes to our own health and lives, these choices are ours to make. Our flexible genetic destiny is in many ways ours to determine, if we know what questions to ask and what to do with the answers.7
To better understand the conceptual basis of our flexible inheritance, let’s take a quick jaunt to the Jean Remy Library in Nantes, France. That’s where, just a few years ago, a librarian sifting through some old files came upon a long-forgotten scrap of sheet music.
The paper was brittle and yellow. The ink had faded into the ancient pulp. But the notations were still clear. The melody was still there. And so it didn’t take long for researchers to determine that this little piece of paper—filed away and forgotten for more than a century in the library’s archives—was the genuine and exceedingly rare product of Wolfgang Amadeus Mozart’s own hand.8
Like all of Mozart’s more than 600 known works, the melody, several bars in D major thought to have been written a few years before the composer’s death, is a set of instructions from the classical composer to all musicians that transcends the centuries. Mozart, it seems, was a fan of the appoggiatura—the sort of brief, dissonant note resolving to a main note that gives Adele’s heartrending ballad, “Someone Like You,” its peculiar despondent charm.9 Though most modern composers would use a sixteenth note instead of an appoggiatura, that’s nothing more than a small step of musical evolution. And so pianists like Ulrich Leisinger, the director of research at the Mozarteum Foundation in Salzburg, Austria, can use the script to resurrect the long-lost tune. And Leisinger, lucky son of a gun that he is, can do it on the very same 61-key piano upon which Mozart composed many of his concertos more than 220 years ago.10
When played, the song crosses the span of space and time like Dr. Who’s rickety old time-traveling police box, materializing in the modern world with a mischievous flourish. To Leisinger’s trained ear, the tune that emerges when the notes are played is clearly a credo—a liturgical melody. That makes it something of a message in a bottle, because although Mozart wrote a lot of religious music in his younger years, some scholars have questioned whether faith played much, if any, of a role in his latter days.
From the handwriting and the paper, researchers have concluded the score was written around 1787, a time when Mozart—then enjoying steady work on the opera-writing circuit—had no financial need to write church songs. Leisinger believes this reveals Mozart did have an active interest in theology late in his life.
All that from a few dozen notes.
That is roughly how we have long understood DNA. In the same way that modern musicians can read Mozart’s instructions and carry them out with near-flawless fidelity, revealing the complexities hidden within, we expect our genetic legacy to be a score upon which is written the music of our lives. And that’s true, to some extent.
But it’s not the whole story. We are now awakening to a new understanding of our genetic selves and even our evolutionary lineage. Far from being enslaved to a destiny encoded within our DNA, like an obsolete iPod eternally stuck on a requiem, we are learning that there is considerable flexibility within all of us. An inborn ability to change tunes, play our music differently, and, in doing so, overcome some of our previous understanding of our somewhat binary Mendelian genetic destiny.
That’s because life, and the genetics that support it, is not like a tattered piece of paper but rather a dimly lit jazz club. Perhaps it is like the Jazzamba Lounge at the Taitu Hotel, in the throbbing center of Ethiopia’s capital city, Addis Ababa, where men and women from every corner of the earth come to drink and smoke and laugh and lust.
Just listen:
Clinking glasses. Shuffling chairs. Murmuring voices.
And then, from the shadowy stage, a base:
Baum-baum-baum bada baum-baum bada.
Then the gentle whispers of a brushed snare:
Sha-sssss sha-sssss sha-sssss—sha-sha-sssss.
A cup-muted old trumpet:
Braaaght bra-der-dah braaaght-der-der-bra-dah.
And finally, a sultry female singer:
Oooooo-yah bada baaaaaagh. Hayah hayah hayah bada-yagha.
Just a basic bass line—and all the majesty and tragedy of life to layer upon it.
Now, it’s true that for us to cross through the sea of developmental milestones and into adulthood, we do need a significant degree of sophisticated genetic orchestration. So we all start with a score. Older than Mozart. Some of the notes are as old as life on Earth.
But there is plenty of room for i
mprovisation built into our lives. Timing. Timbre. Tone. Volume. Dynamics. Through tiny chemical processes, your body is using each gene you carry like a musician uses an instrument. It can be played loudly or softly. It can be played quickly or slowly. And it can even be played in different ways, as needed, in much the way that the incomparable Yo-Yo Ma can make his 1712 Stradivarius cello play everything from Brahms to bluegrass.
That’s genetic expression.
Way down, deep and small inside of us, we’re all doing that very same thing, churning through the tiny doses of biological energy it takes to change the way our genes express themselves in response to the demands of our lives. And just like musicians who let the culmination of their life experiences and current circumstances affect the way they play their instruments, our cells are guided—expressed—by what has been done and is being done to them at every given moment.
Consider that, and then let’s try a little experiment: Stretch out a bit. Move your body. Get comfortable. Now try focusing on your breath. Breathe in, and breathe out. And after a few breaths, tell yourself out loud (or at least in a whisper) that what you do in the world has great value to you and those around you. And now experience how empowering—or just plain silly—this all feels.
There. Right now, inside your body, your genes are at work responding to what you just did, from the moment you began to stretch. Conscious movement is caused by signals sent from your brain, through your nervous system, down to your firing lower motor neurons and all the way to your muscle fibers. Inside those fibers, proteins called actin and myosin are sharing a biochemical kiss, converting chemical energy into mechanical work. And with that, your genes must set to work restoring the chemical ingredients that are necessary every time your brain orders up an action or series of actions—from pressing the volume button on the remote control to running an ultramarathon.
Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes Page 4