Jack Gernsheimer met my car at the bottom of the lane. He looked good this summery Sunday, rested and tan. The logo on his T-shirt was one he and his brother designed years ago, featuring the name of the town they grew up in, which at the time was celebrating its 150th birthday: “Bernville, Pennsylvania, 1851-2001.”
This is a beautiful part of the state, lush green farms in rolling countryside, the Blue Mountains vague in the distance. It’s Updike country; the town of Shillington memorialized in John Updike’s early short stories is less than half an hour away.
I had driven up to spend time with Jack, who has Parkinson’s disease, and his twin brother Jeff, who does not. Because they are identical twins with identical genomes, it may appear to be a mystery that only Jack is sick. Yet scientists have long known that genes alone cannot explain why some people get Parkinson’s and others don’t. While a handful of genetic mutations are linked to the disease, about 90 percent of cases of Parkinson’s are “sporadic,” meaning the disease does not run in the family. And twins, even identical twins, don’t usually get Parkinson’s in tandem. In one of the largest longitudinal twin studies of the disease, Swedish scientists reported in 2011 that of 542 pairs in which at least one twin had Parkinson’s, the majority were “discordant,” meaning that the second twin was unaffected. The discordance rate was higher for fraternal twins, who are no more alike genetically than any two siblings. But even identical twins had a discordance rate of 89 percent.
So if genes don’t explain most cases, how about the environment? Several environmental factors have been linked to Parkinson’s, which has been shown to occur at higher-than-expected rates in, for instance, people who were prisoners of war in World War II. There is also a higher rate in people who live on farms or who drink well water, probably because of exposure to certain pesticides.
But the environmental connection is precisely what makes Jack and Jeff so interesting. For almost all of their 68 years, they have lived no more than half a mile apart. They have been exposed to the same air, the same well water, the same dusty farm chores, the same pesticides. They built their homes a five-minute walk from each other, on two plots of their father’s 132-acre farm in eastern Pennsylvania. And since 1971 they have worked in the same office, their desks pushed together, at a graphic design firm they co-own. All this makes their particular discordancy tougher to explain.
The existence of a pair of twins with identical DNA and nearly identical environments in which only one is sick—that’s a researcher’s bonanza. Whatever difference can be untangled in the twins’ physiology probably relates directly to the disease and its origins. The genome can be held constant; environmental toxins and other exposures can be held constant; what remains, researchers are left to think, might be an odd shift in a particular neural pathway that has a relevant function all its own.
Nothing further happened. Jack drove home and put the gun in a safe hiding place.
For years, the twins have been active participants in Parkinson’s experts’ search for answers. Recently, at the New York Stem Cell Foundation, scientists compared cultures of neurons they made from stem cells harvested from Jack and from Jeff. The Jack-derived neurons, they found, differed from the Jeff-derived neurons in how they produce two important brain chemicals: the neurotransmitter dopamine, and an enzyme called beta-glucocerebrosidase. They also differed in a particular molecular signaling pathway, which was found to be deficient in Jack’s culture but not in Jeff’s. The team’s next focus will be to look at genes found not in the nucleus of the twins’ brain cells, but in the mitochondria floating around the nucleus.
None of this could have been done without cutting-edge stem cell technology. And none of it could have been done without a pair of identical twins with virtually parallel lives.
It’s where those parallel lives diverge, though, that might provide a lasting new insight. Beginning on the day in 1968 when Jack was drafted and Jeff was not, Jack suffered a series of shifts and setbacks that his brother managed to avoid: two years serving stateside in the military, an early marriage, two children in quick succession, a difficult divorce, and finally, in the biggest blow of all, the sudden death of his teenage son.
After these key divergences in their lives, Jack went on to develop not only Parkinson’s but two other diseases that Jeff was spared, glaucoma and prostate cancer. The twins place great stock in these divergences, believing they might explain their medical trajectories ever since. Scientists are trying to figure out whether they could be right.
Jack and Jeff Gernsheimer look very much alike: tall, slender, with long oval faces and thinning gray hair. But they have different personalities—Jack is introverted, Jeff more gregarious—and different ways of confronting their darkest emotions. “He’s stoic,” Jeff says about his brother. And while Jack generally is “a mellow guy,” he added, in times of his greatest stress he was “probably a pressure cooker inside—but that wasn’t apparent to me.”
Growing up in Bernville (current population, 956), the twins lived a happy small-town life, playing soccer, basketball, and baseball, joining the marching band (Jeff on trombone, Jack on drums), earning good grades, getting along fine with the other 29 students in their graduating class. They were tethered in work and play, in harmony and disharmony, regularly rotating through what they called an “annoyance cycle”: best friends for a while, then arguing about something stupid, then quickly making up and being best friends again. Sometimes the fighting was psychological; when they were in elementary school, Jeff made Jack cry by convincing him, bizarrely, that he was adopted. Sometimes it was physical, as at the memorable family dinner when the teenaged twins ended up wrestling at the dining room table, locked in combat because Jeff said Jack was hogging all the clams.
Their lives diverged between the ages of 18 and 25, tilting their paths off course just enough to remain, forever after, the tiniest bit askew. First they chose different colleges: Jeff went to Moravian College in Bethlehem, about an hour from home; Jack went further away, to Syracuse University. They both reported to the draft board in 1968, but only Jack passed the physical. Jeff, who had had a childhood infection that left him nearly deaf in one ear, was classified 4-F.
The twins were living together in Manhattan in the summer of 1968 when the draft notices came in the mail. Jack was out of town, so Jeff opened both. He was devastated to see that Jack was 1-A. It was sheer dumb luck that had made him fail his physical, Jeff thought; his hearing was particularly bad that day, probably because he had taken a hot shower that morning and his ears were clogged. In Jeff’s mind it was Jack who should have gotten the draft deferral. Jack was the one with the good job at an advertising agency, the steady girlfriend, the grown-up attitude; Jeff was the expendable one, with no real obligations and no immediate prospects. So Jeff considered switching identities. For a few weeks, unbeknownst to his brother, he toyed with the idea of just reporting for duty and saying he was Jacob Gernsheimer, sort of like Don Draper in reverse.
Jack never would have allowed it, of course (and the plan never got past the rumination stage anyway). He was born three minutes earlier and had always acted like the big brother; it was he who rescued Jeff, not the other way around.
When Jack got home from the Army in late 1970, he was already married to his college sweetheart. The following summer the twins started Partners Design, working out of the original farmhouse on the land their father had owned, living together above the studio along with Jack’s wife and their new baby daughter, Jessica. A year and a half later, Jack’s son Gabriel was born.
The twins’ business thrived, and in 1979 Jeff moved into his own home, which he built on his one-third plot on the old family farm out of recycled materials from a Pennsylvania barn. The next year he married Jan Barnett, a teacher from Philadelphia who later admitted that at first she’d had trouble telling her date and his twin apart.
In the mid-1970s, there was trouble on the town zoning board, where Jeff sat as a volunteer. The board voted against the pet project of a local builder, who threatened violence in a way that was convincing enough for Jack, at least, to take seriously. During one particularly contentious meeting, Jack drove home to get the pistol he had bought to protect Jeff from the “thug.” He returned to the board meeting, leaving the gun in the car under a floor mat, intending to run back to get it if the builder’s threat ever materialized. But nothing further happened, and Jack never had to leap to Jeff’s rescue the way he’d pictured it. He drove home and put the gun in a safe hiding place.
For a while, Jack mistook his Parkinson’s symptoms—primarily a profound fatigue that just wouldn’t quit—as the late effects of anesthesia, after he had his prostate removed for prostate cancer in 2009. After a few months of feeling exhausted he went to his internist, who said this sounded like something more than a lengthy post-surgical recovery. He referred Jack to a neurologist, who diagnosed Parkinson’s disease, a neurological disorder in which cells in a structure of the midbrain called the substantia nigra lose function and stop producing dopamine, the neurotransmitter responsible for many functions, including motor control and the brain’s reward system. Typical symptoms include stiffness, tremor, problems with gait, depression, and occasionally cognitive decline.
Around the time of Jack’s diagnosis, he was introduced to Susan Solomon through a mutual friend. Solomon, a successful entrepreneur and businesswoman, had recently founded the New York Stem Cell Foundation (NYSCF, pronounced “NIE-sef”), believing stem cells were the fast track to a cure for diabetes (which affected her son) and other diseases.
When Solomon heard that Jack was an identical twin, and that his twin was healthy, she could tell they would make great subjects for her scientists, who use stem cell technology to study a variety of degenerative diseases.
To get a personalized embryonic stem cell, scientists start by taking some of a person’s cells, usually skin cells from the upper arm, and growing them in a Petri dish. In another dish, they remove the nucleus from an unfertilized human egg, and replace it with the nucleus of a cell from the skin cell culture in a procedure called nuclear transfer. What they end up with is a human blastocyst that contains the skin cell donor’s DNA.
The technique for creating human embryonic stem cells was discovered in 1998 using leftover fertilized eggs from IVF clinics, and was instantly controversial because it involved the creation and destruction of human blastocysts. President George Bush imposed a moratorium in 2001 on federal funding to derive new cell lines for human embryonic stem cell research, so other sources of funding materialized out of necessity. One of these was NYSCF, founded in 2005.
Cautiously, I asked about what happened to his son. Jack told the story straight, looking directly at me and barely blinking.
The controversy about stem cell research has cooled somewhat, largely because of the discovery of another way to derive pluripotent cells without using blastocysts. Developed in 2006 in mice, and in humans the following year, it involves treating adult skin cells with four specific chemicals (signaling molecules) to turn those cells back to their pluripotent state. This is the method NYSCF scientists used in their study of the Gernsheimer twins.
The study began with Jack and Jeff each undergoing a small punch biopsy on his arm to generate a few thousand skin cells. Then the scientists, led by neurobiologist Scott Noggle, grew the skin cells in two separate cultures and treated them with the signaling molecules. The hardiest of these cells were grown for eight or nine weeks into different pluripotent stem cell lines, a few for each twin.
In nature, these pluripotent cells would then diverge into one of three types of progenitor cells: those that give rise to brain and skin, muscles, or gut. From there, further decision points occur in embryonic development: the progenitor brain cell can develop into either a neuron, say, or a glial cell, either a forebrain neuron or a mid-brain neuron, and on and on toward further refinements. In the lab, scientists can stack the deck using more signaling molecules, forcing the development of whatever cell type they desire.
The beauty of stem cell cultures is that they behave in the dish similarly to how they would in the body. That’s what happened in this case. The mid-brain dopaminergic neurons grown from Jack’s cells produced abnormally low amounts of dopamine. The Jeff-derived culture produced normal amounts.
But here was the first surprise: Even though Jeff showed no clinical signs of Parkinson’s or any other neurological disease, the Jeff-derived culture was not exactly normal. Both twins, it turned out, had a mutation on a gene called GBA (a mutation already known to be associated with Parkinson’s disease), and as a result, both of their brain cell cultures produced just half the normal amount of an enzyme linked to that gene, beta-glucocerebrosidase. They also both produced three times the normal level of alpha-synuclein, a brain protein usually broken down by a process involving the GBA enzyme. Alpha-synuclein is thought to be related to Parkinson’s, possibly by leading to the formation of the toxic lesions known as Lewy bodies that are a hallmark of the disease.
So rather than answering questions about the twins’ discordance, these findings only raised more. Jeff had the same Parkinson’s mutation his brother had, and his brain cells in culture behaved just as abnormally in relation to the GBA enzyme and alpha-synuclein. Yet he apparently has been spared. It was a puzzle. The scientists hoped the answer existed somewhere in those two Petri dishes.
After Jack met me at the bottom of the lane, we drove up together to his house, which he and his second wife, Nancy Wolff, built in 1990, shortly after they were married. Like Jeff’s, Jack’s house is made of materials from a local barn. It is located on his one-third of the property, just a bit further down the lane from Jeff’s. (The twins’ younger sister, Sharon, who lives with her husband and their twin daughters in New Jersey, will soon build a house on her portion of the land for when she retires.) Nancy was in the garage, swimming in the indoor pool they had installed a few years ago as part of the project of keeping Jack physically fit. Nancy, a copyright attorney in New York, has a friend who invented Endless Pools, and he gave her one when he heard about Jack’s diagnosis, knowing that regular exercise can help stave off the worst symptoms of Parkinson’s.
Since 2009, Jack has been on a regimen of L-dopa, which helps with motor symptoms like tremor and rigidity by boosting dopamine in the brain. He moves slowly and sometimes stiffly, but manages to exercise almost every day, either walking around his property or on the treadmill he’s had sunken at the bottom of the Endless Pool, swimming, or going to the gym to lift weights or walk the treadmill. He also still goes to work three or four days a week at his and Jeff’s design firm, sitting at a desk pushed up against his brother’s that looks out over an expanse of woods.
Jack’s voice has gotten softer, and he says he has some trouble keeping in mind the sequence of complicated steps, like following directions to somewhere new. He sometimes fails to find the word he’s looking for. “That’s the worrisome thing, that my memory isn’t what it was,” he told me. “Though it’s hard to know how much of that is the disease, and how much of that is simply aging.”
During my visit last summer, Jack and I sat down at the kitchen counter, a cozy spot at one end of the wide-open first floor of his house, overlooking a 3-acre pond fringed with a profusion of orange day lilies. Cautiously, I asked about what happened to his son. All I knew, based on our earlier conversations, was that he had a son who died at 14, and that he and Jeff both think the grief he suffered in the aftermath helps explain the physical burdens he’s shouldered ever since. Jack told the story straight, the way he tells everything, looking directly at me and barely blinking, in a quiet voice and without much inflection. The calm gaze, the low volume, the lack of apparent emotion could be symptoms of Parkinson’s, but they’re also partly the way Jack has always been. He was talking, softly and evenly, about Gabe, but he was also talking about his own residual pain.
The year was 1987. “I was doing some acting at the time,” he said, “and I was involved in a piece that dealt with the Vietnam War.” The play was Streamers by David Rabe, and after Gabe went to see his father perform, “he was anxious to find out more about the war.” Like any good father, Jack supported his son’s interest, taking him to see Full Metal Jacket, renting videotapes so Gabe could watch some of the older Vietnam movies at home.
One of those movies was The Deer Hunter, the 1978 film starring Robert DeNiro and Christopher Walken as two soldiers, childhood friends (who were, coincidentally, also from small-town Pennsylvania) who are imprisoned and tortured by the Viet Cong. As Gabe and his friend watched it, they got into a discussion about the scene in which the prisoners are forced to play Russian Roulette. If it were me, Gabe told his friend, I would never just sit there and agonize over it; I would get it over with quickly, I would just do it. And with that, according to the friend, Gabe went to get the pistol he knew his father had hidden away, got the bullets he knew were kept separately, put one in the nine-bullet chamber, spun it once, put it to his head, and shot.
“I blame myself,” Jack said, barely audible.
Later, when Jeff came by for lunch at the picnic table out back, we talked some more about Gabe’s death. The summer before Gabe shot himself, Jeff and his wife Jan, pregnant at the time, had taken Gabe with them on a vacation to Nantucket. Jeff said it was a wonderful week. At one point Gabe, always something of a risk-taker, concocted a primitive set of wings, with Uncle Jeff’s help, out of some old sheets and a few strategically placed boards. Then, wearing a goofy pair of shorts he and Aunt Jan had sewn together out of material festooned with flags, he went running off a sand dune, jumped, and seemed for one short moment to fly.
Jeff’s chin quavered and he lost his voice. “I think of Gabe every day,” he managed to say. Jack sat at the table, gazing quietly at his mourning brother.
To the twins, the “pressure cooker” way Jack dealt with stress, most grievously the loss of Gabe, helps explain Jack’s added health burden today: the Parkinson’s, the glaucoma, the prostate cancer. Jeff said those might be “physical manifestations” of the different ways they handled stress. “Jack internalizes more than I do,” he said.
The connection between stress and disease is a lively research topic, as scientists discover how life experiences alter gene expression and contribute to diseases ranging from diabetes to the common cold. But while statements about the “gene-environment interaction” have become a familiar trope, the twins’ story offers a different way to look at it. Traditionally, “environment” is defined as external events that occur over a lifetime, or the impact of those events at the molecular level, which is in the realm of epigenetics. According to Steve Cole, a professor of medicine at the University of California, Los Angeles School of Medicine, the relevant aspect of “environment” in terms of the twins might be something more interior and personal. Cole is interested in “the environment we create in our heads”—not what literally happens, but how the individual experiences what happens. “That is the most interesting aspect of the story of the twins,” he told me recently. “Their experiential environments.”
When they try to explain their divergent medical histories, the twins return to the tyranny of small differences.
Jack and Jeff’s understanding of their respective experiential environments is that Jack’s is the more stressful. And some research suggests this might have particular relevance to Parkinson’s disease. In 2002 at the University of Pittsburgh, neuroscientists subjected rats to stress through physical restraint, and found that the stressed rats were more likely than non-stressed rats to experience damage to their dopamine-producing neurons when later injected with a toxin. This might be an indication of “neuroendangerment,” lead author Michael Zigmond told me recently: Rather than stress producing damage directly and immediately, it might increase the vulnerability of dopamine-producing cells to a subsequent insult.
Zigmond, a professor of neurology at Pitt, said neuroendangerment is tricky to study, because the connection between early-life stress and late-life disease can be easy to miss. “The stress can occur at one point in time,” he said, “and the impact on neurodegenerative disease—Parkinson’s disease and also stroke and Alzheimer’s disease—can happen years later. By then the connection between the early stress and the neurological disease may be forgotten.” He hazards a guess, based only on the information he heard from me, that something like this might be going on in Jack’s case.
Or maybe Jack’s Parkinson’s is linked to an intermediate step: chronic inflammation. That’s the mechanism by which stress can lead to neurodegeneration, according to Cole. The inflammatory immune response is “baked in by evolution to help defend us when are feeling threatened,” he told me. “It probably made sense for millions of years, when the threat correlated with microbes. Unfortunately, the inflammation that drives that priming comes with some penalties”—among them, damage to the brain cells. Cole said it’s “plausible” to think the differences in the twins’ medical status can be traced to differences in their life histories, which in turn led to differences in their immune systems. Exhibit A: Jack has psoriasis, a skin condition linked to autoimmunity and chronic inflammation. Jeff does not.
These days, it’s Jeff who protects Jack. Instead of splitting the workload at their design firm 50-50 the way they used to, Jeff does most of it now. That’s been the hardest adjustment, because Jack was the better designer. “But I think at this point maybe I’m more objective about a design and a solution,” Jeff said. “At this point, maybe more than in the past, it might be that he says, ‘I nailed it,’ and we look at it and I have to say, ‘Um, I don’t think that you did.’ ”
In solidarity with his twin, Jeff also signs up to be the normal control in whatever Parkinson’s study he hears about, hoping to help uncover some new information in time to help Jack. He gets MRI scans, gets hooked up to EEG machines, takes dozens of pencil and paper tests to measure his cognitive abilities, and dozens of physical challenges to measure his balance and muscle control. He’s probably the most thoroughly investigated healthy man he knows.
The search for answers to the puzzle of Jeff’s good health, despite the abnormalities in the Petri dish, continues. Late last year, the NYSCF scientists, led by Noggle, described their work on the twins’ cells (as well as the cells of one other Parkinson’s patient and four controls) in the journal Cell Reports. They were able to find a few functional differences between Jack’s cells and Jeff’s, and to highlight abnormalities in one particular pathway involving the enzyme MAO-B (monoamine oxidase-B).
After identifying the GBA mutation the twins share, and observing high alpha-synuclein levels in both cultures, the scientists searched harder for what might differentiate Jack’s and Jeff’s functioning brains. There was a chance, they thought, that one might have developed a new, tiny mutation during his lifetime that the other had not. This led them to a closer study of their genomes.
First the team screened for the 66 mutations known to be associated with Parkinson’s. But they found nothing other than the GBA mutation they’d already found. Next they screened for the 39,000 known “single nucleotide variants” in the genome that only one twin might have had. SNVs are instances in which a single nucleotide—among the 3 million or so in the human genome—has been switched, deleted, or duplicated. They found 11 SNVs, including nine linked specifically to Parkinson’s disease, but they found them in both twins—meaning SNVs could not explain why Jack was sick and Jeff was not.
The next series of tests finally uncovered a relevant difference: Jack had abnormally high levels of MAO-B, which is involved in the breakdown of dopamine. Jeff’s MAO-B levels were only slightly above normal.
This was provocative. It suggested a possible molecular mechanism by which stress could lead to neurodegeneration: via monoamine oxidase, which sits on the outer membrane of the mitochondria and has been linked to the oxidative stress that can kill off brain cells.
What’s nice about this finding is that it suggests a possible therapy for Parkinson’s. There are already drugs on the market, called MAO-B inhibitors, that treat high levels of the enzyme. When Noggle’s team introduced one such MAO-B inhibitor, Rasagiline, into the Jack-derived brain cell culture, they reduced MAO-B levels and, more important, increased the amount of dopamine those brain cells produced.
Now the question is whether Rasagiline can work clinically. Some studies have shown improvement of Parkinson’s symptoms with Rasagiline at low doses, but not at high doses. Other studies indicate that patients given MAO-B inhibitors have higher mortality rates overall.
So it’s too soon to recommend any kind of treatment change for Jack, or for anyone else with Parkinson’s disease. But the findings do show something interesting about Jeff: that it’s possible to have one or more genetic mutations associated with a condition, yet somehow to avoid whatever else transforms a genetic tendency to a genetic destiny. And they suggest a next step for research on the twins—studying their mitochondrial genes.
Identical twins occasionally have different sets of mitochondrial genes (of which there are just 37, versus 22,000 or so in the whole genome), if the mitochondria in the cell body divide up unevenly when the egg splits in two. The exact rate at which this uneven split occurs hasn’t been studied in detail, said Noggle. But based on a preliminary look at Jack and Jeff’s mitochondrial DNA, he said there’s a “pretty high likelihood” that theirs might not be identical. If that pans out, he said, his team might be on the road to finding “a potential explanation for susceptibility not just to Parkinson’s, but to other neurodegenerative diseases” like Huntington’s and Alzheimer’s. The NYSCF scientists won’t know anything for at least a year, Noggle added. That’s the way this kind of knowledge accrues—much more slowly than anybody would like.
As for Jack and Jeff, when they read the Cell Reports paper, they tried not to feel disappointed. Its take-home message appeared to be that not much can be done at the moment to ameliorate Jack’s symptoms (nor to prevent them from developing in Jeff, though he insists he never worried about that; all his concern for the future, he says, is focused on Jack). “Unfortunately,” Jeff said, “there’s a fair amount of testing still to be done.”
For now, when they try to explain their divergent medical histories, the twins return to the tyranny of small differences: Jack’s more introverted personality, rockier life, quieter grieving style. In this belief they tap into the suspicions of a small cadre of neuroscientists trying to pinpoint the connection between stress and neurodegeneration. Maybe the twins are on to something the scientists are on the verge of identifying. Or maybe the brothers who have been all but inseparable are trying to protect themselves from the cruel realization that fate can unspool in dissonant ways.
Robin Marantz Henig is a contributing writer at The New York Times Magazine who has written online for The Atlantic, New York, NPR, and Slate. She co-wrote her most recent book, Twentysomething, with her daughter, Samantha Henig.