Wow! Thats what I said out loud after I read first few lines. This is an unique and precious view into health which happens very rarely - unveiling the complexities of not just Parkinson's but life itself.
I highly recommend reading this synopsis of Jack and Jeff's life:
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.
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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.
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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.
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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.
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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.”
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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.
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