My Father’s Strength

Personal Essay from the NY Times

My Father’s Strength

 

Private Lives

Private Lives: Personal essays on the news of the world and the news of our lives.

On the afternoon before my college graduation in 1999, there was a ceremony for graduates who were getting department prizes. My father was a New York City tunnel worker (a “sandhog”) and at that time he was working on Roosevelt Island, a 20-minute drive from Barnard’s campus. He always showered before leaving the job site, and on that day he’d brought khakis, a freshly pressed shirt and tie and the new jacket my mother had gotten him for his 55th birthday. I remember what he was wearing because it was the first time I noticed him holding a handkerchief, which he used throughout the ceremony to dab the corners of his mouth. After, when we were discussing where to have dinner, I spotted a narrow river of saliva traveling down the side of his chin.

“Dad,” I said, pointing. As he wiped it away I felt a little ember of worry flare up in me, but about what, exactly, I wouldn’t have been able to say.

A year later, he was at work several hundred feet below ground when he slipped and fell on the curved bottom of the tunnel. He tore his rotator cuff and needed surgery, but we were relieved it wasn’t worse. He’d been a sandhog for 30 years at that point, and had his share of scars. When I was in grammar school he got caught between a screed used to level concrete and the platform from which the concrete was poured. He ended up getting “squeezed,” as he puts it. During that hospital visit, after looking at X-rays of his deeply bruised hips, the doctor asked when he’d broken his back. “Never,” he said, but the doctor insisted, pointing to a spot on the image that showed his spine had broken and healed.

“How does a person break his back and not remember?” my mother still asks when the story comes up. He always gives the same answer, which is that for some people it’s easy to break something without realizing. My mother and sisters and I love when he takes this position because it’s so ludicrous. Imagine!

His physical strength was his currency, and when he wasn’t working he kept busy around the house. I’d go home on a given weekend to find he’d built a deck, or had cut down a dead tree and dug the giant root out of the ground. Once, because it needed to be moved, he crouched under an ancient piano and lifted it on his back while my mother shouted “Willie! You’ll kill yourself!” My sisters and I clapped and cheered.

Only 56 when he hurt his shoulder and had to go on leave, my father expected to quickly recover and work well into his 60s, as many sandhogs do. But there were basic things he couldn’t do even three months after the surgery. He’d get one arm into his jacket while the empty sleeve flapped somewhere behind him. Straining to reach it, he’d turn around and around like a cat trying to catch its own tail. Sometimes he’d need help trying to bend his rigid arm. “It’s my bad shoulder,” he explained, but the doctor suspected something else.

He was told he had Parkinson’s disease, a progressive disease of the nervous system, at the end of 2000, just before Christmas. I met him and my mother at the hospital, and stood with my back to the wall as the neurologist had him walk back and forth along a short hallway, tap his feet from heel to toe, touch his fingertip to his nose. I thought it was a big waste of time until I noticed him struggling. The doctor pushed him at the shoulders — gently, but enough to raise my hackles — and then watched as he staggered. After, when we were seated in his office, the doctor told us he’d known it was Parkinson’s the instant he saw my father in the waiting room.

“The mask,” he said. “No expression on his face.”

“Are you sure?” I said. “I think that’s normal for him.” Everyone ignored me.

“It’s much better to know,” my mother said later, as we walked to the car. We studied my father to see if he agreed. I reminded them that the doctor had mentioned new research, treatment methods to slow the disease’s progress. My mother’s handbag was stuffed with pamphlets.

“Willie?” my mother ventured, and then burst into tears.

“I think we all need a cup of tea,” he said.

We braced ourselves for sudden change, but once he started a light dose of medication it was as if the clock had turned back. We exhaled, marveled at how a few little pills a day could make such a difference. He seemed younger, and we dared hope his case was mild. Then, as the years passed, we learned that though the drugs gave him a lead for a while, the disease always caught up. He’d be having an average day — he’d walk a few miles, tinker in the garage — and then, as he described it, he’d “fall off a cliff.” He focused on trying to recognize when he was approaching the cliff so he wouldn’t be left stranded somewhere far from home, unable to move.

Then there were the side effects of the medication. My father, to be sure, is not a talker. It’s not that he’s bad at communicating; it’s just that he uses silence as much as he uses words and most people are too impatient to hear what those silences are saying. So I shouldn’t have been surprised when I accompanied him to a checkup in 2008 and the doctor asked casually about the hallucinations. “Are you still seeing those men come into your room at night?”

“Yes.”

“How many?”

“Six, like always.”

“Anything else?”

“They wear hats now. And they keep their backs to me. I think they’re playing cards.”

“Anything else?”

“Sometimes that other man still tries to come in through the window.”

After leaving the appointment, we’d crossed the George Washington Bridge before either of us said anything.

“So,” I considered how to begin. “Does Mom know you see men come into your room at night?”

“Yes. I used to shout at them and she’d wake up.”

“Are you dreaming when it happens?”

“No. I’m awake.”

“O.K.”

“I know they’re not there to hurt me.

“O.K.”

“I know that now, so I don’t shout.”

But he did shout. In November 2010, when I was seven months pregnant with my second child, my husband, Marty, our son and I moved in with my parents for six weeks while we were waiting to close on our house. The first night we spent there, Marty and I bolted out of bed around 3 a.m. because my father was shouting at a volume I’d never heard him use in my life. “My name is William Keane!” he bellowed. “I come from Ireland!” He sounded afraid, defensive, as if this information might ward off someone or something that had mistaken him for someone else. I went into the family room where he now slept in a hospital bed — half expecting to find a stranger pointing a gun — and though his eyes were open he didn’t seem to notice me there. Then he quieted down, a prisoner to his body until the morning, when his first dose of medication would kick in. If he had an itch he wouldn’t be able to scratch it. If a fire broke out he might not be able to flee. Whoever or whatever was threatening him now was something only he could see.

I told my mother the next morning, expecting it to be big news, but without even turning from the counter she said that she’d meant to tell us about that.

Over the years my mother has tracked down every tool that might help him. She, more than any of us, has set her will against this disease, constantly searching for ways around it, getting frustrated when the doctors don’t do more, as if the cure for Parkinson’s is a secret they all know and are just too selfish to share. When we remind her that he’s actually doing as well as can be expected, she just doesn’t believe it. We consulted a neurologist who specializes in deep brain stimulation, a treatment where a pacemaker-like device is attached to the brain, but learned he’s not a good candidate. He has a special chair that can both recline flat and push him up to standing, grabbers on long poles to pick things off the floor, gadgets to help put on socks, shoes with elastic laces.

He’s had a few falls that I know of, and probably more that I don’t. When he can’t get his hands out in time he takes the brunt of the fall in his upper body, his face. It’s often difficult for him to eat, and one of my constant fears is that he’ll choke because the muscles of his throat fail him. But as his body gets worse he seems to grow more patient, more at peace. The doctor always asks if he tries to leave the house every day, and I was surprised to learn that a lot of people with Parkinson’s don’t bother trying to go out at all. There are some days when that’s all he does — try to leave the house — and if he fails all day he tries again the next. He’s never lost his temper about it.

This fall, my mother decided it was time to transform their narrow downstairs bathroom into a handicapped bathroom, everything wide and open enough for a wheelchair to roll into the shower and turn around. It was a huge project — the contractor had to move the sewage line — and several times my father asked why in the world they were going to the trouble, especially since my mother was so stressed about it, dragging home heavy samples of tile, trying to find the right sinks and toilets. We were all home for Thanksgiving when she spread an array of paint cards before us and said that although she liked cool colors, Dad liked earth tones so that’s what we should consider. “Dad,” I said, “have you ever said the phrase ‘earth tones’ in your life?” My sister laughed and my mother got upset, accused none of us of taking an interest.

He insisted once again that the current bathroom was fine, and Mom threw up her hands and shouted that a wheelchair won’t fit in the current bathroom.

“Why are we talking about wheelchairs?” he asked calmly. “I’m not in a wheelchair.”

“You’re not in a wheelchair yet,” she said. “What about five years from now?”

“Jesus, Mom,” I said. “Do you have to be so mean about it?”

And then, looking back and forth between them — him silent, her furious — I understood that only one of them believed he had five years left.

There are more than half a million people in the United States who have Parkinson’s disease. People don’t die of Parkinson’s, they die with Parkinson’s. They choke. They have a fatal fall. They grow weak and vulnerable to other illnesses.

For now, my father still has good days. One recent morning when I was visiting, he sat with my mother to pay bills and balance their checkbook, a chore they’ve done together every month since they were married. His column wasn’t adding up. He did it again. The pen he uses has a tube-grip that makes it several times thicker than a regular pen and reminds me of my sons’ first crayons. Writing his signature half a dozen times takes the wind out of him.

He’ll turn 70 next month, and I hope he sees 75, 80, 85. I hope I wake up one morning and the top news story is that the cure for Parkinson’s has been found. “It’s not impossible,” I say. “Nothing is impossible,” he says.

When I told him over the winter that I wanted to write an essay about him, about Parkinson’s, he went quiet for a long time and I prepared to hear him forbid it. I told him that if he didn’t want me to, I wouldn’t.

“People would find it interesting?” he asked after a while, puzzled.

“Maybe.”

A snow plow passed on the street. He wouldn’t be able to walk outside until the sidewalks were cleared of ice, but when he felt good he often stood at the open garage door for a while to breathe in the fresh air. It seemed to revive him.

“O.K.,” he said. “Remember to say I’ve been luckier than most people.”


Mary Beth Keane is the author of “Fever: A Novel of Typhoid Mary.”

Unique protein interaction

Unique protein interaction may drive most common genetic cause of Parkinson’s disease

San Francisco, CA—January 7, 2013—The most devastating aspect of Parkinson’s disease may not be its debilitating symptoms, which rob its victims of their ability to control their own movement. It may not be the millions around the world and their families who suffer each day from the disease’s harmful effects. Instead, it may in fact be that its root causes remain largely a mystery. But now, scientists at the Gladstone Institutes have discovered how the interplay between two proteins in the brain fuels the degradation and death of the class of brain cells, or neurons, that leads to Parkinson’s. These findings, which stand in stark contrast to conventional wisdom, lay much-needed groundwork for developing treatments that target the disease’s elusive underlying mechanisms.

In the latest issue of the Journal of Neuroscience, now available online, scientists in the laboratory of Gladstone Investigator Steve Finkbeiner, MD, PhD, harnessed the power of their one-of-a-kind robotic microscope to track the lifespan of individual neurons over time. The microscope has been used to study a variety of neurodegenerative diseases, and in this study, they focus their attention on LRRK2—the most common genetic cause of Parkinson’s.

Scientists have long known that mutations in LRRK2 cause misfolded versions of the LRRK2 protein to accumulate in neurons. The prevailing hypothesis has been that misfolded LRRK2 boosts the activity of a type of enzyme called kinase, and that this heightened kinase activity is what drives cell death. Scientists have also looked to the fact that mutant LRRK2 tends to clump together into so-called inclusion bodies (IB’s) as another contributor to the disease’s progression.

“As a result, researchers have used the presence of IB’s and heightened kinase activity as a proxy for measuring LRRK2′s harmful effects, rather than measuring LRRK2 levels directly,” explained Dr. Finkbeiner, who is the associate director of neurological research at Gladstone as well as a professor at the University of California, San Francisco, with which Gladstone is affiliated. “But we were unconvinced that these were the main drivers of cell death—so we decided to take a closer look at what was happening inside the cell.”

When studying neurodegenerative diseases such as Parkinson’s, which are defined by the degradation and death of neurons, traditional tools usually only allow researchers to track neuronal death at the population level. But Dr. Finkbeiner’s revolutionary microscope enables researchers to follow the lives of thousands of individual neurons—offering the clearest view into which events during the lifetime of the cell play a role in its death.

In the latest issue of the Journal of Neuroscience, Steve Finkbeiner (L) and Gaia Skibinski demonstrate how a unique protein interaction may drive the most common cause of Parkinson’s disease.

(Photo Credit: Chris Goodfellow/Gladstone Institutes)

The researchers generated neurons from two sources: from rats genetically modified to have mutant LRRK2, and human neurons derived from the skin cells of LRRK2-related Parkinson’s patients. They then tracked these cells over time, monitoring the buildup of mutant LRRK2 and how that buildup led to cell death.

“Interestingly, we found that neither IB’s nor kinase activity were the direct cause of cellular toxicity leading to neuronal death,,” said Gladstone Staff Research Scientist Gaia Skibinski, PhD, the paper’s lead author. “Instead, the underlying cause of cell death appeared to be tied directly to the accumulation of diffuse mutant LRRK2.”

But as the research team peered even closer into the lives of these neurons, they found something intriguing: a unique interplay between mutant LRRK2 and alpha-synuclein, another protein that has long been associated with Parkinson’s. Research has shown that Parkinson’s patients with LRRK2 mutations often show an abnormal accumulation of alpha-synuclein. But until now, the exact nature of the relationship between these two proteins remained unclear.

“Importantly, we found that in both the rat and human cellular models, removing alpha-synuclein reduced cell death caused by mutant LRRK2,” continued Dr. Skibinski. “When we looked closer, we found that loss of alpha-synuclein led to an immediate drop in LRRK2.”

The team hypothesizes that, in patients with mutant LRRK2, the build-up of alpha-synuclein hinders the cell’s ability to clear away LRRK2, leading to its accumulation. Over time, the buildup of LRRK2 becomes toxic to the cell, and the cell dies.

“The discovery of a synergistic relationship between two proteins long known to play a role in Parkinson’s is a huge step towards developing drugs that attack the disease’s underlying mechanisms,” said Dr. Finkbeiner. “As we continue to unravel the precise functional relationship between alpha-synuclein and LRRK2, we are well on our way to halting the onslaught of Parkinson’s on the brain.”

 

The consecutive images are of the same two neurons, imaged each day for five days. The top neuron does well throughout the five days. However the lower neuron begins to degenerate on the third day. And by the fourth day, it is gone.

By longitudinally tracking neurons the Gladstone research team has much greater power at picking up differences in neurons that had mutant LRRK2, and those that did not.

(Photo Credit: Gaia Skibinski)

Yeast and stem cells

New Method Uses Yeast and Stem Cells to Reveal Promising Drug Targets

- Nov 15 2013

In laboratory studies using yeast and human cells, scientists have discovered a compound that reverses the toxic effects of alpha-synuclein, the protein that accumulates in certain brain cells, leading to Parkinson’s disease (PD). The studies, supported in part by the Parkinson’s Disease Foundation (PDF), were published online in two reports in the October 24 issue of Science Express.

Typically, one of the first steps in testing whether a chemical compound might be an effective new drug is to see how it interacts with target molecules in test tubes. Researchers led by Susan Lindquist, Ph.D., at the Whitehead Institute in Cambridge, Massachusetts, have developed an alternative — a way to test potential therapies in living yeast cells, which are surprisingly similar to human cells. After creating a strain of yeast with the hallmark of the disease — alpha-synuclein protein build-up inside the cells — they screened nearly 200,000 drug compounds. They found one that could reverse the toxic effects of alpha-synuclein.

A second study was then led by Vikram Khurana, M.D., Ph.D., a contributor to the yeast study, who was supported by the PDF-ABF Clinician-Scientist Development Award (jointly funded and sponsored by PDF and the American Brain Foundation). He and his colleagues tested the compound in human nerve cells that carried mutations in the alpha-synuclein gene. These nerve cells were created by transforming the skin cells of two people with genetic PD into stem cells: a woman carrying a mutation in the alpha-synuclein gene and a man who had three copies of the alpha-synuclein gene. 

Results

  • The researchers first identified the toxic effects of alpha-synuclein in yeast cells, including cellular stress and a build-up of waste products.
  • The researchers then proved that these effects were found in the human neurons and were due to the alpha-synuclein mutation. 
  • A chemical compound identified in studies with yeast, called NAB2 (an N-aryl benzimidazole analog) successfully reversed the toxic effects in the human neurons.

What Does It Mean?

This study demonstrates a new way of discovering potential new drugs for PD and other neurodegenerative diseases.  

Indeed, Dr. Khurana and his colleagues proved the effectiveness of the new drug-screening method by identifying a chemical compound that may have the potential to treat Parkinson’s. The compound works by reversing the toxicity of alpha-synuclein. While it is widely known that alpha-synuclein accumulates in aggregates in the brains of people with PD, it is still unclear whether alpha-synuclein is acting alone, triggered by something else similar to an avalanche, or whether it accumulates because something else is also toxic to the cell. If alpha-synuclein is found to be the toxic cause of PD, this compound sounds promising for drug development.

To move forward, scientists must test the compound in animal models of Parkinson’s. If successful and safe for animals, the compound must then undergo similar testing in humans.

Many years in the making, this success of this new method underscores the vital need to support basic research in the effort to end Parkinson’s — a need that is wholeheartedly endorsed by PDF.

References: Yeast Reveal a “Druggable” Rsp5/Nedd4 Network that Ameliorates α−Synuclein Toxicity in Neurons, Daniel F. Tardiff, Nathan T. Jui, Vikram Khurana, Mitali A. Tambe, Michelle L. Thompson, Chee Yeun Chung, Hari B. Kamadurai, Hyoung Tae Kim, Alex K. Lancaster, Kim A. Caldwell, Guy A. Caldwell, Jean-Christophe Rochet, Stephen L. Buchwald, and Susan Lindquist. Science 1245321. Published online 24 October 2013 [DOI:10.1126/science.1245321 http://dx.doi.org/10.1126/science.1245321

Identification and Rescue of α-Synuclein Toxicity in Parkinson Patient–Derived Neurons, Chee Yeun Chung, Vikram Khurana, Pavan K. Auluck, Daniel F. Tardiff, Joseph R. Mazzulli, Frank Soldner, Valeriya Baru, Yali Lou, Yelena Freyzon, Sukhee Cho, Alison E. Mungenast, Julien Muffat, Maisam Mitalipova, Michael D. Pluth, Nathan T. Jui, Birgitt Schüle, Stephen J. Lippard, Li-Huei Tsai, Dimitri Krainc, Stephen L. Buchwald, Rudolf Jaenisch, and Susan Lindquist. Science 1245296. Published online 24 October 2013 [DOI:10.1126/science.1245296] http://www.sciencemag.org/content/early/2013/10/23/science.1245296

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