HD66: Search for a cure or a killer?

by Babs Carryer

  She’s very good at what she does. She’ll do what it takes. She’ll take care of my dad in the best way possible. When it comes to the final steps, she’ll know what to do. She’s just that way. I didn’t get that gene.

  I had seen chorea, the Tourette syndrome of the body, before. When I saw it in my father, it became personal. The next day, he knocked a lamp over. On Sunday, when I had to leave to go back to Pittsburgh, he fell in the bathroom. I noticed that someone had removed the lock on the door. It will only get worse.

  It’s not supposed to happen this way, not to me. Your work and your family are not the same. Quixotic is a business. We can save lives, sure. But my father’s life? Mine? There is no separation now. I think about how everyone talked about the passion of an entrepreneur in grad school. They have no idea what that really means.

  …….

  “I got this thing called chorea in my head

  wanna walk but I fall down instead

  folks say "Woody, he's just drunk again"

  but I haven't had a drink since I don't know when

  besides...I only drink when I'm alone...or with somebody”

  Woody Guthrie

  On the plane on the way home, I glanced over some recent articles. “HD symptoms can sneak up on you,” I read. “The healthier a patient is, the more he successfully fights the onset of the disease,” another article said. My dad’s symptoms seem to have bucked the norm and were progressing rapidly.

  HD affects only about 30,000 new patients each year in the U.S., so it’s considered an orphan disease. This terrible disease is a business opportunity for Quixotic. “The HD66 treatment will mitigate the symptoms and terrible desecration that happens to a person with HD,” I wrote in the most recent business plan.

  I remember Errol’s description at a conference, “The science behind HD66 is simple. The magic of chromosome four. The misfortune of HD lies within a solitary gene, HTT, which, is, as you know” he said, looking at the audience of scientists and physicians over his glasses, “an excessive repeat of a DNA sequence – CAG. If you have more than 40 repeats of that one little CAG sequence, the codon, then you are doomed. You WILL develop HD. Your future is foretold and unavoidable.” I remember Errol pausing and looking at the crowd. “The longer the repeat of the CAG codon, the earlier and more severe the onset of the disease. The symptoms of HD are relieved only in sleep, and, ultimately, in death. The brilliant machinery of our bodies can be undone by this tiniest of faulty cogs, a repetition of a bad sequence lodged on every chromosome four in every cell.”

  A betrayal of the body, I called it.

  I know that the data on Huntington's is unequivocal. It’s genetic. The mutation that causes Huntington's is dominant. The disease does not skip generations. Anyone with more than 40 CAG repeats on chromosome four shares the same fate. No amount of love, religion, or hope deters the disease from its course. What’s in store for my dad is athetosis. His fingers and toes will become crimped and rigid, and the ever increasing chorea will overwhelm him, leaving him writhing on a bed that he will never leave.

  The HD gene is passed from generation to generation. If a parent has it, you have a 50-50 chance of inheriting the mutant gene. The conundrum is that, if you don’t know you have it, you might pass it on to your children. It’s a vicious cycle. Now, I know the extent of the viciousness. There are no instances of HD appearing without family lineage. Today, with the genetic test for the disease, that will occur less and less. If you know a parent has it, then you too can have that test. So you can know. I can know.

  My dad’s mother and her family didn’t have a clue. It was the 1970s. Granny Prince died in her early 60s. In a family of ranchers in Eastern Oregon, she wasn’t the go-to-the-doctor type. Her decline was painful to watch, my dad told me years ago. But she couldn’t have known that it was Huntington’s unless she knew that it came from her parents. The mutant gene of Huntington’s wasn’t found until 1993. There were tests prior to that, but they involved multiple family members and they weren’t even that accurate. Post mortem, an autopsy could reveal that the caudate on both sides of the brain lacked the normal convex shape, the typical and healthy bulge into the anterior horn of the lateral ventricles. But who ordered that kind of confirmation?

  On the ranch outside of Bend, where I have only been once, it was Darwin’s law all the way. “I didn’t get to complain,” I recall my dad telling me. “In fact,” he told me, “none of us got to do much of anything outside of help with the cattle and mending fences.” I had two uncles. The eldest died in Vietnam. The next one was a renegade and, I think, ended up in a Canadian jail. Dad was the youngest. His father passed away before I was born. So did Granny Prince. There was no one left to know that the repeated gene resides in him. And, possibly, in me. I feel the soft weight of her pearls around my neck.

  Errol loved Woody Guthrie’s songs. He sang them all of the time when he thought no one could hear him. Woody got HD from his mother. Two of his daughters have it. Woody’s wife, Marjorie Guthrie, founded the Huntington’s Disease Society of American (HDSA) in 1968. Woody wrote a song about Huntington’s. I had heard Errol sing it. It had new meaning as I listened more carefully to the lyrics playing on my phone.

  “If you can't remember how I died remember how I lived

  and if you can find it in your heart to forgive

  know that the piece of brain that had to fall

  never affected my love for you at all

  I'm gonna play this thing 'till they find a cure.”

  Should I get tested? Yes is the obvious answer. If I do, and am found to have that gene, what do I do?

  I’ve read stories about people with HD, including emotionally-charged articles about some who have committed suicide rather than suffer the ignominy of the slow death and loss of control that comes with the disease.

  How do you live your life if you know you will have that kind of end? How do you deal with having no future? The only drug that is currently on the market for HD helps to alleviate symptoms; it does not target the CAG repeats in the huntingtin protein directly. The drug was approved by the Food and Drug Administration in 2008 and addresses chorea by increasing the amount of a neurotransmitter in the brain called dopamine that is important in motor functions. The drug also has unintended side effects that include insomnia, drowsiness, nausea, and restlessness. My dad is not taking it. I probably wouldn’t either.

  How do you marry? If you know that you have it, you can’t morally have kids. I didn’t call Neal from Amherst. No one at Quixotic either. I can’t see that their knowing will help. But I will sure as heck find out if my dad can be part of any clinical trial. Is it too late for that? Can HD66 cure him?

  Chapter 11

  That same year

  As I squeeze into the shuttle that takes me to baggage claim after that Thanksgiving weekend, I resolve not to tell Neal about the Huntington’s in my family. Not until I am ready and have some answers for myself. I’ll tell him that my dad is sick, but I won’t fess up as to what it is, or that it is hereditary. I’ll buy some time to debate with myself if I should tell him and when Should get tested first?

  I met Neal at CMU while we were getting our MBAs. He’s of Indian heritage but born and raised in the U.S. by expatriates from Allahabad. We took a vacation last fall in India to visit some distant relatives. They took us to the Ganges where they performed spiritual rituals. We went to the Taj Mahal, and I can still see that striking white building when I close my eyes. It’s an extraordinary structure, with its embedded gems. It was the first time Neal had seen it too, and we spent hours there in spite of the heat. It was there that I thought about spending the rest of my life with Neal. But I don’t know. I’m focused on my career, on Quixotic. I don’t know if I want to settle down with one man, have a family, all that stuff. My life at the Coho in Amherst was not exactly normal; I don’t know what normal looks like. Now, there may be no normal anyway.

  Neal works for his own startup, CivicEssence. I’ve
told him a million times that’s a terrible name, but he laughs at me and says, “So come up with an alternative, Miss Marketing.” All of his employees are CMU and Centre-Pitt alums. He’s been able to bootstrap his startup, raising a bit of capital from high-net-worth individuals, angels. He’s not gone through painful institutional funding rounds like we have at Quixotic.

  Most of our classmates ended up in New York City or San Francisco. But Neal loves Pittsburgh. “That’s because you’re from Detroit,” I once taunted him. “Pittsburgh’s a step up!”

  But Neal was unfazed. “Look at what you can get here in the way of houses,” he retorted.

  He’s right. Pittsburgh houses are beautiful – big, old fashioned charm. I think about the Google ad to recruit employees to Pittsburgh when they opened up its office here, which is one of their largest offices outside of the Mountain View, California. All the ad said was “Five bedrooms, hardwood floors, fireplace, large yard, great schools, $250,000. Apply Google Pittsburgh.” They got so many applicants they had to take the ad down.

  I get what Neal is saying. I love it here too. And him? Isn’t this what you’re supposed to have in a partner – synergistic goals and views on life? Love? Who beats two entrepreneurs, two companies, one family?

  …….

  I see his little blue Honda approach outside of baggage claim. As he jumps out and we embrace hello, I realize that it’s easier not to think about my dad, my own dilemma. We hug for a long time, and he kisses me. I never want to let go.

  “I missed you so much,” he says into my hair.

  “I missed you too.”

  “No more vacations apart, OK? Let’s find a way to do them together. What about December?”

  “Sure. But I’m tired. Let’s talk about that later.”

  “Soon, OK?” He puts his fingers on my pearls. I cover his fingers with my hand.

  As we drive to my apartment I look over at him, his steady and handsome face. I can’t tell him. I can’t not tell him. It will come up. Neal has made it clear that he is a one-horse kind of guy and that I am it for him. He has hinted before that we should spend Christmas together, not go to our separate families, but go somewhere special. I suspect that he wants to pop the question, to give me a ring. I know him, and I know this is the way that he would plan it. He will get down on his knee, I am sure. I suspect I would say yes. What if he wants to be traditional and talk to my father?

  Late that night, another sleepless one, with Neal breathing quietly and peacefully on one side, and Arwen purring on the other, I debate with myself. My struggle is the same as millions of others in similar situations. Personalized medicine can give great freedom – we can predict our own futures – but it also causes great ethical dilemmas. Given that there is no viable treatment for HD, diagnosis is a death sentence. Who wants that? Do I want Neal to be my Dottie? Is that fair? Would he sign up for that? Can HD66 stop this cycle? For me and others?

  As the clock reads 2 a.m., Arwen stretches and rolls on her back for me to rub her tummy. My thoughts circle round and round. Will Neal still want me if he knew that we couldn’t/shouldn’t have children? He sighs in his sleep. I reach over and kiss him, knowing that I can’t face hurting him. He is number three of four kids; he loves his siblings, his family. He’ll make a great dad.

  “Hey beautiful,” he says, eyes half open, and reaches to pull me to him.

  Chapter 12

  January 10, that same year

  Dawn is still an hour away as Errol stood at his bedroom window looking out at the soft snow that fell during the night. The dream haunted him – again. The Voice.

  Luna whined. “Sh,” he told her, softly lifting her off the bed. He didn’t want her thumping off the bed and waking Amy. He had removed her collar so that her tags wouldn’t make any noise. He picked it up from his bedside table, and it clanked. “Shit, sorry, honey,” he said in response to Amy’s grunt.

  He made his way carefully downstairs, struggling with the squealing dog in his arms. As he let her down she yelped in excitement. “Sh!” Errol opened the hall closet and reached for his cross-country skis. It had been snowing for two days; now it was deep enough. He strapped on Luna’s blanket and hooked on her long leash. She walked on her hind legs whining with excitement as he laced up his ski boots. She barked impatiently. Errol clamped his hands on her jaw, prompting a shriek of surprise. Both hands on her muzzle, he heard his skis clatter loudly to the floor. “Shit!”

  “PLEASE, Errol,” Amy begged from upstairs.

  “Of course, love. I’m out the door. Go back to sleep.” The sleigh bells on the front door were still jingling as he stepped out onto the front porch. Luna skittered ahead down the steps, pulling him. Their prints were the first on the sidewalk, and they jogged down the hill and up the steps at the end of the block to Highland Park. The snow gleamed, pristine and pure. Errol strapped on his skis, turned on his headlamp, and started the rhythmic strokes – glide, push, skate, push. He entered the park’s running path, which was illuminated by the street lights that circle the drive around the park. Luna was ecstatic, her airplane ears flapping and baying as she leapt in and out of the drifts. When they arrived at the back entrance to the zoo, Errol punched in the security code to open the gate. Dena, the zoo director, had given him that code a few years ago. The code still worked. He didn’t come to the back door of the zoo very often, but, when he did, he appreciated his easy access. Dena was a near miss. I’m glad I didn’t do that to Amy. He grimaced as he saw Luna leaving little yellow signs along the way. Oh no, there’s a brown sign.

  Errol steered towards the polar bears. He knew that they’d be out and happy in the snow. “Just the bears and us,” he told Luna, and she bah-roo’d her agreement, pulling Errol down the path.

  He had been bothered for weeks. He was experimenting with a new molecular design for HD66. Not for Huntington’s, which was well on its way to commercialization, thanks to Quixotic, but for Parkinson’s Disease. Errol had worked his whole life on solving conditions related to the basal ganglia in the brain that play a central role in many neurological conditions, including Huntington’s. But they also figure in Parkinson's, which involves degeneration of the dopamine-producing cells in the substantia nigra, a component of the basal ganglia. Parkinson’s represented a much bigger market than Huntington’s. That was not the only reason he was interested in the disease, he told himself, planting his poles and stopping to watch the polar bears frolic in the snow. But still, it would be a great additional asset for Quixotic if he could make it work. If.

  His interest in Parkinson’s began about a year earlier with his colleague, Maya Pendyala. She had been researching Parkinson’s for the last few years. Maya was convinced that the siRNA approach that Errol was using with HD66 – maybe a variation of the treatment, and injectable – could work on a key Parkinson’s protein, alpha-synuclein.

  He was skeptical, but she had insisted. “There is evidence of the proteins interacting,” she had informed him with a burning passion that reminded him of a younger self. Maya was in her mid-30s, thin and dark with long gleaming hair and deep brown eyes with flecks of gold. She was intense.

  “You know that it’s generally agreed that each aggregation-prone protein is characteristic of a specific disorder. But we know now that aggregation-prone proteins can co-aggregate and modify each other's behavior, suggesting this process could contribute to the overlap in clinical symptoms across different diseases. It’s possible that once your treatment for HD is in the brain, it will work with any protein, including the Parkinson’s alpha-synuclein. I think it will work. I need your help!”

  “I don’t know if it will work,” Errol had responded truthfully.

  Shaking her black ponytail, she looked into his eyes, “Errol, please.”

  “It’s a stretch, but we can try,” he had agreed, noting her big smile of appreciation.

  Since then, Errol had been working with his students on chemical variations of HD66 to impact the substantia nigra in the br
ain. So far, nothing worked. It was frustrating to see so little progress. “Don’t give up,” the Voice had told him.

  Note to self: Change protocol and work with lengthened carbon chain.

  He dialed a familiar number. He needed to talk to the only one who would understand.

  “Errol, what is it?” murmured a sleepy Brie.

  …….

  12 days later, January 22

  It was midnight; Errol couldn’t sleep. Cautiously, he went downstairs to make tea and read over his lab notes. Luna followed him, her tags jingling noisily as she thumped down the stairs. He had given up taking her collar off. Either way, he seemed to wake his wife. He ignored the moan of frustration from upstairs and studied his notes. He was stymied after two weeks’ work on expanding the carbon chain and testing on mice. No net improvements found. “Do not look back; look forward.” The Voice was never far behind.

  He’d met with Maya last week. They continued discussing MPTP, which she had explained causes Parkinson's by destroying dopaminergic neurons in the substantia nigra of the brain. “MPTP, which chemically breaks down to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is a sad story,” she had elaborated, gesturing with her lovely brown hands. “In the 1970s, a chemistry graduate student in Maryland tried to synthesize a similar compound, which is the synthetic opium-like drug, MPPP, or 1-methyl-4-phenyl-4-propionoxypiperidine. Unfortunately, he accidentally synthesized MPTP as an impurity in the MPPP. Within days of injecting the drug, the young man exhibited signs of Parkinson’s.” Maya paused and shook her long hair. Her soft brown eyes were so sad Errol thought he might drown.