Son’s genetic disorder drives mom’s quest
At age 50, midwife whose son has Angelman syndrome goes back to school to learn how to cure him.
At age 50, Terry Jo Bichell, a midwife and mother of five with no training as a researcher set out to cure Angelman syndrome.
It wasn’t a mid-life crisis, a fit of reinvention as her four daughters left the house. It was a pure desire to help her son, Louie, 16, and the thousands of other children like him who are living with Angelman syndrome, a disorder marked by delayed brain development, lack of speech, uncoordinated motor function, behavior difficulties, seizures and sleep disorders.
“Angelman is caused by just one gene. Why don’t we have a drug that turns on that gene?” Bichell wondered.
“I just didn’t want to sit around complaining about other scientists not doing it. There can’t be anyone more motivated than me, so I should get off the couch and go to school and figure out how to turn on the gene. Why not?”
Soon after Louie was born in February 1999, Bichell sensed something was wrong. He wasn’t breast-feeding as well as his four older sisters had, and wasn’t meeting developmental milestones, except that he smiled and laughed earlier than expected. (The syndrome is marked by frequent laughing, smiling and a generally happy demeanor.)
“As a midwife, I couldn’t take no for an answer on the breast-feeding. I had told a thousand other women they could breast-feed, and wasn’t going to let my own baby get away with not doing it,” Bichell recalled. “The pediatrician told me he was going to be fine. He was my first boy and they’re different than girls. She said I’m almost 40, maybe I’m more neurotic.”
She and her husband, David Bichell, M.D., now chief of pediatric cardiac surgery at Monroe Carell Jr. Children’s Hospital at Vanderbilt, would often flip through his medical books looking for an answer to Louie’s delays.
When Louie was finally diagnosed with Angelman syndrome around his first birthday, Terry Jo was working in Mexico as a midwife with her mother and four children in tow, while David stayed behind to work in San Diego. She walked two miles to the closest Internet café and started Googling.
“It was like the door opened. It was like somebody said, ‘OK, now you have work to do.’ ”
She found out the first international Angelman conference was in six weeks in Finland, and recruited her mother to come along to help care for Louie. Like most children with Angelman syndrome, Louie has difficulty sleeping, waking often in the night and still requiring a special adult-sized crib to keep him safe.
“Finland in July is 23 hours of sun, and I have a kid with a sleep disorder,” Bichell recalled. “It was ridiculous. In the middle of the night he would be wailing, and I would pace the lobby so my mom could get some sleep.”
Also sleepless was Art Beaudet, M.D., the scientist who originally discovered the Angelman gene (or “the Yoda of the 15th chromosome,” as Bichell calls him). They struck up a friendship in the wee hours, and the Bichells began supporting Beaudet’s research to find a way to turn on the dysfunctional gene.
At the conference, Bichell saw that the scientists weren’t really connecting with the families, and made it her mission to speed their discoveries from the lab into clinical trials. She became involved with various Angelman groups and supported researchers working in the field.
Angelman syndrome, named for British pediatrician Harry Angelman, who first described the disorder in 1965, occurs in one in every 10,000 to 20,000 births. It is the medical school textbook example of genomic imprinting, a phenomenon that silences genes from either the mother or father. In Angelman syndrome, the maternal gene UBE3A on chromosome 15 is either missing or broken — it fails to produce necessary proteins. The paternal gene is silenced — turned off — in everyone, with or without Angelman syndrome.
“Terry Jo took it by the horns,” David Bichell said. “The interest had been purely scientific — genomic imprinting, isn’t that wacky? They really had blinders to turning that into a treatment. All along she has been pushing their scientific agenda into the clinic. Then, carrying the ball all the way down the court, she decided to be more educated and figure it out herself.”
Back to school
Bichell enrolled in the Vanderbilt Brain Institute’s neuroscience graduate program in 2010. She joined the lab of Kevin Haas, M.D., Ph.D., and began looking at the amount of neurotransmitters in the brains of mice with Angelman syndrome. Her mice showed abnormal increases and decreases in neurotransmitters but research colleagues in Memphis found the opposite pattern. There was no explanation for this difference, so Bichell drove to Memphis to make sure they were doing their dissections exactly the same.
“It’s easier for me to find a babysitter at night, so I would put Louie on the bus at 9 in the morning, get to work about 11 and do all my dissections between 5 and 8 in the evening. (The researchers in Memphis) were doing theirs at 9 in the morning,” she said.
Time of day was the only difference, and Bichell latched onto the idea that the biological clock, or circadian rhythm, is important in Angelman syndrome.
Long before her scientific training, Bichell started logging Louie’s sleep patterns and noticed a five-week cycle.
“He would get more and more off over a month’s time, then have a disastrous week and be back to normal. I really wondered if there was something about the gene that he’s missing that functions in the biological clock.”
More experiments she performed with Carl Johnson, Ph.D., and Shuqun Shi, Ph.D., showed that mice with the disorder had a 25.5-hour day, and the results were published in February 2015 in the journal Current Biology.
These findings could have huge implications for upcoming clinical trials for treatments for Angelman syndrome. There are several known ways to turn on the dormant paternal gene, including a brain cancer drug called topotecan and a compound made of a tiny DNA sequence known as an antisense oligonucleotide, which “unsilences” the paternal gene. Another recent discovery is a way to deliver the gene directly with a viral vector into the brain, Bichell said.
“We are doing more experiments on the circadian aspects, using the new compounds and viral vectors in the mice to see if we can normalize the circadian rhythms,” she said.
Such therapies could potentially reverse the effects of Angelman syndrome. A properly functioning biological clock could be an immediate signal that the treatments are working.
“We’re hoping this circadian knowledge will give the pharmaceutical firms a biomarker. When the gene is turned on, the mice’s clocks are normalized within a day. Anything you can change in a day is a great biomarker,” Bichell said.
“I was so naïve. I thought by the time I finished grad school we’d have that gene turned on. Now that I know more about science, I realize it was crazy! But really I’m behind where I thought the research would be. I really thought we would have it in kids by now.”
Thinking about future kids
The Angelman community was extremely reluctant to use the word “cure,” but Bichell knew there had to be a drug that would turn on the gene, and eventually decided to find it herself. She’s not at all disappointed other scientists beat her to it.
By late 2015, there were three drug companies, Isis, Agilis and Ovid, saying they plan to start clinical trials in 2016.
“There is a cure in sight, and I want to help them get their drugs into kids,” Bichell said.
Meanwhile, Louie is a 9th-grader at Hillsboro High School, in Nashville, Tenn. He’s a bit of a celebrity among his classmates and their families, and gives exuberant greetings to everyone he meets.
“Louie is a good kid. He’s got a great sense of humor and is very affectionate and super attached to us. He does walk and does feed himself, and he’s better at sleeping now that I know how sensitive he is to light,” Bichell said.
She hopes to finish her Ph.D. in the spring of 2016, then get involved with clinical trials or help translate scientific information for families and donors. Her husband is proud of her perseverance.
“There are a thousand points of ‘no’ along this pathway and she’s just pushing them aside. She doesn’t let anything be an obstacle to what is her clear mission,” he said.
“And it’s all with sobering understanding that pretty much everything she’s driving toward may be too late for Louie. But that doesn’t change her resolve. She really is thinking about future kids.”