{"id":756,"date":"2015-08-21T19:50:59","date_gmt":"2015-08-21T19:50:59","guid":{"rendered":"https:\/\/www.mc.vanderbilt.edu\/vanderbiltmedicine\/?p=756"},"modified":"2021-08-11T19:41:36","modified_gmt":"2021-08-11T19:41:36","slug":"sons-disease-prompts-moms-scientific-quest","status":"publish","type":"post","link":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/sons-disease-prompts-moms-scientific-quest\/","title":{"rendered":"Son\u2019s Disease Prompts Mom\u2019s Scientific Quest"},"content":{"rendered":"
\"Photo<\/a>
Photo by Daniel Dubois<\/figcaption><\/figure>\n

At age 50, Terry Jo Bichell, a midwife and mother of five with no basic science training, set out to cure Angelman Syndrome.<\/p>\n

It wasn\u2019t a mid-life crisis; a fit of reinvention as her four oldest 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 the disorder marked by delayed brain development, lack of speech, uncoordinated motor function, behavior difficulties, seizures and sleep disorders.<\/p>\n

\u201cAngelman is caused by just one gene. Why don\u2019t we have a drug that turns on that gene?\u201d Bichell wondered.<\/p>\n

\u201cI just didn\u2019t want to sit around complaining about other scientists not doing it. There can\u2019t 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?\u201d<\/p>\n

Sleepless nights<\/strong>
\nWhen Louie was born in February 1999, Bichell immediately sensed something was wrong. He wasn\u2019t breast-feeding as well as his four older sisters and wasn\u2019t meeting developmental milestones, except he smiled and laughed earlier than expected. (The syndrome is marked by frequent laughing, smiling and a generally happy demeanor.)<\/p>\n

\u201cAs a midwife, I couldn\u2019t take no for an answer on the breast-feeding. I had told a thousand other women they could breast-feed and wasn\u2019t going to let my own baby get away with not doing it,\u201d Bichell recalled. \u201cThe pediatrician told me he was going to be fine. He was my first boy and they\u2019re different than girls. She said I\u2019m almost 40, maybe I\u2019m more neurotic.\u201d<\/p>\n

She and her husband, David Bichell, M.D., now chief of pediatric cardiac surgery at Monroe Carell Jr. Children\u2019s Hospital at Vanderbilt, would often flip through his medical books looking for an answer to Louie\u2019s delays.<\/p>\n

When Louie was finally diagnosed with AS 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 2 miles to the closest Internet caf\u00e9 and started Googling.<\/p>\n

\u201cIt was like the door opened. It was like somebody said, \u2018OK now you have work to do.\u2019\u201d<\/p>\n

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 AS, Louie has difficulty sleeping, waking often in the night and still requiring a special adult-sized crib to keep him safe.<\/p>\n

\u201cFinland in July is 23 hours of sun, and I have a kid with a sleep disorder. 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,\u201d Bichell recalled.<\/p>\n

Also sleepless was Art Beaudet, M.D., the scientist who originally discovered the Angelman gene (or \u201cthe Yoda of the 15th chromosome,\u201d as Bichell calls him). They struck up a friendship in the wee hours, and the Bichells began supporting Beaudet\u2019s research to find a way to turn on the paternal gene.<\/p>\n

At the conference, Bichell saw that the scientists weren\u2019t 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.<\/p>\n

Angelman Syndrome (AS), named for British pediatrician Harry Angelman who first described the disorder in 1965, occurs in one in every 10,000-20,000 births. It is the medical school textbook example of genomic imprinting, a phenomenon that silences genes from either the mother or father. In the case of AS, the paternal copy of gene UBE3A on chromosome 15 is turned off, and the maternal copy fails to produce the necessary proteins.<\/p>\n

\u201cTerry Jo took it by the horns,\u201d David Bichell said. \u201cThe interest had been purely scientific\u2014genomic imprinting, isn\u2019t 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.\u201d<\/p>\n

Back to School<\/strong>
\nBichell enrolled in the Vanderbilt Brain Institute\u2019s 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 AS. 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.<\/p>\n

\u201cIt\u2019s 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,\u201d she said.<\/p>\n

Time of day was the only difference, and Bichell latched onto the idea that the biological clock, or circadian rhythm, is important in AS.<\/p>\n

Long before her scientific training, Bichell started logging Louie\u2019s sleep patterns and noticed a five-week cycle.<\/p>\n

\u201cHe would get more and more off over a month\u2019s time, then have a disastrous week and be back to normal. I really wondered if there was something about the gene that he\u2019s missing that functions in the biological clock.\u201d<\/p>\n

\"+<\/a>
+
Carl Johnson, Ph.D., and Terry Jo Bichell study circadian rhythm in Angelman Syndrome. Photo by Joe Howell.<\/figcaption><\/figure>\n

More experiments she performed with Carl Johnson, Ph.D., and Shuqun Shi, Ph.D., showed that mice with AS had a 25.5-hour day, and the results were published in February in the journal Current Biology.<\/p>\n

These findings could have huge implications for upcoming clinical trials for treatments for AS. There are two known ways to turn on the faulty gene\u2014a brain cancer drug called topotecan and binding a DNA sequence known as an antisense oligonucleaotide\u2014that could potentially reverse the effects of AS. A properly functioning biological clock could be an immediate signal that the treatments are working.<\/p>\n

\u201cWe\u2019re hoping this circadian knowledge will give the pharmaceutical firms a biomarker. When the gene is turned on, the mice\u2019s clocks are normalized within a day. Anything you can change in a day is a great biomarker,\u201d Bichell said.<\/p>\n

\u201cI was so na\u00efve. I thought by the time I finished grad school we\u2019d have that gene turned on. Now that I know more about science, I realize it was crazy! But really I\u2019m behind where I thought the research would be. I really thought we would have it in kids by now.\u201d<\/p>\n

The Greater Good<\/strong>
\nThe Angelman community was extremely reluctant to use the word \u201ccure,\u201d but Bichell knew there had to be a drug that would turn on the gene, and eventually decided to find it herself. She\u2019s not at all disappointed other scientists beat her to it.<\/p>\n

\u201cThere are two drug companies, Isis and Ovid, who say they are starting clinical trials in 2016. There is a cure in sight, and I want to help them get their drugs into kids,\u201d she said.<\/p>\n

Today, Louie is an a ninth-grader at Hillsboro High School. He\u2019s a bit of a celebrity among his classmates and their families, and gives exuberant greetings to everyone he meets.<\/p>\n

\u201cLouie is a good kid. He\u2019s got a great sense of humor and is very affectionate and super attached to us. He does walk and does feed himself, and he\u2019s better at sleeping now that I know how sensitive he is to light,\u201d Bichell said.<\/p>\n

She hopes to finish her Ph.D. this summer and then be involved with clinical trials or help translate scientific information for families and donors. Her husband David is proud of her perseverance.<\/p>\n

\u201cThere are a thousand points of \u2018no\u2019 along this pathway and she\u2019s just pushing them aside. She doesn\u2019t let anything be an obstacle to what is her clear mission,\u201d he said.<\/p>\n

\u201cAnd it\u2019s all with sobering understanding that pretty much everything she\u2019s driving toward may be too late for Louie. But that doesn\u2019t change her resolve. She really is thinking about future kids.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"

At age 50, Terry Jo Bichell, a midwife and mother of five with no basic science training, set out to cure Angelman Syndrome. It wasn\u2019t a mid-life crisis; a fit of reinvention as her four oldest daughters left the house. It was a pure desire to help her son Louie, 16, and the thousands of…<\/p>\n","protected":false},"author":211,"featured_media":761,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"_links_to":"","_links_to_target":""},"categories":[14,23],"tags":[],"class_list":["post-756","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-vm-features","category-vm-summer-2015"],"acf":[],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/cdn.vanderbilt.edu\/t2-main\/medschool-prd\/wp-content\/uploads\/sites\/82\/2015\/08\/USE20150703DD0161.jpg","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/pcDnub-cc","_links":{"self":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts\/756","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/users\/211"}],"replies":[{"embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/comments?post=756"}],"version-history":[{"count":1,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts\/756\/revisions"}],"predecessor-version":[{"id":3144,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts\/756\/revisions\/3144"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/media\/761"}],"wp:attachment":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/media?parent=756"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/categories?post=756"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/tags?post=756"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}