Stories about: People

Science Seen: Disrupted developmental genes cause ‘split brain’

split brain syndrome
The two halves of the brain on the right, from a patient with the DCC mutation, are almost completely disconnected. The mutation — first recognized in worms — prevents axons (nerve fibers) from crossing the midline of the brain by interfering with guidance cues. Image courtesy Ellen Grant, MD, director, Fetal-Neonatal Neuroimaging and Developmental Science Center.

Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.

Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically.

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With no time to lose, parents drive CMT4J gene therapy forward

CMT4J
Talia Duff’s disorder, CMT4J, is a rare form of Charcot-Marie-Tooth. It has been modeled in mice that will soon undergo a test of gene therapy, largely through her parents’ behind-the-scenes work.

In honor of Rare Disease Day (Feb. 28), we salute “citizen scientists” Jocelyn and John Duff.

When Talia Duff was born, her parents realized life would be different, but still joyful. They were quickly adopted by the Down syndrome parent community and fell in love with Talia and her bright smile.

But when Talia was about four, it was clear she had a true problem. She started losing strength in her arms and legs. When she got sick, which was often, the weakness seemed to accelerate.

Talia was initially diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an autoimmune disease in which the body attacks its own nerve fibers. Treated with IV immunoglobulin infusions to curb the inflammation, she seemed to grow stronger — but only for a time. Adding prednisone, a steroid, seemed to help. But it also caused bone loss, and Talia began having spine fractures.

“We tried a lot of different things, but she never got 100 percent better,” says Regina Laine, NP, who has been following Talia in Boston Children’s Hospital’s Neuromuscular Center the past several years, together with Basil Darras, MD.That’s when we decided to readdress the possibility that it was genetic.”

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Honoring rare disease ‘citizen scientists’

citizen scientists

The global theme of this year’s Rare Disease Day (February 28) is research, and in keeping with that, we salute a very important group of people: citizen scientists. These can-do patients and family members are putting previously undiagnosed rare diseases on the map and driving the search for treatments. Citizen scientists play multiple roles: They keep scientists focused on therapeutic development, conduct online research to connect ideas, set up patient networks and data registries, raise money and start companies. They’ve earned a voice in clinical trial design and were instrumental in the passage of the 21st Century Cures Act.

Meet a few citizen scientists who have inspired us recently.

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Abraham Rudolph, MD: The path of a pediatric cardiology pioneer

Abraham Rudolph MD
Rudolph (left) at Boston Children’s Hospital with Cardiologist-in-Chief Alexander Nadas, MD, c. 1958.

Abraham Rudolph, MD, who recently turned 93, has watched his chosen corner of the medical profession — pediatric cardiology — grow from rudimentary beginnings into a robust, multivariate discipline. Yet while his name is known worldwide in pediatric cardiology circles, he entered cardiology more than 50 years ago only by happenstance.

Born in South Africa in 1924, Rudolph came to the United States in 1951 to train in cardiology by invitation of Charles Janeway, MD, then Physician-in-Chief at Boston Children’s Hospital. Concerned about providing for his wife and newborn daughter, he chose cardiology over hematology or neurology because it offered a salary; many other physician-training opportunities at the time were unpaid. That first year, as the hospital’s first cardiology fellow, he made $3,000 — thanks to a family donation.

He stayed on for nine years, becoming director of the cardiac catheterization laboratory. There he found his focus.

“I became more and more interested in the physiology of the circulation, particularly the problems surrounding infancy,” he said in a 1996 interview with the American Academy of Pediatrics. “At that time, there were relatively few places that were doing anything about infants with heart disease. Most of the emphasis was on older children.”

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Infant behavior, dyslexia and war orphans: A portrait of Peter Wolff, MD

Peter Wolff MD
Peter Wolff c. 1977 (Ed Fitzgerald/Boston Globe)

Peter Wolff, MD, recently retired from Boston Children’s Hospital after more than 60 years in service to clinical psychiatry, behavioral science research and ethical oversight of human subject research.

When he started as a psychiatrist at Boston Children’s Hospital in 1956, Peter H. Wolff, MD, was seeking a deeper understanding of infant behavior. At a time when psychoanalysis was the framework for understanding the infant psyche, Wolff applied scientific methods used to study animal behavior — carefully observing an animal in its natural environment and seeking to discern patterns. His approach would revolutionize our understanding of infancy.

“We knew a great deal about a stickleback fish, the graylag goose by just watching what they do in the field — field observations — but nobody had ever done that with humans,” Wolff shared in an interview in 2009, “and it seemed to me a logical thing to try to do that.”

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Science to care: Q&A with Boston Children’s Hospital’s new Chief Scientific Officer

David Williams, MD
David Williams, MD

When Boston Children’s Hospital decided to hire its first chief scientific officer (CSO) in eight years, the institution sought an individual who could spotlight the hospital’s robust scientific enterprise and effectively connect it to clinical medicine and industry. David Williams, MD, president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and director of clinical and translational research at Boston Children’s, was the ideal choice.

An award-winning researcher, Williams trained in the clinic but also pursued basic science, developing techniques for introducing genes into mouse and human blood cells. He focused on blood stem cell biology, leukemia and gene therapy to correct genetic blood disorders, becoming a 16-year Howard Hughes Medical Institute Investigator, a Member of the National Academy of Medicine and a Fellow of the American Association for the Advancement of Science. He has secured multiple patents for techniques still in use today.

Williams spoke about his vision as CSO to align basic research and clinical care at Boston Children’s and the challenges ahead.

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From math major to transplant pioneer: An interview with William Harmon, MD

William Harmon MD
William Harmon, MD, c. 1996

William Harmon, MD, a pioneer in pediatric dialysis and kidney transplantation, passed away on May 29, 2016 after 45 years at Boston Children’s Hospital. He was 72 years old. Starting as an intern in 1971, the year the hospital performed its first kidney transplant, he worked his way up to Nephrologist-in-Chief, a position he held for 25 years.

Harmon was passionate about caring for children with end-stage renal disease (ESRD), pioneering techniques and devices to adapt hemodialysis to infants and young children. He helped get NIH support for child-specific transplant research and led multiple clinical trials of treatment protocols to help children not only tolerate their transplants, but thrive. He also worked to ensure that government guidelines and legislation on ESRD and kidney transplant gave priority to children.

Harmon was the first chair of the pediatric committee of the United Network for Organ Sharing (UNOS) and the first pediatrician to chair the New England Organ Bank’s Board of Directors. He was passionate about teaching, training more than 65 pediatric nephrology fellows.

Below are lightly edited excerpts from interviews with Harmon, most recently in 2014.

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Inspired research in newborn lung disease: Stella Kourembanas, MD

Stella Kourembanas
Stella Kourembanas in the NICU with Julian (photos: Katherine Cohen)

During the NICU rotation of her clinical training, Stella Kourembanas, MD, sat at the bedside of newborn babies with hypoxia. The newborns weren’t getting enough oxygen and were suffering from pulmonary hypertension — abnormally elevated blood pressure in the lung’s blood vessels. What was triggering these patients’ disease?

Kourembanas decided her fellowship research would focus on determining how hypoxia triggers the blood vessels to become abnormal. She built her career, showing how hypoxia affects the endothelial cells that line blood vessels: what genes are turned on, how they regulate interaction between cells and how that affects the lung vasculature.

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I feel good! How mood influences time management

time management and mood
(JESHOOTS/Pixabay)

Most theorists boil human behavior down to a pursuit of pleasure. Yet all of us engage in mundane, even unpleasant activities. It’s called being an adult, right? Happy Monday!

But Maxime Taquet, PhD at the Computational Radiology Laboratory at Boston Children’s Hospital (who by day helps conduct advanced brain imaging in children with neurologic conditions) wondered why. If we’re such pleasure-seekers, how do we muster the will to do our taxes or vacuum the house?

Taquet, with Jordi Quoidbach, PhD, of the Department of Economics and Business at the University Pompeu Fabra in Barcelona, and other colleagues developed a smartphone app to track the activities and moods of more than 28,000 French-speaking people for an average of 27 days. At random times during the day, the app asked users to rate their current mood on a scale of 0 to 100 and indicate what they were doing at that moment from a list of options.

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Citizen science: Genetic bone disease fuels a teen’s passion for research

citizen science

When I was just 3 months old, I was diagnosed with fibular hemimelia, a rare genetic condition that affects about 1 in 50,000 people. It manifests itself as the lack of the fibula bone, a key structural bone in the lower leg that provides major stability in the ankle and knee.

Fibular hemimelia leads to a severe leg length discrepancy — which, in my case, would have amounted to over 6 inches without treatment. Prior to my time at Boston Children’s Hospital, the go-to cure was amputation — replacing my lower leg with a series of prostheses.

Luckily, at the time of my diagnosis, leg-lengthening surgeries were just being approved in the U.S. My parents couldn’t bear to part with my leg, so over the course of 18 years, I have undergone 13 procedures to combat my leg-length difference, starting at age 5. This early exposure to the medical field, coupled with encouragement from teachers, led to a passion for science.

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