Boston Children’s Hospital has a storied history of breakthrough research. It’s where Sidney Farber discovered that drugs could treat cancer, where Nobel laureate John Enders made critical advances in the development of the polio vaccine, and where pediatrician T. Berry Brazelton delivered parenting advice for decades and introduced his famed Touchpoints program. Boston Children’s routinely draws more research funding from the National Institutes of Health than any other pediatric hospital — and most adult hospitals. It has a million square feet of research space spread across its buildings, much of it dedicated to specific ailments. But it also has sweeping research programs crossing disciplines — by October 1, it will have sequenced the genes of 1,000 patients with rare or unexplained diseases, and those of their parents. The sequencing program, a pilot, aims to deepen understanding of these diseases, in hopes of finding new treatments.
What follows are five more potential leaps forward out of the hospital’s labs.
1. Reconnecting ACL tears
The most dreaded injury in sports has been treated the same way for decades. When people suffer a torn anterior cruciate ligament, the knee is reconstructed using one or two ligaments from elsewhere in the leg, followed by six to nine months of rehabilitation. Of the roughly 100,000 people who undergo ACL reconstruction each year, most — teenagers included — will start experiencing arthritis in the repaired knee after 15 to 20 years.
Dr. Martha Murray became an orthopedic surgeon in part because she wanted to find a better approach. The obvious fix is stitching the ACL back together, but when that has been done, it tears again more than half the time. Murray wondered if there was a way to keep those tears from happening.
After 20 years of work, she’s developed a new technique called bridge-enhanced ACL repair. Instead of relocating a tendon, she places an implant between the torn ends of the ligament, infuses that implant with the patient’s blood, and stabilizes the repair with stitches. This combination provides a bridge that should stay in place long enough to let the ACL heal.
Preliminary research on animals suggests Murray’s scaffolding will help people with ACL tears avoid arthritis. Later this fall, Murray will get results from a clinical trial she ran comparing 65 people treated with her approach with 35 who got conventional ACL reconstruction. She’s cofounded Miach Orthopaedics to produce the implant, should the current trial lead to federal approval. If it does, that could mean bringing the implant to market by the end of 2020.
2. Blazing a trail to better vaccines
Our immune system is rarely more challenged than just after birth. Millions of newborns die worldwide from infections, for reasons we don’t fully understand. Dr. Ofer Levy is creating models of the newborn immune system to probe the source of its weaknesses.
Levy, who directs the precision vaccines program at Boston Children’s, and his colleagues build simulated human immune systems in lab dishes, then test potential vaccine candidates on them. One target is the respiratory syncytial virus (RSV), the number one cause of hospitalizations for babies in the US.
He also wants to develop new vaccines that are more effective and easier to administer, even ones that can be personalized by age group, sex, or geography. The 30-member team of doctors and scientists has been studying the impact of the bacille Calmette-Guérin (BCG) vaccine, given mostly to newborns in the developing world to prevent tuberculosis. Versions of the vaccine appear to work differently in different places. In studies in West Africa, the BCG vaccine seemed to strengthen a baby’s overall immune system — infants vaccinated at birth were 50 percent less likely to die of any cause in the first month of life than ones who didn’t get it. It’s a mystery why this happens in just one part of the world. Levy and his colleagues hope that if they can unravel the clues, it will lead to more targeted vaccines.
The group also is working to reduce the number of doses required for existing vaccines, and understand why some vaccines are less effective in babies and the elderly. Levy also is collaborating with his wife, Dr. Sharon Levy, who directs the adolescent substance use and addiction program at Boston Children’s, and Dr. David Dowling, a vaccinologist in his lab, as part of a new effort looking at a vaccine for opioid users (for more on their research, click here). Their goal is to prevent fentanyl — a synthetic opioid that’s been blamed for most of the opioid-related deaths — from entering the brain, in turn preventing overdoses in youths who’ve become addicted to opioids.
3. Identifying the genetics behind seizures
When Dr. Annapurna Poduri finished her training in pediatric epilepsy 15 years ago, there were only a few genes known to be related to its trademark seizures. Since then, medical researchers have discovered hundreds of genes connected to the condition. But the most effective way to stop seizures in some types of epilepsy remains unchanged: Surgically removing the chunk of the brain where the seizures begin.
Zebrafish — yes, those staples of home aquariums — are helping to provide the answers Poduri seeks. As director of the epilepsy genetics program at Children’s, her lab includes banks of zebrafish. The same easy-to-modify genes that allow them to be turned electric green or cosmic blue make them good models for studying genetic diseases. Plus, they are genetically similar to humans, so Poduri can use the fish to see how specific genes relate to epileptic seizures. Zebrafish also help her study potential medications, since those can be added to the water the fish swim in.
Even with the zebrafish, Poduri has many questions to answer before developing new kinds of alternatives to brain surgery. It remains a challenge to pinpoint the genes that cause a particular child’s seizures. The standard blood or spit tests used to identify genes (or genetic sequences) might not accurately pick out the genes underlying someone’s epilepsy, because some genetic mutations arise in the womb, creating a mosaic of brain cells with genes slightly different from most brain cells and cells in the rest of the body. Right now, the only guaranteed way to find the genes is to analyze brain tissue taken during the brain surgery to stem seizures. Eventually, Poduri hopes to identify the genes using DNA from spinal fluid instead.
4. Boosting the immune system to fight cancer
Immune therapies leverage our own immune systems to fight cancer, offering the potential for lifelong remission from the disease, often with fewer side effects than chemotherapy or radiation. Though developed for cancer in adults, which can differ from childhood versions, immunotherapy has also provided nearly miraculous results in some children with blood cancers. It has, however, been a disappointment for most solid tumors in children. Dr. Natalie Collins, a pediatric hematologist-oncologist, and her Boston Children’s colleagues are working to change that, hoping to build on the tradition established decades ago by Sidney Farber.
It’s tricky to research childhood cancers — they occur relatively rarely, accounting for less than 1 percent of cancers. This makes it hard for researchers to find enough patients to do things such as run clinical trials to test new therapies. Collins says being at Boston Children’s helps, because the hospital draws more cancer patients than she’d have at most other places, giving her a better shot at making progress.
Collins uses genetic sequencing and other techniques to help her better understand how patients’ immune systems respond to cancer. One aim, she says, is to predict patient responses, to avoid wasting precious time on treatments that won’t help.
Although it will still be a long time before pediatric cancers can routinely be cured with immune therapies, Collins draws inspiration from the few success stories she’s seen so far. “Those patients make you want to keep going,” she says.
5. Working to solve sickle cell anemia
Manny Johnson Jr. needed a change. The 21-year-old had been born with sickle cell anemia, a genetic mutation that causes red blood cells to become rigid and pointy. That shape makes them prone to clotting, which can cause intense pain, as well as organ failure and other serious problems — Johnson had a stroke at age 4. After that, he went every month to get a blood transfusion, which kept the disease at bay, but took hours to complete. And at some point, the transfusions would no longer be effective.
So when doctors at Boston Children’s wanted a volunteer to test an experimental gene therapy, Johnson was game, even though the doctors would need to kill his damaged red blood cells using chemotherapy. They’d then replace them with versions of his own red blood cells they’d genetically modified. If it worked, he wouldn’t need transfusions anymore. And it could help others with sickle cell, including his 7-year-old brother, Aiden.
Researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center knew that some children with the sickle cell gene mutation didn’t get sick. Those kids had a second mutation that meant their bodies kept making fetal hemoglobin, a protein that usually disappears by age 1. The researchers, led by Dr. David Williams, chief scientific officer at Boston Children’s and a pediatric hematologist, thought advances in gene editing would make it possible for them to alter genes so fetal hemoglobin could be produced after age 1. That would be easier than correcting the sickle cell mutation itself.
Johnson was the first patient in a clinical trial for the new gene therapy. In the spring of 2018, he spent a month at Boston Children’s as his red blood cells were destroyed and rebuilt. He hasn’t needed any treatments for sickle cell since. Two more young adults with sickle cell have since been treated at Dana-Farber/Boston Children’s with equally powerful results. Next up: One teenager with the disease, and then — if all goes well — two younger children.
There are also other gene therapy trials underway, at Boston Children’s and elsewhere, and a variety of experimental therapies, including one that aims to trigger fetal hemoglobin production using just a pill. All the activity has created new hope within the sickle cell community — the disease affects 100,000 Americans and millions more worldwide, but until 2017 hadn’t had a new treatment approved since the 1990s. “That’s why the community is excited,” Williams says, “because it’s been so long coming.”