Corinna Kadis flips through the family album. She smiles, just like in the photo. Exhausted but proud, the Cologne native cradles her first child in her arms—Fenja. Shortly before Christmas 2015, the family of three is finally complete. A few pages later: Fenja in the hospital. Her skin has a yellow tint. The baby is seriously ill. When Fenja is six weeks old, her parents hold her tiny hands and accompany their baby through the brightly lit tunnel of beds to the operating center.
300 kilometers away in Ludwigsburg, Laura Wiedmann also has such a photo book. Fenja and Laura’s son Matt are two of only about 65 children born with biliary atresia each year in Germany. “The bile ducts are underdeveloped. Bile can’t drain from the liver. Without treatment, this quickly leads to liver cirrhosis and eventually organ failure,” explains Dr. Leonie Schumm. As a clinician scientist at Charité Berlin, she researches this rare disease. The Alliance4Rare initiative of the Eva Luise and Horst Köhler Foundation supports young scientific talents like the 32-year-old and creates opportunities for intensive research despite a busy clinical routine.
Top cause for pediatric liver transplants
Prof. Dr. Philip Bufler, director of the Department of Pediatrics specializing in Gastroenterology, Nephrology and Metabolic Medicine at Charité, and Dr. Milad Rezvani brought Leonie Schumm back to Berlin from Zurich for the research project. Milad Rezvani is a pediatrician, liver specialist, and head of the only Emmy Noether Junior Research Group funded by the German Research Foundation (DFG) focused on pediatric liver diseases. For the Alliance4Rare project, he has built a consortium of international experts. Since his studies, the 40-year-old has focused on children’s liver diseases—especially biliary atresia, the leading cause of pediatric liver transplants.
Surgery is only successful long-term in 40-50%
The approach of this research project is ambitious: it aims to pave the way for antibody therapy against biliary atresia. Because there are currently no drugs available. For babies with this diagnosis, the first step is usually directly to surgery. The operation meant to help Fenja and Matt is called hepatoportoenterostomy, or the “Kasai procedure”—named after Japanese pediatric surgeon Morio Kasai, who performed it for the first time in the 1950s. Leonie Schumm knows this procedure well: “It’s essentially a surgical trick: a loop of small intestine is sewn directly onto the liver. It replaces the blocked bile ducts and channels the bile into the intestine. This is vital for these small patients, as it’s the only way to restore bile flow.”
After the operation, Fenja’s family album shows a return to normal: trips to the beach, a little brother, starting school, and horse pictures replace the hospital photos. For Matt, this is not yet the case. Just three weeks after the Kasai, it’s clear: the trick didn’t work. At four months old, he needs a liver transplant. “Unfortunately, the Kasai procedure is only successful in the long term for 40-50 percent,” explains Milad Rezvani.
Searching for the difference
Milad Rezvani and Leonie Schumm are specifically investigating what makes the outcome of this procedure so different between Fenja and Matt. Their key question: Why do some children with biliary atresia need a transplant after Kasai surgery and others don’t? “Data suggest that biliary atresia starts even before birth, and chronic inflammation is involved. We want to find out which immune cells are part of this process. If we understand that, we can develop new medications,” says Leonie Schumm. The researchers believe that the key is in the liver. The team is building a biobank and analyzing tissue samples from two groups: the Fenjas, who remain stable after Kasai, and the Matts, who need a transplant.
Like Google Earth for organs
The liver samples are no bigger than a fingertip—at most. “You really have to take care of them,” says Leonie Schumm. The tiny samples, taken from children during the Kasai surgery or a biopsy, are prepared for further analysis. Using a microtome, an extremely precise and sharp blade, she cuts the tissue into fine slices. Five micrometers thick—that’s 0.005 millimeters, ten times thinner than a hair. “We stain these with fluorescent antibodies and look at them under the microscope.” Her microscope is nothing like the one from high school biology classes. Instead of an eyepiece and focus knob, it’s a highly modern, computer-assisted system that shows the enlarged tissue samples on a screen. “We look at the liver and keep zooming in,” she explains. Kind of like Google Earth. “First to the tissue level, then the cellular level, then even deeper—to the molecular level.”
Leonie Schumm and Milad Rezvani work with Prof. Dr. Christian Conrad’s laboratory at the Berlin Institute of Health at Charité. There, biologist Dr. Robert Lorenz Chua—also funded by Alliance4Rare for two years—quantifies the RNA molecules in every single cell, allowing him to see if “healthy” or “sick” cell programs are running. “Like on a map, we can show where the sick cells cluster in the tissue,” says Milad Rezvani. The innovative part: “Our research goes beyond simply describing cell changes. We’re looking at how diseased tissue actually behaves and functions. That gives us clues about disease mechanisms.” This is made possible by so-called “functional avatars.” It sounds a bit like science fiction: in the lab, the team grows “organoids”—tiny, organ-like structures—from tissue samples in a test tube. Each is derived individually from the patient. “We found that organoids from biliary atresia patients form bile ducts much less effectively than those from the control group,” says Milad Rezvani. “Then we can see what happens when we add immune cells,” adds Leonie Schumm. One day, this might allow them to test new drugs.
The hope: medication instead of transplants
Some organoids even represent embryonic and fetal developmental stages. “That’s important because we’re pretty sure that biliary atresia usually develops during the phase when the liver and immune system are forming.” The research project has a year and a half left to run. Leonie Schumm and Milad Rezvani are confident that by then, they’ll be able to say which liver target molecules future therapies should focus on. “Maybe even how we can make it so children no longer need transplants.”
Matt will soon turn seven. At the end of summer, his album will get a picture of his first day at school. He recovered well from his transplant. His mother Laura was able to donate a piece of her own liver. Organ transplants are a remarkable achievement of modern medicine that save lives. But the goal of biliary atresia research is to avoid these major interventions after which children must take medication for life.
Nine years after her Kasai surgery, Fenja is a happy third-grader who—much to her mother’s surprise—loves math. Sometimes, Corinna Kadis is overwhelmed by thoughts: Why did it have to be my daughter? How long will Fenja stay healthy? Will she need a liver transplant after all? Milad Rezvani, Leonie Schumm and their team are hopeful they’ll soon find the answers to some of these questions in their lab.
You can find this article and much more about our commitment to rare diseases in the Annual Report of the Eva Luise and Horst Köhler Foundation.
