How the touch of a baby girl led to life-saving technology

In the middle of an October night six years ago, a nine-month-old girl reached out and lightly touched the hand of her doctor. In that moment a bond was formed between doctor and patient. For Dr. John Kheir, a first year fellow in pediatric critical care at Boston Children’s Hospital, it was a moment that would influence the course of his life. The infant was suffering from pneumonia, her breath labored and heavy as she was admitted to the top-ranked hospital. Minutes later a code blue was announced. The team rushed in to a gruesome sight: the baby lay lifeless on the bed, her face covered in blood. The blood, John knew, had come from her hemorrhaging lungs.

The team carried out what John would describe as ‘a well run code.’ They immediately placed a breathing tube, began CPR, administered drugs. The team realized that the baby had low oxygen saturation, that her red blood cells were simply not carrying enough oxygen. They placed her on a heart-lung bypass machine. Just as it sounds, this machine takes over the function of the heart and lungs, pumping oxygen into the body. The problem was that it couldn’t get the oxygen her body desperately needed fast enough. That little girl would never have another chance; she would die three days later.

As so many physicians do, John stayed up late that night thinking about what had gone wrong and what he could have done differently. The procedures had been done perfectly; the team was coordinated and efficient. The hospital was one of the best in the country. The problem was the technology. There was simply no way to get oxygen to the patient fast enough.

Many medical fellows pursue research projects that lack originality.  Some complete retrospective research projects – looking back at how patients were treated and what outcomes they had.  Others complete prospective projects – a clinical trial, for example, of a defined therapy that may or may not benefit patients. For John, a fellow early in his training, his path would be quite different.

While most fellows would have only pondered the possibilities of an independent, translational research project, John acted on it. The idea of injecting oxygen into a patient who can’t breathe isn’t new. In the 1900s, doctors experimented with injecting oxygen directly into the blood stream. The oxygen gas aggregated together, forming air bubbles. This caused a pulmonary embolism, a dangerous condition where an artery in the lung is blocked off from circulation. An embolism can be fatal. John dreamed of the perfect solution to this problem; a new type of micro-particle, a lipid shell surrounding a core of pure oxygen. This dream was based on micro-particles already in existence, lipid encapsulated particles that deliver drugs for chemotherapy, heart disease, and diabetes, some of which are used clinically.

So while John knew that the technology existed, he didn’t know how research worked. He knew he needed collaborators. He emailed several people who were already working in related fields, hoping to find that one person out there willing to take a risk on his idea. One of those emails worked. Dr. Mark Borden at U.C. Davis, a chemical engineer, also early in his career, agreed to get on board. Borden believed in the project so much that he worked on it his spare time. Together, they devised a tiny micro-bubble, 20 times thinner than a human hair, containing pure oxygen. This micro-bubble could be rapidly injected into a patient whose lungs had stopped working, keeping the needed oxygen in their blood.

John’s dreams didn’t come to fruition until he contacted Dr. Frank McGowan. McGowan was a busy, senior scientist, yet he was astounded at the unique nature of the project. They submitted their first grant together. That early funding, only $10k, didn’t last long. John was suddenly thrown into the world of research. The project struggled as John grappled with learning the basics of conducting research and developing an entirely new set of methods to make the bubbles, and his animal model, work.  He decided to shoot for the moon.  He started an in vivo proof of concept study. This meant that he would inject the micro-bubbles he made in the lab directly into rabbits that were asphyxiated. His experience as a physician shaped his motivation to test the clinical feasibility of the concept.  He explains this motivation, as he “didn’t want to waste a lot of time if it wasn’t going to work in the end.”

Armed with a new grant, John began his experiments in rabbits. The rabbits were anesthetized and ventilated in 11% oxygen, inducing hypoxia. This is where the level of oxygen doesn’t match the need of the body, similar to a patient whose lungs are no longer able to pump oxygen back into the bloodstream. John, ever hopeful, injected 15 rabbits with the micro-bubbles that contained oxygen. The rabbits died instantly.  It was a terrible moment. John knew that he would have to go back through every detail of the study. And it wasn’t as if he didn’t have anything else to do. In addition to fabricating the micro-bubbles and running the animal experiments, he still had his clinical duties. It was a balance that very few physicians are capable of.

It was on the eve of the next animal trial that he learned that someone had called in sick. He would have to be on back-up call as chief fellow. It was horrible timing; he also had to make micro-bubbles for the experiment that next day. As he ran back and forth between the ICU and the lab he couldn’t help but think, “Is this total insanity?” As it would turn out, that next day, John would finally have a taste of success. The first animal that survived was from micro-bubbles he made while exhausted, running around the hospital all night. John believes that his “naiveté is important,’ that it’s part of what made the research work. Because he didn’t know what he was getting into, he plunged headfirst into a risky adventure. Published in Science Translational Medicine this past July, he’s now injected 18 rabbits, all of which have survived. He’s able to keep these rabbits alive for 15-20 minutes under conditions that should kill them. The hope is that these micro-bubbles could one day be injected into patients whose lungs stop working in emergency conditions, such as a nine-month-old girl with pneumonia in the pediatric ICU.

John is now looking at the big picture of this research. He’s working on improving the micro-bubbles, removing all impurities. The group is doing pre-clinical testing to ensure the procedure is safe. John hopes the micro-bubbles will enter clinical trials in the near future. John is now junior faculty at Children’s. One day, when his micro-bubbles are injected into a patient, he will call the parents of that nine-month old girl he met six years ago. A girl whose name he will never forget, whose memory lives on in miniscule oxygen bubbles, destined to save countless lives.

Hear John talk about his research in his own words here