The project got off to a slow start. The funds were delayed, and all three engineers had rocket science “day jobs” to work around.



They began with a schematic on how their device works. A person blows into a tube and breath gases are collected in a pressure-regulated cylinder that directs a controlled gas stream across a mid-infrared laser beam. When the beam hits ammonia, the molecules absorb specific wavelengths of light. A photodetector measures the amount of light that passes through the ammonia, then custom software calculates quantities of ammonia and plots it on an easy-to-read graph on a laptop computer. The device also measures carbon dioxide as a way of telling the software that one breath cycle is complete and another one is beginning.



The first prototype used a clear quartz tube for the gas cylinder, which Miller purchased for $50 on eBay from an equipment salvager in Austin, Texas. The breathing tube was attached to one end of the cylinder. Flow meters, pumps and valves were attached to the other end, all scavenged from the rocket lab. These would direct the gas stream across the laser beam. Optical mirrors directed the laser beam onto the photodetector. Initially, the prototype was built on an 8- by 4-foot table with a Rube Goldberg array of gas-handling tubes, pumps and pressure gauges sprawled above and below. The team began to make its first measurements of breath ammonia, and during the first trial runs realized why no one had ever successfully developed an ammonia breath analyzer.



“Ammonia is a nightmare to work with,” says Spearrin.



Because the molecules are highly soluble in water and have an unstable electrical charge, they tend to stick to everything, including the inside of the human mouth and the walls of plastic tubing. So they switched to nonstick Teflon tubing. Temperature fluctuations distorted ammonia measurements, so an on-board heater and insulation had to be added to the device.



Finally, after six months of tweaking, the team brought its second-generation prototype into a quarterly grant-review meeting. The prototype was packed inside a custom box, which was placed on a wheeled cart. Beneath were a data acquisition system and various measurement instruments, all of which would be miniaturized into a more compact format in a commercial product.



A volunteer from the meeting blew into the tube, and a graph of the levels of ammonia and carbon dioxide in that given breath appeared on the computer screen.



Enns’ first impression of the rapid, easy-to-use device was “jaw-dropping amazement.”



We have liftoff



With the help of Enns, the engineers received Institutional Review Board permission to test their ammonia breath analyzer on human subjects, specifically two 16-year-old boys admitted to the hospital for hyperammonemia. These teens were representative of their target patient population — they were cognitively and physically impaired from ammonia surges. One used a wheelchair. Both spoke slowly, in broken sentences.



It brought home the importance of why the team was working on the breath analyzer project.



Their plan was to have the teens blow into the device’s breathing tube after each of their blood draws over the two or three days it would take to normalize their ammonia levels. But they soon realized that it was difficult to explain to the teens how hard to blow.



Finally, Strand figured out a strategy that worked. He gave the boy the tube and said, “Pretend that this is your elephant nose and make a sound like an elephant.”



This insight prompted the team to redesign the software to provide visual feedback that showed patients when they were blowing hard enough. They also started designing a passive, under-nose breathing tube that could be used without active blowing, which will be necessary for some patients but requires more sensitive detection.



Patient testing also refined their thinking on the technological advantage their device brings to the field. The major weakness of the ammonia blood test is that by the time the results are received by a treating physician, it is hour-old information that may not represent the true ammonia levels of a patient. The breath analyzer enables super-fast, repeatable testing so ammonia levels can be verified and treatment can begin immediately.



“Babies breathe so fast that it’s hard to get an accurate ammonia reading using a device with a slow response time,” says Spearrin. “What our device is really good at is rapidly measuring intra-breath dynamics, showing how the chemical composition of a breath changes over time.”



In just a year, the team had gone from a rough idea on paper to a working prototype, patient-tested. This is warp speed in the medical device world. They are also preparing articles for publication describing the underlying spectroscopy, the device and, ultimately, their clinical studies.



Spearrin didn’t realize how hard this project was supposed to be until he called a respected expert on hyperammonemia for advice. Before Spearrin could ask his questions, the expert said, “You’ve chosen a horribly challenging project because ammonia is the most difficult molecule to measure and newborns are the most difficult patient population to work with.”



Spearrin replied, “But we’ve already built a working proto­type and we’ve tested it on two patients.”



In the fall of 2015, the team is planning a second, larger patient trial that will involve younger children. There’s a good chance Ethan will be in that trial. Since they finished their first prototype, they’ve received grants from the NIH’s Small Business Technology Transfer program and the Wallace H. Coulter Foundation. The Stanford Office of Technology and Licensing has filed a provisional patent, and the team has formed a company, Lumina Labs. The company, funded by the NIH small business grant, has established a research consortium with Enns and Stanford.



“What impressed me about this development team is that they really listened to all the advisers’ technical concerns, methodically addressing each one. And they did so while still getting a prototype into testing amazingly quickly,” says Solomon.



Waiting to exhale



Five years after his birth, Ethan Pham, with chubby cheeks and bear-cub ears, looks and acts like a typical kindergartener. His mother — a halo of dark hair framing her ivory face — plays with him as he sits in his hospital bed, happily singing with cartoon farm animals on TV. On the bed tray is a sheet of paper where he has practiced writing his name with crayons.



Ethan is recovering from a surgical procedure to insert a tube through his chest into an artery of his heart. This permanent IV port will make it easier for the care team to quickly administer ammonia-grabbing drugs when needed. In the past, a nurse would have done this by inserting a syringe into an arm blood vessel, but with so many pokes over the years, it became hard to find an undamaged, free-flowing vein. He’s also under observation for high, unexplained fluctuations of ammonia.



It takes a dedicated team to keep Ethan alive. His family, schoolteachers and medical practitioners are continually on the lookout for signs of high ammonia levels. Episodes can happen at any time. Each incident means a 30-minute drive to the critical care unit, where staff members stand ready to draw blood. Ethan’s medical team — his pediatrician, Rebecca Fazilat, MD, at Sutter Health San Jose; Enns; and the hospital staff at Stanford Children’s Health — is on call 24/7.



Many times the ammonia blood tests, which can be done only at the hospital, are wrong or ambiguous. If the test is positive, it typically takes a day or two in the hospital to normalize the ammonia levels, with repeated blood tests every few hours. Sometimes the family is halfway home when a nurse calls them back to redo a test. Ethan has spent about half of his kindergarten year in the hospital.



Ethan’s teachers have been trained to accommodate his condition. His work areas must be extra clean and sick kids need to be kept away. His diet is carefully monitored — no birthday cake, since he can’t digest it. Ethan doesn’t have the muscle strength to climb on the playground equipment, so he often sits on the side, playing with his plastic farm animals or trying to kiss Catherine, a girl in his class he really likes.



Nguyen and Pham, like most parents who have children with metabolic defects, are perpetually fatigued. When Ethan is in the hospital, Nguyen stays by his side and her husband joins her after work. They often eat dinner at the hospital cafeteria. Nguyen’s parents and sister live close by, and they help out when they can. For Nguyen, it’s a full-time job keeping Ethan from slipping into an ammonia-induced coma.



What keeps them going is their faith (Nguyen is a Catholic and Pham is a Buddhist) and the hope that someone, maybe even the rocket men, will find a better way to test ammonia levels in children with metabolic diseases at the hospital and at home. This would allow Ethan, with his enduring strength, and his family to live a more normal life.



Blue-sky thinking



It’s worth looking at the breath analyzer project and asking, what can fuel more of these big ideas in medicine?



Spearrin recently summed up what motivated his team: “For us, it’s not that ammonia sensing is the perfect challenge. It’s that the breath analysis field is underdeveloped. We’re leaders in this particular gas-analysis technology, and there are clinical researchers here at Stanford really open to collaborating with us. It gives us a chance to make a significant contribution through cross-disciplinary efforts.”



What worked was to empower an ambitious team of young engineers to look at an old medical problem with fresh eyes. They were given starter funds to try out their big ideas without fear of failure. There was institutional buy-in, making it acceptable for people outside of the medical system to observe, ask questions and change the way things have been done in the past. And they were given access to mentors who could inspire them, help remove bureaucratic roadblocks and keep them from making big mistakes.



Strand adds, “Being in a clinic and working with kids gave me a unique sense of purpose that I haven’t felt in my research before. I’ve had the good fortune of getting to be part of a lot of exciting and challenging research, but never where the need is so tangible, urgent and, most certainly, so personal. It makes a difference if this problem is solved today instead of tomorrow.”



Of course, anyone familiar with medical device development would be quick to add that there’s a tremendous amount of work to be done before the ammonia breath analyzer is widely available. There need to be more prototypes. Clinical trials. Independent validations. But one thing we all can probably agree on is this: Medicine needs more rocket scientists.