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This story is from the Anamnesis episode called Eureka and starts at 4:28 on the podcast. It's from , President and CEO of the Feinstein Institutes for Medical Research at Northwell Health in Long Island, New York.
Following is a transcript of his remarks:
Kevin Tracey, MD: I think there are a few patients in every physician's life that you never forget -- you never forget the patient, and you recall every little detail of the case -- and Janice is one of those patients for me.
When I was a neurosurgery resident at the New York Hospital in the 1980s, I took care of a little girl named Janice who had crawled under her grandmother's legs in the kitchen when her grandmother was cooking dinner, and the woman tripped over the baby and spilled a pot of boiling water onto her grandchild. Janice was my patient in the burn unit, and although she did very well for a couple of weeks, inexplicably she died in my arms of overwhelming shock a few days before we were planning to send her home, and her death from shock haunted me.
I remember when she came into the hospital, I remember how innocent she was because she had done nothing wrong. She was 11 months old and was playing in the kitchen.
I remember her face was cherubic and sweet and unburned. She was innocent at every level. And I remember like it was this morning when I had to tell her grandmother and her mother that she had gone. I remember the mother dropping in a faint onto the floor after screaming. I remember being unable to explain to anyone, my colleagues or friends or family, why she had died.
We looked for evidence of an infection. We looked for cardiac problems, and even at autopsy, the report came back negative. There was no clear reason why she'd suddenly gone into shock.
So I decided to begin studying this problem, and that was in July of 1985, and I've been basically working on the problem ever since.
Within a few years my colleagues and I at the New York Hospital and at Rockefeller University had discovered that TNF [tumor necrosis factor], a molecule made by the immune system, is the reason Janice had gone into shock and died.
The textbook said that what caused shock from an undetected infection might be endotoxin, bacterial endotoxin, and what we learned in the subsequent couple of years is that endotoxin doesn't kill directly. Endotoxin kills because it turns on the immune system to overproduce TNF and other molecules like that. From that fundamental knowledge, from Janice's death, came the idea to block TNF using monoclonal antibodies, which are now used by millions of patients.
Amy Ho, MD (host of Anamnesis): Janice was Dr. Tracey's "eureka" patient, where he realized there was something going on that needed discovery. And it led to a eureka discovery in the laboratory about TNF.
Tracey: It was a feeling of seeing the future where millions of patients would get a drug and alleviate their suffering. It was a feeling of joy. It was a feeling of privilege and honor to be standing in a laboratory, in an animal facility, late at night. It was about 1 or 2 o'clock in the morning by the time we realized that there were two animals side by side, and the first one was the control and was near death, and the second one was absolutely fine, with no evidence of shock or an inflammation.
Helping Millions
It was a feeling of happiness and joy. Because when you see a path from the laboratory, using a monoclonal antibody in this case, that you knew could be used in a human being, and you saw it work and in such a dramatic fashion, such that one animal's inflammation had killed it, and four feet away on the table next door was an animal that by all appearances was completely protected from inflammation, it was a feeling of elation. There we were, five or six of us, and we lit cigars. We talked for about an hour about how this would be one of those moments we would never forget, because the world would benefit from this success.
Ho: The discovery of TNF has led to blockbuster monoclonal antibody drugs for rheumatoid arthritis and other conditions that have benefited millions, just as Dr. Tracey and his collaborators foresaw in that eureka moment. But it hasn't been the answer to all inflammatory conditions, and it might not have been what would have saved Janice.
Tracey: The monoclonal antibodies that block cytokines are very good at treating chronic diseases that help about half of the patients who have these chronic auto-inflammatory or autoimmune diseases. But the treatment of acute shock is still very problematic, because when cytokines cause acute septic shock or acute ischemia-reperfusion injury it happens very quickly. And so by the time shock has occurred and organ damage has occurred, the animals are out of the barn and coming in with the drugs at that point is often too late. We see this now with COVID, where once patients pass the point of being critically ill from cytokine storm activation and from molecules like TNF and other inflammatory molecules, once the patients are so sick that they're in shock like Janice was, it's often too late to interrupt the cascade with these kinds of drugs.
How Discoveries Lead to More Discoveries
Ho: But like most eureka moments, this one stood on the shoulders of other discoveries and provided the foundation for further discoveries. Tracey's journey [of discovery] is still underway.
Tracey: Twice in my life, experiments in the lab opened my eyes to the possibility of therapies for people that would potentially change the lives of millions of people. The first time was when we gave monoclonal anti-TNF antibodies to baboons with overwhelming inflammation and we saw them recover. We realized that the use of monoclonal antibodies blocking TNF could change the lives of people with inflammation, as it has since done for patients with rheumatoid arthritis or inflammatory bowel disease. The second time that happened was working in the laboratory and applying an electronic nerve stimulator to the vagus nerve of a rat and seeing that the neurological signals in the vagus nerve turned off TNF production in the rat.
My colleagues and I realized almost immediately that it should be possible to develop vagus nerve stimulators to treat patients with rheumatoid arthritis and inflammatory bowel disease, as has been done since, and potentially affect the lives of those patients using an electronic device instead of drugs.
What never changes for me, and a constant in my life, is a laboratory environment where you can ask questions about basic disease mechanisms and test them in experiments, get the answers to those questions and experiments, and then imagine and enable people, and mechanisms, and processes, to move those ideas from the laboratory into clinical testing.
It's a continuous process for my colleagues and I, to worry about the problem in the beginning, offer a solution based on animal results and laboratory results, and then either start the company to test the idea in the clinic or work with companies whose mission it is to do the clinical testing in the clinic, because we want to know the answer to the question, "Does it work?"
This Is What Keeps Me Going
That's what drives my colleagues and I every day, is trying to produce knowledge to cure disease. Not knowledge for the sake of knowledge, but knowledge that we can understand at the level of molecular mechanisms in the laboratory, we can test in preclinical laboratory studies in animals, and then test again in human clinical studies.
Every step is fascinating. Every step requires different levels of expertise and different types of professionals with different types of professional backgrounds, and every step is exciting.
When you see something like a vagus nerve stimulator or monoclonal anti-TNF go all the way through the process from an experiment in your own laboratory, all the way through into clinical testing and into clinical availability and success, it's the best feeling in the world. It's the best career path anyone could have. I feel like the luckiest man in the world being able to work in this space.
Check out other stories from the Eureka episode including "Screaming Patient, No Restraints" and "Diagnosing the Mind of a Special Patient"
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