[Music] [Music] [Music] [Music] [Applause] 30 years ago I was training to be a neuros surgeon and I met a patient named Janice who changed my life I was prepared and accustomed to fractured skulls gunshot wounds brain injury but none of that prepared me for what happened to Janice Janice was 11 months old and was crawling across the kitchen floor as her grandmother was cooking dinner she crawled under her grandmother's legs just as the woman turned to drain a pot of boiling pasta water into the sink she stumbled spilled the water on her granddaughter and Janice's
entire body was scalded she was my patient in the burn unit for a month where every day we changed her dressings gave her antibiotics did multiple skin graft surgeries and hope for the best that she wouldn't get sepsis and an infection and she did very well well for a month in fact at the end of which she actually celebrated her first birthday and the next day I remember standing in the doorway to her room at lunchtime watching her feed from a baby bottle and thinking it was almost a miracle that we were even thinking about
sending her home just then her eyes rolled back in her head and she went into shock I ran into the room cradled her on my left arm and started giving her mouth to mouth while the nurse called the cardiac arrest the code went on and on and on it seemed like an eternity but it was no use she was gone she had died in my arms it was the saddest thing and worse I had to talk to her family and I couldn't explain what happened she'd been doing great there was no bacteria in her bloodstream
there was no signs of infection there was no reason to think this would happen and the more I looked into the problem the more I realized that basic science lacked a fundamental understanding of why septic shock occurs so 30 years ago I decided to go in the lab and study that problem and my Laboratories have been pursuing that question ever since we started with a large team of people at Wild Cornell Medical Center and at Rockefeller University and what we found Chang the way the world thinks about how the body responds to infection we found
that it was not bacteria directly that caused shock but rather the immune system the immune system producing a molecule called tumor necrosis factor or tnf now tnf is made by white blood cells and macras and in small amounts it's good for you it's very beneficial but if tnf becomes overproduced it damages organs causes blood pressure to plummet and can cause lethal shock knowing this my colleagues and I were able to develop monoclonal anti-tnf antibodies and we gave these for the first time to baboons in septic shock these were big experiments and they would often go
till the wee hours of the morning and I can remember the first time we did this it was about midnight and there were five of us standing around watching astounded as a baboon recovered from septic shock because we had given it monoclonal anti tnf we within a relatively short period of time less than 10 years monoclonal anti tnf was approved for clinical use by the FDA and now millions of patients with rheumatoid arthritis have received benefit from monoclonal anti tnf as gratified as I was by that and as as as exciting as it was to
be part of that I found myself still thinking about Janice and what had happened why is tnf overproduced in some cases and not others so in my lab we studied tnf and tried to understand how the body controls tnf being made and down the hall in my neurosurgery Clinic I examin patients patients with diseases of the brain and spinal cord and I tested their reflexes I tapped their knees with a rubber Hammer I strok their corneas with a cotton gauze and I knew that reflexes are absolutely critical to maintaining healthy organ function and I knew
that disaster strikes when reflex reflexes fail when the brain swells and bends the brain stem and cuts off those brain stem reflexes patients can die from uncontrollable hypertension or apnea or Cardiac Arrest now neither myself nor anyone else connected reflexes to tnf at that time until an accident happened in my lab in the lab we were studying rats with a stroke and we were putting an experimental drug into the brains of those animals and when we did that as expected putting the drug in the brain of the animals blocked the tnf in the brain what
we didn't expect was that the tnf was also blocked in the heart and in the gut and in the liver and in the spleen this was baffling it made no sense because there were no known connections from the brain to control the tnf production in the immune system so my K and I searched for the answer to these connections and we searched for the neural connections that could explain how the brain could control the tnf response in the body and the search ended on a nerve called the Vagas nerve the Vegas nerve is one of
the most important nerves of the body it's like a transatlantic undersea cable that carries tens of thousands of individual wires to the all the organs of the body it wanders through the body and brings these n nerves to the organs and at the nerve endings those nerves control the activity of cells in the organs that keep them functioning in a healthy range what we realized from a long series of experiments was that the Vegas nerve was carrying the off switch the Vagas nerve was controlling tnf and we proved this in rats by electrically stimulating the
Vagas nerve and finding that it turned off tnf in the body we published that paper in nature because we realized we discovered a reflex that controlled the immune system we were incredibly excited and I remember soon after at lunch I wrote on the back of a napkin the idea to do this in patience and we would put a small stimulator on the Vegas nerve in the neck of patience and turn it on and the electrons in the stimulator Would S signals down the Vegas nerve that would turn tnf off in the body and I imagine
that this might be a way for patients to have a device using electrons to replace monoclonal anti-tnf so as excited as I was about this in order to do a clinical trial I needed much more I needed to understand mechanisms mechanisms are key to understanding how to develop drugs or devices and unless you can understand mechanisms you can't solve the problems so in the lab my colleagues and I spent many many years mapping in Exquisite molecular detail the mechanisms to explain how signals traveling in the Vegas nerve would control tnf and what we found is
that the signals were relayed to to the spleen and inside the spleen those signals are converted from electrical to chemical the chemical signals activated a white blood cell called a t- cell which also responded by making another chemical called acetylcholine the acetylcholine targeted the macras at the end of the line the macras making the tnf the acetyl choline turned them off so what we showed was that we could trace the electrical signals from the Vegas nerve in the neck all the way into the cells making the tnf and we learned how to turn it off
we were incredibly excited now to move this into the clinical tests and what we did was start a drug company called Uh set point and set point set about doing the clinical tests Seto recruited one of the leading rheumatologist in the world Paul Peter Tac to do a clinical trial of Vegas nerve stimulation in patients with rheumatoid arthritis patients came into the trial with very high levels of tnf they also had severe disability severe pain in their joints swelling inability to move neurosurgeons in the trial implanted Vegas nerve stimulators much like I showed you on
that cartoon of few minutes ago and turned them on and within days tnf levels started to fall and by day 42 in the trial tnf levels were nearly normal and more exciting yet the patients felt better their pain went went away their the swelling in their joints improved and their Mobility came back this has been much talked about in the press and one patient in particular talks about how some mornings before the trial she couldn't grasp a pencil she couldn't dress herself without assistance she couldn't take long walks something that she' really enjoyed but after
the trial she's off her medications her pain is gone she's taking long walks and she's riding her bicycle 20 mile round trips to the Dutch Coast on weekends it's fantastic now I get emails almost every day from patients who tell me they don't want to take their drugs they don't want the side effects they would rather have a device delivering electrons to replace drugs it's a big idea there are billions of neurons in the body that interact with almost every cell in the body and at each of those nerve endings molecular signos control molecular mechanisms
that can be defined and mapped and potentially put under control many of these mechanisms are also involved in important diseases like cancer Alzheimer's disease diabetes hypertension and shock it's very plausible that finding neural signals to control those mechanisms will hold promise for devices replacing some of today's medications for those diseases and creating new treatment options this is an idea that has gone beyond the patient stories and Beyond the basic research hundreds of millions of dollars of new research investment are pouring into this space from the NIH from DARPA from GSK and from other companies and
more is coming from government from Academia from private philanthropy and from other Industries it's an incredibly exciting time for this field of bioelectronic Medicine and let me tell you what we're doing about it we're building a new center a major new center for bioelectronic medicine at the Fein Institute in New York where we will like the drug companies have done for a 100 years begin with the molecular mechanisms begin with molecular me molecular medicine medicine in a time that molecular biology is teaching us tremendous new insights into mechanisms of disease we'll capitalize on those insights
but rather than screen for molecules to hit those targets we will screen for neural Pathways and neurotransmitters to control those targets and then build devices to modulate those nerves to therapeutic Advantage for the patients we're well down the path to this process and we're extremely optimistic the story about tnf and the Vegas nerve stimulator shows that this is feasible and we're only limited by our ability to do research and identify additional new neural circuits and additional new targets so I told you that I'm a neurosurgeon studying inflammation some of you in the room room know
that that's pretty unusual um and I told you why I'm studying tnf and inflammation but something else happened that I didn't tell you which is why I became a neurosurgeon in the first place when I was 5 years old we were living in Western Massachusetts is in a small town with my father and my brother and baby sister and my mother started getting headaches my father drove drove us all down to Yale where my mother's father my grandfather was a professor of Pediatrics within a few days my mother's life ended of a brain tumor at
Yale and I remember after the funeral talking to my father and my grandfather and saying what had happened and why and he began to teach me about the brain and he taught me about its complexities and he taught me about its importance in making us who and what we are so for as long as I can remember I wanted to be someone who understood the brain and invented things to help other kids with their moms so they wouldn't have to go through what I did I don't think you can prepare a lifelong journey I certainly
didn't plan mine but I do think that the combination for me of Neuroscience and molecular medicine has put put me in a unique position to think about to imagine using technology to replace drugs this is this is happening now this is not in some distant far off time and place it's happening today and I'm very optimistic that some of the diseases my grandfather used to study like whooping cough and polio which you can only find in the back rooms of libraries and forgotten books now that's what's going to happen to some of the diseases of
our future Society I believe strongly that there'll be a time when Janice and many others like her won't die because of breakthroughs in bioelectronic medicine thank you [Music] [Applause]
