Happy Monday, everyone!
It’s been a while since I’ve published anything on the website; life has been in transition over the last few months (in a good way), and now, I’m at the beginning of a new adventure: as the Director of Education and Outreach at the Feinstein Institute.
I’ve held a lot of different titles in thirty years: daughter, sister, wife, friend, student, teacher, shopkeeper, board secretary — I could go on and on — but the one that feels so intrinsically interwoven into my soul, into the core of my existence, is the title of storyteller.
Because of my generally lighthearted and giggly demeanor, it isn’t always obvious that I’m constantly observing what’s around me, taking it in, making connections, and seeking metaphors to life — but my personal favorite is examining the series of events that led to where we are, at this moment — and then dreaming of where we can go from here. What was the character’s ‘why’? Where was the plot twist? What conflicts stood in the way? How did the character reach the a-ha moment, and most importantly, where do we go from here?
I’m not a fan of endings — mostly because I don’t believe that anything is ever truly an ending, but instead, a continuation. Sometimes it looks like a fork in the road — two roads diverged in a wood, and I — I took the one less traveled by — and that has made all the difference. When Robert Frost wrote those words, I think he knew that either of the roads would have been worthwhile, yet sometimes, the road that’s chosen not only changes the course of our own life but that of so many others — and those are my favorite stories to tell.
As I begin this new chapter — walking down this new road — I’d like to begin by telling you the story that inspired me to choose this path. My favorite part of this story is that sometimes while we are on one road, seeking one outcome, we serendipitously stumble upon something we didn’t expect along the way — and in this story, it changed not only my personal life but will change the lives of millions of others.
It all started in 1985. Dr. Kevin J. Tracy began his research with a focus on sepsis, and years later, by a sequence of serendipitous events, he landed on the Vagus Nerve — and unlocked the answers to so much more.
The story begins with a little girl named Janice who changed the course of history through the legacy left by her short life and a doctor that adored her.
While Dr. Tracey was in the midst of his residency as a neurosurgeon, a patient named Janice turned his world upside down. She was just shy of only a year old when 75% of her body was scalded with hot pasta water; her grandmother was making dinner and Janice crawled under her legs just as the grandmother went to pour the boiling water into the sink.
Janice was in the burn unit for a month.
Just when things were starting to take a turn for the better, she celebrated her first birthday, and they were all preparing for Janice to go home – a miracle, given the month that this little girl had endured. Instead, one day, while being fed a bottle by a nurse with Dr. Tracey looking on, amazed that this little warrior was doing so well, her eyes rolled back in her head and she went into shock.
After having a team of doctors and nurses work on her for over an hour, she was gone.
Dr. Tracey couldn’t wrap his head around what had happened. She had no signs of infection or bacteria in her blood. Why, and how, could sepsis just spontaneously occur?
In the more than thirty years that followed, he and his team of researchers made major discoveries that ended up each being building blocks, leading from one thing to the next, until eventually, the search landed on the Vagus nerve.
In the year after losing Janice, Dr. Tracey went to work to uncover his ‘why.’ He began his research alongside Steven Lowry, Anthony Cerami, and Bruce Beutler. Across the street, Lloyd Old had recently discovered the cytokine that ended up being called TNF (tumor necrosis factor). Beutler began producing large amounts of TNF, which Dr. Tracey would transport across campus to his lab, and inject unsuspecting rodents (under anesthesia). There, he realized that it wasn’t bacteria that was certain to cause septic shock – it was large amounts of TNF.
Others questioned this – one prominent surgeon at the time asking why the immune system would create its own demise via TNF – but Dr. Tracey responded that it wasn’t the TNF itself, but the amount of TNF.
He then went on to create the antidote – an antibody called ‘monoclonal anti-TNF’ that he and his team developed in 1986. If you’ve ever been on Remicade, Enbrel, Humira, or the other TNF-inhibitors, those medications are the result of Dr. Tracey’s development of this antibody. People didn’t believe him back then that monoclonal anti-TNF would help patients with chronic inflammatory diseases – but it has. Millions have benefited, seeing their disease activity decrease, or completely get put into remission, due to this discovery.
In 1994, Ona Bloom joined Dr. Tracey’s lab and focused her research on macrophages, a white blood cell that is present during infection. She specifically wanted to see if macrophages (the white blood cells) produced a cytokine as a result of infection. A cytokine is a protein that is released by cells to communicate with or alter the behavior of other cells… cytokines are basically the messengers as well as the front-line soldiers.
Her search landed on HMGB-1. This confused both she and Dr. Tracey, because HMGB-1, while a protein, wasn’t considered a cytokine, but instead was a normal component of cells – specifically, it was thought to only play a role in DNA. At the time, though, Dr. Tracey and Bloom thought it couldn’t also be a messenger and soldier cytokine, they thought. Because at the time, HMGB-1 was not thought to play a role in the immune system’s function.
I like to think of HMGB-1 as the Jekyll and Hyde of the body. He (the HMGB-1, yes, is a ‘he’) is just walking around all innocently, acting like he’s just a normal component of a cell, just lending to DNA and all that jazz – but then something happens and he puts on a mask and overproduces inflammation, becoming his own evil twin.
Or, if you are a Matrix fan (I’m not, but I’ve painstakingly sat through it), it’s like when Agent Smith learns how to replicate himself – in this case, the body is Neo (Keanu Reeves), and Agent Smith is the HMGB-1.
The HMGB-1 discovery was put aside, but Dr. Tracey couldn’t shake the idea that maybe it was a cytokine. So, he and his team set out to prove a theory that it could be.
Then, Haichao Wang came into Dr. Tracey’s lab. Sooner or later, in collaboration with the Karolinska Institute, Dr. Tracey and his team witnessed that the evidence was stacking up to show that HMGB-1 was indeed a mediator of inflammation – proving that it had two roles, with a cytokine being one of them.
In fact, it turned out that HMGB-1 activated macrophages to release other pro-inflammatory cytokines, such as TNF. It appeared that HMGB-1 was the sergeant deploying his front-line platoon.
Wang then developed the anti-HMGB-1 antibody to use in situations where it was being overproduced.
In 1999, Huan Yang came along and joined the lab and discovered that when measured with a control group, mice injected with HMGB-1 developed a disease that aligned with that of severe sepsis.
When Yang gave mice with lethal peritonitis – an inflammation of the abdominal wall that can very quickly result in sepsis – the anti-HMGB-1 antibody, she discovered that 80% of the time, the mice resumed normal function.
This discovery proved that HMGB-1 plays a crucial role in both the development of severe sepsis in some patients, as well as a crucial factor in dying from it. Further, Dr. Tracey has stated that future treatments for septic shock and severe sepsis may differ from patient to patient – and antibodies that go after specific cytokines will be needed, for cytokines that we may not even know of yet. In the meantime, though, HMGB-1 has proven to play an important role in the inflammatory response for severe sepsis (as well as arthritis).
Importantly, it was also discovered that injury can cause HMGB-1 to leak from cells that are injured or dying – which means that Janice’s burn wounds could have leaked an overwhelming amount of HMGB-1 (and the pro-inflammatory cytokine troops, like TNF, IL-10, and others) into her already fragile system.
Right around the same time that Ona Bloom isolated HMGB-1, Marina Bianchi came along and joined Dr. Tracey’s lab. She was focused on trying to find a chemical to turn off excessive TNF production; specifically, she was exploring the ability of the molecule CNI-1493 to chemically turn off TNF. Dr. Tracey and his team developed the molecule CNI-1493; it is not a biologic, and has been shown to be more effective than biologics due to the fact that patients do not develop antibodies against it. (The drug name is now Semapimod and is not available for public use at this time.)
They found that the CNI-1493 did, indeed, work – so they spent the next five years exploring the possible uses of their molecule for its anti-inflammatory effects.
At the heart of disease lies inflammation. Dr. Tracey and his team knew this, so they used CNI-1493 for experiments on stroke, brain injury, sepsis, septic shock, arthritis, infection, and inflammatory bowel disease.
As expected, the CNI-1493 greatly improved all of the above.
And then an accident happened in the lab.
Dr. Tracey and the team were experimenting with the molecule used on rats that had experienced a stroke. Strokes occur due to a series of events that, for lack of a better phrase at this late hour, essentially makes shit hit the fan in the brain. This causes TNF to be released by the cells affected, which can result in more brain damage.
They decided to inject CNI-1493 directly into the brain of the rats to see if it was more effective than when injected into the bloodstream intravenously.
It turned out to be more effective, which they expected – but what they didn’t expect that TNF was diminished in the body as well. The rats were relieved – while Dr. Tracey and the team were astonished.
Where was the connection between the brain and the body that allowed the brain to effectively shut down cytokine production everywhere?
They sought to uncover the mechanism in action – think of the mechanisms in a car, the connections between the key ignition and the engine. When you turn the key in the ignition, mechanisms of action in the engine occur in order for the car to start. Dr. Tracey discovered that there must be a mechanism allowing the brain to communicate with the immune system in the body.
His search landed on the Vagus nerve, also known as the ‘wandering nerve’ because it is connected to all of the immune system’s organs. He theorized that if the Vagus nerve was electrically stimulated, it would communicate using neural pathways to shut off cytokine production between the brain and the immune system.
In Fatal Sequence, Dr. Tracey’s book detailing these discoveries, he refers to a 1981 quote by Robert Good:
“Immunologists are often asked whether the state of mind can influence the body’s defenses. Can positive attitude, a constructive frame of mind, grief, depression, or anxiety alter ability to resist infections, allergies, autoimmunities, or even cancer? Such questions leave me with a feeling of inadequacy because I know deep down that such influences exist, but I am unable to tell how they work, nor can I in any scientific way prescribe how to harness these influences, predict, or control them. Thus they cannot usually be addressed in scientific perspective.”
And then Dr. Tracey and his team came along – and found the scientific perspective by which to connect the mind to the body – and saved my life, and will save the lives of millions of others because of it.
In Fatal Sequence, Dr. Tracey says that Janice’s septic shock and severe sepsis likely were caused by the misfiring of neural pathways that normally would regulate the release of cytokines, but for Janice, and millions of others that suffer from cytokine-based diseases, the neural pathway was damaged – and allowed cytokines to run rampant. He says that the consequences of such are “like brake failure in a fully loaded truck rocketing down a twisting mountain road.”
At the end of Fatal Sequence, Dr. Tracey says of Janice, “I know that her immune system’s fatal sequence burned itself out in four weeks, but I do not like to think of it that way. I find it more reassuring to think that Janice, like an angel, lives on in the efforts to define and understand the nature of the individual cytokines involved in her septic shock and severe sepsis and the way in which her body fought to prevent their release. Her indirect legacy can be found right now in the scientific literature, online at PubMed under the keyword cytokine. I like to think of this work as an unfinished mural stretching for miles around a city or large university, being painted around the clock, every day, by students, scientists, and investigators who do not know each other and cannot see each other because the wall is too long. They may not even know what is being painted on the far side, but they are driven to paint it perfectly, and finish the job, motivated by their own angels. I am confident that someday, I hope soon, the work will be done, and this mural will be a guidepost for the weary patients and their families awaiting cures for cytokine-based diseases.”
The work that occurred over those thirty years was the birth of bioelectronic medicine. Each step and discovery was a building block that led from one thing to the next. These researchers’ discoveries occurred over decades, by small incremental steps of progress, that all led to uncovering the mystery of inflammation — and in turn, changed my life, and will change the lives of so many others.
There is still much work to be done that is currently underway at the Feinstein Institute (and other great research centers all over the world). At Feinstein’s Center for Bioelectronic Medicine, researchers and engineers are working every day to target molecular mechanisms to create new devices to treat diseases and decode neural pathways to restore movement to patients with paralysis. Dr. Theodore Zanos and his team are decoding the language of the Vagus nerve, and now, Dr. Valentin Pavlov is on a quest in his lab to understand the role of the Vagus nerve in sepsis. I can’t wait to tell you about the work that they are doing — and tell the stories of the work happening in the center’s other labs.
There is still much to do, but for what has been done already, I feel indebted – to Janice’s legacy, and to the road that Dr. Tracey took as a result of the love of a child, and the hope to live in a world where little girls like Janice not only recover but thrive.
As I begin down this new road of my own, my goal is to play the small part that I may in telling the story of the research (and researchers) who are rewriting the future of healthcare in order to advance research and expand access — and advocating for patients whose own stories will be rewritten because of this new era of bioelectronic medicine.
Buckle up, buttercups. It’s going to be quite the ride. 🙂