This is the second of an eight-part patient advocacy manifesto, I Dissent.

Buzz Aldrin on the moon on 20 July 1969. Photograph: Neil Armstrong/Nasa/EPA'

“No man can fully grasp how far and how fast we have come, but condense, if you will, the 50,000 years of man’s recorded history in a time span of but a half-century. Stated in these terms, we know very little about the first 40 years, except at the end of them advanced man had learned to use the skins of animals to cover them. Then about 10 years ago, under this standard, man emerged from his caves to construct other kinds of shelter. Only five years ago man learned to write and use a cart with wheels. Christianity began less than two years ago. The printing press came this year, and then less than two months ago, during this whole 50-year span of human history, the steam engine provided a new source of power.

Newton explored the meaning of gravity. Last month electric lights and telephones and automobiles and airplanes became available. Only last week did we develop penicillin and television and nuclear power, and now if America's new spacecraft succeeds in reaching Venus, we will have literally reached the stars before midnight tonight…

If this capsule history of our progress teaches us anything, it is that man, in his quest for knowledge and progress, is determined and cannot be deterred.” ~ JFK

THE INFLAMMATORY REFLEX

While using devices to treat different conditions like arrhythmias and epilepsy has been in vogue for a while now – with the first pacemaker making its debut in 1958, and the first vagus nerve implant for epilepsy approved for epilepsy in 1997, it was Dr. Tracey’s discovery of the inflammatory reflex and the molecular basis of using nerves to treat inflammation that structured the field of bioelectronic medicine into the trifecta of neuroscience, molecular medicine, and bioengineering.

While training to be a neurosurgeon in 1985, Dr. Kevin Tracey was treating a patient in the burn unit – an infant named Janice. Janice’s grandmother was boiling a pot of water for pasta and when she went to drain it in the sink, she tripped over Janice, not realizing she was underfoot. The boiling water scalded most of Janice’s tiny body. Over the course of the next month, she was treated with antibiotics and multiple skin graft surgeries. Right before her first birthday, they were preparing to send her home: a miracle considering what she had been through. As Dr. Tracey stood in her doorway watching a nurse feed Janice from a bottle, Janice’s eyes rolled back in her head, and she went into shock. She died in Dr. Tracey’s arms.

This haunted him. She had no bacteria in her bloodstream. There was no sign of infection. He couldn’t let go of the fact that there was a missing link in basic science. So, he decided to balance his clinical rotation with research – no easy feat. Others told him he wouldn’t be able to do it and it would be impossible, but his new wife said to him, “Only I get to tell you that! Is this what you want to do? Then get up, go to work, and do it.” So, he did.

After Janice’s death in 1985, Dr. Tracey 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). Dr. Beutler began producing large amounts of TNF, which Dr. Tracey would transport across campus to his lab and inject 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.

The result of this discovery was the creation of Remicade, Enbrel, Humira, or the other TNF-inhibitors.

The medical community didn’t believe him back then that the body’s overproduction of TNF was the cause of disease. Now, it’s undeniable. Dr. Tracey’s research has been cited so often that he is in the top .01% of cited scientists in the world.

This work led to two more major discoveries: classifying the phenomenon of the body reacting and then overreacting to insult and injury as what is now known as the inflammatory reflex and discovering that the vagus nerve is vital to its mechanism. Replicated by countless studies in research institutions all over the world, Dr. Tracey has since proved and elucidated this discovery by demonstrating that by electrically stimulating the vagus nerve, the overproduction of inflammation can be effectively turned off in the immune system — without side effects.

This, thankfully, is what happened to me.

BRIEF FLASHBACK

In 2002, I was diagnosed with Crohn’s disease and seronegative spondyloarthropathy arthritis, which is known to not only attack joints, muscles, tissue, and ligaments, but also organs, including the heart, and to top it off, I was eventually also diagnosed with ankylosing spondylitis as the inflammation attacked my spine.

In the 15 years that followed, I dealt with colitis flares that left me doubled over in pain, dehydrated, and malnourished, sometimes only able to be nourished by a PICC line in my arm. Inflammatory arthritis spread from my ankle to every small and large joint in my body, as well as my jaw and my spine. Over that same time period, I ended up with two skin ulcers on my legs called pyoderma gangrenosum that each took 18 months to heal — one of which left a crater in my right shin that I still get scar tissue pain in.

I was prescribed 22 different biologics and DMARDs, all of which failed, leaving me battling active disease from the time I was thirteen until I was twenty-eight. I was hospitalized half a dozen times and spent more than one hundred days and nights in the emergency room due to either colitis flares, multiple blood clots, or frequent cardiac episodes due to inflammation attacking my heart. Sometimes I needed a cane to get around; after long periods of immobility, I needed a walker to regain balance, and at my worst, I relied on a wheelchair.

Every time we tried a new drug, we weighed our options of disease activity versus potential side effects and black box warnings, and my mom would say that we just had to try this next option until the next best thing came out. When Sean and I were first dating, and then married, he and I would count down the days until the next dose of whatever medication I was on at the time – and then we would wait for me to recover after the infusion, which often knocked me out for a few days.

Nonetheless, whenever a drug failed and there was a new one to try, we had hope. Maybe this would be the one that would put me into remission. That never turned out to be the case. But each time, we hoped so.

However, while the options that I had over those fifteen years did not allow me to thrive, they kept me alive until I would find the therapy that would.

Princess Ka’iulani didn’t have the privilege that I did to cycle through twenty-two medications to buy her time.

If I lived in her time, or even eighty years after her time, I would’ve died too.

Even with the options I had – I almost did.

Dr. Tracey continued his research after the development of monoclonal anti-TNF because he, too, knew there had to be a better way.

And he found it.

THE BENJAMIN BUTTON EFFECT

After successful pivotal and phase one trials for rheumatoid arthritis, SetPoint Medical announced a clinical trial to test vagus nerve stimulation in Crohn’s disease in 2017. My husband and I sold everything that wasn’t nailed to the floor and crowdfunded enough money to go to Amsterdam for six months to participate.

On June 22nd, 2017, a small electrode was implanted in my neck, wrapped around my vagus nerve. Two weeks later, on July 6th, my vagus nerve stimulator was turned on. Within days, my pain decreased significantly and within weeks, my joint swelling did as well. Two months later I was in remission for the first time since my diagnosis, nearly sixteen years prior.

When my device is active, it sends an electrical signal from my vagus nerve to my spleen. There, that electrical signal becomes chemical.

A neurotransmitter called norepinephrine interacts with t-cells in my spleen, which then releases acetylcholine, another neurotransmitter.

At that point, the acetylcholine travels to the macrophages – which are white blood cells – and tells the macrophages to turn off the overproduction of inflammation.

Stimulating the vagus nerve allows for it to have the reflexive action that evolution intended it to.

Mark Twain once wrote that “Life would be infinitely happier if we could only be born at the age of eighty and gradually approach eighteen.” For those wondering what it feels like to have bioelectronic medicine as a treatment for Crohn’s & inflammatory arthritis: this is what it has felt like for me. I call it ‘The Benjamin Button Effect.’

It has now been five years since my surgery and life looks nothing like it did before. Prior to vagus nerve stimulation, I had to think about what movements it would take to button a shirt, brush my hair, or wash a dish. Nowadays, it’s difficult to imagine where I’d be without this revolutionary field of medicine.

At the conclusion of the clinical trial, I emailed Dr. Tracey to thank him for saving my life, and I told him that I wanted to do something to help accelerate access to more patients and advance research. When we later met, I gave him my cane to be his daily reminder that I no longer need it because of him. We’ve been working to advance research and expand access ever since.

And what we are all up against to get this to the finish line can’t be overstated.

THE RULES OF THE RIVER

Over the last five years, I’ve been finding my sea legs in this arena, and I have been reflecting on and formulating a view of what I feel is most effective in my advocacy efforts to advance bioelectronic medicine therapies.

My goal is to ensure clinical adoption of bioelectronic medicine therapies to benefit the maximum number of patients; after working in this field for nearly five years, I feel that this is best achieved by working within the world of medicine and science, and I do not seek to work outside of it.

Right now, I am working to advance promising clinical trials, some of which are currently underway, and others that are being designed for rollout in the coming months that I’m very excited about. Conducting clinical trials such as these significantly advances getting these therapies into the hands of patients, safely and effectively.

It’s been a journey, and no journey of great importance is without frustration. When the work matters a great deal, it is tempting to take a side door to get it out to the masses immediately – but what I have learned in life is that a revolution must be hinged on reason; there are no shortcuts to create meaningful, lasting change.

With that in mind, there are three things that I think about when it comes to accelerating the translation and clinical adoption of bioelectronic medicine – and in my personal and professional efforts in patient advocacy, these guideposts have become my non-negotiables.

These are what I am referring to as my Rules of the River.

The first Rule of the River when it comes to advancing this field is that all advocacy of bioelectronic medicine must be deeply rooted in science.

In a field as new as this, and an age warring over science and medicine, it is so important to advocate with evidence. There’s a time and a place to tell personal stories and opinions, but to win the era and ensure the field’s everlasting impact on patients requires stacking up the facts — an important phrase I learned early on in my advocacy journey. To do so requires understanding what’s happening both at the bench as well as the stats from clinical trials so far, and the ability to relay that information effectively to a variety of audiences.

It also requires that we first understand exactly what bioelectronic medicine is, and what it is not.

So, what is it? Well, bioelectronic medicine is the trifecta of three fields of science: neuroscience, molecular medicine, and bioengineering. Importantly, all three must be represented for it to be considered bioelectronic medicine, which requires knowing what each field contributes to the trifecta.

So, let’s break that down into what we know: bioelectronic medicine is an emerging field of neuroimmunology that uses neuromodulation devices to target specific molecular pathways by stimulating nerves and utilizing neurotransmitters to achieve a targeted outcome.

We need to know what nerve is being targeted (neuroscience), we need to know the mechanism of what exactly is happening when stimulating that nerve, from the moment of stimulation to the moment it reaches its target (molecular medicine), and to do so, we need to engineer devices that we understand the mechanics of (bioengineering).

We can go so much further into detail – what is the vagus nerve? Where does it ‘wander’? Why is it called the ‘Inflammatory Reflex?’ What is the origin of the signals that travel down the vagus nerve? What is a cytokine? What is a neurotransmitter and what role does it play in the mechanism?

As you can see, it’s important to do our homework. (And I encourage you to begin with the journals posted here, and the educational materials I’ve developed or contributed to, including a bioelectronic medicine glossary here, a timeline of bioelectronic medicine’s milestones here, and the origins of bioelectronic medicine here).

This is a heavy lift – because as an advocate, it requires a deep understanding of science, and a willingness to learn more — and a willingness to keep learning more.

Right now, we are at a particularly delicate period in advancing bioelectronic medicine: there are a lot of hammers looking for nails.

At this stage, there will be a lot of companies throwing their hat into the ring to sell devices that they don’t fully understand the mechanism of. What’s more, there will be self-proclaimed ‘coaches’ who, quite frankly, are peddling patients for their own financial benefit and notoriety; doing so is not patient advocacy – it is only self-serving.

This brings me to the second Rule of the River when it comes to advancing the mission of this field: the necessity of randomized clinical trials to determine the safety and efficacy of devices.

There’s an old saying that my parents used to tell me when it came to evaluating someone’s character or intentions:

If it looks like a duck and quacks like a duck, it’s probably a friggin’ duck.

In our everyday life, most of the time, we know when we’re being sold. We all try to hurry past the kiosks at the mall that chase us down with their As Seen on TV gimmicks. We can recognize the door-to-door salesman and the telemarketer. The problem in this field, though, is if we don’t first deeply root ourselves in the science, it is easy to be sold goods because someone packages them in a box that they have labeled ‘bioelectronic medicine’ – but do so without studying the device or its mechanism. You can’t stick a fork in an outlet, get zapped, and call it bioelectronic medicine, because it’s not. Sure, there’s a device and an electrical charge, but the only mechanism at play is the unfolding of an idiot.

This is why the ‘gold standard’ of science is so necessary: bench research that elucidates the mechanism in the lab, the engineering of devices that specifically target that mechanism, and lastly, investigation in randomized clinical trials to thoroughly evaluate safety and efficacy.

In a randomized clinical trial, there needs to be what’s called a placebo control – which can also be called ‘sham,’ meaning that for a period of time, patients in the control group think they are receiving active treatment, but they aren’t.

(In current clinical trials, like SetPoint Medical’s Reset-RA study for rheumatoid arthritis, trial participants in the control group for 12 weeks but are then transitioned to active stimulation for the remainder of the study.)

This is what is known as the gold standard of science, as it allows for the investigators to determine the efficacy of the therapy and differentiate between how patients who are getting active therapy respond versus patients who aren’t getting active therapy.

While safety is often viewed as an afterthought to efficacy, it is of the utmost importance. It is imperative that a device’s safety profile is evaluated in clinical trials to determine not only the right parameters of stimulation but also ensure that the device itself doesn’t cause harm.

When patients choose to electrically stimulate on their own with an untested device bought off the shelf or at the behest of a ‘coach,’ the patient risks accidentally using too high of voltage, potentially resulting in worsening their inflammation, or damaging tissue. This not only is potentially harmful to a patient who is already suffering, but also to the countless patients who will suffer if these rogue efforts cause the field of bioelectronic medicine to be set back a decade in approval and clinical adoption.

What’s more, different disease indications require different levels of stimulation. The epilepsy parameters for VNS aren’t the same as those used in most of the trials evaluating VNS for inflammation, nor are those parameters the same as those in depression or migraine.

While I empathize with a sense of desperation and urgency, these procedures are in place for a reason. If a device hasn’t been tested and evaluated in clinical trials, there is no way to tell if it is safe or effective.

Lastly, this brings me to my third Rule of the River: it is imperative to work with and have the support of physicians and respected scientists to advance this field.

What we are up against in this field is not only getting clinical trials up and running, and eventually, FDA approval, but also transforming the paradigm of how physicians view medicine. The problem, though, is that when something is so new, it’s very easy for a field to be written off as ‘alternative’ by medical professionals – and it is why I have based my advocacy so deeply in the science, clinical trial evidence, and the regulatory procedures that will ensure adoption into clinical practice – because that is how we have the greatest impact on patients.

While it takes time to make our way through those necessary, and sometimes, quite frankly, aggravating and painstaking steps, if we do not follow those steps, we set the field up for failure — because without those procedures, it will be packaged and sold by those looking to make a quick buck and peddle desperate patients for cash, and will not be practiced in the mainstream clinical setting where it will have the greatest impact on patients and transform the paradigm of how the medical field views and treats disease for not only our generation but those who come after.

This field needs to earn the respect of physicians so they are willing to adopt new therapies into clinical practice. Coming out of the gate sooner with untested devices may feel right, but it doesn’t help the highest number of patients – all it does is give us instant gratification.

What we really need in this field is for advocates to spread awareness on social media channels by sticking to the science, speak with their own doctors about the science and clinical trials so far, and coordinate efforts with physicians and respected scientists to develop widespread clinical trials to pave the way for FDA approval. By doing so, we achieve two things that are contingent on the other: we utilize the gold standard of science, setting the field of bioelectronic medicine up for success, and in doing so, we set the maximum number of patients up for success and the opportunity to thrive.

Vagus nerve stimulators have been implanted in over 125k+ patients with epilepsy in the last twenty-five years, and the safety profile for those FDA-approved devices is undeniable. Now, we need to advocate for trials and expanded access to the inflammatory settings to benefit more patients, for today and future generations.

By ‘many dints of victories’ – we will, indeed, see the field of bioelectronic medicine through to the other side: that glorious place where it is practiced every day in clinics and hospitals all over the world, no longer a revolution to be fought for, but a fact of life to be lived among.

To achieve that mission, I use my three Rules of the River above as my guiding lights – because one day, I hope to live in a time where this field doesn’t require advocacy, and it just, simply, is.

Once upon a time, the Notorious RBG said it best:

“Real change, enduring change, happens one step at a time.”

PHARMA V. DHARMA

Researchers around the globe are working tirelessly to advance the field of bioelectronic medicine, from its global scientific home of the Feinstein Institutes to the Karolinska Institute (the home of the Nobel Prize) in Sweden to the University of Wisconsin-Madison and the University of Washington, to the Israel Institute of Technology, to Cambridge, as well as the work occurring in industry by General Electric, SetPoint Medical, Cala Health, Iota Biosciences, Spark Biomedical, GSK, and more.

At the Feinstein Institutes, researchers are focused on every aspect of bioelectronic medicine, from decoding neural signals to understanding the role each signal plays in the immune system, to identifying molecular targets, to developing devices that will be implanted on the nerve to achieve a targeted outcome. The vagus nerve is made up of between 80,000 to 100,000 fibers, each sending specific neural signals back and forth between the immune system and the brain.

So far, Dr. Theo Zanos’ lab has successfully decoded the neural signaling of two cytokines: IL-1 and TNF, finding that each cytokine triggered its own specific response signal. His lab also found the neural signal for glucose, which will allow for the modulation of insulin for diabetics.

Continued research and discovery of specific neural signals will allow the bioengineering lab, led by Dr. Timir Datta, to develop devices that customize stimulation based on an individual’s specific needs. For instance, I have a device that is an off-the-shelf stimulator that has been used in epilepsy for 20 years, and it only sends a few signals down to my spleen. The newer devices will be able to not only send more targeted signals but also read incoming signals and then respond accordingly based on the need.

The possibilities for treating specific diseases are endless: Feinstein’s researchers are exploring the role of the vagus nerve in sepsis, diabetes, arthritis, Crohn’s, lupus, and obesity, and there is something called the ‘neural tourniquet’ that is in trials for treating hemorrhaging for soldiers wounded in war and postpartum mothers.

Led by Dr. Jared Huston, the neural tourniquet has shown that by stimulating the vagus nerve externally, we can prime platelets in the spleen to prepare them to respond more effectively to hemorrhaging, reducing the amount of blood loss by up to 50% and decreasing the amount of bleeding time by 40% due to expedited clot formation at the site of the injury.

What’s more, this year Dr. Sangeeta Chavan and her team discovered a small cluster of neurons within the brain stem that is responsible for the production of inflammation in the immune system, traveling by way of the vagus nerve.

While it’s been known that the vagus nerve is a vital part of the mechanism of the ‘Inflammatory Reflex’ and that stimulating the nerve inhibits inflammation and cytokine production, it was not yet understood the origin of where the signals that travel down the vagus nerve come from. Dr. Chavan and her team discovered that anti-inflammatory (cholinergic) neurons from the brain stem’s dorsal motor nucleus communicate with the spleen by way of the vagus nerve.

This is wildly significant and a major advancement and milestone in the field of bioelectronic medicine. The more that we understand the functional neuroanatomy of the origins of how our immune system functions as a result of not only nerves, but our brain itself, the better we can create devices and therapeutics that target certain outcomes to prevent, treat, and cure the diseases of today.

The basic principles of this new field boil down to these three questions:

What is the mechanism of action that allows the device to work?
Why does that mechanism work that way?
How does this benefit patients, and how can we create the best device that allows for maximum patient benefit?

All of those questions matter when it comes to this revolutionary field of bioelectronic medicine.

Further, the field of bioelectronic medicine has led to the discovery that paralysis need not be a permanent problem, but instead, something treatable by stimulating nerves. At Feinstein, led by Chad Bouton, our researchers are doing just that by developing a product called ‘the sleeve’ that paralyzed patients can wear over their arm to cause movement, allowing them to utilize both their fine and gross motor skills to have the independence they so desire. More recently, Bouton and his lab have developed newer brain-computer interfaces that not only restore a patient’s ability to move, but also their sense of touch.

The Feinstein Institutes has established both public and private partnerships with both industry and government entities such as GE, SetPoint Medical, Unit Therapeutics, Spark Biomedical, DARPA, and more, who are working to advance the research of using neural pathways and neurotransmitters to control and treat diseases, as well as develop more therapies and devices such as ultrasound therapy and more to modulate the immune system without the use of drugs.

The hurdles we face in broader deployment of translating this bioelectronic medicine from bench to bedside are philosophical, financial, and bureaucratic. From a philosophical standpoint, we are asking the medical community to think about disease in an entirely new way.

Science advances rapidly at the speed of Moore’s Law, but acceptance of progress often follows a longer arc. In 1900, Lord Kelvin announced at the British Association of Science, “There is nothing new to be discovered in physics now. All that remains is more and more precise measurement.”

Meanwhile, in Zurich, Einstein was working out his theory of relativity and spacetime.

While more than a century separates us from those milestones, the bones of dogma haven’t changed much. The idea that humanity has reached its peak follows each generation, yet progress prevails.

While pharmaceutical companies often create new biologics that target generally the same mechanism, if not for a slight change in cytokine or subunit, those doing novel research like bioelectronic medicine are uncovering new mechanisms. Rather than profit at the forefront, it is a matter of duty and progress.

What’s more, until now, the medical community has been broken down into specialties that view the body through different organs, systems, and functions, and not as a whole – until now, the central nervous system and immune system weren’t thought to interact with each other. Now, we know that they interact intimately, communicating constantly and altering the other’s responses based on infection and injury, and neural mechanisms that either function as they should, or don’t – which then allows inflammation to run rampant.

Rather than treating patients like they can be broken down into parts – between gastroenterology, rheumatology, cardiology, neurology, and the like – we need to look at the patient’s pathology as a system that works in conjunction with all of those parts. That is going to require changing the hearts and minds of those who have been practicing medicine for decades and have learned about the body differently than we understand it today.

I knew that would take time to accomplish this, but I also knew that there are many doctors who know patients need better treatment options – and maybe would become champions of heralding in a new era of scientific exceptionalism.

The miscalculation I made, however, was to assume that the biggest barrier to patient access would be a powerful pharmaceutical industry.

Perhaps it is. But not in the way I previously thought.

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“Part Three: The Stakes” coming tomorrow.

The Wandering Nerve

PART TWO: WE GO TO THE MOON.