The Focus of His Energy

Neal Kassell is on a mission to bring focused ultrasound therapy to the masses.

About seven years ago, Beverly McGowan noticed a tiny involuntary movement in the fingers of her right hand while she was on the computer—the sort of tick most people wouldn’t think twice about. But for her it was like a disturbingly unwelcome alarm bell. She knew all too well what it could be. Her father had suffered for years from essential tremor, a movement disorder similar to Parkinson’s. What would she do?

McGowan had watched her father deteriorate for years, falling under the tremor’s thrall to the point where he was no longer able to eat or get dressed by himself in his later years. Now it was starting with her. How would this affect her professional life? How would it impact her passion for hiking and taking nature photographs in the wilderness around her in her home state of Montana?

A nurse practitioner, she had a highly demanding but professionally rewarding job at the local VA hospital working with military veterans, some of whom suffered from their own movement disorders. But as McGowan’s tremor advanced—more quickly than she had seen with her father—it rapidly and unforgivingly began to impact her work. Her hands would shake so much she couldn’t hold a pen. Her speech was affected. The stress of not being able to speak or write while she was seeing patients only made matters worse. Eventually she had to give up seeing them at all.

“It was obviously negatively affecting my patients as well, who were watching me struggle,” McGowan says. “That’s one of the biggest reasons I decided to step out and get my tremor fixed—I needed to go back to work.”

Turning to the internet, McGowan discovered a relatively new, still somewhat obscure therapy called focused ultrasound that uses the energy of sound waves to heat and destroy the problematic pieces of brain tissue that cause tremor. It was not like deep brain stimulation, a standard approach to treating tremor that requires implanting electrodes in the brain. Focused ultrasound would not require any surgery. Several clinics across the United States were already doing this new procedure, including a major medical center in nearby California.

She also turned to the internet to help pay for the procedure, which, despite the fact that it had been approved by the U.S. Food and Drug Administration (FDA) two years earlier, it was still not reimbursed by her insurance. So she took the unusual approach of starting a GoFundMe page, and succeeded in raising tens of thousands of dollars needed to pay for her treatment and travel to Palo Alto where the treatment would take place.

On the day of the treatment, she showed up at the clinic at 6:45am. Her hands were shaking so badly she couldn’t hold a glass of water without splashing. She had spent weeks preparing herself for this, doing mindful meditation exercises to gird against the stifling claustrophobic confines of the MRI in which the procedure would take place. Stanford University Medical Center, where the operation was performed, combines its focused ultrasound with MRI so that their doctors can use real-time imaging to guide the treatment.

Her head was immobilized and shaven. She was fitted with a water-circulating skull cap to keep the rest of her head cool while the focused sound waves heated up their target deep within McGowan’s brain. After many hours and many rounds of preparatory imaging in and out of the massive, clicking, donut-shaped magnet, she was ready for the treatment. The gantry mechanically moved her into the MRI again.

And then the procedure was done—its results profound and immediate, McGowan says. Her hands stopped shaking. She was discharged that afternoon, and when a reporter spoke to her last week, she shared a video of herself with her cat, hand-feeding a deer in her front yard.

Destroy what you want and nothing you don’t

Stories like McGowan’s are footnotes in a growing movement within modern medicine to find ways to apply focused ultrasound for treating everything from depression, to hypertension, to glaucoma, to OCD, to cancers all over the body.

“It’s still a niche area—not a tool that’s broadly available yet,” says Pejman Ghanouni, who treats patients with focused ultrasound at Stanford University where McGowan herself was treated. “It’s not a technology everyone’s aware of.” Ghanouni is one of the people who wants to change that because of the minimally-invasive promise of focused ultrasound. Basically, he says, “you destroy what you want to destroy without damaging anything in between.”

“It used to be called medicine’s best-kept secret.”

If Ghanouni is something of an evangelist for the technology, he is hardly alone. Stanford was recently named a center of excellence by a nonprofit called the Focused Ultrasound Foundation, which funds research using the technology and advocates for its widespread adoption—and two years ago was named a top 10 medical research foundation by the organization Charity Navigator.

“[The technology] used to be called medicine’s best-kept secret, but I think we’ve made substantial inroads into changing that,” says Neal Kassell, a career neurosurgeon who started the Focused Ultrasound Foundation 14 years ago and continues to lead it today.

It’s hard to talk about promoting focused ultrasound without talking about the foundation—and impossible to do so without focusing on Kassell, who has emerged over the last dozen years as something of an evangelist-in-chief for the technology. To listen to him talk is to hear hope vocalized—hope for the thousands and thousands of people whose lives, he says, will be saved by focused ultrasound in what he calls a coming “revolution in therapy.”

Kassell can talk with scholarly authority about the business landscape of medical devices, the technical aspects of how physical sound waves interact with human tissue, and the rigorous if sometimes opaque demands of federal regulatory oversight. But if an interview he recently gave NEO.LIFE is any indication, what he likes to talk about the most are people.

“It’s all about the patients,” he says.

The writers, the tumor, the technology

Focused ultrasound promises to help people with many different neurological conditions—everything from epilepsy, Huntington’s, and neuropathic pain to major indications like Parkinson’s and Alzheimer’s, which exact a devastating toll on people and their loved ones.

“You come down with one of these diseases, and everything changes—all of it,” says Jonna Mendez, a personal friend of Kassell’s who advocates for the foundation from time to time as a member of its council. A career civil servant with the Central Intelligence Agency, Mendez ended her career with the gobsmacking title Chief of Disguise, and she recently co-authored a book about spying in Moscow during the Cold War in the late 1970s with her husband Antonio Mendez, who passed away from Parkinson’s two years ago. Another lifelong CIA agent, her husband orchestrated the rescue of U.S. embassy workers from Iran after the overthrow of the Shah and was the inspiration for Ben Affleck’s character in the Oscar-winning movie Argo (2012).

Approved for treating essential tremor in the United States, there are a handful of other indications for which focused ultrasound is also approved, including uterine fibroids, which are painful growths within the uterus that are often treated via hysterectomy, a major surgery that removes a woman’s uterus. The list also includes prostate cancer and bone metastases.

Cancer is a major ambition for focused ultrasound advocates. For many people with cancer, treatment options are far too few—either because they have already gone through one or more rounds of standard treatment or because they are not good candidates for traditional treatment because of the size or location of their tumors—in the brain, on the bone, or hidden within the pancreas or liver.

State of research and regulatory approvals by body system [PDF]

All that is just the tip of the iceberg. Proponents of focused ultrasound have major ambitions to treat all kinds of cancers as well as many other diseases. Kassell’s foundation has a list tracking the more than 130 separate indications for which treatments are somewhere in the pipeline, and speaking with him gives the impression that he knows precisely where each one of those approaches is in its clinical development—and exactly where his organization could help.

The foundation has raised some $150 million so far and has spent more than 60 percent of it on research, largely through external investigator-initiated grants, where a researcher proposes a study and submits a budget and plan of attack. Many of the grants they fund are high-risk, early-stage, one-year awards of $100,000 or so. That’s modest in comparison to routine research awards by the major U.S. funding agencies, but it can be a lifeline for early-stage projects, often allowing investigators to gather the crucial results they need to apply for larger grants from the National Institutes of Health (NIH) or other funders.

“You have to have the funding to get the data first so you can get NIH funding,” says Zhen Xu, a biomedical engineering professor at the University of Michigan who has received some of this early-stage research funding from Kassell’s foundation. She works on ways of enhancing the natural human immune response to cancer by exposing tumors to microbubbles and then blasting them with ultrasound waves, a technique called “histotripsy,” which creates mechanical forces that cause the bubbles to cavitate, liberating molecules hidden within a tumor. Those molecules, markers of the cancer cells, will then trigger an enhanced immune response that has the potential to kill the tumors.

A similar approach is being developed for treating brain cancer by directing sound energy at blood vessels inside brain tumors. Brain cancer is notoriously difficult to treat for many reasons, one of which is that a major feature of brain tissue is the blood–brain barrier formed by tight junctions between the endothelial cells lining the blood vessels that course through the brain. Normally biological drugs won’t cross this barrier, but the experimental approach with focused ultrasound, blasting microbubbles in proximity to tumors, can temporarily open the blood-brain barrier, allowing such drugs to cross over. That’s another application Kassell’s foundation has taken an interest in.

“It’s always those pioneering efforts that are the most difficult to find support and resources for,” says Andrew von Eschenbach, who is the president of Samaritan Health Initiatives and an adjunct professor at the University of Texas MD Anderson Cancer Center in Houston.

Approved indications and manufacturers [PDF]

A former commissioner of the FDA and one-time director of the National Cancer Institute, von Eschenbach has served on the board of the Focused Ultrasound Foundation and now serves on its council. And he’s not the only big player Kassell has helping him. Famed author of legal thrillers John Grisham joined the foundation’s board a few years ago after both his mother and sister were diagnosed with cancer.

“It really was a wake-up call for me,” writes Grisham. “I decided I wanted to get involved here and try to help spread the word and raise awareness about this technology.”

Grisham wrote a short book called The Tumor. The kindle version is available for free on Amazon, and as of the beginning of last month it had been downloaded nearly a million times. “I like to say that it’s the most important book I’ve ever written,” Grisham tells NEO.LIFE, “because it’s raising awareness about a technology that is revolutionizing medicine and saving lives.”

A dream come true

To really appreciate Kassell’s motivations and the ambitions of his foundation, it’s necessary to know something about his early career as a brain surgeon—a lifetime helping patients that began, strangely enough, with a failed math class.

At 16, Kassell limped to the finish of his high school calculus class. He wanted to take the course again over the summer, but his school said he would have to wait for the regular semester. So he decided instead to go work as a volunteer in a research laboratory for an old camp counselor he knew from summers past who was now a medical student working at the South Jersey Medical Research Foundation. Kassell worked in that lab all summer, and when the school year started, he continued.

“He gave me the opportunity to help him in the operating room, which was really exciting for a 16-year-old kid—like my dream come true,” Kassell recalls. “We would start experiments late in the afternoon when I got out of school that would run all night.”

The work was rewarding, if exhausting. Through the end of high school, Kassell would get up, go to school, and then race over to the lab where he’d sometimes sleep over to tend to his experiments through the night, crashing for cat naps on the benches in the lab, in the recovery rooms, or on the operating room tables themselves. Then he would get up and do the whole thing again.

After two years of maintaining this brutal schedule, he finished high school and enrolled at the University of Pennsylvania. While there he continued to work in the lab, but his subsequent years of burning the candle at both ends took a toll on his grades. When his class was ready to graduate, the university informed him he was nowhere close to walking in commencement. His cumulative GPA was 1.1 out of 4—basically averaging a failure. He would have to repeat many classes.

“They told me if I wanted to graduate, I’d have to go for another two and a half years, which I didn’t find appealing,” Kassell says.

So instead, he took the unlikely route of applying to medical school with no college degree at all. He was accepted—but the only reason, he says, was that he had done so much work in the lab. He had so many publications by then that several neurosurgical residency programs were already grooming him for one of their coveted residency spots, even supplying him with acceptance letters for four years down the line when he completed medical school.

“In the unlikely event I ever got into medical school,” Kassell says.

So his not-quite-alma mater, the University of Pennsylvania, accepted him as an MD/PhD candidate, and over the next four years, he finished his coursework, got married, and had a couple kids, all the while working in the laboratory. But after four years, though he was granted his medical degree, the university refused to let him proceed with his PhD thesis.

“They said, ‘Oh sorry—we made a little administrative mistake. We can’t give you a PhD, even though you’ve done all this work, because we don’t give PhDs to people who don’t have undergraduate degrees,'” Kassell recalls.

“Yeah, yeah, yeah … well … I did all the MD stuff—I just didn’t get the PhD,” he says.

Like a hot knife through bureaucracy

Kassell spent the early 1970s in neurosurgical residencies, first in Pennsylvania and later in Canada, learning everything about surgical treatment in his specific area of interest, vascular aneurysms in the brain. Then he took his first job at the University of Iowa in 1977. In 1984 he moved on to the University of Virginia, where he became co-chair of one of the best neurosurgery programs in the world.

Part of the recruitment offer from UVA was a promise by the university to purchase a gamma knife package—a new instrument that was to be only the second or third operating one in the world in the 1980s. “I said [to them] this is really hot technology—this is going to be a game changer for a lot of neurosurgical conditions,” Kassell recalls.

“I lived through the experience of taking a new, highly disruptive, non-invasive therapeutic technology from being a sort of experimental or research device to being a commercial treatment device that could be used and sold in a lot of places around the world,” he says.

“It’s always those pioneering efforts that are the most difficult to find support and resources for.”

But he also describes the experience as agonizing. It was filled with slow, painful steps, not all of which were obvious at the beginning. Even after getting regulatory approval from the FDA, there was the matter of getting medicare and the insurance companies to pay for it. There was the problem of getting acceptance from the medical community. Would doctors embrace the gamma knife and recommend it to their patients? There was the challenge of public awareness. Would people elect to have this sort of surgery even if it was offered to them? And there were numerous turf battles between radiation oncologists and neurosurgeons. But those hurdles were surmounted and passed, and by the turn of the century the gamma knife had become more of a commonplace tool.

Then about 17 years ago, Kassell had a singular moment of clarity. He encountered another new technology—focused ultrasound—and heard that familiar echo of what seemed to him a game-changing technology that promised to disrupt medicine again.

The accidental anesthesiologist

Sometime after the turn of the century, Kassell was struggling to find a way to help a large number of people for whom modern medicine seemed to offer no hope. They all had tumors in surgically inaccessible locations—or cancers for which they had already tried every combination of surgery, radiation, and chemotherapy to treat and had “maxed out,” in Kassell’s words.

There was nothing else left he could offer them—or was there?

Serendipity came in the form of a chance encounter with a visiting Dutch cardiac anesthesiologist. The Dutchman told him of an experimental imaging application using ultrasound to measure blood flow in the heart by bursting microbubbles and watching the microbubbles clear.

“He said, ‘Why don’t you try that in the brain,’” Kassell recalls. “So we did—we started to do experiments, and we were successful in measuring blood flow.”

What happened next changed his life forever.

“I was driving home from the hospital at 4:30 in the afternoon—and I can tell you exactly the location, and it was 4:30,” Kassell says. “The light bulb went off in my head and went off really brightly.” Somehow, he bet himself that very moment, there must be a way to use ultrasound to treat these otherwise untreatable brain tumors.

He raced home, opened up the internet, and quickly discovered that others had long been working on this idea. Why hadn’t he heard of it? Kassell was far from discouraged—if anything, he was energized. He tracked down a small company in Israel that was partnering with GE on some early focused ultrasound applications, and he began forming plans to create a new focused ultrasound research center at the University of Virginia, much as he had done twenty years earlier with the gamma knife.

The gamma knife center had been an economic and academic success, attracting patients and trainees from across the United States and around the world, saving lives, generating research papers, and bringing revenue into the university. But as he began drumming up interest within the university for establishing a new center, he quickly grew frustrated at the slow progress. A friend suggested he start a 501(c)(3) nonprofit instead.

“It took me about a week to realize that while UVA dithered, we could do things—support research and engage in other activities around the world,” he says. “So that was the genesis of the Focused Ultrasound Foundation.”

The focus of his energy

Kassell and his partners started the foundation in October 2006, first analyzing the medical landscape and then forming a strategy for speeding up the process of bringing focused ultrasound to the people—funding early research, dispensing advice to researchers and companies, educating providers and patients, pushing for its widespread availability and use, and advocating for the applications of the technology to become reimbursable standards of care.

Focused ultrasound today is a lot like where MRI was decades ago—very early in its market development.

The foundation feels familiar in that sense. Lots of nonprofits advocate for patients and caregivers, fund research, or raise public awareness. But while other nonprofits tend to focus on specific diseases, Kassell’s foundation champions a specific technique across many diseases. There are perhaps no other foundations focused on a single medical technology.

Russ Carson, cofounder of the private equity firm Welsh, Carson, Anderson & Stowe is a foundation donor. He says he has seen the march of a technology from the lab to ubiquity before. A long-time investor in health care and information technology companies, he says focused ultrasound today is a lot like where MRI was decades ago—very early in its market development.

“It’s almost a direct parallel,” Carson says. “MRI in its early days was a very expensive technology that was very sexy and very exciting—but it had to figure out how to get its customers reimbursed.”

Had an organization like the Focused Ultrasound Foundation existed in the early days of MRI scanning, Kassell says, it might have shaved a decade off the time it took for MRI to become mainstream. That’s his goal, he says—the focus of his energy. “Every month that we can shave off the process translates into a reduction in unnecessary death and disability and suffering.”

Currently there are more than 50 manufacturers of focused ultrasound instruments, with application to numerous diseases, reflecting a somewhat fragmented early marketplace. Many of these companies were started by scientists and engineers, so one of the things the foundation has done since its inception is to dispense advice, helping them recognize all the chokepoints and pile on effort to get their technologies through regulatory approval and on up through the pipeline to becoming available.

What are these chokepoints? The most obvious one is all the steps involved in regulatory approval. Focused ultrasound instruments are considered Class III devices by the FDA, since they are used for treatment, and that necessitates satisfying the most rigorous regulatory process of completing a pre-market approval application and conducting human trials to establish safety and efficacy. There really are no shortcuts.

Vowing to put himself out of business

The speed with which COVID-19 vaccines have progressed through clinical trials is really the exception that proves the rule that FDA approval in reality takes years—sometimes even decades. At the end of the day, the FDA is going to do what the FDA needs to do, says von Eschenbach, the agency’s former commissioner.

“We all need that—we all want that,” he says. “We don’t want modalities to be flying out there by a bunch of cowboys causing problems and harm.”

The foundation’s role is focused not so much on the regulatory agency itself as on the companies, doctors, and scientists who are trying to make new treatments, helping them navigate the demanding gauntlet of regulatory approval.

“We’ve become the catalyst—the driving force for the entire field,” Kassell boasts. But what has allowed them to play this role, he added, is the foundation’s reputation for being “a trusted, independent, unbiased third party with total transparency and an extreme degree of accountability.”

Unbiased—but not unenthusiastic. Probably nobody in the world is more bullish on the future of focused ultrasound than Kassell. He has predicted the technology will create a multi-billion dollar industry and has vowed his foundation will fade as the market rises, saying he will be out of business in 10 to 15 years.

Such claims raise the question: Is he correct? Will the market really grow so big so fast? Is this really the technology that is going to change brain surgery and a hundred other treatments forever?

“We’ll know in the next 10 years,” says Carson.

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