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A Conversation with Kate Rosenbluth of Cala Health


Kate Rosenbluth, daughter of a musician and neuroscientist, is an engineer, neuroscientist, and entrepreneur. Her journey from aspiring architect, to mechanical engineer, to Stanford Biodesign Fellow, to start-up CEO is filled with magical stories that wend their way through Frank Lloyd Wright's Fallingwater, through Andy Grove's tutelage, rotten watermelons, and more.


You may know the story of Cala Health and its wearable technology to halt essential tremor, but I assure you that you couldn't begin to guess at the journey that led Rosenbluth, along with her co-founder, Scott Delp, to starting the company that will change millions of lives.

Rosenbluth is an engaging story teller with some impressive tales in her arsenal. Take a listen and be prepared to be mesmerized.


PARTIAL TRANSCRIPT:

JoJo 0:00

Hello, everyone. Thanks for tuning in to another episode of Skraps. It's our podcast dedicated to bringing you the fun, frightening, and fantastic stories behind some of the world's most interesting scientific innovations. We always appreciate your support of Skraps and I'm shamelessly going to ask you to go two steps further. And I'll ask you to sign up for episode alerts at SkrapsofBrilliance.com. And then to rate us and review us on your favourite podcast platform. This is the best way for us to reach new listeners and to keep the show going.

I'm JoJo Platt and as always that ever ebullient Arun Sridhar is here with me. Our guest today is Kate Rosenbluth, founder of Cala Health. And just a little bit of background here, essential tremor and we'll call it ET for short, is a neurological condition that causes shaking of the hands sometimes the head and the voice. It's often confused with Parkinson's disease. But it's not a condition that restricts itself to the elderly. Some researchers estimate that between 4 and 5% of people between the ages of 40 and 60 already have ET. It was previously called ‘benign tremor’. But after recognising the severity of decline in the quality of life, they appropriately drop the word benign. And the first line therapy for ET tends to be a drug therapy either propranolol or primidone, or combination of the two. And unfortunately, as with most drugs, they carry side effects. They aren't always effective, and they can be difficult to tolerate. Sadly, the second line treatment is also a pharma solution. So, after one fails or can't tolerate the drug cocktails or the Botox injections, DBS finally gets its date in court. And while it can certainly be effective, DBS isn't right for everyone. And it requires a surgical procedure which can intimidate many potential candidates. So enters Kate Rosenbluth, and during her time at the Stanford Biodesign programme, she determined that these fates should not be the only choices for this growing population. Cala Health’s Trio device is pioneering new treatments that have truly advanced the way we look at bioelectronic medicines, as well as the potential and capabilities of wearable devices. Fortune magazine rightly recognised Kate on their 2020 list of 40 under 40. She's a neuroscientist and an engineer. She's raised over $80 million in private funding for Cala. And she's launched a product that will change the outcomes, lives, and activities of millions of people. We're honoured to have you on scraps today. Kate, thanks for joining us.

Kate 2:59

Thanks for the great introduction and looking forward to this conversation.

Arun Sridhar 3:03

Thanks, Kate. Welcome to the show, again, from my side. I think let's actually maybe start from the very early days in your scientific journey. Because I think you've spoken publicly about Cala and the product and everything. But that is an untold story, or at least most people don't know that side of you the personal side of Kate Rosenbluth. So would you be kind enough to share with us how you came to do what you did, because a small kind of PubMed search for me kind of at least based on your work at UCSF looked like you were working on drug delivery platforms for the brain and not necessarily neuromodulation, so to speak. So it'll be a fantastic Listen, to actually have you say all of all of these various steps that you've taken in your life.

Kate 3:52

Thanks. My scientific journey has certainly been a meandering one that converged ultimately in what became Cala Health and thanks, JoJo for the wonderful introduction there.

I'll go all the way back to the beginning. So I was born in Toronto, Canada. My mother was a musician. She was a classical pianist and record producer. And my father was a professor of neuro sociology at the University of Toronto. He really focused on the neuroscientific underpinnings of major social drivers like economic investment, religion, just recently, he actually published on COVID. And it's wonderful how our academic interests have woven back together as I dove into the field of neuroscience.

He and my mum actually met at a Dylan party that was at the University of Toronto. It was a party that he thought was quite obviously for Bob Dylan, and my mom arrived thinking it was for the poet Dylan Thomas. So But they hit it off and eventually I came along.

My grandfather was an architect in the modernist movement he loved when I was growing up, regaling us with stories about you know, Frank Lloyd Wright's antics. I remember a dinner at Fallingwater, one of his famous houses, where someone pointed out that the water was leaking through the ceiling and dripping onto their plate. And he said, “Oh, so you should probably move.”

So, I really, in high school, you know, I spent many long hours putting tiny roof shingles and pathway pavers, you know, onto the models at his architectural firm. And also learning what was at the time very early CAD - computer aided design. I was set on becoming an architect, like him, really following in his footsteps. I saw architecture as a perfect convergence of math, physics and art, and really being a place where innovation actually made lives better. Yeah, where you take things like math and science and, you know, apply them for the betterment of humanity. Yeah. And I didn't really say sort of at the time, I didn't really see areas like biology, or neuroscience as places for innovation like I do today, where I think that they are some of the most exciting fields for really radical innovation.

So after that, my father was actually born and raised in California in one of the neighbourhoods up in Sacramento, really built on the GI Bill after the Second World War. And for college, I came out to California I did my undergraduate at Stanford University. Stanford didn't have a pre architecture programme, so I studied mechanical engineering. And in my, in my freshman year, I received a small diversity grant for women in engineering, from Dr. Noe Lozano, really one of the national leaders, I would say in promoting diversity in engineering. I visited a few research labs, and I was absolutely enthralled by a project in the laboratory of Professor Scott Delp. So if you fast forward to today, Scott Delp is actually my co-founder at telehealth, but we didn't start working on neuromodulation we started working together on dinosaurs, and ostriches.

Arun 7:30

That is one thought that I don't think many people actually know. So this is this is that story. So I actually know Scott from all of his biomedical engineering work, and publications.

Kate 7:43

Scott is just an incredible, you know, scientific innovator leader in the field of bioengineering. He was one of the founders of the bioengineering programme at Stanford. And his research has really spanned everything from musculoskeletal modelling. He actually started a company that became the motion analysis corporation that does a lot of the AR and VR work behind things like the animation industry, you know, movies like Avatar, etc. Um, he also today is well recognised as a leader in the field of optogenetics. Which we'll get to that was really my transition from drug delivery to your earlier question over to neuromodulation was through gene therapy for optogenetics. So for light based excitation of the nervous system. At the time when I met Scott when I was a freshman, my first task was to measure every muscle, an insertion in an ostrich limb. This ostrich was literally so big that we first weighed it on a scrap yard like scale. We weighed a truck with the ostrich in the bed, then took the ostrich off the bed of the truck and weighed again and took the difference. That was the official measurement of the ostrich’s weight. So while the work was really, you know, stinky and tiresome, it also thought it was absolutely fascinating. I was hooked. I couldn't believe I could actually get paid for doing work that was this much fun.

The team that Scott and I were working with at the time. John Hutchinson is now a professor of evolutionary biomechanics at the Royal Veterinary College in England, Professor Rob Siston that at Ohio State, there's just I mean, there's just such a wonderful sort of world and team based around the graduates of Scott’s lab, in building out that field. And to be clear, the work wasn't all about ostriches. Turns out, ostriches have about the same limb dimensions as humans. And the lab was developing technologies for musculoskeletal models to help kids with diseases like cerebral palsy to walk better. Building individualised models and then testing things like if you did a tendon reinsertion surgery, if you move the location of the muscle, how would that change the child's gait? Yeah. Um, I'd also say thinking back on that time of undergrad that, you know, Stanford was really steeped in an entrepreneurial culture, you could really dream of changing the world, surrounded by stories like Hewlett and Packard. Google's astronomical growth was really around that time that went public right around when I graduated. I remember in the spring of 2003, using Facesmash, which was Mark Zuckerberg precursor to what became Facebook, and just, you know, really thinking about some of these new technologies, what was possible. I spent the summer of my senior year working at a strange little start-up called Epoch Innovations. You've probably never heard of it because it quickly crashed and burned. But it really was my first introduction, or I suppose after my father reintroduction to neuroscience, as well as the culture of innovation and failure. Epoch was way ahead of its time, it was using heart rate variability as biofeedback for treating dyslexia,

Arun 11:14

Oh, wow. Okay, way before even people kind of now use heart rate variability for closed loop, kind of feedback on many different therapies in identification, wow, which year was this case.

Arun 11:28

So this would this would have a company I believe, that started around 2002. It was a couple years in, when I was working there in 2004. It was actually technology that was licenced in from some really brilliant Israeli scientists. And then the company was built by some of the what, what people call the PayPal mafia. So Epochs Chief Financial Officer, was Keith Raboy, who then went on to square etc. And, and, you know, Keith, Elon, Musk, SpaceX, and Tesla, there was a group of people who really came out of that PayPal world, and just have had a huge impact, you know, on innovation. So, among other things, you know, even though Epoch Innovation itself failed, I'd say it really introduced me to that idea sort of fail fast, of you're going to try and change the world, just be really fearless about keeping truly focused on you know, people's lives on making their lives better. And don't be afraid to go out there and fail. I think of it as a Thomas Edison's quote, what did he say? He said, if I if I have succeeded, it's because I failed 1,000 times. Yeah. And what I loved about working at Epoch was they're very, they're at Epoch Innovations was that culture of, you know, try it, learn. Keep moving, keep picking yourself up. So I'd say after that summer, I was pretty hooked on neuroscience and the brain and figuring out better ways that we could use emerging technologies, like wearables, like the integration of computing, with neuroscience in order to deliver better therapies. Yeah. So around that time…

Arun 13:15

So, that actually took you to UCSF then.

Kate 13:18

That actually took me to Berkeley first. So, um, around that time, I met a very special boy. Now my husband, who's also a med tech entrepreneur, and an incredible father to our two kids who are seven and nine. He was at Berkeley. So I hopped across the bay to start a PhD there in mechanical engineering. Berkeley was also where my father had been a student back in its 1969 heydays.

I started at Berkeley in a really interesting research group under the leadership of Dr. Paul Wright. I worked on energy harvesting from piezo electric's working on adapted basically, adaptations of distributed what were called Smart dust networks, that self powered self assembling networks off vibration. So this was technology first introduced in fields like manufacturing where there's a lot of heat and vibration in the plants. And you could use a distributed smart network to monitor that, or things like the sensors tumbling and streams for doing environmental monitoring. And what I wanted to do was use them for implanted medical sensors for brain diseases. The research centre had a fantastic and very memorable name. It was called CITRIS like the fruit and it stood for the Centre for Information Technology Research in the Interest of Society.

ARun 14:50

That's a mouthful.

Kate 14:51

It's a mouthful. Someone must have been very happy when they had their Scrabble letters out and put them together and wrote the word CITRIS So I loved I love that intersection of medical and technology research but quickly ran up against the problem that Berkeley didn't have a medical school. So I switched PhD programmes into bioengineering, which was the only joint programme between UCSF which had a world class medical school just across the bay, so that I could basically match courses in electrical engineering at Berkeley, with courses like brain mind and behaviour at UCSF.

So you can see where this is starting to head towards what became a career in neuromodulation. I joined the Laboratory of Dr. Sarah Nelson, she sadly just recently actually passed away after a valiant battle with one of the cancers that she studied. She was really a pioneer in the field of magnetic resonance spectroscopy, which was an emerging field sort of within magnetic resonance imaging MRI.

As sort of a fun aside, explaining what we're doing in spectroscopy, MRI was basically invented by incredibly brilliant, but also incredibly lazy graduate student. So he was tasked with performing magnetic spectral analysis on hundreds of test tubes, a very manual and laborious process requiring loading each one into a Magnetic Spectrometer. But he realised that if he lined up 10 of them in a row and put a magnetic gradient across them, he could use a Fourier analysis to extract the 10 spectra at once. And then he realised that he could make a 10 by 10 grid of test tubes. And then he realised he could make a 10 by 10 cube of test tubes. And all of a sudden, he was doing you know, 1000 test tubes at once. So basically, the idea of magnetic resonance spectroscopy is to reimagine each time and location in the brain each, you know, 3d pixel, often called a voxel, sort of as a tiny, tiny test tube. And then to use the information about chemicals like choline, creatine and lipids to non invasively detect brain disease to study things like cancer metabolism.

So, when I joined in 2004, Sarah had just installed one of the world's first seven Tesla MRI scanners, this thing was huge, it was so large and unshielded, that they literally had to build the building around it. But it offered incredible resolution down to about a third of a millimetre or just a few, you know, human hairs, which was incredibly exciting for the study of brain disease. Before we were, you know, allowed to put a human in it, we had to do a lot of painstaking work on optimising pulse sequences and coils a lot with electrical engineering.

Arun 17:48

You’re almost taking me back to a bio physics degree when I actually learned about principles of NMR and MRI.

Kate 17:56

That’s wonderful. And, and, and networks of tiny little arrays of test tubes in the brain. Um, so around that time actually, you might really enjoy this then we weren't allowed to put humans yet in the magnet, but we had to do all of that work. And so I remember thinking you know, there's got to be a way to make this a lot more fun than imaging phantoms, which are, you know, balls of saline. So I started poring over the, the fruit and vegetable aisles that are local, Mexican and Chinese grocery stores. And you know, picking the oddest looking but roughly head sized specimens, leaving them to rot at home, so that their insides got nice and interesting and then imaging them in the scanner.

Arun 18:49

Oh boy.

Kate 18:50

So as a pro tip, anything of the watermelon family is a particularly fabulous number that has so much fluid and therefore you actually have quite a bit of kind of opaqueness to it and MRI.

So around that time I started thinking about new ways, you know, to use the MR signal for objective measurement that was biologically interesting. I got really interested in sort of the phase of the signal because iron is magnetically susceptible. So much like, you know, a paperclip it's not magnetic on its own, but if you expose it to a magnet or a magnetic field, it becomes magnetised. You know, that's why you can pick up a paper with a magnet. Yeah, um, irons also really interesting biologically, because it's involved in a lot of processes in the brain. Haemoglobin, icheme in blood is rich in iron. When you get small micro bleeds in the brain, you're left with tiny iron depositions. Yeah. While that's well known, I'd say at the time better known in areas like traumatic brain injury that you end up with these microbleeds, it was less well understood and very scientifically interesting in areas like Alzheimer's disease. It had been debated for some time whether Alzheimer's is first and foremost a neurodegenerative condition or possibly also a vascular condition. And around that time, actually, you know, microbleeds were of great interest in Alzheimer's, because some of the vaccine trials, in Alzheimer’s had been halted for causing microbleeds in the brain.

I got really interested scientifically in neuro inflammation in both sort of, I'd say neuro inflammation, bleeds, etc, in Alzheimer's, as well as multiple sclerosis. And that's because another rich iron source in the brain is macrophages. Macrophages are basically the garbage collectors. They gobbled up junk, they become rich in iron. So what we showed is that an inflammatory lesions in the brain like in MS in multiple sclerosis, you could actually use the phase two trace the influx of iron to a lesion to trace the inflammation, days or weeks before it became visible by the other commonly used methods. Like most typically, you inject tracer, like gadolinium into the blood and then see where it crosses the blood brain barrier, and you get a nice bright, you know, signal on the MRI.

I thought this was a really what I what I loved about that work was sort of really seeing how you could take that combination of, you know, engineering of the coils and the pulse sequences, etc, with biology, and bring those together to actually study human disease. And around that time, I also started working nights and weekends at the biotech company, Genentech, which was Genentech was just south of UCSF, and south San Francisco. And the phase imaging work was really interesting to Genentech for their work on areas like Alzheimer's and multiple sclerosis as well, particularly because it could be used both pre clinically non-destructively and also clinically in human studies.

Genentech was really my first experience in pharma and opened my eyes to understanding sort of more of the molecular and cellular level of disease.

Arun 22:30

But then from there, you actually went from doing your work there at Genentech back to Stanford, to join the Biodesign programme. So how did how did that transition after a while?

Kate 22:44

That was a really interesting transition. So I'll walk you through that journey. So, when I was at when I was doing work with Genentech, very, you know, interested in very interested in these areas like Alzheimer's disease. I started really learning a lot more about cancer, about areas like gene therapy, as well. Um, you know, in the world of Genentech, there's just incredible scientists, you know, you look at Mark Tessier-Lavigne was then the head of R&D at Genentech. He left soon after he's now president at Stanford. Sue Desmond-Hellmann was then the President of Product Development. You know, she went on to become Chancellor of UCSF and then eventually to the Bill Gates, Melinda Gates Foundation, where she was just recently stepping down from her CEO role. And so I think what was really interesting to me at that time, was really sort of seeing how people from the more sort of pharmaceutical and biotech side were so focused on the cellular level understanding of biology that I got really interested in, in gene therapy. Around that time, Dr. Flip Sabes at UCSF was using is interested in using 7T MRI to visualise exactly where a viral infusion into the brain went for the purpose of optogenetics. So he was wanting to basically transfect different neuronal subtypes, so that you could actually use different lights, different colours of light, like a blue light and a yellow light to excite different neuronal subtypes. This is the field of optogenetics. And that was where I got started getting involved in neurostimulation. Because we were doing things like actually comparing the time course of biologic response to electrical versus optical stimulation.

Around that time, a very fortunate email came in, you might enjoy this story. I was sitting at home one day with you know, Have a cup of tea. And I was reading the biography of Andy Grove. Andy is just incredible. He was a Hungarian Jew and when he was young and you know, the Nazis occupied Hungary, he had to take on a false identity. He lived through communism. He literally walked on foot into Austria when he was 20, barely speaking English, emigrated to New York. And fast forward. He was the CEO of Intel through its explosive years. I mean, he literally created Silicon Valley. So I was reading this biography and you just completely in awe of him, and I looked down at my phone. I'm thinking generation wise, it was probably an iPhone 2. And there was a simple email that said, Hi, Kate, would you like to meet for coffee? Andy Grove, SARUS with an address in Los Altos. And I literally thought this was so strange. I wondered if someone was playing a practical joke. And I sceptically headed down to find him in a one room office with a receptionist and I nervously walked up to shake his hand. And I'll never forget, he paused and he gave me a quizzical smile. And he said, “I'm not sure if I should shake your hand or punch you in the stomach. I need to toughen you up.”

I said, “Thank you, I think I'll I think I'll take the handshake.”

And, you know, so began a mentoring relationship that really forever sort of has, has impacted how I think about particularly management and innovation. And this was actually what got me into the field of Parkinson's disease. Because it turns out that I had two connections to Andy. One was that his Parkinson's foundation called the Kinetics Foundation, had recently endowed a neurosurgery gene therapy lab at UCSF. Andy had Parkinson's, it was quite pronounced at that point. And he convinced me to join Chris Benkovich’s lab as their first sort of an only at the time only in house engineer.

Then the second piece, the second way that I was connected into Andy was actually through the Grove Family Foundation, he had been considering giving a substantial donation to Berkeley to reimagine how we teach medical technology innovation, and to do it with a highly scalable model. So unlike sort of the small fellowship or apprenticeship programmes, to do it more like an MBA, and that actually became what now at Berkeley is a really terrific programme called the MTM which is the masters of translational medicine. And it basically teaches a lot of the innovative innovation you know, everywhere from sort of design practices through to you know, biostatistics through to regulatory and reimbursement, classes, etc.

I started working with Andy on creating that programme. Really his drive to reimagine medical innovation had actually come from when early in his career, he had prostate cancer. And I remember in his office, he had the, the front page of a Fortune magazine. And he was just outraged about how untransparent or inaccessible information on comparing the pros and cons of different treatment options was when he had when he had prostate cancer. And he basically said, If you compare, you know, the chip wars, that led to the dramatic competition between Intel and its competitors, that was really what drove what people call Moore's law, which is named, for Intel's founder and Andy's predecessor in the CEO role, Gordon Moore. And Andy came into the field of medical innovation, basically saying, we need to do this too, we need to have objective measures by which we can compare different therapeutic options.

So, I suppose I'd got connected with Andy sort of through those two different paths of medical innovation and then of gene therapy in Parkinson's disease. And that was what sort of led to that coffee. And that was what led me down to the role of down into taking this postdoc that was in gene therapy.

Arun 29:31

It's almost you almost connect the Silicon Valley to biotechnology to bioelectronic medicine, right? I mean, it's like, I mean, you're probably the only person that I know of who actually has staggered the three kind of zones, because I know people have transitioned from pharma into neuromodulation and otherwise, but this is the first time that somebody has transitioned from Silicon Valley or has connections through their life experiences to all the three areas. Fantastic.

Kate 30:02

Well, I like I like that positive framing, I think that there was a lot of moments where I was wracked with self-doubt of, you know, my meandering decision making in order to pursue the next great innovation.

At that time, even to that convergence of those fields, Intel was working on doing objective motion based sensing in Parkinson's. And at the same time, you know, at UCSF we were working on it was a v2 gdnF. So basically, taking the outer shell of adeno associated virus, to attach to brain cells, and then using that to transfer the DNA sequence for glial derived neurotrophic factor. And I just thought it was so interesting, sort of spanning these two worlds of, you know, sensors and wearables and home monitoring, with sort of the world of neurosurgery - and particularly, you know, comparing the electrical to the genetic, different interventions.

You know, one other one other area, I would add, for you into sort of that convergence of the what I sort of see as the pharmaceutical medical device and tech industry is I was really fortunate during that postdoc to get a lot of exposure to corporate initiatives, really discovering the headaches of things like trying to bring together companies from those three spaces. So the GDNF gene licence was from Amgen to a small company, pharma company called Amsterdam molecular therapeutics. We then were using modified equipment from deep brain stimulation implantation, so technologies from device companies with a custom built formula. And we were working with a Munich based software company called BrainLab to do the predictive modelling and the real time infusion tracking in an MRI scanner. So I even moved over to Munich to work some time as a scientist in residence at BrainLab in order to you know, make that happen.

Arun 31:54

Because a fantastic city, I just love Munich.

Kate 31:57

It is wonderful, great beer gardens, too.

It’s really interesting thinking back on back on it is, you know, when I started thinking about how to do innovation at that convergence, - fast forward a bit and this initiative completely failed. But I tried to start a neuro tech incubator at UCSF, I discussed that with then Chancellor Sue Desmond Hellman, who I knew from my previous work with Genentech. And I believed in you know, I still believe that public universities really have a duty as a public service to free up the integration, sort of, of this convergence of drugs and devices and software to really accelerate that, you know, early discovery work before getting hung up on things like the legal terms of downstream co-branding and distribution. So I think one of the things that was quite a fortunate for me was that when it came to starting Cala, or raising venture fund financing, which includes several strategic investors, I had already sort of had a, I don't know what to say, I'd already had a good beating, I understood the headaches of doing convergence research across these multiple fields. So I think that you know, in retrospect, when I look back at the documents that Sue and I were discussing of the vision for that convergence into a neuro tech incubator, sort of amazingly a few steps down the road that actually became Cala Health.

JoJo 33:47

We started out you have this rich history and pharma, you've clearly got the business side of things dialled in quite a bit. How did you start looking at a non-pharmacological solution for essential tremor? I understand you have an engineering background, and your mind thinks that way. But it doesn't seem like at that moment, you were surrounded by people who are encouraging you to go in that direction.

Kate 34:16

Around that time, I went back to Stanford, to do a second postdoc to be a fellow in the Biodesign Innovation Programme. Around that time, my husband and I learned Actually, we learned I was pregnant with my first child, we thought we'd probably try to have a second soon after, and I thought this is a really unique moment to do something different, ideally, with a very flexible schedule for babies. I remember you know, I visited Biodesign when I was a week past my due date, I interviewed with a newborn you know, in a tiny carrier and then I started into the fellowship straight after my maternity leave. Um, where Biodesign is really unique, I mean, where essential tremor was nowhere on my radar at that time was that Biodesign is really steeped in the theory that true innovation comes from deep understanding of the need. So needs driven innovation. All new fellows start with months of observation in Stanford hospital and clinics. The basic idea is that if you see a need once, you know it's at least a small need, if you see it 10 times, 100 times, you know, it's a bigger need. And this is sort of emphasised there. This is very different from asking people what their needs are, or reading reports on what other people say the needs are. I think of it often with the great quote from Henry Ford, who, you know, was the inventor of the Model T, the first mass production automobile, who said, If I'd asked people what they wanted, they would have said faster horses.

It was really only by spending time observing that what people then really wanted actually was affordable, accessible mass transportation, that he focused on automobiles instead of on faster horses, I think of it on a sort of on radical innovation versus more incremental innovation.

As part of bio design, you know, I followed around any doctor, nurse back office billing practitioner, willing to have me along. And what really struck me was how many patients with hand tremor did not have Parkinson's disease. I was very familiar with Parkinson's from my neurosurgery, postdoc work. And what I learned is that of the 8 million people in the US who have hand tremors, 7 million of them have essential tremor. And it's only around 1 million that have the much more commonly known Parkinson's disease. And many of the people with essential tremor are tremendously impacted by it.

So, JoJo, as you mentioned at the outset, about tremor, essential tremor originally being referred to as benign, non parkinsonian, tremor. You know, it used to be a sort of catch all category. When you meet these patients.

I remember one gentleman in particular, you know, he was just tears streaming down his cheeks, he had, he had learned he was not a candidate for deep brain stimulation, a brain surgery that requires you know, implanting a battery pack in the chest wall running a lead wire up, you know, under the skin through the skull, and then and then implanting a lead in the brain. And he wasn't a candidate for the surgery. And he was just crying, saying how, you know, he couldn't write a note to his wife, he couldn't sign a cheque. He couldn't hold a cup of coffee. It was just, you know, devastating his life.

I thought, you know, what if we could re-engineer the Deep Brain Stimulation system, what if we could turn it on its head, where if you can run a wire into the ventral intermediate nucleus in the thalamus into VIN, and send an electrical pulse in and that is incredibly effective in treating a central tremor. But the nervous system itself is a system, a series of beautiful wires with really precise, you know, connectivity between different regions. And in particular, we know the median nerve which is accessible at the wrist, right where it goes close to the carpal tunnel. The median nerve was well known in neurophysiology work to excite the ventral intermediate nucleus.

So we came up with this idea of sort of reverse engineering the circuit, and instead of implanting a battery pack to stimulate the brain, instead, in order to treat the hand, even though the symptom is present at the hand, it's caused by a central oscillatory signal in the central tremor circuit, the thalamic circuit. And so what we realised is that potentially we could actually stimulate at the risk to send a signal to the VIN to interrupt that same circuit as DBS and use that to control the tremor, non invasively. And we tried it and it worked.

Arun 39:05

So that is that is excellent, excellent segue to one of the questions that I've been wanting to ask you for a long time Kate. Which is, I think, whenever people think of medical devices, especially neuromodulation, and clinical de-risking, I think this is a fantastic example of both reverse engineering as well as proving that the therapy works. So can you just share a bit more light in those early days as to you said that the median nerve kind of connects directly to the brain region in the thalamus? And then how did you demonstrate that stimulation of the median actually produces the silencing of the excitatory patterns in the thalamus did you actually measure it in the brain during brain surgery to demonstrate that that is indeed happening? I mean, that'll be fantastic for people to listen because ultimately, it's a mechanism driven therapy that you that you've kind of developed at Cala, so it'll be fantastic for people to understand that type of innovation because people are not usually used to talking about that, because most people who are who are not exposed to neuromodulation they think it's science fiction. It's still Voodoo. It's changing in a great way. But it'd be fantastic to hear somebody who was developed a product say, how they how they deal is that therapy?

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