Destroying Tumors With Sound: Histotripsy with Dr. Zhen Xu

The discovery that became histotripsy

0:00In front of me, I saw there was like almost like a smoke coming out of the pig heart tissue, but it can't be because it's in a water tank. And within a minute, I saw a hole through that pig heart tissue, and I thought I was dreaming. The 11 rats treated, nine of them, not only the tumor didn't spread, the remaining tumor were just gone. We're looking for it everywhere, we couldn't find them. So this crazy patient went out and ran 20 miles within the first week of her tumor treatment. [From First Principles trailer]

A PhD student and a heart problem

0:51you've had an incredible career with histotripsy. It's something that you kind of started before we get into some of the later stages where now you've co-founded a company and you're doing all these amazing things. You were once a grad student in the University of Michigan. So I wanted to start there because I think that's really the genesis of this story and also why you're getting this award. It was in the 2000s and you were under Charles Cain at the University of Michigan. And someone had asked if there's a way to use ultrasound to make surgery like manipulations inside tissue without actually doing the invasive stuff that

1:33comes with it. Did he just put this on your desk one day or how did you get involved with it as a grad student? Yeah. So in 2001, I came to the United States to do graduate study in biomedical engineering. And so I was a first year PhD student. Yeah. And Dr. Achi Ludomirsky, so he is a pediatric cardiologist. So he just came to the lab meeting one day and he was telling us how he was operating on patients and their babies, very young kids with congenital heart disease, very sick. And he actually operated on their heart and they would

2:19die on the surgical table. So that he asked, can you invent a technology that can perform the real surgery without incision? And he emphasized on real surgery because there was radiation and there was a different form of ablation technology, which means that you use different energy, microwave, radio frequency, even ultrasound laser to heat up the target tissue and the thermally heal the tissue, but you don't remove anything. So it's no use to him. And then in order to save his patients, he need to do the

3:01real surgery and there was no way of doing it. And then he posed that as a challenge to the group. And I was a very young and naive student and I was so inspired by him. So after Dr. Ludomirsky left, I went to my PhD mentor, Charles Cain, and said, I wonder that to be my PhD dissertation. I had no clue how to do it, but that just sounds so inspiring. Yeah. Yeah. That's definitely something a first year PhD student would do. I had nothing to lose. I was young. Like if you're like four or five years in, you're like, maybe I'll just try and graduate. Okay. And I had no clue. Yeah. And there were already previous technologies that

Heat vs. sound: how histotripsy works

3:45used ultrasound, as you said, but this was more, but this was for ultrasound heating. Yes. So there was previous technology, which is referred to high intensity focus ultrasound, HIFU, but it's for thermally generating heating, and then you can kill the target tissue that way. So it's like cooked tissue, right? But there's no way at the time to do mechanically in a non-invasive way to remove tissue. And still, even nowadays, histotripsy is the only technology that can

4:26perform mechanical non-invasive surgery. So that is distinctively something entirely new and different. Yeah. And the principle of histotripsy is you use the ultrasound, which is effectively sound waves, like laser beams of sound waves in some sense, that is getting focused to create cavitation, right? So it's like bubbles. Now, the idea that sound could create bubbles, was that already sort of an established reality at the time? Yeah. So here's what you see how it works. Like you said, ultrasound deliver from outside body, focused to really

5:10precise millimeter region in the tissue, generate bubbles, and the bubble expand and collapse and mechanically pull apart the cells in the target tumor, for example. And using sound to generate those bubble activity, which is charmed cavitation, was a known phenomenon for almost 50 years at the time. But however, it was always viewed at this uncontrolled random phenomenon, and that's harmful. The reason is that it was discovered and mostly in the sense

5:54where you have ultrasound imaging, right? And they generate cavitation in the lung because our lungs full of air bubbles, and then you can cause damage, unwanted damage. And at the time, even though it's a phenomenon known for years, the conventional belief is that it cannot be controlled to do anything really beneficial if you don't have injected gas nuclei or gas bubbles already in a controlled way, meaning that the only way to control cavitation is you actually inject bubbles and you

6:36know this bubble is in here with a specific number, concentration, then that's the only way to generate controlled cavitation. And when even we see control, we see a sort of adjustable term, how comfortable you can be. So we're talking about hysterectomy in the sense that we don't inject anything and that we just utilize the air pockets that we already have in our body, which we do because we're breathing air.

Gas pockets, and why not the lungs

7:06Right. So there's dissolved gases in the fluid. But it's the future by the lung. So the dissolved gas pockets in the tissue, like in our liver, in our pancreas, heart, they are nanometer gas pockets. Really, really tight. And it's very hard to damage cavitation from those nanometer gas pockets because their surface tension are extremely high. We're talking about 200 to 300 times of the time. And then, you know, can possibly control the generation

7:50and the activity of cavitation in your human body to do things like non-invasive surgery. That was considered impossible. That was okay. I see. I see the point. Yeah. And like in lungs, because the lungs have so much, such a higher, let's say partial pressure of gases. Just so many large bubbles. You're going long and use ultrasound, you're gonna explode the lungs. Interesting. Okay. So people don't want to go too long to do this cavitation thing. And I also need to say that histotripsy is great, but so far we cannot treat lung cancer because lung is just full of large air bubbles.

8:32But it has been used to treat other parts. Yeah, yeah, yeah. And it's kind of scary that the heart is right next to the lungs. So there are ways that you need to do it very carefully. We'll talk later, but right now, the clinical use of histotripsy, so far the FDA approval is to treat liver cancer. And then clinical trials of pancreas and kidney and other things. So we are, you know, away from them.

The first paper (2004)

9:06That makes sense. That actually makes sense. Very cool. And so, you know, the first paper that you had, I believe this was in 2004, where it's in the IEEE journals, I believe. And I have a few figures from there where you show that you can cause tissue, you can like bore holes in tissue using this cavitation approach. And then you also use like Doppler imaging to show that like fluids can cross this hole and things like that. But there's like some interesting stories that I've heard

"Don't read any papers": Yellow Pages and pig hearts

9:41about this paper, about like the fact that your lab mates thought that the ultrasound was too loud. And that was maybe an impetus for you to make it quieter. And maybe that. Yeah. So what happened is why, you know, basically volunteered myself to look for this impossible non-invasive surgery technique. And I came in with no background in ultrasound therapy at all. And I was like, how do I do it? And I talked to Charles Cain, my mentor, and trying to get guidance. And Charles literally said, um, you know, just go ahead and

10:22explore and don't read any papers. And I was like, Oh my God, why? And he said, you're doing something entirely new. And I don't want your innovative mind to be limited by the conventional thinking. So I, you know, like just don't read papers and I go and explore. So what I did is I started to open up the yellow page. I don't know if nowadays kids even know that, but you know, it's a phone book. So I found a number from, uh, for a local slaughterhouse. Cause I said, I need to get some tissue to do experiments. If I, you know, I, I was trained as an engineer. So if I, uh, don't know anything and I just should try.

11:07And because, uh, Dr. Ludomirsky mentioned a congenital heart disease. So I said, okay, what do I get? So I called a slaughterhouse and they were slaughtering pigs every week. And I said, can I come and get some hearts from the pig? And they were not selling those. So I went, uh, you know, I would go, uh, every Thursday morning at them. And then, uh, uh, the owners just like take me to a huge dumpster, uh, where they dump all the organs. And he just gave me like this plastic trash bag, just, you know, take whatever you want. You got it for free? Um, well, they figured out very quickly. I immediately got it for free. It was five bucks and 10 bucks.

11:49They made it out of business. So I would get a pig hearts by dumpster diving every week in a local slaughterhouse. And they get that, you know, trash bag back to the lab, but now do experiments, uh, uh, by dissecting a heart tissue, uh, right. And, and then try ultrasound, the parameters on those. And I tried, uh, you know, weeks and a month and a whole year, uh, I was, you know, I failed and failed and failed and didn't get anything. Uh, and for ultrasound therapy, a typical thing you do is, uh, well, ultrasound is called ultrasound because it's beyond our hearing range, right.

Too loud: rethinking the ultrasound pulse

12:30And our hearing range for human beings is from 20 Hertz to 20 kilohertz. Uh, and, uh, but ultrasound therapy is like, I do bursts of ultrasound waves and use different power so that I can see if they can do anything. And the burst of this ultra, you know, burst of ultrasound that will repeat them. And then the repeating of this ultrasound wave burst are within our hearing range and they are powerful. So, so they're loud. So my lab mates are like, you're too loud, not only you're failing and you're loud. And I was like, okay. Oh, you know, I, I was desperate, you know, I was trying

13:10everything. So, uh, I thought two things. One is as engineer, uh, you know, if a hammer doesn't work, I try a bigger hammer. So I just increase the power. Secondly is, uh, uh, if he thinks I'm too loud, then I will make it quieter by repeating those bursts beyond our hearing range, 20 kilohertz. Ah, okay. So, so the ultrasound is like really fast. And I'm using, you know, like, uh, beyond, you know, uh, uh, I was using a frequency that's 700 kilohertz, five megahertz and those were high. But the bursts of the waves were within our hearing range. So in order to make it quieter, I made it so that it's 20 kilohertz.

13:54But in order to do that, which means I have to make those bursts really, really short. So 20 kilohertz, meaning that I'm repeating every 50 microseconds. So my bursts have to be a few microseconds, which should fit enough. But which is a stupid thing to do because like ringing a bell, it takes time to ring up to the full power. Ultrasound is the same way. You need to have enough of the length in order for the ultrasound wave to reach its high power. So I'm basically cutting my ultrasound wave pressure way down by doing this short microsecond ultrasound pulse, while I think I should go, you know, bigger

14:37hammer, right? But I was like, okay, I will humor him because nothing worked anyway. And so I tried a microseconds ultrasound pulse at as high a power or pressure as I possibly could get. And I repeat them really fast.

"Almost like smoke": the 2002 discovery

14:56And I remember I had that piece of pig heart tissue in the water tank. And in front of me, I saw there's like, almost like a smoke coming out of the pig heart tissue, but it can't be because it's in a water tank. And within a minute, I saw a hole through that pig heart tissue. And I thought I was dreaming. Cause it's like, I dreamt it so many times. And I was like, this can be too, this just can be too. So I repeated second time and I repeat it again. And my rule of thumb is if we repeat three times, it must be true. And that's why I started running into Charles' office and I like, Charles, Charles,

15:38you need to come over. Something really special just happened. And that was in 2002 when I first discovered hysterectomy. That is such a cool story. So from dumpster diving, you went from dumpster diving for pig hearts to like this eureka moment. My site, you know, special silent whole sequence. And then the funny thing is, even though it was occurring, supposedly repeating beyond our hearing range, but when cavitation occurred, it make this crackling sound. So it's still not really quiet. But that was a serendipity that led to the discovery and honesty speaking at

16:18the time, I had no clue what was the underlying mechanism. I had no clue how it worked. So I first discovered this specialized parameter set, this magic parameter set. Then I had to go back. It was really funny because, you know, this big discovery, I was so proud of it. And literally within a month later, I went to Charles' office again. And I said, Charles, there's good news and bad news. And Charles is like, what? I was like, good news is I was able to repeat it. So it's true. So it's true. Yeah.

16:59The bad news is I just broke the most expensive piece of equipment in the lab and I'm too poor. I can pay for it. But I realized at the time that histotripsy required a very different set of equipment. And it just couldn't be produced even with best commercial ultrasound equipment at the time. So then, you know, that's why after I published that paper and presented it to the scientific peers, they all came back and said it's impossible.

17:39Why is the parameters you talk about cannot be produced by any commercial ultrasound equipment, even the best one. Secondly is that nobody had a clue how it worked. We think it's cavitation, but how do you possibly control cavitation to do this? So it's impossible. No equipment, no mechanism. So it was a eureka moment followed by a long period of time where I had to really figure out, you know, give up our own equipment and really understand

Building the equipment, and the Edison system

18:14the mechanism. Yeah, actually one of the things I wanted to talk to you about was like, you know, the grad students in your lab today, because histotripsy has become such a flourishing field, there's probably like custom equipment that now manufacturers build specifically for these types of experiments, right? But at the time, as you were saying, like you had to build custom ultrasound equipment. Was it the power? And like the fact that these waveforms, you have to like fit the waveforms into this Gaussian envelope that repeats every whatever? It was actually turned out, it was that, you know, because we need required microsecond, very short courses at a really high instantaneous pressure,

18:59just for that microsecond pulse. Like I said that you can't even ring up to the full amputee. But you could wait for a long time for the next pulse to come. So the cumulative power is actually low. We actually intentionally make it low so that we can avoid heating. We want to maximize the cavitation effects and also control it. So we need to build a specialized ultrasound equipment to produce microseconds ultrasound pulse like an imaging system, but with like 100 times higher power, higher pressure. So that's kind of the challenge because nobody had a need for that

19:40before. And it's a new kind of need. That's why a specialized equipment has to be developed for that special purposes. And then now, even nowadays, there is a commercial, it's a clinical system, which is this Edison system produced by HistoSonics for patient treatment. But the research equipment are still in a build and develop in our own lab. And that's why it's harder for other researchers to do this research. And that's why recently I established this histotripsy center at University of Michigan,

20:20and to really enable the researchers to do histotripsy work by opening up and provide access to those equipment that we build and also technical expertise entirely free. So people who want to investigate histotripsy for new disease treatment or combined with drugs, they can just come in and use the equipment for free. And we can even ship a system out to other people to do those work also for free. Yeah, that's pretty incredible actually. You could have made a nice buck with that if you didn't do it for free.

21:03Well, my intention, research is a solid foundation to enable more clinical translation, like commercialization. And my intention is that I have seen histotripsy is a platform technology that can be used to treat many new disease, including different type of cancer and even brain disease. So we can actually treat through the skull to do precise non-invasive surgery. So it's really incredible. And I have received emails from patients every single day and they ask, why can

21:45I actually get the treatment? I have all different disease. So my hope is by opening up to enable thousands of researchers to do this, we can quickly get more results to enable clinical translation so that we can help as many patients as fast as possible. And that's the impact I want to make rather than just trying to sell the system to the researchers. I want to mobilize and just go to patients.

Through the skull, and controlling the bubbles

22:21Actually, we covered the transcranial paper in our rundown episode. Yeah, we started with this human skull that they were shooting stuff through to make sure that it would go through a human skull as well, which I thought was pretty incredible. So I wanted to get back to, you know, people said that it would be okay. So now you've done cavitation. Let's say, let's say you've performed controlled cavitation using ultrasounds. Fine. How do you control it? That's the next big thing. It's impossible to control.

23:01And so I have, I wanted to talk to you about two figures from one of your papers that I, as a physicist, I really liked, especially, so this first one is about the nonlinear nature of cavitation probability with respect to pressure. It's kind of like a switch that allows you to control the location on top of the pressure wave itself. And like you're kind of beating the diffraction limit in some sense, which I thought was kind of cool. Yeah, so what happens is that we're all breathing air, like I mentioned. So we add nanometer gas pockets in tissue filtered by the lung and

23:46it's super stabilized with this really high surface tension.

The physics: pressure waves, bubbles and cells

23:51What happens is that ultrasound is a mechanical wave. So it propagates by vibrating particles in the media, and when you actually compress the particles, it creates a positive pressure. Then when you kind of pull particles apart, it creates an active pressure. And if you imagine there's a balloon and you want to make the balloon to grow, what you do is that you want to make the pressure outside actually lower than the inside of the balloon so that you can overcome the tension of the balloon. So the nanometer gas pockets, what happens is the surface tension is 200 to 300 times of the atmosphere if it's in a water molecule environment, right?

24:36And we as humans, 70% of us are just water-based. And so most tissues are water-based, then the rest will be fat and you have bone, right? So if you have this water-based tissue and the gas pockets in there is 200 to 300 times of the atmosphere as a surface tension, then supposedly what you need to do is within really short duration instantaneously make the pressure outside and lower than the inside, meaning that I need to achieve 200 to 300 times of the negative pressure

25:17within microseconds region. Now I can explode that nanometer gas pockets to really large, right? And that's the trick. So we're producing a pulse wave with 200 to 300 times the negative pressure within microseconds, expand that nanometer gas pockets to from nanometer to 100 micro, then you take that pressure away, then we will just collapse. So don't keep it going literally microsecond, expand, then take it away, then let it collapse, then that is almost like a micro, micro bone, right? So you will produce this mechanical stress to the cells when the bubble expand, it

26:03crush the cells, squeeze it, when you collapse, you pull cells apart. So it's mechanically pulling cells apart. And because the water molecule surface tension is so consistent, therefore it's a threshold, you have to cross that threshold with your ultrasound pressure, then you generate bubbles, and if it's lower than the threshold, you don't generate. So even though the ultrasound focus for transducer typically is like a couple millimeters, if you make it so that your region that exceeding the pressure threshold, the limit to generate cavitation, and that's the region that

26:45measure. So that's the region where you can generate cavitation and it can be even less than millimeters, right? And beating the diffractional limit and the lower you don't have any activity, which is really cool and very helpful because if you think about using heating as a mechanism, heating is always heating, you can have high heating, low heating, so higher energy give you a high heating, lower energy give you low heating, then there's a linear thing and there's a perfusion too. Yeah, there's diffusion from... Yeah, so your accuracy is low because you can't just say, hey, I heat this region, then everywhere else I don't heat, it's a continuous

27:26thing, you're drinking everything. Radiation is the same thing, you have radiation, high dose, low dose in the beam pathway. So, but with histotripsy, the beautiful thing about here is that it's a threshold phenomenon, so either within the focus exceeding that threshold, you have cavitation, you have damage, and outside you have no damage. So really it's a very highly accurate treatment and because of threshold phenomenon. On top of that, it's a mechanical damage, so it really determined by the mechanical property of target tissue and naturally our major blood

28:09vessels, nerves, bile ducts, those structures have high mechanical strength and more resistant to mechanical damage. So we actually have been able to preserve those critical structures because they are naturally designed to resist positive blood flow, that kind of thing. So we are able to go in, treat tumor without damaging the vessel and treating inoperable, surgically inoperable tumors sandwiched between two vessels where vessels remain intact. It's really incredible.

Ten years to understand it

28:47Yeah, yeah, okay, that makes total sense. And like when you were going about trying to figure out this non-linearity, like what is the, this was part of like you discovering what is the mechanism by which cavitation happens, right? How much of it was like in the dark, just shooting around? It's pretty much all in the dark. We actually spent, after my initial discovery in 2002, literally we went back and spent almost 10 years developing the equipment and the investigation mechanism. And by one tree investigation mechanism, we had to use

29:27ultra high-speed camera because we're talking about microbubble happening within microseconds. So really, we're looking for this tiny little thing happening within very short amount of time. And it, you know, you were talking about doing treatment for menace, but really what's really happening is within microseconds. So you really have to go in and really test it out and trying to capture the precise timing of these really fast events and also tiny events. So microscope high-speed camera and do experiments day in and day out and hoping

30:08you can capture that moment. And this honest speaking that no sane person will give you money to do, right? Like the companies or the investors would never give you any money to do this kind of work. So it was so fundamental and so, you know, really looking in the dark and turning impossible to possible that kind of thing. And the way, you know, federal funding was so helpful here. We were able to get funding from National Institute of Health saying this is worth looking into and go and figure out to the mechanism on the right mechanism. So we really spent 10 years in and out just trying to figure out how it

30:51works. And almost only by understanding how it works, then we can optimize and design our parameters to do the best non-invasive surgery for human patients. Yeah. I mean, as you said, this is 2004 and then this is 2014. So there's 10 years in between first discovering it and really having some sense of how to control the thing and what's actually happening. So for those 10 years, like, did you ever, was there ever a time where you were like, maybe I need to go do something else? You know, cause that's, that's a long time. People realize that I, you know, the FDA approval was 2023.

31:32I initially discovered 2002. So it was 21 years. And then that people always ask me like, have you thought about, you know, that doing something else really, right? Cause it's like, not just 10 years, it was more than 20 years before I even had any real impact on humans. I would say after 2014, it's like, okay, I've got a good handle on this. Right. But like between 2004 and 2014, that's 10 years. You're like grad school, early career pro-doc. And assistant professor. Yeah. So, you know, 10 years on your mind. Tenure, the professor tenure, not the 10 years, but kind of, yeah. I think two things. One is scientists are programmed differently in

32:18our brain, right? To most people, it can be frustrating that in the dark. To me, I was curious and this potential excitement that this is unexplored, right? Nobody knew. And that's why it's so cool to me that I can make a discovery that can potentially have a big impact. And also it's associated with a real application

Surgery keeps getting smaller: from ether to Star Trek

32:46of this potential non-invasive surgery. And if you actually are looking at how medicine is practiced, right. And it's, there has been, we have been going from stone age only just a hundred years ago to now where we are, and it's all fueled by medical innovation. So in 1860, when anesthesia was invented, that's when people first time could do real surgery, right? Before you get something, you die, right? And that happened. Then in 1900, Marie Curie discovered

33:27radiation and that basically resulting in this whole radiation oncology thing. And we take radiation treatment so grateful, but it's really started, even not to that, you know, like a hundred years ago. And then, 1960 were the optical people discovered that the optical fiber can made it so small and still light and without burning things and optical lens can made it so small. So that lead to what's called endoscopic surgery, right? So they can put your small optical camera and go in and do mini surgery. So you don't have to just cut open the big thing.

34:10So I had my gallbladder removed with scandoscopic surgery with four little holes. My father had it removed with a 13 centimeter incision, right? So everything is moving. Medicine has, you know, from less and less invasive and less toxic. And I saw this opportunity that I was looking for something that's entirely non-invasive and non-toxic. And I really thought, even though I was way ahead of curve and people thought I was crazy, but I thought the Stargate thing where you have people go in and you can, you know, sit in there and Star Trek, right? Like you can perform the Star Trek, you know, you can perform the non

34:52-invasive surgery, then you come out. Yeah. Just scans you and then you're like, fine. You scan you, you're fine. Yeah. I really thought that could be a reality. And I was working towards that. So it's a 10 year long road, but a scientific discovery that can be entirely new and a potential non -invasive surgery that, you know, maybe I will, is this possible? I will not be the one who actually make it happen. And I'm lucky that I made it happen, but someone will make it happen. But if I have, you know, may do something to contribute towards that, you know, some future thing, I still thought that could be a very impactful thing.

35:34And I couldn't think of anything better to do for my career anyway. So I thought, why not? Right? Yeah. Yeah. I'm fair enough. I mean, it's kind of your baby because you started it in 2002, 2004, right? So there's always like that belief that, okay, if I like found it, I'm going to be the one that like, if I don't do in some sense. Right. Yeah.

The surprise: an immune response

35:58That totally makes sense. Yeah. That's an incredible story. And, you know, one of the, one of the things I wanted to ask you about, you know, I was, as, as we were doing the deep dives into some of your papers, one thing that struck me was how histotripsy doesn't just, doesn't just accomplish its goal of using mechanical degradation to take out tumors. It also somehow supercharges the immune system. So you've got this paper here where, um, we have, um, I believe. Yeah. It's a mouse tumor model. Uh, and, uh, what we did is, uh, there's a primary

36:40tumor is a meninoma. So it's dark. You can see it. And also the mouse had an injection of the cells to form tumors in the lungs. So it's a pulmonary metastasis. What happened is that, uh, we had treated the tumor primary tumor, uh, and the found that there not only is a substantial increase in the immune response measured by the CDH plus T cells, but very, very, uh, you know, this kind of astounding effect is the, after primary tumor treatment, the lung metastasis, the tumors substantially shrunk.

37:22And it can only be explained by histotripsy actually stimulates the immune system and the immune system attack the tumor. We didn't even treat and make it shrinking. And this is, you know, basically what you're expecting new in therapy to do, but we are not even checking any drugs. Right. I mean, it's so striking. It's like an action at a distance. Um, so, so, so, so this is actually another surprising finding. Yeah. That's what I was going to ask. Like there's no way this was planned. No. So what happened is that when we, uh, you know, we're doing a clinical translation, uh, and, uh, eventually decided to attack the liver cancer.

38:07Okay. Uh, uh, and it was a long story and the liver cancer eventually determined to be, uh, this, uh, uh, clinical trial they were going to go down to.

Why liver cancer, and 9 of 11 rats

38:16And also another, uh, just a little quick thing, uh, that people, most people don't know the reason we started liver cancer was because my former PhD student, uh, Eli Wasasich, and he's actually now a professor at Virginia Tech. He was doing PhD with me and we're doing his literacy. He came into my office, uh, uh, after he came in as a new student and he said, I have to do liver cancer as my PhD dissertation, uh, because my mother died of liver cancer when I was a little kid. And, uh, this is, you know, I, I just have to do it. And I, I, I was like, yes, absolutely.

38:59Right. You know, how can you, how can you decline? So, so we started doing liver cancer work and then the whole field is like, okay, first you crazy woman want to do non-invasive surgery. Now you want to use a mechanical non-invasive way to treat cancer. Everybody was freaking out because what if you disrupt cancer cells, and you just help spread the tumor and the cancer everywhere. Yeah. Yeah. You're just like, you're like stirring it up and then, and then it goes everywhere. Yeah. So everybody had this huge concern that histotripsy will actually increase the chance of metastasis because it's mechanically break up tissue.

39:43But what happened is it's not mechanically breaking up tissue. histotripsy is mechanically breaking up the tumor cells, but regardless there was this big concern. So we had to go and do experiments. So what did is we actually had a rodent model and the first actually set of study was in rats where they had liver tumor and we intentionally treat 50 to 75% of the tumor and say, okay, in a worst case scenario, not only break up the tumor, we left something behind. Now we follow them long-term to see if we increase the metastasis rate, right?

40:25Like look for any kind of cancer within the lung at different locations and within the liver in different locations and outside the liver. And it was, and we started our experiments. I still remember we had two batch, one is control mice and one is treated by histotripsy, 11 in each batch. Control mice all died within two to three weeks. It's a super aggressive type of HCC, the hepatocellular carcinoma, primary liver tumor after tumor inoculation. The 11 rats treated, nine of them, not only the tumor didn't

41:08spread, the remaining tumor was just gone. We're like looking for it everywhere. We couldn't find it and we're like, what happened? Why did the residual tumor go away? Because we didn't treat that. And that was completely... That was a completely surprising finding. We were all shocked. Yeah. And where I guess something must be going on. So then I, you know, reach out to Cliff Cho who is this clinical scientist, a surgeon and a cancer immunologist. Now we did this study that you just talked about that paper and he help us looking to measuring all kinds of immune response.

41:48So it turned out that cancer, it does two things very well. And again, I'm also an engineer, so I'm doing this really basic chart. So why is that cancer heights, right? And that's why, you know, you have the patients who is cancer, supposedly a foreign thing come in, our body should kill it. But for cancer, especially surgeon cancer, like pancreatic cancer, brain cancer, you don't even find them until it's very late stage, because it hides so well. Yeah. It like suppresses the immune response around it. Right. And then it also escapes the pathway that body kill it. So what happens with histotripsy is that we disrupt the tumor cells with bubbles

42:33and open up the cell memory, allow the tumor engine to come out. And that's the first step. And the body, and that histotripsy, actually, you know, if you look at texture, it's literally liquefied this tumor into this acyclic debris, then the body absorb it, absorb it through metabolism process. So it doesn't stay there, go to bloodstream, right? So tumor energy come out, and then the body start looking for things. And not only just at the location of the treatment, because it's circulating in the body. So immune system is just circulating and looking for tumor everywhere. And also we trigger this immunological cell death.

43:15So it really start this whole immune cycle. And then the body is helping now really stimulate this immune response and use our immune response to attack the other tumors as well. And, and it, of course, is a process can vary a lot from tumor to tumor, patient to patients, and also with histotripsy to parameters you use can be different. We do, we do see in small fraction of the patients that we treat one tumor, other tumor shrinking, and the we're in the process of studying, how do we really optimize our patient parameter to maximize the immune

43:59response for that patient and combined with drugs, so that we expand this non-invasive focal surgery to eventually systemic cancer treatment. And only at that time we can talk about potential cure, right? And especially for advanced cancer stage. Yeah. Yeah. I mean, it was, it was absolutely incredible when I was reading this and yeah, as you said, I mean, you're a ultrasound engineer by heart. Um, and so you, you called up a collaborator, um, mentioned his name again. Yeah. So he, so, you know, how, how, how was that conversation?

44:39Like, was he at first, like, there's no way, or was he immediately like, I can maybe guess that a mechanism. Well, he doesn't know the mechanism, but he was very open-minded. Uh, he was doing, uh, looking at immune response induced by other forms of treatment, surgery, potentially other patients. And so he was like, okay, you know, let's take a look at least. Right. Um, but I think, uh, it just kind of show you how, um, you know, my career was a series of serendipity, uh, leading to surprising, uh, scientific discovery. And also, uh, I started it with ultrasound engineer, but along the way I

45:24learned so much. It was a continuous learning process over my whole career by working with many, many different collaborators and educating me and keep advancing this. And, and, and, and that's, you know, even though I have been working on only one thing for my entire career so far, uh, but it has been all extremely interesting. Um, and I think that's kind of how the scientific discovery, um, at least in my case goes, is like you, you find, uh, things, um, and, and then you lead to new things, uh, at, at, and I

46:06never, uh, just kind of, you know, ditch away any potential questions or anything. I always trying to, you know, keep an open mind, trying to address it. And if I don't understand, I try to look for and find someone who potentially can help me understand it and keep, and then that's how things get pushed forward. Yeah. And was he also at University of Michigan? Yeah, he was, uh, I was introduced to him because he, he, uh, was at University of Michigan and, and moved from Wisconsin and I had some friends from Wisconsin and now also, uh, uh, and then he also, uh, knew someone from HistoSonics company

46:46I co -founded. So, so really just a kind of different connections. Yeah. Yeah. Okay. Yeah. And now there are more considering knowledge is working on it. So it's really, really becoming this, uh, new field. And it really, uh, a lot of, um, answer question right now is, uh, kind of, this new field with a lot of unknown, uh, now, like we can really go in and explore. Yeah. I mean, this is pretty recent. This is 2020. So, you know, Yeah. And that's the first paper. Yeah. So, so, so it's a really, uh, really, it is a really new field and I invite everybody to call me.

#HOPE4LIVER: the clinical trial

47:19Yeah. Yeah. I mean, it's an incredible paper. And then finally the last sort of visual that I wanted to talk to you about was, um, the recent hashtag hope for liver 2024 paper. Um, this, what we're looking at is, uh, hepatocellular carcinoma on an MRI scan. There's a before and immediately after histotripsy. And then I think this is, uh, 30 days after histotripsy. And you're missing one year. Yeah. Yeah. Well, there's a, there's a one year. Oh, there is a one year. Okay. So I, I think I got this from your paper. It's even newer. Oh, it's an, it's an even newer paper. Okay. Yeah. Um, I think this was the, the first one and maybe, maybe it was there,

48:02but I got like the free version on NCBI website. You had, there's a 30 day follow-up paper. Then there's a year follow-up paper. So the year follow-up paper is very recent. Oh, it's very recent. Yeah. Very recent. And, uh, and it's, uh, uh, so this is, uh, the multi central clinical trial that led to the FDA approval for non-invasive histotripsy treatment of tumors in the liver. Yeah. Uh, and the showing, uh, that why is safe. So the site, the adverse events reach is very, very low. And the second is, uh, uh, you can see on the MRI, uh, scan that the, the tumor they

48:42treat, the reason the abrasion zone is large is because, uh, clinicians always want to treat with a margin, right? Cause there's always cancer cells you can't see. Yeah. Like it didn't show up in the MRI. So they want to really make sure you, you reach everything, but that histotripsy treatment region, uh, like this kind of liquid get absorbed by the body pretty fast. So if you see 30 days already shrinking substantially in one year, it's like the tumor is surgically reset. It's gone. Oh, so, so I would imagine there it's like, it looks like normal liver tissue. Yeah, pretty much. So, uh, so at the, uh, 30 days follow up the technical

49:23success reach on imaging, meaning that the clinician can confirm on imaging that this is a region, and that I treat this region successfully, it's like 96%. And when you follow up the local tumor control rate, meaning that you actually, you know, you killed it, uh, it's 90%. So, which is a very good result. So really another thing about this is that because it's non-invasive, so it's like, not like surgeon can go in and cut it and see everything directly in their own eyes.

How a treatment works

49:59So it's relying on imaging. So it's, you see it, see it. So it's image guided. Uh, and if you actually looking at a treatment is, uh, the, the clinician going on image, they outline where your tumor is. Uh, then there is a software program, create a path for the robot arm. So the treatment head is controlled by a robot arm. So it creates a treatment scan path for the robot to scan through, uh, to make sure the tumor is covered with a margin. And then the treatment itself is automated. So after the, uh, clinician pan out and confirm everything is okay, they click a go

50:42button. Then literally, uh, the treat, the, uh, robot arm just scan it through, uh, the region, uh, and, and the, you know, and doing the treatment, you can still see what's going on. So there's actually this real time image guidance and monitoring because it was a bubble generated our natural contrast agent for ultrasound. So we can see that. So even though you don't open the patient up, there's no incision. You actually can visualize what's going on to maintain a high treatment accuracy, safety, and efficacy. Yeah. That makes sense. And like the fact that it's imaging along with automation

51:24and robotics, I mean, I can imagine there's a lot of space for artificial intelligence and the technologies that are being developed today in robotics to expand this further. Have you been doing work exploring those options? Definitely. So there is a room for AI to assist in many aspects of this whole treatment planning, uh, treatment, uh, delivery and the treatment follow-up thing. But however, cause we actually recently had a meeting with the clinicians on this too. And they asked, however, uh, I assured clinician that we still need a clinician to be responsible, right.

52:06And to say, this is the part I want to treat and to be there to make sure that's really the part you treated. Right. Uh, and, and if there is, you know, cause you know, God forbid something may happen, you know, there's not always a hundred percent to be there if something unexpected happens and they can deal with it right

Recovery and the 20-mile-run anecdote

52:27away. So, uh, our hope is we're using all the advanced technology to make the clinicians' jobs easier and to make the experience for the patients better. Cause our patients after treatment, they return home almost all of them immediately after procedure. There's no hospitalization. Wow. Um, because you're not, there's no surgery. Yeah. That's funny because patient, we cover, you know, some patient will recover and say, are you sure you did something to me? Cause you know, you, you, you don't have the incision. Yeah. Therefore you don't feel it. When they go home and they have supper at home, they return to, you know, normal activity.

53:10We had a crazy patient. Okay. She had her tumor and, and she was a runner. Okay. So she couldn't run because her tumor pressing on the nerves for a few years. So she couldn't run, uh, because of the pain. Right. And then she had the tumor treated by because even though absorption of this by the body take can take a, you know, month, you see it pretty fast, but the tumor is liquefied right away. Oh, so there's no mechanical stress anymore. So, yeah. So there is a basic liquefies or soft enough. So she immediately, like the pain disappeared. Right. So this crazy patient went out and run 20 miles within the first week of her tumor

53:53treatment. I don't add, you know, I would not advise any. I bet her clinicians were not happy about that. But she was like, she was so, uh, excited to have her like that. Right. Right. Right. And, and, um, I think that it's not just about curing patients or treating patients. It's also about the quality of life, right? You can get the cancer treatment and the cancer treatment is, uh, cancer is awful. The, the, the, the things that people don't think about is the cancer treatment is really, really awful, right? You talk about surgery painful, you talk about chemotherapy, it's horrible. Like you are getting all kinds of side effects, not

54:35just the hair falling out, like lack of appetite, right? And then you, you're just feeling your body aching, even your teeth, you know, loosen up and all it's create, you know, it just really, uh, a lot of bad effects, radiation is also toxic. So this is a way to give patients not only, you know, a potential treatment, um, for patients who run out of options, you know, don't have anywhere to go, but also for patients who have options, but they view this as a way to, uh, get cancer treated, but still maintain that quality of life. Therefore it gave that hope. So it's not just awful, awful, awful, right?

55:18Like there's a hope that you can do treatment and still can have your normal activity. So that's why the non-invasive treatment, I think in the future would be a way to go. Yeah. Wow. And this is 2024. And so the recent paper that's, uh, that follows up for a year, this is like very recent cutting edge stuff, I guess. The recent paper is part, I think it's actually 2026, probably this year. Yeah. I probably, I probably didn't see it. Yeah. Cause I think I ranked like by citations just cause it's more recent, doesn't have as many citations as this one. So then I just thought like, yeah, that's, you know, that's a lesson for me, future Krishna, when you're looking for papers, don't

56:01just, don't just order by citations. But that's really new though. If you are now within the field, it's very hard for you to actually, you know, being able to get, so I'm actually impressed how you were able to pick out, you know, kind of the paper representing, uh, I would say the game-changing moments of the technology development. So it's actually very nice selection that you have here.

The future: worldwide, kidney, pancreas and brain

56:24All right. Thank you. Yeah. Um, that's, that's a great compliment. Um, I wanted to ask you about the future. So, I mean, as you said, this is like happening now, right? Um, how do we expedite this thing? Cause this needs to like be in every hospital if this is like how great it is. So, so give you a status of a current field is, uh, so far, uh, five thousand patients have been treated, even though it's only like five, uh, three years after AB approval. So it's pretty fast. Okay. So yeah, that's great. And it's all liver? So, uh, uh, so it's proof of liver tumor, but we have seen, uh, some clinicians

57:07doing off-label treatment to think other organs within abdominal region, but primary is liver. And that, uh, it come from 200 sites, clinical sites, uh, mostly within United States, but they are, uh, patients also treated in Hong Kong, Taiwan. Uh, there are also clinical trial, or we also have the CE mark, uh, which is, uh, equivalent of AB approval in Europe. Oh, okay. So that also proved, and also they're

57:51and yeah, so this is kind of, you know, pretty brutal thing. Uh, and, um, there are clinical trials, uh, uh, for tumors in the kidney. Uh, and actually that trial have already been completed and submitted to FDA and there's an ongoing trial for tumor in the pancreas. Oh, so, so that's kind of current status already pretty, pretty big. Uh, and, um, but it is a platform technology that can be used for many, many things. Anything you can think of that a non-invasive removal of tissue can be beneficial for the patients, uh, that it can be potentially useful.

58:33And we are currently looking at different type of cancer, such as, you know, beyond liver kidney pancreas also breast prostate uh thyroid uh, and, you know, like, uh, sarcoma, which is tumor come, coming from muscle and, uh, uh, fat, uh, even skin, just, you know, different type of cancer. Uh, also again, um, brain, I think is something I really want to push for because our neurons cannot be regenerated, right? You, when you do surgery in the brain and a neuron, even, you know, only a few, if you damage and if they are functional neurons can, you know, cause a patient to even

59:16paralyzed, right? So I think, Oh, and like, and like to get to the spot, you have to, you have to kill all the neurons, like on the way down. Right. Right. Okay. Yeah. So, so now in these, uh, so like a brain surgery, uh, you know, you shouldn't treat it, uh, really, uh, lightly because neurosurgeons are fully aware that it, you know, they can basically damage functions. Right. And so, um, so I think this is where his urgency can also be super high impactful because we can treat a target tissue without damaging those neurons in a way. Uh, and we're not looking at just cancer. We're looking at stroke. We're looking at a certain brain tumor, but we're looking

1:00:00at like functional disease, such as epilepsy, right? Things that you can possibly, uh, you know, but beyond that, we are also combining his urgency with drug delivery and, and we have ultrasound ways that can intrude the drug delivery that we can incorporate into the same system. There's also, we are, uh, now we have an all in one system where I can use the same system to treat through the skull to do non-invasive brain surgery, but also doing neural modulation, modulating the neurons, doing, uh, drug delivery through the blob ring barriers, all those combined together.

1:00:42So I think in the future, by doing a multimodal thing combined for the enhanced treatment therapy, uh, is a way to go to really bring a maximum benefits to the patients. And I actually don't think this is a science fiction. It's actually can happen in the near future. Uh, and that's why I'm really, again, doing this histotripsy center to mobilize as many scientists as I can possibly push to, to fund this together. So I think the, uh, future is, and I making announcement here

1:01:24that we are entering a new era of non-invasive surgery and it's already starting.

The Golden Goose Award and federal funding

1:01:34That's amazing. So the Star Trek hospital pod is actually becoming a reality. Well, I mean, I could talk to you about this, um, for several more, at least, at least a few hours more, but I know that you are a very busy person because today you have won the Golden Goose awards of 2026. So congratulations on that. I don't want to keep you any longer, but, um, it's, it's really incredible. Some of the work that you do. Congratulations. Thank you. And then I do want the audience to know the AAAS Golden Goose Award. Uh, the one big thing is to, uh, to really emphasize how federal funding is

1:02:15impacting the research and the, not just research, but research that produces a big impact on our society. And I do want to note that, uh, for the histotripsy, it's just an example of the research that had been heavily funded by, uh, the federal funding. And in my case, uh, more than 90% of my research was, has been funded by national Institute of health and age. And especially at the beginning, when no investor, no company would be willing to put a penny in to this at an early stage of the discovery, where the, uh, go government step

1:03:01up, NIH step up and said, we will, you know, fund you to do very innovative work and not funding over the 20 years, uh, federal funding, I H founded, uh, uh, about like $40 million, but it has resulted in FDA approval, more than 5,000 patients treated. And HistoSonics is valued at 3.75 billion with a B and 500 employees. And the value is really climbing up. Uh, and HistoSonics, uh, was named this year by time, uh, as one of the top 10, uh, influential companies

1:03:45in life science and, uh, healthcare. And, you know, I'm, I was named by time 100 global healthcare, but that's, that's a different, but I just, you know, this is showing that, um, that the government funding for research, uh, really produces, uh, the, you know, big impact on healthcare and our society economy. And this is precisely the reason that United States is leading the technical innovation. And if we want to keep doing so and keeping being the leader and this is the biggest driver of the economy going, we need to support federal funding for

1:04:30research.

Sign-off

1:04:31Yeah. Like, I don't think I could have said it any better myself. Thank you so much. And, uh, we'll see you later this evening at the library of Congress for your awards. Thank you.

Outro

1:04:41[From First Principles trailer]