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Destroying Tumors With Sound: Histotripsy with Dr. Zhen Xu · From First Principles

0:00
And in front of me, I saw there was like almost like a smoke coming out of the pig heart tissue.
0:08
But it can't be because it's in a washer tank.
0:11
And within a minute, I saw a hole through that pig heart tissue.
0:16
And I thought I was dreaming.
0:18
The 11th mass treated,
0:21
Nine of them, not only the tumor didn't spread, the remaining tumor was just gone.
0:28
We were like looking for it everywhere we couldn't find out.
0:30
This crazy patient went out and run 20 miles within the first week of her tumor treatment.
0:50
So you've had an incredible career with histotripsy.
0:54
It's something that you kind of started.
0:56
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.
1:06
So I wanted to start there because I think that's really the genesis of...
1:10
this story and also the genesis of why you're getting this award.
1:14
It was in the 2000s, and you were under Charles Kane at the University of Michigan.
1:20
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 comes with it.
1:35
And did he just put this on your desk one day?
1:38
Or how did you get involved with it as a grad student?
1:41
Yeah, so in 2001, I came to the United States to do graduate study in biomedic engineering.
1:52
And so I was a first-year PhD student.
1:55
And Dr. Ahilu Domerski, he is a pediatric cardiologist.
2:00
So he just came to the lab meeting one day, and he was telling us how he was operating on patients.
2:09
And they are babies, very young kids with congenital heart disease.
2:14
Right.
2:14
Very sick.
2:16
And he had to operate on their heart, and they would die on the surgical table.
2:21
Oh, wow, okay.
2:21
So that he asked, can you invent a technology that can perform the real surgery?
2:29
without incision.
2:30
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 thermally heal the tissue.
2:54
But you don't remove anything.
2:56
So it's no use to him.
2:58
And in order to save his patients, he needed to do the real surgery.
3:02
And there was no way of doing it.
3:04
And he posed that as a challenge to the group.
3:08
And I was a very young and naive student, and I was so inspired by him.
3:14
So after Dr. Rudomirsky left, I went to my PhD mentor, Charles King, and said, I want that to be my PhD dissertation.
3:24
I had no clue how to do it, but that just sounds so inspiring.
3:27
Yeah, yeah, that's definitely something a first year PhD student would do.
3:31
I had nothing to lose.
3:32
Yeah, yeah, yeah, exactly.
3:34
I was young.
3:34
Like if you're like four or five years in, you're like, maybe I'll just try and graduate.
3:40
Okay.
3:40
And I had no clue.
3:41
Yeah, yeah.
3:43
And there were already previous technologies that used ultrasound, as you said, but this was for ultrasound heating.
3:50
Yes.
3:51
So there was previous technology which is referred to high-intensity focus ultrasound, high-food.
3:58
But it's for thermally generating heating, and then you can kill the target tissue that way.
4:07
So it's like cooked tissue, right?
4:09
But there's no way at the time to do mechanically in a non-invasive way to remove tissue.
4:20
And the seal, even nowadays, hisotripsy is the only technology that can perform mechanical non-invasive surgery.
4:31
And so that is distinctively something entirely new and different.
4:37
Yeah.
4:38
And the principle of histotripsy is you use the ultrasound, which is effectively like sound waves, like laser beams of sound waves in some sense, that is getting focused to create cavitation, right?
4:50
So it's like bubbles.
4:51
Now, the idea that sound could create bubbles, was that already sort of an established reality at the time?
5:00
Yeah, so here's how it works.
5:04
Like you said, ultrasound deliver from outside the body.
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Focus to really precise millimeter region in the tissue.
5:14
Generate bubbles.
5:15
And the bubble...
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expand and collapse and mechanically core apart the cells in the target tumor, for example.
5:26
And using sound to generate those bubble activity, which is charmed cavitation, was a known phenomenon for almost 50 years at Quine.
5:38
However, it was always viewed as this
5:43
uncontrolled random phenomenon, and that's harmful.
5:47
The reason is that it was discovered, and mostly in the sense where you have ultrasound imaging, right?
5:56
And they generate decadentation in the lung because...
5:59
our lungs full of air bubbles.
6:01
Oh.
6:01
And then you can cause damage, unwanted damage.
6:07
And at the time, even though it's a phenomenon known for years, the conventional belief is that it cannot be controlled.
6:16
I see.
6:17
To do anything really beneficial if you don't have injected blood,
6:26
gas nuclei, gas bubbles already, you know, in a controlled way, meaning that the only way to control captation is you actually inject bubbles and you know this bubble is in here with a specific number, concentration, then that's the only way to generate controlled captation.
6:46
And when even we see control, we see a sort of, you know, the adjustable charm, how control you can be.
6:52
So what we're talking about, hysterectripsy, in the sense that we don't inject anything.
6:59
And we just utilize the air pockets that we already have in our body, which we do because we're breathing air.
7:06
Right.
7:07
So there's dissolved gases in the fluid.
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But it's a future by the lung.
7:11
So the dissolved gas pockets in the tissue, like in our liver, in our pancreas, heart, they are nanometre gas pockets.
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Really, really tight.
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And it's very hard to damage cavitation from those.
7:28
Anatometric gas pockets, because their surface tension are extremely high.
7:33
We're talking about 200 to 300 times of the atmosphere.
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So they are super stabilized.
7:40
And it was just, you know, belief that you just can't, you know, can't possibly control the generation.
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and the activity of cavitation in a human body to do things like non-evasive surgery, that was considered impossible.
8:00
That was, okay, I see.
8:02
I see the point, yeah.
8:03
And like in lungs, because the lungs have so much, such a higher, let's say, partial pressure of gases.
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Just so many large bubbles.
8:11
You go in lung and use ultrasound, you're going to explode the lung, basically.
8:16
Interesting, okay.
8:17
People don't want to go to lung to...
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do this cavitation thing.
8:22
And I also need to say that histotripsy is great, but so far we cannot treat lung cancer because lung is full of large air bubbles.
8:32
But it had been used to treat other parts.
8:35
Yeah, yeah, yeah.
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And it's kind of scary that the heart is right next to the lungs.
8:40
There are ways that you need to do it very carefully.
8:45
Right.
8:46
We'll talk later, but right now, the clinical use of histotripsy, so far, the FDA approval is to treat you.
8:58
liver cancer.
8:59
Yeah, yeah.
8:59
And then clinical trials, the pancreas and kidney and other things.
9:03
So we are, you know, still, you know, away from them.
9:06
That makes sense.
9:07
That actually makes sense.
9:08
Um,
9:10
Very cool.
9:11
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.
9:21
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.
9:32
And then you also use like some Doppler imaging to show that like fluids can cross this hole and things like that.
9:39
But there's like some interesting stories that I've heard about this paper, about like the fact that your lab mates thought that the ultrasound was too loud.
9:47
And that was maybe an impetus for you to make it quieter.
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And maybe that...
9:52
Yeah, so what happened is that I basically volunteered myself to look for this impossible non-invasive surgery technique.
10:05
And I came in with no background in ultrasound therapy at all.
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And I was like, how do I do it?
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And I talked to Charles King, my mentor, and trying to get guidance.
10:18
And Charles literally said,
10:21
you know, just go ahead and explore.
10:24
And don't read any papers.
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And I was like, oh my God, why?
10:27
And he said, you're doing something entirely new.
10:31
And I don't want your innovative mind to be limited by the conventional thinking.
10:38
So I, you know, like...
10:40
Just don't read papers and I go and explore.
10:43
So what I did is I started to open up the yellow page.
10:47
I don't know if nowadays kids even know that, but it's a phone book.
10:51
So I found a number for a local slaughterhouse.
10:55
Because I said, I need to get some tissue to do experiments.
10:58
If I, you know, I was trained as engineer, right?
11:02
So if I don't know anything, and I just should try.
11:06
And because Dr. Ludomirsky mentioned a congenial heart disease, so I said, okay, what do I get?
11:12
So I called the sloshing house, and they were sloshing pigs every week.
11:16
And I said, can I come and get some hearts?
11:19
from the pig and they were not selling those so i went uh you know i would go uh every thursday morning back then and then then uh the owner just like take me to a huge dumpster okay uh where they dump all organ and he just gave me like this plastic trash bag just you know take whatever you want and you got it for free
11:44
Well, they figured out very quickly.
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I immediately got it for free.
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Then it was $5 and $10.
11:49
They made it out of business.
11:50
Yeah, yeah, yeah.
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So I would get pick cards by dumpster diving every week in a local slaughterhouse.
11:57
And they get that trash bag back to the...
12:01
Now do experiments by dissecting the heart tissue, right, and try ultrasound parameters on those.
12:09
And I tried, you know, weeks and a month and a whole year.
12:14
I was, you know, I failed and failed and failed.
12:18
And didn't get anything.
12:20
And for ultrasound therapy, a typical thing you do is, well, ultrasound is called ultrasound because it's beyond our hearing range.
12:29
Right.
12:30
Right.
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And our hearing range for human beings is from 20 hertz to 20 kilohertz.
12:37
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.
12:46
And the bursts of ultrasound now will repeat them.
12:51
And the repeating of this ultrasound wave bursts are within our hearing range.
12:57
And they are powerful.
12:58
So they're loud.
13:00
So my lab mates are like, you're too loud.
13:02
Not only you're feeling and you are loud.
13:05
And I was like, okay.
13:07
You know, I was desperate.
13:09
You know, I was trying everything.
13:11
So I thought two things.
13:13
One is as engineer, you know, if a hammer doesn't work, I try a bigger hammer, right?
13:18
So I just increased the power.
13:20
Second is if he thinks I'm too loud, then I will make it quieter by repeating those bursts beyond our hearing range 20 kilohertz.
13:31
Ah, okay.
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So the ultrasound is like really fast.
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And I'm using, you know, like beyond, you know, I was using a frequency that's 700 kilohertz, by-machers, and those way high.
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Those are, okay.
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But the bursts of the waves were within our hearing range.
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So in order to make it quieter, I made it so that it's 20 kilohertz.
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But in order to do that, which means I have to make those bursts really, really short.
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So 20 kilohertz meaning that I'm repeating every 50 microseconds.
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So my bursts have to be a few microseconds.
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To fit enough.
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To fit enough, right.
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But which is a stupid thing to do because like ringing a bell, it takes time to ring up to...
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the full power, ultrasound is the same way.
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You need to have enough of the length in order for the ultrasound wave to reach its high power.
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So I'm basically cutting my ultrasound wave pressure way down by doing this short microsecond ultrasound pause while I think I should go, you know, bigger hammer, right?
14:39
But I was like, okay, I will humor him because nothing worked anyway.
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And so I tried a microseconds ultrasound pulse at as high a power or pressure as I possibly can get.
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And I repeat them really fast.
14:57
And I remember I had that piece of Picard tissue in the water tank.
15:02
And in front of me, I saw there was almost like a smoke coming out of the pig heart tissue, but it can't be because it's in a washer tank.
15:13
And within a minute, I saw a hole through that pig heart tissue, and I thought I was draining.
15:20
Right, because it's like I trimmed it so many times.
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And I was like, this can be two.
15:26
This just can be two.
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So I repeat it a second time, and I repeat it again.
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And my rule of thumb is if we repeat three times, it must be two.
15:34
And that's why I started running to Charles' office, and I'm like, Charles, Charles, you need to come over.
15:39
Something really special just happened.
15:42
And that was in 2002 when I first discovered Hissotrips.
15:46
That is such a cool story.
15:48
So from dumpster diving, you went from dumpster diving for pig hearts to like this eureka moment.
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My special silent hall sequence.
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And then the funny thing is, even though it was occurring, supposedly repeating beyond our hearing, but when cavitation occurred, it make this crackling sound.
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So it's still not really quiet.
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But that was a serendipity that led to the discovery.
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And honestly speaking, at the time, I had no clue what was the underlying mechanism.
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I had no clue how it worked, why it worked.
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So I first discovered this specialized parameter set, this magic parameter set.
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Then I had to...
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go back.
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It was really funny because this big discovery, I was so proud of it.
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And literally within a month later, I went to Charles' office again.
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And I said, Charles, there's good news and bad news.
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And Charles is like, what?
16:53
I was like, good news is I was able to repeat it.
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So it's true.
16:58
So it's true, yeah.
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The bad news is...
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I just broke the most expensive piece of equipment in the lab, and I'm too poor I can pay for it.
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But I realized at the time that histotripsy required a very different set of equipment.
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And it just couldn't be produced even with the best commercial ultrasound equipment at the time.
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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.
17:39
Why is the parameters you talk about cannot be produced by any commercial ultrasound equipment, even the best one?
17:48
Second is that nobody had a clue
17:51
how it worked, right?
17:53
Like you, we think it's cavitation, but how do you possibly control cavitation to do this?
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So it's impossible.
18:01
No equipment, no mechanism.
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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 the mechanism.
18:16
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 histostripsy has become such a flourishing field, they're probably like custom equipment that now manufacturers build specifically for these types of experiments, right?
18:33
But at the time, as you were saying, like...
18:37
you had to build custom ultrasound equipment.
18:39
Was it the power?
18:41
And like the fact that these waveforms, you had to like fit the waveforms into this Gaussian envelope that repeats every whatever?
18:48
It was actually turned out, it was that, you know, because we need required microseconds, very short courses at a really high instantaneous pressure just for that microsecond pulse.
19:02
Like I said, that you can't even ring up to the full amplitude.
19:06
But you could wait for a long time for the next pulse to come.
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So the cumulative power is actually low.
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We actually intentionally make it low so that we can avoid heating.
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But we want to maximize the cavitation effects and also control it.
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So we need to build specialized ultrasound equipment to produce microseconds ultrasound calls like an imaging system.
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but with like 100 times higher pressure.
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So that's kind of the challenge because nobody had a need for that before.
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And there's a new kind of needs.
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That's why specialized equipment have to be developed for that special purposes.
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And even nowadays,
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There is a commercial histo-chipsy clinical system, which is this Edison system produced by histosonics for patient treatment.
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But the research equipment are still being built and developed in our own lab.
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And that's why it's harder for other researchers to do this research.
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And that's why recently I established this histo-chipsy center at University of Michigan
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and to really enable the researchers to do his or his work by opening up and provide access to those equipment that we build and also technical expertise entirely free.
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So, you know, people who want to investigate
20:39
Here's a chance for new disease treatment combined with drugs.
20:44
They can just come in and use equipment for free.
20:48
And we can even ship a system out to other people to do those work also for free.
20:55
Yeah, that's pretty incredible, actually.
20:58
You could have made a nice buck with that if you didn't do it for free.
21:03
Well, my intention, you know, research is a solid foundation to enable more clinical translation, like commercialization.
21:15
And my intention is that I have seen histotripsy is a platform technology that can be used to treat many new diseases, including different types of cancer, and even patients.
21:29
brain disease so we can actually treat through the skull to do precise non-invasive during surgery.
21:36
So it's really incredible.
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And I have received emails from patients every single day.
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And they ask, why can I actually get the treatment?
21:48
I have all different diseases.
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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 well.
22:07
as fast as possible.
22:09
And that's the impact I want to make rather than just, you know, trying to sell the system to the researchers.
22:16
You know, I want to mobilize and just get this, go to patients.
22:20
Yeah.
22:21
Yeah.
22:21
Um, actually we covered your, uh, the, the transcranial paper in our, in our rundown episode.
22:27
That was, Oh yeah.
22:28
We started with this 2004 one and then, um, but that was one of the ones that we covered where you had, uh, like a, uh, you had a human skull that you were like shooting stuff through to make sure that even the, would go through a human skull as well, which I thought was pretty incredible.
22:43
So I wanted to get back to, you know,
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People said that it would be, okay, so now you've done cavitation.
22:49
Let's say you've performed controlled cavitation using ultrasounds.
22:54
Fine.
22:56
How do you control it?
22:57
That's the next big thing.
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It's impossible to control.
23:01
And so I wanted to talk to you about two figures from one of your papers
23:08
that as a physicist, I really liked.
23:12
Especially, so this first one is about the nonlinear nature of cavitation probability with respect to pressure.
23:19
It's kind of like a switch that allows you to
23:23
control the location on top of the pressure wave itself.
23:30
And like you're kind of beating the diffraction limit in some sense, which I thought was kind of cool.
23:35
Yeah, so what happens is that we all breathing air, like I mentioned.
23:39
So we add nanometer gas pockets in tissue filtered by the lung.
23:45
And it's super stabilized with this really high surface tension.
23:51
What happens is that ultrasound is a mechanical wave.
23:55
So you propagate by vibrating particles in the media, right?
24:00
And when you actually compress the particles, it creates a positive pressure.
24:05
Now when you kind of pull particles apart, it creates negative pressure.
24:10
And if you imagine there's a balloon and you want to make the balloon to grow, what you do is you want to make the pressure outside actually lower than the inside of the balloon so that you can overcome the surface tension of the balloon.
24:24
So the nanometer gas plug is...
24:27
What happens is the surface tension is 200 to 300 times of the atmosphere if it's in a water molecule environment, right?
24:36
And we as humans, 70% of us are just water-based.
24:42
And so most tissue are water-based.
24:45
Then the rest will be fat and you have bone, right?
24:48
So if you...
24:50
have this water-based tissue and the gas pockets in there is two to three hundred times of the atmosphere as a surface tension.
25:00
Then supposedly what you need to do is within really short duration instantaneously make the pressure outside.
25:10
and lower than the inside, meaning that I need to achieve 200 to 300 times of the negative pressure within microseconds region.
25:20
Now I can explode that nanomitric gas pockets to really large, right?
25:25
And that's the trick.
25:26
So we're producing a pulse wave with two to 300 times the negative pressure within microseconds
25:36
expand that nanometer gas pockets from nanometer to 100 micron.
25:42
Then you take that pressure away, then it will just collapse.
25:45
So don't keep it going.
25:46
Literally, microsecond, expand, then take it away, then let it collapse.
25:52
Then that is almost like a micro bond.
25:56
So it will produce this mechanical stress to the cells.
26:01
When the bubble expands, it crushes the cells, squeezes it.
26:05
When you collapse, it pulls cells apart.
26:07
So it's mechanically pulling cells apart.
26:10
And because the water molecule surface station is so consistent, therefore it's a threshold.
26:17
You have to cross that threshold.
26:20
with your ultrasound pressure, then you generate bubbles.
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And if it's lower than the threshold, you don't generate.
26:25
So even though the ultrasound focus for transducer typically is, you know, like a couple millimeter, if you make it so that your
26:36
region that both that exceeding the pressure threshold, the limit to generate cavitation.
26:43
And that's the region that measures.
26:45
So that's the region where you can generate cavitation and it can be even less than millionitri, right?
26:51
And, you know, beating the diffraction limit.
26:53
And the lower you don't have any activity.
26:56
which is really cool and very helpful because if you think about using heating as a mechanism, heating is always heating.
27:05
You can have high heating, low heating.
27:07
So higher energy gives you high heating, lower energy gives you low heating.
27:12
It's a linear combination.
27:13
And there's a confusion too.
27:15
Yeah, there's diffusion from just... Yeah, so your accuracy is low because you can't just say, hey, I hitch this region and everywhere else I don't hitch.
27:25
It's a continuous thing.
27:27
You're checking everything.
27:28
Radiation is the same thing.
27:30
You have radiation, high dose, low dose in the beam pathway.
27:35
But with histotripsy, the beautiful thing about here is that it's a threshold phenomenon.
27:42
So either within the focus, exceeding that threshold, you have temptation, you have damage.
27:48
And outside, you have no damage.
27:50
So really, it's a very highly accurate treatment because of threshold phenomenon.
27:58
On top of that, it's a mechanical damage.
28:01
So you really determined by the mechanical property of target tissue.
28:06
And naturally, our major blood vessels, nerves, bile ducts, those structures have high mechanical strength and more resistant to mechanical damage.
28:19
So we actually have been able to preserve those critical structures because they are naturally designed to resist stress.
28:29
positive blood flow, that kind of thing.
28:32
So we are able to go in, treat tumor without damaging the vessel, and treating surgical inoperable tumors, sandwiched between two vessels, where vessels remain intact.
28:46
It's really incredible.
28:47
Yeah, yeah.
28:47
Okay, that makes total sense.
28:49
And like, when you were going about trying to figure out this nonlinearity, like what is the, this was part of like, you discovering what is the mechanism by which cavitation happens, right?
28:59
How much of it was like in the dark, just shooting around?
29:03
It's pretty much all in the dark.
29:09
After my initial discovery in 2002, literally, we went back and spent almost 10 years developing the equipment and the investigation mechanism.
29:27
use ultra high-speed camera because we're talking about micro-bubble happening within microseconds.
29:34
So really, we're looking for this tiny little thing happening within a very short amount of time.
29:39
And you were talking about
29:43
doing treatment for minutes.
29:46
But really what's really happening is within microseconds.
29:50
So you really have to go in and really test out and they're trying to capture the precise timing
29:57
with all these really fast events and also tiny events.
30:01
So microscope, high-speed camera, and do experiments day in and day out and hoping you can capture that moment.
30:10
And this honest speaking that no sane person will give you money to do, right?
30:15
Like the companies or investors would never give you any money to do this kind of work.
30:22
So it was so fundamental and so...
30:25
you know, really looking in the dark and turning impossible to possible, that kind of thing.
30:30
And the way, you know, federal funding was so helpful here.
30:35
We were able to get funding from National Institutes of Health saying, this is worth looking into and go and figure out the mechanism, on the right mechanism.
30:46
So we really spend 10 years in and out just trying to figure out how it works.
30:52
And only by understanding how it works, then we can optimize and design our parameters to do the best non-invasive surgery for human patients.
31:02
Yeah.
31:03
I mean, as you said, this is 2004 and then this is 2014.
31:07
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.
31:14
Yeah.
31:15
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?
31:24
You know, because that's a long time.
31:26
It's 10 years, but people realize that I, you know, the FDA approval was 2023.
31:32
I initially discovered 2002.
31:35
So it was 21 years.
31:37
And then people always ask me, like, have you thought about, you know, doing something else really, right?
31:43
Because it's like not just 10 years.
31:45
It was more than 20 years.
31:47
before I even had any real impact on humans.
31:50
Yeah, but at least I would say after 2014, it's like, okay, I've got a good handle on this, right?
31:56
But like between 2004 and 2014, that's 10 years, you're like grad school, early career, postdoc.
32:02
Right, and assistant professor.
32:04
Yeah, so, you know, 10 years on your mind.
32:06
Right, right.
32:07
10 years, the professor tenure, not the 10 years, but kind of, yeah, you know, like.
32:13
I think two things.
32:14
One is scientists are,
32:16
program differently in our brain, right?
32:20
To most people, it can be frustrating that in the dark.
32:24
To me, I was curious and this potential excitement that this is unexplored, right?
32:33
Nobody knew.
32:34
And that's why it's so cool to me that I can make a discovery.
32:39
that can potentially have a big impact, right?
32:43
And also it's associated with a real application, this potential non-invasive surgery.
32:50
And if you actually are looking at how medicine works,
32:55
is practice, right?
32:57
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.
33:10
So in 1860, when anesthesia was invented, that's when people first time could do real surgery.
33:18
Right?
33:19
Before you say you get something, you die.
33:21
Yeah.
33:21
Right.
33:22
And that happened in 1900.
33:26
Marie Curie discovered radiation.
33:29
And that basically resulted in this whole radiation oncology thing.
33:34
And we take radiation treatment so grateful bright.
33:38
But it's really started, you know, not to that, you know, like 100 years ago.
33:43
And then...
33:45
1960, where the optical people discovered that the optical fiber can make it so small and still light and without burning things, and optical lens can make it so small.
33:58
So that led to what's called endoscopic surgery, right?
34:02
So they can put a small optical camera and go in to do mini surgery.
34:06
So you don't have to just cut open the big thing.
34:10
So I had my gallbladder removed with scantoscopic surgery with four little holes.
34:15
My father had it removed with a 13-centimeter incision, right?
34:19
So everything is moving.
34:21
Medicine has, you know, from less and less invasive and less as toxic.
34:28
And I saw this opportunity that I was looking for something that's entirely non-invasive and non-toxic.
34:35
And I really thought, even though I was way ahead of curve and the people thought I was crazy, but I thought the Stargate thing where you have people go in and you can sit in there and Star Trek, right?
34:49
You just perform the Star Trek and then you can perform the non-invasive surgery.
34:53
Then you come out.
34:54
Yeah, it just scans you and then you're like fine.
34:56
You scan you, you're fine.
34:57
Yeah.
34:58
I really thought that could be a reality.
35:00
And I was working towards that.
35:02
So it's a 10-year-long road, but a scientific discovery that can be entirely new and a potential non-invasive surgery that maybe I...
35:16
It's possible I would not be the one who actually make it happen.
35:20
And I'm lucky that I made it happen.
35:22
But someone will make it happen.
35:24
But if I have, you know, may do something to contribute towards that, you know, some future thing.
35:31
I still thought that could be a very impactful thing.
35:35
And I couldn't think of anything better to do for my career anyway.
35:38
So I thought, why not, right?
35:41
Yeah, yeah.
35:42
And fair enough.
35:42
I mean, it's kind of your baby because you started it in 2002, 2004, right?
35:46
So there's always like that belief that, okay, if I like found it, I'm going to be the one that like...
35:52
If I don't do this, this is just going to become lost in scientific literature.
35:56
Right.
35:56
In some sense.
35:57
Right.
35:57
Right.
35:58
Yeah.
35:58
That totally makes sense.
36:00
Yeah.
36:00
That's an incredible story.
36:02
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.
36:12
One thing that struck me was how histotripsy doesn't just accomplish its goal of using mechanical degradation to take out tumors.
36:24
It also somehow supercharges the immune system.
36:27
So you've got this paper here where we have, I believe...
36:35
Yeah, it's a mouse tumor model.
36:38
And what we did is there's a primary tumor, it's a melanoma, so it's dark, you can see it.
36:44
And also the mouse had injection of the tumor cells to form tumors in the lungs, so it's a pulmonary metastasis.
36:53
What happened is that we had treated the tumor, primary tumor, and found that there not only is a substantial increase in the immune response measured by the CDH plus T cells, but very, very, you know, this kind of astonishing effect is after primary tumor treatment, the lung metastasis tumors substantially shrunk.
37:22
And it can only be explained by histotripsy actually stimulates the immune system.
37:29
And the immune system attack the tumor we didn't even treat and make it shrinking.
37:34
And this is basically what you're expecting immune therapy to do, but we are not even injecting any drugs.
37:41
Right.
37:42
I mean, it's so striking.
37:43
It's like an action at a distance.
37:45
Yeah.
37:47
So this is actually another surprising finding.
37:51
Yeah, that's what I was going to ask.
37:52
Like, there's no way this was planned.
37:54
No.
37:55
So what happened is that when we, you know, were doing the clinical translation and eventually decided to attack the liver cancer,
38:07
And there was a long story, and the liver cancer eventually determined to be this clinical trial they were going to go down to.
38:16
And also another, just a little quick thing that people, most people don't know.
38:22
The reason we started liver cancer was because my former PhD student, Eli Vesafish, and he's actually now a professor at Virginia Tapp.
38:33
He was doing PhD with me, and we're doing his literacy.
38:36
He came into my office after he came in as a new student, and he said, I have to do liver cancer as my PhD dissertation because my mother died of liver cancer when I was a little kid.
38:52
And this is, you know, I just have to do it.
38:55
And I was like, yes, absolutely, right?
39:00
You know, how can you...
39:02
How can you decline that kind of request?
39:04
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.
39:14
Now you want to use a mechanical non-invasive way to treat cancer.
39:19
Everybody was freaking out because...
39:21
what if you disrupt cancer cells, tumor cells, and it just helps spread the tumor and the cancer everywhere?
39:27
Yeah, yeah.
39:28
So there was... You're just like, you're like stirring it up, and then it goes everywhere.
39:32
Yeah, so everybody had this huge concern that histocripsy will actually...
39:38
increase the chance of metastasis because it's mechanically break up tissue.
39:43
But what happened is, it's not mechanically breaking up tissue.
39:47
Histocypsy is mechanically breaking up the tumor cells.
39:51
But regardless, there was this big concern, so we have to go and do experiments.
39:56
So what we did is we actually had a rodent model.
40:00
And the first actually set-off study was in rats where they had a liver tumor.
40:08
And we intentionally treat...
40:11
50 to 75 percent of the tumor and say, okay, in a worst case scenario, now that we break up the tumor, we left something behind.
40:19
Now we follow them long term to see if we increase the metastasis rate, right?
40:25
Like look for any kind of cancer within the lung at different locations and within the liver in different location and outside the liver.
40:35
And it was, and we started experiments, I still remember we had two batch, one is control mice, and one is treated by histocrypsy, 11 in each batch.
40:48
Control mice all died within two to three weeks.
40:51
It's a super aggressive type of HCC, the hepatocellular carcinoma, primary liver tumor after tumor inoculation.
41:01
The 11 mass treated,
41:04
Nine of them, not only the tumor didn't spread, the remaining tumor was just gone.
41:11
We're like looking for it everywhere.
41:13
We couldn't find them.
41:14
And we're like, what happened?
41:16
Why did the residual tumor go away?
41:18
Because we didn't treat that.
41:21
That was completely surprising.
41:22
Surprising.
41:23
Finding.
41:23
We were all shocked.
41:26
And where I guess something must be going on.
41:29
So then I, you know, reach out to Cliff Cho, who is this clinical scientist, a surgeon and a cancer immunologist.
41:39
Now we did this study that you just talked about that paper.
41:42
And he helped us looking to measuring all kind of immune response.
41:48
So it turned out that cancer, it does two things very well.
41:54
And again, I'm an ultrasound engineer, so I'm doing this really basic chart.
41:58
So why is that cancer height, right?
42:03
And that's why, you know, you have the patients with cancer, supposedly a foreign thing come in.
42:09
Our body should kill it.
42:10
Yeah.
42:11
But for cancer, especially certain cancer like pancreatic cancer, brain cancer, you don't even find them until it's very late stage.
42:19
Yeah.
42:19
Because it hides so well.
42:20
Yeah, it like suppresses the immune response around it.
42:23
Right.
42:23
And then you also escape the pathway that body kills it, right?
42:26
Yeah.
42:27
So what happens with hysterechypsy is that we disrupt the tumor cells with bubbles and open up the cell membrane, allow the tumor engine to come out.
42:38
And that's the first step.
42:39
And the body and that hysterechypsy actually, you know, if you look at texture, it's literally liquefied this tumor into this acetyl debris.
42:49
Then the body absorb it through metabolism process.
42:53
So it doesn't stay there, go to bloodstream, right?
42:55
So tumor energy comes out, and then the body starts looking for things.
43:00
And not only just at the location of the treatment, because it's circulating in the body.
43:05
Yeah, the immune system's everywhere.
43:06
So immune system is just circulating and looking for tumor everywhere.
43:11
And also, we trigger this immunological cell death.
43:15
So it really starts this whole immune cycle.
43:18
And then the body is helping now really stimulate this immune response and use our immune response to attack the other tumors as well.
43:29
And of course, the process can vary a lot from tumor to tumor, patient to patient.
43:37
And also with his or two two parameters you use can be different.
43:43
We do see in small fraction of the patients that we treat one tumor, other tumor shrinking.
43:51
And we're in the process of studying how do we really optimize our attrition parameter to maximize the immune response for that patient.
44:01
and combine with drugs too, so that we expand this non-invasive focal surgery to eventually systemic cancer treatment.
44:12
And only at that time, we can talk about potential cure, right?
44:18
And especially for advanced cancer stage.
44:20
Yeah, yeah.
44:21
I mean, it was it was absolutely incredible when I was reading this.
44:25
And yeah, as you said, I mean, you're a ultrasound engineer by heart.
44:30
And so you you called up a collaborator.
44:33
Yeah.
44:33
Mention his name again.
44:35
Yeah.
44:35
So he so you know, how was that conversation?
44:39
Like, was he at first like, there's no way?
44:43
Or was he immediately like, I can maybe guess at a mechanism?
44:47
Well, he doesn't know the mechanism, but he was very open-minded.
44:52
He was looking at immune response induced by other forms of treatment, the surgery, you know, potentially other relation.
45:02
And so he was like, okay.
45:04
you know, let's take a look at this, right?
45:07
But I think it just kind of shows you how, you know, my career was a series of serendipity leading to surprising scientific discovery.
45:20
And also, I started with ultrasound in the year, but along the way, I learned so much.
45:26
It was a
45:30
career by working with many, many different collaborators and educating me and keep advancing this.
45:37
And even though I have been working on only one thing for my entire career so far, but it has been all extremely interesting.
45:49
And I think that's kind of how the scientific
45:54
discovery, at least in my case, goes.
45:57
It's like you find things and then you lead to new things.
46:05
And I never just ditch away any potential question or anything.
46:12
I always try to keep an open mind.
46:15
Yeah, yeah.
46:15
trying to address it.
46:16
And if I don't understand, I try to look for and find someone who potentially can help me understand it.
46:23
And that's how things get pushed forward.
46:27
Yeah.
46:27
And was he also at University of Michigan?
46:29
Yeah, he was.
46:30
I was introduced to him because he was at University of Michigan and moved from Wisconsin.
46:37
And I had some friends from Wisconsin.
46:39
And I also...
46:42
And he also knew someone from his Sonics company, I co-founded it.
46:47
So it really just kind of different connections.
46:50
And now there are more cancer immunologists working on it.
46:55
So it's really becoming this new field and really a lot of unanswered questions right now is kind of this new field with a lot of unknown that we can really go in and explore.
47:08
Yeah, I mean, this is pretty recent.
47:09
This is 2020.
47:10
So, you know.
47:11
Yeah, and that's the first paper.
47:13
Yeah, so.
47:14
So it's really, really, this is a really new field and I invite everybody to come in.
47:18
Yeah, yeah.
47:19
I mean, it's an incredible paper.
47:21
And then finally, the last sort of visual that I wanted to talk to you about was the recent hashtag Hope for Liver 2024 paper.
47:31
So this, what we're looking at is hepatocellular carcinoma on an MRI scan.
47:37
There's a before and immediately after histotripsy.
47:40
And then I think this is 30 days after histotripsy.
47:45
And you're missing one year.
47:46
Yeah, yeah.
47:47
Well...
47:48
There is a one year.
47:49
Oh, there is a one year follow-up?
47:51
Yeah, yeah.
47:51
Okay, so...
47:52
I think I got this from the- That's even newer paper.
47:55
It's even newer paper.
47:56
Oh, it's an even newer paper.
47:57
Yeah.
47:57
Okay, yeah.
47:59
I think this was the first one, and maybe it was there, but I got the free version on NCBI website.
48:05
There's a 30-day follow-up paper, then there's a year follow-up paper.
48:09
So your follow-up paper is very recent.
48:11
Oh, it's very recent.
48:12
Yeah, very recent.
48:14
And so this is the multi-sensual clinical trial that led to the epi approval for non-invasive hystotripsy treatment of tumors in the liver.
48:27
and showing that why it's safe.
48:31
So the site, the adverse events rate is very, very low.
48:36
And the second is you can see on the MRI scan that the tumor, they treat, the reason the abrasion zone is large is because clinicians always want to treat with a margin, right?
48:48
Because there's always cancer cells you can't see.
48:51
Yeah, like it didn't show up in the MRI.
48:53
So they want to really make sure you treat everything
48:56
But that his or chitzy treatment region, like this kind of acedular liquid, get absorbed by the body pretty fast.
49:05
So if you see 30s already shrinking, essentially, in one year, it's like the tumor is surgically reset.
49:13
Yeah.
49:13
It's gone.
49:14
Oh, so I would imagine it looks like normal liver tissue.
49:18
Yeah, pretty much.
49:20
So at the 30 days follow-up, the technical success rate on imaging, meaning that the clinician can confirm on imaging that this is a region.
49:31
And the attrition this region successfully is like 96%.
49:37
And one year follow up the local tumor control rate, meaning that you actually, you know, you chilled it, is 90%, which is a very good result.
49:48
I mean, that's incredible.
49:50
So really another thing about this is that because it's non-invasive,
49:55
So it's not like surgeons go in and can cut it and see everything directly with their own eyes.
50:00
So it's relying on imaging.
50:02
So you still see it.
50:04
So it's image guided.
50:06
And if you're actually looking at a treatment, the clinician going in on image, they outline where the tumor is.
50:14
Then there is a software program to create a path for the robot arm.
50:21
So the treatment head is controlled by a robot arm.
50:24
Right, okay.
50:25
So it creates a treatment scan path for the robot to scan through to make sure the tumor is covered with the margin.
50:34
Then the treatment itself is automated.
50:37
So after the clinician pan out and confirm everything is okay, they click a go button.
50:43
Then literally the robot arm just scans it through the region
50:51
and cover that region and doing the treatment, you can still see what's going on.
50:55
So there's actually this real-time image, guidance and monitoring because those bubbles generated our natural contrast agent for ultrasound imaging.
51:06
So we can see that.
51:07
So even though,
51:08
You don't open the patient up.
51:10
There's no incision.
51:12
You actually can visualize what's going on to maintain a high treatment accuracy, safety, and efficacy.
51:20
Yeah, that makes sense.
51:21
And like the fact that it's imaging along with automation and 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.
51:37
Have you been doing work exploring those options?
51:39
Definitely.
51:40
So there is a room for AI to assist in many aspects of this whole treatment planning, treatment delivery, and the treatment follow-up thing.
51:54
But however, because we actually...
51:56
recently had a meeting with clinicians on this too, and they asked, however, I assure clinicians that we still need a clinician to be responsible, right?
52:06
And to say, this is the part I want to treat and to be there to make sure that's really the part you treat it, right?
52:13
And if there is, you know, because, you know, God forbid, something may happen, you know, there's not always 100%.
52:21
To be there if something happens
52:24
unexpected happens and they can deal with it right away.
52:27
So our hope is we're using all the advanced technology to make the clinician's jobs easier and to make the experience for the patients better.
52:39
Because our patients, after treatment, they return home, almost all of them, immediately after procedure.
52:46
There's no hospitalization.
52:48
Wow.
52:49
Because you're not... Oh, it's not...
52:50
There's no surgery, really.
52:52
It's funny because patients wake up, you know, some patients wake up and say, are you sure you did something to me?
52:59
Because, you know, you don't have the incision.
53:01
Yeah, yeah.
53:01
Therefore, you don't feel it.
53:03
Right.
53:04
So when they go home and they have supper at home, they return to, you know, abnormal activity on the second day.
53:10
We had a crazy patient.
53:12
Okay, she had her tumor and she was a runner.
53:17
So she couldn't run because her tumor pressing on the nerves for a few years.
53:21
So she couldn't run because of the pain, right?
53:26
And she had the tumor treated by histotripsy.
53:29
Because even though absorption of this vital body can take a month, you see it pretty fast, but the tumor is liquefied right away.
53:38
Oh, so there's no mechanical stress anymore.
53:40
So yeah, so it's basically liquefied, so it's soft developed.
53:43
So she immediately, the pain disappears.
53:47
So this crazy patient went out and run 20 miles within the first week of her tumor treatment.
53:54
I don't add, you know, I would not advise any kind of patient to do that.
53:59
I bet her clinicians were not happy about that.
54:01
But she was so excited to have more like that, right?
54:07
And I think that it's not just about...
54:10
curing patients or treating patients.
54:12
It's also about the quality of life, right?
54:14
You can get the cancer treatment and the cancer treatment is, cancer is awful.
54:20
The things that people don't think about is the cancer treatment is really, really awful, right?
54:27
You talk about surgery, painful.
54:28
You talk about chemotherapy, it's horrible.
54:31
Like you are getting all kinds of side effects, not just the hair falling out.
54:37
like lack of appetite, right?
54:39
And then you're just feeling your body aching.
54:42
Even your teeth, you know, loosen up and all.
54:45
It's just really a lot of bad effects.
54:49
Radiation is also toxic.
54:51
So this is a way to give patients
54:55
Not only, you know, a potential treatment 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 get cancer treated, but still maintain that quality of life.
55:13
Therefore, it gave that hope.
55:15
So it's not just awful, awful, awful, right?
55:18
Like there's a hope that you can do treatment and still can have your normal activity.
55:24
So that's why the non-invasive treatment, I think, in the future would be the way to go.
55:31
Yeah.
55:32
Wow.
55:32
And this is 2024.
55:33
And so the recent paper that follows for a year, this is like very recent cutting edge stuff, I guess.
55:39
Yeah, very, very.
55:40
That's crazy.
55:40
The recent paper is, I think it's actually 2026, probably this year.
55:45
Yeah, I probably didn't see it.
55:47
Yeah, because I think I ranked by citations.
55:50
Yeah.
55:51
And just because it's more recent doesn't have as many citations as this one.
55:54
So then I just thought like... Yeah, it literally just came up.
55:57
That's a lesson for me, future Krishna.
56:00
When you're looking for papers, don't just order by citations.
56:03
No, no, no.
56:04
But that's real new though.
56:05
Yeah.
56:05
If you are now within the field, it's very hard for you to...
56:09
actually being able to get.
56:10
So I'm actually impressed how you were able to pick out the paper representing, I would say, the game-changing moments of the technology development.
56:21
Yeah, thank you.
56:21
So it's actually a very nice selection that you have here.
56:24
All right.
56:25
Thank you.
56:25
Yeah.
56:26
That's that's a great compliment.
56:29
I wanted to ask you about the future.
56:32
So, I mean, as you said, this is like happening now.
56:35
Right.
56:36
How do we expedite this thing?
56:39
Yeah.
56:40
Because this needs to like be in every hospital if this is like how great it is.
56:44
So to give you a status of the coronary food is so far, 5,000 patients have been treated.
56:52
Whoa, okay.
56:53
Even though it's only like three years after epi approval.
56:57
So it's pretty fast.
56:58
Okay, so yeah, that's great.
56:59
Yeah, so- And it's all liver?
57:01
Yeah.
57:02
So it's proof of liver tumor.
57:05
But we have seen some clinician doing off-label treatment to other organs within the abdominal region, but primarily it's liver, in the liver.
57:16
And that comes from 200 clinical sites, patients.
57:22
mostly within the United States, but there are patients also treated in Hong Kong, Taiwan.
57:31
There are also clinical trials.
57:34
We also have the CE mark, which is equivalent of the approval in Europe.
57:40
So that also approved.
57:42
And also their approval in UK.
57:44
There's also clinical trials in Australia, Japan, and...
57:51
Yeah, so this is kind of a global thing.
57:56
And there are clinical trials for tumors in the kidney.
58:03
And actually, that trial has already been completed in the submissive FDA.
58:08
And there's an ongoing trial for a tumor in the pancreas.
58:13
So that's kind of current status already pretty, pretty big.
58:18
But it is a platform technology that can be used for many, many things.
58:23
Anything you can think of that non-invasive removal of tissue can be beneficial for the patients, that it can be potentially useful.
58:33
And we are currently looking at different type of cancer, such as beyond liver, kidney, pancreas, also breast cancer.
58:42
prostate, thyroid, and, you know, like, sarcoma, which is tumor coming from muscle and fat, even skin, just, you know, different type of cancer.
58:56
Also, again, brain, I think, is something I really want to push for because our neurons cannot be regenerated.
59:04
Right.
59:04
Right?
59:05
When you do surgery in the brain,
59:08
And the neuron, even, you know, only a few, if you damage and if they are functional neurons, can, you know, cause the patient to even paralyze, right?
59:17
Oh, yeah.
59:18
So I think... Oh, and like to get to the spot, you have to kill all the neurons like on the way down.
59:24
Right.
59:24
Right, right.
59:25
Right, okay, yeah.
59:28
So, like a brain surgery, you know, you shouldn't treat it really lightly because neurosurgeons are fully aware that, you know, they can basically damage functions, right?
59:40
And so I think this is where histrity can also be super high impactful because we can treat a target tissue without damaging it.
59:50
those neurons in a way.
59:52
And we're not looking at just cancer.
59:54
We're looking at stroke.
59:57
We're looking at searching for a tumor, but we're looking at like functional disease such as epilepsy, right?
1:00:03
Things that you can possibly, you know, treat with ablation.
1:00:08
But beyond that,
1:00:10
We are also combining hisochitl with drug delivery.
1:00:14
And we have ultrasound ways that can improve the drug delivery that we can incorporate into the same system.
1:00:21
There is also, 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...
1:00:39
drug delivery through the blood-brain barriers, all those combined together.
1:00:42
So I think in the future, by doing a multimodal thing combined for the enhanced treatment therapy is a way to go to really bring a maximal benefits to the patients.
1:00:55
And I actually don't think this is science fiction.
1:01:01
It's actually...
1:01:03
can happen in the near future.
1:01:05
And that's why I'm really, again, doing this histotripsy center to mobilize as many scientists as I can possibly push to fund this together.
1:01:18
So I think the future is, and I'm making an announcement here, that we are entering a new era.
1:01:28
of non-invasive surgery.
1:01:31
And it's already starting.
1:01:35
That's amazing.
1:01:35
So the Star Trek hospital pod is actually becoming a reality.
1:01:40
Well, I mean, I could talk to you about this 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.
1:01:55
So congratulations on that.
1:01:57
I don't want to keep you any longer, but it's it's really incredible.
1:02:00
Some of the work that you do.
1:02:02
Congratulations.
1:02:03
Thank you.
1:02:03
And then I do want the audience to know the Triple S Golden Goose Award.
1:02:09
The one big thing is to really emphasize how federal funding is impacting the research.
1:02:18
And not just research, but research that produces a big impact on our society.
1:02:24
And I do want to note that for the history, it's just an example of the research that had been heavily funded by the federal funding.
1:02:37
And in my case, more than 90% of my research has been funded by National Institute of Health, NIH.
1:02:45
And especially at the beginning, when no investor, no company,
1:02:52
would be willing to put a penny into this at the early stage of the discovery where the government step up, NIH step up, and said, we will, you know, fund you to do very innovative work.
1:03:08
And now...
1:03:10
Over the 20 years, federal funding, NIH funded about $40 million.
1:03:17
But it has resulted in FDA approval, more than 5,000 patients treated, and his sonics is valued at $3.75 billion.
1:03:27
With a B.
1:03:28
With a B. Yeah.
1:03:30
And 500 employees, and the value is really climbing up.
1:03:34
And his Sonics was named this year by Time as one of the top 10 influential companies in life science and healthcare.
1:03:49
And I was named by Time 100 Global Healthcare Leaders.
1:03:55
But that's a different thing.
1:03:57
But this is showing that the government funding for research research.
1:04:04
really produces the big impact on healthcare and our society economy.
1:04:13
And this is precisely the reason that United States is leading the technical innovation.
1:04:20
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 research.
1:04:31
Yeah.
1:04:32
Well, I don't think I could have said it any better myself.
1:04:35
Thank you so much.
1:04:36
And we'll see you later this evening at the Library of Congress for your awards.
1:04:40
Thank you.