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Long-term organ cryopreservation and life-sustaining kidney transplantation in a rat model

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Could cryopreservation revolutionize organ transplantation by allowing planned procedures and equitable access through technology like nanowarming, shown to effectively restore full renal function in vitrified rat kidneys?

Image courtesy of interviewee. December 10, 2024

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This video discusses the concept of vitrification and its application in cryobiology, particularly for preserving biological organs. Vitrification involves cooling a biological system, such as an organ, to a glassy state using biologically compatible chemicals to prevent ice formation that could cause damage. The challenge of rewarming bulk biological systems without causing cracks or ice formation is addressed through a technique called "nano warming." This video involves using nanoparticles that heat uniformly throughout the organ, avoiding thermal stress during the warming process.

The speaker reflects on their extensive experience in cryobiology, the excitement surrounding the potential of organ banking, and the ongoing research into successfully vitrifying rat organs and eventually scaling this to larger organs like porcine and human kidneys. The success of their research demonstrates that vitrified rat kidneys can be revived and function normally after being transplanted back into rats.

Moreover, the discussion touches on ethical considerations in organ transplantation, particularly regarding cryopreserved organs and the potential for creating waiting lists for these organs. The speaker outlines future goals, such as expanding the work to include livers and exploring the use of organoids for diabetes treatment. They also mention collaborative efforts aimed at preserving biodiversity, including projects focused on coral preservation.

Overall, the text outlines significant advancements in organ preservation technology, the implications for transplant medicine, ethical considerations, and ongoing research challenges.

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1. **Vitrification Process and its Importance**: Vitrification involves transforming biological systems, such as organs, into a glassy state to prevent ice formation during freezing. This process is crucial for preserving organs without damage, allowing for organ banking and transplantation in the future.

2. **Nano Warming Technique**: The concept of nano warming addresses the challenges associated with rewarming bulk systems, like organs, which typically cool and warm unevenly, leading to ice formation and cracking. This technique employs magnetic nanoparticles to enable uniform warming from within the organ, minimizing thermal stress and preventing damage.

3. **Research Progress and Validation**: The research began with successful vitrification of small organs such as rat kidneys, demonstrating the feasibility of the process. The team is now focused on scaling these techniques to larger organs (such as porcine kidneys) and overcoming associated challenges, including cooling rates and nanoparticle production.

4. **Collaboration and Broader Impact**: The research is part of a collaboration involving multiple institutions and focuses not only on organ preservation for transplantation but also on other biological systems, including cell therapies and biodiversity conservation efforts (e.g., coral preservation).

5. **Ethical Considerations and Future Directions**: As the technology advances, ethical discussions around organ banking, selection criteria, and potential regulatory frameworks are imperative. Understanding the implications of using vitrified organs in transplantation and ensuring equitable access to these advancements is part of the ongoing research and societal dialogue.

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Here are some key quotes extracted from the video regarding vitrification, organ preservation, and the related research:

1. **Introduction to Vitrification**:
- "Vitrification is really about putting a biological system or any system into a glassy state."
- "What we try to do is to add biologically compatible chemicals that would stop that ice formation, and basically you just get ice."

2. **Challenges in Rewarming Organs**:
- "If we can do that inside an organ, then you avoid damaging the organ with the ice."
- "You’re putting something inside the middle that helps it rewarm at the same rate as on the side."

3. **Nano Warming Technique**:
- "Volumetric warming... is the whole idea."
- "We can avoid cracking a whole organ."

4. **Research Progress**:
- "With my colleague Eric Finger... we’re trying to address both the physical as well as the biological... challenges about how you bring this organ back from a vitrified state."

5. **Historical Convideo and Importance**:
- "Somebody had been able to actually vitrify, so put an organ into a glassy state."
- "The concept really is can we create a situation with an organ bank where organs are waiting for patients instead of patients waiting for organs?"

6. **Historical Reference**:
- "A guy named Greg Fahe had shown that you could actually vitrify a whole rabbit kidney."

7. **Experimentation and Results**:
- "We took out... both of the kidneys and just put one dry preserved kidney back into this animal, and then we let the animal live."
- "By 30 days, all of the control rats crop preservation or nano warming versus our nano warmed organ, they were essentially the same."

8. **Scaling Challenges**:
- "We’re trying to move into a porcine system."
- "So we’re, we’re working through all of that... we need to address each one of these challenges."

9. **Ethical Considerations**:
- "To what extent is that organ... the same that would be for transplant?"
- "There are some really... important things to talk about here."

10. **Future Directions**:
- "We’re cautiously optimistic that we will be renewed."
- "One of the issues with pancreatic eyelets is that you never get enough eyelets from one donor to actually transplant into a recipient."

These quotes capture the essence of the research and the innovative techniques being explored in the field of cryobiology and organ preservation.

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Vitrification is really about putting a biological system

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or any system into a glassy state.

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So a lot of times when you take water

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and you drop the temperature of that water

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below zero degrees Celsius, you're going to get ice.

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What we try to do is to add biologically compatible

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chemicals that would stop that ice formation,

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and basically you just get ice.

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So the, the water becomes more

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and more viscous until it turns into a glass.

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And if we can do that inside an organ, then you avoid

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damaging the organ with the ice.

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The problem with that is that people haven't been able

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to re, you know, rewarm a bulk system like an organ.

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And so you'll get cracking,

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and you'll also get ice formation in the, in the middle of

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that organ where it's slow, slow cooling

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and slow warming by diffusion.

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And we've overcome that using this idea called nano warming,

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which is a volumetric warming technique.

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Imagine an ice cube that you take out of the freezer

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and you put it in your drink,

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and, pretty much every time you do that, it cracks.

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And the reason for that is

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that it's still cold in the middle,

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but it's warming rapidly on the sides.

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And that's basically what happens

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to every bulk system when you try to rewarm it.

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Uh, so what volumetric rewarming does is you're putting

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something inside the middle

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that helps it rewarm at the same rate as on the side.

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And if you can do that, you can avoid cracking your ice cube

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and your drink, and we can avoid cracking a whole organ.

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And so volumetric warming, the way we do it is

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with nanoparticles or nano warmers,

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or whatever you want to call them.

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We call them nano warming, is the whole idea.

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Uh, and that allows us to come back fast in a way

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where the ice doesn't form

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and uniformly so that we don't crack the organ.

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And the comparison there in terms

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of the conventional approach is

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that you are not warming from within.

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And so you have both the fact that you're going too slow

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to avoid the ice, so the ice wants

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to form on the way back up.

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And if you don't go fast enough, it will.

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So the, the middle of the organ in

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particular is going to form ice.

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And then the other is the thing we just covered, which is

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that you're, you're warming on

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the boundary, but not the middle.

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So you set up a big temperature gradient

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and that drives thermal stress.

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And thermal stress then drives cracks.

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And this is the same kind of thing that happens in,

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in roadways and in other, physical situations

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that we all see out in, in the world.

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I have been in the field of cryobiology,

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I don't know, 40 years now.

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And when I first was starting as a PhD student,

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there was this great, let's call it our mu,

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our moonshot, if you will.

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Uh, somebody had been able to actually vitrify,

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so put an organ into a glassy state.

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And the whole field was really, really excited about this

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because it suggested that we might, in our lifetime be able

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to bank organs.

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And the reason why that's exciting is

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because, everybody has probably heard in whatever

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country you live in about an organ waiting list.

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And so the concept really is can we create a situation

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with an organ bank where organs are waiting for patients

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instead of patients waiting for organs?

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And that was the big idea.

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So that's why we really excited about this concept.

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If we can make this work for whole human organs, we set off

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to try and go after this moonshot.

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Um, there is a really famous researcher in my field, again,

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this was when I was a PhD student.

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He had published in the mid eighties.

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Guy named Greg Fahe, had shown

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that you could actually vitify a whole rabbit kidney.

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And if you go to Google images

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and you type in vitrified organ,

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this will be your first hit on the images will be Greg's

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vitrified kidney next to a frozen kidney.

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And it's just an iconic image

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that's been driving us all in the field for,

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you know, 40 years.

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And, what we wanted to do,

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with my colleague Eric Finger, who's a, a surgeon,

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and also has a,

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an undergraduate degree in engineering.

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Our labs have kind of merged on this topic

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to try to address this.

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So we're trying to address both the physical as well

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as the biological, I guess you'd call challenges about

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how you bring this organ back from a vitrified state,

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putting it into a vitrified state first,

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and then bringing it back.

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And so we decided to work with rat organs first

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because they're smaller

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and they're a little more, they're much easier to work

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with than a, than a human organ.

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Uh, and it still is.

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You'd think, well, somebody must have done a rat organ

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of some sort, but the reality is that they haven't.

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And in terms of the, the relevance of the size

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of this organ, you can think of pediatric organs.

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Uh, so in other words, there are pediatric patients

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and there are human patients out out there in the world

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that could even benefit from this size of an organ,

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even though it is small, it's a small kidney.

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Uh, but what we did then is we, we found a,

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these biologically, compatible molecules

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that we could actually perfuse into the rat organ so

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that it would actually, then we could drop the temperature

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and the organ would go into the vitrified or glassy state.

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And then we also designed these magnetic nanoparticles

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that we could at the very last moment

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before we cooled the organ,

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we would infuse them throughout the

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vasculature of the organ.

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So they're not in every cell, they're not,

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going into every cell of the, the tissue.

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But in that maybe 15%, let's say, of the organ,

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which is the vascular space, would be filled

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with these magnetic nanoparticles. And

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Then it would all vitrify.

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We would, we would cool it down, it would vitrify.

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We would have it just the same as Greg did, you know,

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some 40 years ago.

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The difference with what, Greg did where he had

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to bring it back convectively, is

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that we could stick it in a radio frequency coil

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and these magnetic nanoparticles then would couple

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with the electromagnetic fields

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and they would begin to warm.

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And of course there's lots of optimization

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and you know, we have to get the field strength right

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and the frequency, and we have to get the right amount

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of the iron oxide in there.

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But we figured all those things out

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and then we rewarmed it in a fast enough rate

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of something like 70 C per minute throughout the organ.

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And we avoided ice on the way back up,

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and we avoided thermal stress and we avoided cracks.

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And then we took these organs

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and we put them back into a rat.

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And it wasn't just a rat that already had two great kidneys,

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which is probably how we would do it

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with a human if we were ever to do this right.

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We would take, an organ

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and the two, kidneys that were in there,

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maybe they wouldn't be working properly,

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but we would then,

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have this extra kidney on top of that.

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Well, in, in this case, we did

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what we would call a worst case scenario.

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So we actually took out, we nephrectomies the, the animal.

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So we took out both of the kidneys

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and we just put one dry preserve kidney back into this

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animal, and then we let the animal live.

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And what we saw was over the course of about two weeks,

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that there was a spike in some of the biomarkers,

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like creatinine, which is one of the things that we try

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to get rid of in, in our blood.

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That's what, the kidney is trying to filter out.

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So there was a spike in that,

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and there was a spike in other biomarkers,

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but within two weeks, without any other help to the animal,

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they were able to come back down to normal, biomarkers

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and, and everything that we looked at, pH, creatinine,

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et cetera, by 30 days, all of the, the control rats

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that had just an organ that was put, put back in no,

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crop, crop preservation

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or nano warming versus our nano warmed organ,

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they were essentially the same, all of the markers.

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And so, you know, this, this animal made it to 30 days.

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We were very excited

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and we also had many of these organs, we kept them

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for different timeframes.

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So one of those organs was actually kept for a hundred days

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in the deep freeze.

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And so when you can go to a hundred days,

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you can go to a hundred years.

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And that's pretty exciting.

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We're in the middle of those challenges right now.

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So we're, we're trying to move into a porcine system.

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And, and again, we're trying to do this step by step and,

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and give ourselves, the,

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the proper challenges, one at a time.

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The porcine kidney, the, the, we're using, a pig

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that's actually the kidney is larger than,

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than a human kidney.

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Uh, so, we are now struggling with,

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actually we turned the problem around.

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So now, now it's a question

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of can we actually cool it fast enough?

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Because as they get bigger, then you have

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that problem as well, right?

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Because you have diffusion also on the way down,

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and you're, you're gonna have the cool,

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the cooling rates will be the, the slowest in the center.

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So we have some,

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physical studies coming out talking about how to do

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that in the best way and the fastest way

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to actually have success for a large system like a kidney

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or even a human liver, and how to do that.

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And so we're, we're, we're working through all of that.

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We think we've got that figured out

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and now we're in the process of,

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making enough nanoparticles.

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'cause you need to scale the nanoparticles

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to have enough to go around.

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And also we're gonna need to have those be GMP, you know,

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good manufacturing, processes and so on.

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So it can be used in a human system.

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Uh, and then we need to have a coil that's big enough

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to actually take these human organs.

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And so we, we are addressing each one of these challenges.

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And, we're cautiously optimistic

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that we'll have something to report in the spring.

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The pore sign organs that we are working with

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are actually larger than the human kidney.

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And so the hope, of course, is that this will translate well

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and, and relatively easily into the human kidney.

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One thing I will point you to, so, so,

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you can see in my background I have, it says,

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well, the, it stands for Advanced Technologies

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for the Preservation of Biological Systems.

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So this is a National Science Foundation Engineering

234
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research Center grant in the United States,

235
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and it's a $26 million five year renewable grant.

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Uh, we just went through our renewal site visit

237
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and we're cautiously optimistic that we will be renewed.

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And, this is,

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over 30 faculty across six institutions.

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Over a hundred trainees, probably 20

241
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or so, technicians and staff that are working on this.

242
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And not just the organ piece.

243
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We're working across all test beds.

244
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So test beds for us are cells for cell therapies, tissues

245
00:11:06.015 --> 00:11:07.935
for drug testing, like liver slices

246
00:11:07.935 --> 00:11:12.055
or brain slices, organoids like pancreatic eyelets,

247
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which is another thing that we're, we're working on

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to cure diabetes.

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Uh, and then whole organs of course,

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and then whole organisms for biodiversity, for instance.

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So we're working on, with the Smithsonian

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to actually create a lunar bio repository that would be like

253
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for fauna, what we have in swell bard for seeds.

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So it's a very big, idea within it.

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We have an ethics group that's led by Tim Pruitt, who's a,

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surgeon who's worked

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with the transplant societies across the world.

258
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And Susan Wolf, who's an ethicist, very famous ethicist,

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she's part of the National Academy of Medicine.

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Uh, and so they just put together,

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a, symposium of papers, actually 10 papers

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that are in the Journal of Law, medicine and Ethics, JLME,

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and it's just coming out.

264
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And there are a series

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of papers talking about not just organs,

266
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but all these test beds

267
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and how they will be ethically deployed

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for societal benefit.

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So I would point you in that direction.

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There's also a paper that just came out

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that Tim Pruitt is the first author on

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in the American Journal of Transplant, talking exactly about

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how this will be regulated.

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00:12:25.545 --> 00:12:29.285
So let's imagine that we actually have a cryopreserved

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organ, a human organ, and we bring it back.

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Is that organ, and this is something Tim goes

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after me about all the time.

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Uh, to what extent is that organ, the same

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as a, an organ that you would have

280
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that would be for transplant?

281
00:12:46.685 --> 00:12:50.305
And, and the reality is that it's not equivalent, right?

282
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We can't claim that this is the equivalent of an organ

283
00:12:54.505 --> 00:12:55.785
that was just taken out of,

284
00:12:55.785 --> 00:12:57.505
let's take the best case scenario, right?

285
00:12:57.845 --> 00:13:00.625
You have somebody in your family who's gonna donate one

286
00:13:00.625 --> 00:13:02.785
of their kidneys to you, and they're in the

287
00:13:02.885 --> 00:13:06.465
or next door, that kidney comes out within, you know,

288
00:13:06.745 --> 00:13:08.145
whatever, half an hour or so,

289
00:13:08.195 --> 00:13:11.105
let's say it comes into the next, or, and it goes into you.

290
00:13:11.835 --> 00:13:14.105
Let's take that as the best possible case

291
00:13:14.255 --> 00:13:16.665
with probably the best immune tolerance, right?

292
00:13:16.845 --> 00:13:19.065
So you, it's in the family, et cetera.

293
00:13:19.885 --> 00:13:21.905
Now, you take a cryopreserved organ,

294
00:13:22.255 --> 00:13:26.065
this organ might be at the end of it's, they,

295
00:13:26.265 --> 00:13:28.065
the organs actually get shopped around.

296
00:13:28.245 --> 00:13:30.105
That's not always known, but it's true.

297
00:13:30.925 --> 00:13:32.705
You need to find the recipient.

298
00:13:33.085 --> 00:13:34.865
So you're calling around to hospitals

299
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to see whether they have a proper recipient for the organ,

300
00:13:38.495 --> 00:13:40.595
and maybe the first hospital doesn't work out,

301
00:13:41.055 --> 00:13:43.515
or the first recipient doesn't work out for whatever reason.

302
00:13:43.575 --> 00:13:45.395
So then you go to the next and the next.

303
00:13:45.975 --> 00:13:47.595
And so this can go on for hours.

304
00:13:48.335 --> 00:13:52.515
So maybe you're at the end of the time that's available

305
00:13:52.655 --> 00:13:55.075
for this organ to actually go directly into a person

306
00:13:55.895 --> 00:13:58.795
and maybe, and, these are all hypotheticals here, okay?

307
00:13:58.835 --> 00:14:00.355
I just want to make sure you understand that.

308
00:14:00.355 --> 00:14:01.995
And I am not a transplant surgeon,

309
00:14:02.415 --> 00:14:06.035
but let's say at the end of this process, you say,

310
00:14:06.095 --> 00:14:08.635
all right, well, this is the, the, the end of the,

311
00:14:08.895 --> 00:14:10.875
the useful life of this organ.

312
00:14:11.605 --> 00:14:13.155
Let's go ahead and cryopreserve it.

313
00:14:14.145 --> 00:14:16.285
And so then you cryopreserve it and, and,

314
00:14:16.505 --> 00:14:18.405
and in so doing, like,

315
00:14:18.405 --> 00:14:20.925
you're not taking it away from somebody, right?

316
00:14:20.925 --> 00:14:22.885
Because that would be unethical.

317
00:14:23.265 --> 00:14:24.685
Why would you take away an organ

318
00:14:24.685 --> 00:14:26.525
that could be transplanted into somebody,

319
00:14:26.545 --> 00:14:29.085
but it's at the end of its useful life, let's say.

320
00:14:29.715 --> 00:14:33.085
Then you do it, but the organ is going to

321
00:14:33.605 --> 00:14:36.165
actually not be exactly equivalent

322
00:14:36.165 --> 00:14:37.725
after the cryo-preservation procedure.

323
00:14:37.785 --> 00:14:41.325
So it's gonna come out and it's probably gonna need some

324
00:14:41.405 --> 00:14:44.085
kind of resuscitation, some kind of rejuvenation.

325
00:14:44.665 --> 00:14:47.965
And there are actually companies out there that do this, EDS

326
00:14:47.985 --> 00:14:49.965
and others that do norm themic profusion

327
00:14:50.025 --> 00:14:53.005
and things that can actually bring an organ back

328
00:14:53.065 --> 00:14:56.685
or make it, more, functional, let's say.

329
00:14:57.425 --> 00:15:01.005
Uh, and then it might be transplanted, but then, or,

330
00:15:01.025 --> 00:15:02.765
or could be a candidate for transplant.

331
00:15:02.905 --> 00:15:06.785
But then you have to ask yourself, who would be the person

332
00:15:07.175 --> 00:15:09.905
that would, receive this organ?

333
00:15:11.015 --> 00:15:13.195
And I am completely speculating here.

334
00:15:14.075 --> 00:15:15.555
I don't know that that would be

335
00:15:16.065 --> 00:15:18.355
what is currently in the organ waiting list.

336
00:15:18.875 --> 00:15:22.715
I think it would be something else, maybe a a a shadow list

337
00:15:22.715 --> 00:15:24.235
or a second list of some sort,

338
00:15:24.935 --> 00:15:26.715
and you would have to elect to be on it.

339
00:15:27.575 --> 00:15:30.755
But, you know, we read in the paper about people who die

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00:15:30.755 --> 00:15:32.435
because they're sitting on the waiting list.

341
00:15:32.765 --> 00:15:36.515
Maybe people even, you know, 40 years old, 50 years old,

342
00:15:36.535 --> 00:15:38.755
or even younger perhaps, or older.

343
00:15:39.415 --> 00:15:41.715
But, you know, if you're a 40-year-old person

344
00:15:42.455 --> 00:15:45.475
and this is the thing that's gonna, you know, make

345
00:15:45.495 --> 00:15:46.795
or break your life

346
00:15:47.935 --> 00:15:49.955
and you can't get the other organ,

347
00:15:50.165 --> 00:15:51.955
would you accept a crop preserved organ?

348
00:15:52.855 --> 00:15:55.235
And so that, that, you know, the answer there, probably,

349
00:15:55.235 --> 00:15:56.835
if it was me, I'd probably say yes,

350
00:15:57.095 --> 00:16:00.595
but an ethicist might say, well, you're being compelled.

351
00:16:02.615 --> 00:16:04.835
So it's thorny.

352
00:16:05.155 --> 00:16:06.915
I mean, there, there's a lot of discussion

353
00:16:06.915 --> 00:16:09.075
that's needed there, but I think it's still,

354
00:16:09.465 --> 00:16:10.835
it's still a great opportunity.

355
00:16:11.255 --> 00:16:15.915
Oregon use policy is different across the world.

356
00:16:16.215 --> 00:16:18.235
So what we do in the United States

357
00:16:18.975 --> 00:16:20.995
is different than in Canada, is different than in Europe,

358
00:16:21.015 --> 00:16:22.595
is different than Japan, et cetera.

359
00:16:23.505 --> 00:16:24.795
Some d some,

360
00:16:24.825 --> 00:16:26.835
some stuff is the same, but some is different.

361
00:16:27.535 --> 00:16:29.555
And so what's interesting is like

362
00:16:29.585 --> 00:16:32.235
what we might call an extended criteria organ

363
00:16:32.375 --> 00:16:34.315
or an organ that we just wouldn't use

364
00:16:34.315 --> 00:16:35.995
because maybe somebody's too old

365
00:16:36.095 --> 00:16:38.275
and that's like a, maybe an artificial cutoff.

366
00:16:38.275 --> 00:16:40.035
It might be whatever age, right?

367
00:16:40.785 --> 00:16:43.075
They don't have the same cutoff in Europe.

368
00:16:43.455 --> 00:16:46.275
So let's say that you then were able to preserve

369
00:16:47.155 --> 00:16:48.975
or whatever, like our,

370
00:16:49.035 --> 00:16:51.375
our preservation technology now could go out

371
00:16:51.375 --> 00:16:52.815
indefinitely if it works.

372
00:16:52.875 --> 00:16:55.335
And when it works, there are other techniques.

373
00:16:55.355 --> 00:16:58.455
So there are people, like Corco, Oregon and me toner

374
00:16:58.455 --> 00:17:01.615
and, others at MGH Massachusetts General Hospital,

375
00:17:02.205 --> 00:17:05.095
they're able to take a human kidney out to 30 days

376
00:17:06.085 --> 00:17:09.075
right now, and they can take a human liver out,

377
00:17:09.375 --> 00:17:10.395
for more than a day.

378
00:17:11.065 --> 00:17:14.985
That already is enough time to allow that organ

379
00:17:15.365 --> 00:17:18.305
to be trans transported in ways

380
00:17:18.305 --> 00:17:20.305
that is not currently available, right?

381
00:17:20.505 --> 00:17:22.985
I mean, we're talking hours typically.

382
00:17:23.485 --> 00:17:26.065
And that hour means like there's, there's gonna be some kind

383
00:17:26.065 --> 00:17:29.665
of a bullseye around wherever the donation is made,

384
00:17:30.085 --> 00:17:32.425
and that bullseye is gonna remain in the United States,

385
00:17:32.845 --> 00:17:36.385
or, you know, speaking from, you know, the US side, the,

386
00:17:36.445 --> 00:17:40.185
if you now extend that timeframe to 20 hours,

387
00:17:40.685 --> 00:17:42.305
30 hours, 30 days,

388
00:17:43.165 --> 00:17:45.545
now you can share organs across continents

389
00:17:45.645 --> 00:17:47.705
and across international borders.

390
00:17:47.705 --> 00:17:51.765
So that opens up really amazing opportunity, I think,

391
00:17:51.785 --> 00:17:54.165
in terms of making sure that there's,

392
00:17:54.915 --> 00:17:56.485
there's going to be adequate sharing.

393
00:17:57.335 --> 00:18:01.415
There are, concerns that can come with this too,

394
00:18:01.415 --> 00:18:03.095
though there really aren't a lot

395
00:18:03.095 --> 00:18:06.015
of transplant programs in Sub-Saharan Africa, you know,

396
00:18:06.015 --> 00:18:07.295
in different parts of the world.

397
00:18:08.505 --> 00:18:11.325
So you don't want this to turn into something

398
00:18:11.325 --> 00:18:12.845
where it's extractive

399
00:18:13.345 --> 00:18:15.685
and you're pulling organs from one part of the world

400
00:18:15.905 --> 00:18:17.965
for the benefit of, of the other part of the world.

401
00:18:18.585 --> 00:18:21.805
So there, there are some really, I think, intriguing

402
00:18:22.105 --> 00:18:23.725
and important things to talk about here.

403
00:18:23.745 --> 00:18:25.765
And, and they, what Susan

404
00:18:25.865 --> 00:18:27.925
and Tim like to talk about is the need

405
00:18:28.065 --> 00:18:31.045
for anticipatory governance around these types

406
00:18:31.065 --> 00:18:33.165
of big platform technologies that are coming.

407
00:18:33.385 --> 00:18:36.165
And they are coming. I have an amazing

408
00:18:36.605 --> 00:18:38.285
collaboration, with Dr.

409
00:18:38.285 --> 00:18:40.925
Eric Finger. He's, he's just an incredibly talented

410
00:18:41.445 --> 00:18:42.885
MD PhD surgeon.

411
00:18:43.545 --> 00:18:44.885
I'm an engineer. And,

412
00:18:45.105 --> 00:18:48.125
and together we're doing what people call team science.

413
00:18:48.265 --> 00:18:50.525
And we're, we're a a piece of this larger

414
00:18:51.165 --> 00:18:52.605
engineering research center grant,

415
00:18:52.865 --> 00:18:55.605
and we're really literally trying to change the world

416
00:18:56.145 --> 00:18:59.605
by making living biological systems available for all right?

417
00:18:59.825 --> 00:19:02.845
So like I said before, cells for cell therapy, tissues

418
00:19:02.845 --> 00:19:05.965
for tissue testing and drug discovery,

419
00:19:06.105 --> 00:19:07.445
organs as we discussed.

420
00:19:07.445 --> 00:19:08.725
And then whole organisms.

421
00:19:09.545 --> 00:19:13.005
Uh, so our next big,

422
00:19:13.355 --> 00:19:16.805
work in the healthcare area is, livers

423
00:19:17.345 --> 00:19:21.175
and kidneys trying to vitify them and bring them back.

424
00:19:22.275 --> 00:19:24.575
And then we're also working on organoids.

425
00:19:24.795 --> 00:19:28.135
So we have a very active program with pancreatic eyelets.

426
00:19:28.135 --> 00:19:30.575
We published in nature medicine a few years ago,

427
00:19:31.315 --> 00:19:32.855
and we have the ability now

428
00:19:32.875 --> 00:19:35.935
to actually vitify pancreatic eyelets and store them.

429
00:19:36.395 --> 00:19:38.575
One of the issues with pancreatic eyelets is

430
00:19:38.575 --> 00:19:41.095
that you never get enough eyelets from one donor

431
00:19:41.795 --> 00:19:45.015
to actually transplant into a recipient and cure diabetes.

432
00:19:45.115 --> 00:19:47.575
So you have to pool those eyelets.

433
00:19:47.715 --> 00:19:49.775
And so now, because of cryopreservation

434
00:19:49.835 --> 00:19:53.215
and our, our protocol, which works exceedingly well,

435
00:19:53.215 --> 00:19:55.335
meant much better than what was conventionally done.

436
00:19:55.715 --> 00:19:57.535
We can actually pool eyelets

437
00:19:57.595 --> 00:19:59.735
and we believe we have the solution

438
00:20:00.035 --> 00:20:01.375
to actually cure diabetes.

439
00:20:01.515 --> 00:20:04.335
And this can be done with isolated eyelets,

440
00:20:04.335 --> 00:20:06.775
but it also can be done with stem cell derived eyelets.

441
00:20:06.775 --> 00:20:08.095
There's a lot of activity

442
00:20:08.315 --> 00:20:10.295
and billion dollar companies that are up

443
00:20:10.295 --> 00:20:11.975
and coming around the world for that.

444
00:20:12.785 --> 00:20:15.125
Uh, and then we want to move into other organoid systems,

445
00:20:15.265 --> 00:20:18.965
so cardiac systems, brain organoids

446
00:20:18.965 --> 00:20:22.215
and other things that can be used for transplant,

447
00:20:22.235 --> 00:20:24.815
but also diagnostic purposes like drug discovery.

448
00:20:25.515 --> 00:20:26.855
So that's the healthcare piece.

449
00:20:27.155 --> 00:20:30.415
And then, the EARC is also working, as I said,

450
00:20:30.475 --> 00:20:32.455
on things like, lunar biorepository

451
00:20:32.595 --> 00:20:33.695
for, for biodiversity.

452
00:20:34.435 --> 00:20:38.055
We collaborate with the Smithsonian on, trying

453
00:20:38.055 --> 00:20:42.295
to actually cryopreserve coral, from endangered areas

454
00:20:42.355 --> 00:20:44.935
around the world, the Great Barrier Reef being one of them,

455
00:20:45.155 --> 00:20:46.735
Hawaii, Esau, Taiwan,

456
00:20:47.325 --> 00:20:49.245
A bunch of different places as well.

457
00:20:49.815 --> 00:20:52.645
We're trying to actually use Coral as a model system

458
00:20:52.745 --> 00:20:54.405
to understand how to work

459
00:20:54.405 --> 00:20:56.885
with endangered ecosystems around the world.

460
00:20:57.065 --> 00:21:00.045
And if we can learn how to do this well with coral, so

461
00:21:00.045 --> 00:21:02.445
for instance, they only spawn a couple nights a year,

462
00:21:03.185 --> 00:21:05.045
if we can gather enough embryos

463
00:21:05.045 --> 00:21:06.365
and then larva,

464
00:21:06.425 --> 00:21:09.085
we actually can do coral aquaculture on land.

465
00:21:10.105 --> 00:21:11.965
And then we don't get the tremendous

466
00:21:11.965 --> 00:21:13.325
attrition that you do in the ocean.

467
00:21:13.385 --> 00:21:15.605
We can actually grow up a lot of these polyps

468
00:21:16.065 --> 00:21:18.245
and then replace them in the ocean under the best

469
00:21:18.245 --> 00:21:19.805
of conditions so that they can grow.

470
00:21:20.385 --> 00:21:23.005
And we could also do things like assisted gene flow,

471
00:21:23.005 --> 00:21:25.245
which has been shown to actually, you know,

472
00:21:25.245 --> 00:21:28.285
bring from one part of the planet where they are doing well,

473
00:21:28.395 --> 00:21:31.325
same species, and then grow them with, you know,

474
00:21:31.325 --> 00:21:34.805
and bring in more genetic variation, more ability to deal

475
00:21:34.805 --> 00:21:38.925
with stress and basically, grow out coral and,

476
00:21:38.925 --> 00:21:40.605
and help that ecosystem survive.

477
00:21:40.785 --> 00:21:43.965
And then figure from there, then you move into what other,

478
00:21:44.185 --> 00:21:46.165
terrestrial or aquatic system

479
00:21:46.185 --> 00:21:48.005
and you can pick other keystone species

480
00:21:48.185 --> 00:21:50.485
and hopefully, assist in that way.

Advancements in Vitrification: Overcoming Ice Formation in Organ Preservation

00:00:00 - Vitrification is really about putting a biological system or any system into a glassy state. So a lot of times when you take water and you drop the temperature of that water below zero degrees Celsius, you're going to get ice. What we try to do is to add biologically compatible chemicals that would stop that ice formation, and basically you just get ice. So the, the water becomes more and more viscous until it turns into a glass. And if we can do that inside an organ, then you avoid damaging the organ with the ice.

00:00:37 - to re, you know, rewarm a bulk system like an organ. And so you'll get cracking, and you'll also get ice formation in the, in the middle of that organ where it's slow, slow cooling and slow warming by diffusion. And we've overcome that using this idea called nano warming, which is a volumetric warming technique. Imagine an ice cube that you take out of the freezer and you put it in your drink, and, pretty much every time you do that, it cracks.

00:01:06 - that it's still cold in the middle, but it's warming rapidly on the sides. And that's basically what happens to every bulk system when you try to rewarm it. so what volumetric rewarming does is you're putting something inside the middle that helps it rewarm at the same rate as on the side. And if you can do that, you can avoid cracking your ice cube and your drink, and we can avoid cracking a whole organ. And so volumetric warming, the way we do it is

Advancements in Nano Warming for Organ Preservation

00:01:39 - or whatever you want to call them. We call them nano warming, is the whole idea. and that allows us to come back fast in a way where the ice doesn't form and uniformly so that we don't crack the organ. And the comparison there in terms of the conventional approach is that you are not warming from within. And so you have both the fact that you're going too slow to avoid the ice, so the ice wants to form on the way back up.

00:02:09 - So the, the middle of the organ in particular is going to form ice. And then the other is the thing we just covered, which is that you're, you're warming on the boundary, but not the middle. So you set up a big temperature gradient and that drives thermal stress. And thermal stress then drives cracks. And this is the same kind of thing that happens in, in roadways and in other, physical situations that we all see out in, in the world. I have been in the field of cryobiology,

00:02:40 - And when I first was starting as a PhD student, there was this great, let's call it our mu, our moonshot, if you will. somebody had been able to actually vitrify, so put an organ into a glassy state. And the whole field was really, really excited about this because it suggested that we might, in our lifetime be able to bank organs. And the reason why that's exciting is

Creating an Organ Bank: The Future of Vitrified Transplants

00:03:11 - country you live in about an organ waiting list. And so the concept really is can we create a situation with an organ bank where organs are waiting for patients instead of patients waiting for organs? And that was the big idea. So that's why we really excited about this concept. If we can make this work for whole human organs, we set off to try and go after this moonshot. there is a really famous researcher in my field, again,

00:03:42 - He had published in the mid eighties. Guy named Greg Fahe, had shown that you could actually vitify a whole rabbit kidney. And if you go to Google images and you type in vitrified organ, this will be your first hit on the images will be Greg's vitrified kidney next to a frozen kidney. And it's just an iconic image that's been driving us all in the field for, you know, 40 years. And, what we wanted to do, with my colleague Eric Finger, who's a, a surgeon,

00:04:14 - an undergraduate degree in engineering. Our labs have kind of merged on this topic to try to address this. So we're trying to address both the physical as well as the biological, I guess you'd call challenges about how you bring this organ back from a vitrified state, putting it into a vitrified state first, and then bringing it back. And so we decided to work with rat organs first because they're smaller and they're a little more, they're much easier to work

Vitrification Techniques for Pediatric Organ Preservation

00:04:46 - and it still is. You'd think, well, somebody must have done a rat organ of some sort, but the reality is that they haven't. And in terms of the, the relevance of the size of this organ, you can think of pediatric organs. so in other words, there are pediatric patients and there are human patients out out there in the world that could even benefit from this size of an organ, even though it is small, it's a small kidney. but what we did then is we, we found a,

00:05:19 - that we could actually perfuse into the rat organ so that it would actually, then we could drop the temperature and the organ would go into the vitrified or glassy state. And then we also designed these magnetic nanoparticles that we could at the very last moment before we cooled the organ, we would infuse them throughout the vasculature of the organ. So they're not in every cell, they're not, going into every cell of the, the tissue.

00:05:51 - which is the vascular space, would be filled with these magnetic nanoparticles. And Then it would all vitrify. We would, we would cool it down, it would vitrify. We would have it just the same as Greg did, you know, some 40 years ago. The difference with what, Greg did where he had to bring it back convectively, is that we could stick it in a radio frequency coil and these magnetic nanoparticles then would couple with the electromagnetic fields and they would begin to warm.

Successful Rewarming and Functional Recovery of Vitrified Kidneys in Rats

00:06:21 - and you know, we have to get the field strength right and the frequency, and we have to get the right amount of the iron oxide in there. But we figured all those things out and then we rewarmed it in a fast enough rate of something like 70 C per minute throughout the organ. And we avoided ice on the way back up, and we avoided thermal stress and we avoided cracks. And then we took these organs and we put them back into a rat. And it wasn't just a rat that already had two great kidneys,

00:06:53 - with a human if we were ever to do this right. We would take, an organ and the two, kidneys that were in there, maybe they wouldn't be working properly, but we would then, have this extra kidney on top of that. Well, in, in this case, we did what we would call a worst case scenario. So we actually took out, we nephrectomies the, the animal. So we took out both of the kidneys and we just put one dry preserve kidney back into this animal, and then we let the animal live.

00:07:25 - that there was a spike in some of the biomarkers, like creatinine, which is one of the things that we try to get rid of in, in our blood. That's what, the kidney is trying to filter out. So there was a spike in that, and there was a spike in other biomarkers, but within two weeks, without any other help to the animal, they were able to come back down to normal, biomarkers and, and everything that we looked at, pH, creatinine, et cetera, by 30 days, all of the, the control rats

Advancements in Organ Preservation Techniques

00:08:00 - crop, crop preservation or nano warming versus our nano warmed organ, they were essentially the same, all of the markers. And so, you know, this, this animal made it to 30 days. We were very excited and we also had many of these organs, we kept them for different timeframes. So one of those organs was actually kept for a hundred days in the deep freeze. And so when you can go to a hundred days,

00:08:30 - And that's pretty exciting. We're in the middle of those challenges right now. So we're, we're trying to move into a porcine system. And, and again, we're trying to do this step by step and, and give ourselves, the, the proper challenges, one at a time. The porcine kidney, the, the, we're using, a pig that's actually the kidney is larger than, than a human kidney. so, we are now struggling with, actually we turned the problem around.

00:09:01 - of can we actually cool it fast enough? Because as they get bigger, then you have that problem as well, right? Because you have diffusion also on the way down, and you're, you're gonna have the cool, the cooling rates will be the, the slowest in the center. So we have some, physical studies coming out talking about how to do that in the best way and the fastest way to actually have success for a large system like a kidney or even a human liver, and how to do that. And so we're, we're, we're working through all of that.

Scaling Nanoparticles for Human Organ Preservation

00:09:33 - and now we're in the process of, making enough nanoparticles. 'cause you need to scale the nanoparticles to have enough to go around. And also we're gonna need to have those be GMP, you know, good manufacturing, processes and so on. So it can be used in a human system. and then we need to have a coil that's big enough to actually take these human organs. And so we, we are addressing each one of these challenges. And, we're cautiously optimistic

00:10:05 - The pore sign organs that we are working with are actually larger than the human kidney. And so the hope, of course, is that this will translate well and, and relatively easily into the human kidney. One thing I will point you to, so, so, you can see in my background I have, it says, well, the, it stands for Advanced Technologies for the Preservation of Biological Systems. So this is a National Science Foundation Engineering research Center grant in the United States,

00:10:38 - we just went through our renewal site visit and we're cautiously optimistic that we will be renewed. And, this is, over 30 faculty across six institutions. Over a hundred trainees, probably 20 or so, technicians and staff that are working on this. And not just the organ piece. We're working across all test beds. So test beds for us are cells for cell therapies, tissues

Advancements in Organ Preservation and Ethical Considerations

00:11:07 - or brain slices, organoids like pancreatic eyelets, which is another thing that we're, we're working on to cure diabetes. and then whole organs of course, and then whole organisms for biodiversity, for instance. So we're working on, with the Smithsonian to actually create a lunar bio repository that would be like for fauna, what we have in swell bard for seeds. So it's a very big, idea within it. We have an ethics group that's led by Tim Pruitt, who's a,

00:11:41 - with the transplant societies across the world. And Susan Wolf, who's an ethicist, very famous ethicist, she's part of the National Academy of Medicine. and so they just put together, a, symposium of papers, actually 10 papers that are in the Journal of Law, medicine and Ethics, JLME, and it's just coming out. And there are a series of papers talking about not just organs, but all these test beds

00:12:11 - for societal benefit. So I would point you in that direction. There's also a paper that just came out that Tim Pruitt is the first author on in the American Journal of Transplant, talking exactly about how this will be regulated. So let's imagine that we actually have a cryopreserved organ, a human organ, and we bring it back. Is that organ, and this is something Tim goes after me about all the time. to what extent is that organ, the same

Transplant Challenges: Cryopreserved Organ Viability

00:12:45 - that would be for transplant? And, and the reality is that it's not equivalent, right? We can't claim that this is the equivalent of an organ that was just taken out of, let's take the best case scenario, right? You have somebody in your family who's gonna donate one of their kidneys to you, and they're in the or next door, that kidney comes out within, you know, whatever, half an hour or so, let's say it comes into the next, or, and it goes into you. Let's take that as the best possible case

00:13:16 - So you, it's in the family, et cetera. Now, you take a cryopreserved organ, this organ might be at the end of it's, they, the organs actually get shopped around. That's not always known, but it's true. You need to find the recipient. So you're calling around to hospitals to see whether they have a proper recipient for the organ, and maybe the first hospital doesn't work out, or the first recipient doesn't work out for whatever reason. So then you go to the next and the next.

00:13:48 - So maybe you're at the end of the time that's available for this organ to actually go directly into a person and maybe, and, these are all hypotheticals here, okay? I just want to make sure you understand that. And I am not a transplant surgeon, but let's say at the end of this process, you say, all right, well, this is the, the, the end of the, the useful life of this organ. Let's go ahead and cryopreserve it. And so then you cryopreserve it and, and,

Ethical Considerations in Cryopreserved Organ Transplants

00:14:18 - you're not taking it away from somebody, right? Because that would be unethical. Why would you take away an organ that could be transplanted into somebody, but it's at the end of its useful life, let's say. Then you do it, but the organ is going to actually not be exactly equivalent after the cryo-preservation procedure. So it's gonna come out and it's probably gonna need some kind of resuscitation, some kind of rejuvenation. And there are actually companies out there that do this, EDS

00:14:50 - and things that can actually bring an organ back or make it, more, functional, let's say. and then it might be transplanted, but then, or, or could be a candidate for transplant. But then you have to ask yourself, who would be the person that would, receive this organ? And I am completely speculating here. I don't know that that would be what is currently in the organ waiting list.

00:15:22 - or a second list of some sort, and you would have to elect to be on it. But, you know, we read in the paper about people who die because they're sitting on the waiting list. Maybe people even, you know, 40 years old, 50 years old, or even younger perhaps, or older. But, you know, if you're a 40-year-old person and this is the thing that's gonna, you know, make or break your life and you can't get the other organ,

Ethical Considerations in Organ Preservation and Policy

00:15:52 - And so that, that, you know, the answer there, probably, if it was me, I'd probably say yes, but an ethicist might say, well, you're being compelled. So it's thorny. I mean, there, there's a lot of discussion that's needed there, but I think it's still, it's still a great opportunity. Oregon use policy is different across the world. So what we do in the United States is different than in Canada, is different than in Europe,

00:16:23 - Some d some, some stuff is the same, but some is different. And so what's interesting is like what we might call an extended criteria organ or an organ that we just wouldn't use because maybe somebody's too old and that's like a, maybe an artificial cutoff. It might be whatever age, right? They don't have the same cutoff in Europe. So let's say that you then were able to preserve or whatever, like our, our preservation technology now could go out

00:16:52 - And when it works, there are other techniques. So there are people, like Corco, Oregon and me toner and, others at MGH Massachusetts General Hospital, they're able to take a human kidney out to 30 days right now, and they can take a human liver out, for more than a day. That already is enough time to allow that organ to be trans transported in ways that is not currently available, right? I mean, we're talking hours typically.

Global Opportunities and Concerns in Organ Sharing

00:17:26 - of a bullseye around wherever the donation is made, and that bullseye is gonna remain in the United States, or, you know, speaking from, you know, the US side, the, if you now extend that timeframe to 20 hours, 30 hours, 30 days, now you can share organs across continents and across international borders. So that opens up really amazing opportunity, I think, in terms of making sure that there's,

00:17:57 - There are, concerns that can come with this too, though there really aren't a lot of transplant programs in Sub-Saharan Africa, you know, in different parts of the world. So you don't want this to turn into something where it's extractive and you're pulling organs from one part of the world for the benefit of, of the other part of the world. So there, there are some really, I think, intriguing and important things to talk about here. And, and they, what Susan

00:18:28 - for anticipatory governance around these types of big platform technologies that are coming. And they are coming. I have an amazing collaboration, with Dr. Eric Finger. He's, he's just an incredibly talented MD PhD surgeon. I'm an engineer. And, and together we're doing what people call team science. And we're, we're a a piece of this larger engineering research center grant, and we're really literally trying to change the world

Advancements in Vitrification for Healthcare Solutions

00:18:59 - So like I said before, cells for cell therapy, tissues for tissue testing and drug discovery, organs as we discussed. And then whole organisms. so our next big, work in the healthcare area is, livers and kidneys trying to vitify them and bring them back. And then we're also working on organoids. So we have a very active program with pancreatic eyelets.

00:19:31 - and we have the ability now to actually vitify pancreatic eyelets and store them. One of the issues with pancreatic eyelets is that you never get enough eyelets from one donor to actually transplant into a recipient and cure diabetes. So you have to pool those eyelets. And so now, because of cryopreservation and our, our protocol, which works exceedingly well, meant much better than what was conventionally done. We can actually pool eyelets and we believe we have the solution

00:20:01 - And this can be done with isolated eyelets, but it also can be done with stem cell derived eyelets. There's a lot of activity and billion dollar companies that are up and coming around the world for that. and then we want to move into other organoid systems, so cardiac systems, brain organoids and other things that can be used for transplant, but also diagnostic purposes like drug discovery. So that's the healthcare piece. And then, the EARC is also working, as I said,

Collaborative Efforts in Cryopreserving Corals for Ecosystem Resilience

00:20:32 - for, for biodiversity. We collaborate with the Smithsonian on, trying to actually cryopreserve coral, from endangered areas around the world, the Great Barrier Reef being one of them, Hawaii, Esau, Taiwan, A bunch of different places as well. We're trying to actually use Coral as a model system to understand how to work with endangered ecosystems around the world. And if we can learn how to do this well with coral, so for instance, they only spawn a couple nights a year,

00:21:05 - and then larva, we actually can do coral aquaculture on land. And then we don't get the tremendous attrition that you do in the ocean. We can actually grow up a lot of these polyps and then replace them in the ocean under the best of conditions so that they can grow. And we could also do things like assisted gene flow, which has been shown to actually, you know, bring from one part of the planet where they are doing well, same species, and then grow them with, you know, and bring in more genetic variation, more ability to deal

00:21:48 - and help that ecosystem survive. And then figure from there, then you move into what other, terrestrial or aquatic system and you can pick other keystone species and hopefully, assist in that way.

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