Wow, the human body can take a beating! We can remove parts of the liver, it grows back. Take out part of the lung, all of the gallbladder, one kidney, a spleen, and the appendix, and still survive and thrive. But we cannot mess with the pump.
This is a QIMR Berghofer Medical Research Institute podcast.
If heart tissue is damaged, it does not regenerate. But Professor James Hudson and his team are on track to completely change the way we treat heart disease. And thanks for popping in to explain it to us, James.
Professor James Hudson (00:42):
Glad to be here.
What was the major challenge for heart disease that started you looking for these kinds of answers?
Professor James Hudson (00:50):
I think that so many people still die from heart disease. It’s a leading cause of death in Australia and in Queensland.
It is different to all those other diseases because the pump is central to everything. Nothing works without the pump and it’s a part of everything else, isn’t it?
Professor James Hudson (01:06):
Yes, that’s right. Without any blood supply, all your organs in your body don’t function. So the heart’s very critical for the way our whole body operates.
Clare Blake (01:16):
So what happens now to heart tissue that’s damaged in a heart attack or heart failure at this stage?
Professor James Hudson (01:21):
There’s a variety of things that can cause damage to the heart. One that we all know and hear about are heart attacks. That’s where part of your heart stops receiving blood flow. What this causes is that part of the heart to die and that part never comes back. So the heart cells you’re born with are essentially the heart cells you die with. When people’s hearts are damaged, you’re only left with a fraction of the cells remaining. So in a really severe heart attack, maybe a billion cells die. Your heart has around 4 billion heart cells in it. Those remaining heart cells have to work extra hard to compensate for the lost cells. This over time progressively leads to deterioration in heart function, other complications and heart failure.
Clare Blake (02:07):
If we think about what we know about the heart is 100% if we know everything, where are we at along the scale percentage wise now?
Professor James Hudson (02:15):
It’s very difficult to answer that question because back in the day, the earth was the centre of the universe definitely, right?
Clare Blake (02:23):
Professor James Hudson (02:24):
So we don’t really know where we sit. At the moment, what I can definitely say is we only know a very small fraction of what happens in biology.
Clare Blake (02:33):
Where did you start looking for treatments that could possibly regenerate heart tissue? Was it a certain class of drugs or a certain therapy or treatment?
Professor James Hudson (02:39):
What happened was, back in 2014, I was lucky enough to start working with a researcher named Enzo Porrello and we started running the lab together. Enzo’s work really pioneered what controls heart regeneration. So prior to his work, what people used to think is only certain organisms can regenerate the heart, such as a zebra fish or a salamander or an axolotl. What Enzo showed is actually in a mammal, so a warm-blooded animal, in a mouse that if you injured the heart shortly after birth, it could fully regenerate. This has now been also shown in larger animals such as pigs. And there’s some case studies hinting that it also occurs in humans. And so what this means is it’s not a genetic difference in these other animals that causes heart regeneration that we might never be able to harness. We have that ability and then we lose it.
Our whole research program in this area is about trying to reawaken that early fetal growth stage in our heart cells so that we can replace the ones that are lost. What we are looking for and what a lot of people in the field are looking for is new therapeutics that can regenerate the heart. So far, we’ve only found a handful. And a lot of them are really challenging to implement. As you know, cancer is also caused by overgrowth of cells. And so we need to be really careful in finding pathways in things we can activate in the heart that’s not going to cause side effects like cancer. And that’s one of the biggest challenges in the field. And so that’s what we’re really working on, is how is the regeneration shut down in the heart so that we can specifically reawaken that process that’s not going to affect the other organs as well.
Clare Blake (04:29):
And now we get to the greatest part of your research for people who go to your lab, and that is the mini hearts. What are they and how are they going to help?
Professor James Hudson (04:38):
So what we do in our lab is we grow miniature human heart tissue. We’ve spent many years developing to a point where we can make miniature 3D tissues. So on something the size of a credit card, we can have 96 human heart tissues. We can give those adrenaline and they start to beat harder and faster. We can do other treatments and study their biology. What we’ve been using those for is to screen for new therapeutics that will reawaken that cardiac regeneration process.
Clare Blake (05:09):
It’s incredible. Tell me about that process.
Professor James Hudson (05:11):
To get the stem cells to begin with, there’s two methodologies that are used. They’re called pluripotent stem cells. So pluripotent means ‘can turn into any cell type in your body’. Stem cell can mean ‘make an exact replica of itself’. And so what that means is we can grow them in billions and billions of cells in the lab whilst maintaining the ability to turn into all the cell types in your heart. And so not many cells can do that.
To get those cells, there’s two major methodologies. One of those is using embryos from IVF samples that were going to be discarded, and around the world a number of those have been turned into embryonic stem cell lines. And the other method, which is more commonly used now, is we can actually take a blood or a skin sample from someone and use a process called reprogramming. And two scientists won the Nobel Prize for this, I think it was 2012. This enables us to turn those other cell types into the stem cells. That’s really powerful because it means that we can have an exact genetic replica of someone in a dish as well.
Clare Blake (06:21):
So the person that it’s come from in terms of the architecture of the heart, how faithful is that in replicating that?
Professor James Hudson (06:28):
So the genetics are very similar. In terms of making the heart tissue, we have to go through a process. So what we do in the lab is we give the cells the different growth factors that your body would normally see when it forms a heart. And we’ve worked out what those are. And so in a two-week period, we can make beating heart cells. Now those heart cells are very embryonic, so they’re going to be very regenerative. They’re not going to function quite the same as your heart does. And so what we do then is we take those and we put them into our 3D organoids where they’re exercised, they’re cultured in a 3D environment. And just like going to the gym and exercising your muscles, this exercises the heart and makes it become more mature. So it’s a better model of an adult heart.
Clare Blake (07:14):
How do you force a bunch of cells into exercise? “Get out of bed!”
Professor James Hudson (07:18):
Yeah. Well, it takes a lot of effort. We’ve carefully designed and engineered exercise posts that they contract against, much the same as if you have in your hand a squishy ball that you squeeze. And so that’s what they’re doing. In our tissues, they have pacemaker cells. So these just spontaneously contract at around one beat per second. And so that’s what dictates the rate in our cells.
Clare Blake (07:44):
And if you look down a microscope and see all these wrapped around those two…
Professor James Hudson (07:51):
They’re elastic posts, like silicon posts, yeah.
Clare Blake (07:54):
And then they contract. And how much the post moves tells you how strong the contractions are?
Professor James Hudson (07:59):
Yeah, that’s correct.
Clare Blake (08:01):
You see a lot of fun stuff down your microscope, don’t you, James? You and your team?
Professor James Hudson (08:05):
Yes. There’s a lot of fun stuff. There’s also a lot of stuff that doesn’t work. So it’s a very laborious and a lot of work goes into the final products that you see at the end, yeah.
Clare Blake (08:18):
It’s been a long haul. I know that you started with literally thousands of drugs that might form new treatments for people with heart disease, and you’ve narrowed it down to just a handful, as you said. That’s been a long hard, tiresome, brutal road.
Professor James Hudson (08:32):
And it still continues. So the lead candidates we have now require a lot more development to get those into something that could be given to a human. And we’re currently working on that. Some of the drug candidates we’ve found, they’re very interesting. We don’t know exactly how they’re working, and that’s what we’re trying to pinpoint so that we can design forms of the molecules that can go into animal and human trials.
Clare Blake (08:59):
So what is the goal here? You see inflammation or damage in the heart, and the end goal is you want to reverse or repair that?
Professor James Hudson (09:06):
A lot of this discussion has been around regenerating the heart, and that’s one avenue typically caused by an insult to the heart, like a heart attack. But there’s other forms of cardiac injury that also occur. One of those is inflammation such as COVID-19 can cause inflammation. This can also damage the heart, but in a slightly different way. It doesn’t necessarily kill the heart cells. So a regenerative approach is perhaps not as appropriate for that type of stuff. And what we see in those hearts is a stiffening of the heart. The heart no longer relaxes properly, it becomes quite stiff, and that would cause the heart to not fill up with enough blood. And so for that particular aspect, we’re focused on a different set of drugs that actually stop that stiffening of the heart tissue.
Clare Blake (09:56):
Somebody who’s had COVID, what are their chances of getting this disease of the heart?
Professor James Hudson (10:02):
At the start of the pandemic, it was shown that (and even some flus can cause this) your heart can undergo stress and you have elevated cardiac biomarkers. But what also happens with COVID is that inflammatory response can be a bit more severe and you can have some endothelial cell dysfunction and other things occurring as well. What we’ve found is that that inflammation process can cause the heart to become dysfunctional. And in a lot of us, that can typically resolve over time. But in some people, particularly people with metabolic disease or diabetes, they’re more susceptible to getting cardiac complications after COVID.
Clare Blake (10:40):
Wow. Is there an age range there?
Professor James Hudson (10:42):
Yeah. Also, people that are older tend to get it. We don’t know the exact mechanisms of why. That’s another aspect of that that we’re working on right now is that relationship between metabolic disease and the inflammatory environment and how that’s causing that dysfunction. That’s something we’re currently looking at in detail because we think there’s an interaction there that’s causing those people to be more susceptible.
Clare Blake (11:08):
Now there’s talk of vascularising those mini hearts and that changes the game again, doesn’t it?
Professor James Hudson (11:14):
Yeah. Well, what we’ve found is for a lot of our work, and this has gone over many years, that the different cell types in our cardiac tissues are really important. So your actual heart, believe it or not, is only around 30 to 50% heart cells that do the function. So your heart’s made up of lots of other cell types. There’s one cell type called fibroblast. They supply a matrix skeleton that keeps the heart together. There’s a real lot of blood cells in there. So these are the ones that supply the blood and nutrients to the heart tissue and remove the byproducts. And then there’s also smooth muscle and pericytes that stabilise those blood vessels.
Now, what we’ve done recently in our work is incorporated a vascular component into those tissues to mimic the blood cells. And even though we don’t perfuse those with blood because our tissues are small enough to get the nutrients, we find that those cells have a key role in the biology of the tissue. So they make the tissues better and stronger. When we hit them with the inflammation signals, having those in the tissue really exacerbates that disease. So we think that a lot of these inflammatory diseases like COVID are causing a pathology in the heart through signaling through the vascular network.
Clare Blake (12:30):
That’s just mind-blowing, isn’t it?
Professor James Hudson (12:33):
Yeah. Well, your body’s a very complicated system and it all talks to each other to try and create a fine balance.
Clare Blake (12:42):
Are there implications further afield for the little mini hearts and what they might offer?
Professor James Hudson (12:46):
Our work on COVID-19 helped form the basis for a phase II clinical trial of a drug in Canada for hospitalised patients with COVID-19. That same company has released a statement where they also want to do a phase III clinical trial for long COVID patients because people with long COVID are known to have increased cardiovascular risk. In terms of our regeneration programs, they continue. And also as we discover more and more about the biology of the heart, we’re figuring out signaling pathways, fibrosis networks, cell to cell communications that might be important for lots of other organs too. We don’t know the full extent of what this will reveal, but that will become more and more apparent over time.
Clare Blake (13:33):
So possibly you could reduce fibrosis or scarring that’s been there for a while?
Professor James Hudson (13:38):
That’s our hope. Not only we prevent it, but some of the therapeutics we find actually can reverse the process as well. And that’s been extremely challenging in this area of research so far.
Clare Blake (13:49):
What about in the long term future? Could you use it as a patch for somebody with congenital heart disease?
Professor James Hudson (13:55):
Yeah. We have a research program together with MCRI, the Murdoch Children’s Research Institute, that is to create patches for people that have heart failure where part of their heart’s damaged and it’s really quite severe. We go in and we add the stem cell-derived heart cells to try and repair that. That requires a lot of work. And that would only be done in certain cases because it would require substantial surgery. But that’s an avenue of research that’s quite promising. And when I did my postdoc in Germany, that was a key focus of our research. In 2021, they started the first trials of heart patches for adults. They’ve now implanted around 10 of those. So that avenue of research is definitely a promising one that will continue to be explored not just by us with this MCRI project, but also by others globally as well.
Clare Blake (14:50):
That’s close once it’s in humans, isn’t it?
Professor James Hudson (14:52):
Clare Blake (14:53):
Well, so the big focus right now if we were going to go up in your lab today, what would we see your team working on?
Professor James Hudson (14:59):
Right now, what we’re trying to do is map out in more detail how the heart works essentially, how different stimuli affect the cardiac tissue and the response. What we want to do is create an encyclopedia of that. And while that’s going to be a lot of effort to get to that stage, what that does is create a benchmark for us that we can use for multiple diseases to really understand which proteins cause improved function, which ones cause decreased function so that we can start to manipulate and come up with therapeutic targets that are specific to certain diseases. And that’s what is the basis of my Snow Medical Fellowship.
Clare Blake (15:45):
It’s extraordinary work. If you’d like to find out more about Professor James Hudson and his team and their work, qimrberghofer.edu.au Thank you so much, James. It’s great. We wish you the best of the luck. We really appreciate you coming in here to give us a bit more info.
Professor James Hudson (16:02):