Dr. Waldemar Hoffmann, Apersys: 0:00

That will allow us to really use discarded organs, recover them on our machine and then transplant them into patients in need. Giving an organ a second chance to save a patient's life.

Alex X-Health.show: 0:14

Hi, I'm Alex and welcome to the X-Health.show, where I talk to visionaries behind the latest innovations in healthcare. For the eXtra health of the future. We're meeting today at Wyss Zurich Translational Center, sitting between the University of Zurich and ETH Zurich, Switzerland. My guest today is Dr. Waldemar Hoffman, the CEO of Apersys. He is a bioengineer and biomedical engineer with years of experience in medtech. Also with years of experience in waiting with his father for a kidney transplant. Apersys is a Swiss startup that developed a perfusion machine able to preserve and recover human organs outside of the human body. What it means is putting a discarded liver onto a machine, treating it, regenerating it, and transplanting into a patient. You'll hear what is the ideal liver grafts and why there's a shortage of them, how to keep a liver a life outside of the human body, the possible future of growing organs. And more. [INTRO ends] Waldemar, you received a liver with a tumor and infections to be transplanted into a patient with a tumor? Why would the patient needs a liver like that?

Dr. Waldemar Hoffmann, Apersys: 1:27

Well, the patient that we had on the waiting list was tumor bearing himself and he was very sick. And with that had a near zero chance to actually obtain a liver from the regular organ donor pool. We were basically looking into an alternative for this patient and that's where our machine and our technology came into place.

Alex Jani, X-Health.show: 1:48

Okay, so why would then the medical stuff allow a liver with a tumor and infections? Because usually it's discarded without even giving any additional thoughts, right?

Dr. Waldemar Hoffmann, Apersys: 2:01

That was the case here as well. This organ was discarded, as you said, due to the tumor, but also due to several infections. And we have already proven with our technology that we can preserve organs for longer time. This time it actually helped us to really look into the current tumor to see, can we treat it? So we put it onto our machine, we treated the infections and we obtained time to evaluate the tumor in the donor organ. And this evaluation led to the fact that we understood, we could take out the tumor, so cut it out of the organ and then provide the organ back to a patient that is in need of an organ – to save his life.

Alex Jani, X-Health.show: 2:38

And how long did you keep it on the machine and treated on the machine?

Dr. Waldemar Hoffmann, Apersys: 2:44

So it was there for three days. Three days were sufficient for the pathologist to really evaluate the tumor and to actually treat the infections. And that is usually done rather quickly with antibiotics, as everybody knows. But the main point was really to evaluate the tumor itself and that needed time.

Alex Jani, X-Health.show: 3:02

You didn't transplant the tumor into the patient with the tumor?

Dr. Waldemar Hoffmann, Apersys: 3:07

No, it was cut out of the donor organ. But in order to do so, to know that the tumor is not producing metastasis or growing further into the organ, we had to evaluate it properly with the pathologist.

Alex Jani, X-Health.show: 3:19

Maybe just let me first ask, how's the patient doing?

Dr. Waldemar Hoffmann, Apersys: 3:22

The patient is doing great. It's been more than three years after the transplantation right now. He has a normal quality of life. I had the chance to meet him in person last October, at the Wyss annual event, where I met him the first time. Seeing that patient is really a huge motivational boost for us, knowing that we can have such an impact. How was the meeting? I mean, how's his life basically after that? Because he was what, at the end of the waiting list or not even on the waiting list for a new organ and his own liver could not basically keep him alive long? Was that the situation? Exactly that was the case. He was basically out of the waiting list already because he was too sick to obtain an organ. He's back to a normal quality of life. There's even a short video about him repairing his motorbike. When we met him, you really don't see that he went through this difficult phase of his life but he's really living a normal quality of life. Him as well as his wife are very grateful that he obtained this second chance in his life.

Alex Jani, X-Health.show: 4:22

Oh, this sounds amazing and we'll

Dr. Waldemar Hoffmann, Apersys: 4:22

The current gold standard is still come back to how was that possible, so how does your steady cold storage, meaning that the organ is taken out, is machine work. But let me first ask you about, how long can according to the current gold standard a liver be kept outside of the human body? You know, I have in my mind this image of an accident, there is a donor after the accident, a deceased person, unfortunately. There is the decision to be made whether it is a Yes or Now, the family is included, very emotional moment and rightfully so. And then the process starts of , who's on the top of the list, line of persons are contacted basically. And there's an alarm somewhere, the medical staff gathers and then the liver goes in an ambulance to another hospital or something. flushed with a cold liquid and then put, very simply said, into an icebox and kept kept there for eight maximum to 12 hours. That's how it's being used nowadays but there are also some other technologies emerging trying to really prolong this time. First – dynamic preservation, so perfusion of liquids. The main drawback currently is really that when you put it on ice, there is no oxygen supply to the organ. Lack of oxygen leads to the deterioration of the organ. And that's what we want to overcome.

Alex Jani, X-Health.show: 6:01

The longer it is outside of the human body, it deteriorates more...

Dr. Waldemar Hoffmann, Apersys: 6:07

Exactly. It takes a bigger damage and with that, basically, the chance of having a successful transplantation is being diminished as well.

Alex Jani, X-Health.show: 6:13

And what are the characteristics of a good or a proper liver graft?

Dr. Waldemar Hoffmann, Apersys: 6:21

That's a very difficult question, because it's very multifactorial. Actually, we are not quite sure and the entire selection process is very heterogeneous. It depends on surgeons, the centers, the healthcare systems you're in and also the geographical location you're at right now. But in general, a good donor is really certainly a young patient, which is otherwise very healthy, and has particularly no existing liver diseases. For example, high fat content or any five fibrotic remodeling, meaning scar tissue on the organ. Then there are also a lot of other risk factors that we need to consider, specifically due to the entire process of obtaining the organ, which is called procurement. This impairs the organ quite a bit. As we've mentioned, you take the organ out, the entire blood supply is cut off and with that there is no oxygen provided. Lack of oxygen leads to a lot of deterioration in the organ. One main reason for that is that the liver itself as a highly active organ. It needs a lot of energy and in order to obtain the energy it needs oxygen. So if we now cut off the entire oxygen supply, every minute counts and the organ is taking the damage. Specifically important with the so called DCD donations, meaning Donation after Cardiac Death, so that heart stops beating – the entire oxygen supply is cut off again and that's where the entire process of deterioration initiates. In summary, if we want to really summarize the entire evaluation process, it's rather complex. It considers a lot of points and leads to a full risk profile of both the organ itself, so the donated organ but also the recipient's. All of that has to match in order to say, Okay, this is a safe transplantation.

Alex Jani, X-Health.show: 8:04

So there is also time needed for this assessment.

Dr. Waldemar Hoffmann, Apersys: 8:09

Exactly.

Alex Jani, X-Health.show: 8:10

And, well, the simplest put, I just want to ask, like, where do the livers come from? And I mean, we

Dr. Waldemar Hoffmann, Apersys: 8:19

There are mainly two sources of organs. One is really from deceased donors, accidents but also elderly patients. There we just distinguish between donation after cardiac death but also donation after after brain death. And those organs, donation afer brain death, they really come with a much better quality, when we look really into the transplantation, because we have the circulation up and running and could maintain the organs. Then there is basically a third source of organs, which is living donations. So it is really the gift of life of one person donating a part of his own liver to somebody else, which usually happens within families or within very close relatives. already mentioned that the person is deceased, right. And I can imagine accidents.

Alex Jani, X-Health.show: 9:03

And this is something totally amazing. I saw, when preparing for this conversation, a video of, actually, two neighbors that one decided to donate part of her liver to her neighbor because she was seeing that she's struggling with a terrible disease and without the transplant, she would not be able to live her life. In both cases, even deceased person, I can imagine this is really an emotional moment because, if you're saying, the brain death, the family needs to accept that and especially after an accident, it's like, is it true?

Dr. Waldemar Hoffmann, Apersys: 9:54

That's really always a difficult situation. That's also why many countries struggle with obtaining sufficient donor organs and other countries try to use their governments to create rules around "opt in" or"opt out" for organ donations. We already see the impact for the "opt out" countries. Where you actively need to opt out, there is much more organs available because people are automatically donors. Whereas in countries where you need to opt in, it's rather difficult because, yeah, as we all we are basically a bit of a lazy population and if we actively have to decide to give a donor a way in case we die, nobody is actually taking this step. That makes it very difficult.

Alex Jani, X-Health.show: 10:38

What's the situation here in Switzerland? And let's say in the US?

Dr. Waldemar Hoffmann, Apersys: 10:42

In Switzerland, it's the opt out system – all the organs are basically, initially donor organs. But then it depends if it's the donation directly for transplantation or for research, those are two different things. In the US, it also depends a bit on the regions but it's mainly also the opt-out system.

Alex Jani, X-Health.show: 11:01

There is a liver and then there are many of them discarded. Why and how many?

Dr. Waldemar Hoffmann, Apersys: 11:10

So again, in the end, it really depends on the geographical region and the healthcare systems. If we look, for example, at the US, into the biggest market, we have around 16,000 livels donated every year. But out of those already 7000 are being discarded right away. So we are left with around 9000 organs a year. And at the same time, we have around 14,000 people on the waiting list. We already see a discrepancy there and a gap. The bigger the gap of organs and thus the organ shortage, the lower quality organs are being actually transplanted and accepted for transplantations, which again, in turn leads to impairment, especially of the recipient sites, and makes it really difficult to maintain the high turnover of organs into recipients. All of this basically leads to the fact that specifically in the US, one out of three patients on the waiting list will not receive an organ in time.

Alex Jani, X-Health.show: 12:01

Because the list is too long, basicly and they won't make it to the top.

Dr. Waldemar Hoffmann, Apersys: 12:06

Well, that's one point, the list is long but on the other hand, we saw that we have around 16,000 organs donated but only 14,000 people on the waiting list. So, there must be a discrepancy. And the discrepancy is the 7000 discarded organs. If we could take those organs, recondition them or improve their quality in such a way that we can use them for transplantation, the liver organ donation gap is diminishing right away.

Alex Jani, X-Health.show: 12:31

Please note, we are not medical doctors. So, please do not consider anything we say here as medical advice. What are the reasons that the livers are discarded and what happens if one such liver is transplanted?

Dr. Waldemar Hoffmann, Apersys: 12:49

For, the discard of livers, there are many reasons. One is basically the risk profile that we have discussed up front, also the time that the organ was cut off the oxygen supply, which is called ischemia time, because you are not perfusing the organ with blood, and with that, no oxygen. So there are very clear boundary conditions. Again, for each region, they are different. That's one issue. Then the assessment of the organ. In many cases, you obtain the organ, and you need to decide right away, to do a transplant or not. And in many cases, surgeons are also risk averse, because they don't want to lose their patient afterwards. They would rather decline an organ if it's borderline than actually transplant it. So if we want to really look into the low quality organs in order to match the demand and supply issue that we have, then that might lead to post-operative complications. Those complications might lead to much longer time in the ICU for the patient. With that, a lot of therapeutic efforts we need to maintain in order to ensure that the patient can survive. Those low quality organs can also lead to organ dysfunctions after transplantation meaning that there are downstream problems like bleeding or coagulation problems with low blood pressure. Then a lot of medication needed in order to support the life of the recipient. In the worst case, the organ that has been transplanted fails and there is a need for re-transplantation or to save the patient's life.

Alex Jani, X-Health.show: 14:17

Also, in these patients that need transplantations, they might have some comorbidities, right, so they they cannot afford, basically, something not functioning or fight to have that organ not being rejected basically, by their body.

Dr. Waldemar Hoffmann, Apersys: 14:38

Exactly, that they are struggling with all their comorbidities and at the same time, they are now obtaining a foreign organ, so their body is also fighting that organ. At the same time, they're dependent on the functionality of this organ. So it's really a very complex situation and in a very fragile situation the patient is in. Especially the first days. If we now, in this case, put a low quality organ in, and the patient has really to wait until the organ actually is able to take up the functionalities and provide the life supporting functionalities that are needed for the patient, this might be already too late for the patient to survive.

Alex Jani, X-Health.show: 15:14

So how did the opposite story start? Because this is actually what you want to. Do you want to take these discarded livers and bring them back to life?

Dr. Waldemar Hoffmann, Apersys: 15:26

That's exactly true. Talking about all the issues that we just discussed, there was the pioneering idea from Professor Pierre-Alain Clavien, who is a renowned visceral surgeon here in Zurich that wanted to maintain organs alive outside of the human body for prolonged times in order to give time for the evaluation of the organ but potentially even treatment or down the road, even regeneration. As he was struggling to build the machine by himself...

Alex Jani, X-Health.show: 15:50

Oh, he tried to do it by himself?

Dr. Waldemar Hoffmann, Apersys: 15:52

Well, he had the idea and he's a surgeon, he definitely wanted some support in doing so. He talked to this Swiss philanthropist who basically shared his vision and wanted to support him. He brought him in contact to the ETH. That's where the entire story started – with a joint effort from the ETH side, where there was support from Professor Philipp von Rohr. Together with Professor Clavien they initiated the project. They got PhD students on board to think about how can we build a device that can maintain organs alive outside of the human body.

Alex Jani, X-Health.show: 16:27

What did they start with?

Dr. Waldemar Hoffmann, Apersys: 16:29

Initially, they started building a very simple blood loop just to perfuse blood in the circuit. Then they moved on rather quickly into organs. Those organs were derived from pork, so porcine organs, because ethically, it's easier to initially start with those organs and they recapitulate very closely the human liver as well in terms of anatomy as in terms of size and functionality.

Alex Jani, X-Health.show: 16:53

[Mid-roll begins] We'll be right back. This episode is brought to you by the X-Health.show and me, Alex. If you still haven't, please hit Follow at the top. That'll help me bring more of these visionaries to you. Thanks a lot. Stay awesome. Now back to the episode. [Mid-roll ends] Okay, and so what was first tested with these pig livers?

Dr. Waldemar Hoffmann, Apersys: 17:40

The first idea was just to initially maintain them alive on the machine. A very simple feasibility test where the device itself that had been built, it's just a perfusion loop, you have blood circulating, is that sufficient to actually maintain these organs alive?

Alex Jani, X-Health.show: 17:57

Because that idea, it wasn't new. This is what I also found out. It is actually something that appeared somewhere in the 20th century – this perfusion machine, right? Why was it then dumped, basically?

Dr. Waldemar Hoffmann, Apersys: 18:10

During that time, there were many more important boundaries and hurdles to overcome looking into the entire field of transplantation. There were technical issues, perioperative care issues but also pharmacological nature issues. So really trying to bring all of this together was rather difficult during that time.

Alex Jani, X-Health.show: 18:28

So the tech wasn't ready, is that what you're saying?

Dr. Waldemar Hoffmann, Apersys: 18:30

The technology itself wasn't ready but also the the entire environment around organ transplantation was not there. Organ transplantation was not yet this life saving procedure that it is right now. Another point was really all the technological advancements. If we look into our machine, we need a lot of computing power at the end because we have a lot of almost real time running, monitoring controls and so on. It needs a lot of effort, a lot of power, which just evolved over the last decade.

Alex Jani, X-Health.show: 19:03

When did you start? When the two professors met?

Dr. Waldemar Hoffmann, Apersys: 19:07

It was in 2015 that the project Liver4Life started. That's basically our origin. From that it really went into initial buildup of a prototype, initial testing and improvement of the procedures but also improvement of the device until we reached the point where we could also maintain porcine livers alive for an extended period of time. That was then the trigger to say, Okay, we managed with porcine livers what's the next step? Obviously, the human livers.

Alex Jani, X-Health.show: 19:33

How long did it take with porcine livers? Because when we speak, like, Okay, we tried it here and then we went to... I can imagine it was years.

Dr. Waldemar Hoffmann, Apersys: 19:44

Overall, it was two to three years until there was a running prototype that proved that using porcine livers we can maintain them on our device.

Alex Jani, X-Health.show: 19:53

And for how long? keep a human liver on a machine now? So nowadays, we can do it up to 14 days. We have published 10 days but for a clinical setting seven days is basically sufficient because we see all the benefits from our machine ocuring during those first seven days.[This conversation continues on the podcast]