In this episode of On the Edge of Breakthrough: Voices of Cancer Research, Dr. Monty Pal sits down with Dr. Alberto Pugliese, Samuel Rahbar Chair in Diabetes & Drug Discovery, chair of the Department of Diabetes Immunology and director of The Wanek Family Project for Type 1 Diabetes. Tune in to discover how Dr. Pugliese’s translational diabetes research, collaborative spirit, and commitment to mentorship are driving breakthroughs in diabetes care.
From a small Sicilian town to the forefront of diabetes research, Dr. Pugliese’s story is one of relentless curiosity and hope. He shares how early family experiences and clinical frustrations inspired his lifelong mission to improve outcomes type 1 diabetes.
The conversation delves into the role of viruses and the microbiome in triggering type 1 diabetes. Dr. Pugliese describes his leadership in the Network for Pancreatic Organ Donors with Diabetes (nPOD), which has enabled collaborative studies showing evidence of chronic viral infections in the pancreas and their potential contribution to disease onset.
This episode also dissects how generous giving becomes the driving force behind groundbreaking research and scientific breakthroughs. Dr. Pugliese shares details of a bold, new nationwide clinical trial led by City of Hope, inspired by philanthropic support from the Wanek Family Project. The innovative trial will assess a combination of approved therapies to investigate ways to preserve insulin secretion and control the autoimmune process in newly diagnosed patients, aiming to accelerate progress toward a cure.
Tune in to discover how Dr. Pugliese’s translational diabetes research, collaborative spirit, and commitment to mentorship are driving breakthroughs in diabetes care.
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Presented by City of Hope: www.CityOfHope.org
I'm Dr. Monty Pal from City of Hope. And this is On the Edge of Breakthrough, Voices of Cancer Research. Each episode, we bring you the minds behind the science, the stories behind the data, and the breakthroughs that could change everything. Let's dive in. Welcome, everyone, to On the Edge of Breakthrough, Voices of Cancer Research. I'm Monty Pal, medical oncologist at City of Hope. I'm delighted today to have Dr. Alberto Pugliese as my guest.
He's the Samuel Rahbar Endowed Chair in Diabetes and Drug Discovery at City of Hope. Alberto, welcome to the program.
Thank you for having me. Pleasure to be here.
Absolutely. And I got to start with your background. I actually took my family for the first time to Italy last year. We went to Milan and Rome and really had a blast out there. And I understand you're from Italy as well.
Yes, I'm from Sicily.
Oh, from Sicily. No kidding? And I understand your path ultimately took you up to Palermo for your training, but tell us about your upbringing.
Well, I was just a kid growing up in a family with two brothers. My family moved around different towns in Sicily because my father worked for a bank, and every once in a while they transfer him to a different office. And we ended up when I was about 8 or 9, moved to Palermo, which is the main town in Sicily, and stayed there until I was 17.
Well, I've got to ask about your path towards medicine and, ultimately, diabetes research. It's interesting your father was a banker, as you mentioned. What sort of got you inspired to go into the field of medicine?
My mother's brother was a physician and was always a very inspiring figure for me. So kind of since I was a little kid, my mind was set that I wanted to be a doctor. And then when I graduated from high school, I remember my father-- I had a conversation with him and to discuss future plans and what type of career to pursue. And since he worked in a bank, he knew that environment well. And so he suggested, well, these are things that you can do if you pursue a career in banking.
And I want to send you, if you like, to one of the top universities in the country where you can get fantastic education. And typically people that graduate from there, they just get hired by banks even before they get their degree. Which would have been probably wiser to listen to him. But it wasn't in my heart. I remember, I actually wrote him a letter to explain why I didn't want to do that, and I rather wanted to be a physician. And he said, no, it's fine. You do what you want. And so that's what I did.
So you ended up tracking in towards medicine. How about diabetes? Obviously, you've made seminal contributions to this field. How did that path come about?
Well, so in part is by coincidence. But when I was a kid, you grew up in Sicily and the food is phenomenal. The sweets are phenomenal. And so as I was growing up, at some point, they discovered that there was glucose in my urine. And they immediately thought that I had diabetes. So all of a sudden, my parents were trying to take away all the sweets and all that, but they wouldn't tell me why. And so at some point, I said, OK, enough is enough. What's going on here?
And they said, oh, well, we are afraid that you have diabetes. I said, what are you talking about? So they took me to a couple of doctors and basically I didn't have diabetes. But that was sort of my first introduction. What I noticed was how terrified they were. And at that time, I didn't know anything about diabetes. I just could appreciate that they were in fear of that. So that kind of stayed with me for a while. Then I went into medical school. And as a resident, I was learning about diabetes.
And towards the end of my training before graduating as MD, I was interning in a department which was specialized in type 1 diabetes, which is very common in children and kids. And so when a patient was diagnosed, it would be referred to us. That is a very dramatic moment in the life of a patient with type 1 diabetes, because all of a sudden, almost out of the blue, they develop symptoms, they get really sick, and sometimes they get hospitalized. Sometimes they can go into a coma. Sometimes they can die.
And so they were referred to us. And so number one, learning how to treat them. Number two, then we have to educate the patients and tell them, well, now you have diabetes. It's going to stay with you for your life. And these are the things that you need to do so that you can be as healthy as possible. And then many of these were children. And then these families would come back with their children for follow up visits, because then you need to continuously monitor them, adjust their therapy, make sure that they're doing the right things and all that.
And very often, these families would come and follow up visit, not just with the kid that had diabetes, but also with the little brother or little sister. And a few months later, the little brother or little sister would also be diagnosed with diabetes. When you meet a new family with a new patient the first time around, you don't know them. But a year later, when the brother or the sister developed diabetes, now they're your little friends because I met them several times.
So that led me to really being frustrated, because I was knowing all of these kids and I could not really do much for them other than say, OK, take a little bit more insulin, a little less insulin, adjust this and adjust that. But that is not a resolution of the problem. As physicians, we want to cure people. We want to resolve the problem, send them home happy and cured. We couldn't cure anybody like that. So I said, OK, maybe I have to do something different here because this is not good enough. And that's what drove me into research.
I'm just curious. I mean, if you go back to that time when you were training and seeing these patients for the first time, I imagine it was a very different state of the science. I'm actually coaching a couple of kids right now in Science Olympiad, something that I really enjoy doing on the side. And one, has type 1 diabetes and it's very well managed with constant glucose monitoring and automated insulin delivery and what have you. But I think back then, the style was entirely different.
Completely different. We didn't have any of these devices. You could, at best, puncture your finger and then have little strips that you would measure the blood glucose. Everything was very primitive. Even the type of insulins that you had that you could inject to control your blood sugar levels were more limited in terms of the choices. We now have very different insulins that behave in different ways in terms of how much you have it and in terms of how much stays in circulation, whether it acts rapidly, slowly. We had a little bit of that, but nothing compared to what we have today.
It's remarkable how that's changed. And I wanted to dive into some of your contributions to the field. But maybe before we do that, tell us about this path that you took from Palermo towards the US. How did that come about?
I realized that I wanted to go abroad and learn and do research abroad. Because the scientific environment is stronger, it's more developed. And I always believed that I would like to be where you can get credit for what you do.
A real meritocracy?
Correct. In Italy, there isn't that much of that. It is very difficult to advance, even if you really deserve it, because there are so many other side interests, let's call them that way, that can get in the way. So I didn't want to be dealing with that part. I remember I talked to my mentors there and so forth, and they encouraged me. And for them was also advantageous because the idea is they send the young people abroad, they get training, they established collaborations with another institution and so forth. Then they bring that person back two or three years later, and that person basically brings that knowledge.
And that way of working and so forth, and establishes a bridge, and that should help the science move forward. The question is when you go is you need to find the resources to go. And so what I did, I took the initiative. I wrote a fellowship grant application. I remember my mentor said, OK, let's see. We can give you a project that we already have written something that you can apply with that. I said, no, I'm going to do my own project.
And I was there at that point in time, like 12, 14 hours a day.
I was always there. I loved it. And I told them, you're not going to see me for a month because I need to study, stay home and write that project.
Wow.
But I'll be back in a month. And a month later, I was back. There were no computers at that time, essentially. I didn't have one. So all typed up on a typewriter. And I presented my mentor with, this is the project that I want to apply with. And he read the title and he said, what is this? I never heard of this. Well, read it and find out. And so he read it, said, oh, OK. So then we applied and we got it.
So you have to tell us, what was the project back then?
It was about studying the role of certain proteins called heat-shock proteins in type 1 diabetes that at that time were being discovered and they could play a role. And actually, we did some research with that and published a paper very early on.
That's interesting because heat-shock proteins as well have been a target of oncology research.
Absolutely.
I remember that about 25 years ago sort of emerging in my field, too. So heat-shock proteins, I don't think ultimately became the major focus of your work. You've had a number of other elements that you've sort of developed, I would say, and been pioneering in diabetes. Can you share that a little bit with our audience?
Sure. I've been looking at type 1 diabetes in many different aspects. I look at it from a point of view of the physician, because I'm a physician by training. So I became a researcher afterwards. So for me, I never had any predilection for any discipline. So people have called me an immunologist and geneticist, a pathologist, a cell biologist, because I've actually operated in all of those disciplines. Except I'm none of those things.
What I tell people is I'm a failed physician.
[LAUGHS] Come on now.
Because I studied as a physician, and essentially, I stopped practicing very early on. So that's why I say I'm a failed physician. But the mentality, my mindset is that of a physician. What I want to learn is not because I am curious about immunology. I am curious about the disease. And my research is really focused on things that-- can they be translated? I try to accelerate the translation. I try to bring things forward to the patient, which takes a long time.
So there are many things that I've been looking at. I've been looking at the genetics. One of my contributions was the study of certain variations in the insulin gene. The insulin gene is the gene that codes for insulin that everybody needs to maintain normal sugar levels. And of course, in diabetes, insulin is what is missing. Because in type 1 diabetes, the cells that produce insulin in the pancreas, which are called beta cells, are destroyed by the immune system.
And so it was known at that point that these variants of insulin gene could alter the risk of someone developing type 1 diabetes. And so we went a little deeper in looking at those variants and the relationship with diabetes risk. And then we contributed a novel discovery, which was that one of the likely mechanism by which this gene was controlling diabetes risk had nothing to do with the pancreas.
And so when we look at the action of a gene, we look where we know that gene is functional, is expressed. And the insulin gene until that point was believed to be only and exclusively expressed in the beta cells in the pancreas.
Right.
Right? So other cells in the body, they don't make insulin. That's why once you lose those beta cells, you have no more insulin. However, what we discovered was that actually there was a little bit of insulin being made, not in the pancreas, but it's a little organ in our chest that is very important in early life to educate the immune system, to respect our body, in very simple terms. We call it immunological self-tolerance.
So this, to me, was probably the most fascinating thing. I mentioned to you that I'm actually of coaching Science Olympiad. And I think back to my medical school days. One of the subjects I'm coaching right now is endocrinology. And there's this standing dogma. Insulin comes from the beta cells in the pancreas. And then I came across your work around the thymus. And I was pretty blown away. Are we kind of teaching folks the wrong thing? Or tell us about, the status of insulin production, I suppose.
So what we discovered was, number one, there was a little bit of insulin made in the thymus, which was in the first place, surprising and unexpected. And then the levels at which that insulin was produced was determined by those genetic variants of the insulin gene.
Got it.
So that if you actually had a genetic variant that was associated with lower risk of type 1 diabetes, you were making more insulin in the thymus. And the concept is that the more you made, the more you could effectively develop immunological tolerance towards insulin. So that was around the mid '90s or so. There were these discoveries-- this one, one of the earlier ones. And I guess, most impactful because it was about insulin, it was human.
And that basically in contrast to earlier beliefs that tolerance could develop in the thymus only for those proteins that were produced there. And that for proteins like insulin, there could not be tolerance developed in the thymus. So that was actually throwing that out the window and saying, no, that's not true. You can develop tolerance to insulin as well because it's made there. Except we didn't know that it was made. So we showed that it was made there. It was genetically controlled.
That's so cool. I thought a tagline for this podcast today could be, if you think insulin is just made in the pancreas, think again. I think that had drawn a lot of listeners.
But the important thing is, especially when we made the discoveries made clear to people, that does not mean that if you had diabetes, you're still making it in your thymus and in control your blood sugar. It's got nothing to do with that. It's a different function, and it's very little of it. So just to make sure that people don't think that that's a solution.
Absolutely. You mentioned this was in the mid '90s or thereabouts. Was this during your time at Harvard? Was this were you already at Miami at that point?
So this was in my early years at the University of Miami. And so that was very good. As an assistant professor, I got a big paper in Nature Genetics and all that. Got a lot of attention. And there were actually two papers that came out back to back. Because there was another group that was pursuing the similar study, and we had actually reproducible results.
And when you think about it, this was really revolutionizing the way that we think about immunological self-tolerance is better when you have two labs independently showing the same thing, that just one where established ideas will probably fight against that and say, wait a minute, something is wrong here. So that helped pushing that concept forward because people say, well, it's coming from two labs.
Yeah, it's always helpful, I think, when there's that supporting evidence.
Absolutely.
The other thing that stood out for me, I was just going through the long laundry list of publications that you've produced over the years. The one thing that really intrigued me was around viruses and the relationship to diabetes. And piecing this together, here at City of Hope, there's huge interest, especially now more than ever around, for instance, the role of the microbiome. And particularly bacteria, I say in the context of oncogenesis.
Am I reading some of the literature right that you've been involved suggesting that there may be a role for enteroviruses and other culprits in diabetes?
Yeah. So this is a question that in type 1, diabetes has been debated for years and years, and is still being debated. So are virus is a cause or a co-factor in the development of type 1 diabetes? And the theory really began in the late '60s with some initial observation. And many, many years later, there have been a lot of studies and lots of papers and so forth. Some supportive of a role for viruses, some not supportive.
But the overall evidence is, I think, really supportive that viruses have a role. So what I did in particular, I put together a collaborative group which was international. And this is in the framework of a much bigger effort that I'm co-director of, and I've been co-director of since 2010. This is called the Network for Pancreatic Organ Donors with Diabetes. And what is that? So when you think about type 1 diabetes, the disease process occurs in the pancreas, right?
And then it is very important to be able to study the pancreas as well as immune lymphoid tissues where the immune cells are. Because the immune cells play a role in the development of the disease. Except that from living patients, you don't have access to those tissues. So how can you figure out what causes the disease if you cannot look at the tissue? It's a big problem.
So for many, many, many years, we have relied on studying rodent models, which can be very helpful. And some models that we studied have tremendous similarities to the human disease as well as some important differences. And in reality, we have seen that in these rodent models, we can try different therapies, for example, in trying to prevent or reverse the disease. The vast majority of them don't work in people. So clearly, we cannot rely exclusively on these models.
My former mentor, late George Eisenman, had this idea that if we could study organ donors and we could screen the organ donor population for measuring auto-antibodies that are associated with risk of type 1 diabetes. So these are typically found in people who have type 1 diabetes. And we know that we can find them in people who are at risk and will later develop type 1 diabetes. So the idea was, if we can screen the organ donor population and we find donors that are positive for those auto-antibodies, that organ donor was probably developed in type 1 diabetes, except that they didn't know it.
Interesting.
So if we could recover their pancreas through organ donation, could we study that? And could we learn about the early stages of the disease processes where perhaps a virus could be there, or other mechanisms of the disease? And so I want to know if when somebody has antibodies, if there is the inflammatory process that causes type 1 diabetes, if it's already in the pancreas. Very simple question. So he started screening organ donors from his own institution in Colorado and did a small pilot study.
And he showed that he could screen. And he found a couple of donors. So proved the concept. And from there, this new program was born. And I helped him participated in this pilot study. And after that, this big effort was launched. It's now become a major asset to type 1 diabetes research, because everybody that wants to study human type 1 diabetes comes to NPOD and asks for, can we have tissues that we can do whatever study that we want to do?
There have been hundreds of investigators involved and hundreds of publications and a lot of discoveries made with the most advanced technologies that you can imagine. And so for me, serving as co-director of that is very exciting. And actually, gives me the opportunity to do so much more for the field that I could do otherwise on my own. And so I actually spend a lot of my time managing that and helping my colleagues from other institutions be successful in what they're doing with the sample tissues.
And I guide them and help them in so many different ways. I find them collaborators and so forth. I actually review every single project that they want to do, because it is actually scientifically evaluated to make sure that it makes sense and is well designed and all of that. And so I know what everybody else is doing. And so I create working groups where people can work together. All of these lengthy explanation to get to your question, which is what did you do with the virus?
So we essentially identify that trying to understand now that we have the access to the pancreas from these organ donors, could we determine if there is evidence of viral infections in those tissues? Because that would help us prove or disprove whether a virus is involved.
Sure.
And to do this, basically, I started having a webinar, which was publicly open and all that. A lot of investigators from around the world participated. And we said, do we want to work together and try and do address this question? And within a couple of hours, we identified a series of questions that we wanted to address, laid the foundation for a study, a collaborative study, which within a short time received a first grant from JDRF, now Breakthrough T1D, for $3 million.
Oh, my gosh.
And so we did this big study, and it took a long time. But the results were published earlier this year with three different papers. And basically, the concept is that we try to look at this question with all kinds of different approaches contributed by different people. And coordinated all of these investigations so that we could have the vital questions asked with different methodologies, but on the same tissues, on the same donors.
So in clinical research, what happens very often is that somebody has access to a population of patients, say 20 patients, 20 controls, they measure x, they report the results. Somebody else measures y on a different population of patients. It's not that common that you measure x, y, z and everything else in the same. So that facilitates that. So we did that and we published the results where essentially what we're saying is, yes, there is evidence that there are viral infections at multiple levels. And there is evidence that these infections primarily target the beta cells that make insulin.
And then there are other signs that are associated with it. So we basically, I think, supported it by looking in the pancreas with type 1 diabetes at different stages. The concept that viral infections are out there. Also, they can be chronic or be repeated infections. And so they are likely contributing to this process. We did not find evidence that there is a massive acute infection that leads to directly the death of the beta cells.
Well, that's one thing that I sort of acknowledged in the papers is that I think there's a very cautious approach to describing the results. So it doesn't veer towards saying there's causality here. The enterovirus necessarily drives the onset of diabetes. But if I could just ask you to speculate a little bit for our audience. I mean, do you there's a possibility that acquiring this enteroviral infection could potentially lead secondarily to diabetes?
Yes, in many different ways. Number one, we know that for sure. So these enteroviruses can infect the beta cells. We've shown that. Whether it's in the pancreas of these donors or experimentally. When those cells are infected, they can become dysfunctional, they can become inflamed. They become more visible to the immune system. What we know that in type 1 diabetes, these beta cells are killed by immune cells that are specifically targeting molecules that are produced by the beta cells.
And it's actually a little bit unclear whether they can also target the virus itself. So that has been investigated. And as part of this group efforts, we've also done a study where we actually mapped out what specific molecules are targeted from these enteroviruses and develop reagents that we can now test whether these responses are, in fact associated with the disease. So that's work that is ongoing.
But also we have shown, and this was unequivocal, that there are immune cells that can specifically target a beta cell molecule and at the same time target a viral antigen. So we call that cross-reactivity. And we show it in the most unequivocal way because that has been suggested for a while. But finally, we actually had the tools to show it where you have essentially the same cell identified reacting with these two different molecules. And that's very important.
So there are many different ways that a virus can really promote the disease process.
I mean, it's just it's amazing to me all the parallel lines of thought between oncology and this line of endocrinology research. I think about some of the work that's happening within our microbiome group, and some sort of putative associations between bacterial pathogens, and creating these mutational signatures in the gut that lead, for instance, to colon cancer. There's a big Nature paper around this a couple of years ago.
Of course, it begs the question of whether or not you can prevent, for instance, colorectal cancer from happening by targeting specific bacteria. I know I'm asking you to speculate here quite a bit. But if you had to envision how we could, say, prevent this type of enteroviral infection, any thoughts around how we might be able to do that?
So actually, a vaccine was developed. And in part the decision from a company to invest and develop this vaccine was supported by the work that I did with my colleagues with the AMPA study. And we actually shared information with them even before it was published. So they were aware that there were supporting evidence. And that was a very important motivating factor for them to say, we're going to put millions of dollars and develop this vaccine.
And so this vaccine has been developed, has been tested in healthy subjects, has been shown to be safe. And has been shown to actually induce an immune response, which is what you want. It has not yet been tested in the context of the disease. And hopefully, it will happen in the near future. That's out of my hands. It's in the hands of a company and all that. But the hope is that this will be forthcoming.
There is a study that was recently published in patients that were recently diagnosed with type 1 diabetes. They were treated with a combination of antiviral drugs. And what they show is that when they were treated, their residual insulin secretion was preserved relative to those that instead were treated with a placebo. So that would provide indirect evidence that the viral infection is important, because if you antagonize it and they're doing better, that means it's got something to do with it.
So there are all different types of evidence that points that a virus is important. Now, is it going to be absolutely true in every single patient? Not necessarily. But it's going to be fairly common, I would say, yes. And possibly, again, it's not maybe the only cause, but it's an important factor.
Yeah, absolutely. And it gets me thinking, too, about the other approaches that people are of stewing over in oncology when it comes to modulating the gut microbiome. I mean, clearly, we could use maybe very selective antibiotics to target these mutagenic strains of bacteria. You could use a vaccine, for instance, to modulate this particular enterovirus in the context of type 1 diabetes. But let's think about diet and lifestyle. Anything you can think of from that perspective that would avoid this? Or is that just too broad an approach?
So there is actually evidence that the microbiome is also altered in type 1 diabetes. And there are a few bacterial strains that have been associated with the risk of type 1 diabetes. There is also evidence that some of these bacteria, believe it or not, make some proteins that look like beta cell molecules. And therefore, it's another evidence of potential cross-reactivity so that they could trigger an immune response that then goes after the beta cells. You were trying to eliminate bacteria, but you're going after your beta cells now because they look alike.
There have been studies where manipulation of the microbiome in the intestine has been shown to actually impact disease progression. So there is certainly a lot of interest in continuing to study that and perhaps trying to bring it towards preventative solution or therapeutic solutions. And bacterias can also be used perhaps to deliver therapeutics. So there are all kinds of possibilities. And certainly, vaccination, if by preventing a viral infection, you can eliminate a trigger of the disease, you're likely going to reduce the risk.
And so my hope is that when they do the vaccination study that I was alluding to before, it will be done in populations that are early in life, identified as being genetically at risk. And you can follow them and determine, are they triggering the autoimmune process or not if they're vaccinated?
That's brilliant. I have to control myself when it comes to talking about the microbiome, because I could go on for hours and hours here. It's just so fascinating. I'll probably come back to it. But before we do jump back to it, I just wanted to ask you, you mentioned mention, perhaps these therapeutic trials of the vaccine are often to the future. But you are actually starting up a trial for type 1 diabetes. Can you tell us about that?
Sure. We're launching a trial that actually is going to be nationwide. It's going to involve about 11 institutions across the country that are very well known for their experience in clinical trials in type 1 diabetes. These are really leading academic centers that have been contributing to type 1 diabetes research and clinical trials for a long time. And these are colleagues that I've known for a very long time. And so we actually have been working on the design of a trial with a certain therapy. And then that study evolved into the ones that we're doing.
And so what we're trying to do here is-- it's actually inspired by the Wanek Family Project for Type 1 Diabetes. This is a family that has made a big donation at City of Hope specifically for type 1 diabetes. And they have inspired us to be a little bit bold in trying to have more shots on goal, trying to be fast and accelerate progress, and to take risk. And so what I did basically, is I started conversations with several of my colleagues and said, we have the opportunity here to launch a trial and to learn if we can control the immune system, and trying to preserve the ability of the pancreas to continue to make insulin.
And so we had a number of conversations, which culminated in everybody coming here to City of Hope for a day and a half, where we closed ourselves in a room. And for 1 and 1/2 days, we work very hard, then discussed and designed this trial. And so it really is a consensus trial from leading experts in the country, which builds on the early success of other trials that have tested these therapies individually. And all of them have been shown to have a good level of efficacy in terms of preserving insulin secretion in a patient that has been recently diagnosed.
When people are diagnosed, they're still making a little bit of insulin. It's not enough that they can avoid insulin injections. But it does help them manage their diabetes better. Now, over time, it will continue to decline and eventually disappear. Can we preserve that? If we can preserve that, we can learn if we can control the autoimmune process. So this patient population is really important because it's the patient population that can tell us whether we are successful at controlling the autoimmune process.
So that's where the trial is designed in patients that have been diagnosed in the previous six months from when the time they enroll.
And what is the nature of the therapy in this trial?
So what we're trying to do is to, in the same trial, test two combination therapies. So not one, two. More shots on goal. There are three individual therapies that we're going to use, three different drugs. One is called thymoglobulin or ATG. And this has been used a lot in transplantation and, essentially, is an immunosuppressive drug. In transplantation is used at certain doses. It was used in earlier trials in type 1 diabetes by itself, a low dose only for two days. And that resulted in through the patients maintaining insulin secretion for up to two years.
Still declining, but not as much as if you were not treated. It was a big difference. The efficacy was really not worth it. But still, there was a decline. And why? Because it's a chronic disease. So when we treat with thymoglobulin we're essentially stopping the immune system. But we're going to stop it for a while, then the immune system is going to come back. Now, you cannot keep treating with thymoglobulin because it's a heavy immunosuppressant drug. And then you don't want to give this to children forever.
So can we follow that treatment, which is quite effective in its own, with some other therapies that are safer and we can give longer term? And try and do either reduce this decline or perhaps even completely stabilize it and prevent it, so that they at least remain stable with whatever insulin ability they had from the beginning, if they can keep it long term. So we're going to follow the treatment with thymoglobulin, with therapy with verapamil, which is very well known drug.
Which has been shown in two clinical trials, both children and adults, to actually help preserve insulin secretion in newly diagnosed patients.
Calcium channel blocker.
Calcium channel blocker. It doesn't only block the calcium channels, it also has an effect on a protein called TXNIP that is very important for beta cell stress, survival, et cetera. So basically, it offers support to the beta cells. And that's very important, because in type 1 diabetes, yes, the final cause is autoimmune destruction of the beta cells. But at the same time when people are diagnosed, they actually have a fair amount of residual beta cells. They just don't work. They are dysfunctional.
So can we actually get them to recover? Which would restore a little bit their function. But also, can we protect them and help them survive in the long term? So that's one approach. On top of it, as a calcium blocker, this therapy also impacts the immune function. And there is data in the literature that support that. So in essence, what we're trying to do is develop a regimen that goes after the immune system acutely to basically give it like a stop, like a jolt, stop now. And then trying to provide coverage that it doesn't come back and it protects that beta cell.
So it's trying to target both the beta cells and the immune system. The other drug is called adalimumab, and it's a TNF alpha inhibitor. So it's an anti-inflammatory agent. A similar drug has been used in another trial in type 1 diabetes, also has been shown to help preserve insulin secretion. So the idea is in this case, we would follow with adalimumab after the thymoglobulin and keep giving it. And again, with the same principle, can we stabilize insulin secretion?
And what's important is that as an anti-inflammatory, it will basically down regulate the immune system. And at the same time when you relieve the inflammation, then the beta cells have a chance of recovering. And so indirectly, it also provides support to the beta cells. The other important thing is that this therapy could also promote the function of what we call regulatory T cells, which are a class of immune cells that's like the police of the immune system that regulates the immune system.
So we could potentially promote the regulation of the immune system, which ultimately, I think is what we really need to achieve to control this autoimmune process. So the trial is designed in a way that we're going to be treating people for three years. Which is actually quite unusual because most trials treat for one year at the most. And then they look for the outcome of the trial at one year.
And because we already know that a one year, these drugs individually have an effect that is measurable, we want to look for the outcome of the trial at two years, which provides several advantages. But most importantly, gives you evidence that you can have a therapeutic effect for a longer period of time. And then extend the treatment to three years. Why? All of these drugs are FDA approved. They're on the market. So if we can show that for three years, we can stabilize insulin secretion, I think that that's a very important achievement.
Because then the question is going to be, perhaps these are drugs that can be used by people. Of course, you want to have FDA support in that and all of that. But it gets us closer to that point where you have some drugs that can be recommended, indicated for people with type 1 diabetes in that situation. And in our field, other than insulin, for a very long time, we did not have any therapy at all approved as a therapy that could modify the disease course. So intervene in the disease process for type 1 diabetes.
And we only had one that was approved a couple of years ago. This drug took about 40 years-- 4-0-- from initial conceptualization, preclinical studies in mice and all of that clinical trials and, finally, to approval. And a lot of this has to do with the times. Now, hopefully, newer drugs will take less time. But there is a lesson there that things take time to move forward. So if we start with drugs that are already out there, we already have taken 20 years out of the development. It's done.
Well, what I think is also really key about this, and what I'm sure is probably not lost on our audience, is that drugs like verapamil have been in our arsenal for cardiovascular disease for eons now. And I think the whole idea of taking these established agents and other diseases and repurposing, if you will, for type 1 diabetes, correct, makes the strategy so much easier. I will say, this is the type of research that can only be done with support, like what we have from the Wanek family.
This is not something that pharma or other entities would get behind. So it really makes this a unique opportunity.
Absolutely. In fact, pharma has somewhat limited interest in developing these type of therapies for type 1 diabetes. Because number one, it is considered not a big market. It's a small market for a pharma. And it is a difficult issue to deal with because for these type of therapies, at this stage, you can only use them very near the time of diagnosis. If too much time goes by, there is nothing left to save, so they wouldn't work. So that makes the market even smaller.
So a gift like such as the Wanek family gives us this freedom that we can do the trial that we feel this is important, this could be impactful. This could translate to patients effectively. We have the ability to do it.
Terrific. Terrific. So certainly, you've mentioned the Wanek family gift and the possibilities that opens up. I'm wondering, what was it that took us to get a world-class researcher like you over to City of Hope? How did we make that draw? I mean, you had a terrific career going on at Miami. What was the pull to City of Hope?
I think the Wanek Family Project was a big draw because of that concept that I could leverage that resource. One of the things that has always been clear in my mind that-- I work for 28 years at the University of Miami, and we also had philanthropic support, quite generous. There was a foundation that supported our institute there. And it was an institute dedicated to type 1 diabetes. So it's not that was the wrong place. It was a great place.
But we were using the philanthropic support primarily to support our own institute. And when I came here, I said, my vision for this is, I don't want a penny. I'm not going to use dollar of the Wanek Family Project for my own research. But I want to use it for big projects, big things that involve other people where we can bring together the best of the best. And that's what I'm trying to do, as long as it's used for the purpose. So that's why I like it that I have that freedom and the support from the institution to be bold and trying to do these approaches.
I love that. And clearly, I think this is a philosophy that you've built over many, many years. I wanted to take you back for a second to your days writing that post-doctoral fellowship application, when you locked yourself in a room for a month to get that ticket to the position here in the United States. These days, getting into science is challenging. Establishing a career is incredibly hard. What's your advice to folks that are breaking into science and scientific research at this moment?
Have fire in the belly. If you don't have fire in the belly, you're not going to make it. So if you have it, you'll know it, you'll make it. That's it.
Simple as that?
It's as simple as that. I think if you have the will, you will make it. But you have to have it.
No, absolutely, indeed. I think it's great to have folks like yourself and other leaders at this organization who are willing to maybe sacrifice their own accolades to bolster the research of others. I think this Wanek family gift application is a great example of that. And I'm sure many careers will probably be built on this trial and others like it, right?
Absolutely. We have a mix of very established investigators and young investigators who are participating in this effort. For them, it's a great opportunity as well. And I've been doing this for a long time, that I actually like to promote the young investigators. They're so bright. They're so up-to-date with the modern technologies. And I think of me as a dinosaur. I want to talk to them because they know those things better than I do. And so I want to get them involved. And at the same time, they learn. And they contribute.
They also get exposed to the more senior people, they get known in the field. That facilitates their professional growth and participation in the science. And so I've done that for many people. And there is an investigator in England that we've worked together for many years. She sees me as a mentor. And a couple of years ago, she received a big, big recognition in England. And so she had to give a big talk. And in her opening slides, she put a picture of her mentors. And then she shared the slides and said, see, you're there.
And we were never in the same institution. But she considered me as a mentor because I did mentor her. For me, it's great to bring the younger generation forward.
What a great feeling. What a great feeling. I'm going to get to a question that we asked everyone who comes onto this podcast. And it's kind of a tough one, but I've asked you a lot of tough questions today. The title of this podcast is On the Edge of Breakthrough, Voices of Cancer Research. What does "on the edge of breakthrough" mean to you?
The edge of breakthrough is trying to do things that improve people's lives as much as possible. That's why I've been always trying to facilitate progress, wherever that might be. I can have an idea. And I might not be the best one to do it, because somebody else might be better than me. And so usually what I do when I have an idea, I think, that person can do better than me. I give them a call. And I'll discuss it with them.
And very often, people say, wow, that's a great idea. I'll try it. And I've done that a number of times. Because for me, the end goal is, let's cure this disease. Let's prevent this disease. I would like to be in a world where I don't have to have these children developing diabetes. That's why I left my country. That's why I left my family. And that's my life mission. And you asked me before what attracted you here.
One other thing that I should have said is that, when I was considering whether to move here or remain in Miami, where I was in a very good position, I was very established. Everybody knew me, I knew everybody and all that. So after so many years, you say, do you really want to change? And in the end, I asked myself, where do I think I can give more of a contribution? Here or there? And I figured that I would be in a better position to give a bigger contribution here.
And at that point, my choice was made. Because I said to myself, if I don't take it, I might as well retire now and go home. Otherwise, I'm reneging myself. So I just said, I'm going.
I love that. I love that. I'm going to ask you something in closing that I've asked every Italian that I've met who's joined our faculty here at City of Hope. Have you found a place here in Los Angeles yet that can match the food in Sicily?
My house.
Your house? OK, got it. OK. I asked Dr. Marcucci. He said, don't even bother. Don't even bother.
It's hard. It's hard. It's hard.
Dr. Pugliese, I so enjoyed this conversation today. What a wonderful talk. And I'm sure we're going to have you back here again.
With pleasure. Thank you.
Thanks for tuning in to On the Edge of Breakthrough. See you next time for more insights from the front lines of cancer research and care.