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  • DiabetesDaily.com Interview video transcript with Dr. Denise Faustman about BCG research to reverse diabetes type 1.


DiabetesDaily.com video Interview transcript with Dr. Denise Faustman  about BCG research to reverse diabetes type 1.

If you prefer to see the video,  the video is featured at the top of http://hdiabetes.com/video.

Interviewer: So I guess here’s my first question. Denise Faustman: Okay. Interviewer: What’s wrong with the immune system in people with diabetes? What’s going on? I want to get to your research, but I’d like to understand the context first. Denise Faustman: Type 1 diabetes is different from type 2. Type 1 is an immune disease and type 2 is more of a brain and muscle disease. They’re both called diabetes. They both cause you to urinate frequently, though the reason you go frequently is very different. So in the case of type 1 diabetes, the cells of your immune system recognize your insulin-secreting cells as bad, as "non-self," or foreign, and they literally kill your own cells that make insulin. As a result, you don’t make insulin and your blood sugar goes up, causing diabetes. Interviewer: Okay, so tell me a little bit about how you got from type 1 diabetes research to the BCG vaccine? Denise Faustman: Well, that’s a long story. (Laughter) Interviewer: We’ll take the five-minute version. Denise Faustman: I got started in diabetes thinking it would be so easy and so straightforward to just replace the part of the body that’s broken. For example, if part of your lung is gone, you would get a lung transplant. Therefore, if you have diabetes and part of your pancreas is gone, just replace the pancreas, right? So I was recruited by Harvard to set up one of the first islet transplant programs outside of St. Louis because I had been one of the early developers of that technology at Washington University. I got recruited here to Harvard and within a short time Dr. David Nathan over in the clinic started working together. We started doing islet transplants, transplanting the cells that make insulin in the pancreas, because we assumed that if you popped in these islet cells from organ donors, you could cure diabetes.

Within three years, we realized it wasn’t working. So we thought "Let’s think about this concept a little bit more," and it became obvious that there was a big gap in the scientific literature.


And this big gap was that everybody was saying, "Oh, my mice are cured, my dogs are cured, and my primates are cured so let’s try this in humans" but these experiments were not working in a type 1 diabetic mouse. All of a sudden there appeared to be this huge research gap between who we were treating in the clinic and how we were testing the models in the lab. So unlike the rest of the world, we stopped the program because we thought, "If my lab can’t take an end-stage type 1 diabetic mouse, put islets in it and cure it, why should we be doing this in humans with type 1 diabetes?" So we stopped the program, even though this decision wasn’t popular. It seemed like type 1 diabetes should be a transplant disease, but if we look at the evolution of science and clinical trials over the last 15 years, most diseases that we thought we could cure with a simple transplant haven’t worked out. I’ll give you an example, because I think it’s a major take-home message for diabetes. For instance, look at cardiac disease. You have major atherosclerosis, leading to a heart attack, so you put a new heart in, and guess what? It’ll only last about five years because you’ve got recurrent atherosclerosis. So if you don’t correct the underlying problem of why your heart failed in the first place, it doesn’t work that well. And look at all these neuron-cell transplants that at first looked like it was really going to work well for Parkinson’s disease. They first did the transplants out in California in people who had drug-induced Parkinson’s disease, and then when they went into people with natural Parkinson’s disease, and guess what? None of the neuron-cell transplants worked at all long term because of recurrent disease - the Parkinson's disease reoccured in the transplants. And in fact, some of that data was just reported in peer reviewed journals over the last three months of people who had recurrent Parkinson’s in their transplants. They eventually died, and sure enough, the grafts were totally recurrent disease.

In diabetes, it’s the same thing. It doesn’t matter if you put islets into a person but don’t modify the original disease condition because the disease reoccurs. We’ve gradually learned from the biology that if you don’t correct the underlying defect, you have no hope of any of these cell transplants working. So that’s why I think there’s a little bit too much hype on the concept that every disease can be cured by cell transplantation. The data’s just not there. So I think that’s how we got going on that theme. That was the 10-minute answer.


(Laughter) Interviewer: Okay, so we now have our pancreas here, and we have islet cells that are being killed off. Is this what’s happening? Denise Faustman: Yeah. Interviewer: And what’s killing them off? Denise Faustman: In immunology we talk about T cells, which are a type of white blood cell. Remember, when you draw a tube of blood, it’s red because there are a lot of red blood cells. But for every million red blood cells, there’s one white blood cell, and white blood cells come in a number of types. One of the types related to diabetes is the T cell, and even a more specific T cell that’s related to diabetes is something called a CD8 T cell. But in general, people talk about T cells, bad T cells killing the pancreas. Interviewer: Is it the CD8? Is that the specific one? Denise Faustman: CD8 cells are the ones that can bind to an islet cell and kill it. CD4 cells, the other subset, probably help early in the disease process, but they aren’t killers. They’re kind of accomplices in the back room. Interviewer: Is this what you can see in a test tube? If you took and islet cell and a T cell, would it – Denise Faustman: Not in a test tube, but under a microscope. Interviewer: Under a microscope you can actually see this process happening? Denise Faustman: Yes. You wouldn’t be able to see it in a gross picture or piece of pancreas but under a microscope – oh, yes, oh, absolutely. You can see bad T cells sitting right on top and within the islet cells. Interviewer: So can I ask a question that’s kind of related? 

Denise Faustman:

Yeah. Interviewer: I know early – when I had diabetes in the early days, there was speculation about what triggered that attack. Denise Faustman: Yeah. Interviewer: And a lot of people were talking about coxsackie virus – Denise Faustman: Oh, yeah. Interviewer: You know, there was some trigger. I mean, it’s sort of off the topic, but do they – have they figured that out yet at all? Denise Faustman: Well, you make T cells throughout your entire life. It’s not like you make T cells the day you’re born, and then that’s your repertoire and you live with that the rest of your life. So you’re pumping out millions of T cells, and it’s an inefficient assembly line because it’s based on evolution. Because your immune system doesn’t know what you’re going to encounter over your lifetime, you make a huge amount of diversity in T cells. However, if you create a huge amount of random diversity, you also create a problem if you don’t kill off the wrong diversity. So we think it’s what’s called a negative selection defect, meaning all the bad guys you made have not been killed off and a few of those bad guys get out into the bone marrow and thymus and get into the peripheral circulation. Interviewer: And so that – whether it’s coxsackie or something else, it helps – sort of triggers it? Denise Faustman: Yeah. Now a lot of people love viral theories, and I’m not dismissing them totally, but a lot of it is a little bit misdirected. If you ask people, "When did you get diabetes?" they’ll usually say, "I had a terrible flu, and within a day or two, I was peeing a lot, and I was lethargic, and I lost a lot of weight, and that virus I got caused the diabetes."

Well, we know that’s not the case. Now there might be some legitimacy that a virus could, with the correct genetics, alter your genes in some way. But it’s not like you got a virus and you got diabetes. You had to have a whole bunch of alterations along the way. But that’s the typical story you hear from a parent, "My kid got the flu, and that’s when he got diabetes."


Interviewer: So is the body always making bad T cells? Is there some sort of screening process that filters them out? Denise Faustman: Everybody, even people without diabetes, is making bad T cells all day long. But it’s like an assembly line where you make a million cars, and only a good one gets out. Well, that’s similar to how your immune system works. It makes a million T cells, and only 1 or 2% should get out. So that quality control checkpoint is really brutal but you probably need that from an evolutionary sense, because if you go to Africa and you get bit by the Zimbabwe tsetse fly, you need to have immunity to that Zimbabwe tsetse fly. You want a lot of diversity all your life, but if your immune system is not very good at fine tuning that diversity, your system can mistakenly let out a few bad ones out in the periphery. Interviewer: Okay, so we have some bad guys now. Denise Faustman: Yeah. Interviewer: Is – how do you go about telling your body to not let these bad guys out, or how – at some point you have to stop these bad – if you want to reverse or prevent diabetes, you could stop the bad guys from getting to your islet cells. Denise Faustman: Yeah. Interviewer: At what part in that process are you gonna look to stop that from happening? Denise Faustman: Up until recently, as you probably know from reading about diabetes, people thought you couldn’t prevent the bad T cells from getting out. People thought if you could screen kids that don’t yet have diabetes, you could intervene to prevent the bad T cells from ever escaping. But that’s not a very satisfactory answer for people here today that have diabetes.

So the reason, I think, people thought you couldn’t identify the bad cells or do anything once you got it was because when you present to the clinic, it’s late in the immunological process. It’s the same for all autoimmune diseases. Once a 50-year-old woman presents in the clinic with huge, swollen joints, she’s already had autoimmunity in the form of rheumatoid arthritis for 10 years. Diabetes is the same thing. You present to the endocrinologist when your pancreas isn’t working but by that time it’s late in the immune process, so you’ve got a lot of diversity of those bad T cells. At that point, you don’t have hundreds of bad ones, you probably have thousands of bad ones, maybe even millions of bad ones. So how would you ever find a way to modify those cells? The concept has been, and in fact, all the historic trials moved forward have been, "You must suppress the entire immune system. You’re never going to find unique signatures of the bad cell." And that’s why the trials up to this point either in pre-diabetics, or new-onset diabetics have been immunosuppressive agents, agents that get both the good T cells and the bad T cells.


Interviewer: And have a lot of side effects. Denise Faustman: That’s right. So in the case of cardiac transplanting, if you don’t have a heart, and you need a heart tomorrow, immunosuppression looks like a really good option because you don’t have any other option – it’s immunosuppression or die. But for type 1 diabetes, it’s not the lifestyle you want. Interviewer: So you can’t go willy-nilly stopping your immune system? Denise Faustman: Yes, that kind of turns you into an AIDS patient. It’s easy to get cancer or other infectious diseases if you have an inactivated immune system. Immunosuppressants are nasty drugs. They look great if you need a heart, but they’re nasty drugs if you don’t need a heart or other organ. Interviewer: So what can you do? Denise Faustman: Well, we worked on trying to identify the bad T-cells. Amazingly enough, we not only found them, but we found out that the bad cells looked different from good cells at the protein level.

People without a scientific background are probably now asking, "What does that mean?" Well, a good illustration of this concept is antibiotics. Everybody in the general population knows and takes antibiotics, and antibiotics are great drugs. When you take an antibiotic it doesn’t kill you but cleans up your sinus infection; it cleans up your ears, it gets rid of the sore on your arm. The reason why that antibiotic works but doesn’t kill you is because it recognizes different proteins and interferes with those proteins in the bacteria, but not yourself. So from the scientific discovery process, understanding differences in proteins, or finding a difference that distinguishes a good cell from a bad cell, or a cancer cell from a good cell, or a bacteria cell from your own cells is essential. If you can identify a difference in proteins, then you can start to think about targeted treatment. However, the process of finding this difference took 18 years. It wasn’t like one week said, "Okay, we’re going to look for protein differences," and then the next week we found them. So over an 18-year period, we started to identify protein differences in the bad T cells versus good T cells, and it was even as good as it gets because the differences were on cell death pathways. So if you’ve got a difference in cell death pathways, you’ve got a way to kill the bad cell.


Interviewer: What’s a cell death pathway? Denise Faustman: If you were to think about a cell as an independent organism that desires to live, you’d see that they have all sorts of ways inside of them to try to survive all the time. But if they’ve got a defect in these methods of survival, then you can capitalize on the defect by making a drug to that targets the defect. Gradually, we realized in type 1 diabetes in humans, as well as mice, since the lab goes back and forth all the time, that they have the same general populations of cells, so we started looking for ways to kill those cells, and then we took the experiments into mice to see what would happen. Interviewer: Now how did you identify – you have a specific protein here, how in the world do you go through all these substances on earth to find something that can attack that particular protein.

Denise Faustman:

We performed what’s known as screening, or drug screen. Once you know the pathway you can find out information from others’ work – other people have worked on these pathways for various reasons. Interviewer: Okay, and what did you end up with that worked? Denise Faustman: We ended up with two ways to kill cells that we wanted to test in the mice, and of course we were bringing these experiments forward in the mice, 18 years later, to try to figure out if we could finally get an islet transplant to work in an end-stage diabetic mouse. Remember, there was no data out there showing that you could get an islet transplant to work in a diabetic mouse – a real diabetic mouse, not one with diabetes induced by chemicals. Interviewer: The fake one’s where you would remove the pancreas or artificially – Denise Faustman: You gave it a chemical that destroyed the insulin-secreting cells. We wanted what we call a real McCoy mouse, a mouse that got type 1 diabetes by an immune attack on its pancreas, that had the genetics that overlapped with the human. There’s a model called the NOD mouse that matches type 1 diabetes and nobody had ever gotten islets to work in these mice. The only way that they would work is if you took that animal, gave it vast amounts of radiation, and put in a new bone marrow. Well, doing that just proves type 1 diabetes is an immune disease, but it doesn’t prove what to do with it. Interviewer: And you ended up with? Denise Faustman: Our purpose was to take those end-stage animals to mimic people who already had diabetes, do an islet transplant, put in the two drugs, and see if we could, for the first time, get islet transplant to work. Well, we discovered something totally unexpected in those animals, and that was the fact that we never needed the islet transplant, because once we got rid of the disease with the drug, the pancreas regenerated. This was a big surprise.

These experiments were a tremendous amount of work and everybody who worked on it deserves credit because of the intensity and commitment. You’re talking about following animals, and incurring animal costs for three to four months, coming in seven days a week to check blood sugars, and giving insulin twice a day for weeks. It’s like intensive care for a little mouse. That’s probably why nobody does these experiments. Nobody in their right mind would do these experiments, because you have to provide 24 hour/7 day a week care. It’s expensive, it takes the mice about four months to get diabetic, so they’re more middle-age than young, and nothing ever seems to work in them.


Interviewer: So that was an accidental discovery? Denise Faustman: Well, I don’t like to call it accidental. I call it hard work on a targeted project that yielded the discovery of spontaneous pancreas regeneration. Interviewer: Well, you’re on the right path. Denise Faustman: I call it good science. We were doing the most important experiment at the very end and that led to these little mice having a good life now even though they were end-stage diabetic. They were running around the cage even though they were old. These guys are old in mouse years. And then we went back to the animal care committee to ask them if we could do a nephrectomy where the islets were, and see if the blood sugar goes up. It was a lot of work and pretty risky, too, because what you’d really rather do is terminate the experiment a little earlier, get the histology, and just prove the mice had the islets. But what these little animals proved to us is that even when we took the islets out, they still had normal blood sugar. So it was a discovery of islet regeneration. We would never have gotten this discovery if we hadn’t followed the animals that long term, and hadn’t really gone the full circle of saying, "Okay, let’s be really thorough here and do the final experiment, and make a perfect figure for a manuscript, and a really pretty picture." Interviewer: And this was published in 2000 and? Denise Faustman: One – that was published in 2001. Interviewer: Okay, and then, since then, what has the lab been working on?

Denise Faustman:

Well, the good news is if you’ve got diabetic mice at home, we’ve got you covered. (Laughter) The other good news is that there are about six other centers worldwide that can now do mouse diabetic cures as well. The diabetic mouse community is very happy right now, and they’re ready to go. (Laughter) Interviewer: We owe you a debt of gratitude. Denise Faustman: Now seven years later, or eight years later, we have a lot a happy mice running around, but we’re also trying to take it to humans. We’d love to have a lot of happy diabetics running around in the lab as well. So the whole purpose in what we work on now – we have very few mice left in the lab – is to try to move this concept into humans. That’s where we are currently. Male 1: In retrospect, BCG seems like an obvious candidate because you already use it for immunotherapy and for several other things, but was it just one of a whole bunch of substances you tried? Denise Faustman: Well, we went to BCG because we knew that the drug we wanted actually was something called TNF. We wanted TNF, but keep in mind drug development is incredibly costly. The average drug in the United States costs a billion dollars to develop – a billion. However, ninety percent (90%) fail. So here we are with a new pathway, new idea, and we want to make a new drug. Well, in academia you can’t make it, so you have to go to one of the big pharma companies and ask them to establish what’s called FDA-approved good manufacturing. This would probably take you five years and cost you nine to twelve million dollars to make one vial that you could use in one patient. So there you are, five/six years later you’ve burned through nine, twelve million dollars, and even then, you can’t go into a human. Now you have to go into baboon studies or primate studies and do all the toxicology in the primate with your good manufactured TNF. Ten years down the line, you’re fifteen million dollars into the project, and you’re finally going to try your first experiment in a human. All that seemed like a really hard pathway to go down, and there was incredible skepticism that you could even reverse end-stage diabetes in a mouse. I mean, nobody believed it, nobody had done it before, let alone the pancreas regenerating.


(Laughter) It was bad enough to say that diabetes was reversed; it was even worse to say that the pancreas regenerated too. In an environment with so much skepticism, we figured, "Who would support that?" So when we realized that the up-front costs would be fifteen or eighteen million dollars before we had even gone into a person, and also take ten years, we started looking at existing drugs that have a side effect of inducing TNF. And when we started screening for those, we found a well-known one that has an impeccable safety profile, called BCG. BCG has the advantage of good manufacturing. Interviewer: Dirt cheap. Denise Faustman: It’s cheap, has a good manufacturing process established, and it’s been in people for 80 years with doses exceeding 4 billion doses. It was the way to go to get this to the public as fast as possible. And again, you have to realize that pharma would not support a trial like this because you’ve got something that’s already on the shelf. It’s like saying, "Aspirin cures heart disease." What company would support that billion-dollar study to prove the dose that helps heart disease? Interviewer: Now is there a chance this would be moderately or a little successful, and then you would need a more specifically-targeted drug? Or do you think that – Denise Faustman: That’s a good question. It’s the equivalent of pig insulin, and how it’s saving people’s lives. However, people are coming along and making better insulin. Look at the field for 50 years, people are making better insulins, more gizmos, more modern – so of course. Interviewer: Let’s go back for a second to our malignant T cells. Denise Faustman: Oh, yes. Interviewer: Okay, so the BCG vaccine goes in there. Is this a temporary – something you have to do over time to continuously reset your immune system?

Denise Faustman:

Remember that the experiments in the mouse that we’ve published showed a one-time treatment only cured the disease, but that was with two drugs. One drug targeted the killer T cells that were right on top of the islet, and the other one targeted the T cell precursor that came just out of the bone marrow. We currently don’t have a generic drug that targets the precursor cell to combine with BCG. So one of the basic science programs we have going in the lab is identify generic drugs that might help us with this pathway ie can we redo the generic concept for the other cell populations of bad cells? We could make a new drug, but nobody’s come through the door with a billion dollars yet. We’re looking, but nobody’s come. So if they come through the door, we’d be more than happy to make the other compound so it’s a one-time treatment. But they haven’t come through the door yet, so we’ll see. Interviewer: So what is the best-case scenario with the BCG cell treatment? Denise Faustman: It’s kind of a graded process of what we’re trying to do. It’s one of the rare trials in the world that’s trying to reverse diabetes in people that already have it. (Laughter) I mean, if you go look at all the trials that are on the Internet, the bravest trials are the ones getting new-onset diabetics within \weeks of diagnosis, to just show a decrease in the rate of insulin secretion deterioration. Just to change in the curve – not regenerate the pancreas in an upward way. So if you exclude islets transplants to transiently reverse diabetes using immunosuppression, nobody’s tried sole immunotherapy in people who have the disease. So the trial is truly unique in that we’re picking the people that already have the disease for the BCG vaccine. And we’re using a generic drug, and we’re trying to kill off these bad T cells so that there’s a chance the pancreas can regenerate. It’s a graded process of giving the drug, proving it induces the TNF that diabetic needs, then doing all these blood assays that we do all the time that you hear about people coming here to prove it kills the bad T cell, define the window for removal of the bad T cell, and look for pancreas regeneration.

It’s a very targeted therapy at looking at small treatment sizes based on mechanism and all these blood tests. So the blood tests are the critical part of this trial.

Interviewer: Okay. We had a ton of people send us questions and a lot of them are – well, as long as we’re telling the truth, we ask you a couple logistical questions. First, do you plan on extending location of trials outside of Boston, or will this be Boston focused? Denise Faustman: Right now we’re doing it here because we only have money to have a trial here. If somebody came in and gave us millions of dollars to set it up at other centers, that’d be great. Because it’s not your typical trial, all the machinery we’ve developed for the blood tests is not portable. To give you an example, one of the large platform machines that we created to separate cells so we can look for the bad T cells, we moved from one side of the lab to the other side of the lab – it took it nine months to get realigned. You know, most people that are coming in have these defects in their T cells, so it’s not like some diseases where – let’s say breast cancer, where 2% of the people have a rare gene, but we don’t know what’s going on in the other 98%. So you’re gonna find out that it’s only applicable to a few. Or it’s not islet transplantation where only 1%, or .5% of the population could ever get the islets if they worked long term. We think that most people with type 1 diabetes, as well as some other subsets of autoimmune disease have these defects. So if we get a therapeutic window, it’ll be broadly applicable, and you might not need to do the blood test in order to start the therapy, and then you could do it at multi-centers. But right now we’re just doing it at one center. It’s hard enough doing it at one center. (Laughter) Interviewer: People asked – I’m passing on. Male 1: But it’s also safe to say, cause we had this conversation in January, this is a really early – it’s not like anyone in this trial is going to come out cured.

Denise Faustman:

Yeah, I mean this is very early. This is phase one trial where we are trying a very, very low dose. Male 1: We’re trying to determine if – switches things around a little. Denise Faustman: 90% of drugs get stopped in phase one from toxicity. We’re in phase one. Now everybody says, "Well, that’s stupid. Why are you doing a phase one with a drug that’s been out there 80 years in four billion doses?" Well, if the FDA asks you to do a phase one, you do a phase one, even though we don’t expect to see any toxicity. We should be able to get to a phase two smoothly. Interviewer: How long do you imagine phase one lasting? Denise Faustman: About 12-18 more months. Interviewer: Twelve (12) more months, and at the end of 12-18 months you want to show that the right things are being triggered, and want to be able to see some regeneration in the pancreas, hopefully? Denise Faustman: Well, that would be a miracle at this dose. But what we would like to see is that all these blood assays are showing that some portion of these bad T cells are disappearing – even for a day. Remember, nobody’s ever shown autoantibodies disappear with any immunotherapy. Nobody’s ever shown the T cells disappear with any therapy. Nobody’s ever shown you can get sufficient TNF induction. All these other parameters, nobody’s ever shown with any drug in type 1 diabetes. Interviewer: So phase 2 would be increased doses to see if you can – Denise Faustman: Phase II has yet to be planned and we need the data from Phase I. So we’ll be monitoring windows. See, if you do a trial that the endpoint’s pancreas regeneration, well, you’re gonna be following thousands of people and doing thousands of doses. So you really want to have surrogate endpoints from the blood only before that. So we’ve worked on all these blood tests to get surrogate endpoints so we can know what the phase one tiny doses are doing.

Male 1:

And back in the 1920s, Banting and Best chop up some pancreatic cells, they get this murky brown mixture, they go to whatever age the kid is, they inject it in and presto, the kid starts to feel a little bit better. And so over time they were viable. That was the 1920s, they didn’t have to worry about the FDA. Denise Faustman: And also, let’s say we did that, do you think anybody would believe us? (Laughter) So when everybody asks why are we going with the FDA, and why are you doing this and doing that, the answer is because we want to set the highest standard for this trial moving forward. The very highest standard. Because the minute you start reporting one person had the return of insulin, I mean – you want to make sure it’s double – triple blinded the whole way. Male 1: I saw an interesting comment. Someone said, "How can you double blind the trial because of this scab you get from this –" Denise Faustman: Oh, you get a Band-Aid on it. So the physician’s not allowed to see. Male 1: Nor is the patient? Denise Faustman: Well, the patient might know. Everybody’s smart enough so the Internet’s going to know if they received the placebo or the drug although the immune response can vary. The physician taking care of the patient won’t know, however. Male 1: Okay, that’s the important thing. Denise Faustman: Yeah, the important thing is that the physician taking care of them won’t know. Male 1: Oh, okay. Denise Faustman: The mouse data we are using to base our trial has been confirmed by seven international labs – same data.

You’ve got the pathway now identified not only in type 1 diabetes, lupus, Crohn’s, Sjogrens and scleroderma. People ask, "Why aren’t you moving faster?" I think it’s because you never know a trial outcome. But it’s something that should be tested rapidly to move forward. Okay? Probably more rapidly than we can move, because as you know we’ve had to raise the money for this trial.

Interviewer: How much money do you need to put the gas down to full – full blower? Denise Faustman: Well, we’ve raised all the money for phase one with the help of the Iacocca Foundation and the Massachusetts General Hopsital, so we’re moving through phase one. But in 12 months, we’ll need to really gear up for phase two funding. The amazing thing about this program is that it’s supported by the public. It’s totally supported by the public. It won’t be shut down because it’s a competing product with insulin syringes or glucose testing or a neuropathy drug. This program will only be shut down if we can’t raise money to move it forward. But it’s totally supported by the public because the public realizes there’s a huge need to try to do something for people who already have the disease and no one’s done trials in this population before. And there’s never been animal data so substantiated in so many diverse ways that it works in end-stage animals. So it definitely should be moving forward. You can’t promise people outcome, that’s why you do the trial. But it’s probably one of the most mechanistic-based trials moving forward in the diabetes field for years and decades. Male 2: You know what? I think those are – I mean, I think I said this to you before. When I first came across your stuff was 2003, and at that stage, a whole lot of people were pooh-poohing this. Denise Faustman: Yeah, yeah. Pancreas can’t regenerate. Male 2: Yeah, and I remember reading the newspaper articles and ending up in tears, and at that stage, I had diabetes for 30 years, and that was the first time I thought, "Oh, this is something that – this makes sense. It makes sense scientifically." Denise Faustman: Yeah, yeah, yeah.

Male 2:

But at the same time, I think I’m not alone in saying, "I’m prepared to work really hard to raise funds for it, and if nothing happens, well, we tried our best." Denise Faustman: Yeah, what else should be tested? I mean, what other protocol do you see out there that’s moving forward that have this substantiated database? Nothing. Male 2: And you know, even if it doesn’t solve it exactly, it’s gonna be a step – a big stepping stone. Denise Faustman: I mean, what happens if we end up defining intervals where half the population restores their pancreas halfway? Well, you’ll never have hypoglycemia again. Female: Yeah, I could live with that. (Laughter) Denise Faustman: We don’t know the outcome until we get there, but we know that humans have these same defects. We know we have this cheap drug to move forward. We don’t know if we can define the intervals. I mean, look at insulin. You still can’t define the intervals (Laughter) 80 years later, or 90 years later. You still can’t define the intervals. So drug dosing is complicated and not easy, but it’s something that should be aggressively moving forward and tested. Male 2: But if someone came to you, say I was a multimillionaire and I came in today and I said, "How much money do you need to fully fund phase 2?" Denise Faustman: About twenty-five million, which is cheap in drug terms. Remember, the enrollment size is per treatment dose per stage diabetes is gonna be tiny and we can move fast. The expensive part is all the blood work. It’s not one of these studies where you have to get 10,000 cohorts on a COX-2 inhibitor to prove it prevents heart disease or something. Interviewer: It’s a lot of time and labor?

Denise Faustman:

It’s a time and labor, but the drug will be rapidly available if we can get it moving, and the guy who donated blood to help us work on the biomarkers yesterday is benefited by the people who came in six years before, and the guy who comes in the next day is benefited from his data, and the guy who comes in Friday is benefited from the people before. So everybody participates at some level if they have an interest in it. I call it a kind of a democratic trial.


Interviewer: In our community, and across the Web, a very common thing for people who have had diabetes for more than five years, starting at six years – [Talking at once] (Laughter) Interviewer: People that have had it for five years say, "I’ve had diabetes for X years, and I’ve been told there will be a cure within 5 years since day 1, and now it’s 40 years, and nothing’s happened." Can you just talk a little bit about – I think people who aren’t scientists or in the lab to think about how science has evolved over that period, and just how the tools have evolved, and our ability to look at cells and understand processes have evolved. What would you say to that person? Denise Faustman: The reason I picked my Ph.D. project was there was a guy named Paul Lacy who had successfully isolated islets from a rat pancreas. And I said, "God, we’re going to have a cure for humans quick." (Laughter) And everybody thought, "Wow, it’ll just take a year or so to get the islets out of humans, and you just transplant them." So in support of that person, even as a developing scientist moving along, some things seem really tangibly reachable. And sometimes people haven’t considered the full picture until you fail a couple times and you realize the size of the problem and how complicated biology is. So in support of what that person has said, I’d say that’s true. Also I’d say that there’s a lot of hype of people saying, "We’re going to cure diabetes" and yet, there’s no data to do it. And the question is, "Where’s the data?" So if people stand on a podium and they say, "I have the secret cell that will cure diabetes," you always have to sit back and ask, "Okay, where’s the data?"

So you can raise a lot of money by not having data. Once you have data, it’s harder to raise money because people can take potshots at the data. But luckily, we’ve gotten through those seven years of people saying, "End-stage diabetic mice can’t be cured." So they’re cured. Seven international labs all have very happy mice. So now how to thoughtfully move that forward to humans, and the database is much more substantial than a lot of database, because we have mechanism. This is a mechanistic-based trial. So it’s not like saying, "Oh, we got something working in mice. Now seven labs all say it works in mice." It’s knowing humans have the same bad white blood cells that we’ve studied for seven years that are also sensitive to the drug and tissue culture. Nobody’s ever had that kind of data before either. And then as the data moves, it’s the fact that all cells are dividing, whether it’s your brain cells or our lung cells. We don’t know the capacity of how far they could go. But if we don’t get rid of the underlying autoimmunity, there’s no chance any cell transplant has a hope whatsoever. So science nowadays costs a lot more money than it ever did in history. It’s also in a very conservative stage where nobody wants to do the important experiments that can change disease, because it’s too risky. So I think once you get this mounting data and you feel that there’s short cuts to move forward with cheap compounds, you definitely should be moving forward.

Interviewer: So are there some – getting political problems with how we’re funding research here? Cause it seems like – Denise Faustman: Most people at my stage get money from the pharma companies who run the trials. I mean, this is a lot of money to sit here and say, "You need to raise this money."

Usually somebody brings you a compound and says, "Dr. So-and-so, I’ve got this new compound, don’t you want to do a phase one, phase 2, phase 3 trial?" And then you go, "Oh, my gosh, look at all this research support if I do this trial." You do it. It’s very uncharacteristic to be raising your money inside to take a generic drug forward. So it’s what we should be doing in academia. We should be thinking about health care costs at this stage of development of drugs, instead of figuring out, "Can we get the drug approved." Because if you get all these drugs approved that take somebody with type 1 diabetes and take their health care costs from $35,000 to $75,000 with continuous glucose monitoring, what are you doing? What are you creating? So I think it’s setting kind of a new standard in a new time in our country to be able to say that we’re thinking about health care costs at the front end, not just the back end, and I think people are voting with their dollars of what they want to see move forward. It’s no longer just, "What new drug can somebody develop?" It’s, "Can you do it, and is it applicable to many people with the disease, not a few select people that could be privileged, and would it be available to all?" So I think that’s a really important thing to think of up front, even in academia.


Interviewer: Well, I think that there are millions and millions of people, and probably the Diabetic Mouse Association who are very excited about the work your doing. Denise Faustman: It’s a fun thing to do, and Mr. Iacocca gets credit for this research, and people vote with their dollars, right? And when we had spent 12 years mapping these pathways, I was at a board meeting with him, and he asked me a simple question. I’d been working in the field a long time, and he says, "Denise, when are you going to cure diabetes?" And I thought, "Oh, god, this guy just doesn’t understand how the field works." (Laughter)

Denise Faustman:

He doesn’t understand that I can’t go take these two drugs that we’ve been working on and just give them to a diabetic mouse. What self-respecting postdoctorate is going to spend five years of his career coming in seven days a week to check blood sugars for something that’s never worked before? The guy’s parents are gonna kill him. He’s not gonna have a job in five years, he’s gonna have more student loans, and I’m not gonna have a job in five years. So if you start to see how research works, research works to take very tiny, safe steps where you don’t change paradigms because it doesn’t disrupt your work, everybody kind of works on the same paradigm, everybody’s happy, and dines out at the same meeting together. But it takes a lot more stamina to say, "I don’t think the paradigms are right. I see a vision over here, and I’m willing to bet my career on it." So very view people are willing to do that. Very few people are willing to produce provocative data that shows you can reverse end-stage diabetes, and then take the flak for it for seven to eight years. So I think the beauty of this is we’re moving in humans. We’re in phase one in humans, and it’s something that the safe approach would have been to say, "Hey, we need to do five/six more years of mice." It’s safe, it guarantees my job, it guarantees my postdoc’s papers. But the unsafe approach that can make a bigger change, but they’re definitely unsafe in scientific and career terms is to turn in to humans. Say, "I believe it so much, I’m willing to go into humans."


Interviewer: Well, we’re gonna find out if you’re right or not. Denise Faustman: Yeah. But you know what? I’m wrong if I don’t test it. I’m 100% wrong if I don’t test it.

Special thanks to DiabetesDaily.com for video transcript.   2008 interview from diabetesdaily.com.


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