IRA FLATOW, host:
You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. Up next, some intriguing and controversial news about research in mice aimed at curing diabetes, type 1 diabetes, which is an incurable form of the disease, which strikes so many people worldwide. We've been following the research of a scientist taking a novel approach to curing this disease. Dr. Denise Faustman announced in 2001 that she could cure type 1 diabetes in mice once she was able to stop the immune system from attacking the pancreas, which produces insulin. Then it appeared that the pancreas could regenerate, and she told us on this program in 2001, that she suspected that adult stem cells in the blood help regenerate the pancreas. She wasn't sure.
In 2003, she published a paper saying that perhaps the spleen was the source of those cells. And according to Dr. Faustman, when she injected spleen cells into her diabetic mice, those spleen cells gave rise to new islet cells. But this week, three independent studies in the Journal of Science both succeed and failed to replicate Dr. Faustman's work. All the teams successfully cured some of their diabetes in their mice, some of their diabetic mice, showing that the growth, there was growth of new islet cells, but they failed to find any evidence that the injected spleen cells were the reason, or that the spleen cells gave rise to new islet cells.
This hour we're going to talk to Dr. Faustman about what these findings mean to her, to her approach, her reaction to it and we'll talk with a scientist about what it takes to get a therapy that works in mice to clinical trials in humans. So if you'd like to join our discussion, our number is 1-800-989-8255. Dr. Denise Faustman is an Associate Professor of Medicine at Harvard Medical School and director of the Immunobiology Lab at Mass General in Boston. She joins us today by phone from her office. Welcome back to the program Dr. Faustman.
DENISE FAUSTMAN, M.D. (Associate Professor of Medicine at Harvard Medical School and Director of the Immunobiology Lab at Mass General in Boston): Oh, thank you, good to talk to you, Ira.
FLATOW: Thank you. Let me also introduce Dr. David Nathan is Professor of Medicine at Harvard. He's also Director of a General Clinical Research Center and Director of the Diabetes Center at Mass General, and he joins us today from his office. Welcome to the program, Dr. Nathan.
DAVID NATHAN, M.D. (Professor of Medicine at Harvard; Director of a General Clinical Research Center and Director of the Diabetes Center at Mass General): It's nice to be with you.
FLATOW: Dr. Faustman did I characterize this thread of your research okay? Did I make a mistake?
Dr. FAUSTMAN: Oh sure, sure, you have a good memory from 2001.
FLATOW: I actually went back, I went back to our archives, looked back at the transcripts of what you said, and my memory was pretty good about that. Tell us, tell us the genesis from 2001, 2003 and up to today.
Dr. FAUSTMAN: Yes, yes. So in 2001 we were doing protocols to try to reverse autoimmunity in these end-stage mice, so that we could do islet cell transplants. And you'll remember islet cells are the cells that secrete insulin.
Dr. FAUSTMAN: And clinically people like David Nathan knew that islet cell transplants were hard to get going or working very well in humans because of this recurrent disease. So our aim in 2001 was to come up with protocols in mice to get rid of the underlying autoimmunity, then do an islet cell transplant, and then see if we could really get normal blood sugars. And that was where we, I got the first jarring data that the mice taught us about. And that data was, there was good news that in these very end-stage mice, we could reverse autoimmunity. We had done the islet transplants, the animals were normal glycemic, and bingo the big surprise was that when we took the transplant out, the blood sugar stayed flat.
Dr. FAUSTMAN: And that, yeah, that was like how could this happen, and sure enough, how it happened was that islet's had reappeared in the pancreas. And in 2001 we weren't allowed to use the word regeneration in that paper. It was restoration of insulin secretion. But now we've moved from that point and in 2003 we were allowed to use the word regeneration, and showed that we could not only do it repeatedly in these end-stage animals, but there appeared to be multiple mechanisms for why these islet cells could reappear in the pancreas. And one way was without any stem cell transplant, another way was actually putting back in precursor cells from the spleen.
Dr. FAUSTMAN: So that's, and then this week as you know, as of today, three groups spent the last three years trying to do these same cures to diabetic mice, that is not human yet, David can talk about that. And show that they too could get long-term reversal of end-stage diabetic mice.
FLATOW: But, they couldn't get, they didn't agree that it was the spleen cells, that were causing it?
Dr. FAUSTMAN: Yes, so there's still debate of how this regeneration slash rescue occurs. We know from our experiments that if the animals are a little bit earlier staged diabetic versus very, very end-stage, that the rescue and regeneration is more driven from endogenous cells. Whether that's a insulin secreting cell dividing into another insulin secreting cell, or your favorite stem cell, there's many of them that have been proposed for the islet, anywhere from duck stem cells, to fat stem cells, to bone marrow cells, but if the animal's a little bit earlier, you can get, without an injection of stem cells, spontaneous healing of the pancreas. So these groups had protocols that perhaps optimized this spontaneous healing.
FLATOW: Mm-hmm. So do you still think that there is some, as you say, perhaps unknown stem cells floating around that come back once you take away the insult to the pancreas?
Dr. FAUSTMAN: Oh, absolutely.
FLATOW: And regenerated?
Dr. FAUSTMAN: Yes, absolutely. I think there's, I think the pancreas is still smarter than us. And I think that it can probably heal by multiple mechanisms. This week, another paper came out from another group in Switzerland showing that in human fat tissue, they had found a similar precursor cell that in culture could form human islets. So these stem cells may be multiple locations in the extricate(ph) part of the pancreas and fat cells in the bone marrow, as well as if you stop the disease in its tracks you may also rescue any remaining islet cells there.
FLATOW: Mm-hmm. David Nathan this must be exciting to scientists but it also must, you know, make you scratch your head and say how soon or will this ever be transplantable, so to speak, to humans?
Dr. NATHAN: Well, it's worth pointing out that Denise's work and the work in science that's being published this week, is all in mice. And so the mice community has reason to celebrate. And, you know diabetes is curable in them, but we still need to demonstrate whether these lessons we've learned in the mouse are translatable to humans. From, I must say when I saw the three papers that are, to a great extent, confirmatory of the major results that Denise found over the last four or five years, I was very pleased. I think that the question of mechanism, is where these cells come from, remains an open question, obviously.
Dr. NATHAN: The three papers could not confirm what Denise had seen. But nevertheless, I mean there are new islets that are secreting insulin and sufficient to cure diabetes. And I think what we need to keep in mind is that the diabetes in these mice, this mouse model of autoimmune diabetes, was thought to be in, irreversible, incurable at the stage in which it was being studied.
FLATOW: Now the mice were fed a cocktail to knock out the immune response. Can that same sort of cocktail be given to people to knock out the immune response?
Dr. NATHAN: Well, it needs to be determined.
Dr. NATHAN: The reason that we've been enthusiastic from the moment that Denise and I started talking about these findings in mice is that it is conceivable that one can use a relatively simple way of manipulating the immune system, at least as the first step, to get rid of the part of the autoimmune response. Deplete these kinds of cells that don't recognize self from non-self, and that makes, of course, for the ability to do some fairly simple early, clinical trials.
FLATOW: Can you do that now, Dr. Nathan?
Dr. NATHAN: Well, I mean so there's some technical reasons why we haven't started it yet. People have wondered, well, you know, this is about three years old, how come you haven't started.
Dr. NATHAN: It turns out that one of the fundamental parts of Denise's studies is that she recognized that there are these abnormal T-cells, this is a white cell that circulates in the blood, and which seems to be the cell, again, that attacks the islet. That is miseducated in a way, doesn't recognize friend from foe. So, it attacks the friendly islet. And she learned that, you know, she could deplete those cells, and that seems to be the basis of decreasing the autoimmunity. We have to be able to measure those cells in a reliable fashion in humans before we can go onto human studies. And Denise has spent the last couple of years trying to develop these methods and translate them from measuring them in mouse to measuring them in humans. As soon as she's developed that tool, then we can go ahead and do the first part of the clinical studies that we want to do.
FLATOW: Dr. Faustman, you going to go out on a limb for us here?
Dr. FAUSTMAN: Well, yes, and there's a great analogy that people with diabetes out there will understand. If David Nathan was in 1920 and he announced over in his research lab, down the street here, that he had discovered insulin, but he didn't know it regulated blood sugars, the chance of insulin ever working in human and not being able to check a blood sugar and dose it is about zero. So we feel, we're in the same boat and to really make these compounds work in humans, we have to have a blood monitoring tool. Because, otherwise, we're going to burn through a lot of money really fast. So...
Dr. FAUSTMAN: ...the big job assignment that comes back to my laboratory here, is taking human blood, isolating these cells and proving we can count them and quantitate them, before David ever starts the trial over in the clinic.
FLATOW: Mm-hmm. Let's say that this does work, just speculation and using your mice as an example. How much recovery was there? And did, was the disease knocked out for good?
Dr. FAUSTMAN: Yes, those are two separate questions. One is everyone confirmed that once you knock out the disease in these end-stage mice, it's gone, and doesn't appear to reoccur. The studies vary, each one individuall,y as well as our data somewhat, in the percentage of animals cured. And there's a pretty good explanation for at least why the one study had a lower cure rate than the other studies. And that's something that we'd actually shown in our 2001 study. And is totally pertinent to what David does over in the clinic. And that is that during this cure period where we're injecting the compound over 40 days, one compound and another treatment over 40 days, if blood sugars are not kept under tight control, the percentage of animals cured is totally different. And maybe David, you want to talk a little bit about tight blood sugar control from your human studies.
Dr. NATHAN: Well, there are several different -- it's worth pointing out that tight blood sugar control is the way that we have currently of controlling long term complications. So, there have been wonderful long term clinical trials that show that even if you diabetes and you're at risk for eyes, kidney disease, nerve problems, heart disease, that by controlling blood glucose levels as close to the non-diabetic range as possible, that you can decrease complications. So, that's independent of any autoimmune affect. It appears to work in Type 1 Diabetes and Type 2 Diabetes. However we've also learned along the way, that if we look at people who have an early stage of Type 1 Diabetes. They've gotten the disease in the last year or so. Some of them have enough beta cells that's the insulin secreting cell remaining that you can actually salvage some of them, at least temporarily. That is that they continue to secrete insulin somewhat longer when you have tight glucose control. On the other hand if they have glucose control that is not close to the normal range, those remaining beta cells fade away very quickly. So again, it's not as if you could rescue them permanently. I'm not saying that. But tight blood sugar control in human diabetes seems to prolong the survival of those remaining beta cells. So maybe that's what's going on in these experiments of the mice. I don't know but that's one possibility.
FLATOW: We're talking about Diabetes this hour in TALK OF THE NATION: SCIENCE FRIDAY from NPR News. I'm Ira Flatow talking with Denise Houseman and David Nathan. Of course when you think about Diabetes you know it's an autoimmune disease. You think about the other autoimmune diseases, you know. Why can't the same kind of research apply to that?
Dr. FAUSTMAN: Well that's actually why probably David and I are excited about bringing this forward to the clinic, because as we were doing mouse experiments, other scientists worldwide were looking at the same bad T-cells in other forms of human auto immunity. And it turns out very similar T-cells that die with these same compounds have been found in Lupus and Scleroderma(ph) and indirectly in subsets of patients with Chron's and Rheumatoid Arthritis. So there maybe subsets of autoimmune patients beyond Type 1 Diabetes that might benefit from this same therapy. Obviously, in those patients you don't need to regrow their islets or rescue their islets but you do need to rescue their target tissues that are being destroyed in different forms of autoimmunity.
FLATOW: Is this is a new type of T-Cell that you've discovered or was this known before?
Dr. FAUSTMAN: It's a new way to identify this T-Cell. Many people had thought that once you had autoimmunity, you had such a big repertoire of bad T-cells that you could never find a marker that would identify that large repertoire of cells, let alone specifically eliminate them. And now, we identify them by actually eliminating them and proving that they can't transfer disease. So in that way it's a newly defined broader subset of T-cells, not just one bad type of T-Cell that can kill only one type of islet cell.
FLATOW: So is there any risk of suppressing parts of the immune system that you don't want to suppress with this...
Dr. FAUSTMAN: Well that's the good news yeah because in many trials that people have participated in Type 1 Diabetes, non-specific immuno suppressive drugs have been the hope. And indeed if you add non-specific immuno suppressive drugs, you can halt the disease or slow it down but you're also halting the good white blood cells and good T-cells. And the compounds we're using appear to only selectively kill the bad T-cells, so the most simplistic way to view these compounds is kind of like an antibiotic. You take an antibiotic and it only kills bacteria, it doesn't kill your cells. That is on a good day, you get the right dose of the antibiotic. So, the antibiotic type drugs appear to have specificity for only killing the disease causing cells. At least in the mice and in tissue culture in human autoimmune cells.
FLATOW: What will...
Mr. NATHAN: It's worth pointing out I think that our first step in human studies, which we're not quite ready to start, will be looking at whether we can suppress these cells. We never thought, I think when we designed the very earliest human studies, that they would necessarily cure diabetes. I think that's really that's far down the road. But the first step will be to see whether we could duplicate what Denise is showing in the NOD mouse at least with regard to depleting these bad actor cells.
FLATOW: And so you have to come up with the protocol for doing that?
Mr. NATHAN: Well, we have a protocol actually to do that, to do that very first step. But it is the first step in what will probably be a sequence, or maybe a long sequence, of studies before we get to the point of curing anyone with diabetes.
FLATOW: You have to find a way of measuring those cells.
Mr. NATHAN: Well, we're working on automating it, and making it more practical, and more reliable, yes.
FLATOW: Well, I want to thank you and wish you luck Dr. Houseman. Every time you come back, you have something new and interesting to tell us.
Dr. FAUSTMAN: Well, thank you for inviting us.
FLATOW: Well, what is it what is your last step? What's your next step on this. I got about a minute left for you to explain.
Dr. FAUSTMAN: Yeah, I guess my last point would be that what we're creating or working on might be applicable to many strategies because in the human pancreas, we still don't know if this rescue slash regeneration that's now been confirmed by many groups is present in the human pancreas. So, indeed the elimination autoimmunity might be a benefit to other approaches that are going to use cellular transplants of diverse sources if the human pancreas doesn't have this regenerative potential.
FLATOW: Dr. Foustman, thank you. Denise Faustman, Associated Professor of Medicine at Harvard. And David Nathan, professor of medicine at Harvard Med School. Thank you both for taking time to be with us today. We'll be checking back with you.
Dr. FAUSTMAN: Thank you, Ira.
FLATOW: You're welcome.
Dr. FAUSTMAN: Bye, bye.
FLATOW: Bye, bye. We're going to take a short break and come back and change gears and talk about depression, new studies on treating depression. So don't go away, we'll be right back. I'm Ira Flatow, this is TALK OF THE NATION: SCIENCE FRIDAY from NPR News.
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