By Researcher pursues a Type 1 cure with a cheap drug | March 9, 2009 5:14 pm
As one of the best-known names in Type 1 diabetes research, Dr. Denise Faustman often finds herself embroiled in controversy — for her methods, for her approach to funding, and even for “cruelly rais[ing]” the hopes of people with diabetes. With so much discussion surrounding her work, we thought it would be good to hear from Dr. Faustman herself. In this part of the interview, Diabetes Self-Management‘s Quinn Phillips and Dr. Faustman discuss the basics of her research.
Quinn Phillips: How did you get started down this research path?
Denise Faustman: I did an MD and a PhD, and in the middle of my PhD, I met a guy who had discovered the first way to get islet cells from a rat pancreas — his name was Paul Lacy [a prominent pathologist who is considered the father of islet cell transplants]. And I thought, oh my gosh, there’s the cure for diabetes! If you can get islets from a rat pancreas, now you can just transplant them like a heart, kidney, whatever. So it seemed like it was a translatable concept, and it seemed so close to human trials. Of course, I did PhD work for six years trying to get islets out of a human pancreas and realized the translation was not so easy. After I got recruited to Harvard, the lightbulb went off that putting islets in people with diabetes is a problem because the disease recurs. So I realized early in my career that there were big challenges out there, and I wanted to do something that related to people but that also used really fundamental science.
QP: What exactly did you do in your mouse experiment?
DF: Well, first of all, people need to know that the autoimmune attack in Type 1 diabetes involves good and bad cells, so we want to go after the bad ones. It’s a concept that people understand: For cancer, you want the magic bullet that kills the cancer cell, not the good cell. And for autoimmunity, like Type 1 diabetes, you want the magic bullet that kills the bad T cell — an immune system cell — and not the good T cell, which helps regulate the bad ones. After about 18 years of work, we found out that we could identify, in mice, the bad T cells and kill them. So we decided to set up the first islet transplants in end-stage diabetic mice. Most of the data that was coming out then — and in news reports that you hear even today — used mice that scientists had artificially made diabetic, not ones with diabetes naturally. So we decided to pick really tough mice, ones with a gene that gives them diabetes, and put in these drugs to kill bad T cells, then do an islet transplant. We said, “Let’s finally get islets to work in end-stage diabetic mice.”
So this is what happened — this is when the science gets good! We saw, in the first series of animals, about 85% of the mice restored to normal blood sugar levels. And then we did something that led to the major discovery in this work: We took the islets out after they had been in for hundreds of days to prove that blood sugar would go up. And what happened was, the blood sugar stayed flat. That was the discovery of this massive islet regeneration that had not been documented before, because the concept was, “you need spare body parts,” so in diabetes you need spare islets. But what these animals showed us is that if you remove the bad T cells in a very targeted way, there’s spontaneous healing of the pancreas. That was in 2001, and in the paper we published, we weren’t allowed to use the word “regeneration.” Nobody believed the pancreas regenerated. But it was not a subtle finding. I mean, there were animals with very high blood sugar and animals with a normal blood sugar level, and you had pancreases harvested from them with big, huge islets in them. So it was not subtle. But it was unreal that this could happen! We set out for 18 years trying to get islets to work in diabetic animals, and instead discovered pancreas regeneration.
QP: Do you think the editors who didn’t let you use the word “regeneration” are emblematic of the medical establishment you’ve been dealing with?
DF: Yeah. I think when data comes out that is what some people call “disruptive data” — in other words, data that doesn’t fit the paradigms everybody is comfortable with — the first response is the normal human response: It can’t be. It can’t be that the pancreas regenerates. It can’t be that you can reverse diabetes if you already have it — if you’re a mouse. But now you can go to seven different centers worldwide, if you’re a mouse, and this therapy works really well. It took about seven years for all the duplication to occur, but if you’re a mouse, everybody’s got you covered!
QP: What drug did you use in the mice?
DF: We used two compounds, two drugs. And the mice never needed to be retreated again in their lives. In the human trials that we’re moving forward with, we have one of those two compounds, the drug BCG, being used. It may not seem like this to the public, but that’s a very rapid move from mice to people. And the reason it’s so rapid is that BCG is a generic drug that’s already approved for other indications. So without the normal delays in manufacturing and huge costs of manufacturing, and primate studies for four or five years, we shaved off probably $20 million and 10 years, by taking this generic-drug approach.
The other drug is a protein complex called class 1 and self-peptide that the good T cells should be using to kill the bad ones. Everybody — every mouse, too — makes T cells all their life. And most of them are rogue, and they should die by a process called negative selection in the thymus or bone marrow, and other locations. But what happens in autoimmunity is a few of these guys escape. They should have died in the bone marrow with class 1 and self-peptide, but it’s not there in diabetics — there’s a deficiency of it, so the bad cells get out. Once they become highly activated and in the pancreatic tissue, just adding back the class 1 and self-peptide doesn’t kill them anymore. That’s what we need the BCG for. In the mice, when we added both class 1 and self-peptide and BCG, it was a one-time treatment. In the human trials we’re just killing the most vicious cells that are attacking the pancreas, using BCG.
QP: How is BCG administered in the human trials? Is it administered just once?
DF: We’re using it in the skin injection form, and we’re actually doing two tiny doses 4 weeks apart. This is still very, very low dosing. It’s kind of like the beginning of insulin, if it were 1920: You’re just hoping you can monitor blood parameters that tell you something’s happening.
QP: So you’re not expecting remission of diabetes in this phase?
DF: Oh no, that’s not going to happen yet. Right now we’re trying to monitor the T cells — we’re looking at good T cells, and we’re looking at the elimination of bad T cells that are autoreactive.
QP: Why are you starting with just BCG?
DF: There are economic reasons to move forward with BCG first. Keep in mind that the average drug in the U.S. costs a billion dollars to develop — so we’re shortcutting this in time and cost by using a generic drug. If Bill Gates came through the door and said, “I want to develop class 1 and self-peptide — hurry up!” we’d be happy to do that. We just can’t raise the money for two programs at once. The generic drug development is totally sponsored by the public, as you may know, since there’s not a huge economic incentive to develop cheap, rapi
d therapies for people wit
h existing diabetes.
Read part 2 of the interview here.
Next week: Dr. Faustman discusses the controversy surrounding funding of her research — including denial of funds from the JDRF — and competing approaches to research by drug companies.
For more information about Dr. Faustman’s research, visit www.faustmanlab.org
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