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When George Gittes, MD, and his research team came across an outcome they weren't expecting, Dr. Gittes’ surgical background helped identify an amazing discovery — using gene therapy to reverse autoimmune type I diabetes without immunosuppression. Dr. Gittes has recently been appointed the director of the Richard King Mellon Foundation Institute for Pediatric Research and co-scientific director at UPMC Children's Hospital of Pittsburgh.
View the transcript for this podcast (PDF)
John Williams: This podcast is for informational and educational purposes only and is not to be
considered medical advice for any particular patient. Clinicians must rely on their own informed
clinical judgments when making recommendations for their patients. Patients in need of medical
advice should consult their personal healthcare provider.
Hi everyone. I'm John Williams, Professor of Pediatrics and Chief of the Division
of Pediatric Infectious Diseases here at the Children's Hospital of Pittsburgh.
Stephanie Dewar: And I'm Stephanie Dewar, Vice Chair Of Clinical Affairs and Program Director of
the Pediatric Residency Training Program and welcome to, That's Pediatrics
from UPMC Children's Hospital of Pittsburgh.
John Williams: Thanks for joining us this week and we are delighted to have as our guests this
week, George Gittes who's a physician and the surgeon and chief here at
Children's hospital. Dr Gittes, maybe you could just tell us a little bit about
yourself and what you do and then we'll talk about your research.
George Gittes: Okay, John. Yeah, so I'm a pediatric surgeon, which means I trained in general
surgery and then did specialty training for focusing on children. And also during
that time and prior to training, I was heavily exposed to research. So that's really
helped to define me as what is generically called a surgeon scientist. So I divide
my time between doing clinical surgery and basic research. And the career has
evolved from that training to sort of climbing the academic ladder to the point
where I was graciously offered the Chief of Surgery position here at Children's
Hospital of Pittsburgh about 12, 13 years ago and it's been a great experience so
Stephanie Dewar: So I'm wondering if you could tell us a little bit about your recent study that was
published about Type One Diabetes?
George Gittes: So that was a a fairly exciting and serendipitous result that we achieved and
have since publishing it with potential applications to patients with Type One or
Juvenile Diabetes. There's been quite an onslaught of inquiries from patients
and families to me directly about clinical trials. But basically what it consisted of
was gene therapy and gene therapy for the most part in this country involves
using viruses that are carriers for genes that you, in particular, want to
introduce into cells to change them and make them better in some way. And we
stumbled onto it because my research is for many, many years been focused on
the pancreas, which is where the insulin cells live. And we were studying at a
very basic level how the pancreas develops and how the cells form and what
determines which cell is which and why is the insulin cell an insulin cell.
And as part of those investigations, we really sought after various techniques
that would allow us to explore in more detail at the cellular level what was
happening. And along those lines, we engineered some viruses and wanted to
give them to the pancreas and that way introduce special genes into the cells of
the pancreas. But the problem is just giving the usual gene therapy, which is just
by an injection in the bloodstream, it was ineffective. So we had to develop a
special technique that involves going into the inside of the intestine where the
pancreatic juices that help digest food drain out and infusing the virus upstream
back up into the pancreas. And that turned out to work really well.
The surprising result was that when we infuse the correct genes within the
viruses, we were turning other hormone producing cells, insulin is an important
hormone that is defective in diabetes, we turned the other hormone producing
cells into insulin producing cells. And that was fairly exciting. But then the real
excitement occurred when we tried this in mice that are very similar to juvenile
diabetic patients. And the problem with these individuals is that their body
reacts to the insulin cells and kills them. So the obvious assumption was that if
we try this gene therapy to make new insulin cells in this environment where
the immune system just attacks the cells and kills them, it's not going to work. It
shouldn't work and those cells should be killed just like the normal original cells
were killed. But the exciting thing was that they were not. And we think that
what is going on, and we've done several followup studies to show that the new
cells that form, their insulin cells aren't perfect. They're a little different. And
that difference is enough to trick the juvenile diabetic or type one diabetic's
immune system to thinking that they're not actually insulin cells and they don't
pay attention to them at least for quite awhile.
And the fact that we could do a single infusion of this virus and nothing else,
including no immunosuppression or anything else was fairly exciting. And
nobody's ever done that without immunosuppression in these mice. So we're
now moving on to try to get to the clinic.
John Williams: So, okay, this really blows my mind. You basically, if I understand, you took a
virus and squirted it into the pancreas to convince non-insulin cells to be insulin
cells and then they escaped the immune system to stay there. So is there any
technical reason that you couldn't do that in a human and what could happen? I
have a sister-in-law with type one diabetes. I mean, is this going to turn her into
Frankenstein or could this really work in a human?
George Gittes: Well, yes, the short answer is absolutely could work in humans. We've received
some additional funding in support of that concept. The other kind of cool thing
about this is, in order to do this infusion into that little tube in the pancreas and
profuse it, you don't need to do surgery. You can go through the mouth and
then go down through the intestine via the mouth and you find a little opening
and put a little tube into that opening and squirt, as you say, the virus back up
into the pancreas.
We have shown in the human tissues that the hormone cells that turn into the
insulin cells will do the same thing in a Petri dish with the virus. We know that
that part should work. What we don't know is whether the infusion in a living
human or a living animal with a pancreas similar to a human will work because
the mouse pancreas is a little bit different. But we do feel that if we can get this
to work in a higher animal, which we are doing now with promising early results,
that we would be able to transition immediately to human trials.
Stephanie Dewar: So this is really very interesting and exciting. A question that might come to
some people's mind is that you're infusing a virus into a person, is there any
concern or risk that there'll be an infection with that virus that actually might
make the patient worse?
George Gittes: No, these are specially engineered viruses that can't really divide and spread.
And there are lots of gene therapy trials right now going on in all throughout the
world using these viruses and a lot of the concerns and problems that used to
exist many years ago have all been sort of figured out. The other thing that
important to know is that the exposure of these patients to virus in general is
much, much lower because the infusion is only directed to the pancreas. Small
amounts of virus. We probably get out a little bit, but this is dwarfed by the
huge amounts of virus that have to be given when a patient receives it in the
bloodstream because it goes everywhere in the body.
George Gittes: Correct.
Stephanie Dewar: So it's an interesting, I don't quite get the connection of how that happens and
how you become interested in the pancreas of mice.
George Gittes: So in many respects, 99% of the pancreas is not hormone producing. It's
produces digestive juices that go into the intestine. That's why that duct is there
that we put the virus into. But so when I first started my research way back
when in medical school and early residency, that would be back in the 80s, I was
focused on the pancreas because of the surgical relevance that it has. We as
surgeons operate on the pancreas for many different conditions, not diabetes.
But over the ensuing few years it became quite clear that the focus on the
exocrine pancreas, the non hormone producing pancreas, it doesn't reflect as
much disease processes out there when you have the biggest disease problem
in the US overall, the number one biomedical cost, number one reason for
kidney failure, amputations, blindness. There's something like 30 million
patients in the US that have some form of diabetes. Another 60 million that are
a borderline diabetic. So clearly my focus, if I'm going to be studying the
pancreas needed to switch. Of course it's been a nagging annoyance in my
whole career that my research focus really doesn't, it's not a surgical disease,
diabetes, so it hasn't really aligned with my clinical practice and I'm very jealous
of my colleagues whose research topic aligns perfectly with their clinical work
because it's just much easier.
John Williams: Yeah, but they're not getting to put these like cool gene therapy viruses into
mice to cure diabetes. I mean, anybody can do surgery on a mouse, but what
you're talking about is, that's pretty cool stuff. Is type one or juvenile diabetes
the most common or the major pancreatic disease in children?
George Gittes: Yes. Yeah. The other ones are fairly rare. They're either a rare birth defects,
occasionally that rare inflammation called chronic pancreatitis. And those
probably make up 5% versus 95% diabetes.
George Gittes: That's correct. Those procedures are done by the transplant surgeons and what
they do is they remove the entire pancreas. First of all, they don't do pancreas
transplants really for diabetes so much anymore. They do islet transplants, but
even those are fraught with problems. One fascinating thing that most people
don't realize is the immunosuppression that you have to give for a transplant,
which is sort of transplant immunology and it's called allorejection is not
effective in treating autoimmune disease. They are different pathways, so in
order to fight the immune rejection of islet transplantation in a patient that is
type one diabetic and received islet transplant, you need to fight both of those
immune systems. The alloreactivity and the autoimmune. It's quite a bear. And
the idea that we can potentially do this procedure where A, you're not giving
any transplant, it's their own cells that are turning into insulin cells and B, these
seem to somehow go under the radar of the autoimmune system is a potentially
exciting. Although I must say in surgically the procedure that we worked out in
mice and are now doing a nonhuman primates, that was all feasible because of
my experience in surgery. Working out those techniques and how to do it and
especially now in the nonhuman primates could not have been done by a non
Stephanie Dewar: So really the good news, just to go back to what you were saying about the
immune suppression, is that you're able to potentially offer a therapy without
potentially making the patient sicker with the treatment to avoid rejection of
the transplanted Beta cells basically.
George Gittes: That's right. That's right. And again, the procedure's noninvasive through the
mouth and could potentially just obviate their need for exogenous insulin for
John Williams: Well, speaking as a non-surgeon, you definitely don't want somebody like me
trying to do these techniques in a mouse or in a nonhuman primate, let alone a
human. So, Dr. Gittes, where, with this procedure, although it sounds like from
the paper which we should note was published in Stem Cell in January of this
George Gittes: That's correct.
John Williams: It sounds like it was really geared towards type one or juvenile diabetes. Would
it also work for type two or adult onset diabetes?
George Gittes: Absolutely. The problem in type two diabetes is still a Beta cell or insulin
producing cell failure. It's a little different because they tend to have a different
constellation of problems. They don't attack their own insulin cells, but their
insulin cells sort of burnout and fatigue because they've been trying to
overcome a resistance of the body to insulin's actions. And that burnout can be
greatly improved or helped or cured, potentially, by recruiting new insulin cells
and these would again come from these other hormone producing cells.
The other thing that's really interesting about this is that the specific cells that
are turning into insulin cells make another hormone called glucagon. And
glucagon is supposed to be the counterregulatory or anti-insulin hormone and
they're supposed to be in balance. But when you run out of insulin, you have
this unopposed glucagon which drives your blood sugars higher and higher and
higher. So the fact that we're actually turning these glucagon cells like making
the bad acting hormone, turning them into insulin cells and therefore
decreasing the bad one and increasing the good one is kind of a nice double
John Williams: You're turning bad guys into good guys.
George Gittes: Right.
John Williams: I like it.
Stephanie Dewar: So Dr Gittes, I'm just curious what we can expect moving forward. My first
question is do you have collaborators in other locations? Are there other people
helping you with this research? And what timeframe are we looking at here to
move forward when we could potentially think about curing diabetes?
George Gittes: So my collaborators, much of it is related to the gene therapy because I'm not
knowledgeable about that and I've been educated that the nonhuman primate
work, although it's not an autoimmune juvenile model, it is a proof of principle
that it's translatable. And when I met with them, they felt that that was really
what was needed was success in a nonhuman primate model and that's all and
then move straight to human trials. In terms of the other collaborators, the
immunologists have been very important and there's John Piginelli at Children's
and to some others who are expert in diabetes immunology has been very
helpful. So I think your question about where, when, what's the time frame and
where are we going? You're asking the same question all these families and
patients are asking me. And we've been at this with a nonhuman primates for
three years. And there's been a lot of stumbling blocks, a lot of hurdles, and we
had no success for the first two years. And we figured out that there was a
technical problem with the way that we were doing the infusion that we've
fixed. And now we are seeing a reaction of the cells of the glucagon cells to
potentially turn into insulin cells. They haven't done it yet and the animals are
having some unstable physiology because of things that we weren't anticipating.
And one of the problems is the first thing that's happening, before they were for
these bad cells turned into good cells, is they stop making the bad hormone. But
the problem is there is a dependence develops where their blood glucose stays
high, but when you take away that source of making it high, it drops way, way
too low. They have sort of lost the ability to kind of regulate it properly. So
that's what we're dealing with now. But I think that's a good problem to have
because it means we're getting close.
Stephanie Dewar: So I'm just curious. That's an interesting to recognize, how long does that
problem persist and would that mean that a person after this type of a therapy
as we move forward, would need to be in a hospital and have that monitored
for a period of time before we can let them return to their regular life?
George Gittes: That's right. Probably would be, I don't think it would be more than a few days,
but I think it would be something we would have to monitor fairly closely and
we didn't anticipate that. So we weren't set up properly with these nonhuman
primates to deal with that in an effective way. So that's why we've lost some
time there. But I think once this is working, the numbers I'm guessing are
around, if we can do about eight to 10 of these where it works, I think we've got
a green light.
John Williams: Well it's also a great example of how, even though humans are not mice and
we're not nonhuman primates, you really, there are things that you can learn in
these animals settings. My kids have taken part in research trials in vaccine
trials, but I wouldn't sign my kid up to be the first living creature to get a therapy
that hadn't been tested in some other kinds of animal so you can learn these
George Gittes: Yes. And a nonhuman primate work is very expensive and very slow moving
because there's a lot of regulation, a lot of costs. So it's a little frustrating. But
we're slugging through it and we're getting there.
Stephanie Dewar: This sounds to me like you stumbled onto something that you weren't looking
for in search for something else.
George Gittes: That's right.
Stephanie Dewar: So you don't have any personal or professional mission to solve diabetes, but
you found this way to change the pancreas.
George Gittes: Yeah, I mean that's, the generic term for it is serendipity. And this clearly was
serendipity. But you have to be prepared. I mean serendipity, another person
who might've had a similar result and not realized. So is if you're prepared and
you kind of have a, and that's why I think a physician scientists, in my case
surgeon scientists, bring such value to research because we have the backdrop
of knowing more details about diseases and how some unexpected or finding
rather than being dismissed as, oh, it didn't work the way we thought it would,
actually has a whole different meaning that we know of because of our clinical
John Williams: You know, I'm reminded Dr Gittes, Louis Pasteur famously said, "Chance favors
the prepared mind." So I think that's a question I wanted to ask you. Your mind
is prepared for this as a clinical practicing surgeon who takes care of patients
when you make this research discovery. But I wanted to ask how you sort of
balance those two things that, as you said, are very different. Being a practicing
surgeon, operating on children versus doing basic research in the lab. How do
you balance those and what do you get from each of those?
George Gittes: So it's an extremely difficult balance and the balance gets more and more
difficult as science progresses and med and clinical medicine progress. So in the
days of Louis Pasteur, it wasn't that hard because things weren't that different, I
would say even 40 years ago in surgery and maybe to the same in non surgical
specialties, the models that we use were whole animals and physiology and
whatnot. A lot of it was very similar. Now we're talking about single cell RNA
sequencing and complex DNA analysis. This has very little application to clinical
medicine, certainly for a surgeon. But I need to maintain my surgical skills. So
the divergence of the complexity of these two areas is more and more challenge
every year. It just takes a lot of energy, a lot of time to read and keep your skills
up. And it's a huge challenge.
John Williams: Are they fulfilling to you in different ways? Do you get different things out of
these two aspects of your professional life?
George Gittes: Yeah, I'm like a kid in a candy store. It's absolutely fulfilling to have this breadth
of exposure and working with all assortments of types of people, hardcore,
basic scientists. And then on the clinical side, of course, all the nurses that are
caretakers, other doctors that don't have this variety in life. So yeah, it's quite a
Stephanie Dewar: Well, we're so happy to have had you join us today, Dr Gittes. This is very
exciting news and information and I'm anticipating your future success.
George Gittes: Sure.
John Williams: Yeah. Thanks, Dr Gittes, for joining us and thank all of you for listening. We'll
talk to you next time.
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