Current Status of Pancreas Versus Islet Transplantation

(whooshing) (clicking)
(beeping) (whimsical instrumental music playing) – What I’d like to do in this lecture is, I don’t know. I’d like to make it a little interactive, and I know I may have to
stop that after a while if it looks like we’re going too long, but please feel free to
interrupt me as we go. We’re gonna sort of move through this talking about three different
ways of dealing with surgical treatment for
our beta cell replacement as a way we can perhaps
treat and ultimately really make a dent in the
treatment of diabetes. So the first part’s gonna be on solid organ pancreas transplantation. Chris and I are both
pancreas transplant surgeons, and so, I’m gonna talk
a little bit about that, then I’m going to talk about, the second phase of the lecture’s gonna
be about cellular transplants, where we just, we’re
transplanting the whole pancreas, really, for 5% of the cells
that sit in these things called the islets of Langerhans. And so, it makes sense if we could just isolate those islet cells
out of the pancreas, and transplant those. It’s a much easier operation. So, oh, that’s not
really even an operation, it’s a procedure. And then, finally, I’m gonna talk about a strategy that I think
will ultimately be a real cure for diabetes, in terms of being able to provide enough of this donor tissue. Right now, we’re so
dependent on deceased donors. In the United States,
or just in the Bay Area, we have about 250, we
have 250 donors a year. Those are people who’s families have generously consented to donate. You can image, just to give you an idea of what our kidney
transplant waiting list is. At UCSF it’s almost 5,000 people, and we’re only doing 250 donors a year, and we have to share those organs with a couple of other institutions. So you can see, we’ve got a
real problem with donor source, and we have to figure
out a better strategy. So the last part of the
lecture’s going to be how we can get away from
using deceased donors as a means for moving
forward with transplantation. So Dr. Freise and I also do
liver and kidney transplants, and I have to tell you, of all the things that we’re doing in the
world of transplantation, I think the most significant advances are happening in the
world of beta cell therapy and pancreas transplantation. We’ve gotten better at
pancreas transplants. We’ve gotten better at islet transplants, in terms of producing
insulin independence. I’ll talk about both of those. We can make people insulin independent with a pancreas or an islet transplant. So we have a cure for diabetes. It just is not applicable to the vast number of
people that have diabetes. We know that the
hemoglobin A1C normalizes. What is hemoglobin A1C? It’s a monitor. So I don’t know if any
of you have diabetes. I’m sure some of you do. If you really take good care of yourself, and you can keep your
carbohydrate load under control, you can normalize your hemoglobin A1C. So hemoglobin A1C is a way
we can draw your blood, and see whether you have
glycolated hemoglobin, which means your control isn’t so good. So normally, hemoglobin
A1Cs are less than maybe 6.8 is considered the high end of normal. So a lot of folks who have diabetes live by this number every day. Every month they check,
oh, I’ve got good control, ’cause my hemoglobin A1C is less than 6.8. So you do a pancreas
transplant, it normalizes, and not only that, if you
have a successful transplant, you can prevent the devastating
complications of diabetes. So the retinopathy that
can lead to blindness, the nephropathy that can
lead to kidney failure, neuropathies, tingling
in the fingers and toes that lead to your inability to actually feel where your walking. So you can do some significant
damage to your bones in your legs. So this was the cover of the “American Journal of Transplantation”
just over a year ago, and it was really interesting. They based this cover on some of the work that we’d done here at UCSF, and it’s asking the question, “What’s the best treatment for diabetes?” Is it this guy here? That’s a pancreas. Is it this guy here? Those are islet cells. Or is it this guy in the
back that’s a computer? You know, we can put a man on the moon. It seems to me you could put a chip into your body that can sense blood sugar, and deliver insulin appropriately. It’s called closed-loop pump, and there’s a lot of companies
out here in the Bay Area that are perfecting the
closed-loop pump as a easier treatment for diabetes. So this article asked, “Which one of these is going
to win at the poker table?” Well, we’ll have that discussion now. So many years ago, there was
a trial called the DCCT Trial, which was a trial where
people with diabetes were either treated with
standard insulin therapy, intensive insulin therapy. This is the standard insulin
therapy, is this red line. Intensive insulin therapy,
which is this blue line, or a pancreas transplant,
which is this yellow line. Well, here’s the line
right here, the solid line, that’s the normal hemoglobin A1C level, and you can see, the pancreas transplants, boy, they put you right
in that normal range, and they keep you there. So pancreas transplants work. It’s just a big operation, and I’m gonna tell you
a little bit about it, but the reason I’m telling you about it is it tells you what the possibility is if we can replace these beta cells. Yes? – [Audience Member] What
happened in year four with the pancreas transplants? – Year four. Oh, I can’t tell you. You know, it’s just a blip. Because hemoglobin A1C’s
vary, even internally so. I wouldn’t say it’s significant, and it’s still within the normal range. So, you know, there’s no question that the longer you go out, you know, graphs fail
after some period of time. So, you know, maybe it’s starting to go, but I don’t think that’s
what that reflects. So the other thing that you
have to know, is people, there’s a lot of folks who really, really do tight control, this
intensive line here, of their blood sugars. The problem is, is if
you do it too tightly, you become hypoglycemic,
and that’s very dangerous, because you, you know, when many of you may have seen it in folks with diabetes,
they can lose consciousness, or they get really goofy, and you have to give ’em
sugar really quickly, or they get into a lot of trouble. And the more intensive
the insulin therapy, the more they get into trouble. So just goes to show, that really, if we could replace the beta cells, they seem to be doing the best. We also know that if you can
normalize your hemoglobin C, you get down here, you don’t get those
secondary complications of retinopathy,
nephropathy, and neuropathy, and you can see this. As the hemoglobin A1C goes up, those secondary complications
just start to happen, and that is why doctors and nurse
practitioners are out there telling you to get your
hemoglobin A1C under control, but it’s not that easy, or it’s much easier said than done. I can’t even take an
antibiotic for one week without screwing up the
dosage, and missing a dose. So my hat’s off to the
folks with diabetes who really try to be really fastidious. It’s a challenge. So how do we do pancreas transplants? I’m not going to go into the great technical details of that. There’s a few things I do wanna tell ya. This is a pancreas over here, and this is a kidney over here. When we do a kidney transplant, we plug it into the blood vessels that go down to your legs. And we actually, usually
plug the kidney into the blood vessels that
go down to the left side, and the pancreas into the right. Now, the pancreas, the thing that makes pancreas
transplants so difficult, is it is an organ, that
when we’re in medical school we’re taught never to play
around with the pancreas, because it is a fragile organ. Why is it fragile? Well, it happens to harbor
these islets of Langerhans, but it’s only 5% of the cells. It’s these little islands in the pancreas, and the rest of it, about
85% of the pancreas, makes digestive enzymes, now, you tell me how in
the evolutionary scheme these little fragile islets ended up sitting in the pancreas? I can’t give you an answer,
but that’s where they are, and when people have type 1 diabetes, those little islet cells get attacked. It’s not even the whole islets. The islets contain a bunch of hormones. One of the hormones is insulin. And if you look at the
pancreas, it looks normal. If you look at islets, it looks normal until you sting for beta cells. Beta cells are the cells
that produce insulin, and low and behold, type 1,
people with type 1 diabetes don’t have those cells anymore. It’s an autoimmune process. So when we transplant the pancreas, if something goes wrong with it, those digestive enzymes get activated. The pancreas makes these digestive enzymes normally in the body. The pancreas sits right
in the middle of the body in a really tough spot, and it drains, the digestive enzymes
drain into the duodenum, the first part of the small bowel, and we sew the pancreas of the donor, a little segment of the
duodenum of the donor, and we attach it to the recipient’s bowel. So all those enzymes, we
don’t really care about ’em, because folks with diabetes
make normal amounts of enzyme, but we have to get rid of ’em, and so the enzymes just
drain into the bowel, and then ultimately get absorbed. It is that anastomosis where
we sew the bowel to the bowel, the donor bowel to the recipient bowel. If the digestive enzymes get
activated, it can wreak havoc. It can start digesting all the tissue, and the blood vessels, and it becomes a very dangerous situation, and that is why pancreas transplants are technically challenging. We’ve learned how to do it. We’ve gotten really good at it, but we can only use the
best quality donors. Now, that sounds a little weird, but what’s a good donor? A good donor is somebody who is young, maybe somebody who’s had a trauma, otherwise perfectly healthy, but they were in a bad bike accident, and they hit their head,
and so they’re braindead. Those are the people that
make very ideal donors, and their pancreas doesn’t
have a lot of fat usually, and it’s the easiest to transplant. So I can’t tell you enough, it’s a challenging operation, ’cause we don’t wanna
excite that pancreas. We don’t wanna get those
digestive enzymes going. And so, we only, about maybe
somewhere around 15% of, remember, I told you that
there’s about 250 donors in the Bay Area a year? Only 20% of those, less than 20% of those are suitable for pancreas transplantation for the reasons that I just told you. So as we’ve gotten better at it, and I’m gonna show you the
results in just a second, we’ve extended the criteria for who can have a pancreas transplant. I don’t wanna confuse you too much, because, by and large, because
it’s such a big operation, and we have such few donors, we have traditionally
put a pancreas transplant into a patient who has
diabetes, and type 1 diabetes, that’s the classic, and they progress to
end stage renal failure, because they’ve had problems controlling their
diabetes their whole life. So they need a kidney transplant, and we maybe about 30 years ago, decided let’s do a
pancreas with the kidney, then they’re not on insulin, and they are not on dialysis. A really nice result. So the bulk of the pancreas
transplants we’re doing today, there are still about 80% are simultaneous pancreas kidney transplants, but now, we’re also doing
pancreas after kidney transplants, and more interestingly, we’ve done a few, every year
we do a few patients that don’t have kidney failure,
but they have diabetes that they cannot control. They end up having these
hypoglycemic attacks. Their blood sugars go down, and they end up in the hospital, and they end up afraid that
they’re gonna end up in a coma because of low blood sugars. Those are the patients with
life threatening diabetes, and then, those patients, we
do a pancreas transplant in. But you understand, if we’re doing a kidney transplant anyway, they’re going to need immunosuppression, the drugs to prevent rejection. So that’s how we started. But now that we’ve gotten better, we’re extending the criteria for it, and I’m gonna talk a little
bit about that in a second. So a lot of the data I’m
going to show you is from some data from our own institution, but some data from the National and International
Transplant Registry. If you look at the patient’s survival who got a simultaneous
pancreas kidney transplant, and we’re talking five-year survival, you can see that for all
three classes of transplants, and I’m just gonna really
focus on the simultaneous pancreas kidney transplants, SPK. The patient survival is around 85, close to 90%, at five-years. Pretty good. What about the graft function? Graft function for the kidney, we say it’s a success if
they’re not on dialysis. For the pancreas, we say it’s a success if they’re not on insulin. So, again, let’s just look at simultaneous pancreas kidney transplants. Here’s the results. 80% success out to
five-years for the kidney, and somewhere just over 85, I’m sorry, just over 77%, I think, for pancreas. So it’s pretty sustained graft success. It’s not 100%, but it’s pretty good. And then, I think we’ve
gotten so much better. I don’t know if you’ve been to lectures when we talk about immunosuppression. I’m sure you’ve had, a few of
these lectures have included a discussion of the medication
to prevent rejection. That’s the Achilles’
heel of transplantation. ‘Cause we have to prevent rejection, so we have to slow down the immune system. In folks with diabetes, type
1 diabetes, it’s even worse, because they have an autoimmune disease. Their immune system went awry, and they started to destroy
their own beta cells. That’s type 1 diabetes. When we do a pancreas transplant, these patients are still primed
to attack the beta cells. They have the autoimmune disease, but now we’re also
putting in foreign tissue. Allo transplants, it’s called. Transplantation from somebody
else, another human being, but they’re not HLA matched. They’re not tissue-type matched. So now, we have to overcome autoimmunity, the thing that caused the
diabetes to begin with, and alloimmunity, the
rejection of foreign tissue. We have figured this out. When I started in 1990 here at UCSF, our rejection rates of either
the kidney or the pancreas were up over 80%. We figured out how to treat it, but every time you treat rejection you give more immunosuppression, and immunosuppression does just that, it suppresses your immune system, so it makes you more
vulnerable to infections, and more vulnerable to cancers,
skin cancers especially. So we’ve gotten better at that. Look at that. We’re down to 10 to 15% rejection rates using sort of novel immunosuppression. I’ll talk a little bit about that later. So now that we’ve gotten good with treating patients
with type 1 diabetes with pancreas transplants,
we’re wondering, can we expand the criteria a little bit? Can we go to older patients? Can we go to patients that are maybe a little bit bigger? And most importantly,
can we push the limits to include patients with type 2 diabetes? What is type 2 diabetes? Type 2 diabetes is many
different kinds of, it’s adult-onset diabetes, usually, and it’s not autoimmune. It’s because people perhaps they get a metabolic disfunction, sometimes it’s from obesity. You’ve seen that. If you have diabetes, and you lose weight, the diabetes can go away sometimes. But there’s other people
with adult-onset diabetes that aren’t particularly overweight. They have a metabolic problem. We don’t really understand it, but we’re now finding that we can maybe cure type 2 diabetes with
pancreas transplants, and I’ll say why that’s
relevant in just a minute. So I told you we wanted to start, most of our patients, when
we started to do this, were type 1 diabetics who were
in their maybe 20s and 30s, and that’s when they progressed
to end stage renal failure. But now, with the better
management of diabetes, we find our recipients
aren’t progressing to end stage kidney disease
until an older age, and if you look at the
registry, look at this, the oldest patient
population does just as well, maybe a little bit better
than the young folk. So we’re not limiting
our recipients anymore. It really is about how good the heart is. We gotta make sure the heart will tolerate a major procedure. I’ll talk about that too. But look at this. That green line is people
getting transplanted, the SPK, simultaneous pancreas kidney transplants with type 2 diabetes, and all of a sudden, from 1997 to 2017, the frequency of people with type 2 diabetes
has gone up to 18%. If we had an unlimited
source of beta cells we probably could manage
type 2 diabetes as well. So we’re looking at that. And look at this, if you
look at patient survival for the type 1s and the type 2s, go out three or four years, it’s over 90%, and then, look at the difference of the insulin independence. The type 1s and the type 2s, they do almost equivalently. That’s not statistically significant. So I think we’re going
to start moving toward figuring out which type of people with type 2 diabetes can benefit. Chris talked about what
an epidemic we’re having. It is, I think, maybe ten-fold more common to have type 2 diabetes
in the US than type 1, – Can I ask a question?
– and, yeah, sure. – [Audience Member] You
began your talk by saying, “The major limiting factor was the availability of the organ”.
– Absolutely. – [Audience Member] But yet
now, you’re expanding to, by a huge number.
– Hold that thought. Yes, you’ve hit the nail on the head. It’s a problem. There’s many patients
who can benefit from it, but not enough organs. So you might ask why we even
started to expand the criteria? Because patients with type 2 diabetes, there’s many who look just
like the type 1 diabetics, and why shouldn’t they have a shot at it if they met certain criteria? It gets a little complicated. We’ll get back to that, because that’s the million dollar question. If we had an unlimited source, then we would do type 1s and type 2s. We limit the number of type 2s to type 2 patients who
sorta look like type 1, so they’re not overweight,
and things like that. So because now we’re transplanting people with type 2 diabetes, type 1 diabetes is really
much more prevalent in the Caucasian population. Type 2 more common in
people of African descent, and you can see, that now that
we’ve expanded the criteria, now we’ve increased the
frequency of transplantation in people of African descent. And there’s one other group
that I have to tell you about. The last time I talked at this, at the Mini Med School was about transplanting
people infected with HIV, because I started here in 1990, so I’ve seen the full spectrum
of what can happen with HIV, and we started to see a number of type 1, people with type 1 diabetes who also, unfortunately, got HIV. And now we’ve done, I
think, eight transplants, eight pancreas transplants in
people with type 1 diabetes, and we’ve had really great success. So HIV is no longer a
contraindication to transplant. So let me just review a few things. The pros of successful
pancreas transplant. It’s a single organ. We can get insulin independence
with a single organ. It prevent hypoglycemic unawareness. You don’t see patients passing
out from low blood sugars. It normalizes hemoglobin A1C. It improves the quality of life. I can tell you, there are patients who have
had pancreas transplants who have had tough operative
courses, very tough. Every last one of ’em will ask you for another
pancreas transplant if they’ve enjoyed any
insulin independence at all. You know, folks with diabetes
tell me that they have dreams. In their dreams they see
themselves without insulin. That is their dream, and that dream is realized
with a pancreas transplant, and it’s a very motivating force. There’s no question it
improves the quality of life. I don’t need to take a survey on that. Peripheral neuropathies,
that tingling in the hand, tingling in the feet, that
very slowly gets better. And most interestingly,
if we do a pancreas with a kidney transplant, you
don’t get recurrent disease in the kidney transplant. So the same thing that caused
diabetes to begin with, if we don’t put a pancreas transplant in the recipients will ultimately
develop kidney failure in the transplanted kidney. If we do a pancreas with a
kidney, that doesn’t happen. So while it sounds great, we don’t have enough of them. Not only that, what’s another big problem? It is a big operation. You need a really good heart
to tolerate this operation, and very few patients, and I’ll show you how
few in just a minute, are fortunate enough to
get a pancreas transplant. So let’s talk about the
cells in a pancreas. Remember, I told you a pancreas is, you know, about this big, and it’s like as flat as
a pancake, but it’s long, and we can isolate the 5%
of cells in those islets, and transplant those islets. How do we do that? Well, this is a little complicated, but if you look at this, this is a system that we
set up in our lab here where this is, it looks like a bomb. You actually put the pancreas in that, and then you start to use
this continuous circuit where you add an enzyme, and
gradually digest the pancreas, and as you do that, the
islets start to come out. The islets are stained with dithizone. They stain islets red. All that white stuff,
that’s acinar tissue. So you can see, the majority of the tissue
is acinar tissue, not islets. The acinar tissue is what
makes the digestive enzymes. We can then use a centrifuge
and a density gradient to purify those islets. That’s what the purified islets look like. They actually, you can
see them, but they fit. The one million plus islets in a pancreas fit on the tip of my finger, and we can put ’em in a syringe, and suspend in ’em in
one to two CCs of fluid. This is what the
pancreatic duct looks like after we’re done with the digestion. And then we take these cells that fit into one to two CCs of fluid, and our interventional radiologist can actually put a needle into
the liver through the skin. They numb you up, and it could be done as
a same day procedure. And they cannulate what’s called the portal system of the liver. It’s a vein that goes into the liver, the islets flow out, and there they sit in the periphery of the liver, and make insulin, and it’s really cool. We never really had success
with allo-islet transplants, in terms of getting insulin independence, until the year 2000. And then, James Shapiro,
who was up Edmonton, Canada, and his colleagues up there found that if they just
didn’t give one infusion of islets into the liver,
but did two, or three from two or three donors, and avoided certain kinds
of immunosuppression, they could get insulin independence. And, in fact, they increased
their insulin independent rate with islet transplants from around 10% all the way up to 90%. But here was a problem. Early on, the islets worked, but they only worked for one to two years, and then, all of a sudden, they started to require insulin again. So many people wondered,
why were the islets, whole pancreases were tolerating
it, the islets didn’t live, and there was a lot of speculation. But it turns out, that the liver is not the
best place to put islets, and we think maybe 20%
of the islets survive when we put ’em in the liver. The rest don’t survive. The other problem is we weren’t using the right kind of immunosuppression. Since that time, and I don’t wanna go
through every step of this, but the five-year
insulin independent rates have improved across the world. And you can see, right
now, UCSF, here we are, we have 80% of our patients
were insulin independent at five-years with a
particular, very potent immunosuppressive regimen that we used. So we’re getting better
at islet transplantation. This shows you that variability that you see in blood sugars, that this top line here, goes away when you get a successful
islet engraftment. And a group up in Canada,
they ultimately showed that those same things that got better with pancreas transplant, the
retinopathy, the nephropathy, got better with the cellular transplants. It wasn’t quite as good. The islets, you saw five-years,
they were mostly working. By 10-years, not so well. And part of the problem was
the immunosuppression we use, the drugs to prevent rejection, are very toxic to the islets, and they’re probably
toxic to the pancreas, but the pancreas, all the islets survive
when we transplant ’em. When we do an islet cell transplant, we think only 20% are surviving. There’s two drugs. CNI stands for calcineurin inhibitors. You don’t have to know
anything about that, except cyclosporine and Prograf, drugs you may have heard about, the common immunosuppressive agents, they’re toxic to beta cells. They’re toxic to the kidney. And what do we use to
do immunosuppression? We use a drug that is toxic to the kidney that we transplant, and it’s toxic to the beta cells. Well, without going into
too much detail on this. There are two drugs that
we were fortunate enough to experiment in our kidney
transplant recipients that have no beta cell
toxicity, and no nephrotoxicity. They’re not toxic to the kidney. They’re not toxic to the beta cells. It’s called Belatacept. It’s a drug that blocks the immune system. When you a T-cell, the
T-cells cause rejection, and if you block some of the signals, the second signal to that
T-cell from the antigen, instead of activating the T-cell, the T-cell becomes quiescent, and that’s what Belatacept does. So what I want you to remember about it, is it’s a drug that doesn’t
cause kidney damage, and it doesn’t cause
toxicity to the beta cells, the cells that produce insulin. And there was another drug on the market, exact same criteria, doesn’t cause kidney failure, it doesn’t cause kidney toxicity, and doesn’t cause beta cell toxicity. It’s called Efalizumab Raptiva. So we use those two drugs in a trial that the JDRF sponsored, and this was sponsored
in about the year 2002. So I have the benefit
of being old enough now that I’ve been able to follow
some of these patients, and I called one of the
patients this morning to see if she could come. She lives two blocks from the hospital. And I’m going to tell you about her. She couldn’t come. She’s down in Monterey, and couldn’t make it back up in time. But I’m going to show the results. The BEL right here, those are patients who
received Belatacept. Efalizumab is the patients
that received Raptiva. And you can see, there’s two patients who got one infusion of
islets, insulin independent. Out 10-years with one infusion of islets. That is a great result. Yes, sir? (audience member speaking faintly) So that’s how I’m gonna finish my talk, because that’s the other
million dollar question. You guys are hitting the
problems that we’re dealing with. But I wanna address that
for just a second, because in animal models, when
Chris and I were working on our degrees in the lab, we were doing islet transplants in rats, and I started that in 1985, and we thought islet transplants
was just around the corner, ’cause we put ’em into the
kidney capsule, bizarrely enough. We just put them in different places. And in an animal model, we could get ’em workin’
the kidney capsule, and we could get ’em to work in the liver. In humans, for some reason, the only place we could get
engraftment was in the liver, and we also know that blood, so we injected it into the blood, and it goes out into the
sinusoids of the liver. Blood is toxic to islets, and that’s probably why
20% of ’em, 80% of ’em die. It’s not the ideal spot,
and that’s a major problem. So these patients that
are insulin independent, they probably are insulin independent with a very small percentage
of the islets functioning. I think there’s something else
going on in those patients, because I don’t think it’s enough islet mass to sustain ’em. But those two patients are
still insulin independent. One of the patients
was insulin independent for about a year, then we
gave her a second transplant, a second infusion, and chugged along for
about another five-years, and then became insulin
dependent, and that was that. And so far, we haven’t moved forward with another transplant there. The third patient there was insulin independent for
about five-years, and then, gradually, it started to
require a little bit of insulin, and only very recently, became insulin dependent again. That’s our one patient in the whole series that still needs insulin. Because the next patient
down had two transplants, loved to be insulin independent, and said, “I want a third islet transplant”, and we didn’t think it would be successful so we did a pancreas transplant, and now she is insulin
independent at about 12-years. So of the patients, three are insulin independent, one with a pancreas transplant,
one just lost function, and the other has partial function. Now, the Efalizumab group,
two patients in that group too became insulin independent
with a single infusion. I’m going to talk about
EFA-4 patient right here. That was the patient that
I wanted to come tonight, but I’ll tell you about her in a second. The other patient is on
almost no immunosuppression. She lives in Colorado,
and is insulin independent greater than 10-years. So two of those patient too,
insulin independent long-term. One patient required a
second infusion of islets at just about a year and a quarter, and then stayed insulin independent for about another nine-years. Recently started to take
oral medication for diabetes. And then, two of the
patients had two transplants, like being insulin independent, and we went on to do pancreas
transplants in both of them, and they’re insulin independent now out more than 10-years. So pancreas transplants, a
little bit bigger operation, but they sustain islet function
for a longer period of time. So now, I just wanna
show you what can happen with these patients who
normalize their hemoglobin A1C. In the Belatacept group, all five patients normalized their hemoglobin A1C. The same with the
patients with Efalizumab. When we give them a glucose challenge, and then measure C-peptide, C-peptide is a measure of
your insulin production. The higher C-peptide, it’s
a piece of the insulin. And they have a normal
response to C-peptide, and most importantly, I
wanted to show you this, because the glomerular filtration rate, which is a measure of kidney
function, did not decrease. It actually got better in both groups. So this drug that we used
that avoided kidney toxicity, and avoided beta cell toxicity, worked. So we’re pretty fond of these drugs. Efalizumab had got pulled. I’m not even going to get,
it’s not available anymore, but Belatacept is. Now, I’m going to tell you about one other very bizarre finding that we had, and this may play into some of the other lectures
you’ve had on immunosuppression. In the patients that got Efalizumab, that’s the drug that’s been
pulled from the market, it’s an adhesion. It blocks the way the T-cells interact with the vascular endothelium. Suffice it to say, that in those patients, for an unknown reason, this group of cells called the T-regs, the T-regulatory lymphocytes went up after we gave the drug. This is something we didn’t see. Now, again, I don’t know many lectures you’ve had about the T-regs. The T-regulatory lymphocytes,
those are the good guys. They’re the cells that come in to quiet down the immune response. So for some reason, in these
patients that got Efalizumab, the frequency of those
cells in periphery went up, and if you look at this one patient, 70% of her circulating lymphocytes were T-regulatory
lymphocytes, the good guys. We didn’t see that with Belatacept, and it was another good drug. But the reason I bring up
this one patient here is she had an incredible course, and I just wanna tell you, remember, I told you a lot of immunosuppression
can cause cancers? At about four-years, she
developed what’s called lymphoproliferative disease, which is a proliferation
of lymphocytes that is transitioned into cancer, and when we see that, we have
to stop immunosuppression, and we stopped her immunosuppression, and treated the
lymphoproliferative disease with a drug called Rituximab, and the disease went away, but we did not wanna put her
back on immunosuppression. We did not wanna risk her
life for insulin independence, and I wish she was here, ’cause she’s great with audiences. She talks about it, because I said to her, “Sandra, you know, do you want to stop immunosuppression?”,
and she said, “Absolutely”. She said, “I love being
insulin independent, but I need my immune system back”. So we stopped immunosuppression, and that was six-years ago, and she’s still insulin independent. So she’s insulin independent on no drugs. We’ve made her tolerant. I’m not really proud of the
way we made her tolerant, but this combination of drugs, and I think it’s that
really profound frequency of T-regulatory lymphocytes that were seen in the beginning, that tricked the immune
system into thinking those cells were her own. And there is, Chris, were there any
lectures on T-reg therapy? So one of the things
that’s going on at UCSF, and many places across the country, they’re trying to generate
these T-regulatory lymphocytes, the good guys, the ones that
suppress the immune system, and I can’t really tell you
how those trials are going, but she naturally induced her
own T-regulatory lymphocytes, and indeed, she’s tolerant to this day, and she could really, I
wish she would come here, ’cause she was a perfect recipient, because really understood
what was going on, and knew when to call it
quits, and then got lucky. She says she wanted you to know she feels like she’s the luckiest person. Although, her path to get
there was not always so easy. So now, remember, I told
you this picture that was generated in the “American
Journal of Transplant”? It was the cover, because
it was really the first time that the results of islet transplantation were getting close to that of
whole pancreas transplants. And so, they were asking this question, “Which should we do again?” Unfortunately, it’s so problematic. Look at the cost of pancreas transplants and islet transplants. They’re the same. Exorbitant. But insurance will not
pay for islet transplants. It is not FDA approved
in the United States. And that, you are going
to see a lot in the media in the next six months about that, because, pretty much, islet transplants, outside of experimental protocols, has been stopped in the United States. All the results, we did an NIH sponsored
trial in the United States to get this approved. The trial finished six-years ago. Canada, the United Kingdom, Australia, they all used our results to
get their governments to pay, but they have national health insurance, and they support islet transplants. Not in the US. We’ve been shut down. I am doing a clinical trial that I’m gonna get to in just a second. But outside of clinical trials we haven’t been able to do it. We’re trying to change
it to get it better. Okay, now I’m going to
stop talking about, yes? – [Audience Member] One other question. You mentioned how
complicated and difficult the pancreatic surgery were expensive. – Yes, but there’s another part of it. So this going to sound very,
very vulgar to you now. When we do a solid organ transplant, Medicare has to pay for the
cost of all the donors, but the way it works, is when a
donor’s declared braindead, and a family has seen
through this tragedy, and volunteered that they could have their organs for transplantation, the patients are in an intensive
care unit, on life support, and so, I can’t tell you how much it costs to keep a patient on life support
in an intensive care unit. It’s somewhere around $15,000 a day. I mean, it’s crazy. All the costs of maintaining
a donor go into this pot, and say, Dr. Freise is going
to do a liver transplant, and the liver is in Denver, Colorado. We have to send our team
out to go get the liver, and the cost of a leer jet back to here. All of that cost is put into a pot, the cost of preservation fluid. In the end, what they do, is they divide up the
cost for all the organs. So a liver, what is the going
rate for a liver right now? $60,000, I think. A pancreas is 50,000. Kidneys are $45,000. That’s just the cost of the organ, and that’s just so the non-profit donor
organization recoups the cost. It’s supposed to balance. So the cost of a pancreas is $50,000. The cost of an islet transplant’s $50,000. $10,000 for using the GMP facility to isolate the islets. Immunosuppressive drugs. By the time you’re done, and
then sometimes, for islets, we need two donors. Now we’re up to $100,000, and X, Y, and Z. So the $138,000 is the cost of the organs for the average transplant, so it’s somewhere between
one and two pancreases, ’cause we just added ’em all up, and that’s how we did this number. So that’s where these figures are crazy. What does it really cost
to do an islet transplant? When I talk to my colleagues in Australia they make fun of us. They just say, “Well, you guys are crazy”. “We don’t have to pay out that.” “You know, it’s $3,000 to
do an islet transplant.” So it’s (exhaling), it’s a really hard question, and I’m going to give you a solution that’s going to help us quite a bit. So, (clearing throat), this picture was made by Julie Sneddon, who’s one of our, she’s great. She’s a islet biologist
here, a stem cell person. And if this represents the
one and a half to two million people with type 1 diabetes, we’re only talking about type I diabetes, and we look at the number of people in the United States that
benefit from a pancreas, or an islet transplant, look right up here, ’cause
it’s going to show you. Right there! That is the number of people that we’re helping with transplantation. That little guy right
there, that green dot. Our supply is limited. We’ve gotta do something different. I think the technology that we’ve learned, and how to do this, is
going to be applied, but we need a new source. This isn’t science fiction. We’re there, because there
are a number of people who can take a stem cell, either embryonic or an IPS, people can take their own cells, and convert ’em into stem cells, and then make ’em
differentiate into a beta cell, or a beta cell cluster, and they can do that in the course of what normally in development
takes nine months. They can do it in about five weeks. It’s pretty incredible. And there are two, there’s
actually three groups in the United States now that can produce beta cell
clusters from stem cells. Both from embryonic and from
IPS, or derived stem cells. So we’re there. We’ve got the beta cell source. Yes, sir? – [Audience Member] So have you used the– – Yes, that’s exactly right. If you can use their own cells, and they can make ’em using IPS cells. That’s a little trickier than using an embryonic stem cell line
that you can pull off the shelf. Keep in mind, though, remember, type 1 diabetes
is an autoimmune disease, so you don’t have to worry about, if you make ’em from your own cells, you don’t have to worry
about alloimmune rejection. You only have to worry
about autoimmune rejection, but you still would
need immunosuppression, and I can get into that a little bit too, because there’s ways
of getting around that, but that is, the alloimmune
response, by the way, is much more potent than
the autoimmune response. If you can block the alloimmune response, you can block the autoimmune response. So probably, there’d be
less immunosuppression to prevent the recurrence of the diabetes. But suffice it to say, there’s two groups. One in Boston and one up in Vancouver that have made these insulin producing clusters of cells. The problem with stem cells is they are pluripotent, and they’re at risk for
forming other cells. The more differentiated the cells, the more likely that
you’ve got a pure beta cell that won’t make a little tumor, but the problem is, in
a lot of mouse models we’ve seen the stem cells that function, they also produce these little tumors. They’re not cancerous,
but they’re teratomas. They’re not normal tissue, and they’re little tumors, and they grow. You can imagine, if we
took these stem cells, and injected them into the liver, all over the liver, and they
started to make little tumors, then we’d have to cut out the liver, and do a liver transplant. That’s just not doable. Now, I say that because I think we’re getting very close
to having beta cells that won’t make these little tumors. But personally, when I
talk to patients right now, I’m gonna put ’em in the liver. I won’t take that risk. Some people may, and some
patients wanna take that risk. I don’t. I won’t do it, not yet. Not until I’m convinced that
they’re not pluripotent. So we’ve talked about the
problem with the liver. Even under the best of
circumstances only about 20%, maybe 30%, are surviving. So we need a new place, and we have been beating our heads against
the wall about this, because say we took those stem cells, and could put ’em into the
arm just under the skin, and they made a tumor. Well, not a cancer, but a tumor. If that happened, I’d say, “Oh, I’ll just numb it
up with some lidocaine, and we’ll cut it out”. That’s a risk I’d be willing to take. I think most patients would
be really to take that risk. That’s the site we wanna go to. The problem is, there has
been very little success in putting the adult
islets into the muscle, or into the subcutaneous form. We’ve tried. Here’s what happens. And this is gonna get a little confusing, ’cause I’m going to talk about using some human cells, some mouse cells. I’ll try to clarify. If we take mouse cells that express something that you can
monitor with fluorescents, and you take mouse cells, and you put ’em into
the subcutaneous place, or you put ’em into the
kidney capsule of a mouse, you can see that, and then we can monitor
by the fluorescents how many of the islets survived. You can see, if you we
put ’em into the kidney, somewhere around 30% survive. If we put it into the subcutaneous space just underneath the skin,
almost non of ’em survive. Stem cell-derived beta cell clusters, we were able to study these. Matthias Hebrok, who works
in our diabetes center, who’s our stem cell guru here, who also has stem cells, who’s made beta cells from stem cells. If we take those cells, and we put ’em into the kidney capsule, interestingly, they do
a little bit better, but when you put ’em in the
subQ, only 40% of ’em survive. And then, if you try to
put a capsule around ’em to prevent the immune system, which a lot of people
are very interested in, none of ’em survive. So how can we make the desert bloom? How can we make this a great
place to grow the islets? And we have tried. So Qizhi Tang, who is one
of our transplant PhD. She runs one of the transplant labs. She’s tried to provide extra
oxygen, extra nutrients, made an ambiance like a pancreas, and even put the islets into scaffolds. Each one of those incrementally
makes the survival better, but we were never getting
insulin independence. And then I have a resident
who’s working in my lab, Casey Ward, who, literally,
about two and a half years ago, said when he was going
to spend time in the lab he wanted to study the
use parathyroid tissue to see whether that would
make the islet survive. Why is that? Okay, so now let me just
jump tracks a little bit. The thyroid gland, you know it’s up here, and the parathyroid gland sits up, is four little dots, little beans that sit
on the thyroid gland, and they each have different roles, but when you have thyroid cancer, sometimes you have to take
out the whole thyroid, and you do not wanna render
a patient hypoparathyroid, ’cause the parathyroid sometimes
come out with the thyroid, or sometimes they take parathyroids out for a variety of different reasons. But we found a long time ago, that if you’re worried
about the parathyroid, taking out too much parathyroid tissue, if you implant some of it
into the forearm, it survives. So Casey, my resident, was
just on an endocrine rotation over at Mt. Zion where he was
doing parathyroid transplants. Another hormone, just like islets. Islets are a hormone producing organ. And he said, “Well, what is
it about the parathyroid?”, and he did a simple experiment, and these are always the
ones that seem to work. He just mixed the
parathyroid with the islets, and low and behold, he got 100%, 100% of the islets to survive
in the subcutaneous tissue. Not only that, now, when
we took adult human islets, adult islets, and put them into a mouse
that’s immunodeficient, which means we don’t have to
worry about the immune system, we could with a minimum, a
marginal mass of human islets reverse diabetes in the mouse. We cured diabetes with adults islets in the subcutaneous
position for the first time, and they survived only with
this parathyroid tissue. He then went on to use
Matthias Hebrok’s stem cells, and these fluoresce, they’re human cells, they fluoresce, they’re human beta cells, and he found that they also survived, but only when he transplanted
with human parathyroid. And finally, and most
really exciting results, if he took human parathyroid with human stem cell-derived
beta cell clusters, and put ’em into the subcutaneous, actually into the muscle
right here in the forearm, and waited six weeks, he could reverse diabetes
in all of the mice. It was the first time we
were able to reverse diabetes with a stem cell in the
subcutaneous position. And, you know, really exciting. These lines right here,
insulin independent only when we used a parathyroid gland. So now, the sky’s the limit, right? Because now we’re thinking, I
have approval to do a trial. We’re starting it next month where we’re going to take people who are already on immunosuppression, people who have had a kidney transplant, and have type 1 diabetes, or people who have a liver transplant, and have type 1 diabetes, and we’re going to use adult islets, and we’re going to put it into the brachioradialis
muscle, right here, just about a centimeter under the skin, and we’re going to transplant
it with parathyroid tissue from the same deceased donor, and we wanna see if we
can repeat what we’ve seen this profound effect of human
parathyroid on human islets. If that works, we’re ready to
do stem cell-based therapies. The stem cells are there. They’re ready to try them. I just won’t put them into the liver. Some people will probably
put them into the liver. I’m not ready to do that, but I certainly will put them here, and not only that, it looks like they’re going
to survive better here than they have in the liver by
using the parathyroid gland. Not only that, now, if the
parathyroid tissue is working, there’s a lot of people
that are already jumping on using pig islets, using pig
parathyroid and pig islets, because if you can just put ’em here there’s very little risk. Porcine insulin reverses diabetes. I personally would like
to go the stem cell route, but there’s some, I
know there’s one person barking up the tree to use xeno islets right now in parathyroid. So we’re at a whole new juncture, and I’m really excited
about the potential, because if you could take stem cells, we can just pull ’em off the shelf, not only can we help people
with type 1 diabetes, we can probably treat a lot of
people with type 2 diabetes. It just is the question
of immunosuppression. If we can derive the beta
cells from IPS cells, your own cells, and you have type 2 diabetes, then you wouldn’t need immunosuppression. Only type 1s would need immunosuppression. So we’re going to enter
a really exciting year. Now, I say all this, and I’ve
gotta be honest with you, I’ve been here before. I’ve been excited about islet transplants. The islet transplant
community and Dr. Freise is just sitting there smiling at me, because he knows we’ve said, “Islet transplantation is
right around the corner”, and you’ve heard it over and over. But honestly, we’ve seen the
success now in the liver, and I’ve got my fingers and toes crossed that we’re going to have
success in the next year. We should have an answer, and then we’ll jump right into stem cell-based trials fairly quickly. So I’m really optimistic. I know I’m always optimistic, but I am truly much more positive about the direction of this,
and it requires an army. I mean, if I show you all
the people here at UCSF, that’s the person, that’s Qizhi Tang who runs our immunology lab. Steve is our senior, just
finished chief resident. He’s now our fellow. Mike German, you may know
some of these people. Mike is a beta cell biologist. And that’s Julie who made that cell of a, that slide with the two million people. Jeff Bluestone is an immunologist. Then this is Matthias
Hebrok, and his group, who make stem cells. This is Tejal Desai. Tejal is the chair
person in bioengineering, and she’s working on the biosynthetic membranes
to protect islets. And that is my colleagues
in the islet lab. That’s Greg Szot, who
is the national leader in being able to extract those, he get an islet out of a rock. He’s amazing. And Andy Posselt’s one
of my surgical colleagues who really runs the islet program. Linda is a nephrologist
who also works in the clinical research lab. Joan and Tara, they’re our nurses. And Trish Brennan right there is running the trial that we’re just going to, and if any of you wanna
talk to us afterwards, Trish is here. This parathyroid trial which we’re, that trial, by the way, is sponsored by the California Institute
of Regenerative Medicine. I don’t know if you know serum. Ah, I think it was in the, no, in the 2000, early 2000s when George Bush was president, and there was a ban on
federally funded stem cell work. The taxpayers of California, largely because of Nancy Reagan, actually, went out and she got bipartisan support for the stem cell
initiative, and it passed by 68% of the California voters. We’re always ahead of the curve here. 68% voted to fund it. And this has spun off a
lot of stem cell trials, and my trial is one of the
last ones that’s being done as part of that initiative. It’s going to be up
for reelection in 2020, and we’ll see what happens. And that is my surgical colleagues there, who always give me a hard time, but really have provided
me the time that I need to do some of this work. So thank you, Dr. Freise. And I’m going to end there, and just open this for questions. Thank you. So, yeah, it does. It works just like the parathyroid tissue. So there was a few questions there. So what is in the parathyroid? We have a good idea what it is. 5% of the cells in the parathyroid turn out to be a stem cell. Not a stem cell, an adult stem cell, a precursor for what we
call the endothelium, and there’s CD, I can go into
the detail of the phenotype. Suffice it to say, those cells
produce a bunch of factors. Some of the factors protect the islet in a hypoxic environment. Some of the factors cause angiogenesis, or the formation of blood vessels. So it produces a bunch of factors, and we know what they are. We know what most of them are that cause the islet to survive while the new blood supply
is moving towards them, and we think that’s why
they’re doing so well. There’s a lot of reasons. It’s even unpublished right now, Casey and Tang are about
to publish all the results with all the factors and
what we know up to date, but we have a pretty good
idea what the cells is. What’s interesting about
these precursor cells, if we could learn how to
derive those from stem cells, now we don’t need the
parathyroid tissue anymore. We just need those cells, and
you can derive those cells. There’s people that are very
close to deriving those cells. Now, you can take those off the shelf. You could take the beta
cells off the shelf, and we won’t be dependent
on donors anymore, and that’s where we have to go. So pretty exciting. The parathyroid, it still
produces parathyroid hormone, so. Oh, that’s a really good question too, because, no, is the answer. When we transplant a pancreas,
I think Chris would agree, you might wanna weigh in on this, but we like to take
donors that are slender, because the pancreas is encased in fat, and the technical complications
when you have a fatty organ, much higher risk of infection. So we tend to lean, smaller donors. A big guy, I would be okay. My pancreas would be okay. Well, I’m too old, but my
pancreas would be okay. But a 6’2 male, that pancreas is gonna
be hard to transplant, just ’cause it’s big, and
got a lot of fat around it, but that pancreas has
a lot of islets in it. So we could use that pancreas for islets. And so, right now, I don’t think
the best donors for islets, they’re not the same as the
best donors for pancreas, okay? So that’s a really important question, and we have to discuss
that, ’cause right now, we have to use the tissue we
have as efficiently as we can. Every donor, every donor
we have saves a life, and we can’t afford not to use it. So I think this islet, we should save the
really perfect pancreases from young, slender donors
for pancreas transplant. We should use bigger donors,
could be a little bit fat, but no diabetes, those
islets are really good, and we can get a lot of ’em. So important. – How about an injury?
Yeah? – [Audience Member] Can you be injured? – Yeah, and that’s the other thing. I wish Greg, I should’ve
invited a lot of these people. Greg, this guy right here, tells me that he doesn’t like the
really young donors for islets, ’cause the collage and the tissue that holds ’em in is stronger, so it’s easier to shake the
islets out from older donors. I think way older donors, probably not. But in Japan, one of our fellows is over there. I was just visiting him. And it’s amazing what they do in Japan. They take donors for pancreas transplants that are in their 60s, and they have just as
good of results as we do, and the reason that they do that, is they don’t have a choice. You know, brain death laws hasn’t made it, of all the places the world, Japan is just about the
last to accept brain death. They’ve changed the law so that
brain death is permissible, but the culture has not changed. So they use every donor. So they’re using older donors for pancreas transplants, and islets. Greg likes the older
ones better for islets. His ideal donor is between
40 and 50, probably. So that’s what a lot of, you know, because there’s some doggone reason the pancreas, the islets like the pancreas, and the problem is the
pancreas is this nasty organ that you cannot touch, and if you inject the islets into it, you might turn on those digestive enzymes. But people have tried it in animal models for the very reason. It sorta makes sense. One of the things that’s
really interesting, you were asking, “What’s in the
parathyroid that does this?” Turns out, that parathyroid hormone, if you stain a pancreas,
it has this thing called parathyroid hormone-like production. It’s all over the pancreas. So now we have an idea,
low and behold, wow! This parathyroid hormone, there
it is right in the pancreas, and maybe that’s why the
islets like the pancreas, but that was a total back. I’m making us sound very smart. We just threw the kitchen
sink, and what lit up, and that’s what lit up. So there you have it. Yes? – [Audience Member] Is there
a capsule around the pancreas? – There is. It is a really thin capsule, and we try really hard not
to mess up with that capsule. So yeah. Surgeons, in general, hate the pancreas, because it is a, let alone transplant it. Man, people think we’re nuts
for transplanting pancreases, because of how fragile they are. But we do, we teach our fellows this very gentle technique
for procuring the pancreas where you almost don’t touch it. You pull it up by the spleen
which it’s attached to, and then just gently cut around it. But yeah, it’s a very
hard organ to work with. You think just like we
think, I’m telling you. So we’ve done a few things. So we think that the
islets don’t like blood, so there’s a capsule around the liver too. So a lot of people think, “Yeah, can you get ’em just
under there in the capsule?” And in the kidney, in animal models, we put ’em right under that capsule. We probably could try with a pancreas. We probably could try, but we’re scared of it. (laughing)
So. Yes, sir? – Around them?
– Yeah. So are you an engineer? – [Audience Member] Yeah. – You see, that’s exactly right. When we do a pancreas transplant, so we reconstruct the
blood supply to a pancreas before we put it in. And so, yes, and we don’t disturb the
blood flow to the islets. They’re preserved. So what the parathyroid tissue is doing, is it’s protecting the islets while the new blood supply develops. And one other interesting thing. The islets have a blood supply. They have vascular endothelium in ’em, and it turns out, that
that vascular endothelium is preserved if you culture it with stuff that the parathyroid produces. So not only are we increasing the rate at which the blood supply improves, we’re protecting the blood
supply that’s in the islets that was sorta destroyed
when we isolated them. But that’s the problem
with cellular transplants, and that’s why this
parathyroid thing is so cool. It’s sort of figured out. The parathyroid has figured out how to survive until the
blood supply develops. I could show you pictures
that would blow you away of the vascular tree in two days when you put the parathyroid in. It’s really cool. So a lot of people have said we should use the
patient’s own parathyroid, but I don’t wanna mess around
with surgery in the neck. I think it’s, we’re using the same donor that the islets came from. That’s our plan right now. And ultimately, like I said, we wanna derive those cells in the parathyroid from stem cells. It’s not that far. None of this is science fiction. People much smarter than me at this institution are doing it already. Yes, sir? In five weeks you could take a stem cell, and push it toward a beta cell cluster. I don’t know how, you know, I don’t know how you make new organs yet. I’m not in that business, but that’s, well, it’s going to happen to, but I think these beta cells
take five week to grow. It’s pretty amazing. Just using a bunch of
differentiation, growth factors, and these guys have figured it out. This, by the way, if any of you are in, interested in getting
down into the weeds about these stem cells, this reference
I found really great for, it’s pretty high level,
but if you’re, you know, if you’re tuned into the science lingo, it’s a great review of where they were at with stem cell therapy in 2015, but that guy who wrote
that is the guy who’s, it’s this right here. Those are his cells, and they’re the other cell line that’s ready to go into humans. – [Audience Member] May I
ask just one last question? – Sure, one last question. Yeah, so very interesting. What happened is it was, so these are all immunosuppressive drugs. The way we get drugs in transplant now, is we repurpose drugs that
are used for other reasons. The drug that Efalizumab was being, and the same with Belatacept, both of them were being used for autoimmune diseases, rheumatoid arthritis, psoriasis. So there was a study of 4,000 patients, 4,000 with psoriasis that
they used Efalizumab for, and while we were doing our trial, four of the 4,000 people developed something called
JC virus, which is fatal, and so they stopped it, but the trial was being
used for psoriasis, and the average age was
something like 65 to 70, somewhere in there, and the patients were
giving it continuously. We just wanna use it for induction, you know, at the time of the transplant, or maybe for two or three months, but they used it for two or three years, and they got this problem with JC virus, and it was pulled from the market, and we can’t get it back. We tried to get it back just to try it, and for experimental use, and they won’t do it. It’s a great drug. It’s great drug, because it’s given
subcutaneously every two weeks, that’s it. So you could imagine
for folks with diabetes who are using to giving insulin shots, all they have to do is
psst every two weeks into the subcutaneous tissue. But it’s a no go. It didn’t fly. It’s really sad. We’ve tried. We’ve tried to get it back. (upbeat instrumental music playing)

event_note February 21, 2020

account_box Jim Crook


2 thoughts on “Current Status of Pancreas Versus Islet Transplantation”

  • All of this… is a result of nuclear bomb testing …. Nuclear power… They ALL vent and leak …. But you people are paid to LIE that's why it's a nuclear End one way or the other the math said so

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