James Shapiro: “Cutting Edge Islet and Stem Cell Transplant Therapies in the Clinic for Diabetes”

James Shapiro: “Cutting Edge Islet and Stem Cell Transplant Therapies in the Clinic for Diabetes”


FRANK: Good afternoon. Thank you for joining us. I’m really excited to
introduce Dr. James Shapiro. Dr. Shapiro’s been working
on diabetes research for a long time, and
in particular he’s credited with
developing the Edmonton Protocol for human islet
cell transplantation, which was published in the New
England Journal of Medicine in the year 2000. He’s currently
continuing this research at the University of
Alberta in Edmonton, Canada. And he also holds the
Canadian Research Chair in transplantation and
regenerative medicine. Dr. Shapiro’s received
quite a lot of awards, including a Hunterian
medal from the Royal College of Surgeons of England. And he’s also
recently been inducted as a fellow of the
Royal Society of Canada. And with that, please help
me welcome Dr. Shapiro. DR. JAMES SHAPIRO: Frank,
thank you very much indeed. It’s very kind of you
to invite me to Google. I’m very impressed
with my tour so far. And I’m very excited
about the discussion that we’re going to have
later on this afternoon. So it’s a great privilege
to be here and be with you and share our hopes and trials
and tribulations and progress in some of the treatments for
the condition of diabetes. So we’re trying
to get to a point where we have
diabetes cured once and for all for the future. But it’s not easy to do
that in one fell swoop. So we’ve got several
strategies, and it’s really a team and global effort
in diabetes research, to try and take a point
where we have insulin today and hopefully no injections,
no monitoring for the future. And I’ll try and take
you along that journey of cutting edge islet and stem
cell transplant treatments in the clinic for diabetes
as we move forward today. So diabetes. Most of you will know
what diabetes is, but just the start
of the basics. Diabetes is a condition
where patients lose the ability to
adjust their blood sugar. And there are two main
types of diabetes– there are several subtypes–
but two main types. Type one, where the
pancreas basically has lost its ability
to make insulin. The cells in the pancreas
that make insulin are called islets of Langerhans. And inside those collections
of cells there are beta cells, and those are the beta cells
are the ones that make insulin. So in someone who has
type I diabetes then the body has basically destroyed
those cells– destroyed the beta cells inside the
pancreas inside the islets that make insulin. So the patients have an
absolute deficiency of insulin. And the other type
of diabetes– which is of course much more common
and increasing in number as well– is type 2
diabetes, where patients become resistant to insulin. And therefore when
they receive insulin, or the pancreas
is making insulin, the body’s needs for
insulin are basically what the pancreas can
release is insufficient. So diabetes is a very
common condition. There are about
381 million people with diabetes in
the world today, based on the world estimates
from the Diabetes Federation 2013. Type I diabetes represents about
10% of the world population. By 2030, this population with
type I and type 2 diabetes will double. So it’s going to be a huge, huge
health burden for the future. The national cost of diabetes
in this country and the US alone is greater than $245
billion estimated last year. And that increased from
$174 billion in 2007. And clearly, with
the massive increase in numbers of patients
with diabetes, this is going to become
uncontrollable and super saturate the ability
of health care systems to deliver appropriate care. So insulin has been around for
a long time, as some of you may know. Banting/Best– and this
is Frederick Banting in the physiology laboratories
in London, Canada in 1920, 1921, 1922 when the
team was working on the discovery of insulin
Banting, Best, Collip, and Macleod. And insulin injection
therapy clearly has been life-saving for many,
many patients with type 1 and some patients
with type 2 diabetes. So injections of
insulin from the outside can substitute for the pancreas’
ability to make insulin. And we measure insulin
in the number of units. So most patients will take 20,
30, 40 units on insulin a day. And they measure the number
of units of insulin– it was a crude amount– it was
the amount of insulin needed, one unit of instant to cause
hypoglycemia in a rabbit. That’s how they
originally discovered it when Banting and Best
were working on this. Diabetes is a dangerous
condition to have overall. Kidney failure is a
problem– 25 times more risk than the
general population. Heart attacks– two to
five times more risk than the general population. Strokes– two to
three times more risk. And life expectancy for
patients with diabetes is at least 10 years shorter
than the rest of the world without diabetes. Diabetes is the leading
cause of vision loss in working age adults. It’s the commonest cause of
end stage kidney failure, and of non-traumatic
lower limb amputations, because the blood
vessels basically become destroyed when the
body’s glucose becomes awry. There’s been lots
of improvements in the treatment of diabetes
over the course of time. As I mentioned, before
the discovery of insulin in 1921, 1922, diabetes
was a fatal condition. When insulin was first
tried in patients, it led to complications–
infection, sepsis. Then there’s been
various improvements in different types of insulin–
short acting, long acting insulin– in different
ways of delivering insulin over the course of time,
including insulin pumps, including continuous blood
glucose monitoring systems. And the whole idea here is to
try to tighten up the sugar control so that patients
are at less risk of getting the end stage complications
of diabetes– the micro and the macro
complications of diabetes. And the reverse side
of that equation is we try to tighten
up the control as the patients get much
more of this condition, which is a iatrogenic condition–
in other words, caused by doctors– which is
called hypoglycemia. So when the blood sugar falls
below a certain threshold, then patients
become susceptible, because the brain absolutely
requires glucose to function. As soon as the blood glucose
drops below a certain level, then the brain can
no longer function. So islet cell transplantation
has been around since the 1970s experimentally. And first trials in patients
happened in the 1980s. And it really took
off in 2000, and there have been several done. I’m now going to
explain and tell you the story about
transportation shortly. But really our indications
for islet transplantation have been to try to reduce
this risk of hypoglycemia, reducing the risk
of lows in patients that are needing insulin. So why do we try to run
the blood sugar low? This is really based on
some very large trials in patients with diabetes. We know from these
curves for example, as we try to tighten up
the blood sugar control, we can definitely reduce
the risk of complications such as this one on the right,
called retinopathy, which is where the blood vessels in
the back of the eye accelerate, and grow, and cause
the blindness. But, as we tighten
up the control, then patients are more and
more at risk of getting lows. And we measure this by
the glycated hemoglobin, which is a marker in the
bloodstream that really tells you how good or
bad the blood sugar control is over several months. So here’s a patient that’s
wearing a state-of-the-art continuous glucose monitor. And you can see across
day one and day two, this patient has quite
wide fluctuations in blood sugar control. And at 8:00 in the
morning on the second day, you can see the
blood glucose drops, the patient is on their
own, not monitored. And unfortunately,
that patient’s found dead in bed
at 9:00 an hour later, from a fatal
hypoglycemic event. And fortunately, this
is relatively rare, but it does happen. And it happens in young
adults with type 1 diabetes that have poor control. Now this is what we can achieve
today with an islet cell transplant in the
lower panel here. You can see very
wide fluctuations in blood sugar over
the course of time, up until that red arrow
when the patient receives an islet transplant. This is a transplant that
actually is done in Miami. Dr. Camillo Ricordi shared
this slide and data with me. But it’s very typical of
what we can achieve routinely with an islet cell transplant. And here you can see, after
the islet transplant, when the patient discontinues
insulin, the blood sugar control becomes very tight,
is in the normal range or near normal range. The price of this however,
is that the patient needs a procedure– a small
procedure to receive cells– and has to have
immunosuppressive drugs in order for the body not
to reject these cells. They’re transplanted
cells from organ donors, and they are
therefore potentially foreign to the body. And also the process
that caused diabetes in the first place, which
is an autoimmune process, meaning the body attacks itself. This will happen
again after an islet transparent to the new cells,
unless the anti-rejection drugs are given. So there’s been real progress
in islet cell transplantation. I’ll explain that to you. But I think we’re somewhere
along this hype cycle right now, perhaps
somewhere along the slope of enlightenment. We haven’t got to
Nirvana yet, but we’re trying to get there along
the plateau of productivity. And still I think
if you can read and you can Google lots
of negative reviews on islet transplantation,
because I think the knowledge
in this area probably hasn’t reached all
of the community. But I’m sharing with you
today some of the progress. But there’s been progress
throughout diabetes. And here for example,
is a trial that was just completed in
September last year, looking at a special instant pump that
switches off when the blood sugar reaches a certain low
threshold, low glucose suspend. And when this is
applied to patients, then the risk of patients
getting hypoglycemia is certainly a lot less
than it would be otherwise. So there’s been
lots of progress. And I’m also very
excited this afternoon to meet with your Google
contact lens team. Because I think the areas of
monitoring for blood sugar control, and our
ability to monitor the function of our cell
transplant therapies over time with this
kind of technology will be enormously informative
and allow us to tighten up our control, minimize
the stress on the cells, and allow us all to learn a
lot about controlling diabetes. So who do we offer an
islet transplant to today? We have two real
major categories– those with patients who have
an islet transplant alone. In other words, they haven’t
had a previous transplant. They have to have
type 1 diabetes for more than five years. They have to fail on all the
standard therapies, including insulin pumps if available. And we have various
scoring systems, which I won’t dwell on,
but they’re basically to demonstrate that the
patient has severe lows, despite their ability to control
the glucose as best they can. And about 5% to 10% of
the population with type 1 diabetes– at least
in Canada– would fulfill these very
strict criteria to justify adding
immunosuppression and receiving a cell infusion. The other side of
the equation are patients who have already
had a successful transplant, like a heart, a lung, or in
this case, a kidney transplant. So they’re already on
the anti-rejection drugs, so they don’t have to
face any additional risk except from the minor risk
of the procedure required to put the cells in. And islet after kidney
transplant, or second category, is becoming a very
successful category too. So we began with the Edmonton
protocol in the year 2000. It didn’t just
begin from nowhere. It began from 30
years of research in small and large
animal models. And a terrific collaboration
with several international centers across the world. And I think that’s one of the
privileges involved in science and in diabetes
research, is that we have a very, very close knit
community of scientists working together, willing to share
information and ideas to allow us all to
get to the next step. And it probably is
modeled very nicely in the Google organization. So we published this in 2000. This is the New England
Journal of Medicine, where our first seven
patients receiving islets under the Edmonton protocol–
that we called subsequently the Edmonton protocol–
where all the patients that had the transplants were able to
come off insulin and remain off insulin for a period of a years. And in fact, now 15 years
later, two of the original 12 are still completely
insulin-free with full function. And we’ve just
refined this treatment over the course of time to
try and further improve it. So this was what we call
the Edmonton protocol. We gave two sets
of islet infusions. Initially around 5,000
islets per kilogram based on the recipient’s weight. And then we have
another infusion to provide enough
cell mass to make it sufficient insulin
for the patient. Then we gave these two
anti-rejection drugs– sirolimus and tacrolimus– and
an antibody at the beginning. And we subsequently
changed these drugs now to more standard drugs,
because we encountered quite a lot of side effects
from the sirolimus drug. But it was certainly
very successful in allowing us to
begin our first trials. We then replicated these
trials in Miami, Minnesota, and in our own site in
Edmonton in 118 patients, and were able to replicate
this quite successfully in 82% percent of patients
coming off insulin. And then we moved forward with
the immune tolerance network and carried out a large
international trial in the US and Europe, testing
the Edmonton protocol. And we published that too
in the New England Journal. So where are we today? So we’ve treated in
Edmonton over 200 patients– 218 patients– who’ve
received 460 transplants. So you can see that
most patients require– in our center at least–
two islet infusions to provide sufficient
mass for them to come off insulin
for a period of time. We’ve received in
Canada patients from all across the country. Last year we did a record
number of islet transplants in Edmonton. We did 66 islet
transplants at Edmonton. And we’re quite proud of that. We’ve kept our teams very busy. Across the world,
currently there’ve been over 1,000 islet
transplants done at least 30 different
international sites. And so I’m going
to explain to you know how we get the islets out. That was a picture,
by the way, of islets under a microscope stained
with a dithizone dye that stains the zinc. Because zinc and
insulin are very closely linked Studying the
zinc inside the islet, so you can see then quite
clearly under the microscope. Those are very pure
islets ready for infusion. But we don’t just get
the islets from anywhere. They come from a human pancreas. So I’m just going to walk
you through this process, because it is quite a complex
process that our team has to do in Edmonton. So here they take
a pancreas, they canulate the pancreas duct. And as we’re going through
the video here on the right, I’ll show you the
graph on the left there is all those little dots, sort
of like the stars in the night, every one of those represents
over 1,500 islet isolations done by our team over
the last 15 years. There’s a human
pancreas on the right, you can see it being distended
with collagenase enzymes before we chop it up and put it
in Camillo Ricordi’s chamber. So there’s Doug shaking
the chamber there. This team’s a very
well-knit team. They work day and night
to prepare the cells. Once the cells are
digested, then we purify them on a continuous
ficoll gradient on a cool code machine. And there’s Doug and Tatsuya
and the team at Edmonton that prepare these cells for us. They’ve done a
terrific job for us. You can’t see that
graph on the right, it’s a little too small for
you, but basically the number of islets they get
out of the pancreas today is double
the number that we were able to get in
2000, when we first began the Edmonton protocol. And their success rate in
being able to take a pancreas and provide enough
cells to transplant has also increased to
around 60% to 70% percent. The actual transplant
part is very, very simple. It doesn’t require
a transplant surgeon to do this, fortunately. So the transplant is done
in the x-ray department under local anesthetic. Here’s a patient who
is awake, chatting away during the procedure. We use fluoroscopy x-ray so we
can see where the needle goes. We thread a catheter into
the main portal vein there, and then we simply drip
the cells in under gravity. And we measure the
portal pressure while we do this, we give
heparin to prevent blood clotting at the end, before
we pull that catheter out. Because we learned this perhaps
in our first early cases, when we pulled the
catheter out of the liver, we initially got bleeding. So we found that when we put
this paste in along the track as we pull it out, we
mix it up with contrast so that we can see it being
injected on the x-ray screen. You’ll see that in a second
here as we load the syringe, this is Aventine paste. So as we pull the catheter out,
we plug the track in the liver. And that has eliminated
the risk of complications such as bleeding after
the islet transplant So this is a very
safe procedure. And if we look at the
number of patients we’ve treated over the course
of time now, 97% of patients survive. And these are
patients, of course, who have had longstanding
diabetes, who are at risk of many
different things. And of the few deaths that
we’ve encountered over 15 years have been mainly
cardiovascular deaths in patients with
longstanding diabetes. So heart attacks, basically. So we’ve had four patients
die of heart attacks. One patient had a possible
Creutzfeld-Jakob disease. And one patient had
fatal hypoglycemia after an early transplant
where the cells failed. So none of these deaths have
been related to the transplant or to the anti-rejection
drug treatment today. So this has been a
very safe transplant, certainly the safest transplant
that I’ve been involved in. There have been adverse events. We can go through
these, but I won’t go to them in too much detail. A couple of patients
over 15 years– 1.4%– needed to go on to get
a kidney transplant, because the drug we give to
prevent rejection to crolimus does have kidney side effects. Now what about performance? Are we doing better over time? So if we look at the
function of cells over time, in the red line here. So every molecule
of insulin that’s made by the cells,
another molecule is made called C-peptide. And we can measure the
C-peptide in the bloodstream with a simple blood test. So you can see that over
the course of 15 years, 73% of patients continue
to make C-peptide to a sufficient degree that
controls the hemoglobin A1c, therefore reduces
their risk of getting the complications of
diabetes, and prevents the patients from getting
hypoglycemic events. So this is a real advance,
particularly for patients that have really recalcitrant
risk of hypoglycemia. So these patients are
very well protected. But what we did see in the
early Edmonton protocol series is that a large
number of patients did need to go back on to
small amounts of insulin– around 15% of patients–
by the 15-year mark. And so we’ve spent
a lot of effort now in the last
several years seeing if we can improve these results
over the course of time. And if you can think of
the number of the cells that we transplant in to
liver here as a bucket, and the cells are being
lost through little holes in the bucket, we’ve
been working in science to see if we can plug
the holes in the bucket to try to allow more cells
to survive over time. So we’ve been looking
at various pathways to reduce early
damage to the cells, trying to prevent them from
being rejected and preventing leg graft loss, and
then really trying to improve the number
of cells that we put in at the beginning, so that
we can have many, many more patients with fuller
function and more durable function over time. Now because type 1 diabetes
is an autoimmune condition, as we mentioned
at the beginning, there is a risk of the
autoimmunity coming back again. And here’s a patient’s
biopsy– and I won’t go through
too much details– but you can see on
the right hand side, there are islets
surviving quite well, but no beta cells in
that biopsy, which is from Dr. Razinia’s group in
University of Massachusetts. So we need processes that
can control rejection, reduce inflammation, and allow the
patients to become tolerant. In other words, for
the future, we’d like to have a cell
treatment that we just put into the patients that
the patients won’t reject on their own, and won’t need
lifelong anti-rejection drugs. And we’re all trying
to get to that point where we can achieve that. And controlling this triangle
is a bit of a challenge, but we’re working on
it very intensively as a global community of
diabetes research scientists. And we’re trying various
different maneuvers– I mentioned a few of them that
I won’t go through the details– but I’ve mentioned a few of
them that we’re trying presently in Edmonton. Now I showed you that
falloff an insulin independence rates
at five years. And now there are 6 centers
across the world that have insulin-free
rates with islet cell transplant of five
years, more than 50%. And this is an
important milestone, because it’s exactly the
same rate that we would see with a whole pancreas
transplant alone, so a big operation
in comparison. Putting a whole
pancreas transplant in, connecting the blood vessels
up, and the risks from that. We can achieve today– at
least in these 6 centers– very similar results to the whole
pancreas transfer alone, with a simple
injection in the site. So in trying to control
the immune response. We’ve tried this
treatment in Edmonton now in over 100
patients– I need to update those
numbers– on over 100 patients in various
different protocols over the course of time. And what we found in our
earlier analysis is basically if we look at the
C-peptide rates, they’re very similar,
perhaps a little bit better with the the
Alemtuzumab than they were with the Edmonton
protocol, 84% at seven years with C-peptide function. And if we look at the
independence rates– these are patients who are
fully free of insulin– again, ongoing data still in analysis
phase, but 58% of our patients, when we last analyzed
this at seven years, were still free of insulin. Significantly improved from
our original Edmonton protocol data, where currently at 15
years, just 11% of patients remain insulin-free. I mentioned the hemoglobin
A1c– the glycated hemoglobin– this marker in the
bloodstream that tells you how good the blood
sugar control is. And you can see at the
beginning where it says pre there, on the left hand
side of your screen, that the levels are
around 8% or 9%. And the red line
is the threshold of what a normal
person would have, who doesn’t have diabetes. Now as we bring the line closer
and closer to the red line, then the risk of getting
secondary complications is obviously reduced markedly. But normally, if we did
that with injected insulin from the outside, the closer we
got to the red line, the more and more dangerous hypoglycemias
the patient would have. Well after the islet
cell transplant, we can achieve the
below the red line or under the red
line very reliably without the risk
of hypoglycemia. And these graphs show you the
different measures that we use. Beforehand, you see
the patients have a sky-high risk of hypoglycemia,
and this score is about five on that score. On the hypo score,
it’s around 1,200. And afterward, you
can see it’s almost undetectable over
the course of time. So patients are
completely protected, as long as the cells
continue to function, from hypoglycemia and
swings in blood sugar. So this is a very
effective treatment for controlling blood sugar. [VIDEO PLAYBACK] -I feel my control
now is the best it’s ever been in 20 years. [END VIDEO PLAYBACK] DR. JAMES SHAPIRO:
What about the risk of the secondary complications? There are several
centers looking at this. Garth Warnock Vancouver has
looked at this quite closely. What he finds in a control
group with islet transplant versus conventional, or best
medical care insulin therapy, is the islet transplant group
has much lower hemoglobin A1c in the green. They have less risk
of eye disease. And their kidneys are
actually protected, despite the fact that they
are receiving tacrolimus. So this is very
encouraging data to suggest that an islet or
other cell transplant, or stem cell transplant in
the future for diabetes, will have these
similar effects, being able to protect against
the secondary complications of diabetes. We’re working with the
US FDA quite closely in two major trials were part
of the clinical islet transplant consortium. One is called CIT-06 and
one is called CIT-07. And basically to
make it very simple, one is islet after
kidney transplants, in the 07 one are islets alone. These trials are now
completed or undergoing a very detailed analysis with
the FDA, and very likely, these two trials will
lead to the FD awarding a biological license for
islet transplantation, allowing Medicare, Medicaid,
and third party payers to potentially reimburse islet
transplant in the US, which has been a major limiting factor
in terms of the numbers of cell transplants done in the US. We’ve been very fortunate
in Canada however to have the Canadian government
pay– the Alberta government, I should say– pay for
the Canadian transplants to this point. And a similar thing
has happened in the UK with the National Institute
of Clinical Excellence paying for islet transplant
through the UK government. Same thing in Australia, same
thing in Europe, and Geneva, and in several other countries. So hopefully this will
happen very soon in the US. Several groups have
reported the ability to achieve what I showed you
with two islet transplants with a single donor
islet infusion. And this would be
important because it would allow twice the
number of patients to receive transplants from
a limited donor source, from organ donors. And so several centers
have been able to do that with different strategies. But still this is a challenge,
I would say, for us. Only about 10% of our
patients in Edmonton are able to achieve insulin
independence routinely. If we don’t select the donor,
we don’t select the recipient entirely. What we do find if we look
at Melena Bellin’s analysis? Looking at all the
patients treated that are participating in these
centers, that at five years, if we give an anti-inflammatory
treatment at the beginning called Tanacet– which prevents
an inflammatory agent called TNF– if we switch that
off at the beginning, we can have many, many
more patients of insulin at five years. Seems to be very important
to suppress inflammation at the beginning. So we’ve done studies in mice. We always take things back
to mice and test things. And we tested another compound
called Anakinra, which is another antibody–
which is also an anti-inflammatory one used
in inflammatory bowel disease and another condition
called psoriasis– and we found that this is
a very effective treatment to allow human islets
to engraft in mice. And we’ve been able to take that
treatment across to the clinic and treat many
patients that way. We’ve also been trying to
switch off the cell death pathways in this pathway
called apoptosis. So cells die by
different processes, but we’ve tried several agents
to switch off cell death. These are called pan
caspase inhibitors, because they switch off
all the major cell death pathways that lead
to this apoptosis. And when we’ve tested these in
our mouse models and our pig models, we find that
these caspase inhibitors can reduce the tiny
number of islets needed to reverse diabetes
by about 80%. So they make a big,
big difference. And we’ve tested
this several times in various different
combinations and various different ways. And we’ve moved on and carried
out the early clinical trial with these that looks–
well at this point, it’s difficult to say whether
it’s had a big impact. But we’re still working on it. So we recognize today that
islet transplantation, the way it is today,
because patients need immunosuppression, because
there is a shortage of organ donors, could only
really address a very narrow band in
the spectrum of patients with diabetes. And we’d like to get
to this point here where we can treat all
the patients that are just diagnosed with diabetes, that
have difficult to control diabetes, that have
chronic type I diabetes, and also those that
have type 2 diabetes– the entire spectrum of diabetes. And we recognize
that if we keep going the way we are going
on that one track, we won’t be able to address
that entire spectrum. So what next? So we’re looking at
alternative retrievable sites to put in islets today, or stem
cells potentially tomorrow. And here’s a trial
that we’re actively involved in now with a
company called Sernova. And this is a device
that goes under the skin. It’s the the size and
shape of a tea bag. And it basically threads
in under the skin. We leave it there for
about a month or two. And while it’s
under the skin here, the body makes new blood
vessels that grow in. And this is a sort of in
response to a foreign body. Then we take those rods
out when we come back. And we can do this under
a local anesthetic, we can do this under
a general anesthetic. And then we can infuse
ourselves along that track, and basically put the cells
in under the skin instead of in in liver. Now that may be an advantage,
but as we think to the future, as we think about
use of stem cells, it might be safer to put
them in a retrievable place where we can take them
out if we need to. So if we put them under the
skin instead of the liver, it’s a much simpler maneuver
to take the cells out. So we’ve done this so
far in a few patients, and it’s looked
somewhat promising in terms of being able
to show cell survival. But this is still ongoing,
and we’re looking at the data closely. We’ve also been looking at what
we call the deviceless method. So we put a tube under the skin. We leave the tube under the
skin– a simple catheter that we use routinely
in the x-ray department. We leave that catheter
under the skin for a month. We take the calculator out,
and then we put our cells, or stem cells, or
islets, or whatever kind of cell population
we want to put in, in this track, which has now got
lots of nice new blood vessels. And here you can
see islets surviving in that round area
that used to have the little catheter
on the top left there. And the cells work very well. And you can see with the
catheter placed under the skin, and then we put the
cells in the blue line, blood glucose comes
down quite nicely, It takes a few weeks to do so. And you can see on
the right, we get lots of nice new blood
vessels growing in to supply these cells. So I mentioned islet transplants
today, and stem cells tomorrow. So I think we are
getting very close now to being able to move
forward with stem cell treatments instead of islet
cell transplant treatments for the next round of
trials for the future. There are several
groups across the world working on stem cells. And I’ll show first
just one that we’re collaborating with,
Maria Nostro and Gordon Keller at the
University of Toronto have made a stem
cell line that makes human insulin– the human beta
cells, basically– from stem cells. And we’ve been able to reverse
diabetes quite effectively in mice and our deviceless
model with that cell system. We’ve also been testing out
to see if the cells turn out to have what’s
called a teratoma, or risk of awry cells, then
they can be transplanted still in this deviceless space
and not breach the space, so we can still
potentially remove them. We’ve also been working
for the last 10 years with a company called
Viacyte down in San Diego. And we’ve been very
excited by that progress in developing a human embryonic
stem cell line that they have shown can reliably
make human insulin, and can be potentially
transplanted, and can cure diabetes in
mice when transplanted. And this group has
been very innovative and shown these
cells to be safe, to have no risk of the
teratoma that I mentioned. And they are now carrying
out a clinical trial that we’re looking
forward to participate in, where we’re going to put
these cells inside what’s called an immunoisolating
device, so that the immune
system can’t directly get cell-to-cell contact
with the transplanted cells. And the idea of that
is that we wouldn’t have to give the
anti-rejection drug treatments if it’s effective. So we’re looking forward
to starting these trials with Viacyte within
the next few months. Now in parallel, there’s
lots of other treatments that could
potentially switch off the autoimmune pathways
in type 1 diabetes. And Jeff Bluestone,
from San Francisco here, has summarized all
the different pathways that can be switched off in type
1 diabetes, all the studies, all the antibodies, all
the drug treatments that can be given to try
and control diabetes. And it’s obviously
a very complex one. We’ve amassed a team in
Alberta to try and address one or two of these
together with industry and a large collaboration
of scientists in Edmonton and Calgary. We’re going to do
two different trials. One is trying to get
patients’ own stem cells to regenerate
their own pancreas as soon as the patient is
diagnosed with diabetes. In other words, resetting
the immune system and getting the
patient’s own cells to turn back and
repair the beta cells. And then the second
strategy we’re using is the Viacyte cell transplants
to try to treat patients just like we would at the
Edmonton protocol type treatments that I
showed you about. So the immune reset
is moving forward. We’ve got our plans in place. We’re just putting
them through ethics and through Health
Canada right now. We’re going to give antibody
treatments at the beginning to reset the immune system. We’re going to take the
patient’s own bone marrow cells and re-transplant those
up into the pancreas to allow those cells to
repair the injured pancreas. Then we’re going to give a
treatment for the first year, called a GLP-1 analog,
that will help to further regenerate and
accelerate the growth and repair of injured islets. So we have a lot
of things to do, and we’re very, very
excited about it. We’re also working
with another technology called normothermic perfusion. And this is going
to I think really revolutionize all areas
of transplantation. So most the time you can see
those boxes on the right, that’s how we carry
organs around, in ice. So hearts, lungs,
livers, kidneys, and the pancreas
for our islets– we carry them in these boxes. So we’re just about
to start a trial with a group at the
University of Oxford, and a company called
OrganOx, where they have one device that
we could put a liver on, which is in this
bottom left panel. There’s other companies that
have a device for hearts, for lungs. And here’s one that
we’re testing out for pancreas transplantation. So in other words, instead
of putting the organ in ice and having it
injured, we can keep it perfectly alive–
like the heart’s beating there– outside the body. And so as soon as
we transplant it, it can be in perfect
condition when we transplant these organs. It’ll make a big, big difference
to the safety of transplants, and also to make sure that
the transplants really work before we put them in. And the idea here is that we
can deliver oxygen, deliver nutrients, provide a
physiological temperature, and provide an ideal
environment for the organ while it’s outside of the body. So we’re very excited about this
technology as well as we move forward. And this is the liver machine
that we’re about to test. And the company who
came to San Diego to the World Transplant
Congress mentioned to me that they’d love
to have Google’s logo on the outside of the box. So, if you’re interested
in working with them, just let them know. So let me sum up. So I showed you that we’ve
made a lot of progress in the treatments of diabetes
over the course of time. That insulin dependence
rates have improved a lot. That several centers now have
over half of their patients still free of
insulin at five years after an islet transplant. That we’re looking now to
other alternative sites for infusing islets
under the skin. I didn’t mention
other sites that we’re about to test with
the Pittsburgh group, including the lining
of the stomach. We’re about to start trials with
Viacyte on their embryonic stem cell treatments. And we’re also looking
at regeneration trials to regenerate and repair
the pancreas and the islets that at the moment a child or
adult is diagnosed with type 1 diabetes. So there’s a lot of
things happening. I think we’ll make
a lot of progress. So finally today, I’m very much
looking forward to discussing with the contact lens team
our opportunities of working together in cell
transplant monitoring, and also with the
Google Glass team, looking at the role
of the Google Glasses and state-of-the-art monitoring
and complex surgeries. A guy was telling
me about the use of these in lung
transplantation. I think we could apply this
very easily also in liver transplantation, maybe join
the pancreas islet isolation. I think also this could
allow us to communicate far better as scientists from
one institution to another. So instead of me being in
Edmonton, another group being in San Francisco,
another group being in Australia, another
group being in China, we could make a
scientific community that is basically global
and one, and allow us to work much closer together. And that’s what I’m
very excited about. So on behalf of our
pre-clinical team scientists that have done all the
hard work– our PhDs, our master students,
our post-docs, and technicians that
have done really all the hard work and
pre-clinical testing– on behalf of our
large clinical team that has basically helped up
prepare the islet transplants. So thank you very much
indeed for the opportunity to present to you
this afternoon. I look forward to
answering your questions. [APPLAUSE] AUDIENCE: My name is Zerga. I actually work on
the iris and basically the contact lens project here. So I’ve heard some questions
about the cells you infuse. So can you tell us some very
basic biology of those cells? So when you inject it into the
blood vessels of the kidney, where do they end up? So do they actually stay
there and live in the kidney? Or do they end up
in the pancreas? DR. JAMES SHAPIRO:
So the question is– so we transplant our
cells inside the liver. So it’s a local injection
literally inside like this, under x-ray. And we get the radiologist
to put a catheter into the main vein that
goes up into the liver. It’s called the portal vein. And it’s like a tree. It has main trunks, and
it has little branches. And the islet cells, the
vary in size, from about 50 microns to 150
micrometers in size. Some are larger– 400 or
500 micrometers in size. And basically they
go up this tree, and they go far along
the tree until they get into a blood vessel
that’s smaller than they are. There they get trapped. And basically a little bit of
blood clot forms around them, and a local inflammatory
reaction– then new blood vessels grow in
inside the liver. These cells are not going
back into the pancreas. We could potentially put
them in the pancreas, but it would be very, very
technically difficult to do so. It would be risky. It could case pancreatitis. It could be a difficult
place to put them. It just so happens that the
liver is a very effective place to put these cells. AUDIENCE: [INAUDIBLE] DR. JAMES SHAPIRO: Potentially
they can grow anywhere. The question will be will
the cells work as effectively in another site as they
do currently in the liver. And we don’t know that yet. AUDIENCE: How do they
communicate with the body? When do they know
when to generate– DR. JAMES SHAPIRO: How do
they communicate with the body was the question. So the islets have
sensors on them. So they have glucose
receptors and they can sense the blood
sugar, much the same way you do with a skin test when
you take a drop of blood. They’re listening to the
blood stream, monitoring it constantly, all the time. And as soon as the blood glucose
goes high, then in concert, they all release just the
right amount of insulin that’s needed in a
very dynamic way. And as the blood sugar drops
below a certain threshold, they all shut off, so
they stop making insulin. So it’s a much more precise
way of regulating blood sugar than if you inject
insulin from the outside. So it’s able to do
that because they’re a collection of cells
there that adjust insulin. And i didn’t mention, the islets
have several cell populations int them. The have the beta cells
that make insulin. They also have another
cell population called alpha cells
that make glucagon. And glucagon makes
the blood sugar go up. So you have what’s called
counter regulatory control. So with counter
regulatory control, you can keep your blood sugar
in a very precise balance. AUDIENCE: Hey, Dr. Shapiro. My name’s Joel. My wife has lived with type 1
diabetes for nearly 40 years. And she had a couple questions. The short one is– do you
transplant the entirety of the islet, or
just the beta cells? And the more interesting,
or more complex question is– are you
modifying the islet cells prior to transplant to reduce the
chance they’ll be attacked by the same antibodies
that originally killed of the islet cells? DR. JAMES SHAPIRO: So the
islets that we transplant are the collection
of all the cells. So there’s five– I mentioned
two cell types– there are actually five or six
different cell types. Maybe there’s even more that
we haven’t discovered yet. But the islet is sort of
an organelle collection of several types. We think that the islet
needs all of those cell types in order to survive
in the longer term. If you just took out
all the beta cells and transplanted them, they
might work for a while. But maybe the beta
cells on their own, without the rest of
the supported matrix and the ability to communicate
with each other in this sort of local mode, maybe they
wouldn’t work as well. We don’t know that. But we transplant
all of the cells. And so the second question was– AUDIENCE: Do you do anything
to modify the islet cells prior to transplant? DR. JAMES SHAPIRO:
Do we do anything. And so, the islets are
taken out of the pancreas in that process. We keep them in culture. Now in the old days, in the very
first experiments we’ve done, there was a lot of different
innovations that we had done. You could treat them
with ultraviolet light. You could treat
them with x-rays. You could treat them
with high oxygen. And these would alter what
is called the immunogenicity, or the ability of the body
to recognize them as foreign. We haven’t done so
much of that now. But potentially you
can do a lot of things to manipulate the
cells in the Petri dish that could alter the
ability of the body to recognize them as foreign. we could wrap them in
a seaweed membrane, an algenate microcapsule. We could add other
products locally around the islets
to protect them. So an islet in some way
has a lot more potential than the other
transplants that we do, where we don’t have that ability
to alter them in the dish. But we haven’t explored that
perhaps to its full potential. Yeah, you’re quite correct. AUDIENCE: I noticed
in one of the slides that the A1c’s
that were reported, or that were monitored in your
patients, seemed to improve over time after the
transplant, not just initially. And given the propensity
of these cells to degrade, I was surprised that it
got better as time went on. DR. JAMES SHAPIRO: I think
that’s partly a function– well I should say hemoglobin
doesn’t drop immediately. The reason for that is it
takes two or three months to have an effect. So if you have bad
control, then you suddenly go to perfect control,
the next A1c test is reflecting what happened
three months earlier. So there’s a lag in
its ability to measure. It’s designed that
way, because it is meant to tell
you what’s happened over the last few months. So that’s why you’re
seeing a delay. It’s not so much that control
is improving over time, but I think it’s more that. AUDIENCE: And just sort of
a more general follow up. I’ve been diabetic for 25 years. And ever since I
was diagnosed I’ve been following the news media
and basically, the light at the end of the tunnel has
been there the whole time. Does seem to getting
brighter, but what is your take on kind
of a realistic timeline for– I realize it’s
all speculation. DR. JAMES SHAPIRO:
So if I send you back to your office this
afternoon in Google and say, I want you to tell me
in a week how long it’s going to take to
finish a project. Maybe you’ve got all the
algorithms straightened out, and you can tell me it’s
going to take exactly a week. I think for this, because
it’s a biological system, it’s working humans, it’s
not just all of that. We also have to deal with
the regulatory agencies as soon as we want to
do something different. We’ve got to justify
what we’re doing. They often tell us to go
back and do more experiments. So you’ll notice I never
mentioned the five year cure. I never said, well, we’ll
do this in five years or we’ll do it in 10 years. What I will say to you
is that in 2014 we’re doing far more in
this year than I ever dreamed we would
be at this point. So my impression is that we’re–
all of us as a community– are moving faster. We haven’t got there yet. I don’t know how long it’s going
to take to get to the light at the end of the tunnel. But I know that’s
where we want to be. But it’s going to
take what it takes, provided we’re all
working intensively in the right direction. AUDIENCE: My name is Steven. I also work on the
contact lens project. And so I have a
question a little bit related to Zach’s question. The islet function is
said to be modulated by the autonomic nervous
system, parasympathetic, and sympathetic nervous system. Alpha and beta insulin
and glucagon production. And so if you place these cells
underneath the skin, what’s the effect of breaking
the autonomic link so you have some autonomous
function in response to glucose. You cut off this nervous
system link, so– DR. JAMES SHAPIRO:
You’re quite correct. So the islets that
are transplanted are completely detonated. They don’t have any
nerves going into them. Potentially the nerves
can grow in over time, along with the new– blood
vessels happen first. Potentially they can
become integrated. But the nerve end
growth isn’t essential. So perhaps it helps with the
a cued release of insulin in the normal individual
who’s stressed. But most of the time these cells
can respond very effectively to the local environment. So you don’t need innovation. And they clearly
can work just fine, as I showed you,
without innovation. You can divide the
vagus nerves in patients that don’t get diabetes. Often we do that for
other conditions. So it clearly plays
a role somehow, but it’s probably
a very minor role, because it’s just
completely redundant. You don’t need it. AUDIENCE: So there
was a research article that I came across recently
about activating islet cell production in the
gastrointestinal tract. And I was wondering if
you could talk about that. I don’t recall seeing
it on the slides. DR. JAMES SHAPIRO:
So there’s a group led by Dr. Tim Kieffer
in Vancouver, who’s worked on trying to
convert the cells in the gastrointestinal
tract into becoming insulin-making beta cells. That’s really his
area of expertise. He’s made a lot of progress
over the course of time. But I don’t think I can
beyond that comment directly on his work, because I haven’t
been directly involved in it. But it’s exciting. AUDIENCE: How does the
life look for the patient after the transplant, in terms
of taking the immunosuppression drugs, and what’s
the cost of it, and how often it has
to be administered. And what are the
side effects of it? DR. JAMES SHAPIRO: Right. So the standard
anti-rejection drugs are usually taken twice a day. And most patients tolerate
these extremely well. And we do a lot of
testing beforehand to weed out the odd patient
that won’t tolerate it well. So we look for patients who
have bad kidney function, and we won’t give them a
transplant, because we don’t want to push them
into kidney failure. But it’s usually a twice
daily drug regimen. Most patients tolerate
it quite well. Some people get a
tremor in the hands. Some people got
some leg swelling. Some people get mouth ulcers. There’s various
different side effects– the whole panoply
of side effects can happen– bit generally most
patients tolerate them well. One thing we don’t hear though
in the islet transplants is to avoid the steroids. So steroids used to have
a lot of side effects after transplant. They would give you
puffiness in the face, actually cause diabetes
in some patients, cause overweight, cause various
issues, mood disturbance. So we’re not giving
any steroids at all in the islet cell transplants. So the side effects are probably
minimized because of that. They’re not zero. And the side effects that you
don’t see but you worry about are the risk of cancers
and the risk of infections. So we tell every
patient coming in that they have an increased
risk of certain cancers, skin cancers, blood cancers,
and certain infections that could potentially kill them. And the way I look
upon it and discuss it with the patient is if they have
bad control of their diabetes anyway, then the risks
attendant to the drugs are actually a
drop in the ocean, very small compared
to the big risks they face every day
from their diabetes. If they have perfect
control of their diabetes, then it’s a different matter. Is they are well-controlled
with insulin, then on the other hand,
I would say, “Well, you don’t want to face
the risk of infection. You don’t want to face the
increased risk of cancer if your diabetes is being
managed perfectly the way it is already.” And that’s really
the rationale for us picking the worst of the worst
patients in terms of the blood sugar control. Insulin is of course very cheap. The immunosuppressive
drugs can be expensive. The costs are changing
over the course of time now because all of the
patents on these earlier drugs have ended. So there are generics coming in,
and the costs are coming down. They’re still not zero. And it depends on the patient’s
drug plan and their ability to get reimbursed for it. So in Canada, most the time
it has not been a problem. Occasional patients have not had
full coverage for their drugs. But generally it can be managed. FEAUDIENCE: Could you comment
on the transition from islets to stem cells? How do you make
them differentiate into the right thing? And does it happen inside
or outside of the body? DR. JAMES SHAPIRO: Stem cells
are, of course, exciting in many ways, because it
means that instead of relying on going through that complex
process of making the cells, you have a limitless
supply that could treat the whole population
in the world with Type 1 and Type 2 diabetes. That would be really,
really exciting. But as you move
forward, you’ve got a whole new gamut
of testing to do. You have to be sure
they’re going to be safe. You’ve got to be sure
that when you put them in, they’re not going to cause
uncontrolled drop in blood sugar. We don’t think that’s
going to happen. But it could. We’ve got to be sure
that they’re not going to turn into
cancers, or precancers, or some other worrisome
transformation once we transplant the cells. We know that islet cells,
when we transplant them, stay very stable. But these other
cells– these stem cells– they can turn
into any cell potentially. So there’s a lot of
caution as we move forward, as well as a lot of excitement. So it has to be done very
carefully, step by step. Can we make the cells
differentiate and make them into perfect islets
and stable islets before we transform them? That’s what we’d like to do. But the stem cell scientists
that make these cells have not yet been able
to completely overcome that hurdle. So they’re giving us the cells
that they make– manufacture– are still these pre-islet cells. And they turn into islets
once they’re transplanted. So they’re working
very hard trying to understand the
messaging systems in the body as an
embryo grows, what controls the differentiation,
what controls the stabilization from
one step to the next. And I think until they’ve done
that fully, we’ll probably still be transplanting these
precursor cells for a while, until we have the–
yeah, ideally we’d like to have perfect human
islets, look like human islets, they taste like human islets,
they work like human islets, and they stay that way forever. But I don’t think
we’re there yet. And perhaps we’re
never get there. But hopefully we will. FEAUDIENCE: I
understand that you know, when you were
first doing trials, you were using the worst case
scenario patients– terribly brittle diabetics– in
whom you were hoping to provide some relief
without causing long term complications from all of the
immunosuppressants and robbing Peter to pay Paul. So I’m wondering now
in the current trials, if we’re starting to
broaden those inclusion criteria a little bit? Or where are we now with that? DR. JAMES SHAPIRO: We haven’t
really broadened the criteria. So very fair question. We haven’t done that. We’re still concentrated
on the brittle patients. Occasionally, we’ll see a
patient come to us and say, “I’m just tired of
having diabetes. I’m tired of testing. I’ve worked pretty hard at it. I’m tired of it. But my control right
now is pretty good.” That’s a hard one for
us, because we say, “OK. We understand where you’re at. But we don’t want to
do any harm to you.” It’s so much easier to take
somebody who you’ve worked on, you’ve tried. If despite your best
efforts as a diabetes and an endocrinologist
to control them. If you fail, then there’s
nothing else left. And then it’s easy for us. So have we reached
the point where we could transition and
open it up to more patients? I think we probably have. I mean, I think at
the beginning we didn’t know what
the real risks were. We didn’t know what the
risk of plotting off the vein and the liver,
the portal vein thrombosis would be. We didn’t know the
risk of bleeding. The procedure risk. We knew there’s be a risk of
cancers and life-threatening infections, but we didn’t really
have a quantification of it. I think now, and
I’ve shown you data, I think we do have
quantification of it. So we could have a very fair
discussion with the patient. Say look, these
are the real risks. These are the potential
benefits to you. If you like it. Sure. And I think to
get to that point, we probably need to do a
randomized controlled trial. Best instant therapy against
the islet transplant. And you come in with a
ticket at the beginning, you either win an
islet transplant, or you win the pump. And the problem with that–
we want to do that trial. We’d all love to do that trial. The problem is, who’s
going to fund it? Who’s going to pay for it? And we don’t have anybody
that’s come forward to say, we really want to do that trial. We’ll fund it for you. Maybe Google would. FEAUDIENCE: What would the
cost of a trial like that be? And not that any of our
budgets can cover that, but and also if we were wanting to
donate to diabetes research, are there any
organizations that you think are particularly–
maybe excluding yours– to be unbiased, although
you can mention it, that you think would
be particularly useful? DR. JAMES SHAPIRO: OK. Maybe I’ll answer
the second one first. So there are several
organizations– international organizations
that raise money for diabetes. Juvenile Diabetes Research
Foundation, The American Diabetes Foundation, Canadian
Diabetes Foundations, and many others. So I don’t think I can
concentrate on one. It wouldn’t be fair
for me to do that. What I will tell you is that
in order to get to this point, we’ve all done a
lot of research. And in order to get
to the next point, we’ve got an enormous
amount of research to go. And I’m not sure that any of
these organizations, including the NIH, including the Kidney
Institute of Health research, including several other global
funding research organizations. We’re challenged. We don’t have sufficient
funds to accelerate this. And so we need funds. So if we wanted to
do a trial, and let’s say we powered it
reasonably with five or 10 years of followup, and we
looked at complications. And we wanted ideally, probably
50, 60 patients in each arm. And the control
group patients would be receiving standard
diabetes care anyway, but they would
need extra testing. And in the islet transplant
group you can– in Canada, it cost us $75,000
per transplant. Two transplants, $150,000
in the first year. Probably some additional
research costs for patients. So $200,000. I don’t Know. If you want me to
guess, it’s the order of the maybe $10 million. $10
million to $20 million perhaps. I’d have to work it out more. But it’s not billions. It’s doable. FRANK: OK. And with that, thank
you all for coming. And thank you very
much, Dr. Shapiro for taking the time
to speak to us today. [APPLAUSE]

4 Comments

  • kevin christy says:

    the body has basically destroyed the cells, is absolute nonsense. the comment is so stupid i can't believe it was said. "the BODY destroyed the cells" I'm willing to face the challenge. and then there is a book about evolution ? my comments about evolution are archived at twitter. the beginning of evolution is the moment that organic becomes an extension of inorganic by the catalyst water. i want to hear this person explain water in cells,that are dysfunctional but still exist.
    slayerwulfe cave

  • สมชาย อิ่มโพธิ์ says:

    สวัดดีครับ ทุกท่าน และ ไม่มี เลป สำหรับ ทดลอง จา การจลอง และ ต่อ ทดสอบ แต่ ใช้การวิเคราะห์ จาก ธรรมชาติ ที่ผ่านมา และ เชื่อว่า ขณะ ปัจจุบัน ทุกท่าน ก้าวไกล กับ งานสเต็มเซลล์ และ เรา นำเสนอ เพื่อ เปรียบเทียบกัน ของ งานนัวตกรรม สเต็มเซลล์ ครับ เพื่อ การจัดให้ เหมาะสม สอดคล้อง ับ รูปแบบ การตอบสนอง ความต้องการพิ้นทวีป และ อื่นๆ คือ วิธี ลดเงื่อนไข และ สร้างสนับสนุน การนำใช้ ครับทุกท่าน เพื่อ การขยาย งานวิจัย ของ สเต็มเซลล์ ครับทุท่าน

  • Charles Chu says:

    funny thing is this guys reviews have basically written my dissertation. "is islet transplantation a viable treatment for T1DM"

  • Peter Wood says:

    Having had an islet cell transplant and being free of T1 diabetes I can agree with everything said. Type1 diabetes is when your islet cells die quickly after being attacked by the immune system. In my case it happened overnight, so is very different to type2. The trade off, immunosuppression is no fun but better than death from nocturnal hypoglycemia.

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