frank: good afternoon. thank you for joining us. i'm really excited tointroduce dr. james shapiro. dr. shapiro's been workingon diabetes research for a long time, andin particular he's credited withdeveloping the edmonton protocol for human isletcell transplantation, which was published in the newengland journal of medicine in the year 2000.
he's currentlycontinuing this research at the university ofalberta in edmonton, canada. and he also holds thecanadian research chair in transplantation andregenerative medicine. dr. shapiro's receivedquite a lot of awards, including a hunterianmedal from the royal college of surgeons of england. and he's alsorecently been inducted as a fellow of theroyal society of canada.
and with that, please helpme welcome dr. shapiro. dr. james shapiro: frank,thank you very much indeed. it's very kind of youto invite me to google. i'm very impressedwith my tour so far. and i'm very excitedabout the discussion that we're going to havelater on this afternoon. so it's a great privilegeto be here and be with you and share our hopes and trialsand tribulations and progress in some of the treatments forthe condition of diabetes.
so we're tryingto get to a point where we havediabetes cured once and for all for the future. but it's not easy to dothat in one fell swoop. so we've got severalstrategies, and it's really a team and global effortin diabetes research, to try and take a pointwhere we have insulin today and hopefully no injections,no monitoring for the future. and i'll try and takeyou along that journey
of cutting edge islet and stemcell transplant treatments in the clinic for diabetesas we move forward today. so diabetes. most of you will knowwhat diabetes is, but just the startof the basics. diabetes is a conditionwhere patients lose the ability toadjust their blood sugar. and there are two maintypes of diabetes-- there are several subtypes--but two main types.
type one, where thepancreas basically has lost its abilityto make insulin. the cells in the pancreasthat make insulin are called islets of langerhans. and inside those collectionsof cells there are beta cells, and those are the beta cellsare the ones that make insulin. so in someone who hastype i diabetes then the body has basically destroyedthose cells-- destroyed the beta cells inside thepancreas inside the islets
that make insulin. so the patients have anabsolute deficiency of insulin. and the other typeof diabetes-- which is of course much more commonand increasing in number as well-- is type 2diabetes, where patients become resistant to insulin. and therefore whenthey receive insulin, or the pancreasis making insulin, the body's needs forinsulin are basically
what the pancreas canrelease is insufficient. so diabetes is a verycommon condition. there are about381 million people with diabetes inthe world today, based on the world estimatesfrom the diabetes federation 2013. type i diabetes represents about10% of the world population. by 2030, this population withtype i and type 2 diabetes will double.
so it's going to be a huge, hugehealth burden for the future. the national cost of diabetesin this country and the us alone is greater than $245billion estimated last year. and that increased from$174 billion in 2007. and clearly, withthe massive increase in numbers of patientswith diabetes, this is going to becomeuncontrollable and super saturate the abilityof health care systems to deliver appropriate care.
so insulin has been around fora long time, as some of you may know. banting/best-- and thisis frederick banting in the physiology laboratoriesin london, canada in 1920, 1921, 1922 when theteam was working on the discovery of insulinbanting, best, collip, and macleod. and insulin injectiontherapy clearly has been life-saving for many,many patients with type 1
and some patientswith type 2 diabetes. so injections ofinsulin from the outside can substitute for the pancreas'ability to make insulin. and we measure insulinin the number of units. so most patients will take 20,30, 40 units on insulin a day. and they measure the numberof units of insulin-- it was a crude amount-- it wasthe amount of insulin needed, one unit of instant to causehypoglycemia in a rabbit. that's how theyoriginally discovered it
when banting and bestwere working on this. diabetes is a dangerouscondition to have overall. kidney failure is aproblem-- 25 times more risk than thegeneral population. heart attacks-- two tofive times more risk than the general population. strokes-- two tothree times more risk. and life expectancy forpatients with diabetes is at least 10 years shorterthan the rest of the world
without diabetes. diabetes is the leadingcause of vision loss in working age adults. it's the commonest cause ofend stage kidney failure, and of non-traumaticlower limb amputations, because the bloodvessels basically become destroyed when thebody's glucose becomes awry. there's been lotsof improvements in the treatment of diabetesover the course of time.
as i mentioned, beforethe discovery of insulin in 1921, 1922, diabeteswas a fatal condition. when insulin was firsttried in patients, it led to complications--infection, sepsis. then there's beenvarious improvements in different types of insulin--short acting, long acting insulin-- in differentways of delivering insulin over the course of time,including insulin pumps, including continuous bloodglucose monitoring systems.
and the whole idea here is totry to tighten up the sugar control so that patientsare at less risk of getting the end stage complicationsof diabetes-- the micro and the macrocomplications of diabetes. and the reverse sideof that equation is we try to tightenup the control as the patients get muchmore of this condition, which is a iatrogenic condition--in other words, caused by doctors-- which iscalled hypoglycemia.
so when the blood sugar fallsbelow a certain threshold, then patientsbecome susceptible, because the brain absolutelyrequires glucose to function. as soon as the blood glucosedrops below a certain level, then the brain canno longer function. so islet cell transplantationhas been around since the 1970s experimentally. and first trials in patientshappened in the 1980s. and it really tookoff in 2000, and there
have been several done. i'm now going toexplain and tell you the story abouttransportation shortly. but really our indicationsfor islet transplantation have been to try to reducethis risk of hypoglycemia, reducing the riskof lows in patients that are needing insulin. so why do we try to runthe blood sugar low? this is really based onsome very large trials
in patients with diabetes. we know from thesecurves for example, as we try to tighten upthe blood sugar control, we can definitely reducethe risk of complications such as this one on the right,called retinopathy, which is where the blood vessels inthe back of the eye accelerate, and grow, and causethe blindness. but, as we tightenup the control, then patients are more andmore at risk of getting lows.
and we measure this bythe glycated hemoglobin, which is a marker in thebloodstream that really tells you how good orbad the blood sugar control is over several months. so here's a patient that'swearing a state-of-the-art continuous glucose monitor. and you can see acrossday one and day two, this patient has quitewide fluctuations in blood sugar control.
and at 8:00 in themorning on the second day, you can see theblood glucose drops, the patient is on theirown, not monitored. and unfortunately,that patient's found dead in bedat 9:00 an hour later, from a fatalhypoglycemic event. and fortunately, thisis relatively rare, but it does happen. and it happens in youngadults with type 1 diabetes
that have poor control. now this is what we can achievetoday with an islet cell transplant in thelower panel here. you can see verywide fluctuations in blood sugar overthe course of time, up until that red arrowwhen the patient receives an islet transplant. this is a transplant thatactually is done in miami. dr. camillo ricordi sharedthis slide and data with me.
but it's very typical ofwhat we can achieve routinely with an islet cell transplant. and here you can see, afterthe islet transplant, when the patient discontinuesinsulin, 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 smallprocedure to receive cells-- and has to haveimmunosuppressive drugs
in order for the body notto reject these cells. they're transplantedcells from organ donors, and they aretherefore potentially foreign to the body. and also the processthat caused diabetes in the first place, whichis an autoimmune process, meaning the body attacks itself. this will happenagain after an islet transparent to the new cells,unless the anti-rejection drugs
are given. so there's been real progressin islet cell transplantation. i'll explain that to you. but i think we're somewherealong this hype cycle right now, perhapssomewhere along the slope of enlightenment. we haven't got tonirvana yet, but we're trying to get there alongthe plateau of productivity. and still i thinkif you can read
and you can google lotsof negative reviews on islet transplantation,because i think the knowledgein this area probably hasn't reached allof the community. but i'm sharing with youtoday some of the progress. but there's been progressthroughout diabetes. and here for example,is a trial that was just completed inseptember last year, looking at a special instant pump thatswitches off when the blood
sugar reaches a certain lowthreshold, low glucose suspend. and when this isapplied to patients, then the risk of patientsgetting hypoglycemia is certainly a lot lessthan it would be otherwise. so there's beenlots of progress. and i'm also veryexcited this afternoon to meet with your googlecontact lens team. because i think the areas ofmonitoring for blood sugar control, and ourability to monitor
the function of our celltransplant therapies over time with thiskind of technology will be enormously informativeand allow us to tighten up our control, minimizethe stress on the cells, and allow us all to learn alot about controlling diabetes. so who do we offer anislet transplant to today? we have two realmajor categories-- those with patients who havean islet transplant alone. in other words, they haven'thad a previous transplant.
they have to havetype 1 diabetes for more than five years. they have to fail on all thestandard therapies, including insulin pumps if available. and we have variousscoring systems, which i won't dwell on,but they're basically to demonstrate that thepatient has severe lows, despite their ability to controlthe glucose as best they can. and about 5% to 10% ofthe population with type 1
diabetes-- at leastin canada-- would fulfill these verystrict criteria to justify addingimmunosuppression and receiving a cell infusion. the other side ofthe equation are patients who have alreadyhad a successful transplant, like a heart, a lung, or inthis case, a kidney transplant. so they're already onthe anti-rejection drugs, so they don't have toface any additional risk
except from the minor riskof the procedure required to put the cells in. and islet after kidneytransplant, or second category, is becoming a verysuccessful category too. so we began with the edmontonprotocol in the year 2000. it didn't justbegin from nowhere. it began from 30years of research in small and largeanimal models. and a terrific collaborationwith several international
centers across the world. and i think that's one of theprivileges involved in science and in diabetesresearch, is that we have a very, very close knitcommunity of scientists working together, willing to shareinformation and ideas to allow us all toget to the next step. and it probably ismodeled very nicely in the google organization. so we published this in 2000.
this is the new englandjournal of medicine, where our first sevenpatients receiving islets under the edmonton protocol--that we called subsequently the edmonton protocol--where all the patients that had the transplants were able tocome off insulin and remain off insulin for a period of a years. and in fact, now 15 yearslater, two of the original 12 are still completelyinsulin-free with full function.
and we've justrefined this treatment over the course of time totry and further improve it. so this was what we callthe edmonton protocol. we gave two setsof islet infusions. initially around 5,000islets per kilogram based on the recipient's weight. and then we haveanother infusion to provide enoughcell mass to make it sufficient insulinfor the patient.
then we gave these twoanti-rejection drugs-- sirolimus and tacrolimus-- andan antibody at the beginning. and we subsequentlychanged these drugs now to more standard drugs,because we encountered quite a lot of side effectsfrom the sirolimus drug. but it was certainlyvery successful in allowing us tobegin our first trials. we then replicated thesetrials in miami, minnesota, and in our own site inedmonton in 118 patients,
and were able to replicatethis quite successfully in 82% percent of patientscoming off insulin. and then we moved forward withthe immune tolerance network and carried out a largeinternational trial in the us and europe, testingthe edmonton protocol. and we published that tooin the new england journal. so where are we today? so we've treated inedmonton over 200 patients-- 218 patients-- who'vereceived 460 transplants.
so you can see thatmost patients require-- in our center at least--two islet infusions to provide sufficientmass for them to come off insulinfor a period of time. we've received incanada patients from all across the country. last year we did a recordnumber of islet transplants in edmonton. we did 66 islettransplants 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 islettransplants done at least 30 differentinternational sites. and so i'm goingto explain to you know how we get the islets out. that was a picture,by the way, of islets under a microscope stainedwith a dithizone dye that
stains the zinc. because zinc andinsulin are very closely linked studying thezinc inside the islet, so you can see then quiteclearly under the microscope. those are very pureislets ready for infusion. but we don't just getthe islets from anywhere. they come from a human pancreas. so i'm just going to walkyou through this process, because it is quite a complexprocess that our team has
to do in edmonton. so here they takea pancreas, they canulate the pancreas duct. and as we're going throughthe video here on the right, i'll show you thegraph on the left there is all those little dots, sortof like the stars in the night, every one of those representsover 1,500 islet isolations done by our team overthe last 15 years. there's a humanpancreas on the right,
you can see it being distendedwith collagenase enzymes before we chop it up and put itin camillo ricordi's chamber. so there's doug shakingthe chamber there. this team's a verywell-knit team. they work day and nightto prepare the cells. once the cells aredigested, then we purify them on a continuousficoll gradient on a cool code machine. and there's doug and tatsuyaand the team at edmonton
that prepare these cells for us. they've done aterrific job for us. you can't see thatgraph on the right, it's a little too small foryou, but basically the number of islets they getout of the pancreas today is doublethe number that we were able to get in2000, when we first began the edmonton protocol. and their success rate inbeing able to take a pancreas
and provide enoughcells to transplant has also increased toaround 60% to 70% percent. the actual transplantpart is very, very simple. it doesn't requirea transplant surgeon to do this, fortunately. so the transplant is donein the x-ray department under local anesthetic. here's a patient whois awake, chatting away during the procedure.
we use fluoroscopy x-ray so wecan see where the needle goes. we thread a catheter intothe main portal vein there, and then we simply dripthe cells in under gravity. and we measure theportal pressure while we do this, we giveheparin to prevent blood clotting at the end, beforewe pull that catheter out. because we learned this perhapsin our first early cases, when we pulled thecatheter out of the liver, we initially got bleeding.
so we found that when we putthis paste in along the track as we pull it out, wemix it up with contrast so that we can see it beinginjected on the x-ray screen. you'll see that in a secondhere 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 eliminatedthe risk of complications such as bleeding afterthe islet transplant so this is a verysafe procedure.
and if we look at thenumber of patients we've treated over the courseof time now, 97% of patients survive. and these arepatients, of course, who have had longstandingdiabetes, who are at risk of manydifferent things. and of the few deaths thatwe've encountered over 15 years have been mainlycardiovascular deaths in patients withlongstanding diabetes.
so heart attacks, basically. so we've had four patientsdie of heart attacks. one patient had a possiblecreutzfeld-jakob disease. and one patient hadfatal hypoglycemia after an early transplantwhere the cells failed. so none of these deaths havebeen related to the transplant or to the anti-rejectiondrug treatment today. so this has been avery safe transplant, certainly the safest transplantthat i've been involved in.
there have been adverse events. we can go throughthese, but i won't go to them in too much detail. a couple of patientsover 15 years-- 1.4%-- needed to go on to geta kidney transplant, because the drug we give toprevent rejection to crolimus does have kidney side effects. now what about performance? are we doing better over time?
so if we look at thefunction of cells over time, in the red line here. so every moleculeof insulin that's made by the cells,another molecule is made called c-peptide. and we can measure thec-peptide in the bloodstream with a simple blood test. so you can see that overthe course of 15 years, 73% of patients continueto make c-peptide
to a sufficient degree thatcontrols the hemoglobin a1c, therefore reducestheir risk of getting the complications ofdiabetes, and prevents the patients from gettinghypoglycemic events. so this is a real advance,particularly for patients that have really recalcitrantrisk of hypoglycemia. so these patients arevery well protected. but what we did see in theearly edmonton protocol series is that a largenumber of patients
did need to go back on tosmall amounts of insulin-- around 15% of patients--by the 15-year mark. and so we've spenta lot of effort now in the lastseveral years seeing if we can improve these resultsover the course of time. and if you can think ofthe number of the cells that we transplant in toliver here as a bucket, and the cells are beinglost through little holes in the bucket, we'vebeen working in science
to see if we can plugthe holes in the bucket to try to allow more cellsto survive over time. so we've been lookingat various pathways to reduce earlydamage to the cells, trying to prevent them frombeing rejected and preventing leg graft loss, andthen really trying to improve the numberof cells that we put in at the beginning, so thatwe can have many, many more patients with fullerfunction and more
durable function over time. now because type 1 diabetesis an autoimmune condition, as we mentionedat the beginning, there is a risk of theautoimmunity coming back again. and here's a patient'sbiopsy-- and i won't go throughtoo much details-- but you can see onthe right hand side, there are isletssurviving quite well, but no beta cells inthat biopsy, which
is from dr. razinia's group inuniversity of massachusetts. so we need processes thatcan control rejection, reduce inflammation, and allow thepatients to become tolerant. in other words, forthe future, we'd like to have a celltreatment that we just put into the patients thatthe patients won't reject on their own, and won't needlifelong anti-rejection drugs. and we're all tryingto get to that point where we can achieve that.
and controlling this triangleis a bit of a challenge, but we're working onit very intensively as a global community ofdiabetes research scientists. and we're trying variousdifferent maneuvers-- i mentioned a few of them thati won't go through the details-- but i've mentioned a few ofthem that we're trying presently now i showed you thatfalloff an insulin independence ratesat five years. and now there are 6 centersacross the world that
have insulin-freerates with islet cell transplant of fiveyears, more than 50%. and this is animportant milestone, because it's exactly thesame rate that we would see with a whole pancreastransplant alone, so a big operationin comparison. putting a wholepancreas transplant in, connecting the blood vesselsup, and the risks from that. we can achieve today-- atleast in these 6 centers-- very
similar results to the wholepancreas transfer alone, with a simpleinjection in the site. so in trying to controlthe immune response. we've tried thistreatment in edmonton now in over 100patients-- i need to update thosenumbers-- on over 100 patients in variousdifferent protocols over the course of time. and what we found in ourearlier analysis is basically
if we look at thec-peptide rates, they're very similar,perhaps a little bit better with the thealemtuzumab than they were with the edmontonprotocol, 84% at seven years with c-peptide function. and if we look at theindependence rates-- these are patients who arefully free of insulin-- again, ongoing data still in analysisphase, but 58% of our patients, when we last analyzedthis at seven years,
were still free of insulin. significantly improved fromour original edmonton protocol data, where currently at 15years, just 11% of patients remain insulin-free. i mentioned the hemoglobina1c-- the glycated hemoglobin-- this marker in thebloodstream that tells you how good the bloodsugar control is. and you can see at thebeginning where it says pre there, on the left handside of your screen,
that the levels arearound 8% or 9%. and the red lineis the threshold of what a normalperson would have, who doesn't have diabetes. now as we bring the line closerand closer to the red line, then the risk of gettingsecondary complications is obviously reduced markedly. but normally, if we didthat with injected insulin from the outside, the closer wegot to the red line, the more
and more dangerous hypoglycemiasthe patient would have. well after the isletcell transplant, we can achieve thebelow the red line or under the redline very reliably without the riskof hypoglycemia. and these graphs show you thedifferent measures that we use. beforehand, you seethe 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, youcan see it's almost undetectable overthe course of time. so patients arecompletely protected, as long as the cellscontinue to function, from hypoglycemia andswings in blood sugar. so this is a veryeffective treatment for controlling blood sugar. [video playback]
-i feel my controlnow 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 severalcenters looking at this. garth warnock vancouver haslooked at this quite closely. what he finds in a controlgroup with islet transplant versus conventional, or bestmedical care insulin therapy,
is the islet transplant grouphas much lower hemoglobin a1c in the green. they have less riskof eye disease. and their kidneys areactually protected, despite the fact that theyare receiving tacrolimus. so this is veryencouraging data to suggest that an islet orother cell transplant, or stem cell transplant inthe future for diabetes, will have thesesimilar effects, being
able to protect againstthe secondary complications of diabetes. we're working with theus fda quite closely in two major trials were partof the clinical islet transplant consortium. one is called cit-06 andone is called cit-07. and basically tomake it very simple, one is islet afterkidney transplants, in the 07 one are islets alone.
these trials are nowcompleted or undergoing a very detailed analysis withthe fda, and very likely, these two trials willlead to the fd awarding a biological license forislet transplantation, allowing medicare, medicaid,and third party payers to potentially reimburse islettransplant in the us, which has been a major limiting factorin terms of the numbers of cell transplants done in the us. we've been very fortunatein canada however
to have the canadian governmentpay-- the alberta government, i should say-- pay forthe canadian transplants to this point. and a similar thinghas happened in the uk with the national instituteof clinical excellence paying for islet transplantthrough the uk government. same thing in australia, samething in europe, and geneva, and in several other countries. so hopefully this willhappen very soon in the us.
several groups havereported the ability to achieve what i showed youwith two islet transplants with a single donorislet infusion. and this would beimportant because it would allow twice thenumber of patients to receive transplants froma limited donor source, from organ donors. and so several centershave been able to do that with different strategies.
but still this is a challenge,i would say, for us. only about 10% of ourpatients in edmonton are able to achieve insulinindependence routinely. if we don't select the donor,we don't select the recipient entirely. what we do find if we lookat melena bellin's analysis? looking at all thepatients treated that are participating in thesecenters, that at five years, if we give an anti-inflammatorytreatment at the beginning
called tanacet-- which preventsan inflammatory agent called tnf-- if we switch thatoff at the beginning, we can have many, manymore patients of insulin at five years. seems to be very importantto suppress inflammation at the beginning. so we've done studies in mice. we always take things backto mice and test things. and we tested another compoundcalled anakinra, which
is another antibody--which is also an anti-inflammatory one usedin inflammatory bowel disease and another conditioncalled psoriasis-- and we found that this isa very effective treatment to allow human isletsto engraft in mice. and we've been able to take thattreatment across to the clinic and treat manypatients that way. we've also been trying toswitch off the cell death pathways in this pathwaycalled apoptosis.
so cells die bydifferent processes, but we've tried several agentsto switch off cell death. these are called pancaspase inhibitors, because they switch offall the major cell death pathways that leadto this apoptosis. and when we've tested these inour mouse models and our pig models, we find thatthese caspase inhibitors can reduce the tinynumber of islets needed to reverse diabetesby about 80%.
so they make a big,big difference. and we've testedthis several times in various differentcombinations and various different ways. and we've moved on and carriedout the early clinical trial with these that looks--well at this point, it's difficult to say whetherit's had a big impact. but we're still working on it. so we recognize today thatislet transplantation,
the way it is today,because patients need immunosuppression, becausethere is a shortage of organ donors, could onlyreally address a very narrow band inthe spectrum of patients with diabetes. and we'd like to getto this point here where we can treat allthe patients that are just diagnosed with diabetes, thathave difficult to control diabetes, that havechronic type i diabetes,
and also those thathave type 2 diabetes-- the entire spectrum of diabetes. and we recognizethat if we keep going the way we are goingon that one track, we won't be able to addressthat entire spectrum. so what next? so we're looking atalternative retrievable sites to put in islets today, or stemcells potentially tomorrow. and here's a trialthat we're actively
involved in now with acompany called sernova. and this is a devicethat goes under the skin. it's the the size andshape of a tea bag. and it basically threadsin under the skin. we leave it there forabout a month or two. and while it'sunder the skin here, the body makes new bloodvessels that grow in. and this is a sort of inresponse to a foreign body. then we take those rodsout when we come back.
and we can do this undera local anesthetic, we can do this undera general anesthetic. and then we can infuseourselves along that track, and basically put the cellsin under the skin instead of in in liver. now that may be an advantage,but as we think to the future, as we think aboutuse of stem cells, it might be safer to putthem in a retrievable place where we can take themout if we need to.
so if we put them under theskin instead of the liver, it's a much simpler maneuverto take the cells out. so we've done this sofar in a few patients, and it's lookedsomewhat promising in terms of being ableto show cell survival. but this is still ongoing,and we're looking at the data closely. we've also been looking at whatwe call the deviceless method. so we put a tube under the skin.
we leave the tube under theskin-- a simple catheter that we use routinelyin the x-ray department. we leave that catheterunder the skin for a month. we take the calculator out,and then we put our cells, or stem cells, orislets, or whatever kind of cell populationwe want to put in, in this track, which has now gotlots of nice new blood vessels. and here you cansee islets surviving in that round areathat used to have
the little catheteron the top left there. and the cells work very well. and you can see with thecatheter placed under the skin, and then we put thecells in the blue line, blood glucose comesdown quite nicely, it takes a few weeks to do so. and you can see onthe right, we get lots of nice new bloodvessels growing in to supply these cells.
so i mentioned islet transplantstoday, and stem cells tomorrow. so i think we aregetting very close now to being able to moveforward with stem cell treatments instead of isletcell transplant treatments for the next round oftrials for the future. there are severalgroups across the world working on stem cells. and i'll show firstjust one that we're collaborating with,maria nostro and gordon
keller at theuniversity of toronto have made a stemcell line that makes human insulin-- the human betacells, basically-- from stem cells. and we've been able to reversediabetes quite effectively in mice and our devicelessmodel with that cell system. we've also been testing outto see if the cells turn out to have what'scalled a teratoma, or risk of awry cells, thenthey can be transplanted still
in this deviceless spaceand not breach the space, so we can stillpotentially remove them. we've also been workingfor the last 10 years with a company calledviacyte down in san diego. and we've been veryexcited by that progress in developing a human embryonicstem cell line that they have shown can reliablymake human insulin, and can be potentiallytransplanted, and can cure diabetes inmice when transplanted.
and this group hasbeen very innovative and shown thesecells to be safe, to have no risk of theteratoma that i mentioned. and they are now carryingout a clinical trial that we're lookingforward to participate in, where we're going to putthese cells inside what's called an immunoisolatingdevice, so that the immunesystem can't directly get cell-to-cell contactwith the transplanted cells.
and the idea of thatis that we wouldn't have to give theanti-rejection drug treatments if it's effective. so we're looking forwardto starting these trials with viacyte withinthe next few months. now in parallel, there'slots of other treatments that couldpotentially switch off the autoimmune pathwaysin type 1 diabetes. and jeff bluestone,from san francisco here,
has summarized allthe different pathways that can be switched off in type1 diabetes, all the studies, all the antibodies, allthe drug treatments that can be given to tryand control diabetes. and it's obviouslya very complex one. we've amassed a team inalberta to try and address one or two of thesetogether with industry and a large collaborationof scientists in edmonton and calgary.
we're going to dotwo different trials. one is trying to getpatients' own stem cells to regeneratetheir own pancreas as soon as the patient isdiagnosed with diabetes. in other words, resettingthe immune system and getting thepatient's own cells to turn back andrepair the beta cells. and then the secondstrategy we're using is the viacyte cell transplantsto try to treat patients
just like we would at theedmonton protocol type treatments that ishowed you about. so the immune resetis moving forward. we've got our plans in place. we're just puttingthem through ethics and through healthcanada right now. we're going to give antibodytreatments at the beginning to reset the immune system. we're going to take thepatient's own bone marrow cells
and re-transplant thoseup into the pancreas to allow those cells torepair the injured pancreas. then we're going to give atreatment for the first year, called a glp-1 analog,that will help to further regenerate andaccelerate the growth and repair of injured islets. so we have a lotof things to do, and we're very, veryexcited about it. we're also workingwith another technology
called normothermic perfusion. and this is goingto i think really revolutionize all areasof transplantation. so most the time you can seethose boxes on the right, that's how we carryorgans around, in ice. so hearts, lungs,livers, kidneys, and the pancreasfor our islets-- we carry them in these boxes. so we're just aboutto start a trial
with a group at theuniversity of oxford, and a company calledorganox, where they have one device thatwe could put a liver on, which is in thisbottom left panel. there's other companies thathave a device for hearts, for lungs. and here's one thatwe're testing out for pancreas transplantation. so in other words, insteadof putting the organ in ice
and having itinjured, we can keep it perfectly alive--like the heart's beating there-- outside the body. and so as soon aswe transplant it, it can be in perfectcondition when we transplant these organs. it'll make a big, big differenceto the safety of transplants, and also to make sure thatthe transplants really work before we put them in.
and the idea here is that wecan deliver oxygen, deliver nutrients, provide aphysiological temperature, and provide an idealenvironment for the organ while it's outside of the body. so we're very excited about thistechnology as well as we move forward. and this is the liver machinethat we're about to test. and the company whocame to san diego to the world transplantcongress mentioned to me
that they'd loveto have google's logo on the outside of the box. so, if you're interestedin working with them, just let them know. so let me sum up. so i showed you that we'vemade a lot of progress in the treatments of diabetesover the course of time. that insulin dependencerates have improved a lot. that several centers now haveover half of their patients
still free ofinsulin at five years after an islet transplant. that we're looking now toother alternative sites for infusing isletsunder the skin. i didn't mentionother sites that we're about to test withthe pittsburgh group, including the liningof the stomach. we're about to start trials withviacyte on their embryonic stem cell treatments.
and we're also lookingat regeneration trials to regenerate and repairthe pancreas and the islets that at the moment a child oradult is diagnosed with type 1 diabetes. so there's a lot ofthings happening. i think we'll makea lot of progress. so finally today, i'm very muchlooking forward to discussing with the contact lens teamour opportunities of working together in celltransplant monitoring,
and also with thegoogle glass team, looking at the roleof the google glasses and state-of-the-art monitoringand complex surgeries. a guy was tellingme about the use of these in lungtransplantation. i think we could apply thisvery easily also in liver transplantation, maybe jointhe pancreas islet isolation. i think also this couldallow us to communicate far better as scientists fromone institution to another.
so instead of me being inedmonton, another group being in san francisco,another group being in australia, anothergroup being in china, we could make ascientific community that is basically globaland one, and allow us to work much closer together. and that's what i'mvery excited about. so on behalf of ourpre-clinical team scientists that have done all thehard work-- our phds,
our master students,our post-docs, and technicians thathave done really all the hard work andpre-clinical testing-- on behalf of ourlarge clinical team that has basically helped upprepare the islet transplants. so thank you very muchindeed for the opportunity to present to youthis afternoon. i look forward toanswering your questions. [applause]
audience: my name is zerga. i actually work onthe iris and basically the contact lens project here. so i've heard some questionsabout the cells you infuse. so can you tell us some verybasic biology of those cells? so when you inject it into theblood vessels of the kidney, where do they end up? so do they actually staythere and live in the kidney? or do they end upin the pancreas?
dr. james shapiro:so the question is-- so we transplant ourcells inside the liver. so it's a local injectionliterally inside like this, under x-ray. and we get the radiologistto put a catheter into the main vein thatgoes up into the liver. it's called the portal vein. and it's like a tree. it has main trunks, andit has little branches.
and the islet cells, thevary in size, from about 50 microns to 150micrometers in size. some are larger-- 400 or500 micrometers in size. and basically theygo up this tree, and they go far alongthe tree until they get into a blood vesselthat's smaller than they are. there they get trapped. and basically a little bit ofblood clot forms around them, and a local inflammatoryreaction-- then new blood
vessels grow ininside the liver. these cells are not goingback into the pancreas. we could potentially putthem in the pancreas, but it would be very, verytechnically difficult to do so. it would be risky. it could case pancreatitis. it could be a difficultplace to put them. it just so happens that theliver is a very effective place to put these cells.
audience: [inaudible] dr. james shapiro: potentiallythey can grow anywhere. the question will be willthe cells work as effectively in another site as theydo currently in the liver. and we don't know that yet. audience: how do theycommunicate with the body? when do they knowwhen to generate-- dr. james shapiro: how dothey communicate with the body was the question.
so the islets havesensors on them. so they have glucosereceptors and they can sense the bloodsugar, much the same way you do with a skin test whenyou take a drop of blood. they're listening to theblood stream, monitoring it constantly, all the time. and as soon as the blood glucosegoes high, then in concert, they all release just theright amount of insulin that's needed in avery dynamic way.
and as the blood sugar dropsbelow a certain threshold, they all shut off, sothey stop making insulin. so it's a much more preciseway of regulating blood sugar than if you injectinsulin from the outside. so it's able to dothat because they're a collection of cellsthere that adjust insulin. and i didn't mention, the isletshave several cell populations int them. the have the beta cellsthat make insulin.
they also have anothercell population called alpha cellsthat make glucagon. and glucagon makesthe blood sugar go up. so you have what's calledcounter regulatory control. so with counterregulatory control, you can keep your blood sugarin a very precise balance. audience: hey, dr. shapiro. my name's joel. my wife has lived with type 1diabetes for nearly 40 years.
and she had a couple questions. the short one is-- do youtransplant the entirety of the islet, orjust the beta cells? and the more interesting,or more complex question is-- are youmodifying the islet cells prior to transplant to reduce thechance they'll be attacked by the same antibodiesthat originally killed of the islet cells? dr. james shapiro: so theislets that we transplant
are the collectionof all the cells. so there's five-- i mentionedtwo cell types-- there are actually five or sixdifferent cell types. maybe there's even more thatwe haven't discovered yet. but the islet is sort ofan organelle collection of several types. we think that the isletneeds all of those cell types in order to survivein the longer term. if you just took outall the beta cells
and transplanted them, theymight work for a while. but maybe the betacells on their own, without the rest ofthe supported matrix and the ability to communicatewith each other in this sort of local mode, maybe theywouldn't work as well. we don't know that. but we transplantall of the cells. and so the second question was-- audience: do you do anythingto modify the islet cells prior
to transplant? dr. james shapiro:do we do anything. and so, the islets aretaken out of the pancreas in that process. we keep them in culture. now in the old days, in the veryfirst experiments we've done, there was a lot of differentinnovations that we had done. you could treat themwith ultraviolet light. you could treatthem with x-rays.
you could treat themwith high oxygen. and these would alter whatis called the immunogenicity, or the ability of the bodyto recognize them as foreign. we haven't done somuch of that now. but potentially youcan do a lot of things to manipulate thecells in the petri dish that could alter theability of the body to recognize them as foreign. we could wrap them ina seaweed membrane,
an algenate microcapsule. we could add otherproducts locally around the isletsto protect them. so an islet in some wayhas a lot more potential than the othertransplants that we do, where we don't have that abilityto alter them in the dish. but we haven't explored thatperhaps to its full potential. yeah, you're quite correct. audience: i noticedin one of the slides
that the a1c'sthat were reported, or that were monitored in yourpatients, seemed to improve over time after thetransplant, not just initially. and given the propensityof these cells to degrade, i was surprised that itgot better as time went on. dr. james shapiro: i thinkthat's partly a function-- well i should say hemoglobindoesn't drop immediately. the reason for that is ittakes two or three months to have an effect.
so if you have badcontrol, then you suddenly go to perfect control,the next a1c test is reflecting what happenedthree months earlier. so there's a lag inits ability to measure. it's designed thatway, because it is meant to tellyou what's happened over the last few months. so that's why you'reseeing a delay. it's not so much that controlis improving over time,
but i think it's more that. audience: and just sort ofa more general follow up. i've been diabetic for 25 years. and ever since iwas diagnosed i've been following the news mediaand basically, the light at the end of the tunnel hasbeen there the whole time. does seem to gettingbrighter, but what is your take on kindof a realistic timeline for-- i realize it'sall speculation.
dr. james shapiro:so if i send you back to your office thisafternoon in google and say, i want you to tell mein a week how long it's going to take tofinish a project. maybe you've got all thealgorithms straightened out, and you can tell me it'sgoing to take exactly a week. i think for this, becauseit's a biological system, it's working humans, it'snot just all of that. we also have to deal withthe regulatory agencies
as soon as we want todo something different. we've got to justifywhat we're doing. they often tell us to goback and do more experiments. so you'll notice i nevermentioned the five year cure. i never said, well, we'lldo this in five years or we'll do it in 10 years. what i will say to youis that in 2014 we're doing far more inthis year than i ever dreamed we wouldbe 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 goingto take to get to the light at the end of the tunnel. but i know that'swhere we want to be. but it's going totake what it takes, provided we're allworking intensively in the right direction.
audience: my name is steven. i also work on thecontact lens project. and so i have aquestion a little bit related to zach's question. the islet function issaid to be modulated by the autonomic nervoussystem, parasympathetic, and sympathetic nervous system. alpha and beta insulinand glucagon production. and so if you place these cellsunderneath the skin, what's
the effect of breakingthe autonomic link so you have some autonomousfunction in response to glucose. you cut off this nervoussystem link, so-- dr. james shapiro:you're quite correct. so the islets thatare transplanted are completely detonated. they don't have anynerves going into them. potentially the nervescan grow in over time,
along with the new-- bloodvessels happen first. potentially they canbecome integrated. but the nerve endgrowth isn't essential. so perhaps it helps with thea cued release of insulin in the normal individualwho's stressed. but most of the time these cellscan respond very effectively to the local environment. so you don't need innovation. and they clearlycan work just fine,
as i showed you,without innovation. you can divide thevagus nerves in patients that don't get diabetes. often we do that forother conditions. so it clearly playsa role somehow, but it's probablya very minor role, because it's justcompletely redundant. you don't need it. audience: so therewas a research article
that i came across recentlyabout activating islet cell production in thegastrointestinal tract. and i was wondering ifyou could talk about that. i don't recall seeingit on the slides. dr. james shapiro:so there's a group led by dr. tim kiefferin vancouver, who's worked on trying toconvert the cells in the gastrointestinaltract into becoming insulin-making beta cells.
that's really hisarea of expertise. he's made a lot of progressover the course of time. but i don't think i canbeyond that comment directly on his work, because i haven'tbeen directly involved in it. but it's exciting. audience: how does thelife look for the patient after the transplant, in termsof taking the immunosuppression drugs, and what'sthe cost of it, and how often it hasto be administered.
and what are theside effects of it? dr. james shapiro: right. so the standardanti-rejection drugs are usually taken twice a day. and most patients toleratethese extremely well. and we do a lot oftesting beforehand to weed out the odd patientthat won't tolerate it well. so we look for patients whohave bad kidney function, and we won't give them atransplant, because we don't
want to push theminto kidney failure. but it's usually a twicedaily drug regimen. most patients tolerateit quite well. some people get atremor in the hands. some people gotsome leg swelling. some people get mouth ulcers. there's variousdifferent side effects-- the whole panoplyof side effects can happen-- bit generally mostpatients tolerate them well.
one thing we don't hear thoughin the islet transplants is to avoid the steroids. so steroids used to havea lot of side effects after transplant. they would give youpuffiness in the face, actually cause diabetesin some patients, cause overweight, cause variousissues, mood disturbance. so we're not givingany steroids at all in the islet cell transplants.
so the side effects are probablyminimized because of that. they're not zero. and the side effects that youdon't see but you worry about are the risk of cancersand the risk of infections. so we tell everypatient coming in that they have an increasedrisk of certain cancers, skin cancers, blood cancers,and certain infections that could potentially kill them. and the way i lookupon it and discuss it
with the patient is if they havebad control of their diabetes anyway, then the risksattendant to the drugs are actually adrop in the ocean, very small comparedto the big risks they face every dayfrom their diabetes. if they have perfectcontrol of their diabetes, then it's a different matter. is they are well-controlledwith insulin, then on the other hand,i would say, "well, you
don't want to facethe risk of infection. you don't want to face theincreased risk of cancer if your diabetes is beingmanaged perfectly the way it is already." and that's reallythe rationale for us picking the worst of the worstpatients in terms of the blood sugar control. insulin is of course very cheap. the immunosuppressivedrugs can be expensive.
the costs are changingover the course of time now because all of thepatents 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'sdrug plan and their ability to get reimbursed for it. so in canada, most the timeit has not been a problem. occasional patients have not hadfull coverage for their drugs.
but generally it can be managed. feaudience: could you commenton the transition from islets to stem cells? how do you makethem differentiate into the right thing? and does it happen insideor outside of the body? dr. james shapiro: stem cellsare, of course, exciting in many ways, because itmeans that instead of relying on going through that complexprocess of making the cells,
you have a limitlesssupply that could treat the whole populationin the world with type 1 and type 2 diabetes. that would be really,really exciting. but as you moveforward, you've got a whole new gamutof testing to do. you have to be surethey're going to be safe. you've got to be surethat when you put them in, they're not going to causeuncontrolled drop in blood
sugar. we don't think that'sgoing to happen. but it could. we've got to be surethat they're not going to turn intocancers, or precancers, or some other worrisometransformation once we transplant the cells. we know that islet cells,when we transplant them, stay very stable.
but these othercells-- these stem cells-- they can turninto any cell potentially. so there's a lot ofcaution as we move forward, as well as a lot of excitement. so it has to be done verycarefully, step by step. can we make the cellsdifferentiate and make them into perfect isletsand stable islets before we transform them? that's what we'd like to do.
but the stem cell scientiststhat make these cells have not yet been ableto completely overcome that hurdle. so they're giving us the cellsthat they make-- manufacture-- are still these pre-islet cells. and they turn into isletsonce they're transplanted. so they're workingvery hard trying to understand themessaging systems in the body as anembryo grows, what
controls the differentiation,what controls the stabilization fromone step to the next. and i think until they've donethat fully, we'll probably still be transplanting theseprecursor cells for a while, until we have the--yeah, ideally we'd like to have perfect humanislets, look like human islets, they taste like human islets,they work like human islets, and they stay that way forever. but i don't thinkwe're there yet.
and perhaps we'renever get there. but hopefully we will. feaudience: iunderstand that you know, when you werefirst doing trials, you were using the worst casescenario patients-- terribly brittle diabetics-- inwhom you were hoping to provide some reliefwithout causing long term complications from all of theimmunosuppressants and robbing peter to pay paul.
so i'm wondering nowin the current trials, if we're starting tobroaden those inclusion criteria a little bit? or where are we now with that? dr. james shapiro: we haven'treally broadened the criteria. so very fair question. we haven't done that. we're still concentratedon the brittle patients. occasionally, we'll see apatient come to us and say,
"i'm just tired ofhaving diabetes. i'm tired of testing. i've worked pretty hard at it. i'm tired of it. but my control rightnow is pretty good." that's a hard one forus, because we say, "ok. we understand where you're at. but we don't want todo any harm to you." it's so much easier to takesomebody who you've worked on,
you've tried. if despite your bestefforts as a diabetes and an endocrinologistto control them. if you fail, then there'snothing else left. and then it's easy for us. so have we reachedthe point where we could transition andopen it up to more patients? i think we probably have. i mean, i think atthe beginning we
didn't know whatthe real risks were. we didn't know what therisk of plotting off the vein and the liver,the portal vein thrombosis would be. we didn't know therisk of bleeding. the procedure risk. we knew there's be a risk ofcancers and life-threatening infections, but we didn't reallyhave a quantification of it. i think now, andi've shown you data,
i think we do havequantification of it. so we could have a very fairdiscussion with the patient. say look, theseare the real risks. these are the potentialbenefits to you. if you like it. sure. and i think toget to that point, we probably need to do arandomized controlled trial. best instant therapy againstthe islet transplant.
and you come in with aticket at the beginning, you either win anislet 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'sgoing to fund it? who's going to pay for it? and we don't have anybodythat's come forward to say, we really want to do that trial.
we'll fund it for you. maybe google would. feaudience: what would thecost of a trial like that be? and not that any of ourbudgets can cover that, but and also if we were wanting todonate to diabetes research, are there anyorganizations that you think are particularly--maybe excluding yours-- to be unbiased, althoughyou can mention it, that you think wouldbe particularly useful?
dr. james shapiro: ok. maybe i'll answerthe second one first. so there are severalorganizations-- international organizationsthat raise money for diabetes. juvenile diabetes researchfoundation, the american diabetes foundation, canadiandiabetes foundations, and many others. so i don't think i canconcentrate on one. it wouldn't be fairfor me to do that.
what i will tell you is thatin order to get to this point, we've all done alot of research. and in order to getto the next point, we've got an enormousamount of research to go. and i'm not sure that any ofthese organizations, including the nih, including the kidneyinstitute of health research, including several other globalfunding research organizations. we're challenged. we don't have sufficientfunds to accelerate this.
and so we need funds. so if we wanted todo a trial, and let's say we powered itreasonably with five or 10 years of followup, and welooked at complications. and we wanted ideally, probably50, 60 patients in each arm. and the controlgroup patients would be receiving standarddiabetes care anyway, but they wouldneed extra testing. and in the islet transplantgroup you can-- in canada,
it cost us $75,000per transplant. two transplants, $150,000in the first year. probably some additionalresearch costs for patients. so $200,000. i don't know. if you want me toguess, it's the order of the maybe $10 million. $10million 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, thankyou all for coming. and thank you verymuch, dr. shapiro for taking the timeto speak to us today.
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