Islet Transplant - Towards a Cure for Diabetes

Head Table Guests

Heather C. Devine, Associate in Litigation, Fasken Martineau Dumoulin LLP and Director, The Empire Club of Canada; Reverend Kim Beard, Christ Church, Brampton; Justin Van Leeuwen, Senior Student, Editor of the Yearbook, Parkdale Collegiate Institute; Jim O'Brien, CEO, Canadian Diabetes Association; Lillian Morgenthau, President, Canadian Association of Retired Persons (CARP); Ann Curran, Director, Corporate Development International and Second Vice-President, The Empire Club of Canada; Michael Fleming, Director, Health Care Policy and Strategic Relations, SmithKline Beecham Pharma; Ronald F. Forbes, President and CEO, Juvenile Diabetes Foundation; and Geoffrey C. Mitchinson, Vice-President, Public Affairs, Glaxo Wellcome Inc.

Introduction by Catherine Steele

It is my privilege to welcome our guest speaker, Dr. James Shapiro. Last May, Dr. Shapiro and his team of researchers at the University of Alberta made an amazing discovery. He and his team had successfully transplanted human pancreatic cells or islet cells into seven people living with severe diabetes. These seven Canadians with chronic or type 1 diabetes are now living free of dependence on insulin injections.

Thanks to the work of Dr. Shapiro and his team, diabetics may soon no longer require daily insulin injections. His research and discovery were so amazing that in July U.S. President Bill Clinton praised the team and announced that its research would be replicated at nine other health-science centres.

Dr. Shapiro's discovery could be the breakthrough in diabetes, a disease that has effects and impact so far reaching.

For example:

• Over two million Canadians live with the disease.
• Heart disease is two to four times more common in people with diabetes than without.
• Diabetes is a leading cause of adult blindness.
• In Canada, people with diabetes account for 28 per cent of all new cases of serious kidney disease.
• Worldwide, half or more of all non-traumatic limb amputations are due to diabetes.
• The number of people with diabetes in an unhealthy weight range or living with obesity is double the number found in the population without the disease.

Dr. Shapiro is the Director of the Clinical Islet Transplant Program at the University of Alberta. And his interest in islet transplantation goes back to when he was a medical student.

Born in Leeds, England, he gained his medical training at the University of Newcastle-Upon-Tyne and further trained in surgery at the University of Bristol. He has received many outstanding awards based on his experimental studies including the much-admired Hunterian medal from the Royal College of Surgeons in England and the gold medal in surgery from the Royal College of Physicians and Surgeons in Canada.

He has led the Clinical Islet Transplant Program at the University of Alberta since 1997. He is also published in several journals such as the prestigious New England Journal of Medicine, Transplant International and The British Journal of Surgery.

It is an honour to have one of Canada's pre-eminent researchers with us here today. It makes me hopeful that I may one day soon be able to look back and say: ""I met the man who cracked the riddle of diabetes.""

Ladies and gentlemen, please welcome Dr. James Shapiro to The Empire Club of Canada.

James Shapiro

Catherine, those were very generous words and what a true honour it is to be able to join you today at the Empire Club.

The Edmonton protocol towards a cure for diabetes. You know where Edmonton is and you know why we love working there as researchers. It is not hard to see that in the winter months we would rather focus our efforts in the laboratory than wander outside. We enjoy being there and focusing on research. We have a terrific team.

There are very strong research links with diabetes that go back a long time. Banting and Best's discovery in 1921-1922 revolutionised the course of diabetes, but it was a biochemist from the University of Alberta, James Bertram Collip, who contributed very greatly to that with his use of alcohol to extract insulin from the pancreas and allow the blood sugar to fall for the very first time in a 14year-old boy.

The discovery of insulin truly was a remarkable discovery and it prevented acute and sudden death in patients with diabetes. What it did do though was convert this condition into being the chronic and the incurable illness that it is today. We know that many patients will end up with severe end-stage complications of the disease. Diabetes in the U.S., the world and Canada now affects 6 per cent of the population, is the third-commonest disease and the fourth-leading cause of death. The incidence is rising across all age groups. If we take type I and type II diabetes together, there are 130 million patients with this disease in the world. The incidence is going to rise in the next 25 years to 300 million. Right now in the world there is a new case diagnosed every three minutes. Half of these individuals will develop kidney failure.

Diabetes is a huge cost to our Canadian society, to our health-care system and to the world health-care systems. In Canada we spend about $5 billion per year managing the complications of diabetes. In the United States they spend $44 billion per year; $98 billion in total if you add up all the management of the secondary complications. It is a huge cost to our society.

Do we have any better way of controlling diabetes than with standard insulin injection treatment? We have a number of choices in this wonderful new millennium. We can give standard injected insulin treatment. We can give it more frequently in a so-called intensive regime. We can implant a little pump or have a patient wear a pump on the outside, that will deliver insulin not perfectly but it may improve control. In very select individuals we can carry out a whole pancreas and kidney transplant procedure. This is a big invasive operation that takes about six hours to complete and is potentially fraught with complications and is not right for everybody with diabetes.

The idea of taking 1 to 2 per cent of cells inside the pancreas gland and transplanting them instead to treat this condition is a remarkable idea but it has been around a long time. We can't take credit for that. The first transplant occurred 107 years ago in Bristol, England when a 13-year-old boy came into hospital with diabetes. That was 27 years before the discovery of insulin. He received a transplant. Not a transplant from a human donor like we use today but a transplant from a sheep's pancreas. That was 50 years before the discovery of the way the immune system works and was destined to fail. But at least the idea and the concept were there.

What is an islet? That is an islet in the middle of the screen there. It's a multi-cellular structure; a little ball that you can just about see with your naked eye if you strain it. It's less than 0.1 millimetre in diameter. You can just see it as a tiny speck. In the middle of that speck it's a bit like a chocolate. In the centre of the ball are the cells that make insulin responding from moment to moment to our needs. For example if we have just eaten a nice meal, those cells will respond and make more insulin to try to keep our glucose, our blood sugar, in perfect control. They switch off too if they are making too much. The cells on the outside also help regulate insulin production. Under the microscope there, you can actually see some of these cells releasing insulin. They all work together in a similar way to instruments in an orchestra.

An author and a mother wrote to me recently: ""I didn't know anything about diabetes. I thought my daughter could just take insulin and everything would be fine. I was so wrong. In her senior years of college the blood vessels in her eyes started to rupture. At 22 she had lost every bit of sight. At 28 her kidneys failed and at 35 an infection in her leg led to an amputation and at the age of 40 she died in her sleep from a heart attack.""

These are the complications of diabetes that we need to control, reverse and prevent by carrying out this transplant. I mentioned to you that the idea of doing the islet transplant procedure is not that new. In fact if we look back over the last 25 years, there have been 447 attempts in patients, but only 10 per cent or fewer of those patients were able to come off insulin for prolonged periods of time. Scientists in research laboratories working in this area were becoming dismayed with no new contributions coming out of those laboratories during the last five years or so.

We thought we should make one last attempt to see if we could make this treatment work? We stood back and asked ourselves: ""Why were the transplants not working?"" There was so much success in other fields of transplantation. When we did a heart transplant or a liver or a kidney transplant we expected 90 per cent of those grafts to work perfectly."" In our situation fewer than one in 10 were working. We asked the question: ""Why?"" I think the answer really came to us in the drugs we were giving to prevent rejection because the high doses of steroids and the cyclosporin drug we were giving to stop rejection can actually cause diabetes in patients who don't normally get diabetes. We asked ourselves: ""Are there some newer drugs available we could use that would not cause diabetes but would be just as good or even better at stopping rejection?

This is a very exciting time to be working in research; a fantastic time to be working in transplantation because there are many new advances in drug treatments. There has been an exponential increase in the number of new drug treatments available to us in the last five years or so and three drugs really stand out--Sirolimus, Taccrolimus and an antibody. We felt we could use them together. The names don't matter but the way they work really does. The Sirolimus or Rapamycin is very much a Canadian discovery. It was discovered by a doctor who was working in Montreal and he discovered it in soil samples taken from Easter Island or Rapanui. That is how it got its first name--Rapamycin. We wanted to use it together with a couple of other agents so we would have a three-pronged attack on the immune system to stop the immune system from being activated and stop the immune system from seeing these cells as foreign.

There's another force that could act in the body of a patient with diabetes to destroy these cells-the autoimmune process, the very process that destroyed the cells in the first place. We were trying to put all this together with extensive work in the laboratory over several years and we had no idea whether the solutions we would come up with would really work. We wanted to make sure we'd put enough cells in for transplant. We wanted to use the right drugs and we wanted to make sure we provided maximum protection against the autoimmune and alloimmune forces. We put all this together as a puzzle and called it the Edmonton protocol. This really summarises it: using only the three drugs, no steroids; making sure those islet cells were of very high quality; transplanting immediately; using no foreign proteins that could be damaging; and being prepared to put in enough cells to be sure that there was enough insulin that could be produced.

At the same time advances in anti-rejection treatments were occurring in the laboratory. There were also tremendous collaborative advances in the way we prepared the cells in the laboratory using an enzyme called liberase or a collagen enzyme that helped digest the pancreas so that we could extract just these cells that make insulin.

I'm just going to slowly walk you through this process. Here's Dr. Lakey working in the laboratory; it's about two o'clock in morning. This pancreas has been flown to us from Halifax in Canada. We are very fortunate because we receive organs from right across the country. That is a human pancreas taken from the same organ donor who would give a heart, lungs, livers or kidneys for transplant. We put a little tube inside the duct inside the pancreas and we pump in that white powdered enzyme, the liberase enzyme. Here is Dr. Lakey working and pumping the enzyme through the pancreas. At this stage, it looks more like an omelet than anything else. We then take the omelet and chop it up into scrambled egg. We then put the scrambled egg into a cooking pot or a recording chamber. Here is Dr. Lakey now at about three o'clock in the morning shaking the chamber, shaking those cells loose from inside the pancreas. We look under the microscope, we see when the cells are free, and at the moment they're free we cool the system down. We dilute it and at that point we have tissue with the islets in the middle there--that little red dot--which is what we really want to be transplanting into our patients. We don't really want to transplant the rest of it--the parts of the pancreas that would help us normally digest. Fortunately for us the little red dot in the middle is a little bit lighter than the rest of the tissue so when we put it in a centrifuge we can actually purify it very quickly. This is the centrifuge system that we use. That bit of the process is completed in about 10 minutes. Thus we have a preparation of tissue in the bottle there on the left which is too impure to transplant into a patient. We purify it and then at the end of the process we have a teaspoonful of tissue or less-less than five ccs. It is totally pure and ready to infuse into a patient. You can see under the microscope the little red dots which are the islets of Langerhans. Alongside these is actually a needle, an insulin needle, seen under the microscope magnified. The cells are pure and ready for a transplant.

We bring the patient into hospital but we don't use the operating room. The procedure is done in the X-ray department. The patient is awake. Expert radiologist colleagues place a very fine needle in through his or her side through the liver and seek out a vein called the portal vein. There they thread a little tube down the vein so that they can then inject the cells. Here is a picture of the vein going up to the liver. When they inject the cells this is exactly where they are going to go. They will go to both sides of the liver and at that point the liver will take over the functions of the pancreas.

The injection procedure itself is incredibly simple. All we do is connect up the syringe and inject. The injection process takes about five to 10 minutes. The patient is completely awake as we do it and at the end of the procedure we just pull out the tube and the patient goes back to the ward. It is such a simple procedure in fact that the patients don't need to go to the intensive care unit or to be a long time in the hospital afterwards. It's a day case procedure with more than three-quarters of our patients sent home within 24 hours of the procedure. Here is one of our patients, a lawyer from downtown Edmonton, back in his office within 12 hours of his transplant.

Our data was originally presented in The New England Journal of Medicine back in July. Our first patient was a teacher working in Yellowknife. He had such severe diabetes that he was in constant coma or near-constant coma from severe reactions. The transplant fixed him. It fixed the next four patients and now we are up to 14 patients. The last patient was transplanted a couple of nights ago before I left to come here. All of these patients are doing very well and as you can see from this picture they don't have the swollen faces we would normally associate with patients who have had steroid treatment after a transplant. These patients are not given a drop of steroid because the other drugs are so powerful. They tolerate the anti-rejection drug treatments very well indeed.

Now to follow-up on the 14 patients. The first patient was treated 20 months ago and the average time following treatment in the first seven is now 18 months. All of these patients had very brittle diabetes meaning that they could fall into a coma very easily. The risk of coma truly interfered with their quality of life and was a danger to themselves and other people around them. If these individuals were driving a car they could fall into a reaction without realising it and put themselves and other people in danger. The transplant completely fixed that and led to a dramatic improvement not only in diabetes control but all those dangerous comas were avoided so their quality of life increased dramatically. We've had sustained insulin independence now up to 20 months. Two of the 12 have what we call borderline type II, where they need insulin for very short periods of time. The rest of the patients are doing extremely well and have very stable control. These two patients I think will do well but they need an additional boost possibly with some drug treatment or maybe with some more islets to improve their overall function, but we haven't lost any function in these grafts as far as we can tell.

This is an important image. It shows you the kind of control that a patient has on insulin treatment across the 24-hour period of a day. This is averaged over a month and you can see tremendous variation in the control. This is the best that somebody can do with injected insulin treatment. When we stop the insulin injections and do the islet transplant this is the kind of control that a patient would have. The highs completely disappear, the lows completely disappear, and it's this kind of control that in the long run I truly believe will stop and even perhaps reverse some of those devastating complications of the disease that we mentioned.

The insulin requirements fall dramatically. We do a first transplant and then we do a second or double-donor transplant. The insulin requirements then fall to zero. A marker of how good the control is in the blood over time is completely normalised a year after transplant. We haven't seen any rejection and we haven't seen any of the autoimmune process come back so far. We think that the drugs are very effectively controlling that.

We put a little needle into the side of one of the patients and took a biopsy. This is a biopsy taken inside the liver, and here you can see inside the liver. Here is the islet sitting very happily, functioning without any inflammation. It is very stable. If we stain for insulin in that little piece of tissue, here is the insulin being made by those cells inside the liver. They function very nicely in that environment.

Where have we reached? Is this a cure for diabetes for everybody? I would say definitely not right now. We have reached a point where this is a major step forward but it is not the total cure for all. How do we get there? I think what we have to do now is reproduce what we've done in Edmonton in a multi-centre international trial. And then we want to move forward and have success with a single donor instead of the double-donor transplants we've had to perform thus far. Thirdly, I think we need to get to a point where we don't have to give such powerful anti-rejection treatments in order for the cells to survive. These drug treatments have some potential risks. There is a very small but potential risk of inducing a cancer or increasing the risk of infection. We want to avoid those risks so that we can broaden the indications to treat everybody with diabetes who could benefit. If we're to do that we would need an additional source of cells so that we have enough to go around for everybody-the type Is, the type IIs, all those 130 million patients worldwide. And that truly is a major challenge that needs major research to get there.

The multi-centre trial which we are heading from Edmonton is moving ahead very rapidly now. We've just had approval through the F FA in the United States. We will be completing 40 transplants within the next 12 months or so in 10 centres across the world. This is what President Clinton said: ""If we can reproduce these preliminary findings it could put a cure for diabetes within our reach. That would be a true miracle."" We are moving ahead. Six centres in the United States, ourselves in Canada and three centres in Europe-Switzerland, Italy and Germany-will be partners in this trial.

We want to have success too with just one donor instead of the two donors that we use now. To do this now we are giving about 10,000 of these cells per kilogram based on the weight of the recipient. We need to shift this curve so that we have more success with just one donor. There are very many exciting strategies that we will be testing in the very near future. This is why it is such a wonderful area to be working in.

These are the drugs that a patient has to take to prevent rejection right now. A handful of drugs. Again we want to get to the point where we don't have to give those drugs in the long term and can therefore avoid the risks. We want to get to the point where the graft is completely stable and we don't need the drugs. I think then, and only then, can we broaden this to include children.

I mentioned to you that there's a risk of getting a cancer with the drug treatments. One of the cancers that can occur is called a lymphoma. We think that the drugs that we give right now could have a risk of around 1 per cent.

We know that a patient who has diabetes is not without risk but we have to balance the risk of the diabetes against the risk of these treatments, We have to be sure we do no harm in every individual we consider for transplant. I think with tolerance research treatments we should be able to diminish that risk. Once we get to this stage, whether it is 0.1 per cent or 0.01 per cent, then, and only then, can we broaden the indications. In the near future we can trick the immune system so it won't recognise these cells as being foreign. Tolerance research is going to involve blocking antibodies that interfere with the way these two cells stick together.

Finally we need enough islets to treat everybody. The Pope tried to come and help us at the Transplantation Society meeting in Rome a few months ago. He tried to encourage organ donation. Organ donation is obviously the first step and we are very grateful to the donor families that have agreed to provide organs right across Canada to help us in this project as well as helping many patients who have had liver, kidney, heart and lung transplants.

We know there's never going to be enough organ donors for everybody. We need new sources of cells and I think the most exciting and promising area is going to be in stem cells where cells in our bodies can be turned into new islets. All we need are the ways to coax and trick them and there's very promising research to show that in very select situations these cells can make insulin, can respond appropriately to their environment and perhaps eventually will get to a point where they can replace the need for organ donors. And there are other potential treatments or options too including tissue engineering that will allow us to get there.

We can now say that islet transplant for diabetes clearly works. We've gone from a previous very poor success rate of 8 per cent to around 100 per cent. We haven't had any rejection and we haven't had any recurrence of the autoimmune process. We have provided long-term freedom from insulin to 20 months with excellent sugar control and we've provided this at extremely low risk. This is what one of our patients said about this. ""My life has totally changed. Gone is the need to test my blood endlessly. Gone is the need to mentally calculate the nutritional content of every snack. Most of all, gone is the fear of an incapacitating insulin reaction, the kind of reaction that my wife was involved in when she died in a car accident two years ago.""

This is the challenge we are faced with now. I get about 100 e-mails a day: ""How can I get on the list for an islet transplant procedure?"" Clearly we have no immediate solutions for that. We are working hard on organ donation and we are working hard on research. Damage from diabetes doesn't happen in a day. We still have time and we still have hope to stamp out this disease. How are we going to get there faster? We need urgent funding to do that and we need very strong collaborations so we can get the job done.

This is our ultimate goal. Here is Samuel, a child, a French child, in France. His mother wrote to me: ""How can he have an islet transplant?"" He's just been diagnosed with diabetes. We want to be able to offer this treatment to him as a cure at the time he's diagnosed. We are not there yet and we need those challenges solved before we can get there.

I come from a tremendous team in Edmonton at the University of Alberta. Dr. Jonathan Lakey heads up the islet preparation laboratory. Dr. Eddie Ryan is the medical co-director who helps us select our patients and helps us follow them. Dr. Greg Corbett is a scientist with a group who makes sure the cells are safe to transplant in the patients. We have many nurse co-ordinators, collaborators in the hospitals, and transplant surgeons, with whom we work not only in Alberta but right across the country. They provide us top-quality organs for transplant. Finally I have to truly acknowledge the real transplant surgeons in this endeavour-the radiologists, the X-ray doctors, who are passing those needles in. They've taken over our role completely. And we're glad of that. That's how I can come here today while they carry on and do the transplants. We have a wonderful team.

Thank you for your attention.

The appreciation of the meeting was expressed by Ann Curran, Director, Corporate Development International and Second Vice-President, The Empire Club of Canada.