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Interview with James Shapiro

📷 Folio

Journalist: Raj Chakkal

Raj: Welcome to SciSection my name is Raj, and I am a journalist for the SciSection radio show broadcasting on CFMU 93.3 FM. We're here today with Dr. James Shapiro, thank you for taking the time to meet with us and we welcome you onto our show!

Dr. Shapiro: You’re welcome Raj, thanks for having me!

Raj: To be enough can you tell the listeners a bit about your field of research in medicine and what you specialize in?

Dr. Shapiro: Sure, I'm a surgeon I do transplant surgery for my sort of daytime job but it's not exactly a hobby, but my sideline is finding new treatments for diabetes and I've been working on that for 35 years since I was a medical student. I set up a program here at the University of Alberta 20 years ago where we transplant cells into the liver of patients with type one diabetes, we called it the Edmonton protocol. We transplant cells that make insulin and those cells at that time and we continue to do that came from the organ donors the same organ donors that provide heart-lung or liver's potential for transplant. Now because those are foreign to the body just like any other transparent anti-rejection drugs have to be given that we've been working on that area of research now for over the last 20 years. We've gone forward with the advent of protocol and treated hundreds of patients with and share these protocols worldwide and also worked with other researchers that have helped advance them. We’re also now working on some alternative approaches that include stem cells. The reason we're interested in using stem cells is that we believe that that will provide a limitless source of cells to treat all the people in the world with all forms of diabetes, both type one and type 2 diabetes. In the future, there's never going to be enough organ donors to go around with this Edmonton Protocol type of approach and of course, also the other big downside is with the islet cell transplant treatment from the organ donors. We have to give powerful anti-rejection drugs and those drugs have potential risky side effects including increasing the risk of certain cancers and they can also induce life-threatening infections. So, for those reasons, it's desirable to try to find an alternative approach and we've been working in the last several months now on using patients own cells which of course won't be rejected by the immune system because they are entirely compatible, they have the same genetic structure the same HLA types as the body, so you don't need the anti-rejection drugs we believe for that kind of a transplant. So, we've been able to take blood from patients with type one and type two diabetes and other forms of surgical diabetes and manipulate those in the laboratory using techniques that have been well established by other investigators. Including, the Nobel laureate scientist who discovered the way to unlock cells this IPS technology discovered by Shinya Yamanaka. The factors we used were his factors the four Yamanaka factors that basically would unlock an adult cell turn it back in time and allows them to reprogram those cells so that they can become instant producing cells. Many years ago, this seemed like an idea that was akin to alchemy you know almost unimaginable, turning dust into gold, but this is really possible now and it's readily available and these techniques are very reproducible in our lab. We can't take credit for designing these approaches they weren't designed by us but we've been trying to take advantage of it and seeing if we can use it as a way to treat all forms of diabetes with the patient’s own cell transplants in the future.

Raj: Research has been happening at a very increased pace and has COVID affected that any in any way?

Dr. Shapiro: COVID has changed the dynamic in terms of the way we're practicing working right now of course. It's changed it for everybody you know for example I'm sitting here in my basement in a broadcast studio, my basements become very adaptable to film TV interviews to record broadcast-grade audio and now also to see patients. I see hundreds of patients this way over zoom it's is a very effective way to communicate. It saves patients from having to park in the hospital and pay $30, $40 each time they come in. So, COVID has changed the way we practice everything and the same thing with research. So, I think it's actually allowed us to consolidate, plan and come up with the new ideas perhaps in a way that we wouldn't have been able to do previously because we were so much in the thick of it. So, the research team is in some ways less hands-on we are all dispersed but were available and we're coordinating our efforts and I think we're making just as much progress at the end of the day were we spending all the time in the lab which we are not not. So, some of us are but we're trying to distance of course.

Raj: For sure and so coming back to clinical trials were there any implications that came up during your clinical testing of the Edmond protocol or the more revised version?

Dr. Shapiro: There are always issues that come up and that's what drives us to iterate and to change and to improve our practice so that we can try and improve tomorrow to make it better than what it was today. We've been doing that constantly with our program even from the very beginning. I mean for example we use one particular combination of anti-rejection drugs at the beginning we notice because we were giving those are fairly high doses, we had a fair amount of side effects we change those drugs around. We've changed them around many times I think I’ve got around 15 different clinical trials running in different areas of cell transplantation from our program at the present time. Some of which are designed to improve the anti-rejection treatment, some of them are designed to control the autoimmune process that caused type one diabetes in the 1st place. One really interesting and exciting approach is a collaboration we have going on with the University of San Francisco with Qizhi Tang and Jeff Bluestone. We are setting ourselves from patients there and we're getting them to expand and magnify up the numbers of T-Rex. These are special kinds of regulatory T cells that suppress the immune system and basically replace the need for anti-rejection drugs and those cells it takes a team in San Francisco around 2 weeks to manufacture them then they ship them back to Edmonton. We then infuse those cells back into the patients and giving the patients about 1/4 of the dose of the normal anti-rejection drugs that we would give. So, the patients obviously very happy with this and the islet cells seem to be very happy with that approach too. So, we are in the early days in many different trials, but you know there's a lot ongoing and trying to iterate and improve on what we do tomorrow to try to make it safer and more effective for patients. This inroad now into stem cell type pilots is obviously a new road for us. We don't pretend to be the leading scientists at all, but we are trying to learn from them and trying to master these protocols. We are seeing how we can improve these processes so they can be widespread and available for millions of patients in the future with all forms of diabetes.

Raj: So, when you said that this would be available or useful for both type one and type two. Is there any difference between type one and type two in terms of how it would be cured? Or would this work in a similar way for both?

Dr. Shapiro: That's a great question, Raj. So, type one diabetes just to put it very simple for your audience. In type one diabetes the immune system has destroyed the specific cells inside the patient’s pancreas that would make insulin. So, these are the beta cells, and exactly why that occurs has many reasons for it, it's complex, I don't think we have all the answers. In type two diabetes which is of course 10 times more common than type one, the patient has become more resistant to insulin but doesn't have these antibodies that destroy the islet cells. So, the big question really is as we make patients own cells if we do this for type one diabetes can, we make those cells resistant to destruction from that same autoimmune process that destroys the cells in the first place. Well honestly because we've never tested this in patients, we don't know the answer to that yet and there are a number of different strategies that have been proposed to try to overcome the autoimmunity. Some of which is linked to some of the other clinical trials that we’re doing right now in patients with newly diagnosed type one diabetes in other words resetting the immune system. It's a special kind of antibodies that reduce the immune attack and it's looking to be very effective in other areas of our research, but I think it remains to be seen if it can be applied and it is effective with these stem cell treatments. Another approach is to edit the infrastructure inside the stem cells to make them non-amino genic so they can't be seen by even the autoimmune system. Another approach is to try to increase the expression of immunosuppressive molecules on the surface and inside these stem cells. So, for example, PD1 which is PDL1 a very powerful suppressor of immune activation, and if we can for example with gene editing crisper technologies it's quite possible to be able to generate cells with that kind of approach but the manufacturer that sells then, of course, becomes more complex. Another way to manage this is to shield the cells in some way and you can do that either by directly treating the cells and we've got a collaboration with Dr. Ron Evans at the Salk Institute where he has an immune shielding their technology that looks to be very promising. Then finally it's possible to put these cell transplants as we generate them inside some kind of immune isolating device that will shield them also from the immune system there are pluses and minuses with that. The big minuses right now are those shielding devices microencapsulation devices can interfere with the factorization and survival of the cells so it can also limit the ability of the cells to survive. So, there's a lot going on in this space you're right that it's going at a faster and faster pace but we're learning all the time I think from each other and from scientists and trying our best to apply this in different ways. You know you mentioned it transplanting type 2 diabetes. We've never done transplants of this kind in patients with type 2 diabetes yet. We have done whole pancreas transplants as have a number of other programs across the world put the whole pancreas transplants into patients selected patients with type 2 diabetes. That obviously is a risky operation, but it can be very effective, and it clearly suggests that being able to transplant cells can overcome the body's resistance to insulin. So, I'm very optimistic that this kind of a treatment particularly we don't need that rejection drugs will also be very effective in type 2 diabetes.

Raj: For sure and so one other thing that I had was coming off from the organ transplant and type 2. I'm not even close to an expert but when an organ is transplanted, you need to give like medicine or drugs so that the body won't destroy the organ upon contact right away as it's not from that body. As with the cells you said that you need to protect them from the immune system or make them invisible to the immune system. Now is there a way for you to actually have the immune system accept the cells at one point or is the patient going to be on drugs or medication for the rest of your life? That is so that they can use the cells and not have to inject themselves with insulin.

Dr. Shapiro: Okay so, that is an important question, but I think the answer comes with this idea of being able to take patients’ own blood cells. So, if we take patients’ own blood cells, they have the same genetic makeup as every other cell in their bodies so those cells you don't need the anti-rejection drugs. As I mentioned it, we don't know in type one diabetes if the immune system will be completely controlled by that approach or whether those cells will be slowly or even rapidly destroyed. We have to wait and see and do this study in patients but the idea here because the patient’s own cells are being generated none of those anti-rejection drugs would be needed. I think as a result of that you know our biggest hurdles to calling cell transplant treatment a cure is the fact that we don't have an unlimited source of cells and we don't have an ability to transplant cells from organ donors without the need for the anti-rejection drugs. So, if we could overcome those two hurdles as this type of kind of stem cell approach will do I think this may be as close to a cure for diabetes of all forms as we'll ever get. Now there are many complexities in taking that forward from the concept phase and early testing in mice to widespread availability for 422 million people with diabetes across the world. There are going to be many challenges but those are exciting challenges. We've been working with experts in robotic engineering in artificial intelligence and machine learning so that we can develop machine technologies that will help us manufacture the cells right now. Then when we transplant human cells into mice which is what we've been doing the technicians in the staff have to work day and night adding growth factors rocking dishes with a lot of complexity. If we could simplify that process and automate it and make it machine-controlled that process could be much more efficient. We're also working with a group called Lanza and they have an amazing system they call it the cocoon. This system is basically a robotic controlled culture system which is that all the patient’s own cells are basically controlled within the inside of a pod. They envisaged being able to create a room full of these pods and they called it the Orchard for growing future cells and these cells could be used for all kinds of regenerative medicine not just in diabetes.

Raj: Okay for sure and so the last thing is that obviously with technology and you saying if somethings are automated then obviously the process can move even faster. So, determining a timeline for when it will be very easy to get treatment like this in clinics is hard to determine. What would you say is maybe an approximate timeline for when this could be more universally available?

Dr. Shapiro: Okay well also a great but tough question. So, you know I can see as far as like you know as far as I can see it look down to my feet, I can look that look across to the horizon. The further I look the less accurate my estimates are going to be. I know that within the next several months we should be able to move this kind of therapy into a very preliminary safety first-in-human trial. That to my mind is big because I would have said to you a few months ago will take probably five or six years to get to that point. So, I think there are ways that we can step around that and then be able to accelerate that progress. I think if you're asking me how long it is going to take before we can fix this problem and generate cells at a very reasonable cost for 422 million people with diabetes? That is a much bigger question, and I don't know what problems are going to face ahead I mean some of it will be financial I mean for example this work we're trying to raise $22,000,000 by 2022. We have a group that's working alongside is called heading to 2022,, and heading to 2022 it is a committee that is really focused on highlighting the discovery of insulin almost 100 years ago in 1922 when the first patients were treated successfully with insulin. Now 100 years later you know they're all looking and we're looking for something better than insulin because insulin is certainly far from perfect. So, we're trying to raise that kind of funds over the next few years we're looking for a million Canadians to give $22.00 towards the effort on to help us with this kind of effort.

Raj: Hopefully everything goes in your favor and I will definitely try and spread the word and we wish you all the best with further research.

Dr. Shapiro: Raj thank you very much indeed and thanks have me on and great to talk to you.

Raj: Alright guys that's it for this week of SciSection, make sure to check our podcast available on global platforms for our latest interviews.


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