August 19, 2021

One hundred years of insulin and the future diabetes vaccine

By Conor McKechnie and Dodi Axelson

One hundred years of insulin and the future diabetes vaccine

What better way to celebrate 100 years of insulin than with the CEO of the company who is on the verge of giving us a vaccine for type 1 diabetes?

We spoke to Ulf Hannelius in April and 3 days ago we saw the published results of DIAGNODE-2, a Phase IIb trial that evaluated intralymphatic administration of Diamyd Medical’s lead drug candidate Diamyd® (GAD-alum) in individuals recently diagnosed with type 1 diabetes. Congratulations!

Guests who also joined us in this episode are Mark A. Atkinson, American Diabetes Association Eminent Scholar and Anders Ekholm, diabetes patient and parent, and Chairman of the Diabetes Association for Greater Stockholm.

CONOR: So, Dodi, how do you think the world looked in 1921?

DODI: Well, it was the 20s. So, it was roaring. There were a lot of flappers. But on a more serious note, the world was recovering from the Spanish flu pandemic.

CONOR: Yes, and 1921 was a big year for science, Albert Einstein and the Nobel Prize in Physics, the first BCG vaccination against tuberculosis. Rorschach published Psychodiagnostik and proposed the inkblot test. What do you see in all this mess?

DODI: I see an eventful year.

CONOR: Yeah, but that's not all. It was also the year when insulin was discovered.

DODI: So, if I do my math, right, that's 100 years of insulin.

CONOR: Exactly. And it's something that has improved the lives of millions all around the world. Usable insulin was first made by Frederick Banting and John Macleod at the University of Toronto. And then two years later, they were awarded the Nobel Prize in Medicine for it, but it's not quite so simple, because at the time that the Toronto team started their research, Nicolae Paulescu in Romania had already extracted insulin and was showing its efficacy in reducing hyperglycemia in diabetic dogs. And what followed was years of Nobel Prize controversy, right.

DODI: Wow, that is dramatic. So, the first discoverer was from Romania. Just like our executive producer, Andrea.

CONOR: Yep. And 100 years ago, being diagnosed with diabetes was pretty much a death sentence. And today, it's a disease that can be treated thanks to insulin, and thanks to the science and the technology advances that have been made over the last 100 years since it was discovered.

DODI: So, insulin is what matters on today's episode of Discovery Matters.

ANDERS EKHOLM: Thank you for dragging me out of bed so early.

CONOR: This is Anders Ekholm.

ANDERS EKHOLM: I'm Anders Ekholm. The chairman of the Stockholm Diabetes Association and I am a futurologist.

DODI: A futurologist? Well, that sounds fancy. What is that?

CONOR: Well, in Anders' case he's an economist who focuses on exploring predictions and possibilities about the future. Usually, he's out travelling the world giving lectures, but because of the pandemic, he's been at home in Stockholm.

DODI: Yeah, I think I can hear birds in the background. So, what is the backstory here? How did this interest in diabetes begin?

ANDERS EKHOLM: It was when my daughter learned that she had diabetes type 1, she was 14 years. This was about 10 years ago. So roughly 50. I was at age, when we were at the hospital, I also tried to take my blood glucose level, and then it showed higher levels. So, I did investigation at my primary care unit. And it turned out that I had type 2diabetes. So, we were diagnosed at the same time, me and my daughter, she would type 1on me with type 2. And we did this journey together, then.

DODI: Ah, father and daughter on a diabetes journey.

CONOR: Exactly, and for a diabetes patient it affects both your movement, and what you can eat. So, they started experimenting with food deserts without sugar, pizzas without white flour, pretty icky, I guess.

ANDERS EKHOLM: Especially you cannot eat candy anymore, which was a big thing for my daughter, of course, and a lesser thing for me, but you have to always think about what you eat. So, we ate a lot of bad food, actually, during this period, until we finally succeeded in experimenting what would happen when we took away white flour and white sugars from the food.

DODI: So, both Anders and his daughter are diabetic, and I think you don't have to look too far to find somebody you know who is diabetic, I have good friends who are diabetic, my mother-in-law is diabetic, you don't really see it on people right off the bat. So how common really is diabetes.

ANDERS EKHOLM: So, it's about 5% of the total population that has diabetes and the most, about 90% or 95% of those has type 2 diabetes.

CONOR: And Anders emphasizes that the diagnosis affects a whole family. It's not just the one person with diabetes.

DODI: Yeah, so what's the progression of diabetes?

ANDERS EKHOLM: So, in the first years, she had to take one shot every 24 hours with long term insulin and then after each meal, and maybe some more times during the day, let's say like three or four or five times a day, she had to take a shot of rapid insulin. So, it was a lot of needles, a lot of small 'pencils' with insulin. Nowadays, she has insulin pump, so it dramatically has increased her life quality, I think.

DODI: There's so much that has changed during Anders' daughter's life, let alone if you compare to how it was 100 years ago.

MARK ATKINSON: In the early 1920s, or before that, it was a death sentence, meaning most people with type one diabetes would live six months, maybe at the outside of six years.

DODI: Oh, this is a new voice. Who's that?

MARK ATKINSON: So, I'm Mark Atkinson, and I'm a Professor of Pathology and Paediatrics at the University of Florida. I head the diabetes institute at the University of Florida. And for 38 years, I've been a type 1 diabetes researcher.

DODI: Mark really knows the history of insulin.

CONOR: Mark says that in the 1920s, diabetes patients in the US were put into mental institutions.

MARK ATKINSON: But they were being starved because we knew that in order to keep people alive, you had to restrict calories. And so, people were on maintenance diets, they were put through exercise protocols just to keep them alive. But the outcome was not positive.

CONOR: And the discovery of insulin, of course, made it possible for people to get treated. But it wasn't really the end of it.

MARK ATKINSON: Because people in the late 1930s and 1940s that benefited from this, they began to develop eye disease, kidney disease, they develop neurological disease. And so, we entered an era where we knew that this was not a perfect therapy.

CONOR: It wasn't perfect, and science kept looking for better ways. The way we use insulin has evolved over these 100 years. And it's just extraordinary. Insulin used to be extracted from the pancreas of cows and pigs, and that's hard. But now we use a recombinant or biosynthetic human insulin, and scientists have managed to reduce the side effects. And the technology is getting better and better.

DODI: I'm hearing the start of the biotechnology industry, Conor.

CONOR: Yeah, absolutely. You're completely right. Genentech was really the first biotech company to go public, in the early 80s, and it brought, you know, recombinant insulin to the market as the first biotechnology drug which is just so cool. But it's not just about you know, huge things, it's also lots of small innovations.

ANDERS EKHOLM: 20 years ago, you have to have your own rather coarse needles, and you use them over and over and so on. But now there's small needles like 0.25 millimeters with the silicone on so you barely noticed this thing when you take a shot, obviously. And so, it's a huge dramatic actually change.

CONOR: And things like pumps.

ANDERS EKHOLM: The new insulin pumps, the new family of pumps, is like an artificial pancreas. So, they monitor your blood glucose levels continuously and they adapt with the help of artificial intelligence, so that you always have a good blood glucose level. So, this is really a dramatic change.

DODI: Since Anders is a futurologist, what does he see for the future of diabetes patients?

ANDERS EKHOLM: Well, it would be nice with a cure, of course, probably, I think my daughter is one of the first generations that won't have it all her life, it probably will stop being a chronic disease, whether it takes 10, 30 or 50 years. That's hard to guess. But probably we will find a cure.

CONOR: Dodi, I know we don't like to shill for Cytiva, but here's a piece of trivia that's really hard to avoid when we talk about recombinant insulin.

DODI: Are you thinking about how the vast majority of the world's insulin begins at Cytiva?

CONOR: Yes, indeed, the components that we send to manufacturers to create insulin, our customer surveys tell us that about 90% of the insulin in the world is made using Cytiva products.

DODI: I love me some trivia.

CONOR: And if 100 years ago, getting a diagnosis of diabetes was equivalent to a death sentence, its finally become a manageable disease, even if there's no cure, that is the next frontier.

MARK ATKINSON: It was 50 years ago that we began to appreciate that type 1 diabetes was an autoimmune disease. Meaning a situation where the immune response, which is normally there to protect us against viruses, and cancer, or some reason it would go awry in the case of type 1 diabetes and destroy the cells in the body that were responsible for insulin production. Meaning the beta-cells within the pancreas.

CONOR: So that's Mark, again, who started to see that patients have a genetic risk for type 1 diabetes.

MARK ATKINSON: We began to understand that they express these autoimmune markers of the disease, what we call autoantibodies. And that they reacted with islet cells.

CONOR: So, they've been able to use blood tests to identify people at risk for quite a while, but they didn't know how to prevent them from getting the disease.

MARK ATKINSON: And it was quite disappointing. So, this is where I think Diamyd comes into play. Now we can really have a chance to do something, and that's what I think is come along here in the last year or two, that's just so refreshing.

DODI: Okay, what? Let's go back, what is Diamyd?

CONOR: So, let's explain that Mark has been working in close collaboration with a company called Diamyd. And of course, they are based in Sweden.

MARK ATKINSON: I don't want to say that COVID is like type 1 diabetes, not at all, but in similar fashion, vaccinating against COVID, to prevent that disease, Diamyd has come up with a unique way to vaccinate against GAD or Glutamic acid decarboxylase that hopefully will prevent type 1 diabetes and or help those that are diagnosed with the disease.

DODI: We're talking about a vaccine, this is incredible, against type 1 diabetes.

ULF HANNELIUS: In diabetes, I would say we are quite good at predicting who is at higher risk. It's more of a practical matter since today, obviously, healthy individuals are not screened routinely for their risk.

CONOR: So, this is the CEO of Diamyd Medical.

ULF HANNELIUS: Ulf Hannelius, I worked here for five and a half years, and I have a background in biochemistry and molecular biology.

CONOR: And the reason Diamyd is so invested in finding a cure for diabetes is personal. It was founded by the Swedish entrepreneur Anders Essen-Möller, who much like the futurologist Anders Ekholm, has a daughter with type 1 diabetes.

ULF HANNELIUS: He started a company when his youngest daughter got diagnosed with type 1 diabetes. And he basically travelled around the world, trying to find some kind of treatment that could lead to a cure and ended up licensing patients from US universities and then starting the development through the animal models to clinical trials and all the way to phase three and almost all the way to market. It's looking very promising now, and the whole purpose of the company has ever since been to cure the disease.

DODI: So Diamyd says that they're really close to getting a vaccine against diabetes type 1.

CONOR: It's exciting, yes. It has to do with the fact that as an autoimmune disorder like rheumatoid arthritis, or multiple sclerosis...

MARK ATKINSON: ...where for some unknown reason, the body which you know, normally defends us against viruses and cancer, it goes awry and begins to destroy the insulin-producing cells in the body. And when it does that, it does it by attacking certain molecules that we call proteins within the insulin producing cells. One of those two main proteins is this molecule that we call GAD, or glutamic acid decarboxylase.

CONOR: Research over the last decades has shown that there are two main proteins that our immune system targets.

ULF HANNELIUS: So, we want to teach the immune system or re-teach the immune system that, again ''don't attack the instrument production, that's something that belongs in the body''. We do this not by trying to suppress the immune system. We want to use the immune system to our advantage and rather present a single component that belongs in the body but present it in a way that the immune system recognizes and realizes that ''Wait a minute, this is actually nothing that I should be attacking, it's actually belongs here''. And in this way, stop the attack on the insulin producing cells.

DODI: What about manufacturing? Are they in any way slowed down because of more pressing needs that are happening now during this pandemic?

CONOR: Actually, surprisingly, no, because their clinical trials didn't put anyone at risk of getting infections from the Coronavirus. They didn't have to stop the trials. And they doubled down on manufacturing instead, which they previously outsourced.

ULF HANNELIUS: But now, especially since the COVID pandemic, and all the logistic like disruptions in logistic chains globally, and many of these manufacturers actually starting to priorities COVID vaccines and manufacturing those, there was a worry that a company like us we will be de-prioritized regarding manufacturing. We took the decision to actually internalize the manufacturing, so we are now setting up our own manufacturing facility to really take control of the manufacturing part here.

CONOR: So, they've decided to start a factory on their own, up in Umeå in northern Sweden, so they can take control of production and for Ulf, he's also excited that they're creating precision medicine for diabetes.

ULF HANNELIUS: Besides this, to really predict and prevent disease, but also so you don't treat everyone in the same way, that you can really tailor treatments to understand who should be treated with which drug and at what time, it's very exciting that we are actually doing something about that now and moving forward with the first ever precision medicine treatment for type 1. So that's very exciting and all the potential these will give for the future.

CONOR: And for Mark Atkinson, the work isn't finished.

MARK ATKINSON: I could go on and on and on about the ways we've improved lives of individuals with type 1 diabetes over the last 100 years. But that's all we've done. We've improved lives, we have not cured this disease. And that's where I think the next 100 years, and it's not going to take 100 years, but that's where I think we are now. We're going to transform with the century, not just from improving lives, but curing this disease. And that's where I hope Diamyd makes an impact.

DODI: So, I love these stories coming together because it's about it being personal, it's about a discovery, then it's also about being able to manufacture and distribute discoveries. That's really just the whole, you know, soup to nuts kind of story.

CONOR: I know. The marvelous thing for me about it is that if you look back over the last 100 years, what starts with, you know, some really quite difficult science, at the very edge of the science 100 years ago, has kind of just transformed itself into just common knowledge about...

DODI: Mundane!

CONOR: Exactly! And its treatment and we think about what the cutting-edge science of today is going to mean for the patients in the next 100 years.

DODI: What are we going to take for granted? Yeah, it's incredible.

CONOR: And we have this custodial relationship with the progress of the science and the therapies that are our customers are manufacturing.

DODI: Happy Anniversary to insulin! And please give us a rating on Discovery Matters and thank you for listening.

CONOR: Our executive producers Andrew Kilin, the Romanian. Discovery Matters is produced in collaboration with Soundtelling. Production, Tanvir Mansur. Our theme song was written by Thomas Henley. Additional music is from Epidemic Sound.

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