Episode 3: Tracking Ghosts

Bill Hagopian  00:00

What I can tell you about viruses is studying viruses is like tracking ghosts. It absolutely is. It’s incredibly difficult work to do this in the human

 

Jack Faris  00:17

Hello and welcome to our podcast, PNRI Science: Mystery and Discovery, where we go beyond the jargon to dig into the passion and people behind the science. I’m your host. Jack Faris, CEO of Pacific Northwest Research Institute, a 68-year-old genetics and genomics research institute in Seattle. I’m also a regular guy.

 

Anna Faris  00:37

Dad, no, you are not a regular guy. Oh boy,

 

Jack Faris  00:41

here we go. That’s my daughter, Anna Faris, who’s gonna help me out, so to speak, with this endeavor. Anyway, I say I’m a regular guy who happens to spend his days around really smart people, and I’m here to interview pianos, brilliant scientists, to share what excites them about genetic research, what inspired them to become a scientist, and what are those myths that we would love to bust about science. Join me and Anna as we dig into the mysteries that may very well hold the key to our future health breakthroughs. Dad,

 

Anna Faris  01:13

that was great. Oh, I’m really proud of you. Dr, Bill Hagopian and Michael Killian, tracking ghosts in this episode of PNRI Science: Mystery and Discovery, my dad Jack interviews the TEDDY study’s principal investigator, Dr. Bill Hagopian and PNRI TEDDY clinical research manager, Michael Killian, both of whom have been working on this study for 20 years. As part of an international study, PNRIhas been collecting samples from age three months to age 15 for over 20 years to determine the environmental factors that lead to type one diabetes, From blood draws to stool samples to even baby teeth, a bit cool and a bit gross, if you ask me, they share how tracking viruses is like tracking ghosts and why science is so slow. On purpose.

 

Jack Faris  02:13

It has to be slow because it takes years and years to understand the various factors that enter into the development of type 1 diabetes, and let’s appreciate what these families have done, bringing their children from the very earliest months to help us understand how this disease develops. It’s an incredible human story as well as a science project.

 

Anna Faris  02:35

So pull up a chair and enjoy the awe inspiring power of science.

 

Jack Faris  02:45

I find the whole TEDDY project to be profoundly moving. The fact that you two and others on the team have devoted such a big chunk of your lives to this endeavor, and at least as much the fact that these families have given up themselves and their children, quite literally, in the case of blood draws and other tissue samples their time and done it, not only without complaint in most cases, I think, but with An appreciation for what can be gained by doing this. So I’d like to kind of start with the question of why at the individual motivational level. So Bill, I think it’s appropriate to start with you, if you don’t mind. Thank

 

Bill Hagopian  03:35

you. Jack. TEDDY is part of the continuum of type one diabetes research, and the mountain that I chose to climb in my career is type one diabetes. And I started out very early in the late 80s, doing my postdoc, and we developed biomarkers to predict diabetes ahead of time, and we cloned gad from islets and developed that into an auto antibody assay that’s used widely now to predict future type one diabetes, along with genetics, which at the time was HLA, but now it’s genetic risk scores, those provide a full suite of predictors For who’s going to get diabetes, and it allows us to answer some really tough questions that are very important questions about type one. And one of them is, how do you apply this kind of a predictive scheme in a cost effective way to the whole population of kids? And actually, it turns out later we found out adults as well. It’s more adult type one than there is kid type one. It’s buried in a sea of type two diabetes, so it’s hard to find, but we have the tools, as I told you, but for the children to predict ahead of time who’s going to get the disease in a cost effective way, and population based way, is one important. A goal, a second goal is, once you predict, how do you prevent? I mean, what are you going to do with this prediction? Just warn them. If you do, you provide substantial benefit. They look out for early signs and symptoms, and they don’t get as much diabetic ketoacidosis, which is a life threatening situation. So you can give them a lot of benefit just with prediction. But we wanted more. We wanted prevention. And by we, I mean the 5000 people in the world that are working on this, because there it is a big community. We all contribute and work together on this. So prevention now, prevention can be immunotherapy, which is well, prevention could be a number of things or cure. One of them can be transplanting islets into an individual. But also, there’s an even less toxic way to do this prevention, and that is to interrupt some of the environmental triggers of type one diabetes. And we know from epidemiologic studies and the and the geneticists that came before me told us that the etiology of diabetes is 50% what your genetic background is, and 50% something else, black box. But it turns out you can see that you know when, when people move from one area of the world to a different area, their risk of type one diabetes for the same genetic background goes up. And so you know that there’s some sort of environmental trigger there, but that was always a black box. We didn’t really know what it was people would poke at things, but nothing was was really proven. And so TEDDY was designed to fill that gap. I mean, I’m very interested in prediction in general populations. I’m very interested in Teddy to understand environmental triggers, and I’m very interested in prevention. So Teddy fits into all that, and we can go into a little bit later, why Teddy expected that it would fill this gap that had been so difficult to fill before the bytes study design. But let me, let Michael say something,

 

Michael Killian  07:07

I guess I looked at that question slightly differently and kind of why did our families enroll in this? I have two kids, and enrolling at birth for a 15-year project just seems really intimidating to me as a parent, but I think it’s it’s really a testament to the families that we have how much time and commitment they put in this. As we wrap up the study and they finish at 15, we ask them about things that they liked about this project so that we can better design future projects, but it’s also an opportunity for us to find out really what their motivation was. And so many times, even children that never had any signs of showing type 1 diabetes, the parents were like knowing that someone was checking and watching my child, because type one is enough, you know, it’s frequent enough that we all know what it is. We all know someone who’s impacted by this disease, and that, you know one, knowing that someone’s watching their child and then helping with research is just, you know, these are the top reasons why these people stay in the study for so long, so long and

 

Jack Faris  08:24

so many of them, the retention rate being, as I recall, 68% through across the study.

 

Michael Killian  08:31

Yes, which is incredible, because it’s a 20-year project, and I said they stay until they’re 15. Yeah,

 

Jack Faris  08:44

you showed me some years ago a painting that hung on the walls of our institute of a physician looking after a young child. This is probably 100 years ago, and it predated the discovery of insulin as I recall the context, and you spoke quite movingly about the significance of that,

 

Bill Hagopian  09:07

diabetes was absolutely a death sentence before the discovery end of insulin type one diabetes was there’s not enough insulin, nutrients can’t get into cells. You know, no matter what you eat, the body just sort of wastes away. And over the course of a period of years, you would watch your child wither away and die. And, I mean, I can’t imagine anything more tragic than that. So this picture was a picture of a family, parents in the background, just distraught, and a kid laying on the bed, clearly very, very ill, and physician, you know, rubbing his chin, looking at some books, trying to figure out what to do. And it was, it was really moving for me. But after insulin, people survived with type one diabetes. Yes, but it’s not necessarily the case that it’s it’s all a better roses. It’s not. I mean, they get hypoglycemia. They have to give themselves insulin shots. Their activities are curtailed there. At the time that I started this, they were sticking their fingers all the time for blood glucose checks, and it was a very difficult existence. They all got retinopathy and circulation problems in their feet. Not all of them got kidney failure, but 40% did, and the ones that did were even in worse circumstances, getting dialysis and maybe a transplant. So I mean, it’s a bad disease, and technology has made it a little bit better, but it’s still a bad disease, and so we felt like, since there was this time interval between when the antibodies appear and when high blood sugar appears, that we had a window of opportunity. So the idea is to try to save these kids, not necessarily save most of them from death, but save them from ketoacidosis and onset and save them from all the difficulty of taking care of their diabetes and their short term and long term complications. So

 

Michael Killian  11:06

I agree that, you know, technology has gotten a whole lot better. I mean, there are still people that struggle with managing their diabetes. They’re often called brittle diabetics, but they’re they struggle with it, even with the technology. But beyond that, I would say preventing, it’s like the amount of resources. I mean, our healthcare resources, our healthcare dollars, are so limited, and the maintenance for type one diabetes is continuous. I mean, you don’t get let up. And it’s like preventing that disease. It’s like those resources can then be used for other things. And so it’s, I think the benefit is, is beyond the people with type one diabetes, but to the society as a whole.

 

Jack Faris  11:49

And going back to the 20 plus years of effort of Teddy focusing on environmental determinants and environmental triggers, what have we learned that we didn’t know 20 years ago, specifically about triggers that are associated with the higher risk of type one?

 

Michael Killian  12:09

So that’s a big question. That’s 20 years worth of research, right? I think there are, there are a lot of different things that we that we didn’t know. There are a lot of things that were suggested. Viruses have long been thought to play an important role in this process. Teddy has really helped show better how those viruses which viruses are and kind of what that role is. Previous studies, some would say, Okay, well, this virus is a is a trigger. And other studies would say no. And because Teddy is so thorough, and we see these kids every three months, and you know, there’s a lot of blood symbols, we get a better sense of really what those infections are and how long they’re plaguing the child. And so one of the things that we’ve seen is that viruses that, you know, typically viruses shed in the stool every 30 days, but viruses that stick around for two months or longer, they increase the risk. And so it’s not just the virus, it’s kind of how that virus plays in that body.

 

Jack Faris  13:12

Are there any other specific triggers that you would recommend that parents seek to minimize or avoid

 

Michael Killian  13:21

avoiding triggers is is often a little hard. And also, I would say, you know, you have to be kind of careful, because we look at all of this in the context of type one diabetes, whereas when you’re looking at your child, you need to look at your child and their health as a whole, not just in one one thing, but there are some exciting things that Teddy has shown. One of them is the introduction of probiotics. I actually love this finding, because probiotics are very safe. They’re very inexpensive, and one of the things that we that Teddy has shown is that probiotics, in the first month of life, reduce the risk of islet autoimmunity. And so here’s this nice, simple thing that’s readily available that can reduce the risk very quickly without any any bad consequences to the child.

 

Bill Hagopian  14:14

Michael’s first comment about the families being willing to do this, a lot of it depends on the incredible skill of the clinical coordinators in our group and communication, because they are the ones, not me, it’s them that deal with the families, and they are great communicators, and they let people understand that this is a hard study. We empathize with you if you’re willing to do this for your for watching your child, but but also for other children to come in the future, it would be a noble thing to do, and they’ve managed to convey that in a way that people understand. So hats off to them. They’re incredible. They’re incredible communicators, and very consistent in their messaging about environmental triggers. There are other things that we’ve. That are modulators. It’s arbitrary that I call some things triggers and some things modulators, but given that I’ve worked on this for a number of years, maybe you’ll let me do that vitamin D. If vitamin D levels are abnormally low, then there’s more of a chance of autoimmunity, especially if you have certain genes. Vitamin C levels, higher levels tend to protect. Omega three fatty acids, higher levels tend to protect. So all the things that we kind of know are decreasing inflammation a little bit. They have a weak, but significant, scientifically significant modulating effect on the disease. But in reality, we’re most interested in the viruses. What I can tell you about viruses is studying viruses is like tracking ghosts. It absolutely is. It’s incredibly difficult work to do this in the human when you get a viral infection, you don’t know exactly what virus you got unless somebody sequences it. And you know that from the pandemic that we recently had about viral sequences changing and different strains of the virus. But before that, people weren’t really aware these viruses mutate a lot, and especially the small RNA viruses that we think are important triggers of type one diabetes, and so to find, even to understand, which exact virus it is, is difficult. The second thing is to know when they infected you. If you have antibodies, you were infected sometime in the past, but we don’t exactly know when, if you have symptoms and maybe you’re shedding some virus in the stool. And we did collect stool samples as part of Teddy then maybe it’s more definitive, but still very difficult. You can’t really ask somebody, can I sample a little bit of your liver and a little bit of your pancreas and a little bit of your intestines and a little bit of your lungs and your heart and see where the virus spread in your body? They won’t let you do that. They shouldn’t let you do that. So we don’t really know how far the virus spread in the body, for a given infection, how long it was there was difficult to tell. Typically, the viruses that were implicated are the same ones that people have hand waved as being important for the last 60 years, I saw an article in the British Medical Journal in 1968 about Coxsackie B virus and how it was seemed to be associated with type one diabetes. And sure enough, that’s the one, one of the primary ones, that we found. And I think that that’s important to realize, but we found it through sequencing the viruses that were shed in the stool. And as Michael so eloquently alluded to, it’s persistent infection with those viruses. It turns out the plot thickens. The virus becomes mutated, and it stays in the cell for a longer period of time. It can’t leave the cell, so it becomes a longer, more persistent infection, a little bit less virulent, but longer in terms of its presence, and that probably allows the immune system to keep on attacking the beta cell that holds this aberrant virus. And some of this speculation, we haven’t proven that, but there’s now becoming a lot of circumstantial evidence. Another very interesting thing is that by the inclusion of different genetic backgrounds, HLA Dr four versus HLA Dr three, we were able to get a different group of kids that were susceptible to type one diabetes but did not have Dr four. They only had Dr three. And because of that, we were able to identify kind of a second type of autoimmune type one diabetes, the second endotype, if you will. It seems to be distinct from the first one. The first one, which is probably Coxsackie B virus, initiated, triggered, has antibodies that show up in the first few years of life, whereas this other one, they can occur, you know, any time, at least through age 10, with a different auto antibody occur first. The early ones with coxsackievirus and Dr four get insulin antibodies first, whereas the later ones with Dr three, that are spread over a period of between ages three and ages 10, when they first show up, seem to be associated with gat antibodies first. So these are kind of different types, and they may have different triggers. Certainly, the age distribution is different. That suggests it’s a different exposure for the second kind than the first kind. That was a very interesting finding in Teddy that we couldn’t have gotten without our unusual and very, detailed study design.

 

Jack Faris  19:48

You’ve just painted a vivid picture of some of the mysteries of type one diabetes, including the ghost like viruses and these other variations. Michael, I’d like to ask you. So in your 20 plus years of being in this world of type one and dealing with these families, what are some of the common and often regrettable myths and misunderstandings that you get a chance to correct?

 

Michael Killian  20:19

I think one of the things that we’ve understood for a little bit, but understand a lot more now, is really the time that this takes, and that by the time you get by the time your child is sick with type one diabetes, this disease process has actually been going on for years. And, you know, people often say there was this one event, this one infection that then they got type one. And it’s like, reality is, like there were many other things that happened before, and that was just kind of the one thing that put them over the edge, which is, you know, from from our standpoint, this is actually really exciting, because knowing that this takes this disease process takes years, that gives us a greater opportunity to intervene before overt diabetes. Some of the other things is because type one diabetes affects your blood sugar, the thought of eating sugar is going to cause it, and certainly diet plays a big role in type two, but less of a role in in type one. All

 

Bill Hagopian  21:19

that Michael said was absolutely correct, but I should say there’s, there’s an overarching myth that I’ve noticed in our society that I would like to address, and that’s that science is anything abnormally special. All that science is, is a bunch of people in a community wanting to answer a question, what causes this? Or how does this lead to that? So they design artificial situations where something is going to happen one way or the other. They’re called experiments, and a definition of an experiment is a thing where you don’t know what the outcome is in advance, and they run these experiments, and the experiments are different variations, which I think is important, because if you have a whole community of 100 investigators, each designing their experiments slightly different, it cancels out everybody’s weaknesses, and The overall body of information is much stronger. So you run these experiments, you find out what the outcome is that you didn’t know in advance, and then you analyze using mathematics. It’s a very, very simple thing. It’s not magic, it’s not hocus pocus. It’s just a way to try to be as objective as possible in answering a question about what is happening in the natural world. So that’s what we do. That’s what science is. It’s just a formalized way to gather and analyze information. It’s nothing special. It’s nothing special. So

 

Jack Faris  22:56

I’m taking from that that your view is that to the extent that folks hold science as a in particular form of reverence, as something with mystique, is perhaps not to recognize the basic nature of what you’ve just described exactly.

 

Bill Hagopian  23:15

But there is another aspect to it, and that is, if you have these 100 people trying to interpret their results, writing up papers that the other ones critique before they are able to be published. That’s called peer review. You’re going to get a community of opinions. And if something is is the case that 90% of those experimenters kind of feel like it goes this way. This is the explanation. This is the way the natural world works, and maybe 10% feel a different way. That’s a pretty strong consensus. You’re always going to get some people that are not going to agree with others, because maybe they had outlier experiments, or maybe their something else in their life has affected their objectivity, or whatever. But for whatever reason, you’re not going to get 100% consensus, you can always find somebody that disagrees with the majority. And if the majority is 90% of people that do this work, then you have to take it as a pretty strong finding. Oh my gosh, this, you know, 90% of the people that did this came to the same general conclusion. This is a pretty strong finding. But, I mean, if you wanted to manipulate things politically, you could look at the 10% you could say, look, there’s two people that disagree. Well, yeah, there’s always people that disagree, but it’s a community, and it’s a consensus.

 

Michael Killian  24:37

I was going to add to what Bill was saying, it’s like, you know, science is somewhat boring, it’s very slow and it’s very methodical, and that is very much on purpose, which is, I think, in some ways, very different from society right now. We’re expecting answers right away, and it’s like, there’s like, well, well, you’ve been doing this, Where’s, where’s the information? It’s like, No, this. This takes, this takes time. We have to collect all this data and then start the analysis. And so while we’ve been doing this for 20 years and have published, you know, a few 100 papers, it’s like there’s really a lot more. And it’s really the tip of the iceberg of what TEDDY is going to provide to society, into the community.

 

Jack Faris  25:27

Would you anticipate that the data gathered in the 20 plus years of TEDDY will result in discoveries and findings that actually aren’t even anticipated today? Absolutely,

 

Bill Hagopian  25:38

absolutely that’s the case, something I alluded to earlier. How did Teddy fill a gap a need in terms of the way that we study triggers of type one diabetes? Well, the other studies didn’t necessarily start at a very, very young age, and we know that a lot of this triggering occurs in the first couple of years of life. So you have to start by proceeding that with your sampling, so that you can bracket the time that the exposure has occurred and that the reaction, the autoimmune reaction, starts. So Teddy started very early compared to other studies. There was frequent sampling. We sampled every three months for a blood sample, starting with age three months, very, very little babies that we started sampling, we collected a variety of samples. We collected nasal swabs and urine and stool and a little bit of blood, and later on, we even collected figure nails and hair to find trace minerals that accumulate in those, or maybe stress hormones that accumulate in those. So we took the samples and we analyzed them for a huge number of analytes. But also it’s interesting that because Teddy is so unprecedented in terms of the age spans and the frequency of sampling, we were able to study some other autoimmune diseases that are related to diabetes but not exactly the same. One of them is celiac disease, which is the autoimmunity that comes from a trigger called gluten, which is a protein present in wheat. About 1% of people get this kind of autoimmunity, and also antithyroid autoimmunity, which the body’s immune system gets confused and starts attacking the thyroid gland, and there are antibodies to thyroid and whereas that’s more of a disease of adults, it turns out it starts in kids, starts very young, as does the celiac and So we were able to study these things as well, these layers of data, these layers of omics, proteomics, metabolomics, lipidomics, transcriptomics, plus the intensive genetic analysis that we did, remember the genes aren’t something that changed the genes you born with, The genes you die with, but we did extensive analysis of the genes with a couple of very dense microarrays and many of the Teddy kits, we had the whole genome sequenced to fill in the gaps in between the single variants that were present in all these arrays that we did on all the Teddy kits, were able to really, really understand the underlying genetics of the kids that are in the study, and then how, as their islet auto antibodies developed, and then as they eventually developed high blood sugar and clinical diabetes, how all these other signals changed. And so if you look at when a virus infection occurs, and there’s and then there’s an eyelet auto antibody. You can look at all these other levels and try to understand the mechanism by which that virus triggered that islet autoimmunity. And that was the idea is that we would have a the chance to do something really complex, which is to understand the mechanism, a little bit of clues as to the mechanism of action. One

 

Jack Faris  29:02

thing that’s implicit in your description of TEDDY is that even if you had 10 times the budget, you couldn’t do TEDDY in a year. It requires that longitudinal timeframe and tracking kids from earliest months to the age of 15. In the case of Teddy. Michael, I’d love you to talk a little bit about the way in which TEDDY and the TEDDY participants can help shape a more sophisticated and accurate sense of how science works in the broader community. You mentioned that we are an impatient society. We want the answers tomorrow, if not yesterday, but TEDDY is the counter example. So

 

Michael Killian  29:45

TEDDY is but also Bill talked about, you know, we design experiments, and, you know, these are somewhat artificial, and so there are limitations, which is why, you know, the next step is to do a blinded. Control and see really what the what the impact here is. And, you know, no matter how well we try and design an experiment, because we can’t recreate everything that happens naturally. You know, there are limitations on that with TEDDY because it’s such an involved project and so expecting so much of the families, so much, you know, resources from the institutes and from the government to fund it. You know, we really had to limit who we were following in the study. And so really had to take the children who are at the highest risk for type one. And so this does, this does alter what you may see in the wild, type, if you will. You

 

Jack Faris  30:47

I like you both to talk a little bit about how the parents and the children who are part of this are exemplars of the kind of, I’m going to see altruistic behavior that we actually need more of. I would hope that that we could find ways to appreciate more broadly and more fully the contributions that these people make to the advancement of science that can benefit countless people, really, over the years. I mean, if we find a better way to intervene in the progression of type one diabetes, that isn’t good just for this coming generation. It’s good for all generations to come to follow. It is

 

Michael Killian  31:35

amazing and somewhat staggering to think that you know how much these families commit and contribute to this research? It’s one thing. This is this is our job. This is what we’ve decided to do. But these people really are volunteers, and the vast majority of these children will not get type one diabetes, and so these families and these children are here just to help those future generations, and it’s I stand in awe of how much they do and how much they continue to contribute. When these families come in, we do interviews, and we are very much in their lives. We want to know everything from stressors that have happened to any illnesses and everything. And the families are they, they freely give this information. Among

 

Jack Faris  32:28

the things they give are their children, just baby teeth once they fall out. And for most of us, baby teeth are those charming, kind of odd shaped things that we put under the pillow and then manipulate the imagination of our kids, but for your scientists, they are sources of data. And could you tell us just a little bit how that actually works? So

 

Michael Killian  32:51

we wanted to collect baby teeth as a way of looking at exposures. But you brought up the point that, you know, we we put them under the child’s pillow. And so we were like, Okay, well, we’re taking these teeth now. So we, we actually had to generate letters from the tooth fairy saying that it was okay to to give these samples to the Teddy study. But yeah, the teeth are the teeth are exciting. It’s nice because they’re going to come out anyway, but it is exciting in that you can actually peel away each layer of the enamel and kind of see a fossilized record of what those exposures were.

 

Bill Hagopian  33:32

So I imagine from the teeth we can get records of, for example, heavy metal exposures. Now I never thought, and I still don’t think that heavy metals contribute to type one diabetes triggering or risk, but remember, this is our one shot in Teddy to look at all the environmental exposures, and we don’t want to leave any stone unturned. And so looking at heavy metals in urine and looking at heavy metals in teeth, I think is a very important thing to do. There’s also things like trace elements, like selenium. And it turns out that selenium can also be measured, I believe, from these things and teeth and nails and hair, and I think it’s an important immune modulator in some circumstances. And so we wanted to look at that. Another thing is, we wanted to look at whether stress causes or accelerates autoimmunity. And of course, that’s a that’s a well known hypothesis. And so if you measure somebody’s stress hormone cortisol in their bloodstream, you get a snapshot of one point at time, but really it’s the release of cortisol over the course of a day, and then over the course of many days, that really matters the most. And so this cortisol actually accumulates in hair and nails. And so by testing the amount of cortisol in those we can get an accurate sort of idea of sort of how much overall. Overall cortisol, or overall stress the child underwent during a number of months. We started out with hair, and then, actually, it turns out our TEDDY kids were not too keen about cutting off pieces of their hair and giving them to us, because I think it affected how they looked. So we switched, I believe, to nails, fingernails, toenails, or toenails, excuse me, and that worked much better, and everybody was fine with it. So that’s an example of how we adapted our approach to what was necessary by the families. It turns out, when we were starting the TEDDY study that we had certain criteria for high genetic risk, and that was to make the study economical. Even though we spent a huge amount of government money on this study over 20 years, we wanted to make it as economic as possible, and so we started with high risk kids, and we screened them for HLA types as our genetic marker. We got about four or 6000 kids out of the kids that we screened, or even more than that, that were actually eligible for TEDDY and then what did we do to try to recruit them into the follow up? Well, we actually tried the opposite. We tried to scare them away. We said to them, if you are in this study, we’re going to have to get a blood sample every three months, and you’re going to have to fill out a bunch of questionnaires, and it’s a commitment, and you can’t, you can’t quit. Well, you can quit if you want to, but we don’t want to have people quit because then it’s a waste, and we really want people that are firmly committed to being in the study over the long term. So we were honest up front. We told them what was going to be required. We told them it was tough. We got about 14 178 kids, families that agreed to do this the long term follow up, and that’s one of the reasons why we got such great retention after 15 years, it’s still 68% of the kids are participating in one form or another. I should say that the kids really, really are part and parcel to the whole thing. We started out educating them the parents. And the parents would tell their kids, well, you have to do this. But as as the kids got older, it was the kids that the coordinators talked to, and they were the ones that had to be invested in the study and committed to the study. And they were, I mean, they were understanding the science, and they were getting into it and and they were touring labs, and we did science days, you know, Michael developed and ran TEDDY science days. We had one at the Pacific Science Center. We rented out some space, and he did just a masterful job. So

 

Michael Killian  37:49

I would just say, I mean, anyone with children understands trying to get your child to do something and go somewhere where they don’t want to. It’s more than doubles the effort there. And so as the children got older, we thought that, you know, we should really try and engage the children, get them excited in science. And so that turned into a larger consortium effort. And so I like to think that there are a lot of really young scientists out there that are, you know, that are going to become great scientists and discover things, because we kind of sparked that interest in them early.

 

Jack Faris  38:27

That is a happy thought. Indeed.

 

Michael Killian  38:28

I think that is the exact thing that is exciting about science. It’s like, you know, you start off on one path and you don’t know where all that’s going to lead. And certainly with Teddy I feel like, you know, even with our focus on type one, it has led in more directions than than we realized.

 

Bill Hagopian  38:52

Once a person was in TEDDY for a while, we really bent over backwards to give them different tools to be able to stay in the study if they had a difficult circumstance, if they moved to a different part of the state or a different state, we found ways to sample them by mail, mail based kits, and remotely by telephone interview, in order to keep their ability to participate and make it as easy as possible on them, make it practically possible at all for them to take part in this study and continue with it. And

 

Michael Killian  39:23

that was our learning part. We we had to learn. We had our protocol. We had to learn how to really make it work on the ground,

 

Jack Faris  39:31

yeah, to invent solutions to help retain people so that even the underrepresented are still represented

 

Michael Killian  39:39

exactly. You know, TEDDY, it took 20 years to do it. Well, TEDDY is also creating a repository of data and a repository of samples, and that information will be available to future researchers, and so this will the next 20 year project. Doesn’t have to take 20 years we’ve done. All that, all that hard work.

 

Bill Hagopian  40:06

So the extent of what we were able to collect in TEDDY definitely will fit the trumpet model, because there’s so much wonderful data. It complements each other. It was collected in a very rigorous way, by a uniform protocol across all six sites, and there was long retention. I mean that I think it’s absolutely going to lead to many discoveries in many different fields. I alluded to celiac disease and thyroid autoimmunity, but also many other diseases. I should say that the virus stuff is very exciting because it’s very low toxicity, believe it or not, to make a vaccine against a virus, and you can give it very early in life. So this is an exciting way that virus discoveries can lead to prevention of diseases like type one diabetes, I think that’s a really important aspect to to our our virus work, and it’s very exciting. I think also that there may be two different kinds of autoimmunity appearing at different ages and different kids based on their genetic background, because it was completely unknown even, I mean, it was not known for sure that coxsackievirus triggered type one diabetes. We still know for sure, but we have a whole different set of data that suggests that that’s the case, along with everybody else’s data from the rest of the scientific community over the last five decades. That becomes very exciting. But other viruses, we can look for other viruses, and we can find those and immunize against those as well. The beta cell, the insulin producing cell in the pancreas, happens to have a welcome mat that’s part of its genetic makeup. That is laid out. It’s a functional protein that has to do with electrical signals, but it’s it turns out, it’s been used by several different viruses as an entry point into the beta cell. This welcome mat is called the Coxsackie adenovirus receptor. So it may well be that that second kind of diabetes is triggered by an adenovirus, like adenovirus 41 which causes gastroenteritis, causes diarrhea in these kids, and if you know that the duodenum just wraps right around the head of the pancreas, you can understand how an infection in that duodenum might actually cause some ramifications in that in the pancreas.

 

Jack Faris  42:40

Bill, you mentioned the notion new to me, that there are some adult type one folks hidden amongst the much larger type two diabetes population. I’d had not heard about that before, and I think our listeners would be annoyed at me if I didn’t ask you to elaborate on

 

Bill Hagopian  43:01

that. Well, doctors and nurse practitioners are wonderful people who do their best to treat the patients that they see. But it turns out that type 1 diabetes in adulthood comes on a little more slowly. There’s more maybe immune cell regulation that’s developed during the course of a person’s lifetime, kind of looks like type two. There are some clues that it might not be type two. It might be type one. They’re a little thinner, they don’t have a family history of other people with type two diabetes in their family. They may not have type one because it tends to skip generations. So their parents might not have had type one, their siblings might not have had type one, but somebody back somewhere probably did, but that’s usually lost. So these patients look like type two diabetics and but it’s important if you do autoantibodies or C peptide or there’s a number of ways, you can very simply identify among those type twos, who’s a type one, and it’s kind of a little bit of needle in a haystack, because, you know, there’s 20 times 30 times 40 times 50 times as many type 2 diabetics as there are type 1 diabetics that occur in adulthood. And the ducks don’t even think of it, and the nurses don’t even think of it, until they fail their pills and they go, Oh, maybe you have type one. Let’s try you on insulin, which is a difficult thing for patients to go through, and so one of our our goals is also to take the new onset diabetics that occur during adulthood, make sure they get tested for auto antibodies, so we know what kind of diabetes they have, and put them on the right therapy right from the start. If you since the number of years of adulthood is longer than the number of years of childhood. If you add up all the cases of type one diabetes that appear in adulthood, it’s actually twice as many as the number of cases of type one diabetes that occur in childhood. So we called this disease juvenile diabetes. Diabetes, and yet, there’s more adults that have new onset juvenile diabetes than juveniles. There’s a way to find them, and we’re hoping that that makes it into standard medical practice.

 

Jack Faris  45:19

What makes you optimistic about the future of science,

 

Michael Killian  45:23

I think it’s as technology continues to increase, and we’ve seen this in TEDDY over the last 20 years, the things that we can do now, with the samples and the analysis that we can do is just light years ahead of where we were when we started, and so I think that continuing be able to look at things in ways that we never even knew were possible,

 

Bill Hagopian  45:48

I think that one of the things that will drive medical science in the future is the fact that we have two thirds of the work being funded by the government and done by academicians, and the last third being done by companies, which then make a product that comes to market. So that whole thing together sort of drives the whole process. The federal government kind of thinks their job is to facilitate business in the country. I mean, they dig the roads that the loggers use to go into the logging country, and they they do if they facilitate a lot of business activities, you know, and that’s part of their role. And this is always going to be facilitating business activity, this basic science that we do in medicine. And I think because of that, I think it’s important, there’s a real motivation for the government to keep funding it, and for the advances to be made. I also should say that the structure of science has become, you know, pretty rigorous and pretty well defended that, you know, decent journals always have peer review. Articles don’t make it into press unless they’ve been peer reviewed and appear to be correct. Of course, there’s always people chipping away at the edges trying to break down that system, people that could benefit from trickery. But I think that by and away, our scientific system is really intact and really strong and really robust, and the answers that we get are answers that are reliable. So I’m very optimistic that this activity will continue and will continue to make all of our lives better. I

 

Jack Faris  47:26

want to thank you both Michael and Bill for most interesting journey through type 1 diabetes and TEDDY and related matters and thanks again. Cheers.

 

Bill Hagopian  47:39

Thank you. Thank you very much, Jack.

 

Anna Faris  47:42

Thank you for joining my father and me for this episode of PNRI Science: Mystery and Discovery. To learn more about PNRI and get connected to our groundbreaking science, go to pnri.org/connect. We would love for you to join us for a tour of our labs or a virtual event with our scientists. Thank you for listening, and we hope you’re inspired to learn more about genetics and chat with your friendly scientist neighbor. I’m your host, Jack Faris, CEO of Pacific Northwest Research Institute. I’m also a regular guy Dad. What do you think? How’d I do?

 

Jack Faris  48:17
Better!