Stephen Chanock

Bret Kugelmass
We are here today with Dr. Steven Chanock, who is the Director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, which is part of the National Institute of Health. Dr. Steven Chanock, welcome to Titans of Nuclear.

Stephen Chanock
Well, thank you. It's a pleasure to be here.

Bret Kugelmass
Yeah, we're super excited to learn about your field of research. But before we do, we'd just love to learn a little bit about you. Tell us, where did you grow up and how did you get into this space?

Stephen Chanock
Well, I grew up here at the National Institutes of Health. My father was here, I came here when I was two years old. I've been here 63 years, but only 30 years in a professional category. I grew up surrounded by scientists and dancers. My mother's a professional, modern dancer and I myself thought I was gonna have a career in music. And then about age 21, I decided, well, I thought that I could do something socially, even more powerful, and that was to go into medicine, so I chose to go to medical school as I was finishing my college degree in music.

Bret Kugelmass
Did you play a specific instrument or sing?

Stephen Chanock
I played the piano and harpsichord and I studied composition.

Bret Kugelmass
What's a harpsichord?

Stephen Chanock
A harpsichord is a 16th and 17th century instrument that's a predecessor of the piano in which the string is plucked, as opposed to hit by hammers. I have two harpsichords here. The one down here is out of tune, so I'm not going to play that. Upstairs is a new instrument. So I went into the study of Pediatrics, and I had a series of sort of seminal events that that drove me towards cancer. The most important one was the loss of my own brother to a pediatric cancer while I was in medical school. I was learning and steeped in medical education. My own brother, who was a little bit older, developed a rare pediatric cancer treated here at the National Cancer Institute and succumbed within one year. That was quite eventful and had a such substantive impact on myself. And at that point, I decided I really wanted to focus on cancer, particularly pediatric cancer. That led one thing to the next and so my training was in pediatric cancer, up at Harvard in the Boston Children's Dana-Farber, and I started to get very interested in the laboratory, because when I left NIH as a kid, when having grown up there and went to college, the last thing I wanted to do was go into medicine, and even further away from that was research. And so here I am, back in NIH doing research and absolutely fascinated by it.

Bret Kugelmass
And how does that work? When you go to med school, is there a different program if you want to go to the research route? How does it- I've got family members who have become doctors and so I know they go to med school and they do something called an internship and then a residency. How does it work when you're also doing research stuff?

Stephen Chanock
Well, it really selects those individuals who are motivated and want to do that. I did what's called an advanced fellowship in pediatric hematology, oncology and infectious disease, and that requires time in the laboratory. I went for two to three years, stayed five years, and then was recruited 30 years ago, almost the day, came down here to the National Cancer Institute, to the very program in the very ward where my late brother had passed away to be an investigator and devote myself to try and solve many of the problems related to cancers in children, but then I've since transitioned to all cancers. Seeing just the complexity of how cancers develop, and what causes them and their individual manifestations is really scientifically fascinating, but to me is a public health issue. It's a major crisis.

Bret Kugelmass
And why - this is gonna sound like a really strange question - but why do kids get cancer? Like I assume cancer comes from some, I don't know, environmental exposure to something or?

Stephen Chanock
Well, it's an interesting question. Cancer is complex. Each of us are born with our own genomes and our own genetic makeup with subtle little differences in how we respond to things. We see most pediatric cancer is driven by a particular restricted number of activities, exposures, most of which we don't really study and we don't really understand well, and then what the background of that particular person is randomly developed, usually. That's where something happens. It's unfortunate. We're going to talk about the studies where we really have the- Dr. Morton and I are leading it. We really have that remarkable opportunity to actually study something where we know a lot about the exposure in young children and when they developed it and what that looks like. It's a very important question. Pediatric cancer is a tiny fraction of the nation's burden of cancer, but it's a particularly important one, because these are young lives with an entire future ahead of them. We treat well, but not well enough. Until we're at 100%, we don't stop.

Bret Kugelmass
And yeah, we'll get to the specific case that we're going to talk about later on the papers, but I guess, just before that, are there certain cancers that are more common among children? I assume you can get cancer of anything - cancer of blood, cancer of brain, cancer of-

Stephen Chanock
Yes, there are- it's very interesting, because the cancers we see in children usually point towards particular vulnerabilities in different organs in different parts of development. Remember, when children are born, they're not little adults. They evolve, they develop over years, and when those things are going on and the brain is changing, or the liver, or the kidney, or whatever, often it's not a continuous development of growth. There are these spurts or changes and we think that may be important to how we see some of these cancers develop. We know there are particular types of cancer, types of leukemia that are seen in younger children.

Bret Kugelmass
And leukemia is a blood cancer, is that right?

Stephen Chanock
Blood cancer, yes, and that's the most common type of pediatric cancer, what's called acute lymphoblastic leukemia.

Bret Kugelmass
And is that like 50% of all, or what percentage of all?

Stephen Chanock
One third, roughly 1/3 of all pediatric cancers are leukemias. There are multiple types, but the acute lymphoblastic leukemia is about 75 to 80% of that fraction of roughly a third, which are leukemias. And then brain tumors, and then tissue, soft tissues, so what we call sarcomas are seen, or developmental tumors of the kidney, Wilms tumor or neuroblastoma. These are unusual, but they have very interesting, so to speak, footprints when we look at them genetically and in terms of how they develop.

Bret Kugelmass
And then, just so we can proceed along with your career a little bit, you start researching this topic. It's obviously very personally important to you. How does it work? Do you become a junior researcher and then a lead researcher? What is the progression of study?

Stephen Chanock
Those titles all reflect this stage in which someone goes through. I like to think of research as sort of like the medieval guild. If someone wants to be a master shoemaker, you start working next to a shoemaker, you make it for a while and they say, Yeah, you're doing well here, you can make this shoe on your own. And then they sort of watch at a distance and you've done it well enough that sometimes you have to go off and have your own shoe shop to make your own shoes. And the progression of sciences is very similar, I think, in that you work underneath people who were are experts and accomplished and then you acquire more and more of your own responsibility and independence and that takes place over a period of time. Then you show that you can be independent, and then you show that you are really recognized internationally. I'm describing each of these levels or stages, will be described with what's a fellow postdoc, a graduate student fellow postdoc, junior faculty, assistant professor, associate professor, full professor, and then chairman of the department. There is an academic flow. NIH has something similar, it has slightly different names, but they have very similar types of criteria.

Bret Kugelmass
Then do you have to get more and more specialized as you advance in terms of narrowing in? Or can you stay broad within a sector like pediatric cancer?

Stephen Chanock
It depends on the individual. Some people, they're fabulous at studying one thing, and they're going to take that really difficult nut and crack it over 30 or 40 years, and stay focused on that one protein or that one thing. Then there are some who alight on a number of different subjects and sort of see where things are more interesting. I put myself more in that latter category. I have colleagues who- I've been here at the NCI for 30 years - who have been studying and doing incredibly interesting things, but the five genes and the five things that they're slowly but surely pulling apart.

Bret Kugelmass
Yeah, oftentimes, I mean, in my space, whether engineering or energy, oftentimes we find that people are able to derive inspiration from cross-disciplinary cooperation. And so I was wondering if the same is true in medicine, whereby kind of jumping around and maybe kind of touring somebody else's lab, spending a year here, a year there, you're able to pull concepts and ideas that then help further the science of your niche sector as well.

Stephen Chanock
I think that the principle's there. I think that jumping around too much is dangerous. I think that what one of the things that a good scientist should have is the intellectual curiosity to read and to expand their horizons and say, Alright, I don't know much about that, but I'm going to read about that. And I know that Sally over there, or John, knows a lot more, I'm going to talk with them. Maybe there's something that I'm doing that can complement what they're doing and vice versa. I like to think of the organic nature of collaboration. When people are moving around too much kind of makes some of us senior level a little too nervous that- you gotta have your bearings. Again, going back to the medieval shoe builder, you've got to make your shoes. You've got to have your soles, your laces, the size. You have to continually show that you can put finished products out and that you really can have sustained trajectories to the science that you do.

Bret Kugelmass
And then before we move to today's work, were there any other highlights of your career areas that you focused on, that you're world renowned for?

Stephen Chanock
It's a strange question, but okay. I guess I've received awards, because I've been very involved for the last 20 years in mapping parts of the genome that are very important for susceptibility to cancer. And then also, in that process, we are coming across these interesting quality control issues that we've learned and we've been from the leaders of understanding that your genomes fall apart with age. At age 40, 50, 60, you start to have a few more mistakes in the replication of your genome. These things start to select. By age 60, 35% of the men who were listening have part of their Y chromosome that's lost from a good fraction of the circulating blood cells. Now, they don't need it anymore. Is there a relationship for that to risk for cancer and other diseases? That's what we're studying. But, again, that's a really interesting question of how does your genome start to fall apart and what does that mean?

Bret Kugelmass
And as far as - and pardon my ignorance - but you start off, let's say, with one genome, right, when the egg and the sperm first come together, you've got your unique DNA. Then it divides and divides and divides and forms all the different parts. But then does each individual cell start degrading in different ways?

Stephen Chanock
It's a terrific question. We can see, with extended age, yes, and they're very small ways. Every time the cell replicates, there is an error rate. It's very small, 10 to the minus eight pinos, one in between 10 million and 100 million cells. We make errors periodically and part of our program of our bodies is to delete those errors, but sometimes those errors can have an advantage that they can be able to continue on. This gets at really one of the key questions in adults is, how do cancers in adults form? Is it due to these intrinsic background random errors? Are some of those exacerbated by cigarette smoking, UV light exposure, things that are bombarding the genome and increasing the number of these background events, that if they hit the wrong gene in the wrong way, then that cell starts to grow in an uncontrollable way, which is the definition of cancer. We know that there's a constant circumstance, and we know that you do see your genome continually replicating in different cells and there can be errors. There are two ways to look at this. One, it's amazing that life works and it does because the program works really well, and by and large, that happens. But then there are times when the wrong thing happens and we're trying to understand why that happens, how the environment and those proclivities for errors take place to then allow something like cancer or Alzheimer's or diabetes, some of the chronic, some of the acute diseases that we see. I like to be more on the optimistic side that it's remarkable how well the human body works, but it's not perfect. That's something that many of us forget when we go see the doctor thinking everything has to be perfect. Well, you have to take the philosophical view in the same way every shoe is a little bit different with the shoemaker.

Bret Kugelmass
Okay. Now maybe we can kind of bring you guys together and learn a little bit about, where did your paths intersect? Is this the first project you've worked on together? Or have you been bouncing around the same building and bouncing ideas off each other for a while?

Stephen Chanock
The latter, I mean, we've worked together now for 15 years, different kinds of projects and things. Where we work is a very, very remarkable place. It really focuses on what we call "Team Science," so we bring people with different kinds of expertise together to work in teams. Most of the papers that are published by the division are Team Science, where you have multiple people working together. That's really essential. The different expertise have different perspectives and it helps to really enliven, but more importantly, give really important insights.

Bret Kugelmass
I love that idea of Team Science. How do projects originate? Is it a grant process? Is there a big brainstorm session? Is there- here are some top-down from Congress, here are some areas that we're interested in, now go spend this money, How does it happen?

Stephen Chanock
Well, it's a terrific question. The National Institute of Health is a very large funder, and it's made up of 27 institutes and programs. The National Cancer Institute is the largest of those. And within the National Cancer Institute, which has a very large budget, about 85% of the money is sent out in grants that people all over US and some other countries are able to compete and have funding to be able to do cutting edge science that's peer reviewed. A certain amount stays in the intramural program and we're one of the two intramural programs where we are given a budget per year. And then we have 71 senior scientists and a number of other experts who are part of our group, and then we look programmatically and decide what's a high priority, such as studying the genomics of survivors from the Chernobyl accident. The advantage of the intramural program is that we can think strategically over a long period of time. So the studies that you want to talk about with Chernobyl, we have investigators who are going back to the early 1990s that identified, the epidemiologists went there and started to organize and follow individuals over an extended period of time, because we needed to know what the time course would be in which people would develop problems such as cancer or cataracts or heart disease and we're particularly focused on cancer. Our funding is really focused on high priority issues. We like to think of ourselves as sort of doing the people's epidemiology. We do a lot of things that are difficult. We study a lot of subjects that aren't popular. But they're important to know about contaminations in the in the environment, whether they're radiation or from other kinds of things like pesticides, or occupational exposures. I mean, those are the kinds of things that we need to know what those true cancer risks are. That's one of our major goals.

Bret Kugelmass
Okay. That's a great segway into my next question. Radiation: what is the mechanism by which radiation causes a cancer?

Lindsay Morton
Part of what was so exciting about the thyroid cancer genomic sequencing project that we did was that this was one of the first opportunities to actually ask that question, using the cutting edge genomic advances that have occurred in the last few years, as well as all of the incredibly rich data that were collected by the Chernobyl Tissue Bank, and a number of collaborators. Of course, we've known for years that ionizing radiation is a carcinogen. There have been a tremendous number of animal studies, studies just in cells, trying to understand what damage is caused by ionizing radiation and how that might cause cancer. But it's been really difficult to actually link that to specific human tumors. I can give you-

Bret Kugelmass
Why is it difficult? Like, why is one mammal so different than another mammal and the way that ionizing radiation might, I don't know, what does it do? Does it break apart a DNA strand?

Lindsay Morton
It does. It has a variety of different impacts, and this is known from a field that's called radiobiology. It's been known for a long time that ionizing radiation causes a variety of different types of damage in the cell. It's long been thought that the most important was breaking of both strands of the DNA and that those strands either remaining broken or being formed back together, perhaps in error, could cause cancer. But there are other types of damage, as well, that are still being characterized. Some of that is more clustered damage or individual basis, or just single strand damage. And because, again, I was mentioning the advances in genomic technologies, we're still learning how cancers actually develop, then it's difficult to link that actually back to the exposures. A lot of the research that's been done trying to understand the process of cancer development, and all of the different genomic damage that's characteristic of cancer cells, actually has not included any data on risk factors. So it's included clinical data, or pathology data, but not the risk factor data. That was one of the exciting things about the study that we did, where we were able to bring together the exposure data, and all of the genomic data.

Bret Kugelmass
And still on that point, though, not to sound like an evil guy or something, but can't we just like, put a bunch of mice in a cage, blast them with some radiation, and then look at them under a microscope to see what's happening? Is that crazy?

Lindsay Morton
Stephen, do you wanna talk a little bit about animal models versus human?

Stephen Chanock
Okay, well, you can do it, and there is a long history of doing that. But not all radiation is necessarily the same, so to speak. The reason I say that is how much and in what way you get it may be very important. Animal studies have taken rats or dogs and just buzzed them in very high doses. And we've learned some important things from that, but in the human situation, what was really remarkable is, the first time where we knew from the Chernobyl accident from our health physicists, and our remarkable colleagues in Ukraine and elsewhere, exactly how much exposure they had over what period of time, so we can actually map the genetic changes we saw back to discrete, protracted period of time. It wasn't just standing in front of the machine and getting buzzed. We know from other studies where people have developed cancer after receiving radiation on therapy, that there are certain features and they're similar to some of the ones that we've seen, but not always identical. It tells us that it's not an either or comic book model that sometimes gets portrayed as, so how and in what way people get the radiation may be particularly important.

Bret Kugelmass
Now, our audience is very familiar with the types of radiation - alpha, beta, gamma - is that what you're talking about in terms of the differences in different type of radiation?

Stephen Chanock
Among other things, I think, it's there are different types of radiation. And here we were particularly able to look at I-131, iodine, which this setting that was a substantial fraction of what was released in Chernobyl, and it fell in the environment, got into the grass, so the cows started to eat the contaminated I-131 grass, concentrated it in the milk, served it to the young kids - because remember, this was Soviet Union 1986, you didn't have Uber Eats - they ate only, they had very restricted diets that were very, were sustenance diets, but not with any real variety. And so milk was a critical factor in these children that we studied, were drinking lots of milk around that time when it was contaminated. So we can start to understand how the model of the exposure occurs and then what that actually did in the genome. This is the first real look in humans for understanding what- we know ionizing radiation causes cancer. It's an International Agency for Research on Cancer. IR monographs have established this as a Class 1 type of carcinogen, we all know it can cause it, there are things that radiation can do that are very, therapeutically very helpful, but it can also be devastating. And that's that wide range. And now we're in this study beginning to understand what those effects could be that lead to specific cancers.

Bret Kugelmass
And as a result of the Chernobyl accident, other than the local radiation induced harm from the cleanup workers, is this the extent of the harm that was caused, specifically the iodine-131 exposure to children? Because we know that there are a lot of radioisotopes that were emitted, we know a couple of them can find their way into biology, such as strontium and cesium, have we effectively narrowed it down to it was just the iodine-131 that ended up causing the cancers?

Lindsay Morton
I think it's a little bit more complicated than that. The reason we're so focused on I-131 in this particular study was because of the concentration in the thyroid, more thinking about that particular exposure.

Bret Kugelmass
That's my question, the very act of it spreading across half of Ukraine and Belarus, in essence, dilutes things, which makes them less toxic, but the ability for to re-concentrate through the grass mechanism, and then once again, re-concentrated in the thyroid, is that the unique characteristic, or was that characteristic unique to iodine-131 that allowed it to become a potent carcinogen?

Lindsay Morton
I think that is the description of what happened with the I-131. But when we look at our exposures, look at the exposures and the studies of long term health effects and the cleanup workers, we don't just account for the I 131 exposure, we look at other radioisotopes and external exposure.

Bret Kugelmass
Yeah, the ones who are very local, I was thinking more about more of the stuff that got spread out.

Lindsay Morton
More broadly in the residents. And we think about our studies of the adverse effects of the Chernobyl accident in these two categories of what happened with the cleanup workers versus what happened with the residents of public. Fairly quickly, the focus was on thyroid cancer in the young children. But it's really important that we continue to monitor these populations and in fact, have ongoing collaborations and studies where we're looking at other health outcomes in the residents as well as in the cleanup workers.

Bret Kugelmass
How are we able to map the exact exposure of any given individual?

Lindsay Morton
Right after the accident, the Ukrainian government, actually, and Belarusian and Russian governments, actually, made a number of measurements of radioactive iodine, so direct thyroid measurements in the residents and the surrounding areas. And so the team of radiation dosimetrist, the physicists who are collaborators on the project, have worked together to extrapolate information from a combination of different sources, including these direct thyroid measurements.

Bret Kugelmass
And the kids that did end up getting cancer, what was the dose that was imparted on them that trigger that?

Lindsay Morton
There was a whole range. One of the important aspects of our analysis is that we were actually able to do what we call a dose response analysis. Because individuals had different doses, and those doses have been reconstructed, we could actually model the dose level in relation to the level of the genomic characteristics.

Bret Kugelmass
And what was the range, the upper bound and the lower bound of people who got cancer?

Lindsay Morton
Well, in the study from individuals who are unexposed, because we included unexposed individuals who develop thyroid cancer in our analysis-

Bret Kugelmass
-as a control group?

Lindsay Morton
- a comparison group, to individuals who just had a few milligray up to individuals who had more than one gray, estimated radioactive iodine dose to the thyroid. Bret, what I was going to say before, as you were talking about different types of radiation, I also wanted to point out that - we can talk about this more when we think about the implications of this study, but you are asking about the different types of radiation, and that this audience might be really interested in understanding that - in our broader studies in the radiation epidemiology branch at the National Cancer Institute, we consider a number of other effects as well. So it is the type of radiation and here we're focusing on radioactive iodine. I've already mentioned with the cleanup workers, we take into account their more complex radiation exposures. But we study patients who were exposed for both diagnostic and therapeutic medical irradiation, so we think about, it's not just photons, protons, we also think about dose rate and the duration or the fractionation when we start to think of therapeutic exposures. What was the fractionation, what were the fractions of their exposure, so maybe a patient received 30 gray to a particular body region to treat a tumor, so that was this kind of how much of the body is exposed and to what dose level, what type of radiation and at what dose rate. And we try and account for all of those things in our radiation, epidemiology studies.

Bret Kugelmass
And then-

Stephen Chanock
Can I add please, Bret, that I think it's also important to recognize what we're studying here in Chernobyl are those people that have survived to this point. We know that when the accident occurred, there was very high exposure for some who died of acute radiation sickness. They developed leukemia or aplastic, anemia, loss of blood cells in a relatively short period of time. In the chaos of the first few years afterwards, there was not a a structured way to capture those and that's very important to recognize. We're looking at individuals, some of whom had very high levels of exposure, but they've survived and they've gone on and the question that they then subsequently develop the most common type of cancer in younger individuals who see I-131, thyroid cancer, the papillary thyroid cancer, but we were not able to capture all of the cancers that occurred due to this. And this is an ongoing controversy that I don't think anyone will ever be able to fully answer. But we fully recognize that there were many things that occurred around and shortly after the accident that clearly led to cancers that we can't quantify simply because we don't have the information the way we do with the survivors.

Bret Kugelmass
Okay, you're saying among the cleanup workers, those are the ones that are harder to quantify?

Stephen Chanock
Or even the evacuees, people that live there and had- remember, it took a period of time before the Soviet government actually recognized and mobilized, so you had individuals who had days of quite extensive exposure in the Pripyat in that nearby region.

Bret Kugelmass
Exposure to which radioisotopes, iodine-131 or others?

Stephen Chanock
Others as well. And so again, that's a group that we have not been able to study as well. So I think we have to recognize that we are, we've been able to set in at a certain point, but there was a degree of exposure. And this is very important in both the Ukraine and the Belarus as they continue to think about this and how and in what ways they both honor and recognize those things, those health consequences that did occur directly due to the Chernobyl accident.

Bret Kugelmass
And specifically with thyroid cancer, one thing that I've read is that sometimes like they'll detect nodules, and then they won't become malignant. And so now there's like a practice amongst doctors to actually not go in and do biopsies, even if they feel the nodule. How do we tell the difference between something that might become cancerous and something that can definitely become cancerous, and how did they do it back then, from looking at those kids? How did they have the account maybe for over-inspection error?

Lindsay Morton
Remember that, actually, a number of patients who are included on our study were actually diagnosed with their thyroid cancer, perhaps just in the last decade. And so our study is taking place against this whole background of what you're talking about this evolution and our understanding of thyroid cancer development and precursors to thyroid cancer, and really this debate about the best clinical approach to handling thyroid nodules. The complexity of that is certainly one aspect that underlies our analysis, but a fraction of the tumors that were identified in our study were identified through screening. Others were just identified through routine clinical exams, or perhaps even recognition of an enlarged thyroid. But I'm hoping that in future analyses, if we can do a little bit more of this similar genomics work with some of those benign nodules, we'll better understand kind of the genomic progression. But right now, there's not a good predictor for understanding exactly which nodules will go on to develop into a frank malignant tumor.

Bret Kugelmass
And what's the delay between exposure and onset of a cancer, in thyroid cancers and then, let's say, in other cancers as well? Is there a gap between when you're exposed to the radiation and when it becomes a problem?

Lindsay Morton
I think it's really important to differentiate between what what's happening in a specific individual versus what we understand from the larger scale epidemiologic approach. And so, from epidemiologic studies, we generally think of radiation-related solid tumors of taking at least five years, or up to decades to develop.

Bret Kugelmass
And what's happening biologically in that time period?

Lindsay Morton
We haven't known exactly. What we can tell with this particular analysis is that it appears that the ionizing radiation caused DNA double strand breaks in key genes that then allowed those thyroid cells to actually transform into tumor cells. But we don't have, we don't look at tissue, for example, that's been exposed to ionizing radiation over time, taking, for example, multiple biopsies in healthy individuals, you could never do something like that. So we don't know exactly what's happening. It could be that, for the particular type of tumor, ionizing radiation causes damage, but that damage itself is not sufficient to cause cancer. So that cell is sitting there partially damaged from the ionizing radiation, but waiting for another mutation to occur before it actually becomes a cancer. The other thing that's important to remember, and this is something that we really grappled with in our study was, we don't actually know which tumors arose as a result of radiation. And that's this tension that I was starting to, that I was alluding to, and the difference between what's happening in an individual patient versus what's happening on the population level. We know that the likelihood that a thyroid tumor arose due to radiation increases with higher exposure, younger age at exposure, but even for an individual who was exposed to a relatively high dose at a relatively young age, we can't necessarily guarantee, clinically, that that tumor actually arose because of the radiation exposure.

Bret Kugelmass
And yeah, help me understand, just as a reference, what is the background rate of thyroid cancer in a population of this same age group? And then what was the quantity of cancers that we attribute specifically to the Chernobyl event?

Lindsay Morton
It's really hard to actually nail down those exact numbers. And the way that I like to approach those types of numbers from a radiation perspective is to estimate the relative risk, so what's the factor by which it increases, and that depends on the dose. And so we talked about the excess risk per unit dose, whether that's 100 milligray, or one gray. And here we're talking about, for those individuals who had the highest doses, perhaps they saw more than four or five fold increased risk. But it's complicated on the population level to actually measure that, again, because there was all of this screening that occurred as well. So there were some tumors that were perhaps incidentally detected that would never have gone on to become clinically meaningful. And so it's hard to nail down that exact number of saying, well, there would have been X number of tumors and instead now there were Y.

Bret Kugelmass
But just to get a general sense, tell me if I'm wrong, but I heard something like 1% of the population gets thyroid cancer or something in general, like non-radiation related?

Lindsay Morton
It depends a little bit on age.

Stephen Chanock
That's still probably, 1% would be the upper limit.

Lindsay Morton
Exactly. And thyroid cancer is more common in women than in men in the general population. And so it's, as an epidemiologist, it won't surprise you to know that I want to get to that who, what, where, when, and why that was talking about so you can make these broad generalizations that sometimes people want to just say, I want to just a number to hang my hat on.

Bret Kugelmass
Right, I'm not looking for an exact number, just to give our audience a sense of the scale of thyroid cancers that are out there today. So, 1% is a little high, so we're saying like half a percent or something?

Stephen Chanock
You could say in that range, that would be fine. Again, age is really important than this and I think, what's the difference in Chernobyl was that number is much higher. So, depending on the age of the child exposure and the amount of exposure, the younger the child, the higher the dose, the greater the risk we've seen from multiple studies. It's the kids who were 10 or under who had extensive exposure who have very, very considerable elevation of their risk of developing thyroid cancer.

Bret Kugelmass
And the population number that we're thinking around for the children that are attributable to the Chernobyl cancer, is that around 5,000 or so, about how many people?

Stephen Chanock
Again, I think it's sort of misleading to focus on a given number, because you have to look at where the accident took place and the spread of the radiation. And that effect wasn't dichotomous who either were in the zone or not, it just sort of slowly petered out. And what we've learned from the Belarus, Ukraine and Russia, and then their questions in the Baltic states have much lower doses, but nonetheless, are there thyroid, is there an excess of thyroid? These are things that we've been looking at very closely and I don't think anyone would ever want to focus on a particular number. So, I'm not going to say 5,000, because if I say 5,000, it could be 5,001, or 4,999.

Bret Kugelmass
Sorry, I didn't ever mean to focus on numbers. I'm looking for general ranges. I think what I'm trying to get at is, like relative numbers. Let's say, okay, it could be 3,000 to 10,000 even, what I want to do is try to understand a comparison of the cohort that got cancer from, that we think got cancer from Chernobyl, versus the total cohort of people who get thyroid cancer, adjusting for the same things, geography and age, are we saying like around 5,000, compared to around 100,000.

Lindsay Morton
So if you think a little bit, if you want to go back to your number of half a percent or 1% of individuals get thyroid cancer in a given year, and then you can essentially say, depending upon the dose level, maybe that risk was increased by 20% for the individuals with the lowest doses or more like three-fold or four-fold for individuals with the highest doses. But in general, thyroid cancer is still a very rare disease.

Stephen Chanock
Yeah, I mean, we could see from our previous analyses that the relative risk, as Lindsay was pointing out, goes up substantially with higher doses, three or four grade. Kids under the age of 15 could be as high as 20 times. So we know that there's an excess of cancers. And I would say, Bret, one of the things we have to deal with is we look here, we do these population studies, but we recognize a substantial increase in thyroid cancer is a major problem, a health problem for young adults, individuals in those particular countries. And it's that tension between what are these statistics in any single case is a problem and it's a problem for that person and that family. It's 100% or 0%, curing of any individual. It's not, oh, we're gonna get 70% of an individual. And so when you have, in the population level, a substantial increase in thyroid cancer above what you would expect, that becomes a major problem in the Ukraine and Belarus each day established full organizations to search for and take care of the thyroid cancer.

Bret Kugelmass
That's actually one of the things I wanted to get to next and to figure out if that's actually part of the problem that they did that. I'd like to come back to that screening effect problem. Have you guys looked at cases of the screening effect taking place specifically in thyroid cancer in other populations? I've read one study in South Korea, where-

Stephen Chanock
We're very aware of that, but again, this is a population that was looked at quite differently, because we knew there was this very discreet, profound exposure to radiation.

Bret Kugelmass
Right. But so I was going to cite a case in South Korea where they thought there was a nuclear accident. And so they went around with the same methodology and tried to see who had, and they found like a 15 times increase rate of, and so I'm wondering, I mean, that seems kind of similar to the Chernobyl event.

Stephen Chanock
No, they found nodules, not cancer. Big difference, so be really careful what you say. They used a certain apparatus that's very sensitive and when they went in and looked, they saw no difference in the cancers, what they found was that they were seeing the pre-state, or these nodules. And so, again, we're we're having to be we want to be scientifically very accurate. The comparability is really not there.

Bret Kugelmass
That's what I was going to ask, what did they do at Chernobyl? They took out the thyroid and put it under a microscope to make sure it's malignant? How did they do it?

Lindsay Morton
I mean, there are a variety of different screening approaches, right, looking for nodules, and then they made clinical decisions about which nodules needed to be removed. Or actually, as I said, some of the tumors were identified through screening, but others were actually identified just through normal clinical practice. And Bret, one of the things that I think can help is to actually talk a little bit about the thyroid genomic sequencing study that we did, because I think it actually is a totally different way to approach this whole set of questions that can, in some ways, put some of these issues to rest. And the reason is because we had the radiation dose data. What we did was, we did what's called a landscape analysis. We used a variety of different laboratory techniques to characterize the genome of the thyroid tumors. There were 440 individuals in our study, 359 of whom were exposed after the Chernobyl accident, and then the remainder were unexposed, so they were born more than nine months after the Chernobyl accident. And what we were able to do was correlate the radiation dose with the different genomic characteristics. What we found was that there was an increase in the number of DNA double strand breaks, we were talking about this earlier, with increasing radiation dose. And there are a number of really important implications of these findings to address these questions that you were just talking about. We were able to measure DNA double strand breaks in a variety of different ways. When DNA is broken into strands, what can happen, I often use this image with my fingers so that they can just come back together, and if everything, if it's sliced cleanly and comes back together cleanly, then actually there's no damage to the cell. And of course, then there's nothing for us to measure in the lab. What we were able to measure was more when a break had occurred and in order to put the strands back together, the cell had to take out a few bases of the DNA in order to then do that repair. Other times what happened is-

Stephen Chanock
You lose a knuckle.

Lindsay Morton
Yeah, you lose a knuckle. And then in other times what happened is they were actually multiple double strand breaks. And so let's imagine there's one break here and one break here and the cell inadvertently brought together the wrong pieces. We were able to measure all of those in the lab, and then see that the number of DNA double strand breaks, measured in these different ways, all were correlated with increasing radiation dose. The fact that that was our most important finding was really key, because ionizing radiation is not the only thing that can damage cells and cause DNA double strand breaks.

Bret Kugelmass
I was gonna ask about that. Does oxygen also do that?

Lindsay Morton
There are a variety of different mutagens that can cause DNA double strand breaks. One of the hopes in our study, or one of the questions we wanted to explore, was whether we could identify a unique biomarker of radiation-induced tumors, and that addresses everything that we were talking about before. How can you know, for a specific individual, whether radiation causes that cancer, and what if, was that just because of an excess of screening or all of these other factors? We didn't find a unique biomarker of radiation-induced tumors because other chemicals or other exposures can cause DNA double strand breaks. Now, the correlation that we saw between radium dose and DNA double strand breaks was incredibly strong. I've described the study as one of the neatest and cleanest set of findings that I've ever worked with in my career, because no matter how we measured, the DNA double strand breaks or other factors and the results were just all consistent. We often find in our studies, because science is messy, and we're trying to push the boundaries of knowledge that we see some things that line up really nicely. But there's kind of this niggling question of something that looks a little inconsistent. And we don't really know what that means. And here, it's, it's not that we have all the answers from this one study, but it really was striking when I was doing the analyses to see how well everything really did line up.

Bret Kugelmass
That is pretty amazing. How did the, how is the various data presented to you, for both the dose data, and for the DNA data? Is there another laboratory somewhere that has sequenced all this DNA, and then they ship it to you in a vial, or do they ship you guys the literal actual tissue samples, and then you did it with your own DNA sequencer?

Lindsay Morton
We were really lucky for the visionary nature of the scientists who put together the Chernobyl Tissue Bank, which is currently led by Gerry Thomas-

Bret Kugelmass
-yeah, we've interviewed her before as well.

Lindsay Morton
And Gerry, in collaboration with clinicians and scientists in Ukraine and Russia, all the tumors for this study came from Ukraine, collected tumor tissues, and importantly, they were fresh frozen tumor tissues. By… freezing the tumors at the time of surgery, we actually were able to have very high quality specimens and we're really grateful to the patients, for their willingness to contribute to the science and to consent to having their tumor specimens used for research. Some of these tumors were collected several decades ago and there was essentially this understanding, but kind of this hope, almost for the advances in technology, that these tumor specimens would become really important contributions to science, and that's indeed what has happened. So, we received the biospecimens-

Bret Kugelmass
-they literally physically mailed like frozen packages to you guys.

Lindsay Morton
And we have established collaborations with different labs. We have our own lab and other labs that we work with, pathologists, the people who extracted the DNA and RNA, and then actually the laboratory scientists who ran all the different platforms that we were talking about.

Stephen Chanock
And then we have six or seven different major types of analyses that were distributed between our lab and the lab up in Boston. And then we had all the files that we were all able to put together with all the dosimetric and epidemiologic data that we had.

Bret Kugelmass
And sorry, break it down for me again. So you've got the samples, or you got a sequence, some sort of readout from the samples, and then how do you determine from that readout, you were saying something on knuckles and double breaks? How do you backtrack out of that?

Stephen Chanock
Well, we get lots of readouts. There's just not one readout, we did the little bits of RNA, the long bits of RNA, we did the DNA, we did markers of DNA to look at larger fragments. We looked at the telomeres, we looked at the epigenome, so we had all of this data and we know what normals look like, by and large. And so we did this, in each case comparing either the normal thyroid tissue that was taken out at the time from the other side of the thyroid, and or blood, and we make these comparisons asking the question, what's sematic, what's new, what is the cancer have? What do we see in this kind of analysis, okay, and then we could pull those events out and start to organize those and the real focus of the paper is on what are the characteristics of how radiation and the age of exposure, the age of diagnosis, and the actual specific type of mutations in those particular patterns.

Bret Kugelmass
And then we're correlating it to the dose status. Did that come on like, each vial came with. okay, here's what the exposure was, or was it on an individual basis, like literally they were holding a Geiger counter to it, or was it on like a regional basis based on like soil samples and stuff?

Stephen Chanock
All of the above.

Lindsay Morton
It's dependent on the individual. For about 20% of the individuals in our study, we actually had some direct measurements. Some of them were based on additionally an interview others were not. Others were based on direct measurements of individuals who were neighbors and that broadened out. And so we had a sense of the strengths and weaknesses of the dose data as well.

Bret Kugelmass
And how many samples total did you guys get to look at?

Lindsay Morton
We included 440? In this analysis?

Stephen Chanock
440 individuals.

Lindsay Morton
440 individuals, yes, of course.

Stephen Chanock
More samples.

Bret Kugelmass
Were there anything, is there anything in the data that jumped out that we can extrapolate other environmental factors? For instance, were there two people who maybe lived close together that had different dose ranges? And then we can interpret, like, the grass thing that you mentioned? Like this one had a farm that the cows had a larger area to graze on and that type of stuff?

Stephen Chanock
No, we can't play NCIS to that point of sort of looking at the tumors and saying, who lived on the east side of the hill versus the west side? There are some very interesting population genetics questions that is a second wave to help sort of construct what the Ukraine history looks like. We now have these very, very high definition genomes that we can use knowing things about their family histories. But that's not asking the Chernobyl thyroid cancer question.

Bret Kugelmass
One other thing that I heard that I was hoping you guys could comment on, was about these children being under-iodinized to begin with because of not having proper nutrition. Is that part of the study at all?

Lindsay Morton
We don't have any data on iodine deficiency and so it's not a factor that we can take into account. But I would certainly say in the last several decades, that's been an active topic of discussion from a radiation accident perspective.

Bret Kugelmass
Okay, great. And then, in your study, there was also something on hereditary effects and pass on into future generations. Can you talk about that a little bit?

Stephen Chanock
In terms of the thyroid cancer study, that's the second study that you want to talk about?

Lindsay Morton
The trio study?

Stephen Chanock
The trio, I'm not sure, because in the thyroid, we did look at the germline, what you're born with and we didn't really see that these children necessarily had a proclivity to develop this due to genetic mutations or a gene profile per se, to develop thyroid cancer, if there was it was very subtle. And we saw it more in the individuals who did not receive radiation. In other words, if radiation is going to come in, it will supersede any genetic effect is the way we saw that. But are you talking about the second study of the transgenerational?

Bret Kugelmass
Yeah, sorry, that's what I meant to ask about.

Stephen Chanock
Because that's a study we conducted in parallel that we set up about eight and a half years ago, where we went to the NRCRM, which is the big center that follows the liquidators is led by academician the Zika. And we wanted to ask the question, was there going to be what we call a transgenerational effect? To do that we recruited families. And the only way we could do that would be to analyze the entire genomes very carefully in mother, father and child, and identify if there are what we call de novo mutations, which are kind of building blocks of evolution. We talked about this before, every time there is cell replication, there is a chance of, a small chance of an error. And in every child that's conceived, somewhere between 40 and 70, or 80 of these events occur through the 3.1 billion bases. So when I say 40 to 70 to 80 deaths the numerator, the denominator is 3.1 billion bases that could be changed. So we know that there are random errors that take place in the sperm and or the egg, just in healthy, normal individuals. We wanted to ask the question, if there was radiation to the liquidators and a few of evacuees who leave start a family more than 46 weeks afterwards - so in other words, they're no longer at the time of conception in the place of high exposure - could there be radiation in either the testes or the ovaries that then damages the sperm and or the ovum that then subsequently increases the risk for more of these de novo mutations. We've known a fair amount about de novo mutations from studies in Iceland, and here in the United States and Denmark, where people have done this very high definition sequencing. And so we had some standards and ways to approach this. We chose to do this at a level that's up two and a half times more thorough than anyone had ever done, so when we do genome sequences, we talk about running the chemistry at any given basic 20 or 30x in the normal DNA. We did it at 80 to 90x, because we wanted to have so much information and be sure we weren't missing or that something very small was lurking, so to speak. And so we did this analysis in 105 families with 130 children, where we had dosimetric evaluation. It was quite accurate. And we actually went back with dosimeters, those metric experts, and re-interviewed those individuals and updated that. We were able to actually, interesting, some of the individuals we chose as controls who supposedly had no exposure, turned out to have exposures of like 20 milligray, very, very low levels, but nonetheless, they had some kind of exposure that we would need to account for. But similar to our thyroid cancer study, we generated the genomic data and then we looked at that in the context of the range of radiation exposures that we knew for each of the parents, mother and father. And then we asked the question, were the number DNMs, de novo mutations, in the children increased in any way in relation to radiation? And the answer was, we did not see any evidence for a significant change. We know there's a little difference from individual to individual, we were talking about this before with genomic repair and stability, but what we did see, which was very reassuring, is that paternal age is very strong. So as the age of the father increases, by year, there's an increase at the time of conception of more DNMs. Maternal age is a very small-

Bret Kugelmass
And you're saying that has nothing to do with the radiation. That's just, in general, older guys are producing not as good sperm is what you're saying?

Stephen Chanock
Well, you can say it that way. I have to be very careful how to say this. But we know that with each age, each year in age added, you have an increase in the number of DNMs. It's small, one or two. Again, these are relatively rare events, but they can, in the setting of, for instance, autism explain a small but real fraction of autism and other really catastrophic, pediatric neurodevelopmental disorders.

Bret Kugelmass
And it's funny, though, because that's the one thing that people in common lore are afraid of from radiation, are these effects being passed on to children? Has there ever, so you guys determined that in Chernobyl, that was not the case?

Stephen Chanock
We did not see a significant effect. We don't have the precision to say that it never happened.

Bret Kugelmass
Got it. Are there any cases of radiation - because there are only so many big population radiation events - have we ever seen an increase in these de novo mutations from radiation?

Stephen Chanock
Well, not in the way in which we looked at this, and the reason I'm giving that caveat is that we looked at survivors, individuals that left. We clearly know anecdotally, both after the atomic blasts at Nagasaki and Hiroshima, that in a very short period of time, there were fetal loss and in issues around that in individuals who were captured very quickly. Here, these are individuals that leave and start a family and had moderate range dose. We didn't, we were not able to identify people with acute radiation sickness who had four or five gray and then tried to have a family afterwards. That would be a rather unusual circumstance, because we know the fatality associated with four or five gray total body radiation is quite considerable. If you survive, there's a lot of morbidity associated with that. So this was really looking at this question of the larger fraction of survivors are people exposed, the levels that we looked at were substantially higher than what is been seen in Fukushima. We view our results as hopefully very reassuring and helpful to the people Fukushima and thinking, and we know that it's a major issue in returning to those areas, is the risk that childbearing parents have for will there be an effect-

Bret Kugelmass
- the perceived risk.

Stephen Chanock
The perceived risk, yes, exactly. I'm saying, but that's been a major issue. And so we, there's been quite a bit of press and discussion in Japan of these papers that hopefully can help with very important political and social decisions that people have to make.

Bret Kugelmass
And then just on that point, and then we got to wrap up, just comparing Chernobyl to Fukushima. In Chernobyl, we saw this increase in thyroid cancers amongst the children. Do we see any at Fukushima? Have we attributed any increased risk of cancer to Fukushima?

Stephen Chanock
That's a good question, because the screening issue comes back in terms of, do you find nodules? Yes, but how much of that is finding the nodules because you have more sensitive equipment as opposed to the develop-

Bret Kugelmass
-I think in Fukushima, they came in ready with the screening question, and so they did simultaneous tests across different populations that weren't exposed.

Stephen Chanock
And Bret, we know that the incubation period, so to speak, from the time of exposure to developing thyroid cancer, we're only 10 years out from Fukushima. So we-

Bret Kugelmass
That should be enough, right?

Stephen Chanock
That's the start of when we would see that. We see some of our Chernobyl cases occurred earlier than that, but remember, as Lindsay pointed out, many of them are 15, 20, 25 years later. I think we have to be careful in jumping to conclusions one way or the other, because we have not passed through that risk period sufficiently to be able to say, oh, there's nothing or there is something, okay. And there's nothing we can do, we can't rush time. We have to be patient about this.

Bret Kugelmass
Right, but we haven't seen any yet. And in Chernobyl, between years five and 10 we saw a bunch, right?

Stephen Chanock
We saw some, yes.

Lindsay Morton
The dose levels are so different that I think part of, again, what's so important about analyses that take dose into account is that I think it really addresses a number of these different factors.

Bret Kugelmass
Okay. Well, listen, this is a topic I could talk about all day. Hope to have more time with you guys in the future. But for now, let's wrap it up. Thank you guys again so much for your time.

Stephen Chanock
Thank you.

Lindsay Morton
Thanks.

Stephen Chanock
Pleasure talking with you, Bret. Thank you.