Chapter 04: Thyrocalcitonin –Confirming the Marker for Thyroid Cancer

Chapter 04: Thyrocalcitonin –Confirming the Marker for Thyroid Cancer

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Description

In this chapter, Dr. Hill talks about his work in the Department of Medicine when he first arrived at MD Anderson in 1963. He describes discovering a “treasure trove” of cases of medullary thyroid cancer. He sketches his epidemiological studies of families and his study of the nature of thyroid cancers, then goes into much greater detail on his study of calcitonin in the thyroid, determined to be a marker for thyroid cancer, as well as gene-related calcitonin.

Identifier

HillCS_01_20120214_C04

Publication Date

2-14-2012

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Joining MD Anderson; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Discovery and Success

Transcript

Tacey Ann Rosolowski, PhD:

You came in 1963, right?

C. Stratton Hill, MD:

In 1963.

Tacey Ann Rosolowski, PhD:

As Assistant Professor of Medicine, and so what department was your home department at that time?

C. Stratton Hill, MD:

It was just the Department of Medicine. It was a traditional department. What they have now is totally different. I was just in the Department of Medicine. Everybody was in the Department of Medicine. There was a guy there named was Bill Cole. His name was V. William Cole. And there was the endocrinologist they had just fired at Endocrinology because he had— There was some sort of incident with a female or something, so he got fired, and this guy took over. He was not really in charge. They just kind of left it.

Tacey Ann Rosolowski, PhD:

What was your role when you first came?

C. Stratton Hill, MD:

Well, I was to work in Endocrinology, but the slot that they put me in that they had a slot for salary was in Infectious Diseases. All I had to do was just oversee a technician that worked in the lab that did studies on infections that were unusual or something like that, so that was kind of a supervisory role. So I had to do that, so I really wasn’t under Bill Cole, but he and I shared the work. Then I got interested, and I realized that we had a treasure trove, or a mother lode, of diseases of medullary thyroid cancer, because we had families— It’s a hereditable disease, and I took that on as kind of my interest. There was a guy named David Anderson, who was a geneticist, and he and I worked together. He was a PhD, and we went down to— I began to do pedigrees on these families, and I collected that over the years. I did other stuff too, but Bill kind of turned all the thyroid over to me.

Tacey Ann Rosolowski, PhD:

What were the first studies that you did?

C. Stratton Hill, MD:

We did epidemiology studies on the family. [REDACTED]

Tacey Ann Rosolowski, PhD:

What were the trends you were seeing as you collected this genealogical information?

C. Stratton Hill, MD:

We knew pretty much that it was autosomal dominant.

Tacey Ann Rosolowski, PhD:

I’m sorry, what was that? Auto—?

C. Stratton Hill, MD:

Autosomal dominant inheritance. In other words, it’s not sex linked. It’s a somatic gene that it’s linked to, and you’re going to have some people in every generation that are going to have it. I began to collect this. We’ve had patients that come in at—There’s three things that it’s associated with. It’s pheochromocytoma, which is a tumor of the adrenal medulla, parathyroid adenomas and parathyroid carcinomas, and then thyroid cancer. So I began to do that. Thenabout that time, there was a doctor, a scientist in Vancouver, British Columbia. I’ve forgotten his name. I thought I’d never forget his name, but I’ve forgotten his name. But he was true serendipity, and Dr. Rawson was great on serendipity. There was a restaurant called Serendipity 3. You know that one?

Tacey Ann Rosolowski, PhD:

No, I don’t.

C. Stratton Hill, MD:

It’s on 60th Street, between 2nd and 3rd, I believe. No, maybe it’s Lexington and 3rd. Well, it’s on 60th Street, because Bloomingdale’s— It’s on the north side of Bloomingdale’s. Well, it’s the next block over, so it must be 2nd and— Anyway, it’s fabulous. I don’t consider me really having been to New York unless I get there. They have what’s called a frozen hot chocolate. It’s the greatest thing you’ve ever had. Anyway, about this time, there was something, a hormone that had not been identified that everybody thought came from the thyroid gland, and it was named thyrocalcitonin by this doctor in British Columbia. This had to do with calcium metabolism, so it didn’t fit with the thyroid gland. I began to see this information about this particular tumor in the literature, and so I read up on it, and there was a pathologist—I remember his name, [John] ‘Beach’ Hazard—at the Cleveland Clinic who was interested in the pathology, morphological pathology. This was long before the days of the electron microscope. You needed to get into mitochondria and all that kind of stuff. He wrote a big article on that, and so I thought, well, if this cancer is a producer of calcitonin—well, thyrocalcitonin—then if it has to do with calcium metabolism, we ought to infuse calcium into these patients and then take blood at a certain time and we could see—if it ever gets to where you could measure thyrocalcitonin, we could see what happens to it. I began to do that, and in those days you didn’t have IRBs. You could just do it, and so I did that. I would get the blood, and I’d freeze it and save it. And so about the time that this was happening, unbeknownst to me, there was an accident in the laboratory in British Columbia. They were studying this calcium metabolism, and they were doing it in rats. They got rid of the parathyroid glands by opening up the neck, and then they would zap the parathyroid glands with an electric current and destroy it. But they noticed that—and they were having to use a biological assay at the time—that every time they did that there was a dip in the calcium in the rats. By the way, if you need to take a break, we could take one.

Tacey Ann Rosolowski, PhD:

Would you like to?

C. Stratton Hill, MD:

Well, not right now.

Tacey Ann Rosolowski, PhD:

Just let me know, and it’s a quarter of 4:00. Do you want to go for another half hour or 45 minutes?

C. Stratton Hill, MD:

We can.

Tacey Ann Rosolowski, PhD:

Would you like to stop right at 4:00? That’s fine.

C. Stratton Hill, MD:

No, it doesn’t make any difference to me. They told them, they said, “Well, you can’t use this cautery anymore in the lab, so you’re going to have to surgically excise the parathyroids.” Well, they noticed that when they did that, they didn’t get that dip in the calcium level in the blood. So then they thought, “Well, wait a minute. This might be due to damage to the thyroid gland by the cautery.” So then knowing what the embryology was, they then said, “Wait a minute. Everybody has gills in embryonic development, so there are six clefts that may have vestiges of the cleft left.” That’s the so-called branchial cysts because these are called branchial clefts, and it may incorporate a little fluid, and you’ll have a branchial cyst in the neck or something like that, and that’s just because it didn’t close up right. They realized that something called the ultimobranchial body was incorporated into the body of the thyroid gland, so then they started looking at that to see if the substance that accounted for this change in the calcium level was in both cells that were mixed in with the thyroid or the thyroid glands themselves. They said, “Well, what animal is it that the ultimobranchial body remains the ultimobranchial body separate from the thyroid gland?” Well, the one that was obvious to them was the salmon fish. The ultimobranchial body is not incorporated into the thyroid gland. So he started making extracts of the ultimobranchial body, and lo and behold, found out that calcitonin comes from those cells, and so then the first calcitonin meeting. Then they changed the name. It’s not thyrocalcitonin. It’s just calcitonin, because it comes from a different set of cells. So I thought at that time, well, wait a minute. When you do a laryngectomy, or any kind of head and neck surgery practically, they will take out half of the thyroid gland as part of the surgical procedure. So those were the people that we would do these infusions on, and we wanted to identify ultimobranchial cells within the thyroid gland. By that time the— What am I trying to think of? The electron microscope had come into play, and there was a guy right down the hallway from where—that’s the lab—that was doing electron microscopy for somebody else. I said, “Hey, let’s see here what these cells look like.” A chicken also has ultimobranchials, so we got a bunch of chickens.

Tacey Ann Rosolowski, PhD:

Chicken and fish. (laughs)

C. Stratton Hill, MD:

We started looking at the ultimobranchial body, and we could see these granules in these cells. Then we could give them a high-calcium diet, and that would deplete those cells of those granules. We thought, “Well, now we’ve kind of got an idea of what this looks like. We’ll do these people that are going to have surgery the next morning. We’ll just go in there that night and start them on IV with some calcium, or if they already have an IV going, we’ll just add calcium to them.” As far as we could tell, it didn’t hurt them, and you didn’t have to have any permission or anything; you just did it. So we did a study on that and presented that to one of the meetings to show that there were actually ultimobranchial cells within the substance of the thyroid gland. It was not 100 percent, because to have it 100 percent, you’d have to take biopsies of the thyroid. Nobody in their right mind is going to let you do biopsies of their thyroid just for laughs. As far as they were concerned, they got no benefit from it. So we did that, and then the first thyroid— The calcitonin meeting was in London in 1969. I went there to that, and at that time, we only had a biological assay. For a calcitonin meeting, you have to inject that in animals and then measure the calcitonin in the animals—I mean, the calcium level in the animals—and that is tough. That’s labor intense. At that meeting, there were two guys that had a radioimmunoassay for calcitonin. One was at the Royal Postgraduate Medical School at Hammersmith in London, and the other one was at the Harvard Dental School. So I made appointments for them and said, “Hey, I’ve got all these frozen samples of blood of people who have had medullary carcinoma of the thyroid that I have done calcium infusion tests on. Would you like to try your assay out on this stuff?” And they said, “Absolutely.” I had a guy that was absolutely eaten up with medullary carcinoma of the thyroid, and he died, and I had saved a lot of his blood and a lot of his tissue, frozen, so I sent the same sample. I divided the same sample into halves and sent half of it to Hammersmith and half of it to Boston. I didn’t hear and didn’t hear and didn’t hear, and finally I heard from—this guy was Armen Tashjian. That’s a good Armenian name. He was at the Harvard Dental School. So finally I heard from him, and he said, “Well, when I first did this, the reading that we got was so high that I thought there was something wrong with the assay. Since this is a new assay, I thought there was something wrong with it. We had to check it, and we checked it, and we checked it. We checked it, and we checked it. We said, ‘There’s nothing wrong with that assay. This is a high level.’” And then about a week later, I hear from Hammersmith, the same thing. “We just had to check that thing so much because we thought there was something wrong with the assay.” So I thought it’s easier to send this stuff to Boston than it is to London, so I got on a plane. I flew and got this all on dry ice and hand carried it up to Boston. And it turned out that it was— Everything turned out like we thought it was going to turn out. Armen wanted to present this. Still, there were people in the thyroid business that weren’t sure this was not thyrocalcitonin, so he said he wanted to present it to the endocrine society that was going to meet in St. Louis that summer. I said, “That’s great. I’ll present it to the International Thyroid Meeting that’s meeting in Vienna.” He said, “Okay,” so I presented it in Vienna, and he presented in St. Louis. I think I got the better of the deal.

Tacey Ann Rosolowski, PhD:

What were the implications of all this knowledge?

C. Stratton Hill, MD:

That’s a marker for the disease. You can diagnose. We then got these families in and began— And you use that all over, everywhere for that particular disease. And then, of course, it had been found that calcitonin occurs in other parts of the body, so it’s only specific for the medullary carcinoma of the thyroid. The question then arises— The problem that we had was we would have people that we were following along with calcitonin measurements, but they showed no evidence of disease and felt fine. How do you—? What do you do? Do you treat the laboratory results, or do you treat the person? And so we decided that we’d treat the person. So some of those people would have their calcitonin levels go up and no manifestation of the disease. Now, I got out of that when Dr. Clark asked me to be the director of the whole clinic. I had pretty much done all of that. I tried to do some clinical stuff, but this was the first time that they had started expanding. We never had a clinic building separate before, and they were building the clinic building, and so I got administratively tied up. I did that for about five years. Then I decided there was too much administration, and then that’s when I decided that we’d get into the pain part.

Tacey Ann Rosolowski, PhD:

Let me ask you, before we—because certainly that next phase, when you’re setting up the clinic, is really an important—as you said, one of the three parts of your story.

C. Stratton Hill, MD:

Yeah, that was what I had the most notoriety in was in the pain part, and so this other I dropped out.

Tacey Ann Rosolowski, PhD:

Were there other dimensions of that clinical research that you were—? Was it primarily discovering this marker, or were there other dimensions to the research that you were doing?

C. Stratton Hill, MD:

We didn’t discover it. Well, we validated it, basically, and that was published in the New England Journal of Medicine in 1970. I remember Dr. Clark was saying to order 1,000 copies of that, and I said—I thought, “Well, I’m not going to order 1,000 copies. Nobody’s going to want that thing.” We went through 1,000 copies in about two weeks. And I’m not sure. There’s something called a gene related calcitonin, and that’s a little bit different from just the calcitonin that we were measuring. Dr. [Naguib] Samaan, who we recruited here to be the laboratory— He became Chief of Endocrinology. He had gotten his PhD at the Hammersmith in London, and he was Egyptian. He was a great immunoassayist. I mean radioimmunoassayist. So he took over that. We were doing that here, but I’d already done the other stuff with Armen Tashjian. And it just so happens that Dr. [Robert] Gagel— Do you know Dr. Gagel?

Tacey Ann Rosolowski, PhD:

No.

C. Stratton Hill, MD:

He’s Chairman of the Division of Medicine here now, and he trained with Armen Tashjian, so he knew about me before he came here. I think he came to Baylor before he came to MD Anderson, and so I didn’t know that until he told me. He said, “Yeah, I did all my training with Armen Tashjian in Boston.” And then Naguib Samaan knew most all of the big endocrinologists here in the States because he trained at Hammersmith, and they knew each other. There was the guy that became head of endocrinology at Harvard at Mass General. What was his name? I worked with him some, too, in all of this stuff.

Conditions Governing Access

Redacted

Chapter 04: Thyrocalcitonin –Confirming the Marker for Thyroid Cancer

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