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0:00 - Segment 00A: Interview Identifer

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Partial Transcript: "Okay. I’m Tacey Ann Rosolowski and we’re interviewing Dr. Louise Strong at the University of Texas, MD Anderson Cancer Center in Houston, Texas. This interview is being conducted for the Making Cancer History Voices Oral History Project run by the Historical Resources Center at MD Anderson. Dr. Strong holds the Sue and Radcliffe Killam Chair in the Department of Genetics at MD Anderson Cancer Center, and she is of course a full professor in that department. This interview is taking place in a conference room in the Department of Genetics, in the main building of MD Anderson Cancer Center, and this is the first of two planned interview sessions. Today is August 8, 2012 and the time is 10:15. I wanted to just say it’s really a pleasure to be talking to you, Dr. Strong, and thank you very much for taking the time to participate in the project."

Segment Synopsis:

Keywords:

Subjects:

0:52 - Segment 01: Genetics and Cancer in the Sixties and Seventies

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Partial Transcript: "As we spoke about, I wanted to ask you kind of a general question about the history of genetic work, because when you entered the field in the seventies the links—genetics was really just beginning to be understood and I wanted to ask you how it came to be that you made the link between genetics and cancer, and then how that link came to transform—how we understand the way the disease operates?"

Segment Synopsis: In this segment Dr. Strong sketches the first links that researchers made between cancer and genetics in the 1960s and ‘70s. Examination of chromosomal abnormalities in leukemia cells made it clear that cancer was connected to genetics, and research was being done on hereditary factors controlling retinoblastomas in infants. However, since most cancers do not follow an inherited pattern, she explains, most people were not examining the link, focusing instead on viruses and environmental factors. In medical school, her interest in inheritance and cancer made her unusual, as did the fact that she wanted to do research rather than practice medicine.

Keywords:

Subjects: A: Definitions, Explanations, Translations A: Overview A: The Researcher C: Cancer and Disease D: The History of Health Care, Patient Care D: Understanding Cancer, the History of Science, Cancer Research

7:28 - Segment 02: A Lucky Introduction to MD Anderson and Alfred Knudson

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Partial Transcript: "Can I also ask you another question? I’m really curious about that period of time when you were focusing your attention on that link between cancer and inheritance. How did that evolve? How did that idea and commitment to focusing on that area evolve for you?"

Segment Synopsis: In this segment, Strong describes how working on MD Anderson’s pediatric ward during her medical school residency helped convince her to focus on childhood cancer. An even stronger factor was her period of post-doctoral study with MD Anderson geneticist, Alfred Knudson, MD, PhD, who was working on a genetic model for retinoblastoma. Dr. Strong explains the sheer luck of coming into Dr. Knudson’s office and discovering that he shared her interest in inherited factors and could offer her a role on his research project. She also explains some of the characteristics of cancer as a disease that offered specific intellectual challenges.

Keywords:

Subjects: A: Educational Path A: Influences from People and Life Experiences A: Inspirations to Practice Science/Medicine A: Joining MD Anderson A: Personal Background A: Professional Path

13:06 - Segment 03: An Unusual Route to Medical School

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Partial Transcript: "That you walked into that office at that particular moment. That’s pretty incredible. Could we go back a bit and get some background research and then we’ll come back to that moment when you come to MD Anderson and are working with Dr. Knudson because it seems like just a real pivotal—pivotal time obviously. Well, it seems very basic but pretty necessary, just where were you born and when?"

Segment Synopsis: Dr. Strong begins this segment by talking about her deep roots in Texas and Houston. (She is the only one in her family not born in Houston.) She also notes that her mother’s family was in the sciences (her mother’s father was a pediatrician); her father’s family was in law. She excelled in the sciences in high school and majored in both mathematics and biology at the University of Texas-Austin, aiming toward a graduate program in genetics research. (She had been accepted at Stanford University.) She explains why she ended up going to the University of Texas Medical Branch in Galveston, Texas. She also talks about the isolation that she felt in medical school, as one of the only 5% of women in the program, and describes how she combated this by taking every opportunity to study in Houston. This is how she became connected to MD Anderson. She ends this segment with comments on the advances in medical technology (gene sequencing, for example, and the alteration of genes) that hav

Keywords:

Subjects: A: Definitions, Explanations, Translations A: Educational Path A: Experiences re: Gender, Race, Ethnicity A: Influences from People and Life Experiences A: Inspirations to Practice Science/Medicine A: Overview A: Personal Background A: Professional Path

26:45 - Segment 04: A Post-Doctoral Project on Childhood Cancer; Working with Alfred Knudson

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Partial Transcript: "So in 1970 you started your post-doctoral. That’s correct? Okay. Could you tell me about how you were integrated into lab and what you were doing and what that project was all about?"

Segment Synopsis: In this segment, Dr. Strong goes into great detail about her work with Dr. Alfred Knudson during her post-doctoral fellowship. Dr. Knudson had been working on a “two-hit model of retinoblastoma.” Dr. Strong first explains the scope of this study, clarifying that the “two hits” refers to the number of genetic mutations that lead to vastly increased chance for multiple cancers. She explains the hypothesis and rationale of Dr. Knudson’s study: he wanted to identify a scenario where a minimal number of factors and numbers of chromosomal changes would result in cancer. This study revealed that children with retinoblastoma had a mutation in which genetic material was deleted, and Dr. Strong points out that this approach and the outcomes set the stage for the discovery of tumor suppressor genes. She then goes on to describe how her post-doctoral project generalized Dr. Knudson’s model to other cancers.

Keywords:

Subjects: A: Definitions, Explanations, Translations A: Experiences re: Gender, Race, Ethnicity A: Influences from People and Life Experiences A: Inspirations to Practice Science/Medicine A: Overview A: Professional Path A: The Researcher C: Discovery and Success C: Portrait

43:11 - Segment 05: Discovering Contiguous Genes that Control Aniridia and Wilms’ Tumor

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Partial Transcript: "An interesting leadership style, too. Tell me how you came to switch from being post-doctoral to becoming actually a member of faculty here."

Segment Synopsis: At the beginning of this segment, Dr. Strong explains that she became a part time faculty member and had her children after her post-doctoral study. She realized, however, that she “would go nowhere” on part time status and joined the full time faculty with a position in the Medical Genetics Center in 1976. She then describes how she focused her research interests on childhood cancer and genetic epidemiology: she would look at individuals who had had retinoblastoma as tiny babies, who had been irradiated as part of therapy, and who had additional cancers, working with the assumption that this risk came from genetic predisposition. She explains two hypotheses that did not yield results, then explains how she discovered that aniridia (the absence of an iris in the eye) and Wilm’s tumor (of the kidney) are controlled by contiguous genes. She could now go to patients, she explains, and give them information about their risks for developing Wilm’s tumor or passing the predisposition to

Keywords:

Subjects: A: Definitions, Explanations, Translations A: Experiences re: Gender, Race, Ethnicity A: Influences from People and Life Experiences A: Overview A: Personal Background A: Professional Path A: The Researcher C: Discovery and Success

50:46 - Segment 06: The Discovery of the p53 Tumor Suppressor Gene

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Partial Transcript: "I have a list of some the studies that seem to pop out as being really key, and I wonder if maybe you could talk about some of these. One of them was, of course, the work you did on the p53 gene. I don’t know what is the right order to talk about these in so if there’s something you did prior to that that really needs addressing—"

Segment Synopsis: In this segment, Dr. Strong talks about a study that began in the 70s and has still not ended: the study of Li-Fraumeni syndrome. She explains the syndrome, first noting that Li and Fraumeni were unusual epidemiologists who were interested in “outlier, unusual events” that might, nonetheless be significant. They discovered families with many individuals who had multiple cancers and published a paper in 1969 proposing that this was a familial, and thus genetically linked, syndrome. Dr. Strong set up her own study in the 1970s, and she explains that she looked at MD Anderson patients treated for childhood soft tissue tumors between 1944 and the early 1970s, who had survived at least five years. Such a study could not be done today, she explains, given privacy laws.

Keywords:

Subjects: A: Definitions, Explanations, Translations A: Overview A: The Researcher C: Collaborations C: Discovery and Success C: Professional Practice C: The Professional at Work D: Understanding Cancer, the History of Science, Cancer Research

77:20 - Segment 07: The Next Phase of the p53 Tumor Suppressor Gene Story

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Partial Transcript: "So how do you define your own area of specialization?"

Segment Synopsis: Dr. Strong begins this segment by noting that though she is a specialist in the genetic epidemiology, she did not really “fit in Genetics” at MD Anderson because the Department had no human genetics program. (She mentions her joint appointments Pediatrics and Department of Breast Medical Oncology.) She describes how she has brought together teams of people who would never have worked together otherwise and also mentions her ability to get grants and to keep them going for long periods of time, finding new collaborators as others retire or leave. She notes her skills in creating groups that share resources and responsibilities.

Keywords:

Subjects: A: Character, Values, Beliefs, Talents A: Definitions, Explanations, Translations A: Overview A: The Leader A: The Researcher C: Collaborations C: Discovery and Success C: Professional Practice C: The Professional at Work D: Understanding Cancer, the History of Science, Cancer Research

0:00

ROSOLOWSKI:

0:00:02.5 Okay. I'm Tacey Ann Rosolowski and we're interviewing Dr. Louise Strong at the University of Texas, MD Anderson Cancer Center in Houston, Texas. This interview is being conducted for the Making Cancer History Voices Oral History Project run by the Historical Resources Center at MD Anderson. Dr. Strong holds the Sue and Radcliffe Killam Chair in the Department of Genetics at MD Anderson Cancer Center, and she is of course a full professor in that department. This interview is taking place in a conference room in the Department of Genetics, in the main building of MD Anderson Cancer Center, and this is the first of two planned interview sessions. Today is August 8, 2012 and the time is 10:15. I wanted to just say it's really a pleasure to be talking to you, Dr. Strong, and thank you very much for taking the time to participate in the project.

STRONG:

0:00:51.4

Thank you.

ROSOLOWSKI:

0:00:52.3

As we spoke about, I wanted to ask you kind of a general question about the history of genetic work, because when you entered the field in the seventies the links—genetics was really just beginning to be understood and I wanted to ask you how it came to be that you made the link between genetics and cancer, and then how that link came to transform—how we understand the way the disease operates?

STRONG:

0:01:28.4

Well, in the 1960s genetics was really not thought to play much of a role in cancer at all in the sense of inherited genetics—the classic Mendelian-type transmission of genes from one generation to another; however, we did note that tumor cells—at least leukemia cells, which were the ones we could look at most easily—most clearly. We did know that they had some genetic changes. Chromosomes were all mixed up. Now we had only fairly recently figured out how many chromosomes were supposed to be there so they were not—the abnormalities were not clearly identified, but it was clear that leukemia cells looked different than normal cells from a chromosomal perspective.

ROSOLOWSKI:

0:02:16.1

What were the differences?

STRONG:

0:02:18.4

The normal cells—there are twenty-three pairs of chromosomes. In all but one pair they are one from mother and one from father, and they look alike. They're the same size and shape. The sex chromosome pair can be different if it's an XY male. But in leukemias sometimes there were extra chromosomes. Sometimes chromosomes were broken. You saw chromosomes that didn't look like any of the normal chromosomes in some cases, and it was actually known fairly early on that children who had Down syndrome who had an extra chromosome twenty-one also had a higher risk of leukemia, so it was thought that perhaps that chromosome—that extra chromosome played a role. There were also extremely rare instances where it seemed that there was an inherited predisposition to cancer that was passed on, and that was most evident in a rare childhood cancer called retinoblastoma, and it was easy to see that because these are infant tumors. They occur usually before the age of two if it's inherited. So it's easy to see that pattern over generations, and it was a tumor that could be successfully treated by removing the eye, or in some cases both eyes, but it could be successfully treated so these children could grow up, become adults, become parents, and you could see this pattern repeat itself. But to my interest in it, I really came in with an interest in genetics. I got very excited about biology and learning about DNA and genes and what we knew in the sixties, and so my interest in going to medical school was actually to go into genetics—to go into human genetics, medical genetics, and genetics research. I was not the typical medical student. I got interested in cancer somewhat independently because, living in Houston, I had had summer jobs out here at MD Anderson as a student and I had learned to do chromosome analysis, as I mentioned, before ever going to medical school. So I, in trying to figure out if I was going to go into genetics—what area of genetics—it seemed to me genetics and cancer would be a good one, and there were very few people who were really thinking about that as a career path.

ROSOLOWSKI:

0:05:16.3

Why was that? I'm sorry to interrupt you.

STRONG:

0:05:18.9

Well, most cancers did not seem to be following a familial pattern, and you could look at a lot of human disease today where we now know there is a genetic component, but most cases are not black and white inherited. There was interest in environmental factors. There was interest in viruses. We didn't have too many good ideas. We did certainly have the more than ten years, I think, of the Surgeon General's report on smoking, so we knew some environmental factors were important. There was a lot of interest in viruses and there was the national virus program in 1970 I think it was. But genetics was not really a focus at all. So when I was trying to figure out exactly what to do next to get into genetics and cancer after medical school, and knowing that I did not really want to practice medicine and that I really wanted to go into research, I had done electives here at Anderson as a medical student and so when I was here on an elective I went to talk to the Office of Education about the possibility of doing a post-doctoral fellowship, and in particular I wanted to do something in pediatric cancers because it seemed if there was a major genetic predisposition, it would be more likely to show up in pediatrics where you don't have a long latent period like four years of smoking or something. You have something that occurs in a young child. I had been on the pediatric oncology ward, and I knew we had very young children, and I had read about retinoblastoma, for example, and—

ROSOLOWSKI:

0:07:13.6

Excuse me, now were you part of the—were you on the pediatric oncology board when you did a rotation—or how—?

STRONG:

0:07:19.8

I did a rotation as a medical student. You have electives that you can do, and so I had done an elective in pediatric oncology.

ROSOLOWSKI:

0:07:29.2

Can I also ask you another question? I'm really curious about that period of time when you were focusing your attention on that link between cancer and inheritance. How did that evolve? How did that idea and commitment to focusing on that area evolve for you?

STRONG:

0:07:50.6

Well, I was always more interested in why people got cancer, in particular for children. I was always somewhat from a scientific perspective more interested in why did they get that, rather than just thinking about how do we treat it? As I say, I came into medicine with a goal of research in genetics, not focusing necessarily on cancer initially. But once I sort of walked in that door to the office of education at MD Anderson, it wasn't the only thing I was exploring. I was looking at congenital heart disease as another option. I had done electives in that over at Texas Children's as well. But I was incredibly lucky in that the person who was in—who led the office of education at that moment—was someone named Alfred Knudson, and I had no idea who he was or what he did, but he was just the person behind the desk that day. I don't think there is anyone else who has ever held that position at MD Anderson who would have given me five minutes of their time, but he was later also dean of the Graduate School of Biomedical Sciences—an MD/PhD—and he was a geneticist, and he was actually working on a genetic model for retinoblastoma at the time. Now I had not done the homework. I didn't know any of that, and I walked in and said, "I'd really be interested in trying to work out a post-doctoral fellowship. I'd like to do some work in the area of genetics and childhood cancer. Do you think that's a possibility?" He said, "Well, you know I'm actually interested in that area as well." He said, "Would you like to do a fellowship with me?" and I said, "Yes!" So that was just incredibly fortunate. If he had not been there that day I'm not sure exactly what I would have done. I was more interested in cancer than the congenital heart disease for various reasons, but I really don't know exactly what I would have done.

ROSOLOWSKI:

0:10:18.6

Can you tell me, what were those reasons why you were so interested in cancer?

STRONG:

0:10:22.5

Cancer is such a distinct end point. I mean there are lots of diseases that can be sort of a wide range—and, yes, there's a wide range of cancers, but cancer just has an impact, a kind of definitive type statement that not very many diseases have, and for that reason it seemed like it was something that you—as I say, you have an end point—I want to know what caused that—not something that was kind of ongoing or more of a long-term process, at least that was how it seemed to me at that time.

ROSOLOWSKI:

0:11:11.1

So from a research perspective you felt like you could kind of target your—

STRONG:

0:11:14.3

That life was more tangible somehow. Anyway, obviously it was an important disease, and we had a center here in Houston, and so there were resources available to study. I mean to study congenital heart disease you had to be much more of a physiologist and understand why the abnormality caused the problems it did, and it was not as kind of all or nothing.

ROSOLOWSKI:

0:11:54.7

How well prepared did you feel for the post-doctoral you took up with Dr. Knudson?

STRONG:

0:11:59.2

Oh it was great, because I had been a math major as an undergraduate and so what we did were sort of statistical studies, and I knew a little something about childhood cancers because I had spent the time in the clinic and as a medical student you had to also write up a project and that kind of thing so I had learned something from being on the wards as well as from being around MD Anderson and going to lectures and things like that, so I felt as prepared as I might have been and loved working with him and I got a lot of ideas that I still pursue from those years. It was a great experience, and I don't think I had any idea at the time how fortunate I was.

ROSOLOWSKI:

0:13:03.2

That you walked into that office at that particular moment. That's pretty incredible.

ROSOLOWSKI:

0:13:03.2

That you walked into that office at that particular moment. That's pretty incredible. Could we go back a bit and get some background research and then we'll come back to that moment when you come to MD Anderson and are working with Dr. Knudson because it seems like just a real pivotal—pivotal time obviously. Well, it seems very basic but pretty necessary, just where were you born and when?

STRONG:

0:13:34.7

I was born—I was a war baby. I was born in 1944 and my parents had lived in Houston before the war, but my dad was in the judge advocate unit, and he was stationed at San Antonio at the time, so I was born in Brooke General Army Hospital there. My brother was born in Houston. My mother was actually born in Houston, so it's very painful for me to admit that I was not born in Houston.

ROSOLOWSKI:

0:14:00.5

So you really have a sense of yourself as a Texan and a Houstonian.

STRONG:

0:14:03.6

Yes, yes, yes. Both my parents were born in Texas and some of their parents were born in Texas so I have deep roots here.

ROSOLOWSKI:

0:14:15.3

Did you grow up in Houston?

STRONG:

0:14:16.5

I did. I did. So as soon as the war was over they moved back to Houston.

ROSOLOWSKI:

0:14:21.1

I see. Now was anyone else in your family involved in the sciences or in medicine?

STRONG:

0:14:29.0

My mother's father was a pediatrician. Now I never knew him. He died long before I was born, so I never knew him at all. My mother was always sort of interested but she didn't really actively do anything. She had gone to Rice and had I guess also been a math major, and so there was sort of a math/science background from her side of the family. My dad was from a very strong legal background and not really so much involved in sciences.

ROSOLOWSKI:

0:15:13.5

But you gravitated toward the sciences. How early did you know that?

STRONG:

0:15:18.2

Not really until—well, in high school. My first biology class was ridiculous. It was kind of like a general science and I thought I hated biology, but then I really liked physics and, being interested in math, I did things all wrong. I thought chemistry was going to be too much like biology so I didn't want to take chemistry so I took physics. Well, I basically had to learn chemistry; too, to get by in physics so then I went back into chemistry, which was of course very easy having already basically been through it. So I kind of backed into it. When I went to college I definitely was interested in science. I was not pre-med. I didn't really know exactly what I was going to do with it, but I found the things I explored in math, per se, I found became less and less interesting, and I was in plan two at University of Texas, and they kind of make you take—it's basically a liberal arts kind of background.

ROSOLOWSKI:

0:16:26.4

And you went to the Austin branch?

STRONG:

0:16:28.8

Yes, the main campus. So I took chemistry, and they had a biology course, which I took, which was really outstanding, so I got very interested in biology then and—

ROSOLOWSKI:

0:16:44.8

What was it that got you excited about biology in that class?

STRONG:

0:16:48.0

I think it was more the genetics. So I started taking genetics courses, and in those days—and maybe today, too—I went to Lamar High School. I had a very good background. We took calculus and all that kind of thing in high school, so I could place out of a couple of years of math in college, so I had plenty of room to takes lots of biology, genetics—including graduate courses while I was there so I ended up with a double major in math and biology, but the last couple of years were much more heavily biology/genetics oriented.

ROSOLOWSKI:

0:17:24.8

How many women were in the programs you were in at that time?

STRONG:

0:17:31.5

There were a fair number of women in biology. There were certainly plenty of women in plan two. There were very, very few women in the math classes and very few women in the physics classes.

ROSOLOWSKI:

0:17:44.8

What was that like being, you know, "the only woman in the room"?

STRONG:

0:17:49.2

Well, it was a little bizarre, but I think things were pretty—things were very friendly in those days so it was much more painful, I suppose, in medical school because there you're much more isolated.

ROSOLOWSKI:

0:18:15.3

And you went to medical school in the medical branch at Galveston?

STRONG:

0:18:18.2

Right, right, I did. I was planning to go to graduate school up until March of my senior year. I was going to go to graduate school in genetics, and I was actually accepted. I was going to go to Stanford. Then, when I visited with people from Stanford who came to Austin to meet me, everything was so basic lower organism. There was nothing that even approached human genetics or medical genetics at that time, and I was really interested in medical genetics. Then other people began to tell me that, "Well, I know you want to do research in humans, but you're going to have to have an MD degree if you're going to think you can lay hands on people." Even some of the PhDs I was training with at the time actually began to sort of recommend considering medical school. So the reason I went to Galveston was because almost every place else had closed their admissions, and I would have to wait a year. I really was not particularly excited about going to Galveston, but any out of state school or anything was out of reach for another year, and it never occurred to me that it might make sense to wait a year.

ROSOLOWSKI:

0:19:54.1

So you started medical school in 1966? Is that correct?

STRONG:

0:19:58.5

Yes.

ROSOLOWSKI:

0:19:59.1

Now you said—well, tell me about that program, and you also mentioned that you felt rather isolated as a woman, so maybe you can—

STRONG:

0:20:04.6

Well, there were very few women in medical school, and in Galveston in particular it was a—there wasn't much economy there. There were very few other young people. See, when you're at University of Texas campus, even if in your class you're one of the few women, you're surrounded by everybody, and you have plenty of other classes where you're with a mix of people so you meet people and all that. When you go to Galveston Medical School it's very hierarchical and so you're at whatever level you are, and then there are the medical students ahead of you, and then the interns and residents, and then there are the faculty, and there's nobody else to socialize with. I mean there was not much down there. So if you're one of a handful of women in the class and they're all living in the fraternity houses and you're living with one roommate or by yourself and they all fraternize, and when you're in a group that's that many men they don't pay much attention to one—it's not, you know, the manners and things like that are not what you are used to at all. I loved the fact that I lived in Houston—that my parents lived in Houston and I could go back and forth a fair amount, and I made every effort to keep in close touch with my friends in Houston, and I did electives in Houston. I did electives elsewhere as well. I didn't just do that in Houston, but I used every opportunity I could to get off the island.

ROSOLOWSKI:

0:21:59.7

Did you feel that the way that women were isolated had a professional effect within that medical experience? Obviously you made attempts to get out, but if there were women who weren't doing that, could you see that there were some professional effects from that isolation?

STRONG:

0:22:20.6

Well, I think, first of all, we all knew going in that there were not very many women. It's just that I didn't realize how isolated you were when you're five percent of the group and the other group is all—I can't think of a nice way to say this, but there was no reason for them to behave decently down there. There were not a lot of people that they were dating or whatever like that so it was pretty rough, and it was just not much fun. I'm probably exaggerating a bit because we all got through it fine. We did study with people when it was time to study. We were all pretty good students and so some of the other good students would—we'd study together, but it just—it's a very—it was just a little more isolated than I think I was initially prepared for. But it was fine. I mean you got through it and were happy to be out of there. I don't look back on it as my favorite—the favorite time in my life, but I was thrilled to find this position to work in Houston, and at Anderson, even though there were very few women—Anderson was, of course, much, much smaller then, and within a reasonable time period, even as a little post op, you knew a lot of the people. There were certain lectures that kind of everybody went to, and so you learned an awful lot about cancer easily and it was pretty friendly. I didn't have the same sense of isolation that I did in medical school.

ROSOLOWSKI:

0:24:25.2

You had worked in a pathology lab as well at MD Anderson—

STRONG:

0:24:29.6

That was doing—actually that was doing cytogenetics. That was a summer fellowship when I was probably in college and that's where I learned chromosomes—how to analyze chromosomes by the technology that was available in those days.

ROSOLOWSKI:

0:24:47.7

And what was that technology?

STRONG:

0:24:53.1

I said there are twenty-three pairs and you just group them kind of by size and so there were different groups, but within the group it was very difficult to discriminate between one and another. They were grouped by size and shape, but now we know the bands of each chromosome and we know where the genes are lined up and so forth, but we could count chromosomes in those days and we could tell if there was something way out of whack. We could certainly identify Down syndrome patients and, as I mentioned, some of the leukemia chromosome abnormalities were known.

ROSOLOWSKI:

0:25:28.6

You've seen enormous changes in technology, that's for sure.

STRONG:

0:25:32.0

We would have never dreamed we'd be doing the things we're doing now. I had never dreamed in my lifetime I would see that.

Tacey Ann Rosolowski, PhD. 0:25:38.9

What's one of the most amazing innovations that you wouldn't have thought of back then?

STRONG:

0:25:43.9

The idea that we could sequence the genome, the idea that we could then identify sequence variants in genes the way we do. You know, conceptually one could identify that someday in the distant future it could be done, but as I say, that I would actually see it happen was not something that I expected. I just thought we would have projects of trying to locate and identify genes for some of the cancers for the rest of my life. It never occurred to me we would actually sequence them and know exactly what the change was and begin trying to figure out ways to change that and so forth. I just didn't expect to have things move quite so quickly.

ROSOLOWSKI:

0:26:47.0

So in 1970 you started your post-doctoral. That's correct? Okay. Could you tell me about how you were integrated into lab and what you were doing and what that project was all about?

STRONG:

0:27:01.6

Well, actually I was reviewing medical records and medical literature on certain specific childhood cancers and trying to identify—let me go back just a minute—Al had written—he'd really worked out the paper he wrote on retinoblastoma—on a two-hit model for retinoblastoma without me. I was not part of that.

ROSOLOWSKI:

0:27:29.2

I'm sorry, what is that two-hit model? I came across that phrase and—

STRONG:

0:27:35.0

Retinoblastoma was the tumor that was probably the most evident as being inherited in a predictable way. We knew Mendel's peas and Mendelian inheritance and such, and inherited in a dominant way, which would mean that for the gene responsible for retinoblastoma—we assumed there was such—you would inherit one—one that was abnormal—that was mutant—from the parent who carried that, and you would inherit one copy that was normal from the other parent, so now you've got two copies of the gene. That's how your zygote—your embryo starts out—with one good copy and one mutant copy. This zygote develops into a perfectly normal fetus—the right number of arms, and legs, and eyes, and nose—I mean everything is fine, but there is a tendency for tumors to develop in the retina of the eye, and you can see little punctate lesions in some cases where there's more than one separate tumor—independent tumor—not tumors that have spread from one to the other, but independent—and they can develop in both eyes. So, again, that supported the fact that they were independent. They weren't spread from one eye to the other. Now if you look at all children with retinoblastoma, the tumors occur from infancy up to about age four or five. Most of them occur at the younger side of that, and after that it's incredibly rare to see a new retinoblastoma develop, so it was thought that this has to do with kind of embryonic development, and at some point the cells have differentiated and they're not—they can't go backwards. What Al did with the retinoblastoma, he had noticed—and other people had as well—that in the familial cases of retinoblastoma the tumors were most often bilateral—occurring independently in each eye, and they occurred at an earlier age. Now you might think if they're going to develop in both eyes that it's going to take longer, but these were actually occurring—even in both eyes—earlier. So he was thinking in statistical models of, "Okay, you inherit this mutation. What else has to happen for a tumor to develop?" He looked at the age of onset for retinoblastoma in the inherited cases, and he made the assumption that all cases in which both eyes were involved had to be inherited because you had something independent in each eye and because there was very good data for that. There had been studies from registries in some of the Scandinavian countries—you know they have fabulous registries of everything there. They had actually followed children who had had retinoblastoma as infants and who had lived and had children of their own, and if they had bilateral retinoblastoma, the risk of retinoblastoma in their offspring was almost a perfect fifty-fifty. That's Mendelian genetics. If they had had unilateral—just single-eye—retinoblastoma the risk was much, much lower. It was maybe five percent or something, but it was a clear, big difference—and not because they weren't evaluated or anything like that. It was a very big difference. When Al looked at the age distribution he asked, "Okay, we know something else has to happen. If you inherit a mutation, something else has to happen. You're fine at birth. You develop normally. Sometimes one eye is fine. So what is it that has to happen?" As a geneticist you could think about genetic alteration. I think by that point in time—actually from almost early 1900s—there was thought that somatic mutation was possibly important in cancer, and chromosomal aberrations would count as that—extra numbers of chromosomes. It also could be at a single gene level. But that somatic alteration was important in cancer development. It could be caused by smoking. It was kind of a unifying theory that somatic mutations were important in cancer. So he asked whether the age distribution of cancer in those with the inherited form of retinoblastoma—the familial and/or bilateral—did they fit a distribution that would fit a single-hit event—or multiple hits? How many hits? And then how did that distribution compare to the presumably non-inheritable, just sporadic, non-familial unilateral cases?

ROSOLOWSKI:

0:33:14.0

So the hit refers to—

STRONG:

0:33:15.0

The hit refers to the number of mutations. So if you're inherited you've got one hit, and the age of onset distribution of those inherited cases for cancer to be identified—to be diagnosed—really pretty smoothly hit a two-hit phenomena, and the unilaterals hit a kind of messier model. In other words, if you inherit one hit you just have to have one more hit, so that would give you the two hits. So his hypothesis then was that retinoblastoma—one of the things he wanted to ask was what would be the simplest cancer? If you want to get down to the most basic, minimum things for cancer what would be the simplest cancer? Retinoblastoma was a good model because it occurred at such an early age. Then there was the question of what would be the fewest number of genetic changes. Other people had developed statistical models just from looking at age of onset of cancer and there fact that most cancers increase as we age and it's not a straight line. It's not linear. You've got a curved line where it increases more rapidly as you really age, and so those models had predicted cancers may have to have seven or eight or some large number of genetic changes. So one of the questions he was asking was could any cancer be as few as two?

ROSOLOWSKI:

0:34:52.8

Well, I'm seeing the advantage of—or maybe I'm seeing the advantage of working with very, very young children who haven't received the environmental factors.

STRONG:

0:35:02.7

Right. So his model was very simple. It became something that everybody sort of thought at least made sense, and it became widely cited. Now he didn't try to say what that second hit was—whether it involved the other retinoblastoma gene or whether it involved some other gene somewhere else in the genome. That came later. But it set the stage for what came to be known as tumor suppressor genes because we tended to think of genes that would cause cancer as genes that got turned on wrong, and so they made a product that shouldn't have been there and it told a cell to do something. We figured out from chromosome analysis that some children with retinoblastoma had a deletion of a region of a chromosome that we knew from family studies was the region, grossly, that included the retinoblastoma gene, and so this said, "Hmm, how does loss of genetic material predispose to cancer?" That didn't quite fit either. Ultimately, it was shown that for retinoblastoma tumors to develop you basically have a loss of function of both your maternally- and paternally-inherited genes, and one of those may be inherited, and then the other is the second hit, but it's a loss of function. So that's called a tumor suppressor gene because the normal function suppresses cancer, prevents cancer, reduces your risk of cancer, and when you lose that function then cancer can develop. Time Magazine did a little cartoon of two soldiers were the two normal genes, and when you had a single hit you had one soldier that was knocked down dead, and so you just had one soldier, so it was kind of weak, and if anything happened to that guy then he went down and then the obscure, claw-hand of cancer could come. Anyway, I remember that very well. That was how they made a cartoon to depict the tumor suppressor gene and two-hit model concepts.

ROSOLOWSKI:

0:37:55.9

So tell me, you said that Dr. Knudson had worked out a good part of this model before you came to work with him, so what—when you came in—

STRONG:

0:38:06.6

My project was to say, "Is this generalizable? How does this fit some other childhood cancers?" So I reviewed all the medical records of the MD Anderson cases that had been treated here and got the age at diagnosis, and whether it was unilateral or bilateral. We looked at tumors where you could have more than a single organ. In other words, we looked at kidney tumors—Wilms' tumor of the kidney. We looked at neuroblastoma, which can be in the adrenal gland, although also some other places. So we looked at things that had at least paired organs so you could have the ability to say, "Well, those that have more than a single tumor site ought to be inherited by this model and look at the age of onset for those compared to the others." Then research out the—unlike retinoblastoma, familial cases of most of the other is extremely rare, and so we pulled out the few cases in the literature that existed and maybe I dug up a case or two that had been at MD Anderson. Then we did the same type of analysis for Wilms' Tumor of the kidney, for neuroblastoma, and then for a number of other syndromes that are related in some way or another to neuroblastoma, and so we published a series of papers on that, sort of making the case that this two-hit model could be generalized to other tumor types.

ROSOLOWSKI:

0:39:43.6

Tell me about working with Dr. Knudson and what you got from him.

STRONG:

0:39:52.8

He is one of the most thoughtful people I know, and I mean thinking thought, not just being nice. He has always got some new idea. He has got some new way of looking at things. You can take some simple dogma that everybody knows it's this way and he'll have a, "Well, but what if you look at it that way?" kind of approach to things, and he's always gentle and gentleman as well—using those in sort of different ways, but he's excited about science. He thinks about—he's not one of these people that just is driven and intense all the time. He's not that kind of hard-driven person. He's a person who enjoys life but is really never too far away from thinking about kind of the next idea in science.

ROSOLOWSKI:

0:41:12.2

What is his style of working with others—as a mentor or as a collaborator?

STRONG:

0:41:17.0

It's very easy. He gave me books to read. Molecular Biology of the Cell I think was a new ting that was out at that point. So each week we would discuss a different chapter and the concepts about it and such as that, and then we'd go over data of course intermittently and discuss that. He was very easy to work with.

ROSOLOWSKI:

0:41:49.1

Did you feel like he was a mentor?

STRONG:

0:41:50.5

Oh yes, absolutely. Unquestionably.

ROSOLOWSKI:

0:41:53.7

And how did that—I mean what were some of the big lessons you learned from him that carried you forward?

STRONG:

0:42:04.3

I learned a lot about questioning things, about not just assuming that everything was the way people said it was, and I guess I learned to try to think about something from a kind of analytic perspective, and—I don't know—maybe also not to take myself too seriously. I mean he was a very good—and still is a very dear friend. He was just absolutely delightful. He would always have some interesting questions and angles that I would never have thought of. It was just really delightful—

ROSOLOWSKI:

0:43:07.2

It sounds like he was always inspiring innovation.

STRONG:

0:43:09.4

He was. He was, very much so.

ROSOLOWSKI:

0:43:13.1

An interesting leadership style, too. Tell me how you came to switch from being post-doctoral to becoming actually a member of faculty here.

STRONG:

0:43:25.7

Well, of course your goal is always to grow up.

ROSOLOWSKI:

0:43:29.1

But you might have moved to another institution, too.

STRONG:

0:43:31.5

Normal people would. After I worked with him and sort of finished the post-doctoral period it was kind of timing where I became pregnant, and so I worked throughout the pregnancy and then I worked part time for about a year and a half while I had the kids.

ROSOLOWSKI:

0:43:59.3

Where was that?

STRONG:

0:44:01.4

I was in an in-between stage so it really didn't bother anybody much. We had this thing called the medical genetics center that Al was head of, and that involved UT, what's now the School of Public Health. It was a population and demographic genetics group at MD Anderson. So I had sort of a research assistant—not a research assistant—research associate-type position there, but I wasn't really reporting too much to anyone. I was carrying on small projects to be working part time. I could stay up with what was going on. I could write an occasional paper, and I still met with Al regularly.

ROSOLOWSKI:

0:44:49.4

So this was 1973 to 1975?

STRONG:

0:44:52:1 Right, exactly.

ROSOLOWSKI:

0:44:54.2

Sounds ideally suited if you're starting a family.

STRONG:

0:44:56.8

It was. I was very lucky. I was very lucky, but I also realized that I wasn't going anywhere that way. So in 1975 I came back to work full time, and then I certainly kept—

ROSOLOWSKI:

0:45:12.2

How did that happen? I mean did you just sort of ring up Dr. Knudson and say—

STRONG:

0:45:17.1

Well, he called me. I saw him periodically during the time that I was either really on maternity leave or not far, working part time, and so I think basically I called and said I'd like to come back to work, and I knew that there was a position in this medical genetics center, or at least the possibility of it, and he made it very clear now I was no longer his fellow and he'd be interested in talking to me, but I had to try to develop my own career now. That was fine. I mean I hadn't really thought about it, but that was what should happen.

ROSOLOWSKI:

0:45:56.2

So what was going through your mind when you suddenly realized that was the new project—to develop your own career?

STRONG:

0:46:02.4

I had some ideas of things that I wanted to follow up on. When I reviewed retinoblastoma records something that completely surprised me that was not part of his paper at all was the fact that many of the patients that had come to MD Anderson with retinoblastoma didn't come here initially for their retinoblastoma treatment. They were treated by an ophthalmologist somewhere else. We didn't always even have much of an Ophthalmology department. We do now, but there were years where we didn't. What they came here for was that, as they were older, they had developed sarcomas or brain tumors or other cancers. To be ten years old and on your second cancer was clearly out of range. There was something else going on here, and so I was just shocked by this because I found it in way too many cases to explain by chance. Now in those days if you had bilateral retinoblastoma, which was the inherited type, probably the most common treatment was to remove the most-involved eye because you might not be able to save any vision out of that, but then nobody wants to enucleate both eyes in a baby, so then they would irradiate the other eye. Well, we really didn't—I mean we knew then that radiation could cause cancer, but we didn't realize that this might be a uniquely susceptible group. One, they were infants; two, we know they have an inherited predisposition, at least to retinoblastoma; and three, they're getting radiation.

ROSOLOWSKI:

0:47:52.2

Sort of three hits.

STRONG:

0:47:52.6

It's only fairly recently that the ophthalmologists had really taken this seriously, but—anyway—recognize that and began addressing the question of risks for new cancers in childhood cancer survivors and how much of that might be attributable to genetic predisposition like retinoblastoma and/or radiation or, of course chemotherapy is developing during that period as well. Then that got into programs studying childhood cancer survivors in general, and concerned about—well, in the past maybe childhood cancer patients didn't survive, so if it was going to be familial we would never see it because they didn't grow up and have children, but maybe now that we were having survivors—because in the seventies is when we really made a big, big push in terms of having chemotherapy that changed the picture for childhood cancers, and so thinking are we going to start seeing all these familial childhood cancers to not. So I really got into more of that kind of childhood cancer, genetic epidemiology. I did some work with chromosome analysis. We thought at one time maybe when new techniques in chromosome analysis came out we'd be able to see deletions, and that that would increase your risk of a second cancer, but the deletions were really primarily in kids who also had developmental delays and other things, so you had big chunks of genetic material lost. Then I was involved in the studies that showed that the second hit—well, there were people who showed that the retinoblastoma gene was on this chromosome thirteen, and then the question was, "Okay, what is the second hit?" So I was involved in working with some of the people who showed that the second hit was also from the other chromosome thirteen, so that was fun to be able to be part of that mechanistic approach.

ROSOLOWSKI:

0:50:09.0

Well, I have a whole—

STRONG:

0:50:09.2

So I collaborated with a lot of different people who had different expertise, because I did some of the cytogenetics early on, but I was really not primarily a laboratory rat, and I was more comfortable doing more of the statistical analyses but I was very interested in what the molecular biology was going to tell us, and so I collaborated closely with people and I would know the patients and collect the samples and we would help plan the experiments, but using people who had talents that I didn't have and then working with them.

ROSOLOWSKI:

0:50:48.1

I have a list of some the studies that seem to pop out as being really key, and I wonder if maybe you could talk about some of these. One of them was, of course, the work you did on the p53 gene. I don't know what is the right order to talk about these in so if there's something you did prior to that that really needs addressing—

STRONG:

0:51:14.6

Some of the work—so my first paper with Al was on Wilms' tumor of the kidney and so it had a lot of analogies to retinoblastoma, and so then I teamed up with Grady Saunders for a number of years to try to identify the Wilms' tumor gene that was going to be like the retinoblastoma gene, and we did a lot of nice work together, but Wilms' tumor didn't quite work out the way retinoblastoma did. It hasn't been nearly as tidy.

ROSOLOWSKI:

0:51:49.1

What did you discover?

STRONG:

0:51:52.3

I'm just kind of giving you a little background. We didn't actually discover the Wilms' tumor gene. Somebody else beat us to it by a few weeks, but we did a lot of work on showing that it was a two-hit model. It did follow exactly—at the molecular level it followed that same kind of model, but then it turns out that that's true or some Wilms' tumors but not necessarily for all and that some other childhood cancers are much more complicated than retinoblastoma was—assuming retinoblastoma was really unbelievably simple compared to perhaps most. We had really a number of good papers. We identified a gene for aniridia, which was related because we knew that there was a small deletion that involved both Wilms' tumor and aniridia and that they had to be separate genes, but there were—it was what was called a contiguous gene syndrome, so there were patients who would have both Wilms' tumor and aniridia because they had a deletion that affected both of these neighboring genes.

ROSOLOWSKI:

0:53:07.4

What is aniridia? (inaudible, speaking at the same time)

STRONG:

0:53:08.2

It's absence of the iris of the eye. It's actually maldevelopment of the iris of the eye. It may not be completely gone, but it's a congenital abnormality. That was important because initially people didn't know whether it was all one gene that caused these things or separate genes, and so all the work that Al and I had done on Wilms' and aniridia and then Grady and I did sort of sorted that out, and then we actually identified the aniridia gene in Grady's lab.

ROSOLOWSKI:

0:53:39.1

So as you're going along and—I mean I can imagine as you're unraveling the relationships between these different tumors you're also unraveling how the chromosomes operate at a molecular level.

STRONG:

0:53:54.7

Right, yes, and I'm very interested in that. It was just that—I don't know, I guess I always felt like a klutz in the lab, so it was—I loved the work and developing some of the hypotheses, identifying cases, getting the samples, and in some cases actually then going back to the patients and being able to give them new information about themselves or their families.

ROSOLOWSKI:

0:54:22.1

Did that happen in the case of aniridia and the Wilms' tumor?

STRONG:

0:54:24.9

Uh-hunh (affirmative).

ROSOLOWSKI:

0:54:25.6

It did. So can you tell me a little bit about what information were you able to give a patient about that?

STRONG:

0:54:35.5

First of all, it had been known that there could be chromosome abnormalities—I guess that had come out earlier, but we thought it had to be this kind of big, gross thing, and that you could visualize easily. We then found—identified some patients who had Wilms' and aniridia and it wasn't grossly visible, so we were able to prove at the molecular level that the genes were both deleted, and we were able to—the patient and family didn't understand this at all and we were able to kind of sort that out. Then we could go—we could give them risks for having that recur in the next generation and that kind of thing. We could identify those cases of aniridia in which they were at risk for Wilms' and those in which they were not based on the molecular analyses. So those kinds of things. Things that were not clinical tests. In other words, this was done in a research laboratory. Now you're not supposed to tell people research results because it not a CLIA certified lab, but we still do some of that. So all of that was really fun and interesting and then it basically got where I spent more and more of my time with these so-called Li-Fraumeni syndrome families and, again, here there was a very strong relationship to retinoblastoma.

ROSOLOWSKI:

0:56:23.8

Could you describe what Li-Fraumeni syndrome is?

STRONG:

0:56:27.3

First of all, Li and Fraumeni were two people—two individuals at the National Cancer Institute who did lots of surveys of childhood cancers—epidemiologic surveys. They could go to the Bureau of Vital Statistics and review all the records of all the people who had died of Wilms' tumor for example, and in the 1960s pretty much everybody with Wilms' tumor died, so they had a pretty good distribution of what age of onset, whether they were familial or not—some things like that. So one of their surveys was of children with sarcomas. Actually that's not quite right. They were unusual epidemiologists. They were interested not just in the big population things, but they were also interested in things that were just sort of outliers—really unusual events that might be telling you something. So they were referred a family in which there was just all this cancer, and there were cousins that had childhood sarcomas, and childhood sarcomas are not very common, even among childhood cancers, and they have cousins with this, and they had had a lot of other cancers, some of which were unusual—breast cancer in your twenties and maybe early thirties. You know, that's—I mean you're putting all this together in a family, and so they found this one family, and then they kind of began looking around for that and they found a couple of other families. So they wrote up a paper and asked if this was a familial cancer syndrome, and by that they hypothesized it might be viruses. It might be environmental. It might be genetic. They didn't focus on any one possible cause. Of course then people began looking for this clustering of sarcomas and breast cancer and a variety of other tumors. Those papers came out in 1969. So in the early seventies is when I'm looking at childhood cancers—genetics. I thought this was really fascinating and wanted to see if I could reproduce that or if I could do a survey of MD Anderson cases and see is this real. How frequent is it? Could it be genetics? We're beginning to think at least in Wilms' and retinoblastoma there is some evidence for genetics so maybe this is the sarcoma one. Well, then it became apparent that, like retinoblastoma, in Li-Fraumeni patients if you developed lung cancer and were successfully treated you were at high risk of another, and another, and especially in sites where you were treated by radiation. So that was another sort of thing that appealed to my interest that was kind of in a common theme in things that I had been interested in all along. So I set up a study—which one could never do today—to identify all the childhood—I chose soft tissue sarcomas, which are childhood tumors of connected tissue, muscle, that kind of thing, which were mostly what they had seen in this first paper on Li-Fraumeni syndrome. I identified all the patients that had been treated at MD Anderson from 1944 to, I think, sometime in the 1970s and decided that we were going to relocate all of these families and get the family history, and look at risk for second cancers, and hopefully someday do cytogenetics or other molecular genetic studies and see if we found these same kinds of families and how frequent and so forth they were. In those days you didn't have the Internet and all that, but you also didn't have HIPAA and all the privacy laws, so even though many of the children had died—oh, well, we looked at five-year survivors because I wanted to look at those where there was a risk of a second tumor, not those that just died six weeks after they came in, and I also thought those families—even if their child did die—they would be much easier to locate because we had had several years of communication with them. So that was our criteria. Amazingly we had very few people decline. There were a few people that were from out of the country or something we couldn't locate or something, but we found—oh, I don't know—something like ninety-six percent of the eligible—of those who appeared to be eligible and had almost no people decline to give us this detailed family information.

ROSOLOWSKI:

1:01:23.2

Why do you think it was such a high percentage of—?

STRONG:

1:01:24.8

I think because they had had an experience here at MD Anderson that was unique, and they were ready to help any research that might help others with children with cancer. I think it was a factor of I was from their institution and families who have had a child with cancer don't ever forget, and so they were willing to help, but they gave us everybody in the family's name, address, phone number. You know, you can't do that today? So we gathered up all the data and did some statistical analysis and it looked like about five to ten percent of cases came from this kind of familial syndrome. We documented everything they told us with medical records and death certificates. We did have to have authorization for release of information then, but most people were willing to give us that and most hospitals were willing to send us their records or copies of their records. Only Methodist Hospital requested a notarization—an actual notary or something. Anyway, we were able to show that five to ten percent of these patients had families that were consistent with autosomal dominantly-inherited cancer susceptibility, and then we could kind of characterize what were the cancers and so forth and, sure enough, it very much fit the Li-Fraumeni syndrome, but it gave—we tested genetic models and it provided pretty solid data that the subset was due to an autosomal dominantly-inherited gene. We had some that were really big families and so, from a statistical perspective, it was a dominant gene. So then we began collecting samples, and of course not all the people that were statistically in analysis were living and able to give us a sample, but then we started—

ROSOLOWSKI:

1:03:30.7

What kind of samples were they?

STRONG:

1:03:32.9

Blood samples, because by then you could do linkage analysis. You could do a scattering of markers around the genome. It was a pretty low probability when we started, but once you had the sample and you had the DNA you could always go back and use it for better technology or more markers—more dense markers—as that became possible. Again, people were very cooperative. A few people refused to give blood, but not too many. So we had all the blood samples, and we were doing markers, and we tested hypotheses. Was it related to the retinoblastoma gene? No. We tried to do this linkage analysis, but we didn't have enough markers in the genome to really be able to come up with anything very clear. Finally, I went to a meeting at Cold Spring Harbor, and there were all these people giving talks that were doing tumor analysis and DNA virus analyses in different systems, and this gene p53 kept coming up, and it seemed to be involved in so many different types of cancer, and it might be kind of like a tumor suppressor gene, and there were so many different ways it could work in cancer, and I decided it had to be p53, but then—I don't have a lab, and so I talked to a couple of people about it, and there was a whole series of different things that happened and things—this was all very political.

ROSOLOWSKI:

1:05:27.2

How so?

STRONG:

1:05:28.1

Okay, so one of the things we had been doing along the way—before I became confident it was p53—but just some of the research we were doing—we said, "Okay, fibroblasts are the closest thing to a tissue representative of the sarcomas, and so we're going to culture fibroblasts and we're going to look at chromosomes in these fibroblasts, and we're going to treat them with cancer-causing agents and see if they behave differently than normal fibroblasts." To do that we had to get little punch biopsies of skin and grow them up and, again, you could get them at the time somebody was having surgery, and even a little punch—people were—you know, you didn't have to have dozens and dozens of these. So we had these, and the person who was growing these in the lab and going to do all these studies, at one point—well, we saw some chromosomal abnormalities, but one day it was this chromosome and the next day it was a different chromosome in a different culture, and a different chromosome, so one week we were all excited about one chromosome and then another. But at some point—these cells had been in culture for a while, and what happens to normal fibroblasts is at a point they go through senescence. They die if they're not—if they—so called HeLa cells. They die of. Apparently a technician had gone on vacation or something and kind of left these in the incubator, and when he came back there were some really funny-looking cells in there. There were some cells that had gone through senescence like they were expected, and there were some that were really looking funny. They were not senescent, and some of them were growing, and some of them appeared to be possibly transformed or immortalized. Now at this point in time there was no solid basis for normal human fibroblasts ever being immortalized. There had been publications and publications, but it would always turn out they were contaminated with either cancer cells like HeLa cells or they were contaminated with some of the viruses that were in the lab or something—they were always contaminated. So we did lots of different things to prove that they were not contaminated, that they were immortalized, and that if you added in a cancer gene—an oncogene—they would become transformed where you could now inject them into a nude mouse model and they would make tumors. We could not publish this. Nobody—no matter how much we demonstrated that these were—I mean we had normal DNA from the patient. We showed that the markers that she had were still present in these immortalized cells, et cetera. There was no virus. There was no HeLa. There were none of those things. People just didn't really believe it. Well, there was one person who did believe it. He was in Boston, and he believed it because that's what you would expect if you had a mutation in p53.

ROSOLOWSKI:

1:09:18.8

Can you name that person?

STRONG:

1:09:20.2

Steve Friend. Stephen Friend. So he had two things going at the same time. He was working with Fred Li on a family that they had where they actually could do linkage analysis and he was working with us on these fibroblasts to see if—he was a p53 guy. He could sequence the p53 gene. He could actually look for specific mutations. He was looking for mutations in this family of Fred's in the normal DNA and he was looking at the immortalized fibroblasts to see if what had happened was we had an inherited mutation and perhaps an acquired mutation that had occurred in this immortalization and that would make sense that you would then add a RAF to the picture and get a tumor. So all of this happened at the same time.

ROSOLOWSKI:

1:10:19.3

That's amazing. You mentioned Fred. Who was—?

STRONG:

1:10:20.2

Fred Li

ROSOLOWSKI:

1:10:21.3

Fred Li.

STRONG:

1:10:21.9

Li as in Li and Fraumeni.

ROSOLOWSKI:

1:10:23.1

Okay. And Fraumeni's first name is?

STRONG:

1:10:26.3

Joseph Fraumeni.

ROSOLOWSKI:

1:10:27.8

I can't even imagine how excited you all were when this all came—

STRONG:

1:10:31.0

Oh we all went to Boston to write the paper, to see it. We had a nice weekend in Boston and everybody was so excited but scared to death because this is not something you want to leak out, and then you also—you would wake up nights for—you knew things about people that they didn't know about themselves, and you couldn't start counseling them about it at least until it was all peer reviewed and people believed you, and then we had to set up protocols to be able to provide this information because, of course, you didn't have CLIA labs who could do that. So we had to set up a psychosocial study to measure the impact of this information so we could get IRB approval, but the chills of actually knowing that and then looking at the pedigree of four or five generations of people who died of cancers, it literally still gives me chills today sometimes. It was just really scary to know that at a time when you've just never been in a position to know that much about somebody—somebody's family—or to know how it was going to change their lives—or do they want to know? So it was very exciting. Certainly by far the most dramatic of anything in my scientific career.

ROSOLOWSKI:

1:12:05.9

You wanted to work with patients and you found something that really had an impact.

STRONG:

1:12:09.6

We had an impact, yes. So we've not a lot of that since. Anyway, we got together and wrote, and rewrote, and rewrote the paper and got it published in Science, and then, to go back, once that was out, then that paper on the fibroblast was published but nobody thought it was very important anymore because, "Oh well, if it's p53, of course." So that's what I mean, is—you had a really important event that contributed to the identification as p53 as the underlying mutation but you get no credit for it because nobody believed it until you had done the next step, which you didn't know initially.

ROSOLOWSKI:

1:12:57.1

What year was the paper published in Science?

STRONG:

1:13:01.8

1990. So then, you're just overwhelmed. You've got all these samples. You can actually work through all these families and know this person doesn't carry—now we then had a lab here that could work through all the individual samples.

ROSOLOWSKI:

1:13:29.3

Tell me—because that kind of surprised me when you said, "Oh I didn't have a lab." So what was—how did that happen that you came to have the lab—

STRONG:

1:13:39.8

Well, it wasn't my lab. I was involved in recruiting people in the department of genetics and there were people in molecular genetics who don't talk to patients. We always had very good collaboration—interactions—and I knew thinks about the syndromes that they didn't know or understand and they knew things about some of the genes and certainly some of the technology that I didn't know so. I've been very lucky over the years to have very good collaborators.

ROSOLOWSKI:

1:14:09.8

Now it was Steve Friend's laboratory that did all the testing for that first phase of the—

STRONG:

1:14:16.0

The first few cases that were in the Science paper, his lab did, but then we come back to Houston and I've got fifty samples from one family to slog through and ten samples from this family, and we had—I don't know how many families we had at the time but on the order of twenty-five or more, and multiple samples from each of those. So then we didn't know, would all of them have p53? Would some of them? Of course—

ROSOLOWSKI:

1:14:49.3

So you set up a laboratory relationship with people in what departments? Who was working with you at that time?

STRONG:

1:14:54.7

Molecular Genetics. Well, for a short time it was someone named Marc Hansen. Much more of the time it has been with Gigi Lozano in Department of Genetics. The Department of Genetics has changed names several times. It was Genetics. Then it was Molecular Genetics. Then it was Cancer Genetics, and now it's Genetics again.

ROSOLOWSKI:

1:15:18.0

Do I need to ask you about that?

STRONG:

1:15:20.0

No, no. It really had very little to do with me. I was just sort of along for the ride. I was the only person in the department who was not a lab-based person and nobody knew quite what to do with me. That's not quite true. There was someone, David Anderson, who was here when I first started in 1968. He had been here since the early sixties I guess, and he was a statistical geneticist. He and I kind of officed together. We never really collaborated very much because he was interested in adult-onset breast cancer. Lots of people in the world were doing studies of breast cancer, and so I totally always stayed away from breast cancer except when it came into this Li-Fraumeni syndrome, which was, in my eyes, a childhood cancer syndrome first and foremost. So he and I shared offices. We shared coffee pots and support staff and all that thing until he retired, and he retired in about—oh, when did he retire—I guess the early nineties.

ROSOLOWSKI:

1:16:41.7

Now do you identify yourself as a statistical geneticist?

STRONG:

1:16:45.1

No, I'm not that strong a statistical person, and the statistics over the last decade or two with software and that kind of thing and the ability to sequence the genome and then trying to deal with that vast amount of data—I mean that's a whole other world. I can do a few statistical tasks, but I'm really not into—statistical genetics is a whole different field than just statistics in general. It's much more specialized.

ROSOLOWSKI:

1:17:20.3

So how do you define your own area of specialization?

STRONG:

1:17:25.1

Cancer genetics or genetic epidemiology of cancer because it's kind of epidemiological approaches, but the questions you're asking are genetics as opposed to cigarette smoking or air pollution or something. You're looking for big differences.

ROSOLOWSKI:

1:17:50.3

You said—I mean I thought it was kind of interesting that you said that nobody knew what to do with you and—

STRONG:

1:17:56.4

Oh, it's true. I didn't fit. I didn't fit.

ROSOLOWSKI:

1:18:03.7

How did you know that? How did you know that nobody knew what to do with you?

STRONG:

1:18:06.9

Oh it was very obvious. I also had an appointment in pediatrics for a while. I joined appointments in pediatrics for a while and that was good because I was really interested in pediatrics. The only reason I don't anymore was when we started a clinical genetics program here, breast cancer was clearly where it had to start because of the BRCA genes, and so it seemed important for me to have a joint appointment in breast, and so pediatrics was not going to—at least immediately—be a big player in the clinical program, so that was moved. Some of those joint appointments are a little bit arbitrary. MD Anderson didn't have a department that really was a fit for me. I certainly didn't belong in a heavy duty statistics department. Initially statistics here was mainly methodology for clinical trials and such. I wanted to be in genetics. I wanted to be around people in genetics. I wanted to be around people who were doing laboratory genetics, too, but we didn't really have a human genetics program. We just never ever have had that. I sort of broke—I broke a lot of rules so—

ROSOLOWSKI:

1:19:48.0

What do you mean you broke a lot of rules?

STRONG:

1:19:50.5

I wasn't—I was in laboratory depts. But I didn't have a lab. I wasn't boarded in anything to be treating patients. You've got people with MD/PhDs who do all of those things. I really didn't do any of them, and so I think one thing that I did that worked well was bringing together teams of people who probably would never have worked together otherwise. So we had the molecular genetics people. We had some statistical genetics people. Sometimes—some years we had cytogenetics people. We had people who did the cell cultures. We brought together people to focus on a human condition, and probably none of those people would have worked on the human condition otherwise because they would have been dealing with experimental animals—not experimental animals, but animal systems or cell cultures or something else.

ROSOLOWSKI:

1:20:51.0

Now do you see your ability to do that as—I mean certainly it was a natural outgrowth of your own interest in this, but were there some other kind of interpersonal skills that you feel you brought to that that enabled people to work together. I'm thinking down the line we're going to be talking about some of your administrative roles and leadership, so I'm thinking is this how—one way in which your own leadership skills began to show themselves?

STRONG:

1:21:20.8

I think so, because I was able to get grant support for what's called a program project, which are large grants, which is in its twenty-fourth year now and people have come and gone from that.

ROSOLOWSKI:

1:21:37.1

Is this the mutational model project?

STRONG:

1:21:38.6

Yes, that goes back to the early eighties.

ROSOLOWSKI:

1:21:39.6

Yeah, the mutational model for childhood cancer.

STRONG:

1:21:45.5

So people have come and gone. People have died. People have retired. I kind of have been able to recruit people who were interested in these and to be able to have a group that could work together. There are times that people have worked together better than others, but in this way you developed resources—kind of some shared resources—and people working on different aspects of a problem. So for me it's been a very good way to do research. A lot of people wouldn't want to do that. You've got people who have been doing basic things, and sometimes they're really excited to apply it to human genetics.

ROSOLOWSKI:

1:22:42.0

So you're almost like a relay point between the basic sciences and—

STRONG:

1:22:47.1

That's an interesting perspective.

ROSOLOWSKI:

1:22:49.5

You know you're kind of the translator—kind of getting it—well, I'm thinking of course because the whole idea of translational research and bench to bedside and back again—that's so important to MD Anderson. Because you have this perspective that's kind of in between and a mind that takes in a problem that spans both of them—you're able to do that.

STRONG:

1:23:14.4

Anderson views translational research as treatment to basic science and back. They don't really view it as ideology, underlying predisposition, but that's a little bit arbitrary because what happens once you get a cancer? How you go from being predisposed to getting a cancer does fall into that area. I'm really not what most people around here mean when they talk about a translational researcher. They're talking about understanding the basic science, the biology, the genetic changes in the tumor, using that to identify proteins that could be targeted with drugs that could be candidates for treatment. That's kind of the typical way. It's more the notion of understanding the biology of the tumor and using that information to develop targeted treatments.

ROSOLOWSKI:

1:24:24.0

That's what MD Anderson says. What do you say? Do you agree?

STRONG:

1:24:29.1

I think that's what most people mean by translational research at MD Anderson.

ROSOLOWSKI:

1:24:32.7

Right, but what I'm saying—do you see yourself doing translational research?

STRONG:

1:24:37.6' If that's the definition then probably not really. I mean it's not—I don't want to be drawing fine lines in the sand at all. It has translational aspects. It's just not kind of the main thing people are talking about when they talk about translational research.

ROSOLOWSKI:

1:24:58.7

What makes sense to do now? Obviously this discovery of p53 had enormous implications and, sure, spawned a lot of projects. Does it make sense to talk about—to kind of trace that story to its end or do you want to—?

STRONG:

1:25:14.3

Oh, it doesn't end.

ROSOLOWSKI:

1:25:17.5

Okay, that's exciting.

STRONG:

1:25:21.5

We're still following it.

ROSOLOWSKI:

1:25:22.2

That's exciting. Would you like to follow through on that story? We have about twenty minutes left this morning, and then maybe start with something else next time?

STRONG:

1:25:30.2

Sure, that's fine. Well, after that we had to spend a lot of time doing a lot of genotyping and finding out who had what gene or who had changes in the p53 gene and where it was. As with every gene that comes along today, too, you find changes that you don't know whether they're really deleterious or not. Is this just a random variant or is this something that is disease causing? So there's—and that's still ongoing, in terms that we now have well over a hundred families with mutations in p53 and about a hundred and seventy-five that have a similar phenotype, similar cancer distribution and types that do not appear to have alterations in p53, so we're looking to see where they might have genetic changes. We are trying to put together a different team to develop a cancer screening program for these patients. Over the years I've always brought that up to our imaging people and always been told that you cannot—for the tumors we were worried about—brain tumors, bone tumors, sarcomas—that you couldn't image it before it would be causing some kind of symptom. Now imaging has improved a lot in the last few years, too—particularly MRI. CT has improved, too, but it has a lot of—it has a fair amount of radiation associated with it. About a year ago a group in Canada put together a screening program for individuals who carried mutations in this p53 gene, including children and adults, and—of course Canada has a little bit different healthcare system than we do, as you know, but, at any rate, they showed that those—and people could choose to be screened or not, and about half chose to be screened and half chose not to. Nobody knew whether the screening was going to be worthwhile or not. Screening problems always include you're going to find things you don't know what to do with. How many extra procedures are you going to do that turn out to be nothing—or could even be deleterious? How much anxiety are you going to cause? What's the extra cost, et cetera? So nobody knew whether this was really going to work or not. They started this somewhere I guess about mid-2000, and the numbers were small, but with follow up of most of the cases for about five years they were able to show a big difference between those who had been screened and those that had not. Those who had not been screened—I don't believe any of them had survived their cancer. Those who had screened, I think four out of six had. Numbers were small. Some of the cancers were like thyroid, which is rarely life-threatening, but some of them were like brain tumors and sarcomas that are most often life-threatening, and there were enough of those to convince me that this was going to be real. There were two or three other spots who have set up programs just early on. I had talked to our imaging people a couple of years ago, and they were interested in doing it but we just really didn't have all the different clinicians. You need pediatrics and adult, medical oncology. You need imaging. The biggest thing we need is money actually because these are not going to be people who are fully insured and that kind of thing, and MRI, of course, is much more expensive. Anyway, now we do have some possibilities. You can't really carry this very far but, the MRI technology has really improved a lot, and the imaging people are very excited about doing this—both those who are doing research MRI as well as those who are doing state-of-the-art clinical MRI. I think we've gotten the clinical people engaged who are interested. That includes breast, adult sarcoma, pediatrics, and pediatric long-term survivor clinic because some of these patients who were successfully treated in the past are potential candidates now to be entered into screening for their—to detect their next cancer. So this is something I really want to try to get going. Texas Children's is just setting it up and will probably be doing the infant cases because they have a lot more expertise and you don't want to publish that in our MD Anderson book, but to be honest, they do. So it's not all in place at all, and the funding—there are a couple of possibilities for funding. The people who are doing the research—the companies that are doing the research in MRI might, we hope, be interested in seeing this application. Grant money is going to be hard. Once you've had a proof of principal in one place it's going to be hard to get research money. Our CPRIT—the Cancer Prevention—they're only really interested in screening for breast, colon, and—what's the third one—lungs, I think. It might be different than lung. I can't remember. But they only have money set aside for big screening populations for common cancers where you're bringing screening to populations that would not otherwise have access to screening—minority populations, health disparities, that kind of thing. It's possible I haven't found the right person, but I have not found anyone who felt that their screening money was applicable to this situation, although I'm sort of waiting for them to settle down and figure out who is going to take [Alfred] Al Gilman's place and those things.

ROSOLOWSKI:

1:32:56.8

It's really ironic or curious given the fairly recent establishment of a department of cancer prevention here at MD Anderson, and I was curious about your working relationship with Dr. [Charles A.] LaMaistre around those issues and everything that came out of p53 and the implications for prevention. I don't know if you have any—if that connection is worth exploring.

STRONG:

1:33:26.8

There really wasn't a lot of interaction with him along those lines. His focus was on lung and smoking and that kind of thing. MD Anderson has gotten to be so big that there probably are people doing the same thing in different parts of the institution that don't even know each other, but the prevention program clinically has focused again on standard clinic—excuse me, standard screening for common cancers—mammograms, and there is a high-risk breast screening and there is a high-risk GI screening now for genetic high-risk groups and for some rare endocrine inherited conditions there is a—there's kind of a high-risk protocol, but those can all be done. Those things are done basically—the endocrine one is done through paying for—using your insurance. There's no access if you're not covered in some way or another.

ROSOLOWSKI:

1:34:47.3

So it really is a matter of money. It's not as though the discoveries that you have made about this particular syndrome have kind of presented a curveball or some unusual issue of prevention that now a big institution with certain habits needs to address.

STRONG:

1:35:07.5

Well, I think we have probably the largest collection of p53 mutant families in the country. We have a very large sarcoma service. If you take rare tumors—sarcomas are relatively rare tumors—and tumors of young adults—children, young adults, and some older adults, too—but we have one of the largest sarcoma services in the country—probably the largest. There are reasons of that sort that we really should be interested in taking a leadership role. We have outstanding leadership in, I think—I don't know this field very well—but in MRI—developing new technology and so forth. So there are plenty of reasons it would be worth doing, and for those who are interested in things like chemoprevention and such there might be some opportunities there. Again, that's not a field that I feel like I'm really very knowledgeable in, and it's kind of hard to know when you're dealing with tumors that can occur in so many different parts of the body and so many different cell types it's a little hard to kind of get your arms around.

ROSOLOWSKI:

1:36:28.1

But I can see how this—it's almost like how do you package this particular syndrome as something that people can understand would be an opportunity to develop new areas of treatment because it—I mean look how long it's taken you to explain it today.

STRONG:

1:36:51.7

Hours and hours.

ROSOLOWSKI:

1:36:53.7

I mean it's complex and it's almost as if it's a great demonstration of the challenge of cancer and how complicated cancer is.

STRONG:

1:37:03.8

The sense is if you can show something really works in this vey high-risk population, there are going to be other groups that are not quite as high risk. For example, go back to our old friend the retinoblastoma patients. They're at high risk of sarcomas as well—both bone and soft tissue sarcomas. They would definitely be candidates for this kind of screening. The endocrine people want to use it for some of the endocrine syndromes that they don't have good ways to image—some that are in the chest and abdomen that they need a better look at. So if we could—what it would mean setting up—and this is very do-able—it's done not everyplace, but it's done plenty of other places—is called rapid whole-body MRI. So you need to be able to look at the whole body. You don't want to do the left arm, and then the right arm, and then the left foot, and then the right foot and take a week to get everybody—to get one person imaged. So there's something called rapid whole-body MRI, and you can do the whole body. It's not quite as finely imaged, but you can do the whole body in thirty minutes to an hour depending on all sorts of other variables that you can vary—that you can set different ways. That's something that's not available just anywhere. The cost would be in the thousands. It can be covered by insurance, and some places have—in Utah for example it turns out most everybody in Utah has one health system. I don't know whether it's state health—I don't know how that happened, but at any rate, once they convinced this insurance company to cover it for one person, then they'll cover it for everybody that has this gene mutation, and of course Salt Lake has all the Mormon populations and pedigrees and data base so it's a great place to be doing something like that, but they have convinced that most-common healthcare system to cover the screening. Canada and Europe don't have any problems. It's covered. It's just around the US where there's going to be so much variation in resources that it would be a problem. I mean the argument of course is think what it costs to treat one brain tumor. It's certainly order of magnitude, I mean, in life, but even if you just argue cost alone. So these are a lot of the challenges and this is not probably MD Anderson's highest priority by any stretch at present. This will be a bigger challenge than writing a program project grant for primarily laboratory and genetic epidemiological-based studies, but I need to see some of those things—I would like it see those kinds of things covered before I retire.

ROSOLOWSKI:

1:40:32.1

Yeah, I mean saving the human cost—

STRONG:

1:40:36.4

Excessive.

ROSOLOWSKI:

1:40:39.7

Well, shall we stop for today? It's almost—

STRONG:

1:40:41.9

Sure. Yes.

ROSOLOWSKI:

1:40:43.5

It's about four minutes of twelve and I'm turning off the recorder.

1:40:46.7 (End of Audio Session One)