Chapter 04: Research Advances and the Excitement of Scientific Discovery

Title

Chapter 04: Research Advances and the Excitement of Scientific Discovery

Files

Loading...

Media is loading
 

Description

In this segment, Dr. Kripke expands on her research career. She talks about her collaborations with doctors who translated her research into clinical applications. She gives an example of research with liposomes ("fat capsules") to deliver an enzyme to repair DNA damage caused by ultraviolet light: these liposomes worked and also prevented further damage (though have not been translated into therapy for humans). She emphasizes that photoimmunology continues to tease apart the mechanisms that connect UV light to skin cancers. In response to a question about the mental dimensions of the research process, Dr. Kripke explains that interpreting data is like solving a crossword puzzle, but the "exciting part is designing the right experiment,"and "the feeling that you know something or know how to do something that no one else knows. The rest is just doing the work." She describes some of these moments she has experienced in her research career. She acknowledges her many collaborations with her husband, Dr. Isaiah Joshua Fidler ("all of our papers together were the result of an argument") and characterizes the role he has had on her career as an advisor about the processes and politics of science. She says that her daughter (Katherine Kripke) "grew up speaking metastasis and immunology." She also notes that she read Dr. Fidler's papers, that they improved each other's scientific output. (She notes that her own administrative roles have created awkward situations for both of them.)

Identifier

Kripke,M_01_20120328_S04

Publication Date

3-28-2012

Publisher

The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Collaborations; Research, Care, and Education; Career and Accomplishments; Influences from People and Life Experiences; Character, Values, Beliefs, Talents; Personal Background; Discovery, Creativity and Innovation; The Professional at Work; On Research and Researchers; Overview; Definitions, Explanations, Translations; Discovery and Success; Multi-disciplinary Approaches

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Disciplines

History of Science, Technology, and Medicine | Oncology | Oral History

Transcript

Tacey A. Rosolowski, Ph.D

Okay, because I was wondering did you ever work on any or collaborate on any projects that had direct human applications, or were you always, in your words, a mouse doctor?

Margaret L. Kripke, Ph.D

I was always a mouse doctor, but I had some collaborations. I had a lot of dermatologists who came to work with me, and they, of course, did some things on people, so they were the ones who actually translated things from the laboratory into clinical use.

Tacey A. Rosolowski, Ph.D

What were some of the—do you recall some of the findings?

Margaret L. Kripke, Ph.D

I’ll tell you one of my favorite findings. We were interested in understanding what was the initiating event that started all of this cascade of immunological stuff in the skin. What is ultraviolet light really doing? And one of the things that’s been known for a long time that ultraviolet light does is cause DNA damage, and so the question we tried to ask is is it DNA damage that somehow triggers the response that leads to this cascade of immunological events? And I’d found a collaborator who had developed little liposomes, little fat capsules which contained an enzyme—oh, dear.

Tacey A. Rosolowski, Ph.D

We should just pause until these—(audio pauses ) Okay.

Margaret L. Kripke, Ph.D

My collaborator had developed little fat packets that had inside them an enzyme that repaired DNA damage specifically of the kind that’s made by ultraviolet light, and the minute I heard him talk again at the photobiology society meeting, this was a way to address the question that we were interested in. He had been using this in all kinds of other systems, but using these things as an approach to repair DNA damage in the skin of an animal had not been done before, and it turned out that yes, the fat little globules got into the skin. You could trace the enzyme into the cells and into the nuclei, and you could track the enzyme within the inside of the cells in the nucleus of the cell, and they actually worked to repair DNA damage, and they completely prevented the effect of ultraviolet light on the immune system, and so that was very exciting, and so I had a dermatologist from Austria who came to work with me, and he actually did some more experiments in humans.

Tacey A. Rosolowski, Ph.D

Who was the first collaborator?

Margaret L. Kripke, Ph.D

A fellow named Daniel Yarosh, Y-A-R-O-S-H.

Tacey A. Rosolowski, Ph.D

And who was the Australian?

Dr. Kripke

Austrian.

T.A. Rosolowski

Austrian. Oh, I’m sorry. Austrian. I put an extra syllable in there.

Margaret L. Kripke, Ph.D

Peter Wolf.

Tacey A. Rosolowski, Ph.D

And did those findings end up to have some kind of clinical application?

Margaret L. Kripke, Ph.D

The finding I think that had the most clinical application is the finding that UV radiation—exposure to ultraviolet light can decrease immunity to almost anything, not just to skin cancers but to other things as well, and one of the kind of side avenues that we took here was to look at the effects of ultraviolet light exposure on infectious disease models in animals, and other people went on to show that vaccinating in an area that’s been exposed to ultraviolet light decreases the immune response and that there are some effects on the human immune response between light exposure and immune responses to the organisms.

Tacey A. Rosolowski, Ph.D

But it sounds like there’s still a long way to go to discern all of the complexities there.

Margaret L. Kripke, Ph.D

Yes, and therapeutically there are people who are trying to use ultraviolet light to decrease unwanted immune responses in the skin and to get rid of things like—there’s a graft versus host reaction that occurs when you have bone marrow transplantation where the cells, the lymphocytes that you put into the body, react against the recipient, the host, and so people are trying to use ultraviolet light to decrease the skin reaction, and so there is a phototherapy application of the ultraviolet light, but mostly it’s really about understanding the mechanisms by which these very highly antigenic skin cancers are able to grow and defining the role of the immune system in the establishment of skin cancers.

Tacey A. Rosolowski, Ph.D

I was wondering if you could talk about—I’m never quite sure how to ask this question, but I’m interested in the mental process that you go through when you’re doing an investigation, what that’s like, what kinds of—I mean, is it purely intellectual? Is there a sense that you’ve got an inner compass that tells you you’re on the right track? Obviously you’re doing experiments and collecting data and evaluating that data but—

Margaret L. Kripke, Ph.D

But that’s the end process.

Tacey A. Rosolowski, Ph.D

Yeah.

Margaret L. Kripke, Ph.D

Yeah, that’s right. I’ll give you a couple of examples.[CLIP C: Discovery, Creativity and Innovation, C: The Professional at Work] One is a very famous experiment that Josh Fidler and I did, probably the greatest scientific experiment he and I ever did. He had claimed in his usual flamboyant manner that cells in a cancer were heterogeneous and that cells that formed metastases preexisted in the parent population. That was his conclusion, and I kept saying “You have no proof of that. These cells could become metastatic while they’re running around in the body and doing things.” And so we argued and argued and argued about whether that was true or whether it was proved or how we could do it, and I remember distinctly sitting in front of a—sitting doing tissue culture one day thinking about nothing in particular and the light bulb—I mean, literally the light bulb goes off, and I stopped what I was doing. I went into his laboratory—this was in Frederick—went into his laboratory and I said, “I have the experiment to do. I know the experiment to do to settle the question.” And it was cloning, making individual clones out of the tumor and asking—if he was correct then some clones would be metastatic, and other clones would not, and that was in fact the answer. But the fun part is when the light bulb goes off and you have this feeling that all of a sudden you know something or know how to do something that no one else in the world knows, and that’s the exciting part. The rest is just doing the work. The other part that’s really interesting is looking at the data that you’ve got and trying to make sense out of it. It’s like solving a crossword puzzle. How does this work? What does this tell you? What can you learn from this? But the real excitement is in designing the right experiment and loving the fact that you’ve done the elegant experiment, the real definitive experiment that really gives you the yes or no answer, so that was one. END CLIP]

Tacey A. Rosolowski, Ph.D

What were some of the most memorable laboratory experiments, if you can pick one out, for you? I mean, laboratory experiences, I should say, moments in your lab that were just killer.

Margaret L. Kripke, Ph.D

You mean the a-ha moment kind of thing? There were really—there have been several over the years. One was listening to Dan Yarosh’s talk and knowing that that was the approach that would answer the question of is DNA damage important and knowing that if they could get into the mouse skin and if the enzyme actually got to where it was supposed to be that that would be definitively answering the question, and that was very exciting. We had a long and enormously productive collaboration over that issue. Another one was early on, when we were looking at the effects of ultraviolet light on skin cancer development and on the immune response to skin cancers, we started profiling the immunology of the animals. Are they immune suppressed? Can they make responses against anything else? It turns out they can make responses against almost everything else, so the defect was very selective for cancers induced by ultraviolet light, but there were some exceptions. There were some interesting exceptions, and one of the exceptions was that animals that had been exposed to ultraviolet light, one site, and if you then immunized them at a site that was not exposed to ultraviolet light and the immunization was through the skin, the animals didn’t make the immune response. There was a systemic alteration that prevented the animals from making an immune response to a—it’s called contact sensitizers, what you get when you have nickel allergy or some contact allergy. Poison ivy is another example, poison oak, those kinds of things. Those are contact allergies, and ultraviolet light had the ability to turn those down or turn them off, and at first it was kind of annoying because we were so sure this was a selected response because the animals could reject other kinds of cancers. They could reject skin grafts. They could make antibody responses. They could do everything, but they couldn’t do this, and it was kind of an outlier, and then I started thinking about it, and I thought, well, if ultraviolet light can alter the immune response to these chemicals that you put on the skin could you use that—what would be the implications of that for bacteria and viruses and stuff that get in through the skin, and does ultraviolet light play a role there? And it turns out it’s very important in the herpes virus, by the way. And the fact that you could use that as an experimental model to understand the mechanism of what ultraviolet light was doing because you could then use the contact allergy system to follow the fate of the cells that picked up the antigen in the skin. You use a fluorescent antigen in the skin, and then it turns out they travel to the regional lymph node, and you can separate them out, and you can show they have DNA damage in them and so on. It was an a-ha moment that this wasn’t an annoyance. This was a tool that could be used to really go further in the understanding of the mechanisms and what was going on and also perhaps be of some therapeutic benefit, so there you have it.

Tacey A. Rosolowski, Ph.D

That’s a great example. You’ve noted a bit of your collaboration with Dr. Fidler, and I notice that you’ve co-authored papers. Obviously you’ve talked and argued about things.

Margaret L. Kripke, Ph.D

All of our papers were the result of an argument. (laughter)

Tacey A. Rosolowski, Ph.D

In his interview he credits you with asking him some very challenging questions that helped him redirect his research, so I was wondering how you would summarize the effect of this kind of life partnership collaboration on your career.

Margaret L. Kripke, Ph.D

Well, Josh has always been my serious political advisor. He’s much more attuned to the political world than I am, and so he’s been extremely helpful in that regard, and I mean the politics of science and he used to tell me—you know, you send a manuscript for publication, and it comes back, and they say, “Well, we didn’t like this, and we didn’t like this, and we want you to rewrite this and revise that and do 3 more experiments” and whatever. And I would start writing this long, lengthy rebuttal about how they were wrong, and that’s not the way to do it, and they don’t know what they’re talking about. And Josh would—I would say “Look at this for me,” and he’d look at it, and he says, “Do you want to get the paper published, or do you want to be right?” And so that was a real learning—a difficult learning experience for me is to kind of sit back and say okay what do we have to do to get—because if it doesn’t get published no one will ever see it anyway, and so he taught me a lot about the processes of science and the politics of science and also was a very good critic of my work and writing. Was it clear? If he couldn’t understand it, then no one could understand it, so it was a very synergistic relationship, and as I say, most of those scientific publications came out of an argument about who was right and designing the experiment to determine who was correct. The other interesting outcome was that my daughter—I had a 4-year-old daughter when Josh and I were married, and she grew up at the dinner table speaking both metastasis and immunology, and she could spell metastasis by the time she was 7, and she now has a PhD in immunology and works for the National Institutes of Health.

Tacey A. Rosolowski, Ph.D

And her name is?

Margaret L. Kripke, Ph.D

Katherine Kripke.

Tacey A. Rosolowski, Ph.D

How would you say you’ve influenced Dr. Fidler’s career?

Margaret L. Kripke, Ph.D

I like to think that I’ve—I don’t think I’ve influenced it in any way. I like to think that I’ve facilitated some things. I used to spend a lot of time reading his scientific articles, again, for clarity and logic and presentation and so on, the same kinds of things that he did for me as well, and I think we improved each other’s scientific output. It was, in general, a pretty synergistic relationship. Sometimes he would think of things for me to do, new experiments that I could do and vice versa. It was a productive relationship. Pretty boring dinner table conversation if you run into it.

Tacey A. Rosolowski, Ph.D

Well, it sounds like your daughter Katherine definitely profited enormously from it.

Margaret L. Kripke, Ph.D

She benefited. By the time she went to college she already spoke immunology.

Tacey A. Rosolowski, Ph.D

That’s very cool. Now, I read at one point—I hope I got this correct—that when you—that you reluctantly gave up research to really focus much more strongly on the administrative aspect of your career.

Margaret L. Kripke, Ph.D

That’s true. That is correct.

Tacey A. Rosolowski, Ph.D

Okay. And so I wondered would you like to talk about that?

Margaret L. Kripke, Ph.D

I want to say one other thing about Josh’s and my influence on each other’s careers. In some senses it has been difficult in terms of my leadership role. I was the program director in Frederick, and he was one of the people there. Of course, he can never report to me, but it made for an awkward situation, and it probably disadvantaged him in many regards, including one at MD Anderson when I became a vice president because I feel like I had to bend over backwards not to show favoritism in cases where I had the ability to do that, and so he has been very supportive and very long-suffering in that regard. I think—would he have done differently or better? Probably not, but it was not easy for him or me.

Tacey A. Rosolowski, Ph.D

Is there an instance that you feel you could diplomatically share that would—in which you had to make a decision that in another situation—

Margaret L. Kripke, Ph.D

I can’t think of a specific one.

Tacey A. Rosolowski, Ph.D

I was just curious. Yeah, I was thinking that might have—that would bring up some very difficult issues, and I think if you had a 2-career couple there are always going to question about the activities of one that rises into a position of leadership and even more so if it’s a woman in a male-dominated situation.

Margaret L. Kripke, Ph.D

I think Josh has kind of had to make the decision over and over again not to move up administratively, and it has forced him to really define what it is that he—how he wanted to spend his career, so obviously I think he’s made the correct choice. But as I say, it has not been easy always.

Segment 5[T1]

[T1]In this segment, Dr. Kripke talks about her shift from research to administration and her “learning curve” as she grappled with leadership. She talks about her (exclusively) mentors in leadership and also her participation in a program for women in academic medicine, ELAM, the Executive Leadership in Medicine Program in 1996-1997. (She was the only appointee from Texas that year.) She describes being interested in “the science of administration.” She details the lessons she learned during this “phenomenally exciting time” that allowed her to reflect on where she wanted to go with her career. She explains her decision to leave her research career, resulting in her 1998 appointment as Vice President for Academic Programs (promoted to Senior Vice President in 1999 and to Executive Vice President in 2001). She outlines the principles on which she bases leadership and discusses institutional and cultural changes that evolved after 1996, when Dr. Mendelsohn became president, including a new openness compared to the secrecy of previous administrations. She describes how she tried to implement one of her goals as VP for Academic Programs --to “level the playing field” for researchers. She talks about her working relationship with Dr. Andrew von Eschenbach, whom Dr. Mendelsohn appointed to Senior VP of Academic Programs. She describes the scope of her role as Executive Vice President, emphasizing that she had to become familiar with the clinical side of research, “a completely different culture.”

Chapter 04: Research Advances and the Excitement of Scientific Discovery

Share

COinS