Chapter 16: Studies of Pro-Apoptotic Molecules: Translational Research and Thinking Outside the Box

Chapter 16: Studies of Pro-Apoptotic Molecules: Translational Research and Thinking Outside the Box

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In this chapter, Dr. Hortobagyi talks about two related studies of pro-apoptotic proteins (which instruct cancer cells to commit suicide) and reflects on the kind of creative thinking that leads to great discoveries. He begins by explaining how he and Dr. Mien Chie Hung decided to submit a “truly different” proposal to the Breast Cancer Research Foundation (BCRF), one based on the observation that a gene product from Adenovirus-5 and E1A could cause HER2 positive cancer cells to commit suicide. This research proposal was partially funded by the BCRF and also by a SPORE grant. This gene therapy successfully transformed HER2 positive cancer from the most difficult to the easiest disease treated and has been applied to head and neck and other cancers. The next project was based on the observation that the Bik protein in the BCL-2 family was pro-apoptotic. Dr. Hung produced the genetic variant, BikDD, with an enhanced destructive effect.

Next Dr. Hortobagyi describes the new view of cancer that emerged in the 1990s as a result of discoveries in cell biology, and how this has influenced research. In the early 90s, he explains, physicians were working with ideas that had been known in the basic sciences at least ten years earlier. Dr. Hortobagyi explains that through his conversations with Dr. Mien Chie Hung, it began to dawn on both of them how to transport the basic science information into a new context. Dr. Hortobagyi notes that it’s “an epiphany” to take a laboratory observation and then visualize its possible applications in clinical settings. He also connects his ability to think in these translational terms to his interest in setting up multi-disciplinary teams. He then explains an “inherent contradiction of translational research”: despite the prevailing wisdom that scientific thinking is disciplined, and logical, truly important discoveries require that you become undisciplined and think outside the box. Traditional thinking leads back to existing knowledge.

Identifier

HortobagyiGN_03_20130123_C16

Publication Date

1-23-2013

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The ResearcherThe Researcher Discovery, Creativity and Innovation Professional Practice The Professional at Work On Research and Researchers The History of Cancer Research and Care The Administrator Beyond the Institution Career and Accomplishments Institutional Mission and Values Discovery, Creativity, and Innovation Patients, Treatment, Survivors The History of Cancer Research and Care The History of Health Care, Patient Care Global Issues –Cancer, Health, Medicine

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 Ann Rosolowski, PhD:

All right. We are recording. I am Tacey Ann Rosolowski. Today is January 23, 2013. It is about twelve minutes after 1:00. I am sitting in the office of Dr. Gabriel Hortobagyi, and we are about to begin our third session. So, thanks very much for allowing me to come and speak to you again.

Gabriel Hortobagyi, MD:

Thank you for having me.

Tacey Ann Rosolowski, PhD:

We were just plotting and planning our attack here for the first part of the interview. We ended up the last session talking about the Breast Cancer Research Foundation. You spoke a lot about the organization of that and how the foundation started, but I wanted to have an opportunity to ask you more about the research that you are doing with grant funding from that organization. So however you want to organize that story, or I can ask you questions, whichever you would prefer.

Gabriel Hortobagyi, MD:

After I was asked to join the Scientific Advisory Board to the BCRF, our first task was to select the first few awardees. We wanted to make sure that the leading scientists in the major cancer centers were included among those, especially if they had a proven track record of productivity and novel ideas. So, when I came home from that meeting, I immediately contacted my co-conspirator, Mien-Chie Hung, with whom I have had the great pleasure of working for well over twenty years. We put our heads together to come up with a truly different proposal, and we had a number of research projects ongoing and planned at that time. But we said, “Well, let’s do something totally different,” and that’s what we came up with. The first project, which was based on the—actually no. It was the E1A proposal. That was based on an observation that Mien-Chie had made in the lab on a gene product from Adenovirus-5, which is one strain of adenovirus. This gene, E1A, had the property of convincing HER2 positive cancer cells to commit suicide. So we then worked on this concept. Later it became apparent that it was not restricted to HER2 positive breast cancer. In fact, it wasn’t restricted to breast cancer, and eventually it became a broader gene therapy program that was applied to head and neck cancers, ovarian cancers, et cetera. It was—strictly speaking—gene therapy in the sense that we would take this DNA segment, encapsulate in liposomes, and then administer it to patients. We got some partial support for that project from the BCRF. We also got some support for that from our first SPORE application—the Specialized Program of Research Excellence in breast cancer. Then the BCRF funding works one year at a time because, of course, it depends entirely on the success of that year’s fund raising. So, we never got enough in one particular—any one particular year to support the cost of the entire project. But for all the time ever since—I guess 1992 or so—we’ve gotten a very sizeable chunk of funds from the BCRF—of course, upon presenting results and annual reports and then accounting for how we spent the money and whatnot. In retrospect, it was an incredibly wonderful source or resource because it—the BCRF—was willing to take risks with these projects, which were really out of the mainstream and that were considered high risk. I know that Mien-Chie had applied to other more traditional sources of funding not very successfully. So, the two places where we actually found a solid source of support were the BCRF and eventually the SPORE mechanism. So that was good. That was our first project. From there, we went onto the second project, which was based on the observation that one of the proteins that is in the BCL-2 family—this group of proteins essentially modulates the process of cell suicide. Some of them are pro-apoptotic. Some of them are anti-apoptotic. It is the balance of this entire family at any one point in time that determines whether the cell lives or dies.

Tacey Ann Rosolowski, PhD:

I am not sure I understood you correctly. Is that VCL-2 or—

Gabriel Hortobagyi, MD:

BCL-2.

Tacey Ann Rosolowski, PhD:

BCL-2.

Gabriel Hortobagyi, MD:

That is correct.

Tacey Ann Rosolowski, PhD:

Okay.

Gabriel Hortobagyi, MD:

So the cell—the BCL-2 family is a large family of proteins, and its members, of course, determine the direction in which the cell will go. One of the pro-apoptotic molecules was Bik. Dr. Hung in the lab produced a number of mutant versions of Bik. One of them, BikDD, which had two mutations in the molecule, turned out to have a much more enhanced pro-apoptotic activity than the parent molecule. So we ended up using the mutated version—BikDD—for our subsequent experiments and eventually our translational project.

Tacey Ann Rosolowski, PhD:

When did you first discover or—to me it is such an amazing paradigm shift to suddenly realize that you can use these tiny mechanisms within the body itself and harness that to work against disease. That’s just a totally different way of thinking. When did that really enter your consciousness and approach and become a powerful source of inspiration for your work?

Gabriel Hortobagyi, MD:

It’s hard to put an exact time and place because these things happen gradually.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

As a physician, I had a predominantly clinical and empiric training. I went to medical school in the 1960s. So, at that time our knowledge and our understanding of biology—viewed with today’s eyes—was so limited and so primitive. Yet by then there had been a very substantial investment in the basic sciences and in biology in general. But there was a lot of time between the discovery of many of these mechanisms of cell biology and until those discoveries gradually infiltrated our consciousness in medicine. So probably much of what we started to work with in the early 1990s was already known in basic science circles five to ten years earlier. But with many early discoveries, the importance of the discovery is not known until later. Even the discoverer himself—we might have touched in another discussion—sometimes they didn’t know what to do with that. It takes a while of throwing around the idea and digesting it and sleeping on it until you figure out—the light bulb comes on and says, “Gee, why didn’t I think of this?” Probably somewhere in the early 1990s in conversations with my colleague, Dr. Hung, it started to dawn on both of us that there might be possibilities here. Once you then discover that here is an observation that earlier you thought of as—this is just interesting but not a terribly useful piece of information—and now I think of it differently. I think of it as, “Gee, I can take this piece of information and actually take it to the clinic eventually. I see the pathway.” Whether that pathway will turn out to be the right one or not is a different matter. It is really, in a way, an epiphany. Once you take that step—from my point of view as a clinician—I think it is sort of the reverse process for basic scientists like Mien-Chie Hung where he can—instead of just being in his cocoon in the lab looking at, “Gee, let’s learn more about the cell. I don’t quite know nor do I care about where this goes later.” Then in our interactions as we started to jointly think in translational terms—in terms of I am starting to understand the basic biology, and he is starting to understand the clinical needs—putting this together. You sort of pave a translational pathway.

Tacey Ann Rosolowski, PhD:

Well it seemed like that symbiosis between two collaborative thinkers who want to work translationally as well. That seems really key. You’re kind of jump-starting each other—

Gabriel Hortobagyi, MD:

Absolutely.

Tacey Ann Rosolowski, PhD:

—and helping each other out with kind of complementary knowledge fields, if you will.

Gabriel Hortobagyi, MD:

Right.

Tacey Ann Rosolowski, PhD:

Yeah.

Gabriel Hortobagyi, MD:

In a way that was an indirect consequence of my earlier work in trying to bring together physicians of different disciplines because while qualitatively it’s different, it is the same basic concept of first learning to—stepping back and learning to understand why you think of the same problem differently than the surgeon across the table from you or the radiation oncologist across the table from you. Then you try to figure out the why of the differences. Then you try to figure out how these two perspectives can actually merge and become symbiotic and complementary as opposed to being confrontational and—

Tacey Ann Rosolowski, PhD:

Adversarial.

Gabriel Hortobagyi, MD:

—adversarial. The same thing in a way was this coming together of a fundamental laboratory scientist and an empiric clinician, if you wish—realizing and recognizing gradually that there were incredible possibilities in the future for that.

Tacey Ann Rosolowski, PhD:

Is there something different about the—I’ll use the word creative—you would use a different word—but the creative process of visualizing that possible use and then figuring out the pathway to see if it is possible to put that to use in a clinic? You’re taking risks. You’re creating alternative scenarios that you have to work with. Is that process different in translational research and particularly with studies that work with the mechanisms of cell biology? Is that different from other kinds of investigative proceedings?

Gabriel Hortobagyi, MD:

I don’t know that it is really different. But I think there is an inherent contraction in it. So we think of science—true and the best science—as a highly disciplined activity in which you follow some very strict rules in order to develop an appropriate and reasonable hypothesis.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

Then you build a logic-based pathway towards either proving or disproving that hypothesis. You sort of think through the process of how you are going to get there. That is supposed to be at the heart of creativity. In reality, the process of creativity that leads to truly important discoveries has to break that mold because you have to become sometimes undisciplined in order to—what we call today—think outside the box. You have to let a little bit of that rowdy, crazy side of you to say, “I know what the rules are, but I am going to think a little bit outside the rules for a moment.” Then you have to imagine why that might be a better way to think.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

The reason that is important is because the traditional thinking and the traditional and disciplined thinking almost always limits to you existing knowledge. By definition, existing knowledge is limited. All right. So, in order to go beyond that limit, you have to think differently. Otherwise, you always come up with the existing limitation—the wall within which your knowledge exists.

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Chapter 16: Studies of Pro-Apoptotic Molecules: Translational Research and Thinking Outside the Box

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