Chapter 04: Reflections on Research; Becoming a Citizen; Influences: Words of Wisdom

Chapter 04: Reflections on Research; Becoming a Citizen; Influences: Words of Wisdom

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Description

In this character-revealing segment, Dr. Fidler talks about his ability to think outside the box. He recalls becoming a citizen and some of the cross-cultural challenges he faced. He recalls family members who influenced his independent thinking. He reflects on the contributions he has made to his field and the influence of Dr. Judah Folkmann on his thinking.

He ends this session by talking about the implications of his discoveries for research, its links to the current push for individualized care. He also questions how quickly they have been translated into therapies that will benefit patients.

Identifier

FidlerIJ_01_20110926_C04

Publication Date

9-26-2011

City

Houston, Texas

Topics Covered

The Interview Subject's Story - Personal BackgroundPersonal Background Influences from People and Life Experiences Character, Values, Beliefs, Talents

Transcript

Tacey Ann Rosolowski, PhD:

What do you think gave you the ability to do that kind of unconventional thinking?

Isaiah J Fidler, DVM, PhD:

I often wonder. I guess I just in general -- thinking I always am outspoken. Many people don’t like it. Thinking out of the box. Want to be different, that’s all. And I always think -- you have children?

Tacey Ann Rosolowski, PhD:

No.

Isaiah J Fidler, DVM, PhD:

You remember yourself as a child?

Tacey Ann Rosolowski, PhD:

Yeah.

Isaiah J Fidler, DVM, PhD:

What was the first question you asked your parents? A real question. “Tacey, wash your hands.” What did you say?

Tacey Ann Rosolowski, PhD:

Why. Of course.

Isaiah J Fidler, DVM, PhD:

Ah. Why.

Tacey Ann Rosolowski, PhD:

Yes.

Isaiah J Fidler, DVM, PhD:

Not how.

Tacey Ann Rosolowski, PhD:

No.

Isaiah J Fidler, DVM, PhD:

Not what.

Tacey Ann Rosolowski, PhD:

No.

Isaiah J Fidler, DVM, PhD:

Not when. All these are techniques. Why. That’s the question a child asks. Why. Give me a reason. And maybe they were patient with you. “Because you have dirt on your hand.” Why. “Because if you don’t do that I’m going to take something to you.” And I said, “OK, OK, OK.” My father used to say, “You want why? Why. I’m tired of you asking questions.” The why is the question in medicine. Why is there metastasis? Not how. When. If. Seventeen different ways of doing a technique. I’m not a technocrat. Very bad in that. But why leads to a hypothesis. And I was fortunate that I could in my first research position in the dental school, they gave me a goodly amount of money to come and do research. So I could do all those things. Get my preliminary data. Now go write grants. At the time NCI did a smart thing. When I came to MD Anderson I was at NCI. And I had to write proposal for -- they encouraged us to think, don’t compete with everybody else, do something great, etc., wonderful. But when we came to MD Anderson we became regular citizens. And NCI began something that I thought was a phenomenal advance called Outstanding Investigator Award. Outstanding Investigator Award, you had to really compete for that. They didn’t give it to everyone. You had to be moving earth and shaking in your field. But if you received it you were not allowed to compete for any other grants. And I’m one of the very few who was able to renew it. And I had it for 15 years. I think it was $600,000 a year. But I could not write an R01 or P01. This is it. Many of my colleagues said they don’t want it because they have three R01s, they can get $1 million. I said, “But then you’re wasting your time writing grants.” “We don’t care.” And then a lot of people began to complain. “What is different than us?” And instead of saying, “We only have about 20 of them, and we recognize our best scientists like that,” said OK, and they folded. That’s what governments do. So that also encouraged people to think unconventionally. Not to be afraid. We had meetings. We had arguments, etc., etc. I think that’s the reason.

Tacey Ann Rosolowski, PhD:

Couple of just questions to pick up details. What year did you become a citizen?

Isaiah J Fidler, DVM, PhD:

Gee. That’s a tough one. Probably around 1960.

Tacey Ann Rosolowski, PhD:

Was that a big deal to change citizenship?

Isaiah J Fidler, DVM, PhD:

No, because I did not lose my Israeli citizenship. US and Israel recognize dual citizenship. So when I’m in Israel I enter on Israeli passport. When I’m in America on an American passport. Were I required to give up it would have been difficult. But --

Tacey Ann Rosolowski, PhD:

You didn’t have to confront that.

Isaiah J Fidler, DVM, PhD:

The US has recognized dual citizenship with quite a few countries. Israel is one of them. Britain is another. France.

Tacey Ann Rosolowski, PhD:

Have you encountered -- was it difficult for you when you came to this country? Were there a lot of intercultural issues that you had to deal with or challenges?

Isaiah J Fidler, DVM, PhD:

Yeah of course. It was a different culture, different language. Everything was different, especially in Arizona, Oklahoma. I went to Stillwater, Oklahoma, a town of 20,000 people, and 30,000 students. Jerusalem was so far more advanced than Stillwater, Oklahoma. It was a tiny little community. You could walk from end to end. And I went with a good friend of mine. I used to go to church on Sunday because I was -- sort of wanted some religious experience. The closest synagogue was in either Tulsa, Oklahoma City. The food was different. Language was not a problem, because again my English background was so strong. My accent was a problem. I was inducted to the hall of fame of Oklahoma State, and as I received it I told them that when I first arrived I still remember going to eat grilled cheese sandwich which is my -- only thing we could afford. Was delicious. I cannot find that grilled cheese taste again. It probably was the cheapest cheese possible and smeared with some who knows what. It was not butter. But anyhow. And the lady. I said, “Can I have a grilled cheese sandwich?” And she looks at me, says, “Oh you must be a foreigner.” I didn’t know what she was talking about. I went home, and I look in the dictionary. Fern F-E-R-N. God, that’s a plant. Why is she calling me a plant? Then I realized that in Oklahoma fern is a foreigner. And after that everything was OK. I said, “For them to call me a foreigner was a distinct --” everybody’s laughing. But it was true. I had to get used to the accent there. I don’t know. When I left home at the age of 13 to go to a dormitory, so that prepared me not to be home. I was in the army for two years. That was not home. And then I came to the States. It was just a continuation of being on my own. That’s another thing maybe that I was never afraid of. Is to be on my own. Whether I like it or not that’s my life. I had to trust myself.

Tacey Ann Rosolowski, PhD:

And trusted yourself about your scientific directions as well.

Isaiah J Fidler, DVM, PhD:

Well, I imagine so. I don’t know if it’s here. I carry some principle with me. That’s not it. Michael Crichton. There’s no such thing as consensus science. If it is consensus it’s not science. If it is science it’s not consensus. Period. But here are the three principles that I read to students. Only two things are infinite. The universe and human stupidity. And I’m not sure about the former. That’s Einstein. I don’t know the key to success. But the key to failure is trying to please everyone. But this is the best one. If you’re looking for a helping hand you’ll find it at the end of your arm. That’s my grandmother.

Tacey Ann Rosolowski, PhD:

That’s your grandmother.

Isaiah J Fidler, DVM, PhD:

Yeah.

Tacey Ann Rosolowski, PhD:

Yeah. So that independence thing was --

Isaiah J Fidler, DVM, PhD:

No, I mean she --

Tacey Ann Rosolowski, PhD:

-- there in the family.

Isaiah J Fidler, DVM, PhD:

-- used to -- it was -- she didn’t even have to say it anymore. She just went like that. Means go do it yourself.

Tacey Ann Rosolowski, PhD:

Go do it yourself.

Isaiah J Fidler, DVM, PhD:

Grandma, can I have that? She said.

Tacey Ann Rosolowski, PhD:

Go do it yourself.

Isaiah J Fidler, DVM, PhD:

Yeah. You want to do it, do it.

Tacey Ann Rosolowski, PhD:

That’s great.

Isaiah J Fidler, DVM, PhD:

I’m not going to do it for you. So you learn after a while to be totally independent. Then as you get older you realize that there’s no such thing as independent. You’re dependent all the time. You just don’t know it. It’s the seed and soil hypothesis. Seeds are not independent. Soil is not independent.

Tacey Ann Rosolowski, PhD:

Interdependent.

Isaiah J Fidler, DVM, PhD:

If you ask what makes -- if you really study the biology of a lung you realize how it’s regulated by protein that are made by everywhere. If you look at all this complicated diagram of protein and this, and looks like a highway in Los Angeles, OK, but when push comes to shove it’s not that complicated. It’s just that we don’t understand.

Tacey Ann Rosolowski, PhD:

I’m curious on how quickly your research was so -- so revolutionized the field. How quickly were some of these principles taken up and applied to actually intervene in patients’ lives?

Isaiah J Fidler, DVM, PhD:

I don’t know how to say it politely. Probably within a decade. But I don’t think people gave credit. If you say, “Tumors are biologically heterogeneous,” people will say, “Of course they are.” “Who was the first to show it?” “Nobody.” It’s like Luria-Delbruck, same thing, I realize that that’s the way the world is. And they remember who invented a drug, but the principle I’m not sure. If I asked you who got the Nobel for better understanding of the AIDS virus, about two years ago it was the hottest thing. And Robert Gallo didn’t get it and this one in France got it. And today both of them go to the movies, they pay the same ticket. So I don’t know. The question of heterogeneity has influenced the field a lot. The fact that metastases are not random greatly influenced the field. But whether it was taken to patients. In principle yes, in practical I don’t know how to tell you. The fact that tumors in different organs within same patient are different is beginning to penetrate now. And the fact that right now at MD Anderson there’s a big push for what is called individualized therapy. How do you explain individualized therapy? What’s the need? Why do we need individualized therapy if all tumors are alike? If all tumors is one big C, we need one drug and that’s it. For years we were looking for the miracle drug. It’s not there. OK, so all colon cancer. Colon cancer is different than prostate, and prostate different than melanoma, etc., right? But now I’m telling you that not all colon cancer are alike, and not all breast cancer are alike. Some have a receptor for erbB-positive and some are erbB-negative. So even breast cancer are not alike. And now when we’re publishing that gene expression of breast cancer cells growing in different organ are absolutely unique to the organ, then the treatment has to be directed to where the tumor is growing.

Tacey Ann Rosolowski, PhD:

To the soil.

Isaiah J Fidler, DVM, PhD:

To the soil. So that’s another complexity. Is that convenient? No. So we have to finish. But I’ll tell you -- I’ll have to leave in a minute. Surgeons understood that for many years. I’m a surgeon. We refer. For example, a patient that has breast cancer and the tumor metastasize in the lung, and surgical approach is determined to be useful. A thoracic surgeon will operate on the lung. But if the tumor is in the bone it won’t be the thoracic surgeon. It will be an orthopedic surgeon. If the tumor is in the brain no thoracic surgeon will do neurosurgery. Go to the neurosurgeon. So here three surgeons could work on the same patient. If surgery was determined to be an approach to therapy. Where we got spoiled is radiotherapy. You can radiotherapy here, here, here. It’s the same person. But what about oncologists? And you see in oncology you have a breast cancer specialist, and they’ll treat the patient regardless of the organ. Eye cancer specialist. Melanoma specialist. I say, “Folks, keep in mind you’re treating different disease.” “Well, what would you like us to do?” “Well, if it metastasize to the brain, let a neuro-oncologist handle it. Regardless of where the tumor originated from, it’s growing in the brain.” And you’ll see tomorrow the brain is a very unique microenvironment. I could give you the same story on the bone, on the liver. But I’ll choose the brain because that’s where I’ve dedicated the last four years of my life to. And on and on and on. So hopefully that concept, that the microenvironment alters the behavior of the cell. There is adaptation there. And if we can treat the microenvironment we may be able to have one therapy for a single organ. And that’s what the late Judah Folkman -- you know his name, Folkman -- was advocating when he talked about the issue of angiogenesis. Oxygen. This is something we published. Oxygen can only diffuse about 100 micrometer from the blood vessel. And here we published an interesting paper. Excuse me, my back. We published an interesting paper some time ago. Maybe I took it out. Anyhow we took a clinical specimen and measured dividing cells and dead cells’ distance from the nearest capillary. All dividing cells were 60 to 80 micrometers from blood vessels, and all dead cells were 140 and further from the blood vessel. Oxygen only diffuses 100 micrometers. And with all due respect to the world, without oxygen there’s no life. So tumor cells that couldn’t get sufficient oxygen died of hypoxia. OK? So Judah said that unless the tumor develops blood vessels it cannot increase in size. Because of this finding that we had. He was absolutely correct. But you know what objection angiogenesis had? What trouble he had? He was almost thrown out of Harvard because he was so unconventional. He was a pediatric surgeon. Let him go back to surgery. And the senior faculty at Harvard were livid with him. The dean appointed, gave him tenure. He was assistant professor. He says, “I’d like to protect you,” and gave him tenure as associate professor like that. So the rest will know that he is sacrosanct, leave him alone, he’s thinking out of the box. I really wanted Judah to come here for a year when I was the chairman for so many years. “I give you a nice office. Come and escape.” They were attacking him again and again. When he talked about antiangiogenesis therapy. And today you have thousands of people working on it. He was the first to say. He was correct. If you attack the stroma, if you know how to attack an endothelium, the blood vessel cell, whether the oxygen is being given to a sarcoma, melanoma, carcinoma doesn’t matter. They all need oxygen. Attack the stroma. And my conclusion was from the Paget in 1980. The conclusion from the Paget was that metastases occur only when the seed and the soil are compatible. Completely agree with him. Attack the soil, because it’s the same. Much easier. That’s what we are doing now for the brain. OK?

Tacey Ann Rosolowski, PhD:

Well, let’s stop for today, and I’ll let you go. Thank you very much for your time today.

Isaiah J Fidler, DVM, PhD:

You’re very -- End of session one.

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Chapter 04: Reflections on Research; Becoming a Citizen; Influences: Words of Wisdom

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