Chapter 06: Brain Metastasis: Activating the Body’s Capacity to Heal Itself

Chapter 06: Brain Metastasis: Activating the Body’s Capacity to Heal Itself

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Dr. Fidler begins this segment by noting his roles as the president of the International Differentiation Society and as the youngest president of the American Association for Cancer Research. He talks about how leadership of professional societies. He then returns to a discussion of the mechanisms of brain metastasis. He notes that the death of his friend, Judah Folkman, led him to re-evaluate his life and step down from his administrative responsibilities, a move that left him with more time to think about his research and investigate the role of astrocytes. He believes that intervening in the role of astrocytes in interacting with the genetics of metastatic cells has implications for treatment of many different diseases as well as other forms of cancer. He then turns back to a discussion of his work on activating macrophages to attack metastasis, quoting from “The Doctor’s Dilemma,” a play by George Bernard Shaw (1911), to dramatize that the body has all it needs to cure itself: “Nature has provided in the white corpuscle… a natural means of devouring and destroying all disease and germs…. Drugs are a delusion.”

Identifier

FidlerIJ_02_20110927_C06

Publication Date

9-27-2011

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The ResearcherThe Researcher Definitions, Explanations, Translations Overview Professional Practice Discovery and Success Career and Accomplishments Discovery, Creativity and Innovation Influences from People and Life Experiences Understanding Cancer, the History of Science, Cancer Research On Research and Researchers Character, Values, Beliefs, Talents

Transcript

Isaiah J Fidler, DVM, PhD:

Incidentally, Tacey, I was the president of the International Differentiation Society because of my -- I don’t know what to call it. At the time revolutionary strong opinion about differentiation. But it was only logical. And the fact that tumors also differentiate, but at a marginal level. Because some are metastatic, some are not. We talk about that, the other thing is that I’m very proud to tell you I’m the youngest at the time president of the American Association for Cancer Research. No one has ever been elected younger than me. So I keep telling them I want respect because I’m the youngest. Now I’m probably the oldest member.

Tacey Ann Rosolowski, PhD:

Well, congratulations on that.

Isaiah J Fidler, DVM, PhD:

Thank you. But I was the youngest at the time.

Tacey Ann Rosolowski, PhD:

And that was because of your advocacy for differentiation and this new line?

Isaiah J Fidler, DVM, PhD:

No, no, no, differentiation came much later. No, I was really active and very vocal. And I gave great lectures and told jokes and people liked me and they voted for me. It’s a democracy. The vote for president, you open, there are five candidates. And people, three or four candidates. And all the members vote. And because I give keynotes they know who I am. And others, maybe they don’t. It’s just like running for president. They look at the debate. You give a good debate, they think you’re a great president. Well, never mind. I’m not a liberal anymore, so I will keep my mouth shut. A great debater doesn’t necessarily make a great president. But I was very young when I was the president and very radical in many ways.

Isaiah J Fidler, DVM, PhD:

How so? In what way were you radical? Now as you look back.

Isaiah J Fidler, DVM, PhD:

In what way is that we were dependent at the time on a handout from the government to public Cancer Research. OK? And the handout ended. And everybody said, “What are we going to do?” “What do you mean, what are you going to do, we’re going to have a fee, you want to publish, you pay for it, like any other journal.” “Nobody will submit.” I said, “You don’t understand. We’re going to make it so exclusive, everybody would die to publish in now. Because we will be the expensive journal.”

Tacey Ann Rosolowski, PhD:

What was the journal you were --

Isaiah J Fidler, DVM, PhD:

Cancer Research.

Tacey Ann Rosolowski, PhD:

Cancer Research.

Isaiah J Fidler, DVM, PhD:

Guess what? I was right. We made it exclusive. By saying no more anybody can. You have to pay. Now people who couldn’t pay would write a nice letter. And there will be a committee that will say, “Look, this particular person is.” But there is a pay charge in every decent journal.

Tacey Ann Rosolowski, PhD:

I didn’t know that in the sciences that was the case.

Isaiah J Fidler, DVM, PhD:

Oh sure.

Tacey Ann Rosolowski, PhD:

In the humanities that doesn’t happen.

Isaiah J Fidler, DVM, PhD:

Sure.

Tacey Ann Rosolowski, PhD:

Yeah I didn’t know.

Isaiah J Fidler, DVM, PhD:

Sure.

Tacey Ann Rosolowski, PhD:

What are the fees like?

Isaiah J Fidler, DVM, PhD:

I don’t remember. But whatever they were, we became self-sufficient. And I also insisted that we raise the -- when you go to an annual meeting it used to be practically giveaway. “What do you mean giveaway? Other societies charge a fee to attend, we will also charge a fee.” “Nobody will come.” I said, “They’ll come, don’t worry.” And they did. But anyhow, the point of the matter is that the brain story illustrates everything. Cells that reach the brain are different cells than reach the lung, etc. Those that can interact favorably with the microenvironment will survive to grow. Those who cannot interact will die. But we can go deeper than that to say that metastatic cell -- I used to say usurp but most Americans don’t know what usurp is so I say exploit. Usurp is being used more in England than in the United States. I like the word --

Tacey Ann Rosolowski, PhD:

It’s a --

Isaiah J Fidler, DVM, PhD:

-- usurp.

Tacey Ann Rosolowski, PhD:

[ 33:07] -- better word, I think. It’s a better word. It’s different than exploit.

Isaiah J Fidler, DVM, PhD:

They usurp physiological mechanism for their own gain. I say now exploit the host cells for their own gain. And what else can you talk about than astrocytes. Look what they do. They allow you to grow and they protect you from destruction by toxic substances which will reach the tumor cell and the neurons because the blood-brain is leaky. So it’s a perfect example for the seed and the soil. Once again. And it says the following. If you want to treat melanoma in the brain and you go for genes of melanoma, if you want to treat colon cancer in the brain, they do make brain -- lung, breast, you name it, you have to have six different treatments. But if you think, “If I can interfere with those astrocytes.” OK, the astrocyte so far react the same whether you’re colon cancer, breast cancer, lung cancer. They don’t care. If they touch you they send a signal. You upregulate genes. Now we only looked at three. But I already told you we know 250. And in fact because of other reasons -- oh it’s over there. Never mind. I have a list of all the genes that they upregulate. And my God, it gives idea for many other diseases to control by the same mechanism. So if you target the astrocytes, if you target the microenvironment, you don’t only rely on targeting the seed. You target the soil and the seed. You will have twice. Not twice, I shouldn’t say. Say 20 times better chance, because it’s highly synergistic. It’s not one and one. When you target this and that it’s not this, it’s like you’re covering your bases. And if you do the model correctly, the orthotopic, you understand the seed and soil. If you look at metastases different than the primary tumor, you understand the tumors are heterogeneous. If you speak now about individualized therapy you understand there’s no such thing as the big C, all cancers are alike. And just logic, OK? If you look at fact A and fact one and one have to be two. It cannot be seven or cannot be zero. Now some people go one and one is seven, and they are so futuristic that they don’t know how to prove the point. But the majority of people say one and one is one, and they’re afraid to fail. And if you’re afraid to fail you don’t try big things. You try, you move in small steps. So you wouldn’t be exposed to ridicule if you fail. It’s called insecurity. And I figured what happened really was that I was in California asleep ready to give a talk at 10:00 in the morning. And the phone rang at 5:00 in the morning, woke me up. It was a friend of mine, Robert Kerbel from Toronto, who called because he thought -- with cell phone you don’t know where people are. He thought I was in Houston. It’s 7:00 in the morning. To tell me that a good friend of ours, Judah Folkman, died the night before at the Denver airport. Judah was on his way from Boston to one of the meetings in the mountains. And had a heart attack at Denver. I think what happened was he probably was late. He was rushing. He forgot that Denver is 5,500 feet over sea level and not Boston. And didn’t have enough oxygen. I don’t know. Something happened to him and he died. And it really depressed me because I was doing about the same thing. Running all over. I came back and met with Dr. Mendelsohn and I told him that I’m going to be -- we just celebrated my 70th birthday and had a huge symposium in Houston for 45 years to my work in metastasis. And it was a really major major international symposium that Dr. Mendelsohn was kind enough to finance. It was a big success. Really major. All my graduate students, all my fellows came for one day, and then three days’ meeting, with everybody leading in the field came to give a talk. And among them was Judah Folkman. And where are they? To the reception here. President and Mrs. Bush came to the reception. See that over there.

Tacey Ann Rosolowski, PhD:

Oh yes.

Isaiah J Fidler, DVM, PhD:

Says, “To Josh.” And blah blah blah. I’ll tell you about it in a minute. About this insane man who was jumping out of airplanes when he’s 70. But anyhow he and his wife came to the reception. And it was wonderful. But Judah was there. And then two months later he’s dead. So I came back from California. And I told John that I’m really -- I’m too busy. I’m a chairman of a department now for -- I don’t know, 40 years. I’m in charge of a building. I’m in charge of animal facility. I have to do my own work. And I have three grandchildren, I have a wife, I have a farm, I have a horse. I don’t have time to do anything. So two choices. Either I completely retire or he will allow me to step down from my administrative responsibility so I can only quietly do research. And he was kind enough to say the latter is OK. So Dr. Lee Ellis fortunately took over as interim chairman. Doing a fabulous job. Lee is one of my fellows. He’s a professor of surgery and cancer biology. And he is also directing the metastasis program now. And I was allowed -- I don’t go to meetings anymore for example. No more meeting. No more. And if I want I go. But I don’t have to do all the administration. And it simply allows more time to think. And when you see those astrocytes, you have to think. What are they doing? They don’t kill the tumor, or the tumor wouldn’t be there. I already told you that. They either do nothing -- but there’s no such thing as doing nothing. If a cell does nothing, the cell would have been eliminated, whether you believe in creation or evolution, it’s a constant changing area. On my own I keep telling people who don’t believe in evolution, believe in creation, that say, “Read the first chapter in the Bible. What do you mean you don’t believe? Day one this was done, day two this, day three. And it’s in the correct order. How did they know 4,000, 5,000 years ago the correct order?” I said, “Now you’re going to argue with me about a day?” I said, “That’s a day in the life of God. Do you really know? Before man was created, this is a day. A day of God is a day of man? How about if it’s a billion and one year? How about if it’s infinite? There’s no such thing as time? A day in the life of God. So how old is God? 400 years old? 70 years old by your -- what are you talking about? There’s no such thing as time.” So they ask me, “You believe in evolution? You believe in creation?” I believe in everything. Believe means you don’t have data. It’s easy to believe. What do you mean I believe? Yeah of course I believe. You look and you say, “What do they do?” Well, maybe they protect. And you do some experiment. You make a hypothesis. And God almighty, all of a sudden you have a molecule. Now if I did it 40 years ago I would never have a molecule. Because we were not that sophisticated. And 40 years from now the work today is going to look primitive. You really think we reached the end of the road? Come on. I have a computer. I don’t know how to use it. But look at the screen I have. I put a slide on this microscope and it shoots into the computer and I can manipulate. I can do this. Oh my God. Look down there. You see that, Tacey? That’s my fellow computer from Department of Pathology, University of Pennsylvania. They gave it to me as a gift. This is it.

Tacey Ann Rosolowski, PhD:

That’s it, that microscope.

Isaiah J Fidler, DVM, PhD:

Yeah it’s like a $350 microscope today. I worked more hours on that than on this fancy one that is like $5,000, $6,000, $7,000. I learned more from that. Sit in a dark corner quietly, looking, looking, looking, looking. Trying to figure what does it mean. When I ask questions people will say, “Don’t nag us. Go read a book.” You had to do it yourself. There was no such thing as people taking -- nobody -- just learn for yourself. I think that what we know now is a fraction of what we’re going to know years from now. But logic is going to remain. And yes we’re going to have 500,000 new molecule. But what they do and how they do unless you have a certain hypothesis and logic we will never know. There’ll be a list of molecules. So what? So what do they do? We cloned the human genome, didn’t we? It cost us who knows how many billions of dollars. Are we any closer to curing disease? It’s not how, when, what, it’s why that is the central question. OK. Let me tell you a little bit about macrophages, OK?

Tacey Ann Rosolowski, PhD:

OK, OK.

Isaiah J Fidler, DVM, PhD:

Now I became fascinated with macrophages. I had to give it up. We used to be called the M&M laboratory, macrophage metastasis. And the reason I became fascinated with macrophages was because they were -- again when you looked at a tumor you always see macrophages. Turns out that macrophages participate in wound healing. And they produce -- a good friend called Nathan N-A-T-H-A-N wrote in 1980 a review listing 120 proteins that macrophages make. Today it’s probably 2,000. I mean that’s all we knew then but today we -- it’s an independent cell. It’s like an animal inside our bloodstream. One cell can do everything. It’s amazing. And they always participate in infection. They are the phagocytic cell. You have a bacteria, they’ll eat it. Digest it and spit out protein. You have a virus infection. They’ll take care of it. They don’t need antibiotics, they don’t need anything. This is a fantastic play that Bernard Shaw wrote called The Doctor’s Dilemma. In here. So in this play that he wrote there is an argument about modern technology versus the old stuff. “Drug can only repress symptoms. They cannot eradicate disease. The true remedy for all diseases is nature’s remedy. Nature and science are at one, Sir Patrick, believe me. Though you were taught differently. Nature has provided in the white corpuscle as you call them, in the phagocyte as we call them --” these are macrophages “-- a natural means of devouring and destroying all disease germs. There is at bottom only one genuinely scientific treatment for all diseases. And that is to stimulate the phagocytes, stimulate the phagocytes. Drugs are a delusion. Find the germ of the disease. Prepare from it a suitable antitoxin. Inject it three times a day, quarter of an hour before meals, and what is the result? The phagocytes are stimulated. They devour the disease, and the patient recovers. Unless of course he’s too far gone. That I take it is the essence of Ridgeon’s discovery.” This is a play that Bernard Shaw wrote. Copyright 1911. OK, so at the time I became aware of individual who were injecting BCG. That’s a form of tuberculosis bacteria. Bovine tuberculosis bacteria. To stimulate the immune system. And there were multiple multiple publications that BCG can eradicate cancer. But nobody knew the mechanism, etc. And we began to look into BCG and macrophages and tissue culture in animal. But it was very clear that is an unbelievably primitive way to do it. And of course BCG had the downside that it was an infectious agent. It gave a lot of inflammation. Animal were dying from it if you were not careful. And so I was complaining about it in one meeting. And I was approached by a brilliant man by the name of Lajos L-Y-O-S Tarcsay T-A-R-C-S-A-Y. And Lajos tells me, “I work in Ciba-Geigy in Basel. And we have something called muramyl dipeptide. Muramyl dipeptide is in essence -- is a molecule that is BCG, only we reduced it to the real molecule.” BCG was all everything, like a vegetable soup. If you want one you -- the problem with muramyl dipeptide as I discovered was that it goes in and is gone in a matter of a few minutes. So they produced something called MTP-PE, muramyl tripeptide phosphatidylethanolamine, MTP-PE, you don’t need to know more than that. And what happened was that it had phosphatidylethanolamine is a phospholipid. And we began to encapsulate it. I had help from George Poste P-O-S-T-E. George became the president of -- oh God. I’ll remember. A big drug company in Philadelphia. One of my closest friends, I don’t remember the company he ran. But anyhow. Smith Kline & French. But at the time he was at Roswell Park. And at Roswell Park was the creators of something called liposomes or liposomes. They were little structures from phospholipids that now they’re called nanoparticles. Now they gave a big name. New liposomes. And if you can encapsulate liposomes with MTP-PE and inject them, macrophages will go berserk. They’re going to eat it. Because their job is to phagocytose any garbage in the bloodstream. And they did. And when they did they became very angry. When they became angry they began to make cytotoxic molecule. Second thing that was found is that macrophages’ job in the body, physiological role, is to phagocytose dead red cells. Old red cells. Red cells live to about 100, 120 days. And then they’ll be removed and new red cells will come in. And there’s the cycle. How do macrophages distinguish an old red cell from a young red cell? Well, turns out that the membrane of a red cell has three phospholipids, like any other cell. And one phospholipid called phosphatidylserine S-E-R-I-N-E is only exhibit on the inner leaflet. The double leaflet in the membrane. Only inside. When the red cell is old, somehow it flips. And PS comes to the outside. And it’s negatively charged. A macrophage says, “Oh, phospholipid serine, we’re going to eat you.” And they eat the red cell. Any cell that has phosphatidylserine on the outer leaflet, they’re going to recognize. And all tumor cells have PS on the outer leaflet. Normal cells don’t. Except when you get to be old, when they’re going to die, and they will take you out. So tumor cells have negatively charged membrane. And macrophages bind to the tumor cell. But they’re too big to eat and too many of them. Red cell is tiny little thing. The tumor is like a watermelon. This is like a tiny little egg. So they can eat lots of red cells, they can eat platelet, but they cannot phagocytose tumor cells. They’re going to die. But if they have MTP-PE when they bind to a tumor because of PS, they inject toxic molecule into the tumor cell. Tumor cell is going to die. And we published huge number of papers showing that this is how you activate macrophages to kill all kind of tumor cell. Whether benign or malignant, etc. Well, while I’m in Frederick, Maryland a brilliant young pediatric oncologist joined my group. Her name is Genie Kleinerman. Genie with a G. Eugenie or Genie Kleinerman. Genie Kleinerman is now the chair of pediatrics at MD Anderson. And she began to work with the liposomes, MTP-PE on tumors that are growing in the bone. Great result in mice. So she began to collaborate. She came here to MD Anderson with me and stayed with the project on macrophages, macrophages, macrophages. I literally yielded it to her because it was too much for me, and I wanted to focus on my metastasis. And she began to collaborate with another fellow who worked with me. Now he is the chair of veterinary oncology at University of Wisconsin. His name is Greg MacEwen. M-C-E-W-E-N MacEwen. The late Greg MacEwen. Unfortunately he died very young. And Greg was working on dogs that have spontaneous osteogenic sarcoma which is a disease in children where there’s literally no treatment once the tumor metastasize to the lung. At the time she began to work on it, the treatment was to amputate the leg, on and on and on. But if the tumor metastasize to the lung, chemotherapy postponed inevitable death. And all these years she’d been working on getting MTP-PE in liposome to the clinic. And I’m happy to tell you that a few months ago she came here. And a big smile on her face. That it was approved in France and Italy a long time ago. But now England, Ireland, Scotland, practically Europe has now accepted it as the treatment for osteogenic sarcoma in addition to chemotherapy. It’s not to substitute for. Chemotherapy can do so much obviously. But now they’re using this to finish the job.

Tacey Ann Rosolowski, PhD:

To augment it.

Isaiah J Fidler, DVM, PhD:

Right. So what started as a simple observation that macrophages will eat any garbage they want and they’ll eat liposome MTP-PE and we can work with mice, then it went to dogs, then it went to tissue culture, then to children. Now it’s clinically approved in Europe. Why it’s not approved in America, talk to Genie. I don’t know. The FDA is still resisting but all Europe said, “Of course.” So they’re doing it. For many years there was a problem because Ciba-Geigy became Novartis, Novartis dropped the project, and why they dropped the project -- I suspect, I don’t know -- because osteogenic sarcoma is one of those orphan diseases. And if it was for lung or breast or colon everybody would be jumping on it. But osteosarcoma in children is an orphan disease. So not too many companies are interested. And a tiny company bought the rights to it, and they are producing the liposome. And hopefully now that it’s approved it will be tried for many other cancers for which there is no chemotherapy. The macrophages couldn’t care less. They’ll kill you because you express negatively phospholipid phosphatidylserine on your outer leaflet. So that was again the example of host factor that can really work against tumor. Of course today with immunotherapy that has been revived. It was very popular. Then it disappeared. And now we understand better. Immunotherapy is now coming back to the front. But Bernard Shaw said it very well. “Activate the phagocyte. Drugs are a delusion.” There’s no heterogeneity for the macrophage. “You express a negatively charged, we’re going to eat you.” And old cells that are senescent, this is the recognition of senescence, is negatively charged membrane. Now why do tumor cells that divide all the time express senescence phenotype I don’t understand. I don’t really care. They do, and that’s the story with macrophage. OK.

Tacey Ann Rosolowski, PhD:

Shall we take a -- stop for a moment?

Isaiah J Fidler, DVM, PhD:

Yeah please.

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Chapter 06: Brain Metastasis: Activating the Body’s Capacity to Heal Itself

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