Chapter 13: Leukemia as a Key to Understanding
In this chapter, Dr. Freireich presents his theory that the ability to control cancer (determining which cancers will metastasize and kill) will come from research in leukemia because leukemia is a systemic cancer and everything discovered about it is immediately transferable to solid tumors. He talks about molecular and genetic advances in understanding cancer. He notes that we don't need to understand the source of cancer, since will never be eradicate it, we need to understand how cancer operates so it can be controlled. At the end of this chapter, Dr. Freireich observes that individuals understand that tobacco and alcohol have an impact on cancer and health but it is a slow process to regulate against their use.
The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center
The Interview Subject's Story - Overview; Overview; Definitions, Explanations, Translations; The Researcher; The Clinician; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Cultural/Social Influences; Professional Values, Ethics, Purpose; Patients
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History of Science, Technology, and Medicine | Oncology | Oral History
Tacey Ann Rosolowski, PhD:
I guess I was thinking about some more specific examples too. I mean, in the area of what’s going on with leukemia right now, what do you think are the most exciting, promising avenues that people are following?
Emil J Freireich, MD:
Oh, well, I’ve written extensively on the subject. I’m going to give a talk to the History of Medicine Society next month, and the title of the talk is that the cure of cancer goes through leukemia research. If I were controlling the NIH budget, I would put the major part of the budget into clinical research and leukemia research. Why is that? With the other cancers, we have the problem of understanding what’s wrong with them. You have a lump in the breast. You take it out, look in the microscope. It looks like the kind of things we’ve seen where women had cancer all over the place in the breast, so it looks like cancer. Take it off, radiate, operate, do everything. Unfortunately, it doesn’t make any difference. The surgical approach to localize cancers—breast, pancreas, bowel, brain—made the observation that if you take the cancer out surgically—mechanically—the likelihood of it recurring locally is higher than likelihood of it occurring distally. So the obvious thing is to take out more. The surgical business got to the point—when I started cancer research—where the treatment for breast cancer was a hemibody. They took off the upper quarter of the body, and it didn’t affect the mortality, until Dr. Fisher did this great experiment where he randomized women to getting just local treatment and radical treatment. It made no difference. So now we know that’s not the answer. Okay. Well, the next step is local.
Well, the important point is that, for all the solid cancers, we have no idea how to distinguish between things that look like cancer and things that are cancer, that are going to kill you. So the consequence is we do all these silly things—PSA testing for twenty years, killing men’s prostates and torturing them until we finally, twenty years later, figure out it’s no good, mammograms, X-rays—until we figured out the mammograms cause more cancer than they prevent. We don’t have enough of an understanding of the biology of those cancers to know how to tell when a lump in the breast is going to end up in the brain. We talked about metastasis. The Fidler model of metastasis just doesn’t fit with the clinical model, because we have patients with metastasis without a primary. So the occurrence of cancer is something we have to understand.
But the cancer problem resides with those cancers that metastasize. The ones that don’t—when I was a young cancer doctor at NCI in 1955, we took care of a man who had a melanoma on his foot that was so large, it was larger than his head and it was bleeding and ulcerated. He came in, and we took off the melanoma, and he was cured. We have other patients who had melanoma this size and you take off their arm and they end up with brain metastasis. We don’t understand the biology of the cancers in solid organs, but we do know that cancers that are metastatic are the ones that kill people.
I took care of women who had breasts that were the size of footballs, and we took it off and she was cured. It didn’t go anywhere. But my sister had a three-centimeter lesion. She had a radical mastectomy. She had postoperative chemotherapy. She died in three years of metastatic disease. So we don’t understand how to tell the ones that are going to kill from the ones that don’t. Why is that? Part of it is the illusion that’s created by the experimental models. We can reproduce metastatic cancer in animals—all species—and we think they understand it, but we can’t reproduce it in man. And the experimental data doesn’t fit with the clinical data. I’ve written an editorial on that. I’ll give you a reprint if you want.
Leukemia is different. Leukemia doesn’t have a local presentation. We don’t look at the tumor and say, oh, this is going to kill you. Oh, this is not. Once we know you have leukemia, we know what its biology is. So there isn’t any surgery or radiation therapy—all that garbage—prevention and so on—early detection. Leukemia is a systemic cancer from the start. And that’s why all the systemic treatments for all the solid tumors were developed in leukemia, because we realize that, once you have the diagnosis, it’s already systemic so we need systemic therapy. We don’t need to radiate and surgery and all. We’ve got to get after it.
Well, the other advantage is we can examine the leukemia every ten minutes. If you have cancer of the colon, we get one crack at it. You might get two. We have this BATTLE study [(Biomarker Based Approaches of Targeted Therapy for Lung Cancer Elimination Project funded by Department of Defense] where they do biopsies every month, but for leukemia we can do it every day. Not only that, we can grow the leukemia cells in tissue culture. We can transplant them to immunodeficient animals so we can treat them in vivo and in vitro in the test tube, and all the techniques of understanding the biology of cancer come out of leukemia. We understand the chromosomal defect, the genetic defects, and what the genes are, how you control it, and how you regulate it. And that’s the reason there is so much progress in the control of leukemia and lymphoma and the other systemic malignancies that don’t respond to local therapy.
So I think if we propose that translation does not start with knowing all the things in a laboratory about a mouse and the cell culture, and we admit that studying people and the disease we want to conquer is the way to go, and if we admit that we can apply those resources to understanding the nature of leukemia, everything we’ve discovered in leukemia immediately transfers to the solid tumors—immediately.
The first adjuvant trial—I gave you one of my reprints. That’s my discovery. It’s now practiced universally. We now have neoadjuvant therapy, where when a cancer is staged to be potentially metastatic, they get treated with systemic treatment before they get local treatment.
We still have a lot of mysteries in leukemia, but starting with the fact— You see, if you want to understand anything—if you want to understand physics, chemistry, astronomy, anything—the way to do it is learn how to perturb the equilibrium. If you can shake it a little bit, you’ll see what it does. And that’s the beauty about leukemia. We can get the leukemia cells and we can do it. We can study leukemia in experimental animals. We can make leukemia in experimental animals. Starting from the disease, we can move backwards to the basic science. That’s how everything works. That’s how platelets work. That’s how molecular genetics work.
I think I told you about the—it’s part of my lecture I talk about—the discovery of BCR/ABL—the Philadelphia chromosome. That occurred because a pathologist was working with a laboratory guy to try to grow leukemia cells in the laboratory, and they were growing cells and discovered that if they put phytohemagglutinin in to get rid of the red cells, the cells would— And they started to look at the chromosomes. This was David Hungerford and Peter Nowell. They discovered that there was an abnormality in the chromosome—a little break on the chromosome. The first publication was an abstract—two paragraphs—and that discovery revolutionized the whole thing. It led to the realization that there was a neo gene. The neo gene, obviously we need something. It led to Gleevec, and first thing you know, CML, which used to have a median, average life span of three years—ninety percent mortality in five years—now, ninety-five percent of patients are alive in ten years, and all they do is take pills, like taking vitamins—amazing.
Now, we still don’t know how it began—what caused the translocation—but the translation in the laboratory is occurring, and people are figuring out that when the chromosomes are in interface—when they’re all scrambled up in the nucleus—that the BCR and the ABL genes are close to each other, so the possibility of a translocation exists. There’s no virus. So by making progress in the clinic, we can understand the nature of the disease, and that’s why I think when we cure leukemia, we’ll cure all cancer, because everything we’ve learned in leukemia has worked in cancer. The idea of the small molecule started in CML, and now there are small molecules for every malignancy—epithelial growth factor for hormone receptors and so on and so forth.
Tacey Ann Rosolowski, PhD:
I’ve never heard that term. What does that mean, a small molecule?
Emil J Freireich, MD:
It’s a— When I went to medical school in 1944, my advisor said, “If you’re going to be a doctor, you have to read the Zeitschrift.” The Germans developed organic chemistry, and they realized that you can make all kinds of things organic which had nitrogen and carbon. So they went to work systematically making every organic molecule you could, and they published 85 volumes called the Zeitschrift—the work—the writing work of organic chemistry. So if you wanted to get an organic chemical, you just have to look in a book, and it tells you how to make it. The Germans did that between the wars. So I learned German to learn the Zeitschrift. Well, our chromosomes are very complex organic molecules, but some of their functions have been worked out. Gleevec was discovered because it was recognized that the Abelson gene was responsible for phosphorylating other proteins which then became active genes. In order to phosphorylate a protein, this complex molecule had to have a place where it could attract ATP—that’s the phosphorus. So they said, wow—the Nobel Prize has been given for this—if we make something that fits in the ATP binding pocket, they can’t get ATP, maybe the whole thing will be disrupted. That’s how Gleevec works.
So then the idea was if we can identify the essential operating part of any molecule, then we can make something that electrostatically fits in that site and will prevent it from doing that. Well, we have this gang in Harvard, where Dr. Mendelsohn is, called the Broad Institute. They decided to do what the Germans did for organic chemistry. They sat down and, with pencil and paper, generated every conceivable small molecule. Those are molecules that are less than 100 molecular weight or whatever—organic molecules—therefore biologically, potentially active. So today, if you have a target—you’ve heard of targeted therapy. It all started with Gleevec. You just go to the encyclopedia and look for something that might fit, and then you do high-throughput screening, which is you have robots that create—can test 1,000 pounds in an hour against a given target. You find the one that fits best, then you do the stoichiometry, and if it didn’t fit perfectly, you look for something that is a little better. And that’s the way it’s going. So we have small molecules now that can tag every target, and that’s a big discipline. That all started with leukemia, and now it’s spread to lung cancer, to the EGFRs and everything.
When you talk to lay people, they say, “We’ll never cure cancer until we find the cause.” That’s another myth. It’s like we’ll never make advances without basic science. It’s a myth. They are myths that are so attractive to the imagination that people believe them. And the myth starts with things like infections. If you know the bacteria and you can kill it, then you don’t get the infection. If you know the cause, you can develop treatment—if the cause is susceptible to treatment.
We know that the carcinogen in tobacco is responsible for ninety percent of the lung cancers that kill people, but we can’t get rid of that. So it’s one thing to know the cause, it is another thing to be able to do something about it. To our society’s credit, the government is helping reduce the burden of tobacco, but they prevent me from giving patients—dying cancer patients—treatment. They refuse to pass a law banning cigarettes. They refuse to pass a law banning alcohol. Alcohol is the second leading cause of cancer. It’s the leading cause of economic distress in our country, the leading cause of hospitalization, the leading cause of fire, the leading cause of death in automobile accidents. I mean, alcohol is the worst drug in our community. We ban marijuana, but we serve alcohol.
We have a faculty honors convocation where we honor people for research, and when you get done honoring people for their cancer research, you walk out in the corridor, and in the greatest cancer center interviewer the world, there are guys in white coats handing you glasses of carcinogen—alcohol. Drink, get drunk, jump in your car and kill somebody. What the hell. We’re so stupid. We’re regulating the wrong things. People worry about prohibition as a failed experiment, but it isn’t necessary to have prohibition. That was the wrong approach. If you pass a law outlawing alcohol, people can make alcohol in their bedroom. It’s easy. What has to be done is a social contract. We have to stop pretending that alcohol is good for you. Cardiologists tell everybody moderate drinking is good for your heart. Moderate drinking is bad for your heart and bad for your brain. It’s bad for everything. We have to have an ethos where we look at alcohol for what it is. But alcohol is a fine art. I might pay $1,000 for a bottle of vintage, French red wine. Well, take that $1,000 vintage red wine and hand it to someone who’s never had any alcohol, and he’ll go, “It’s horrible!” That’s learned. It’s learned behavior. We learn from our parents. They tell us wine relaxes you.
We ought to have a social contract that smoking is obnoxious. It offends people. Alcohol is dangerous. It kills people. It puts people in the hospital. If that’s the case, then when you come to my house, I don’t offer you alcohol. Fruit juice is okay. Water is even better. So we can’t ban tobacco. We have to have an ethos where it’s not—and we do that pretty well. When I go to the football game, you have to go out on the balcony to smoke. That’s okay.
Tacey Ann Rosolowski, PhD:
Yeah, the regulations about smoking have really made a change.
Emil J Freireich, MD:
Oh, yeah. The airports—go in that room with all the other smokers. When I came here, the heads of the department smoked in our department head meetings—in the meetings. I was the one who said, “Dr. Clark, we ought to remove the cigarette machines from the cafeteria.” And Joe Boyd, our business manager, said, “Oh, no, Dr. Freireich. We can’t do that. We need the income from the cigarette machines.” I said, “What’s more important, the income from the cigarette machines or people dying of lung cancer? Let’s get rid of them.” So, to his credit, Dr. Clark did get rid of them. That’s what we have to do to alcohol.
We don’t need to understand the cause of disease to eliminate it or to control it. We need to understand how disease operates. How does it make you sick? Once we know how it makes you sick, then we can control it.
Diabetics—when I was in intern, my attending was a guy who discovered that restricting sugar in the diet of diabetics would prevent diabetic coma. His name was—he was a great man. But diabetes used to be 100% fatal. Juvenile diabetes, you never reached teenagers. We still don’t know the cause of diabetes, but diabetics have almost a normal life—not quite. But if they’re well-managed, they can live normally. We still don’t know what causes it. It may be genetic. It may be a contrast—that’s all good stuff. In the meantime, millions and billions of people are alive with diabetes, including my wife and my youngest son who take metformin and they’re alive. We don’t know what caused it. We have to turn the control of disease over to physicians who are scientists who work on the problem, not pretend you’re working on the problem by killing boll weevils.
Freireich, Emil J. MD and Rosolowski, Tacey A. PhD, "Chapter 13: Leukemia as a Key to Understanding" (2011). Interview Chapters. 33.
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