Chapter 14: The Partnership Between Basic Science and Clinical Research

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Chapter 14: The Partnership Between Basic Science and Clinical Research

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In this chapter, Dr. Freireich further clarifies his view of the relationship between clinical and basic research. "I want to spend double the money on basic research. The problem is the translation. If you don't have the clinical arm, it's like trying to play the piano with one hand. We need basic sciences to do the rhythm and the clinical scientists to do the melody and then we get music." He talks about some of his collaborations with basic sciences, but also gives examples of how, contrary to popular opinion, patient-oriented research is basic research. He explains why global oncology should be a lower priority than other missions: e.g. funding clinical research, targeted therapy.

Publication Date

10-11-2011

Publisher

The Historical Resources Center, The Research Medical Library, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - Overview; Character, Values, Beliefs, Talents; Personal Background; Professional Path; Overview; Definitions, Explanations, Translations; Professional Values, Ethics, Purpose; Multi-disciplinary Approaches; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Patients

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Disciplines

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

Transcript

Tacey Ann Rosolowski, PhD:

Can I ask you some questions about MD Anderson?

Emil J Freireich, MD:

All you have to do is ask me a question, and I’ll tell you some lies. And I don’t have a noon meeting, I don’t believe, so if you’re not exhausted, we can do as much as you’d like.

Tacey Ann Rosolowski, PhD:

Well, it’d be good to finish up today, if that would work for you.

Emil J Freireich, MD:

I just have to take a peek at my schedule and make sure I’m right.

Tacey Ann Rosolowski, PhD:

I think Joanne said you had a 12:30 meeting, or something around 12:30.

Emil J Freireich, MD:

I’m in good shape.

Tacey Ann Rosolowski, PhD:

I want to—

Emil J Freireich, MD:

But you’re not in good shape. Do you need some water or some food? You’re such a skinny little thing. You have to eat more.

Tacey Ann Rosolowski, PhD:

I’m good. I’m good, really. I had a big breakfast.

Emil J Freireich, MD:

Did you? Do you want a jellybean?

Tacey Ann Rosolowski, PhD:

Oh, I saw your jellybeans out there.

Emil J Freireich, MD:

I’m big on jellybeans. They curb your appetite.

Tacey Ann Rosolowski, PhD:

No, I’m good. Thank you.

Emil J Freireich, MD:

I’m a fat guy. You’re a skinny guy.

Tacey Ann Rosolowski, PhD:

I wanted to get your impressions about some institutional issues that are going on at MD Anderson right now, specifically the idea about global oncology.

Emil J Freireich, MD:

I’m neutral.

Tacey Ann Rosolowski, PhD:

You’re neutral?

Emil J Freireich, MD:

Yeah, they can do what they want.

Tacey Ann Rosolowski, PhD:

Do you think that the institution can be—?

Emil J Freireich, MD:

All those things are important, but it’s only important to people who think they’re important. Global oncology, to me, is very derivative. If we cure leukemia, as I said—the people in the Congo are not treating leukemia as well as we do, but they will.

Tacey Ann Rosolowski, PhD:

But what about the idea that—I mean—as I understand it, the mission of global oncology means basically to disseminate the same kind of healthcare under the MD Anderson name.

Emil J Freireich, MD:

Marvelous. No one can be against that.

Tacey Ann Rosolowski, PhD:

Do you think it’s doable, though?

Emil J Freireich, MD:

Oh, sure. Sure. All it takes is money. As I said, I’m a great believer in freedom. If we have a treatment which costs ten percent of the gross domestic product, and we can only treat ten people out of the first million who have it, I’m in favor of it. Give it to the ones with the most money. They’re the most successful. I believe in free enterprise. I believe in competition. Saving lives in Africa is an activity that people should engage in, and I’m in favor of it, but not me. I’d rather discover things that the people who are saving lives in Africa can use, because there were people saving lives inAfricawhen they were doing nothing. They were all dying.

Tacey Ann Rosolowski, PhD:

What do you think is the most pressing institutional issue here at MD Anderson, aside from the tension between basic and clinical research?

Emil J Freireich, MD:

There’s no tension. There is total collaboration. The tension exists in the policy makers. We adore our basic scientists. I think I already told you, our course in patient-oriented research—we have more PhDs than MDs in that course. Our basic scientists want to cure cancer. That’s why they came here. They’re not working the medical school. They’re working at MD Anderson. Not all basic scientists are doing “basic research” unrelated to the applied problems. Many basic scientists want to make progress. And when we make a clinical observation and we have to get support from our laboratory colleagues, they’re right there, shoulder to shoulder. Our basic science people are with us all the way. They are very important. You can’t experiment on people.

Tacey Ann Rosolowski, PhD:

Who are some of the people you’ve worked with in that kind of collaborative relationship?

Emil J Freireich, MD:

Thousands and thousands. The first thing you do when you discover something in the clinic is go to the fundamental knowledge that basic scientists apply and see if you can apply it. When I was a young physician and we were facing—we had children who were in complete remission who were in a coma. I called our neurosurgeon and said, “Let’s do lumbar punctures.” He said, “You can’t do it. It’s too dangerous. They’re going to be herniated.” So I talked to my colleague in pathology who is a basic scientist, and I said, “Let’s figure out what’s wrong with these kids.” So he got all the autopsies for all the children who died in remission, and we put them on the table and looked at their brains and their spinal cord, and we realized they had meningeal leukemia. Then we talked to our basic scientists about how the spinal fluid works. We had David Hong working on spinal fluid physiology. We figured out that if we put it in here and shook it up, we’d get it up in the brain and could kill leukemia cells. It’s a standard part of the treatment of curing leukemia. It all came out of a collaboration.

Many physician scientists have laboratories. The first step in understanding what you’ve observed clinically is to go to your own laboratory, but you are very limited in time and ability, so you need to find out who is doing that kind of thing. If you’re looking for a virus, you need a virologist. If you’re looking for a cell proliferation thing, you need a cell biologist. One of my closest collaborators was Bun McCulloch, who was the first one to discover stem cells in the hematopoietic system. He received the Lasker Prize. It’s Nobel Prize stuff. He was the one that was responsible for motivating us to do the colony-forming thing and discover the things in the blood and allotransplant. So, yeah, basic science is—I have never said that we should not spend— I want to spend double the amount of money we’re spending on basic science, but the problem is the translation. If you don’t have the clinical arm, it’s like trying to play the piano with one hand. If you want to make progress in controlling disease, we need the basic scientists to do the rhythm and the clinical scientists to do the melody, and then we get music.

Tacey Ann Rosolowski, PhD:

That’s a great metaphor.

Emil J Freireich, MD:

Yeah. There’s no either/or. No one has ever opposed basic science research. That’s very important. But we can’t ask the basic scientists to decide what should be done to patients. That’s a patient-oriented decision, and the basic scientists and the patient-oriented doctors have to work together. It’s like—I’m a big football fan and the game last Sunday—are you a football fan?

Tacey Ann Rosolowski, PhD:

Not really.

Emil J Freireich, MD:

The game was lost in the last six seconds of the game. When our quarterback had the ball on the three yard line and had the choice of trying to pass it—I mean—there were all these defenders—or trying to sneak in by running, he decided to pass it and it was intercepted. So the whole game turned on that nanosecond decision. Why did I make that analogy? I have no idea. Well, it makes the point that a football team—we couldn’t have been on the three yard line if you don’t have an offensive line, a quarterback, a running back. It’s a team activity. All human activity is team activities. There’s some moments when lightning strikes and you discover something great, but even the Nobel committee realizes that it’s very rare that people discover things in a vacuum. They build on the knowledge base that we have, and all progress is collaborative.

When I went to the Cancer Institute [NCI], the first clinical study we did was based on Lloyd Law’s mouse model system. Dr. Fidler couldn’t do any experiments without Lloyd Law’s major discovery. What Lloyd Law did was he was a geneticist, and he learned how to make identical twins as a species of mouse. So today, all the mice that you buy from Jackson Laboratories are identical twins. So you can make a thousand identical mice of A, B, C, D. The one that became most famous was called L1210, which was named after Lloyd Law. His #1210 mouse model was perfect because this arose by taking one of those identical twin mice and painting coal tar on the hairs, and they got leukemia. That leukemia was so malignant that you could take it out and put one leukemic cell inside a mouse and he would die of leukemia in thirty days—one cell. How did he do one cell? It’s brilliant how they did these experiments. Lloyd Law was my next-door neighbor. We couldn’t have done anything without the basic scientists.

They run a culture of these cells through capillaries that are one cell thick, so they’re in a line. They get the microscope and they cut the capillaries so there’s only one cell. They put that capillary under the skin of a mouse and thirty days later he dies of leukemia. So Lloyd Law, when he retired we had a symposium, and Dr. Frei and I and Dr. Zubrod were invited to speak, because he was the inspiration behind all the early studies that we did in childhood leukemia. One of Lloyd Law’s next-door neighbors was a guy named Abe Goldin, also a basic scientist. He wasn’t interested in the biology of it; he was interested in the treatment, so he began to give drugs to the mice that had L1210 leukemia. Then we had a contract with Skipper and Schabel at Southern Research, and whenever we had a clinical question, they would set up a mouse model of the clinical situation and do the experiments in mice so we could do them in vivo. They did all the combination studies in the mice. So don’t let me say anything negative about basic science. That’s terribly fundamental. Everything comes from our understanding of the biology of things.

But, see, Fidler’s stuff is different. That’s not basic; that’s applied. He studies epiphenomenon. The basic science is understanding how these tumors arise, discovering viruses and chemicals. Another next-door neighbor I had when I was at the Cancer Institute was—her name was Stewart. I’ve forgotten her first name. She was a lovely lady. She was in her mid-fifties. She spent her entire life trying to find out if cancers could be transmitted with submicroscopic particles. She discovered the first virus-induced mouse leukemia. Sarah was her name—Sarah Stewart. She was my next-door neighbor. We got very excited about that. We tried to do experiments that treat the virus leukemia, and, as you know, that research eventually led to the understanding of AIDS and the virus that causes T-cell leukemia in Japan. So every physician-scientist’s career depends on collaboration with laboratory scientists because that’s where the concepts come from.

So our first clinical studies were based on Law and Ed Goldman and Schabel and Skipper. They get all the credit. They’re co-authors on all our papers. What is true is the illusion that patient-oriented research is not basic research. That’s the trouble. Because there is basic—I mean—if you want to find out how leukemia is spread to the brain and kills children, you have to observe children. There was no model of meningeal leukemia. We had to discover it ourselves. When we did the pathology and found that the brains were involved, we then discovered that they had freely communicating internal hydroencephalus, which meant that we could certainly do LPs because there was no mass that would displace the brain, so we began doing lumbar punctures. We worked out the whole physiology of meningeal leukemia. We gave intrathecal stuff. We did X-rays to see what happened to the drug when we injected it. Everything depended on basic understanding of what you’re doing. Since we can’t experiment in people, we must experiment in a laboratory, and laboratory experimentation is the doyenne of the basic scientist, but the basic scientist has to be susceptible to collaboration. He has to have an interest in the problem.

Tacey Ann Rosolowski, PhD:

It sounds like a real feedback mechanism.

Emil J Freireich, MD:

It’s a real feedback mechanism. When we founded APOR, the first annual meeting we had we wanted someone who had a Nobel Prize for clinical research. We invited Dr. Brown of Brown and Goldstein. He’s the paradigm of physician scientists. I love Dr. Brown. He’s still alive—Southwestern University. He gave a lecture, and the title of the lecture was Bedside to Bench and Back, and the substance of the lecture—Goldstein and Brown won the Nobel Prize for discovering the things that make cholesterol and cured heart disease. As you know, heart disease is almost gone. I wish we could do that to cancer. And Brown said, the discovery of the anticholesterol agents began with the study of a single patient, and he put her picture up. It was an eight-year-old girl who was born with congenital hypercholesterolemia, and he was a young physician training for internal medicine. He had to take care of this little girl. If you have hypercholesterolemia, you die at the age of ten or eleven of atherosclerotic disease all over—brain, heart—all the organs are dead. So he said, I have to understand why this patient has hypercholesterolemia, so he took her and began to study it in the laboratory, and they drew on the basic scientist. Where does cholesterol get transported? How does it get transported? And they discovered that there was a defect in a specific enzyme which transports cholesterol from the liquid into the intracellular matrix, and when that enzyme was gone, it all accumulated in the blood and then all the cells that don’t need it get it and the whole thing is there. There’s the whole disease.

Now, he’s a clinician, not a basic scientist, so he doesn’t think about how it occurs. He wants to know how to interrupt it. So he went through the world literature, and he looked for compounds, like Zeitschrift and the Broad Institute. He looked for compounds that could affect the transport of cholesterol across the cell. He just searched the literature, and he found some Japanese guy who had worked ten years before and had discovered a molecule that could accelerate cholesterol transport into a cell. So they took that, and they went to the laboratory. They had the cells from this patient and put the—and they discovered the anticholesterol drugs and cured heart disease and won a Nobel Prize and created more human life than anybody currently alive.

You’ve seen the statistics. Less people die of heart disease than cancer now. So that’s the paradigm—bedside to bench and back. So translation—I give a lecture on this to our students. The understanding of any problem requires that you start with the problem and then try to figure out how it got to be a problem. That’s why basic scientists cannot do it. If you’re working on mice, you cannot understand human melanoma. They don’t have it. You can’t work on elephants and giraffes. You can’t work on bacteria. You can’t work on test tubes. If you’re going to understand the phenomena, you have to work on the phenomena. If you want to understand the stars, you have to work on the stars. You can’t sit in the laboratory and make models of the stars. You’ve got to get a telescope and figure out what’s going on. That’s how Galileo got killed, because he insisted that the earth goes around the sun. They didn’t want to believe that.

Basic science is terribly important, but it has to be done in a problem-oriented way. When we wanted to build an atomic bomb, there weren’t any bomb manufacturers who could do that. They needed the guys who understood—they needed Einstein—to understand the laws of physics, but they had to have a problem. They had a direction. They wanted to create a bomb. If you put the geniuses together with the applied people, we had a bomb in no time at all. They did the same thing during the war. That’s where Dr. Zubrod made us physician-scientists, because during the war—I think I told you this analogy already—more people died of malaria, so they created a malaria project. They got all the geniuses—the basic scientists, the laboratory scientists, and the doctors—and said get rid of malaria. That’s what we need to do about cancer. That’s what the Cancer Act was all about. Put the money out there so we can get all the basic science brains, all the translational brains, all the clinical brains in the same room and cure cancer. Let’s do it. There’s no reason not to do it. While people are worrying about global oncology, I want to cure cancer, because until we cure cancer there’s nothing for global oncologists to sell.

Tacey Ann Rosolowski, PhD:

What are the areas of—?

Emil J Freireich, MD:

And don’t write this, but we shouldn’t be wasting our resources on global oncology, because we’re where we should discover the cure for cancer. If we don’t do it here, they’re not going to do it in Africa.

Tacey Ann Rosolowski, PhD:

What are the areas that you think MD Anderson is best placed to make advances in curing cancer?

Emil J Freireich, MD:

Clinical research.

Tacey Ann Rosolowski, PhD:

In clinical research, but are there specific projects you think certain people are working on that are really promising—or certain areas of research?

Emil J Freireich, MD:

A hundred percent of the projects people are working on are very promising. That’s why they’re working on it. People have to follow their nose. This business about targeted therapy, personalized therapy, it’s a very—it’s almost as appealing as prevention is better than cure. It’s a nice idea. But that’s an important area of research. That is, if you can find a reason that the cell is misbehaving, you can find something that will affect it. That’s what we’ve got to do.

When we can cure ninety-five percent of patients with cancer, then we should spend our resources on global oncology. It’s like polio. Until we proved the vaccine could prevent polio, we didn’t give it to everybody in the world. And as you know, there are consequences with polio vaccination. There are some mouse viruses that have been transmitted to people and so on and so forth. All prevention strategies have a cost. People think—you know—the mammography thing, it’s wonderful to have a mammogram every year, but that increases the occurrence of cancer—no doubt about it. Stopping smoking—that has no consequence. That won’t bother you at all. Staying out of the sun—that won’t bother you at all. Not drinking alcohol—that won’t bother you at all, no side effects. Your heart will do just as well without alcohol.

So I went to the faculty senate and said, “I would recommend that we not serve alcohol at MD Anderson at the faculty honor convocation, which the faculty supports.” The executive committee said, Freireich should be fired from the executive committee because he’s offending people. I said, “The only people who want wine after a session are alcoholics. We’re addicted to wine.” Why can’t we get done with the thing and have a glass of juice or sparkling water or something—you know—a Coke. We have to have alcohol. So they rejected it. Then they voted to exclude me from the senate because I was radical. That failed. So then, one day, I introduced a motion on the floor, and it had to be voted on. I got something like six votes. So I’m not the only radical.

Tacey Ann Rosolowski, PhD:

No, you’re not the only radical.

Emil J Freireich, MD:

I think MD Anderson’s mission is to cure cancer, and in order to cure cancer, we have to have the best cancer treatment in the world, because if people are going to expose themselves to risk, there has to be a potential benefit. So there’s no point in offering people innovative treatments unless we’re sure that the potential for benefit exists, because everything has a risk. As you know, when you go to your doctor and he says, “I’ll give you a shot of penicillin,” there are thousands of people in the United States who die of penicillin toxicity today. So it’s not to be taken lightly. You have to be sure that what you’re treating is more dangerous than the penicillin you’re going to get. The same is true of morphine, which is addicting. The same is true of digitalis, which causes arrhythmias. There is no preventive strategy—N-O preventive strategy—that doesn’t have danger to the people who are engaging in that behavior.

A PhD wrote a book that, if you’re interested, I’ll give to you to read. It’s called Is Prevention Better than Cure? She did a financial analysis for her PhD of all the preventative strategies she could find to prevent disease and analyzed the cost/benefit ratios, or the dollars-per-life cost, and there were no preventative strategies that were better than curative strategies. I’ll give you the book.

Tacey Ann Rosolowski, PhD:

Yeah, I’d be interested to see that.

Emil J Freireich, MD:

Here it is. Want to read it?

Tacey Ann Rosolowski, PhD:

Sure.

Emil J Freireich, MD:

Don’t you dare lose it.

Tacey Ann Rosolowski, PhD:

I won’t lose it.

Emil J Freireich, MD:

Louise Russell.

Tacey Ann Rosolowski, PhD:

Louise Russell. Interesting. Funded by the Brookings Institution.

Emil J Freireich, MD:

I don’t know if it’s still in print, but if it is, it’s a valuable book. Don’t you dare lose it.

Tacey Ann Rosolowski, PhD:

I won’t lose it. I promise.

Emil J Freireich, MD:

I treasure it. I couldn’t find the book that was written by Ed Ahrens. That’s another treasure. I hope no one stole it. I should have looked for it when you weren’t here, because you should read that one too. He documents the flow of money away from patient-oriented research—lab research. Gordon Williams, who was one of the three people who started APOR, was commissioned by the Division of Research Grants of the NIH to look at whether a clinical project had the same chance of success as a laboratory one. They published a paper which proved unequivocally that it doesn’t. The study sections are all loaded with laboratory scientists, and these are not the laboratory scientists who are working on potential cures. They’re the laboratory scientists who are working on their metastasis. You can build a whole paradigm in the laboratory of things that have no relevance to the clinical. It might eventually. The stuff Fidler did might be useful some day. It has led to clinical studies. There are people who have given Heparin to people to prevent the metastasis, and of course those studies were all negative.

Chapter 14: The Partnership Between Basic Science and Clinical Research

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