Chapter 10: Four Areas of Research

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Chapter 10: Four Areas of Research

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In this chapter, begins to discuss his research contributions. He first notes that he met Dr. Judah Folkmann (while they were in the Navy) and informally began to study the growth and spread of tumor cells. Dr. Becker notes that some of his observations -made from a pathologist's perspective -contributed to Dr. Folkmann's work on tumor angiogenesis. Dr. Becker then talks about his work in epigenesis (the non-genetic modification of genes) and his work on methylation of DNA (first paper published in 1979). Dr. Becker's laboratory was the first to describe epigenetic processes in cancer. He then describes his recent work with TX-262, a compound that has promising uses in killing pancreatic tumor cells, and goes on to talk about his advances in isolating circulating tumor cells using dielectrophoresis (DEP). Dr. Becker describes how he began to work in this area, his collaboration with Dr. Peter Gascoyne (who came to work with Dr. Becker as a research fellow), and the uses of DEP.

Identifier

BeckerF_02_20120517_C10

Publication Date

5-17-2012

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Definitions, Explanations, Translations; Professional Practice; Influences from People and Life Experiences; Personal Background; Discovery, Creativity and Innovation; Overview; Contributions to MD Anderson

Transcript

One of our researchers—forgive me, but I think it was Richard Behringer or someone else—McKay or something like that—in biochemistry and molecular biology was working on something called “sonic hedgehog,” which sounds like a very fast little thing with spikes, but it’s a gene. When he came and was working on this, it took all my guile to convince people that that might have some clinical application, and now it’s one of the key genes being studied in cancer biology.

Tacey Ann Rosolowski, PhD:

What does it do?

Frederick F. Becker, MD:

In some cases it seems to stimulate the laying down of collagen, which entraps tumors but also makes them much harder to treat. That’s just one of its many, many things.

Tacey Ann Rosolowski, PhD:

What was it that you saw in the early research that convinced you to support him?

Frederick F. Becker, MD:

It was imaginative. It had some basics to it, something fundamental in the way he saw it. We were in the babyhood of genes, remember. You’ve got to remember; when I started we were in the babyhood of computers. So things have become enormous. Let me go back a little bit because you asked about my research. My research has made contributions as follows. First, a vignette. Before I returned to NYU as a faculty member, I spent two years in the Navy at the National Naval Research Institute in Bethesda, Maryland, as part of my military. That alone is worth a book and actually has been written up in a book called Dr. Folkman’s War about Dr. Judah Folkman.

Tacey Ann Rosolowski, PhD:

I think you mentioned last time the funny way that you met him during this period.

Frederick F. Becker, MD:

Yes. The first day there was this tall kind of drink of water, and we both reported at AM to the National Naval Research Institute, and the man on duty—the chief petty officer—said, “What are you doing here?” and told us to go have breakfast because no one worked that early. And that’s how we met. In any case, I just regaled a large number of pathologists with this story that we were working secretly because the Navy let us work on military research, but anything else had to be done on our own in the basement. We were working on how tumor cells grew and spread and had developed a remarkable [apparatus] where we were able to support rabbit thyroid lobes in vitro in a perfusion chamber and planted mouse tumors in them. Then we could actually watch them and measure them growing and detect any cells that came from them in the perfusate. To make a very long story shorter, we were surprised that our tumor nodules grew to about one to two millimeters and stopped growing, but they were viable. How do I know they were viable? Because I’m a pathologist, and I looked, and the cells were perfectly all right. And we were absolutely stumped until I decided one day that there was something funny about them. They had no vessels. They couldn’t vascularize. Judah then realized the importance of tumor vascularization, and when we left the Navy, he spent the rest of his life creating the field of tumor angiogenesis, a gigantic contribution. I counseled him but did not involve myself in that. Maybe a bad choice, maybe not, but it was a perfect example for young pathologists how we can contribute at every level. A simple observation led to the field of tumor angiogenesis. My second contribution; [ ] I began studying the methylation of DNA in the seventies [ ] and in 1979 [ ] published the first paper in the world on epigenetic changes in precancer and cancer, a finding of enormous fundamental interest because today epigenetics is up there with genetics [as a subject of interest].

Tacey Ann Rosolowski, PhD:

Would you describe what that is and why your observation was so significant?

Frederick F. Becker, MD:

Yes. Until then, all of what went on in a cell, and especially in a cancer cell, was thought to be the result of changes in the DNA—in the genome. Earlier papers on other organisms had suggested that the methylation—the placement of a methyl group or the removal of a methyl group—might modify gene expression. Since it did not involve changing the gene system, it was called epigenetics. In other words, parallel but not genetic. Today there are dozens and dozens of ways that have been discovered to modify the gene that are not genetic and hundreds and hundreds of papers trying to alter these epigenetic controls in treating cancer and zillions of other diseases. But actually, my lab was the first to describe it in cancer that there was a change. I’m telling you that with some pride. The rest of my research has involved biophysical changes in cells, which may let us separate cells one from another, and more recently—ten years—on a compound that was developed in my lab I designed that seems to have antitumor properties, but that’s hard to prove sufficiently to get it off the ground.

Tacey Ann Rosolowski, PhD:

What is the name of that compound?

Frederick F. Becker, MD:

TX-262.

Tacey Ann Rosolowski, PhD:

And what does it seem to do?

Frederick F. Becker, MD:

We don’t know. We’re trying to study it in a molecular, but it seems to kill pancreatic tumor cells—even the ones that are resistant to every other agent. But the leap from that finding to getting people really interested is quite an enormous leap—and justifiably so.

Tacey Ann Rosolowski, PhD:

Could I ask you about the dielectrophoresis?

Frederick F. Becker, MD:

(chuckles) Why?

Tacey Ann Rosolowski, PhD:

Why?

Frederick F. Becker, MD:

Yes. It’s very complicated. It’s a bioelectronic mechanism that recognizes differences in the electronic characters of the cell surface. And so by manipulating the bioelectrical exposure of cells, you can separate them based on these characteristics and the cells remain viable. The reason that’s interesting is it means you don’t have to use dyes, antibodies, magnetic things, or anything to do that.

Tacey Ann Rosolowski, PhD:

So the process has no influence on the cell at all.

Frederick F. Becker, MD:

I won’t say that, but the cells are viable and you can grow them; and therefore, if you can isolate, for example, circulating tumor cells, you may be able to test them for their similarity to the primary tumor and the metastatic tumor and therefore predict how you might be able to affect the metastatic tumors, which are generally resistant to any therapy.

Tacey Ann Rosolowski, PhD:

How did you begin to study in this particular area?

Frederick F. Becker, MD:

I had a young woman postdoctoral fellow who got her PhD at MIT—this was many, many years ago—in electronics and fluidics. She moved to Texas, and one of her mentors recommended that if she wanted to know more about medicine and especially cancer she seek a job with me, which she did. She became really quite family. We noticed certain changes and published certain changes in cell configuration when you altered the electrolytes they were suspended in, which seemed to suggest that there might be some bioelectrical component to how their surfaces reacted. And we, through intermediaries, were referred to the laboratory of Albert Szent-Gyorgyi, Nobel Prize winner for the discovery of vitamin C, one time president of Hungary, one of the great resistance fighters in World War II—one of the extraordinary people of our world. He had a laboratory at Woods Hole, Massachusetts. Dr. Szent-Gyorgyi, who was one of the most receptive people of all time, said, “Come up. Bring your cells. Do that.” So we did.

Tacey Ann Rosolowski, PhD:

What is the name of the young woman who—

Frederick F. Becker, MD:

Chunan Li, who I might tell you now is one of the world’s most recognized and respected teachers of tai chi and Buddhist meditation and an advisor to the Dalai Lama. I’ve had all sorts of interesting [people].

Tacey Ann Rosolowski, PhD:

That’s an interesting pathway.

Frederick F. Becker, MD:

I won’t go into that. That’s another book.

Tacey Ann Rosolowski, PhD:

You were saying you were invited to Woods Hole.

Frederick F. Becker, MD:

So there we were in Woods Hole wandering around, and the person we initially thought we were going to work with was not in Dr. Szent-Gyorgyi’s lab. And it turned out, when he actually described what he did, I realized there was no way it could be applicable to cancer cells for a lot of reasons and almost incidentally was introduced to the people in Dr. Szent-Gyorgyi’s laboratory who were studying the reaction of cells to changes in electrical current but in a very hard electrical current called dielectrophoresis or DEP. Both of them, by the way, had been trained at University of Wales. Dr. Szent-Gyorgyi was one of the most receptive people in the world. They were both geniuses of bioelectronics, so we got together and began to do some research, one of which was published in the PNAS. They thought this was a wizard idea, and to make a very long story short, Peter Gascoyne, who is now a professor here in diagnostic imaging—the physics department—when Dr. Szent-Gyorgyi’s lab was finally closed—he was in his nineties—Peter came to me as a research fellow. We set up a research laboratory to study the bioelectrical characteristics of tumor cells and normal cells. He’s been here since, and he’s now a professor. All of that research, which is very productive, has led to instrumentation that seems to be able to separate tumor cells from non-tumor cells and a whole group of applications.

Tacey Ann Rosolowski, PhD:

Tell me a little bit about your collaboration with Dr. Gascoyne. What is it that made you able to work together so well?

Frederick F. Becker, MD:

We are both receptive people, if you look for the single characteristic. He is extremely humble—excessively so. I haven’t been able to beat it out of him. I have no humility. Both of us love to learn, both of us love to create, and so over the years as he became a better and better biologist—to the point where he’s extraordinarily knowledgeable and extraordinarily creative and recognized all over the world for his inventions and use of bioelectricity—I have fumbled along learning a good deal about biophysics and electricity and electronics—not in the sense of his magnitude of knowing technology, mechanics, construction, creation of new devices, but I’m the one who can frequently see how the effect on or with tumor cells or normal cells might be applicable. So it’s a perfect relationship. He’s humble, generous, kind; [ ]. I’m very kind and generous, but we make a perfect pair. I have not been able to turn him into a first-rate gunfighter yet.

Tacey Ann Rosolowski, PhD:

(laughs) But you still have hopes, clearly.

Frederick F. Becker, MD:

I have great hopes. You could ask him that. We have a very familial relationship which, by the way, also includes yelling and screaming, so it’s been very productive.

Tacey Ann Rosolowski, PhD:

When did you begin to work on the dielectrophoresis machine?

Frederick F. Becker, MD:

Twenty years ago.

Tacey Ann Rosolowski, PhD:

But the instrumentation was also twenty years ago?

Frederick F. Becker, MD:

Close thereon because it’s evolved. It isn’t the same. At any one step, he could have stopped and said, “This is it.” And it was. There’s been commercial interest in it from the vultures in the commercial world, but he is one of these people who was never satisfied. It’s almost a fault in research because you have to publish and fund and so on. But he’s doing very well.

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Chapter 10: Four Areas of Research

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