The discovery of angiogenesis inhibitors: A new class of drugs
Pre-Lecture Interview With the Marine Biological Laboratory:
MBL: We are going to be talking about the discovery of angiogenesis inhibitors as a new class of drugs. What should people be listening for in this lecture?
Judah Folkman: I am going to try to show that when tumors first start out, they are very tiny, pinhead size-microscopic. They stay like that almost through one's lifetime, and very few of them switch on and start to recruit their own private blood supply-angiogenesis. After that they can grow to a size that is detectable and causes symptoms. Tumor cells enter the circulation, and some of these cells become metastases in remote organs. I will try to show that these nonangiogenic tumors are making their own inhibitors of angiogenesis. In order to switch on the angiogenic phenotype, a decrease in the inhibitor may be a key step. The switch to the angiogenic phenotype may also involve increased production of angiogenic stimulators by the tumor. So, I will discuss how the tumor has taught us that it contains angiogenesis inhibitors-proteins, which have now been converted to drugs that can be administered to cancer patients.
MBL: What kind of questions might this raise in a young researcher's mind?
JF: Somebody who is just starting? Well, in general people begin to ask about the process itself. Normally, the cells that make up blood vessels are quiet. How are they turned on in the embryo? How do blood vessels grow into the brain and the kidney, and how are they turned off? And then researchers have become interested in how blood vessels are stimulated to grow in cancer and other diseases.
MBL: What kind of questions would you like to see raised tonight by any researcher?
JF: One of the fundamental problems being discussed is how do tumors turn on the angiogenic switch in the first place? We don't know. When angiogenesis is inhibited with drugs (angiogenesis inhibitors), the tumor is still producing angiogenic stimulators. The angiogenesis inhibitor drugs only prevent the blood vessels from responding. But that implies that a patient may have to stay on these inhibitors for a long time or most of their life, like insulin. Cancer patients who are currently in clinical trials, for example on endostatin, are not unhappy about long-term therapy, because they generally are not experiencing side effects. But, if we could ever figure out how to turn off the angiogenic switch, that would be another level of control.
And another important question is how to detect when a tumor has become angiogenic by a molecular test in the blood. Today you can't. But several laboratories are working on this problem.
MBL: So this is the next level of investigation?
JF: It looks like it. We are beginning to see some glimmers that you might someday have a blood test that would indicate the presence of a small angiogenic tumor in the body, even though you cannot locate it by any currently available imaging technique. Most internal human cancers must be located before treatment can begin. Surgery, radiotherapy, and chemotherapy usually cannot be initiated without knowing a tumor's location.
MBL: Noted science writer, Bob Cooke, wrote a book about you recently and it is called Dr. Folkman's War. Is that an apt title? Is that the way you feel?
JF: Well, it is his title, but I think it is good. It fits the book because he spent many years looking at the development of the field of angiogenesis research, and he mainly was fascinated by the obstacles one has to overcome to advance a new idea. A new idea may be very threatening. The more novel it is, the more threatening it can be.
It is difficult for new students who are just beginning their research to understand why any new idea could provoke skepticism or hostility. One example I use to explain to them is to say, "Look, the rules of chess are well established. Everybody who learns chess knows all the pieces and their positions. Okay, if you work and work and become a national chess champion or a world-class champion, and now somebody comes along and says, 'We are going to introduce a new piece. There is a knight and a bishop and there is now going to be a giraffe.' You can see how upset the veteran chess player is going to be. A giraffe? He or she has spent a whole career learning the old system!"
So that is the problem. When there is something really new…people may become very upset, and this book chronicles it. It is part of science. And it also shows that science has built in natural skepticism so that anything that is proposed is constantly questioned. "Prove it to us! Is it reproducible?" Science gradually continues to validate itself. Cooke shows how.
MBL: Did you find that to be particularly offensive? Because you were being questioned and...
JF: All the time and still am.
MBL: ...somewhat ridiculed.
JF: Less now than then, but it goes with being in science.
MBL: Did that bother you?
Jf: Actually, not so much, for two reasons. One is…as a surgeon I had seen tumors and handled them, and saw that the blood vessels converging on the tumor by the thousands, and coming from a long distance, appeared to be new. The tumors were hot when you felt them. But once the tumor is removed from the body, it is cold, bloodless, and under the microscope its tiny blood vessels may be collapsed or compressed. The tumor specimen which the pathologist sees is different in this respect than the live tumor handled by the surgeon. So I kept saying to myself, "I have seen this [tumor neovascularization] personally, and eventually others will see it also."
So experience as a surgeon was a guide. Also, my wife Paula always said, "If you really believe in this, you should keep going. Why should you give up because somebody who works on the problem [of understanding angiogenesis] for a few hours--and you work on it around the clock--tells you to stop? She was usually referring to study section reviewers. And her quote was: "There are only experts of the past. There are no experts of the future."
MBL: Good quote.
JF: And she said, "Just keep that in mind."
MBL: Let me ask you this. What kind of bedtime stories did you get when you were a child?
JF: We were always read to, and we read to our children, and they read to the grandchildren… but the bedtime stories that were read to me, I remember, were the Tom Swift books. We had a whole shelf. Tom Swift and the Electric Flying Machine, etc…it was a boy who was inventing. And then the next books we read as children were Sinclair Lewis--Arrowsmith, Paul DeKruif, The Microbe Hunters, etc., and eventually Madame Curie, and others.
MBL: That is incredible. The Virus Hunters--was that one of yours?
JF: The Virus Hunters was written only in the last few years by Bob Gallo. It is a very good book about the discovery of the leukemia viruses and the AIDS virus.
MBL: What do you find most fascinating about being a scientist?
JF: I think…the absolutely unexpected findings that come up. Discoveries don't come very often so there are only occasional "Ah-ha!" moments in the lab. Usually there are long periods, months and years of failure. Most experiments don't work. Science has a high rate of failure. Things don't turn out like you think, but every once in a while there is a truly fascinating finding, which you never would have expected, and it is incredibly exciting when that happens.
Here is an example. We had a paper just published a few weeks ago, which represents several years of work by a former post-doctoral fellow in my lab, Lars Holmgren, who is now on the faculty at the Karolinska Institute. It had been known that tumor cells are proliferating and dying in most tumors. A few years ago it was shown that the dead cells (called apoptotic bodies), which contained fragmented DNA wrapped in lipids from the leftover cell membrane, were eaten (phagocytosed) by their neighboring tumor cells. It was widely assumed that the DNA underwent further complete destruction once phagocytosis had occurred.
Holmgren found something different. He discovered that large chunks of DNA, and even pieces of chromosomes from the dead cells, entered the nucleus of the live tumor cells. If the tumor suppressor gene p53 was operating normally in that tumor cell, the presence of foreign DNA triggered arrest of cell proliferation and induced cell death. However, if p53 had been mutated or deleted, oncogenes from the dead tumor cell could be transferred horizontally into the live tumor cell. This is a novel mechanism that can explain many phenomena such as rapid spread of drug resistance through a tumor, and also, "aneuploidy," the appearance of extra chromosomes in a tumor.
MBL: And that is what makes science interesting.
JF: Yes. It provides a unifying explanation for previous observations that were difficult to explain. Almost everyone in the lab has read this paper. The new post-doctoral fellows ask, "How did Holmgren come to work on this problem?" And those who were in the lab when he was, reply, "Everyone told him he was wasting his time." It is called career knockout. They said, "This is a crazy idea. You are wasting your time on it."
MBL: Two more questions if I may. What scientist would you most like to work with, either now living or dead?
JF: Well, there are many outstanding scientists. I think if I were starting as a post-doctoral fellow, or if I could take a sabbatical now, I would probably like to go work in Bert Vogelstein's lab at Johns Hopkins. That would be my top choice because he is arguably the most creative molecular biologist in the world that I know of. His experiments are so elegant and I would like to learn from him. Now, I can't do that, so we are doing the next best thing--we are making an offer to one of his post-doctoral fellows, and I hope he will take it.
MBL: And finally one favor, if you will. Could you tell me that story of your Dad? I think it was your father who was going out to get his job…
JF: Yes, he was a young rabbi, just graduated from the Hebrew Union College in Cincinnati. At that time when a young rabbi was being recruited to come to a congregation, it was tradition that he give a brief sermon first, so that his preaching could be judged. His first offer came from a small congregation, which had somehow arranged to hear three candidates for about 15 minutes each. He had memorized his sermon and had practiced it out loud in his hotel room.
The next evening the first person to speak gave Dad's exact talk. Dad told us children some years later, that he didn't know what to do. So when his turn came, he said to the congregation, "In the short time assigned to each of us, I can tell you of only one of my attributes for this position. I have a good memory," and he gave the same talk again. And he was hired.
MBL: Thank you so very much for your time. I wish you a lot of luck.
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