IRA FLATOW, host:
Up next, what goes wrong in the body that turns normal healthy cells in the body into malignant cells growing out of control and forming a tumor?
Scientists are getting closer to understanding what causes cancer and how it starts. And my next guest has made key discoveries in that area - identifying genes that cause cancer when they've mutated, as well as genes that when damaged fail to keep bad cells in check. And now, he's turned his attention the way he calls, the last frontier of cancer research: Understanding how tumors travel to distant parts, distant sites in the body.
He and his research team have published two recent papers in the journal Nature that might explain how cancers migrate. And he joins me now to talk about his research and what we know and don't know about the basic mechanisms of cancer.
Robert Weinberg is the director of the Ludwig Cancer for Molecular Oncology -Ludwig Center for Molecular Oncology, the Daniel K. Ludwig and American Cancer Society professor for cancer research, and a member of the Whitehead Institute at MIT. And he joins by phone from Colerain, Massachusetts.
Welcome to SCIENCE FRIDAY.
Dr. ROBERT WEINBERG (Director, Ludwig Center for Molecular Oncology; Professor, MIT; Member, Whitehead Institute for Biomedical Research): Thank you, Ira. Thank you for having me.
FLATOW: I understand that you're talking to us today from a meeting of cancer researchers. But it's not all what we think of when we picture of scientific meeting. Isn't there a lot of cooking going on in addition to science?
Dr. WEINBERG: Yes. For the last 40 years, three colleagues and I, together with our scientific descendants, have organized this meeting on a high mountain in the Berkshire Mountains in Western Massachusetts. And so for about 48 hours, we're here with about 50 younger people. And the people who are coming to this cancer research meeting are warned not to eat for two days before they arrive.
FLATOW: What kind of stuff you cook up?
Dr. WEINBERG: This year, one of us cooked a fusion cuisine, American fusion cuisine. The other - I cooked up a Greek cuisine last night for 70 people with the help of four people in the kitchen.
FLATOW: Hmm. Talking about cancer research this hour, TALK OF THE NATION: SCIENCE FRIDAY from NPR News, with Robert Weinberg.
Tell us why you call this - I guess, understanding metastases, the last frontier in cancer research.
Dr. WEINBERG: Well, in 1976, we knew almost nothing of why normal cells begin to grow uncontrollably in various tissues throughout the body. Over the subsequent three decades, we really learned lots about that. And we really understand now most of the basic mechanisms that cause cells to proliferate uncontrollably.
FLATOW: We do.
Dr. WEINBERG: Indeed, we do. Not all of them, but the outlines of the solutions are well in sight. There's may be some details that will be learned. But the major question that we still really have not mastered is what allows or enables cancer cells from a primary tumor, where are the tumors first begins to grow, to spread throughout the body where they launch secondary colonies of cancer cells that once calls metastases. It's the spreading of cancer from a primary site that actually is responsible for about 90 percent of the deaths associated with cancer.
FLATOW: Hmm. So if you could learn how to stop the spreading, that's the last piece of the puzzle is what you're saying.
Dr. WEINBERG: Well, that's the last piece of the puzzle in understanding how metastasis occurs. Still, I'd hasten to add there's a long time between understanding what causes a biological process to occur and figuring out ways to stop it.
Dr. WEINBERG: That often take several decades, believe it or not.
FLATOW: Mm-hmm. I believe it.
We're talking about cancer with Dr. Robert Weinberg on TALK OF THE NATION: SCIENCE FRIDAY from NPR News.
As I said in my intro, you made some key discoveries in basic cancer biology, the first human oncogene and the first tumor-suppressor gene. Give us a little thumbnail sketch would you, what each of these do.
Dr. WEINBERG: Well, there's basically two kinds of genes that regulate whether a cell within our bodies begins to multiply or not. One of these is a pro-growth gene, and when it becomes mutated, it forces cells to grow uncontrollably, much like a stock accelerator pedal in a car.
Dr. WEINBERG: And these genes are called oncogenes. There's a second class of genes that functions to hold back the growth of cells, and they're called tumor-suppressor genes, and they function much like the break lining in a car and often they are disabled in cancer cells. And so these two critical classes of growth-controlling genes in different ways deregulate the multiplication of cells in various tissues throughout our body.
FLATOW: 1-800-989-8255. We're talking about cancer this hour. And whenever we talk about medical subjects, I have to repeat the same thing. I'm a broken record. Please, don't ask us to diagnose or give you - you know, advise treatment for you and anyone else who may have cancer or related diseases. It's not really ethical for us to ask Dr. Weinberg what to do about it and…
Dr. WEINBERG: It wouldn't even be practical, either…
Dr. WEINBERG: …because I'm not a real doctor, I'm a PhD who doesn't see patients. And so…
FLATOW: There you go.
Dr. WEINBERG: I'm not even competent to respond.
FLATOW: You said it better than I good - I did. Let's talk about the way you have discovered or the pathways that metastases occur. You've made some interesting discoveries. Can you give us an idea of what those are?
Dr. WEINBERG: Well, the process of metastasis - of spreading from the primary tumor - is extremely complicated. And until the last five years, we never realized how cancer cells were clever enough to master this complex series of steps. What's transpired through the work in a number of laborites - mine is only one of them - is that the way cancer cells acquire this repertoire of skills for spreading throughout the body is to reawaken behavioral programs that are normally operative in the early embryo and enable the normal embryonic cells to move from one part of the embryo to another, thereby allowing tissues to be formed, to be created.
FLATOW: Sort of like hijacking that early mechanism.
Dr. WEINBERG: Precisely. They co-opt this early mechanism. They turn on early embryonic genes that have long lain quiet. And by resurrecting these genes and co-opting them, now cancer cells can, in one fell swoop, acquire a whole repertoire of traits that allows the cell to successfully navigate the blood vessels in the body and ultimately deceive new tumor colonies.
FLATOW: All right. Dr. Weinberg, I'm going to have to interrupt because we have to take a break. We'll be right back with you.
I'm Ira Flatow. This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News.
(Soundbite of music)
FLATOW: You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow.
We're talking this hour about cancer biology with my guest Dr. Robert Weinberg, a member of the Whitehead Institute in MIT.
Our number, 1-800-989-8255. Also, Science School in "Second Life," if you'd like to go over there and find someone with a SCIENCE FRIDAY T-shirt and ask a question.
When I rudely interrupted Dr. Weinberg, he was telling us how he's discovered, and others have discovered, that the part of the way the cancer spreads is that it sort of hijacks the system that embryos use to spread cells around and create new kinds of tissue. Would that be correct?
Dr. WEINBERG: Perfectly. It's correct.
Dr. WEINBERG: Yeah.
FLATOW: I'm done.
Dr. WEINBERG: What's additionally amusing…
Dr. WEINBERG: …is the fact that most of these genes were initially studied in the context of understanding the development of fruit flies.
Dr. WEINBERG: Over the last 30 years, when the fruit fly geneticists applied for cancer research money, they said this will ultimately can give(ph) great benefit on cancer researchers. And the cancer researchers - like myself, chuckled and said, yeah, that's just the way they have approaching on cancer money. But, in fact, they were totally right. Much of what we now understand about metastasis derives from genes that were involved in developing embryos already 600 million years ago and had been inherited by a variety of multi-cellular organisms throughout the years.
FLATOW: Mm-hmm. There is also research talking about a couple of recent papers out in Nature that looked at what are called microRNAs. Can you explain that part?
Dr. WEINBERG: Well, we used to think that the regulatory mechanisms that operate like a circuit board inside cells were composed only of intercommunicating proteins that talked to one other like resistors and capacitors would, for example.
But over the last five years - and it's recognized by a Nobel Prize about a year ago - one has come to realize that there is another group of molecules inside cells that function these circuits, and they're called microRNAs.
FLATOW: Mm-hmm. 1-800-989-8255. Let's go to phones. Let's go to Richard(ph) in Maryland. Hi, Richard.
RICHARD (Caller): Hello.
FLATOW: Hi, there.
RICHARD: I've heard that when a cancer tumor is removed sometimes, it - new tumors spring up. For example, if a tumor is removed from a liver, numerous tumors will appear on the liver. And it seems that that tumor, while it was growing, was somehow suppressing the development of the other tumors. And I wondered if we know anything about how that works.
Dr. WEINBERG: This is a complicated process because one of the things that happens after a primary tumor is removed by a surgeon is that there's a profound wound-healing response that occurs in order to repair the surgically-altered tissue. And when that occurs, there's all kinds of growth stimulatory factures that are released locally. And some of these may actually impinge on rare cancer cells that were left behind by the surgeon, and these rare cancer cells - these minimal residual diseases as they're called, these cancer cells are now stimulated to proliferate, whereas, otherwise, they might have lain latent for many years in the liver in the absence of these stimulatory signals.
FLATOW: Did that answer your question?
RICHARD: So it's the healing process that stimulates those cells?
Dr. WEINBERG: That would be my interpretation, there's increasing evidence for that, but it's not yet something that's a rock solid truth.
FLATOW: Thanks for calling.
RICHARD: Thank you.
FLATOW: 1-800-989-8255. There's a paper out in today's issue of Science that says that cancer may be caused by many low-frequency genetic mutations instead of a few high-frequency ones. Can you explain the difference?
Dr. WEINBERG: Well, there's two ways thinking about the development of a tumor. One is that there's a relatively small number of genes - perhaps as few as half a dozen - that must be mutated in some sequence in order for a normal cell to begin to grow uncontrollably as a cancer cell.
Dr. WEINBERG: The other point of view is that there could be actually large numbers of genes that suffer mutation, often not frequently in any given kind of cancer. And that point of view is pushed and portrayed in the paper that came out today in Science from Johns Hopkins University in Baltimore, Maryland.
Dr. WEINBERG: It's still a matter of great contention and debate since it's hard now at this point whether the data that have been obtained are or not statistically significant in order to prove the point that is being drawn - the conclusion that's being drawn by these researchers.
FLATOW: A question from Prospero(ph) in "Second Life." He says, the gene damage that prevents bad cell suppressors from operating - is damage to a single cell enough to cause a problem? In other words, single cell being damaged, could that start a whole tumor?
Dr. WEINBERG: Well, it's not really a single cell being damaged, a single cell sustained some damage, even its descendants then begin to proliferate for five or 10 years, one of those descendants may then suffer an additional point of damage, and ultimately, this process of accumulating additional damaged genes may take 20, 30, 40 years. And so the descendants of that initial cell may ultimately begin to grow uncontrollably, and as such, begin to create a tumor.
FLATOW: And the process by which that tumor then decides to spread or metastasize is what you're trying to figure out now.
Dr. WEINBERG: Yes. And that's interesting in the following sense. The question for us is, is all the information for spreading and metastasizing within the cancer cell or does the cancer cell also receive instructions from adjacent normal tissue that may enable us to acquire the entire repertoire of traits that are needed in order for the cell to spread. A matter of active investigation in many groups right now.
FLATOW: So it may need a healthy partner, is that what you're saying, for it to spread?
Dr. WEINBERG: Well, in fact, cancer cells, when they grow and form a tumor, they recruit a lot of normal cells from the host. And these normal cells help the cancer cells to survive and to proliferate by providing it various kinds of physiologic support.
FLATOW: They get like blood supply to the tumor, things like that?
Dr. WEINBERG: The blood supply is, in fact, the most visible and dramatic of these normal functions that are supplied by the recruited normal cells. But yet, other kinds of normal cells may actually, once they're recruited in the tumor, begin to release signals that provoke or stimulate the cancer cells to take on invasive behavior, that is the behavior of invading the air into adjacent tissues, and ultimately, to metastasize. So it may be the case that not all the information for invasion and metastasis is inherent in the cancer cells themselves.
FLATOW: Hmm. Very interesting. Let's go to the phones to Julie(ph) in Grand Rapids. Hi, Julie.
JULIE (Caller): Hi. My question was in regards to when he made a comment about the breaks and the break lines, those two genes that seemed to be incapacitated when the metastasizing starts. I was wondering if his research found anything that can possibly build up those genes or, if in the future, they're going to isolate any type of research to see if they can figure out how to build up that wall so that the metastasizing won't begin.
FLATOW: Yeah, Could you put - repair those genes, in other words?
Dr. WEINBERG: Well, there's two kinds of genes. One kind of gene is like a stock accelerator pedal. It pushes the cell or a car to move ahead inexorably. The other kind of gene is the break lining, which halts normal cell proliferation and which is effective in cancer cells. Each one has begun to develop a number of different drugs that can shut down the stock accelerator pedal that can prevent it from functioning, and thereby, deprive cells of the stimulus that is driving them to grow like cancer cells.
It's far more difficult to replace a missing break lining because it's very hard to go into individual cells and insert into them missing genes or missing proteins. So part of this technology is already at hand and begin to be used and applied with some success. Part of it is still far beyond our reach.
FLATOW: Mm-hmm. You mentioned - thanks for calling. You mentioned that the cancer cells may hijack the techniques used by embryonic cells. Is it possible to disrupt the communication between these kinds of cells so that they can't be hijacked?
Dr. WEINBERG: It may be in the future. At present - although, that's a theoretical possibility, at this stage, we don't really know how to do it. But one attractive avenue of research, and ultimately, of therapy development, is to prevent cancer cells from receiving critical signals from their environment that ultimately result in the cancer cells becoming invasive and metastastatic.
FLATOW: You mean from those normal cells we're talking about?
Dr. WEINBERG: Precisely.
FLATOW: And do we know what those signals are that we might block them?
Dr. WEINBERG: We're beginning to learn what they are. They have all kinds of acronymic names like, for example, TJF-beta, TNA-alpha. Are you sorry you asked?
FLATOW: No, no, no. We love to hear this kind of stuff.
(Soundbite of laughter)
FLATOW: But basically - and we know that the cells talk to each other. They send out signals back and forth. And it used to be that in the old days of cancer research - and I'm trying to - correct me if I'm wrong, I'm sure I'll be wrong at something - we just try to kill them with poison, you know, because the cells divided more quickly than normal cells and we killed a lot of normal cells in the process. Now, we're trying to disrupt the signals and maybe target them a little more.
Dr. WEINBERG: Exactly. We're trying to develop drugs that - which are much more selective by killing cancer cells and having relatively little effect on the cells in normal tissues. And there has been some progress made there. We now understand the outlines of the problem. But it will certainly be another decade before there's a significantly large repertoire of drugs that can selectively kill cancer cells while leaving normal tissues untouched.
FLATOW: You know, in medicine, in science, it could be physics, we always hear it's - we were a decades, sometimes we're 30 years away from things. Do you think this is a hard - a good number a decade or you think, well, let's just hope far in the future we really can guess on a date?
Dr. WEINBERG: Well, over the last five years there have been, let's say, three or four drugs introduced in the clinic that have proven to be quite striking in shutting down the growth of the certain kinds of cancers. At the same time, there are probably at least 200 clinical trials running at present throughout the world on various kinds of different candidate cancer drugs. Some of those are actually going to succeed and many of them will fail. But we're now in a period of frenetic drug developments. It's no longer something that one looked forward to as a prospect in some distant time in the future. Right now, things are happening and, indeed, they have been happening over the last five years.
FLATOW: And where would you think the most ready for primetime area is now?
Dr. WEINBERG: The most ready for primetime area, as you put it, would be to figure out new ways of using drugs in combination. In other words, it seems increasingly likely that a single drug will not be able to kill most kinds of cancers and that the real homeruns that will be hit by the oncologists will come when we learn how to use several drugs in combination. And that's still a very elusive trick.
But the truth is one is now using very complex bio informatics algorithms to figure out the points of vulnerability in a cell and thereby predict how different combinations of drugs that hit different parts of the cancel cell could act cooperatively, or synergistically, to kill the cancer cell while leaving normal cells untouched.
FLATOW: The fact that there's this hijacking of the embryonic cell area, does that mean that there's good research that might be done in embryonic cells to figure out how cancer cells may work?
Dr. WEINBERG: Yes, indeed. And that continues to be done in embryonic cells, as I say, amusingly or ironically, by researchers who are studying the development of flies, of worms, even of frogs. Their research has enriched and continues to enrich enormously how cancer researchers perceive the mechanisms that allow cancer cells to spread from the primary tumor to distant sites in the body.
FLATOW: This is TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow, talking with Robert Weinberg, director of the Ludwig Center for Molecular Oncology and a member of the Whitehead Institute at MIT.
You know, we like to think that we're always in a golden era of the future. It sounds very much like we're in that era now.
Dr. WEINBERG: For many years, we were promising great things to happen in the future. But I think, around the year 2000, all of a sudden, some of the promises were realized. I would be the last person to say that in 10 or 15 years, we will be able to cure all solid tumors. I don't think that's going to happen so quickly. But we are going to make some major advances, and certain tumors that were previously thought to be untreatable will begin to prove to be highly treatable and susceptible to the treatments. So it's no longer just hand waving and much smoke and mirrors. It's now some reality that is intruding itself in drug development.
FLATOW: Ronald(ph) in San Antonio. Hi, welcome to SCIENCE FRIDAY.
RONALD (Caller): Hi. How are you doing?
FLATOW: Hi there.
RONALD: Yeah, I was wondering about the effects of uric acid on cancer. I've heard that uric acid very much exacerbates cancer and it's, like gout, it's - there's like a thousand symptoms to gout other than just your big toe hurting. What do you have to say about getting rid of uric acid in your life and eating alkaline vegetables like yellow squash combined with calcium?
FLATOW: Now, we said before that Dr. Weinberg is not a medical doctor. But I'll see…
RONALD: No, but I'll reply.
FLATOW: I'll see if he wants to answer that. Go ahead. Give it a shot.
Dr. WEINBERG: I'll reply. The fact is uric acid is part of our normal metabolism. And what you're really asking is the following question. If there are certain tissue sites throughout the body that are subject to chronic inflammation, are they subject to increased rates of tumor formation? And indeed, we think that's the case. We think that inflamed livers, inflamed breast tissue, inflamed colons, are sites where cancers may arise.
Uric acid crystals, for example, in the bile duct, may serve as an irritant that creates long-term inflammation and they may be important, although, one hasn't proven this yet, for example, cancer of the gall bladder - in the cells lining the gall ducts. As far as uric acid in general, I would say that there's no connection whatsoever between general uric acid levels in the body, epidemiologically speaking, and different kinds of cancer.
RONALD: Normal uric acid levels has no connection, but when you have highly inflated uric acid levels like people that eat a lot of pork and beef might end up with high levels, and after years of your body having to get rid of the stuff and it's ability to get rid of it disintegrates, and all of a sudden, the level start to rise to some extent, what do you think of that?
Dr. WEINBERG: Well, we know once again, from epidemiology, that people who eat a so-called healthy American diet with lots of red meat and lots of animal fat, had significantly increased risk of colon cancer, prostate cancer and possibly, even breast cancer. Although, the last thing is very unclear. And therefore, that these are largely - not largely, but these are in significant part, dietary diseases.
An unanswered question is precisely why the consumption of large amounts of red meat makes one more susceptible to these kinds of commonly occurring cancer. I've never heard the theory of uric acid. There are other theories. But one day, we may learn what it is about the constituents of red meat that can further increase susceptibility in a number of organ sites throughout the body.
FLATOW: Nutrition is a pretty mysterious thing to doctors these days, isn't it?
Dr. WEINBERG: Well, in fact, people 50 years ago would never have agreed to the notion that cancer is a nutritional disease. But as we've learned, though, in recent years, for example, people who have a high body mass index, and therefore, are significantly overweight, have significantly increased risks of a wide variety of cancers throughout the body.
Dr. WEINBERG: So it's no longer an irrelevancy in terms of the origins of cancer.
FLATOW: Well, thank you very much Dr. Weinberg for enlightening us and taking time to talk with us, and good luck to you.
Dr. WEINBERG: It's my pleasure.
FLATOW: Robert Weinberg is director the Ludwig Center for Molecular Oncology, Daniel K. Ludwig and American Cancer Society Professor for Cancer Research, and a member of the Whitehead Institute at MIT in Cambridge.
I'm Ira Flatow in New York.
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