DATE July 6, 2000 ACCOUNT NUMBER N/A
TIME 12:00 Noon-1:00 PM AUDIENCE N/A
PROGRAM Fresh Air
Interview: Dr. Mel Greaves, author of "Cancer: The Evolutionary
Legacy," explains his theory of looking at cancer from a
TERRY GROSS, host:
This FRESH AIR. I'm Terry Gross.
Dr. Mel Greaves is a cancer researcher who would like to answer these
questions: Why does a healthy body get cancer? Why do so many things appear
to cause cancer? Why does it often take decades to emerge? Why does
treatment sometimes succeed and other times fail? He says that to answer
these questions, you need to understand our evolutionary history. Mutations
have enabled human beings to evolve; genetic mutations can also cause cancer,
and genetic mutations can affect the outcome of chemotherapy. In other words,
Greaves says, the perspective that best explains cancer is a Darwinian
Greaves directs the Leukaemia Research Fund Centre for Cell and Molecular
Biology at the Institute of Cancer Research in London. He's also the author
of the new book, "Cancer: The Evolutionary Legacy." The evolutionary
analysis of cancer focuses on what survival mechanisms in the body allow
cancer cells to survive.
Dr. MEL GREAVES (Author, "Cancer: The Evolutionary Legacy"): Well, that's
right. I mean, I think that what the evolutionary picture gives you is an
understanding of why we're vulnerable to cancer. If you address the question,
or ask the question, why is there so much cancer about, part of the
explanation must be the biological evolutionary reasons. We've been set up.
There are reasons why cells and genes are vulnerable to cancer. And then the
evolutionary perspective tells us why human behavior has changed the way that
it has, and why we've been moving, socially speaking, fast track, but our
genetics moves very slowly. So we now have what I think for cancer and for
many other diseases is a mismatch between our nature and our nurture, and
cancer's one of the consequences of this.
GROSS: What do you mean by that?
Dr. GREAVES: Well, I mean that our genetics has programmed our physiology
and our body to behave in a certain way, in essentially a Stone Age existence,
but our whole behavior and our social structures, affecting our diet and our
reproduction, have, of course, changed out of all proportion. But normally in
the wild, when animals change their behavior for a different lifestyle, it
goes along with genetic changes and through natural selection. We've changed
rapidly, very rapidly over the past 5,000 to 10,000 years, and particularly
over the last 100 years, our social patterns and behavior and the stress that
we give to our tissues. And of course, our genes can't take--keep pace with
this. We're not genetically adapt for these stressful type of exposures,
particularly as we're now living very much longer. So there's a mismatch
between our genetic equipment, which equips our physiology to respond and to
repair DNA, and the type of exposures, natural exposures that we now give
ourselves, not just toxic exposures through synthetic chemicals and industrial
pollutants, but natural substances in food and changes in reproductive habits
and our normal hormones, which should be innocuous and beneficial, can become
dangerous under those circumstances.
GROSS: How does the Darwinian picture explain the cell mutations that become
Dr. GREAVES: Well, the thesis there is, first of all, that, somewhat
paradoxically, the way we've evolved over, literally, a million years, is that
our DNA is somewhat mutation-prone, and from a Darwinian evolutionary point of
view it makes sense that our DNA isn't sacrosanct, that it can mutate
occasionally. Otherwise there'd be no evolution, no selection. So DNA is
Then it turns out that cells in our body, or certain cells in our body, that
have been around in creatures for about 500 million years, are programmed to
have cancerous proclivities or activity, to migrate, to move around, to clone
and so on and so forth. So rather surprisingly, perhaps, for your listeners,
our bodies have cancerous credentials. These are normally under control, but
if Darwinian selective pressure gets a chance to operate, survival of the
fittest, then a mutant clone can become the fittest and it will tend to
dominate the body.
GROSS: Do you think that the ability of individual cells to mutate and become
cancer cells is a mistake in the way we were made, or is it the same mutation
process that has enabled us to evolve? Is this just like the downside of the
thing that has enabled us to evolve?
Dr. GREAVES: Yeah, I think it's the latter, Terry, that it's a trade-off,
and if you like, it's a design fault, that in terms of the original
evolutionary setup, it was beneficial to have at least a low rate of mutation
and to have cells behaving the way I just described, territorially as
cancerous cells, and as long as this is kept at a low level, and we don't live
for too many decades, that's all, so to speak, under control and causes no
havoc. The problem comes when those activities become unleashed, and when
more mutations happen than should occur, and when we live longer. There's
more opportunity then for these clones to expand and to express their
GROSS: Now you say that to generate a fully fledged cancer cell, a cell has
to subvert multiple rules of engagement and negotiate major evolutionary
bottlenecks. So what are some of the obstacles that a cancer cell faces in
order to survive?
Dr. GREAVES: Well, not surprisingly, because cells and genes have got these
intrinsic fallibilities, there are lots of safety nets built into the program
of cells in our bodies. For example, one of the things that would tend to
restrict or prevent a cancer cell emerging if it has a mutation that compels
it to divide more quickly is that as cells divide more quickly, there's a
built-in negative response that compels such rapidly dividing cells to die.
So for cancer cells to escape and divide continually, they almost certainly
have to subvert this cell death protective process that we call apoptosis, so
you need additional mutations in the cell death pathway so cells are not
forced to pay the penalty of cell death when they divide.
And then there are territorial restraints within tissues. Tissues are highly
structured architecturally. They're not open planned. So the cells, let's
say, in the lining of the gut or the lung or the breast start to expand as a
clone of cells--a single-cell clone. There will be physical constraints and
physical barriers, so cells have to acquire the ability to break through in
order to migrate, to degrade those types of barriers.
And then there's a third level of restraint that, as cells get bigger, they
run out of oxygen and nutrients, so they'll tend to die also for that reason.
So another trick, so to speak, that cancer cells have to adopt if they're
going to be successful territorially and expand for a period of time is they
have to solicit nutrients and new growth of blood vessels that can sustain
So those are three tricks of the trade, so to speak, that cancer cells have to
adopt, bottlenecks in their development. And unless they negotiate, really,
all of those, they'll not finally disseminate in the body and cause the kind
of havoc we can see in the clinic.
GROSS: That's why, although there's a lot of cancer, not everybody gets it?
Dr. GREAVES: Well, I think, again, there's some extraordinary things here
that I--I'm pretty confident that every single one of us has small tumors in
our body, particularly as we age, and mutant cells in our blood and in our
tissues. But the vast majority of those putative, escapee clones never make
the full journey. They never negotiate all the bottlenecks. And in some
ways, it's surprising that we don't all have lots of cancer, but all these
bottlenecks and controls are fairly robust so only occasionally in a small
minority of cases, a single cell--a single clone breaks through these
different restraints to cause a clinical cancer.
GROSS: If you're just joining us, my guest is Professor Mel Greaves, and he
is the director of the Leukaemia Research Fund Centre for Cell and Molecular
Biology at the Institute of Cancer Research in London. And he's also the
author of the new book "Cancer: The Evolutionary Legacy."
Do you feel like the Human Genome Project, which has mapped most of the genes
in the human body, showing where each gene is located or what each gene
does--do you feel that this project has contributed to our understanding of
cancer and our ability to create treatments for it?
Dr. GREAVES: Well, that's an interesting and in a way quite a controversial
question. First of all, the genome project and the announcement recently that
the provisional map is going to be available very soon is a tremendous tour de
force. It's a wonderful achievement of human ingenuity and technology. But
on the other hand, I personally think some of the claims for it are a little
extravagant. And I'm a bit concerned there may be unrealistic expectations
raised for patients and their families about rapid remedies.
I mean, there are two sides to this coin, if I can just elaborate a little
bit. First of all, as far as understanding cancer is concerned, identifying
mutant genes is extremely important. And what that has already given us and
will give us even more with the genome project is a detailed audit listing of
the mutant genes, including cancer. And the main benefit there might well be
a more accurate, early diagnosis. Accurate, early diagnosis could make a huge
impact on curability, because cancer is almost invariably curable when it's
caught early enough.
But one of the major claims of the genome project, other than the somewhat
absurd claim of immortality that you might have heard, is that we're going to
get new cancer drugs. Now that might be the case somewhere down the line,
five, 10, 15, 20 years. But I think it's a little naive to expect that that
will be rapidly forthcoming. And I say that because we already have quite a
lot of knowledge of mutant genes in cancer. And the problem for us, or the
bottleneck now for the clinicians and the oncologists, is not so much having
mutant molecules to aim our new therapies at. There are huge problems in
delivery of new drugs. And there's a huge Darwinian problem, as I discuss in
the book, that by the time cancer cells become resistant to conventional
treatment, they are so multiple in number, they are so diverse genetically,
that they have ways of escape which parallel antibiotic-resistant bacteria.
So these problems will still exist.
I think the genome project is tremendous; we're all excited about it. We'll
all exploit it. But we have to wait a while for the genome to give us the
details we need. There's a huge gulf between having sequential gene
information and a map and understanding function and abnormalities in the
GROSS: Some people have an inherited predisposition to cancer and I guess the
Human Genome Project will help us understand that. But you say that most of
the cancers really aren't inherited. The genetic mutations are ones that have
happened within the body, not programmed from birth.
Dr. GREAVES: Yeah. That's another important point. I think people sometimes
are not misinformed, but they misunderstand this point about the role of
genetics. I was in a cab, a taxi, in Minneapolis last year when the driver
told me that she thought breast cancer was inevitable because it's in your
genes. And this suggests that people perhaps have gotten an overestimate of
the inherited genetic component. I mean, I think the truth of the matter is
that about 10 percent of cancers overall are caused by inherited mutant genes.
Now 10 percent is a fair number of people, so that's important. The genome
project will help identify all of those genes so that we can screen people and
perhaps take appropriate measures. But the 90 percent of us, the cancers are
caused by mutations that arise sometime during our life span.
Now there's one other aspect to the genome project and genes predisposing to
cancer which is that we all inherit genes that help us to detoxify chemicals,
that help us to fight viruses and so on. And each of us are slightly
different in that respect. So the other aspect, the genetic perspective on
cancer, the genome project, is that maybe if we had a genotype for everybody,
we might be able to predict--and I think it's a very big `might'--who's more
vulnerable than who else with respect to tobacco-induced cancer or breast
cancer and so on. So that's a possibility. In addition to the 10 percent
cancers that one can predict because of mutant genes, we might be able to look
at everybody and make some very rough calculation--and I think it will be very
rough--or risk estimates for particular types of cancer, because the normal
genes, which in their variable form, between you and me and everybody else,
influence risk in the way we confront viruses and chemicals and radiation and
GROSS: My guest is cancer researcher Dr. Mel Greaves, author of "Cancer:
The Evolutionary Legacy." More after a break. This is FRESH AIR.
(Soundbite of music)
GROSS: My guest is Mel Greaves, the author of "Cancer: The Evolutionary
There is one gene you're particularly interested in, in its relationship to
cancer and its potential for treating cancer, and that's gene P-53. What is
it? What's its importance to understanding cancer?
Dr. GREAVES: Well, P-53 was discovered serendipitously. In fact, a
colleague of mine, David Lane, some 15 years ago in London and originally it
was discovered as a component of a virus. It turned out that this is a gene
that we all have; in fact, all vertebrate animals have this gene and
invertebrates have a related gene. And this gene or its product, which is a
protein, plays an absolutely pivotal role in controlling the response of all
of our cells to stress--various forms of physiological stress or DNA damage or
radiation or chemical damage. This is a molecule which senses damage to the
cell and it solicits an appropriate response. An appropriate response
includes repairing the DNA damage, if the damage is too severe, compelling the
cell to stop dividing, or compelling the cell to die.
Now having told you that, I'm sure your listeners could imagine if you had a
lesion in this protector--P-53 protector of our DNA, if you were defective in
this policing service, then when your cells are damaged, you'd be really at
risk because the hazard then is the cell doesn't undergo these appropriate
responses of cell death and repair. It carries on proliferating in the face
of damage. And that, in essence, is what cancerous clones are. They're cells
proliferating when by all rights they should be dead or they should be
sleeping. But they carry on dividing. And the consequence of that is--or a
correlate is that in at least 50 percent of cancers, we see this P-53 gene is
mutated. It's the most commonly mutated gene in cancer. And from the
Darwinian point of view, you can sort of understand why that happens. The
selective advantage for any cell that can get rid of P-53 or its gene or
mutate it so it's inactive, that cell will then be dead, it will have a growth
advantage over all its neighbors that will be dead or sleeping.
So P-53 is a really critical player--not the only one, but a critical player
in the evolutionary development of cancerous clones. And by that token, it
provides a common potential target for therapy.
GROSS: Does that mean that whether you have breast cancer or colon cancer or
prostate cancer, P-53 might be playing a role in that cancer?
Dr. GREAVES: Yes. In almost all types of cancers, particularly as they
evolve to a stage of dissemination from the original site elsewhere in the
body, we find P-53 mutations coming into play and being there very commonly.
GROSS: What percentage of cancers would you say involve a problem with this
Dr. GREAVES: Well, approximately 50 percent have a detectable P-53 mutation
or loss of the gene. And in many of the others, there are other genes
involved that interact with this same protection/damage/response pathway. So
actually in a sense, if we start to broaden it as far as that protection
mechanism, which P-53 is pivotal, is concerned, probably all cancers, if they
are really going to disseminate and cause the problems that we're familiar
with, with drug resistance and dissemination, have a fault or defect in this
GROSS: So to sum up, this P-53 gene when it's mutated can allow a cell to
keep reproducing even though, for all practical purposes, if it wasn't for
this mutation, the cell would die?
Dr. GREAVES: That's right. And it's a double whammy in the sense that in
order for the cell initially--before the clinician comes on the scene, in
order for the cell to grow and survive the stress of spreading around the
body, and all the protection mechanisms, it has to overcome this P-53
protection mechanism. But then along comes the oncologist with his drugs.
Now it turns out that these drugs, as well as radiation, operate by killing
cells, by these same stress-related cell-death mechanisms. But of course, now
the cells are already resistant. They're already been selected in a Darwinian
fashion to divide the very kind of stress that clinicians try to use to
control the cancer. So then you have a way of escape. It's no longer really
surprising but it's difficult to treat disseminated metastatic cancers.
GROSS: So you're saying that because of this mutation, the P-53 gene cancer
cells might be resistant to toxic therapies like chemo?
Dr. GREAVES: Well, that's clearly what one of the reasons why they're
resistant. You can show experimentally in the laboratory that if you take
cells and you cripple their P-53 mechanism, that you greatly increase their
resistance to standard therapies.
GROSS: What are some other keys that P-53 might hold for cancer treatment?
Dr. GREAVES: Well, there's tremendous interest here, both academically and in
biotechnology industries, of a way in which it might be possible using small
peptides that bind P-53--small protein molecules that might restore the
normal shape of the mutant P-53 to restore its function. So that's one very
interesting idea that's being actively pursued.
GROSS: Now let me stop you there.
Dr. GREAVES: Another...
GROSS: Let me stop you there. If that happened, that would mean by restoring
P-53 to its normal function, if would prevent cancer cells from reproducing.
Dr. GREAVES: It might do that. But also, it would then make them vulnerable
to standard treatment.
GROSS: I see.
Dr. GREAVES: They then die in the face of standard treatment rather than
GROSS: I see.
Dr. GREAVES: The other approach, rather than restoring function, is a very
interesting way of turning things around, as a sort of Achilles' heel, and
that's to compel cells that have a mutant P-53 to commit suicide. And there
are some interesting new viral therapies that are in clinical trial at the
moment in which viruses going into cells that have P-53 mutations, viruses
carrying a suicide gene, are inactivated in cells that have a normal P-53 but
in mutant cancer cells those viruses are themselves allowed to proliferate.
The consequence is they express a new type of suicide gene that kills the
cancer cells. So that's another very enterprising and interesting approach.
I'm quite enthusiastic about those. But the problem again from this type of
molecular therapy is the enormous charge of delivering these type of drugs and
compounds and viruses into every part of the patient's body where they need to
GROSS: Can you talk more about the suicide gene? Like what this process of
Dr. GREAVES: Well, this turns out to be an extremely complex network that
evolved at least 500 million years ago. When unicellular animals became
multicellular animals, it was important to control cell numbers. So there had
to be some balance between cell growth and cell death. So genes were modified
and invented that encoded proteins that could induce cell death. Now these
genes turn out to be mostly enzymes. There's a whole cascade of them in a
chain reaction, rather like blood clotting. At the end of the line what these
enzymes do is they destroy the membranes of cells and they cut up DNA in cells
so the cells can no longer function.
And all cells had this built-in suicide mechanism, which may seem
counterintuitive, but it makes sense as a control mechanism. And actually
that suicide mechanism will always be evoked and active in cells unless it's
overruled by cells getting appropriate survival signals from their neighbors
to tell a cell that everything is OK, it's permissible to divide and so on.
Otherwise, this suicide process is activated.
GROSS: And P-53 controls that suicide process?
Dr. GREAVES: It's part of the process. The control is quite complex.
GROSS: Mel Greaves is the director of the Leukaemia Research Centre at the
Institute of Cancer Research in London. His new book is called "Cancer: The
Evolutionary Legacy." He'll be back in the second half of the show. I'm
Terry Gross. And this is FRESH AIR.
GROSS: This is FRESH AIR. I'm Terry Gross, back with Mel Greaves, a cancer
researcher who is studying cancer, its causes and treatment, from the
perspective of evolutionary biology. Greaves directs the Leukemia Research
Centre at the Institute of Cancer Research in London, and he's the author of
the new book, "Cancer: The Evolutionary Legacy."
Now you said that one of the problems with current toxic treatments is that
cancer cells can basically become resistant to chemo, and you compared it to
how certain strains of bacteria become resistant to antibiotics. How do
cancer cells become resistant to chemo?
Dr. GREAVES: Well, I think we now have a fairly clear picture of this. I
mean, we talk about cancer cells as a single-cell clone. They come from a
single cell. It's one of the most important characteristics, and people are
familiar with cloning now through Dolly the sheep and from identical twins.
Had the idea that the thing about clones is that everyone's identical, the
cells are identical. But paradoxically, what happens in cancer, in a
cancerous clone, is as the cells multiply and divide, they become genetically
very diverse in the same way the bacteria actually become diverse as they
proliferate. So by the time you have a million, 10 million, a hundred million
cancer cells in your body, although they belong to one clone, they're not at
all identical. They have lots of genetic diversity, and in a way, they're
But what that gives them, in the short term at least, is a great evolutionary
advantage. Because if you now come along with a drug which kills most of
those calls, 99.99 percent, there will be somewhere in that million, million,
million cells one cell or 10 cells that had mutated a gene that allows them to
resist that particular toxic treatment. So it's a genetic diversity. It's
the trick that cancer cells use. And it would be exactly equivalent to a
rapidly mutating bacterium in a natural environment or bacterium in our body
facing antibiotic challenge.
GROSS: Does that make a recurrence of cancer often more difficult to treat
than the original cancer?
Dr. GREAVES: Yes. That's almost always the case; that often the therapies
that we give, we see a regression of the tumor, a shrinkage of the tumor or
remission. And that's telling us that, again, 99.9 percent of the cells have
been killed by the therapy. But the concern is once the tumor's advanced--and
this almost invariably happens when it's very advanced--there will be the
small number of mutant cells hiding in various places that are resistant to
that treatment for reasons I've just explained, and they now have an
opportunity to expand and, in effect, paradoxically, those treatments, because
they're generally toxic and nasty and kill a lot of cells, create the space
and the environmental circumstances where Darwinian selection, as I call it,
now encourages those mutant cells to expand to become the new dominant clones.
So Darwinian selection works very much against the patient and the doctor in
this context once a cancer has evolved to that stage of being very numerous
and genetically diverse.
GROSS: What are some of the tricks oncologists have of trying to deal with
the fact that the cancer cells are so diverse?
Dr. GREAVES: Well, there are lots of things that can be tried with variable
success. One trick is to give really enormous doses, what Americans like to
call mega-up-front treatment, which I find rather worrying, I have to say,
because the treatments are so toxic and non-specific, but that sometimes is
advantageous. If you give enough toxic treatment, you will kill every cancer
cell. The problem is if you're not careful, you're going to kill vital cells
in a normal patient.
Another trick is to cycle different drugs, different combinations of drugs.
And it used to be thought, not unreasonably, that if you give enough different
drugs, it was unlikely there would be mutant cells that were mutant and could
resist many different types of drugs. But then it turns out something that
maybe we should have guessed, but something that works against us as well,
which is evolutionary, and that's that the drugs we use in the clinic are
mostly derived from natural substances. They're types of chemicals that exist
in the wild, particularly in plants, but elsewhere. And over millions of
years, our cells have acquired simple chemical tricks for getting rid of these
drugs, for pumping them out of cells, for example.
So what now happens when you give multiple different drugs, there may be a
cell that's a mutant. In, for example, the protein pump that sends drugs out
of cells, multiple different drugs, these are very common sort of garbage
collection efflux mechanisms that cells have had for millions of years. So
the drugs we use, because they're non-specific, because they're toxic, are
fairly easily dealt with by some cells and a mutant cell that acquires an
additional extra efficacy in getting rid of drugs is going to have a huge
advantage. So that fools the clinician, unfortunately, with his multiple
drugs. So in a way, what we need is either to get in early, before the clone
is diverse, and early diagnosis, I think, is well-recognized, can lead to cure
in almost all cancers, or we need some forms of treatment that can get around
this type of genetic diversity.
GROSS: Is what you've told us in the past couple of minutes applicable to
radiation as well as chemo?
Dr. GREAVES: Yes, there are the same problems, particularly with the P-53
gene we were discussing, because it governs the cell response to radiation
therapy. But radiation therapy early on in the evolution of a cancer clone
will be much more effective than later for the same reasons as we've run into
problems with chemicals.
GROSS: So do you think that the treatment for cancer will eventually deviate
from the course we're on now of chemo and radiation and head for a completely
different type of treatment?
Dr. GREAVES: Well, Terry, I certainly hope it does, and I think most of your
listeners would hope it does. I mean, to be blunt about this, the treatment
that we use for cancer now is not enormously different from what was used by
the ancient Greeks 2,000 years ago: poisons and gross surgery, mastectomy and
so on. And we really have to get smarter than this. And the treatment,
although to be fair, is sometimes effective--and there are some wonderful
success stories, particularly in childhood leukemia where my own interests are
and a few other cancers. For most cancers, this is very crude, toxic, nasty
treatment. So I'm fairly confident in predicting, as are, I'm sure, many of
my fellow scientists, that 20, 50 years from now, we'll have very different
ways of dealing with cancer. But, you know, I don't think it'll come from any
magic single bullet through the genome project or anything else. And, you
know, we could discuss the ways in which I think cancer might be controlled in
the future, but it won't come from any single magic bullet.
GROSS: Before I ask you about that, I think a lot of our listeners will be
thinking now, does this mean that the doctor on FRESH AIR recommends against
chemo and radiation for people who have cancer today? Do you?
Dr. GREAVES: Well, no, I don't think the doctor does. I mean, I have
enormous sympathy, without wishing to sound patronizing, to oncologists. I
mean, they have to deal with the best they have available. They have to offer
patients the best hope they can give them. And the best thing available at
the moment, is, it so happens, rather toxic treatments, which at least the
supportive care for dealing with that and for the side effects is now much
better than it used to be. But I think your oncologists, if you were to ask
them, were to say, yes, they're crying out for less toxic, more biologically
focused, more specific treatment for earlier diagnosis where less toxic
treatment will be necessary.
GROSS: If you had cancer now, would you go for chemo and/or radiation?
Dr. GREAVES: I'd take into account the sort of cancer I had, because
cancers--here's another confusing point for listeners, perhaps, but cancers
vary enormously in their aggressiveness and their natural history and their
behavior and their response to drugs. There's a huge difference between
leukemia and a melanoma, for example. So I'd take into account the sort of
cancer I had. I'd take into account the stage of the cancer. But I suppose
the acid test for me would be supposing I had a very advanced malignant
cancer, and it would be a toss-up, it would be a close call between having
some horrible treatment that would reduce the quality of my life and going for
a possible cure, and I guess when the chips are down, you go for what's
available. You go for the toxic treatment, and you grin and bear it and try
your luck. But what I would expect is the oncologist to say to me, `Look,
here are the pros, here are the cons. Here's your percentage chance of doing
well here. Here's the risk and here are the side effects.' And I'd try to
make a balanced decision with the help and advice of the oncologist. But, you
know, it really isn't an easy decision.
GROSS: My guest is cancer researcher, Dr. Mel Greaves, author of "Cancer:
The Evolutionary Legacy." More after our break. This is FRESH AIR.
(Soundbite of music)
GROSS: If you're just joining us, my guest is Mel Greaves. He's the author
of the new book, "Cancer: The Evolutionary Legacy." He's the director of the
Leukemia Research Fund Centre for Cell and Molecular Biology at the Institute
of Cancer Research in London.
What is the potential treatment for a cancer that is being researched now that
you're most optimistic about?
Dr. GREAVES: The most promising treatment for me, putting on one side future
genetic approaches that--blue-skies research we don't know about, but the most
promising current approach biologically that I see on the horizon and in the
clinic is what I like to refer to as a Darwinian bypass. And I call it that
because it gets around the problem we were just discussing of cancer cells
being diverse and resistant to toxicity and having ways of escape. And a
very good example of a Darwinian bypass is to aim the therapy not at the tumor
cell itself, but at the territory or landscape through which the cancer cell
has to travel to be successful. And one of the things the cancer cell has to
do and one of the journeys it has to make is to solicit new blood cell
formation, new blood vessel formation around it to provide sustenance and
oxygen and nutrients.
GROSS: To feed the tumor.
Dr. GREAVES: Now this is a process--to feed the tumor, exactly. And this is
a process that's called angiogenesis, new blood vessel formation. And a tumor
needs that to grow beyond a certain size where it initially rises. It also
needs new blood vessels to grow in secondary deposits in the bone or in the
brain or elsewhere. So then there's an idea that a number of people, Juda
Volkman(ph) in Boston at Harvard in particular, have proposed and are now
putting into trial, which is maybe you can aim drugs and therapies of various
kinds at newly growing blood vessels rather than the tumors themselves.
And this is, I think, in principle, a very rational, smart idea. For one, as
I've already said, it gets around the problem of tumor diversity because it's
not aimed at the tumor cells. Secondly, from the point of view of
specificity, we don't normally need dividing, newly formed blood vessels in an
adult, in fact--other than in pregnancy. In fact, they're a nuisance in
arthritis and diabetic retinitis. So we have a potential for real
specificity. And thirdly, the delivery problem that's a real bugbear for
cancer treatment drugs is much less of a problem with aiming therapy at blood
vessels, because they're accessible, by their very nature, in the blood. So
there are at least three major advantages of aiming therapeutic compounds at
dividing newly formed blood vessels necessary for the sustenance of tumors.
And those drugs are in clinical trial, particularly in the US, but elsewhere.
And in animal model systems, there's a great deal of promise. Now, again,
we'll have to wait and see. These things are always more complicated and more
difficult to translate into huge clinical benefit. But that's where my money
is at the moment.
GROSS: From what you've been describing, early detection is crucial in cancer
treatment, to find the cancer before the cells have diversified more, before
natural selection has made the strongest cells the dominant ones. Are there
new early screening methods in the works now that would help us find cancer in
its really early stages?
Dr. GREAVES: Well, yes, there are. I think there are quite exciting
developments here technologically, very dependent upon advances in molecular
biology and molecular genetics. And again, the genome project will interact
with this and facilitate this process. Of course, we've had screening methods
in the clinic for some time. The Pap smear for cervical cancer has been very
effective. There is screening now for prostate and breast cancer. But the
problem with those, particularly the latter two, is they're not smart enough.
They're rather clumsy, rather crude diagnostic techniques. They're not very
predictive of the malignant behavior of the tumor, and they're not very
What we need are smarter screening techniques that can look at, if you like,
the molecular mutant profile of the cancer cells and make some intelligent
prediction about the behavior of that clone and whether it's likely to spread,
whether it's likely to be resistant to drugs, particularly in the context of
breast and--cancer. Because, you know, if the decision is faced by the
patient and the clinician of removing a breast and removing the prostate,
there are major consequences of this, and we're not very good at the moment at
saying what the biopsy result means, and what we lack is the molecular audit.
But this is coming onstream now, now that we know what genes to look at, now
that we have something of an audit, albeit incomplete at the moment, of mutant
genes. So if we have ways of picking up these smaller mutant clones and
making sensible predictions about their likely behavior, I think we'll be much
better at following up screening, picking up in a more sensitive way
potentially malignant clones and introducing treatment selectively where it's
required early on.
GROSS: What would you like to be able to predict about cancer cells?
Dr. GREAVES: What I'd like to be able to do is, first of all, if I thought a
patient had breast cancer or had a neck cancer--let's say breast cancer, that
I had some way, by screening, to survey the whole tissue at a very sensitive
level to see how many malignant--how many mutant clones, I should say, not
malignant--how many mutant clones are there beyond a certain very small size.
Then I'd like to be able to interrogate in a biopsy that mutant clone and to
ask, well, how mutant are you? Are you a sort of minor adolescent type of
mutant clone or are you a clone with multiple changes that looks as though
it's ready to cause trouble? And if it's the latter, I know I have to adopt
fairly radical remedies to get rid of you, and the surgery would have to be
And armed with that information, I would then ask, well, here's a mutant clone
that looks troublesome within the breast. Does that mutant clone already
exist in the local lymph node and in the bone marrow? We now have very
sensitive molecular techniques for that. If I found that mutant clone
elsewhere in the body, then I'd be much more inclined to introduce systemic
treatment with its potential side effects, but, hopefully, less toxic
treatment in the future.
GROSS: Now what about prevention of cancer? Are there new things that you
would suggest or new things that scientists have learned about diet?
Dr. GREAVES: Well, I think this is a terribly important question. Sometimes
when we discuss the cancer issue, you'll have polarized views that we need
gene therapy or ...(unintelligible) prevention, and really, I think a sensible
view of this is that we need all of these things. We need early diagnosis.
We need better non-toxic treatment, more biological treatment for advanced
disease and we need prevention. And I'm really convinced in the future it'll
be a combination of all of those things that enables us to defeat cancer over
the next 20 to 50 years.
But prevention, I think, is incredibly important, and it's one of the great
ironies of all of this magnificent cancer research and cancer biology and
genome project that we could prevent 50 percent of cancers tomorrow if we had
the will to do so because we know the causes. And your listeners will be very
familiar with the fact that cigarette smoking is the major single cause of
cancer. And so in a way, we could control that immediately, and it's somewhat
obscene that so many millions of people are going to be dying of
cigarette-related cancer over the next 20 years despite our knowledge of it.
So cigarette smoking is the single-most important cause not only of lung
cancer but throat and oral cancer, esophageal cancer, pancreatic cancer and
And if I can just mention a couple of other behavior or social aspects that
relate to prevention. Melanoma is probably the most rapidly increasing cancer
in young people at an alarming rate, and there's really no dispute about
what's causing this. It's the vain tendency we all have to like to acquire a
suntan, to roast our bodies, our white, pale-skinned bodies in the midday sun.
Are you familiar with the expression of Noel Coward that mad dogs and
Englishmen go out in the midday sun. And it's quite clear that melanoma rises
primarily as a consequence of ultraviolet rays, mutating genes in cells that
make melanin pigment. This is why dark-skinned individuals are less at risk.
Melanoma is a preventable cancer, and it's an awful aggressive, difficult
cancer to treat once it takes hold. But, you know, rather than think about
how to treat disseminated melanoma, we should just be stopping it.
But as you were asking about diet, and there's pretty good evidence--it's not
conclusive and epidemiologists argue about this--it's incredibly difficult to
study diet, particularly if you're asking people about their diet 20, 30 years
ago when cancers may have started. But on the whole, the evidence suggests
that one of the problems we have in developed affluent societies, as in the US
and in Europe, is particularly early in life, in teen-age years and as young
adults, we have too much energy going in and too little energy going out. And
what this excess of calories does is it partly gets put into fat, which gives
us problems with obesity, and there are health problems there, of course. But
it provides more energy for cells to divide and more hormones to persuade
cells to divide, and there's less cell death. So cell proliferation is
actively encouraged under these circumstances.
And there are other unexpected things as well. It turns out with an
energy-rich diet, estrogen levels in young women are increased. Puberty is
reached at an earlier age. And in the wake of that, there comes problems with
breast cancer, in particular. There are other aspects of diet that are
incredibly important, whether there are sufficient antioxidants in the type of
diet we have, which is a very exotic abnormal diet in evolutionary terms for
primate apes. There's not enough roughage in it. Although people argue about
this, there's little doubt that roughage is one of the components in our
susceptibility to colon cancer. So looking at it in the round, our diets are
extremely abnormal in the evolutionary context. They're dictated more by
economic pressures and style and fashion rather than by bodily needs.
GROSS: I want to thank you so much for sharing some of your information about
cancer with us. Thank you.
Dr. GREAVES: Thank you very much.
GROSS: Mel Greaves is the director of the Leukemia Research Centre at the
Institute of Cancer Research in London. And he's the author of the new book,
"Cancer: The Evolutionary Legacy."
Coming up, Lloyd Shwartz on his trip to the Dresden Music Festival. This is
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
Review: Dresden Music Festival
TERRY GROSS, host:
Before World War II, Dresden was considered the most beautiful city in
Germany. Last month, classical music critic Lloyd Shwartz went to a music
festival there and remembered his first visit more than 30 years ago.
LLOYD SHWARTZ reporting:
One of the most moving places I've ever been to was Dresden, the civilian city
in eastern Germany that the Allies firebombed in 1945. Maybe most Americans
know about this from Kurt Vonnegut's "Slaughterhouse Five." I spent a day
there on a summer vacation trip in 1966. I was a graduate student. I wanted
to go to Dresden because the museum there had two paintings by Vermeer, my
favorite painter, very few of whose works survived. In those days, to get
into East Germany, even for a day, you had to go through a lot of red tape,
pun very much intended. It was a bureaucratic nightmare, but it was worth the
The museum was exceptional, with its great Vermeers, Rembrandts, Titians and
the famous Raphael "Sistine Madonna" with its mischievous cherubs leaning on
their elbows and eyeing the Madonna and baby Jesus floating on a cloud.
Dresden had been one of the cultural capitals of Europe, the German Paris with
its grand palaces, onion-topped church spires and elegant promenade
overlooking an elbow of the Elbe river.
In 1966, the city was still in ruins. You could look right through the
skeletal steeples, at the ugly apartment houses going up in the distance. The
Zwinger, the magnificent palace which housed the old master paintings and the
famous collection of Dresden porcelain, had miraculously escaped devastation,
though the courtyard was still piled with rubble. The whole city was one of
the most heartbreakingly beautiful ruins I'd ever seen.
When I got a call from the German National Tourist Office inviting me to join
a group of media people for a five-day junket to cover the Dresden Music
Festival, I was more than just happy to get a free trip and hear some
interesting performances. Dresden was a city I already cared about. I wanted
to see how it was doing.
East Germany, as we know, even since the reunification, is not exactly
thriving. The population of Dresden has been declining. I was told, though,
that the Jewish population was on the rise, that there are now some 500 Jews
living in Dresden, and a new synagogue is under construction. There are at
least two other sources of hope for this city. The historical buildings are
being lovingly restored or, where restoration isn't possible, completely
rebuilt. `This is one of our new old buildings,' our guide said, pointing out
the beautiful hotel, once a royal palace, where our group was going to have
There are still signs of the devastation, but the magnificence of the
historical district is slowly coming alive again. The other success is the
Dresden Music Festival itself. It was actually started by the Communist
government in 1978. One of the first buildings the Communists reconstructed
was the spectacular 19th century Semperoper House, which was still gutted when
I was there in 1966. This year, the festival's theme was baroque and jazz.
We saw a fascinating, but hard to follow high-tech production of Handel's
opera "Xerxes," and a concert performance by the Dresden Philharmonic of
Richard Strauss' mythological opera "Daphne," which had its world premiere in
Dresden. The conductor was Kristoff Prik(ph), who conducts in
English-speaking countries under the name Parak(ph). Let's say he rose
superbly to the occasion. One of the best concerts took place in a
400-year-old church, the Annenkirche, with glowing acoustics.
(Soundbite of music)
SHWARTZ: The performers were the Baroque Orchestra of Freiberg(ph), maybe
the most accomplished historical instrument ensemble I've ever heard, and the
astounding young German countertenor, Andreas Scholl, already a very big star
in Europe. Chick Corea played a morning concert at the opera house that the
sell-out crowd ate up. Though between his unvarying up-tempo cheeriness and
my jet lag, I snoozed through it.
The liveliest concert took place in the courtyard of the Zwinger Palace, under
a rich midnight blue sky, with the lit-up towers of the city rising above the
palace walls. The lead performers were the rhythmically indefatigable
72-year-old Cuban singer Ibrahim Ferrer and 82-year-old pianist Ruben
Gonzales, the stars of the Buena Vista Social Club. Forty-five hundred people
clapped and sang along for three hours, and by the end, everyone was standing
up and dancing in place. Even the girl reading a letter by a window in one of
the Vermeer paintings across the courtyard must have looked out for a moment
with an expression of sheer joy.
GROSS: Lloyd Shwartz is classical music critic for The Boston Phoenix.
GROSS: I'm Terry Gross.
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